Traditionally, biofeedback was considered to be a stress management technique that targeted sympathetic nervous system (SNS) overdrive with an adrenal medullary system backup. Recent advances in autonomic physiology, however, have clarified that except in extreme situations, the SNS is not the key factor in day-to-day stress. Rather, the parasympathetic branch of the autonomic nervous system appears to be a more likely candidate for mediating routine stress because, unlike the SNS, which has slow-acting neurotransmitters (ie, catecholamines), the parasympathetic nervous system has the fast-acting transmitter acetylcholine.

VAGAL WITHDRAWAL: AN ALTERNATIVE TO SYMPATHETIC ACTIVATION

Porges¹ first proposed the concept of vagal withdrawal as an indicator of stress and stress vulnerability; this contrasts with the idea that the stress response is a consequence of sympathetic activation and the hypothalamic-pituitary-adrenal axis response. In the vagal withdrawal model, the response to stress is stabilization of the sympathetic system followed by termination of parasympathetic activity, manifested as cardiac acceleration.

Respiratory sinus arrhythmia (RSA), or the variability in heart rate as it synchronizes with breathing, is considered an index of parasympathetic tone. In the laboratory, slow atropine infusion produces a transient paradoxical vagomimetic effect characterized by an initial increase in RSA, followed by a flattening and then a rise in the heart rate.² This phenomenon has been measured in people during times of routine stress, such as when worrying about being late for an appointment. In such individuals, biofeedback training can result in recovery of normal RSA shortly after an episode of anxiety.

Historically, the focus of biofeedback was to cultivate low arousal, presumably reducing SNS activity, through the use of finger temperature, skin conductance training, and profound muscle relaxation. More sophisticated ways to look at both branches of the autonomic nervous system have since emerged that allow for sampling of the beat-by-beat changes in heart rate.

HEART RATE VARIABILITY BIOFEEDBACK

The concept of modifying the respiration rate (paced breathing) originated some 2,500 years ago as a component of meditation. It is being revisited today in the form of heart rate variability (HRV) biofeedback training, which is being used as a stress-management tool and a method to correct disorders in which autonomic regulation is thought to be important. HRV biofeedback involves training to increase the amplitude of HRV rhythms and thus improve autonomic homeostasis.

Normal HRV has a pattern of overlapping oscillatory frequency components, including:

• a high-frequency rhythm, 0.15 to 0.4 Hz, which is the RSA;
• a low-frequency rhythm, 0.05 to 0.15 Hz, associated with blood pressure oscillations; and
• a very-low-frequency rhythm, 0.005 to 0.05 Hz, which may regulate vascular tone and body temperature.

The goal of HRV biofeedback is to achieve respiratory rates at which resonance occurs between cardiac rhythms associated with respiration (RSA, or high-frequency oscillations) and those caused by baroreflex activity (low-frequency oscillations).

Spectral analysis has demonstrated that nearly all of the activity with HRV biofeedback occurs at a low-frequency band. The reason is that activity in the low-frequency band is related more to baroreflex activity than to HRV compared with other ranges of frequency. Breathing rates that correspond to baroreflex effects, called resonance frequency breathing, represent resonance in the cardiovascular system. Several devices are available whose mechanisms are based on the concept of achieving resonance frequency breathing. One such device is a slow-breathing monitor (Resp-e-rate) that has been approved by the US Food and Drug Administration for the adjunctive treatment of hypertension.

Improved HRV may suggest an improved risk status: Kleiger et al⁴ found that the relative risk of mortality was 5.3 times greater for people with SDNN of less than 50 msec compared with those whose SDNN was greater than 100 msec. In Del Pozo’s study, eight of 30 patients in the intervention group achieved an SDNN of greater than 50 msec (vs 0 at pretreatment) compared with three of 31 controls (vs two at pretreatment).³ As an additional benefit of HRV biofeedback, patients in the intervention group who entered the study with hypertension all became normotensive.

In a meta-analysis, van Dixhoorn and White⁵ found fewer cardiac events, fewer episodes of angina, and less occurrence of arrhythmia and exercise-induced ischemia from intensive supervised relaxation therapy in patients with ischemic heart disease. Improvements in scales of depression and anxiety were also observed with relaxation therapy.

Other studies have shown biofeedback to have beneficial effects based on the Posttraumatic Stress Disorder Checklist, the Hamilton Depression Rating Scale, and, in patients with mild to moderate heartfailure, the 6-minute walk test.^6–8

The proposed mechanism for the beneficial effects of biofeedback found in clinical trials is improvement in baroreflex function, producing greater reflex efficiency and improved modulation of autonomic activity.

CONCLUSION

A shift in emphasis to vagal withdrawal has led to new forms of biofeedback that probably potentiate many of the same mechanisms thought to be present in Eastern practices such as yoga and tai chi. Results from small-scale trials have been promising for HRV biofeedback as a means of modifying responses to stress and promoting homeostatic processes that reduce the intensity of symptoms and improve surrogate markers associated with a number of disorders.

Traditionally, biofeedback was considered to be a stress management technique that targeted sympathetic nervous system (SNS) overdrive with an adrenal medullary system backup. Recent advances in autonomic physiology, however, have clarified that except in extreme situations, the SNS is not the key factor in day-to-day stress. Rather, the parasympathetic branch of the autonomic nervous system appears to be a more likely candidate for mediating routine stress because, unlike the SNS, which has slow-acting neurotransmitters (ie, catecholamines), the parasympathetic nervous system has the fast-acting transmitter acetylcholine.

VAGAL WITHDRAWAL: AN ALTERNATIVE TO SYMPATHETIC ACTIVATION

Porges¹ first proposed the concept of vagal withdrawal as an indicator of stress and stress vulnerability; this contrasts with the idea that the stress response is a consequence of sympathetic activation and the hypothalamic-pituitary-adrenal axis response. In the vagal withdrawal model, the response to stress is stabilization of the sympathetic system followed by termination of parasympathetic activity, manifested as cardiac acceleration.

Respiratory sinus arrhythmia (RSA), or the variability in heart rate as it synchronizes with breathing, is considered an index of parasympathetic tone. In the laboratory, slow atropine infusion produces a transient paradoxical vagomimetic effect characterized by an initial increase in RSA, followed by a flattening and then a rise in the heart rate.² This phenomenon has been measured in people during times of routine stress, such as when worrying about being late for an appointment. In such individuals, biofeedback training can result in recovery of normal RSA shortly after an episode of anxiety.

Historically, the focus of biofeedback was to cultivate low arousal, presumably reducing SNS activity, through the use of finger temperature, skin conductance training, and profound muscle relaxation. More sophisticated ways to look at both branches of the autonomic nervous system have since emerged that allow for sampling of the beat-by-beat changes in heart rate.

HEART RATE VARIABILITY BIOFEEDBACK

The concept of modifying the respiration rate (paced breathing) originated some 2,500 years ago as a component of meditation. It is being revisited today in the form of heart rate variability (HRV) biofeedback training, which is being used as a stress-management tool and a method to correct disorders in which autonomic regulation is thought to be important. HRV biofeedback involves training to increase the amplitude of HRV rhythms and thus improve autonomic homeostasis.

Normal HRV has a pattern of overlapping oscillatory frequency components, including:

• a high-frequency rhythm, 0.15 to 0.4 Hz, which is the RSA;
• a low-frequency rhythm, 0.05 to 0.15 Hz, associated with blood pressure oscillations; and
• a very-low-frequency rhythm, 0.005 to 0.05 Hz, which may regulate vascular tone and body temperature.

The goal of HRV biofeedback is to achieve respiratory rates at which resonance occurs between cardiac rhythms associated with respiration (RSA, or high-frequency oscillations) and those caused by baroreflex activity (low-frequency oscillations).

Spectral analysis has demonstrated that nearly all of the activity with HRV biofeedback occurs at a low-frequency band. The reason is that activity in the low-frequency band is related more to baroreflex activity than to HRV compared with other ranges of frequency. Breathing rates that correspond to baroreflex effects, called resonance frequency breathing, represent resonance in the cardiovascular system. Several devices are available whose mechanisms are based on the concept of achieving resonance frequency breathing. One such device is a slow-breathing monitor (Resp-e-rate) that has been approved by the US Food and Drug Administration for the adjunctive treatment of hypertension.

Improved HRV may suggest an improved risk status: Kleiger et al⁴ found that the relative risk of mortality was 5.3 times greater for people with SDNN of less than 50 msec compared with those whose SDNN was greater than 100 msec. In Del Pozo’s study, eight of 30 patients in the intervention group achieved an SDNN of greater than 50 msec (vs 0 at pretreatment) compared with three of 31 controls (vs two at pretreatment).³ As an additional benefit of HRV biofeedback, patients in the intervention group who entered the study with hypertension all became normotensive.

In a meta-analysis, van Dixhoorn and White⁵ found fewer cardiac events, fewer episodes of angina, and less occurrence of arrhythmia and exercise-induced ischemia from intensive supervised relaxation therapy in patients with ischemic heart disease. Improvements in scales of depression and anxiety were also observed with relaxation therapy.

Other studies have shown biofeedback to have beneficial effects based on the Posttraumatic Stress Disorder Checklist, the Hamilton Depression Rating Scale, and, in patients with mild to moderate heartfailure, the 6-minute walk test.^6–8

The proposed mechanism for the beneficial effects of biofeedback found in clinical trials is improvement in baroreflex function, producing greater reflex efficiency and improved modulation of autonomic activity.

CONCLUSION

A shift in emphasis to vagal withdrawal has led to new forms of biofeedback that probably potentiate many of the same mechanisms thought to be present in Eastern practices such as yoga and tai chi. Results from small-scale trials have been promising for HRV biofeedback as a means of modifying responses to stress and promoting homeostatic processes that reduce the intensity of symptoms and improve surrogate markers associated with a number of disorders.

Traditionally, biofeedback was considered to be a stress management technique that targeted sympathetic nervous system (SNS) overdrive with an adrenal medullary system backup. Recent advances in autonomic physiology, however, have clarified that except in extreme situations, the SNS is not the key factor in day-to-day stress. Rather, the parasympathetic branch of the autonomic nervous system appears to be a more likely candidate for mediating routine stress because, unlike the SNS, which has slow-acting neurotransmitters (ie, catecholamines), the parasympathetic nervous system has the fast-acting transmitter acetylcholine.

VAGAL WITHDRAWAL: AN ALTERNATIVE TO SYMPATHETIC ACTIVATION

Porges¹ first proposed the concept of vagal withdrawal as an indicator of stress and stress vulnerability; this contrasts with the idea that the stress response is a consequence of sympathetic activation and the hypothalamic-pituitary-adrenal axis response. In the vagal withdrawal model, the response to stress is stabilization of the sympathetic system followed by termination of parasympathetic activity, manifested as cardiac acceleration.

Respiratory sinus arrhythmia (RSA), or the variability in heart rate as it synchronizes with breathing, is considered an index of parasympathetic tone. In the laboratory, slow atropine infusion produces a transient paradoxical vagomimetic effect characterized by an initial increase in RSA, followed by a flattening and then a rise in the heart rate.² This phenomenon has been measured in people during times of routine stress, such as when worrying about being late for an appointment. In such individuals, biofeedback training can result in recovery of normal RSA shortly after an episode of anxiety.

Historically, the focus of biofeedback was to cultivate low arousal, presumably reducing SNS activity, through the use of finger temperature, skin conductance training, and profound muscle relaxation. More sophisticated ways to look at both branches of the autonomic nervous system have since emerged that allow for sampling of the beat-by-beat changes in heart rate.

HEART RATE VARIABILITY BIOFEEDBACK

The concept of modifying the respiration rate (paced breathing) originated some 2,500 years ago as a component of meditation. It is being revisited today in the form of heart rate variability (HRV) biofeedback training, which is being used as a stress-management tool and a method to correct disorders in which autonomic regulation is thought to be important. HRV biofeedback involves training to increase the amplitude of HRV rhythms and thus improve autonomic homeostasis.

Normal HRV has a pattern of overlapping oscillatory frequency components, including:

• a high-frequency rhythm, 0.15 to 0.4 Hz, which is the RSA;
• a low-frequency rhythm, 0.05 to 0.15 Hz, associated with blood pressure oscillations; and
• a very-low-frequency rhythm, 0.005 to 0.05 Hz, which may regulate vascular tone and body temperature.

The goal of HRV biofeedback is to achieve respiratory rates at which resonance occurs between cardiac rhythms associated with respiration (RSA, or high-frequency oscillations) and those caused by baroreflex activity (low-frequency oscillations).

Spectral analysis has demonstrated that nearly all of the activity with HRV biofeedback occurs at a low-frequency band. The reason is that activity in the low-frequency band is related more to baroreflex activity than to HRV compared with other ranges of frequency. Breathing rates that correspond to baroreflex effects, called resonance frequency breathing, represent resonance in the cardiovascular system. Several devices are available whose mechanisms are based on the concept of achieving resonance frequency breathing. One such device is a slow-breathing monitor (Resp-e-rate) that has been approved by the US Food and Drug Administration for the adjunctive treatment of hypertension.

Improved HRV may suggest an improved risk status: Kleiger et al⁴ found that the relative risk of mortality was 5.3 times greater for people with SDNN of less than 50 msec compared with those whose SDNN was greater than 100 msec. In Del Pozo’s study, eight of 30 patients in the intervention group achieved an SDNN of greater than 50 msec (vs 0 at pretreatment) compared with three of 31 controls (vs two at pretreatment).³ As an additional benefit of HRV biofeedback, patients in the intervention group who entered the study with hypertension all became normotensive.

In a meta-analysis, van Dixhoorn and White⁵ found fewer cardiac events, fewer episodes of angina, and less occurrence of arrhythmia and exercise-induced ischemia from intensive supervised relaxation therapy in patients with ischemic heart disease. Improvements in scales of depression and anxiety were also observed with relaxation therapy.

Other studies have shown biofeedback to have beneficial effects based on the Posttraumatic Stress Disorder Checklist, the Hamilton Depression Rating Scale, and, in patients with mild to moderate heartfailure, the 6-minute walk test.^6–8

The proposed mechanism for the beneficial effects of biofeedback found in clinical trials is improvement in baroreflex function, producing greater reflex efficiency and improved modulation of autonomic activity.

CONCLUSION

A shift in emphasis to vagal withdrawal has led to new forms of biofeedback that probably potentiate many of the same mechanisms thought to be present in Eastern practices such as yoga and tai chi. Results from small-scale trials have been promising for HRV biofeedback as a means of modifying responses to stress and promoting homeostatic processes that reduce the intensity of symptoms and improve surrogate markers associated with a number of disorders.

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms emerge following exposure to extreme stress, such as those encountered in the battlefield or as a result of sexual abuse or natural disasters. The ability to employ coping mechanisms affects the disorder’s presentation as well as the frequency, intensity, and duration of the symptoms. The “Wounded Warrior” program at East Carolina University (Greenville, NC) was developed to promote the functional independence of US Marines, including those with PTSD.

STRESS RESPONSE: INTERACTION OF THE BRAIN AND IMMUNE SYSTEM

Walter Cannon coined the “flight or fight” response to stress in the early 20th century, in which he emphasized the importance of the parasympathetic system.¹ In 1988, Folkow clarified the description as an immune response to stress.² The stress response is now understood to be a neuroendocrine function that includes a feedback loop between the hypothalamus and the pituitary and adrenal glands; stimulation of the hypothalamus promotes secretion of corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies the anterior pituitarywith blood. CRH stimulates the secretion of adrenocorticotropic hormone into the bloodstream by the pituitary, prompting the adrenal glands to release the stress hormone cortisol.

Cortisol mobilizes the body’s defenses to meet the challenge of an adverse situation. It modulates the stress response by inhibiting the further release of CRH by the hypothalamus. Cortisol thus protects healthy cells and tissues by inhibiting an overreaction from the immune system. Without this protective effect, the interaction between the brain and the immune system can become dysregulated, increasing the risk of immune disorders.

THE CENTRAL AUTONOMIC NETWORK

The central nervous system that regulates the overall balance of the autonomic nervous system (ANS) has been called the central autonomic network (CAN).³ The CAN helps control executive, social, affective, attentional, and motivational functions. Therefore, the old paradigm of simply decreasing hyperarousal of the ANS to treat negative affective states and dispositions is inadequate. Instead, restoring the appropriate relationship between the ANS and the central nervous system is the aim behind interventions to treat PTSD.

Autonomic, cognitive, and affective functions assist humans in maintaining balance when confronted with external challenges. The CAN controls inhibitory or negative processes that permit specific behavior and redeploy resources needed elsewhere. When negative circuits are compromised, positive circuits develop, resulting in hypervigilance, the symptoms of which can be devastating and, if not ameliorated, can develop into permanent conditions. In one study,Vietnam veterans with PTSD had an 8% reduction in the volume of their right hippocampus compared with veterans without PTSD. Another study calculated a 26% reduction in the left hippocampus and a 22% reduction in the right in veterans with the most severe PTSD compared with veterans who were in combat but had no PTSD symptoms.⁴

A common subcortical neural system regulates defensive behavior, including autonomic, emotional, and cognitive behavior. When the prefrontal cortex is taken “off line” for whatever reason, parasympathetic inhibitory action is withdrawn, and relative sympathetic dominance, associated with defense, occurs.

CONFRONTING HYPERAROUSAL

The question then arises of how to train the ANS to avoid hypervigilance. Growing evidence supports the use of heart rate variability as a predictor of hypervigilance and inefficient allocation of attentional and cognitive resources.

The overall objective of heart rate variability training is to decrease ANS hyperarousal and to improve its balance. “Wounded warriors” learn to control ANS responses to stress-producing stimuli (eg, thoughts, memories, and images associated with combat). The goal of training is to decrease arousal and maintain ANS balance for increasing lengths of time.

Once it was observed that alpha waves were dysfunctional in vulnerable populations, protocols were developed to train alpha and theta waves as a method of improving function. Peniston and colleagues^5–9 showed that increased alpha and theta brain wave production resulted in normalized personality measures and prolonged the period of time before relapse in alcoholics. This protocol has also shown efficacy as an intervention in depression and PTSD.

BIOFEEDBACK TRAINING PROGRAM

The US Department of Defense is studying a combination of central nervous system biofeedback with ANS biofeedback, with the goal of restoring and maintaining tone between the systems.

The training program used in the study lasts 1 month, and starts with a session for preassessment, 16 biofeedback sessions (four per week), a postprogram evaluation, and a 3-month followup. Each week, participants are exposed to stress-producing stimuli that increase in intensity:

• Week 1: Stroop Color Word Test, math stressor, talk stressor/everyday events
• Week 2: Talk stressor, combat experiences
• Week 3: Images and sounds of combat
• Week 4: Virtual Baghdad or Afghanistan (virtual reality exposure)

Each biofeedback session consists of 5 minutes of baseline evaluation; 5 minutes in which the veteran is subjected to the weekly stressor; 20 minutes of heart rate variability and neurofeedback training; 5 more minutes of training with the weekly stressor; 20 more minutes of heart rate variability and neurofeedback training; and finally 5 minutes of recovery.

SUMMARY

Dysfunction in the balance of both the ANS and central nervous system is associated with symptoms of PTSD in combat veterans. Methods that are designed to restore balance in these systems are needed to ameliorate these symptoms. Biofeedback and neurofeedback are safe methods with which to achieve these goals.

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms emerge following exposure to extreme stress, such as those encountered in the battlefield or as a result of sexual abuse or natural disasters. The ability to employ coping mechanisms affects the disorder’s presentation as well as the frequency, intensity, and duration of the symptoms. The “Wounded Warrior” program at East Carolina University (Greenville, NC) was developed to promote the functional independence of US Marines, including those with PTSD.

STRESS RESPONSE: INTERACTION OF THE BRAIN AND IMMUNE SYSTEM

Walter Cannon coined the “flight or fight” response to stress in the early 20th century, in which he emphasized the importance of the parasympathetic system.¹ In 1988, Folkow clarified the description as an immune response to stress.² The stress response is now understood to be a neuroendocrine function that includes a feedback loop between the hypothalamus and the pituitary and adrenal glands; stimulation of the hypothalamus promotes secretion of corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies the anterior pituitarywith blood. CRH stimulates the secretion of adrenocorticotropic hormone into the bloodstream by the pituitary, prompting the adrenal glands to release the stress hormone cortisol.

Cortisol mobilizes the body’s defenses to meet the challenge of an adverse situation. It modulates the stress response by inhibiting the further release of CRH by the hypothalamus. Cortisol thus protects healthy cells and tissues by inhibiting an overreaction from the immune system. Without this protective effect, the interaction between the brain and the immune system can become dysregulated, increasing the risk of immune disorders.

THE CENTRAL AUTONOMIC NETWORK

The central nervous system that regulates the overall balance of the autonomic nervous system (ANS) has been called the central autonomic network (CAN).³ The CAN helps control executive, social, affective, attentional, and motivational functions. Therefore, the old paradigm of simply decreasing hyperarousal of the ANS to treat negative affective states and dispositions is inadequate. Instead, restoring the appropriate relationship between the ANS and the central nervous system is the aim behind interventions to treat PTSD.

Autonomic, cognitive, and affective functions assist humans in maintaining balance when confronted with external challenges. The CAN controls inhibitory or negative processes that permit specific behavior and redeploy resources needed elsewhere. When negative circuits are compromised, positive circuits develop, resulting in hypervigilance, the symptoms of which can be devastating and, if not ameliorated, can develop into permanent conditions. In one study,Vietnam veterans with PTSD had an 8% reduction in the volume of their right hippocampus compared with veterans without PTSD. Another study calculated a 26% reduction in the left hippocampus and a 22% reduction in the right in veterans with the most severe PTSD compared with veterans who were in combat but had no PTSD symptoms.⁴

A common subcortical neural system regulates defensive behavior, including autonomic, emotional, and cognitive behavior. When the prefrontal cortex is taken “off line” for whatever reason, parasympathetic inhibitory action is withdrawn, and relative sympathetic dominance, associated with defense, occurs.

CONFRONTING HYPERAROUSAL

The question then arises of how to train the ANS to avoid hypervigilance. Growing evidence supports the use of heart rate variability as a predictor of hypervigilance and inefficient allocation of attentional and cognitive resources.

The overall objective of heart rate variability training is to decrease ANS hyperarousal and to improve its balance. “Wounded warriors” learn to control ANS responses to stress-producing stimuli (eg, thoughts, memories, and images associated with combat). The goal of training is to decrease arousal and maintain ANS balance for increasing lengths of time.

Once it was observed that alpha waves were dysfunctional in vulnerable populations, protocols were developed to train alpha and theta waves as a method of improving function. Peniston and colleagues^5–9 showed that increased alpha and theta brain wave production resulted in normalized personality measures and prolonged the period of time before relapse in alcoholics. This protocol has also shown efficacy as an intervention in depression and PTSD.

BIOFEEDBACK TRAINING PROGRAM

The US Department of Defense is studying a combination of central nervous system biofeedback with ANS biofeedback, with the goal of restoring and maintaining tone between the systems.

The training program used in the study lasts 1 month, and starts with a session for preassessment, 16 biofeedback sessions (four per week), a postprogram evaluation, and a 3-month followup. Each week, participants are exposed to stress-producing stimuli that increase in intensity:

• Week 1: Stroop Color Word Test, math stressor, talk stressor/everyday events
• Week 2: Talk stressor, combat experiences
• Week 3: Images and sounds of combat
• Week 4: Virtual Baghdad or Afghanistan (virtual reality exposure)

Each biofeedback session consists of 5 minutes of baseline evaluation; 5 minutes in which the veteran is subjected to the weekly stressor; 20 minutes of heart rate variability and neurofeedback training; 5 more minutes of training with the weekly stressor; 20 more minutes of heart rate variability and neurofeedback training; and finally 5 minutes of recovery.

SUMMARY

Dysfunction in the balance of both the ANS and central nervous system is associated with symptoms of PTSD in combat veterans. Methods that are designed to restore balance in these systems are needed to ameliorate these symptoms. Biofeedback and neurofeedback are safe methods with which to achieve these goals.

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder whose symptoms emerge following exposure to extreme stress, such as those encountered in the battlefield or as a result of sexual abuse or natural disasters. The ability to employ coping mechanisms affects the disorder’s presentation as well as the frequency, intensity, and duration of the symptoms. The “Wounded Warrior” program at East Carolina University (Greenville, NC) was developed to promote the functional independence of US Marines, including those with PTSD.

STRESS RESPONSE: INTERACTION OF THE BRAIN AND IMMUNE SYSTEM

Walter Cannon coined the “flight or fight” response to stress in the early 20th century, in which he emphasized the importance of the parasympathetic system.¹ In 1988, Folkow clarified the description as an immune response to stress.² The stress response is now understood to be a neuroendocrine function that includes a feedback loop between the hypothalamus and the pituitary and adrenal glands; stimulation of the hypothalamus promotes secretion of corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies the anterior pituitarywith blood. CRH stimulates the secretion of adrenocorticotropic hormone into the bloodstream by the pituitary, prompting the adrenal glands to release the stress hormone cortisol.

Cortisol mobilizes the body’s defenses to meet the challenge of an adverse situation. It modulates the stress response by inhibiting the further release of CRH by the hypothalamus. Cortisol thus protects healthy cells and tissues by inhibiting an overreaction from the immune system. Without this protective effect, the interaction between the brain and the immune system can become dysregulated, increasing the risk of immune disorders.

THE CENTRAL AUTONOMIC NETWORK

The central nervous system that regulates the overall balance of the autonomic nervous system (ANS) has been called the central autonomic network (CAN).³ The CAN helps control executive, social, affective, attentional, and motivational functions. Therefore, the old paradigm of simply decreasing hyperarousal of the ANS to treat negative affective states and dispositions is inadequate. Instead, restoring the appropriate relationship between the ANS and the central nervous system is the aim behind interventions to treat PTSD.

Autonomic, cognitive, and affective functions assist humans in maintaining balance when confronted with external challenges. The CAN controls inhibitory or negative processes that permit specific behavior and redeploy resources needed elsewhere. When negative circuits are compromised, positive circuits develop, resulting in hypervigilance, the symptoms of which can be devastating and, if not ameliorated, can develop into permanent conditions. In one study,Vietnam veterans with PTSD had an 8% reduction in the volume of their right hippocampus compared with veterans without PTSD. Another study calculated a 26% reduction in the left hippocampus and a 22% reduction in the right in veterans with the most severe PTSD compared with veterans who were in combat but had no PTSD symptoms.⁴

A common subcortical neural system regulates defensive behavior, including autonomic, emotional, and cognitive behavior. When the prefrontal cortex is taken “off line” for whatever reason, parasympathetic inhibitory action is withdrawn, and relative sympathetic dominance, associated with defense, occurs.

CONFRONTING HYPERAROUSAL

The question then arises of how to train the ANS to avoid hypervigilance. Growing evidence supports the use of heart rate variability as a predictor of hypervigilance and inefficient allocation of attentional and cognitive resources.

The overall objective of heart rate variability training is to decrease ANS hyperarousal and to improve its balance. “Wounded warriors” learn to control ANS responses to stress-producing stimuli (eg, thoughts, memories, and images associated with combat). The goal of training is to decrease arousal and maintain ANS balance for increasing lengths of time.

Once it was observed that alpha waves were dysfunctional in vulnerable populations, protocols were developed to train alpha and theta waves as a method of improving function. Peniston and colleagues^5–9 showed that increased alpha and theta brain wave production resulted in normalized personality measures and prolonged the period of time before relapse in alcoholics. This protocol has also shown efficacy as an intervention in depression and PTSD.

BIOFEEDBACK TRAINING PROGRAM

The US Department of Defense is studying a combination of central nervous system biofeedback with ANS biofeedback, with the goal of restoring and maintaining tone between the systems.

The training program used in the study lasts 1 month, and starts with a session for preassessment, 16 biofeedback sessions (four per week), a postprogram evaluation, and a 3-month followup. Each week, participants are exposed to stress-producing stimuli that increase in intensity:

• Week 1: Stroop Color Word Test, math stressor, talk stressor/everyday events
• Week 2: Talk stressor, combat experiences
• Week 3: Images and sounds of combat
• Week 4: Virtual Baghdad or Afghanistan (virtual reality exposure)

Each biofeedback session consists of 5 minutes of baseline evaluation; 5 minutes in which the veteran is subjected to the weekly stressor; 20 minutes of heart rate variability and neurofeedback training; 5 more minutes of training with the weekly stressor; 20 more minutes of heart rate variability and neurofeedback training; and finally 5 minutes of recovery.

SUMMARY

Dysfunction in the balance of both the ANS and central nervous system is associated with symptoms of PTSD in combat veterans. Methods that are designed to restore balance in these systems are needed to ameliorate these symptoms. Biofeedback and neurofeedback are safe methods with which to achieve these goals.

Question from audience: Why does the Cleveland Clinic start its healing services program preoperatively rather than postoperatively?

Dr. Gillinov: We have a fairly well defined preoperative set of medical tests, and during this process nurses present patients with materials that explain the experience, and nurses and doctors make themselves available in special classes to answer patients’ questions. In doing so, we have increasingly identified patients preoperatively who have stress or problems.

Last week I saw a woman who had a leaking mitral valve, but her symptoms were out of proportion to her disease. She had loss of energy and appetite, and she wasn’t eating much. She was depressed and our team picked that up. She actually never had to undergo surgery. We referred her to a psychologist and, according to her son, she started to feel better. By starting preoperatively, we’re sometimes able to pick out things that we should treat instead of heart disease.

We also provide guided imagery and massage preoperatively.

Dr. Duffy: Healing services is on standing preoperative orders at the hospital. The team goes in proactively and asks, “In addition to your open heart surgery on Wednesday, is there anything we can do to support your emotional and spiritual journey here today?”

Terminology also matters. The term “healing services” is a safe umbrella under which we include biofeedback as one of the services, but it encompasses pastoral care, hospice care, and palliative care. The way it’s integrated into a care model is important. If it’s reserved for end of life, it might be viewed as defective or as a death sentence, so we want the healing services team to be proactive.

Question from audience: How does the primary care physician fit into all of this? I believe that if the physicians in the hospital want to gain patient confidence, they’ll show that they’re communicating well with the primary care physician.

Dr. Gevirtz: The primary care physicians are incredibly open to this idea. They have 12 minutes to deal with people with fibromyalgia, irritable bowel syndrome, chronic pain, noncardiac chest pain, etc. What are they going to do in 12 minutes? They’re grateful if they have a handoff, especially if it’s in the Clinic itself.

Question from audience: Are there any thoughts on making biofeedback part of general training rather than using it just for patients who’ve already experienced trauma?

Dr. Gevirtz: We did a study in which we showed that a biofeedback technician in the primary care setting saved the health maintenance system quite a lot of money, but the administration couldn’t decide whose territory to take to give us an office, so it ended the program.

Dr. Russoniello: How we enable greater access to our intervention is an important question. I see people quit the program if they can’t get access to biofeedback. In an effort to enhance compliance, we’ve incorporated biofeedback into video games, working with a couple of private companies to develop them.The idea is that persons playing the video game can accrue points to enhance their overall score if they perform paced breathing or some other form of biofeedback. Early indications from focus groups are that people will like this.

We have already shown in randomized controlled clinical studies of depression and anxiety that certain video games can improve mood and decrease stress.There is a big movement to get products in people’s hands to help them manage their health.

Question from audience: How much overlap is there between biofeedback methodologies—enhancing heart rate variability, vagal withdrawal, neurofeedback, and electroencephalographic feedback—in the systems you’re targeting and what are the unique contributions of each?

Dr. Gevirtz: We follow a stepped-care model. We start with the simplest and move on to the more complicated technologies. Two published studies with long-term followup showed the effectiveness of a learned breathing technique in alleviating noncardiac chest pain. Simple biofeedback wasn’t even needed. Three years later, the patients were better than they were at the end of the actual training. If you can do it simply, then you do it, and if it doesn’t work, then move on to more and more complicated techniques, with neurofeedback being the last resort.

Question from audience: Has anybody measured the physical impact of stimulating multiple systems on the study subject? In other words, can it be damaging to overstimulate these systems at the same time?

Dr. Gevirtz: We’ve been trying to do that. Recurrent abdominal pain or functional abdominal pain is the most common complaint to pediatric gastroenterologists. We have 1,800 patients a year who make it to the children’s hospital level with this complaint. These are kids who are suffering with very great pain and we we’re pretty sure it’s an autonomically mediated kind of phenomenon. We’re able to measure vagal activity in these kids in ambulatory settings at school and have found very little vagal activity before treatment. After training, they were able to restore vagal activity, and it correlated at the level of 0.63 with a reduction of symptoms. I think it’s important to try to tie the physiology to symptoms. It’s not always easy to do but we’re trying.

Question from audience: I’d like to pick up on two topics that Dr. Duffy raised: the business of medicine and the proposal for informed hope rather than an informed consent before surgery. Something that I see with patients and families at times is this magical expectation promoted by the business side that medicine can do these amazing and wonderful things and doesn’t have any sort of weaknesses. I wonder what role unrealistic expectations promoted by the media, advertising, and others may play in the stress of patients, caregivers, and physicians who need to try to meet the expectations of infallible medicine?

Dr. Duffy: We’ve spun so far the other way with our advanced technology that we’ve lost the human side, especially the concept of a relationship and giving people hope even though they have a terminal condition. It’s a balance between the art and the business of medicine. It’s about setting realistic expectations and realistic hope.

Question from audience: Why does the Cleveland Clinic start its healing services program preoperatively rather than postoperatively?

Dr. Gillinov: We have a fairly well defined preoperative set of medical tests, and during this process nurses present patients with materials that explain the experience, and nurses and doctors make themselves available in special classes to answer patients’ questions. In doing so, we have increasingly identified patients preoperatively who have stress or problems.

Last week I saw a woman who had a leaking mitral valve, but her symptoms were out of proportion to her disease. She had loss of energy and appetite, and she wasn’t eating much. She was depressed and our team picked that up. She actually never had to undergo surgery. We referred her to a psychologist and, according to her son, she started to feel better. By starting preoperatively, we’re sometimes able to pick out things that we should treat instead of heart disease.

We also provide guided imagery and massage preoperatively.

Dr. Duffy: Healing services is on standing preoperative orders at the hospital. The team goes in proactively and asks, “In addition to your open heart surgery on Wednesday, is there anything we can do to support your emotional and spiritual journey here today?”

Terminology also matters. The term “healing services” is a safe umbrella under which we include biofeedback as one of the services, but it encompasses pastoral care, hospice care, and palliative care. The way it’s integrated into a care model is important. If it’s reserved for end of life, it might be viewed as defective or as a death sentence, so we want the healing services team to be proactive.

Question from audience: How does the primary care physician fit into all of this? I believe that if the physicians in the hospital want to gain patient confidence, they’ll show that they’re communicating well with the primary care physician.

Dr. Gevirtz: The primary care physicians are incredibly open to this idea. They have 12 minutes to deal with people with fibromyalgia, irritable bowel syndrome, chronic pain, noncardiac chest pain, etc. What are they going to do in 12 minutes? They’re grateful if they have a handoff, especially if it’s in the Clinic itself.

Question from audience: Are there any thoughts on making biofeedback part of general training rather than using it just for patients who’ve already experienced trauma?

Dr. Gevirtz: We did a study in which we showed that a biofeedback technician in the primary care setting saved the health maintenance system quite a lot of money, but the administration couldn’t decide whose territory to take to give us an office, so it ended the program.

Dr. Russoniello: How we enable greater access to our intervention is an important question. I see people quit the program if they can’t get access to biofeedback. In an effort to enhance compliance, we’ve incorporated biofeedback into video games, working with a couple of private companies to develop them.The idea is that persons playing the video game can accrue points to enhance their overall score if they perform paced breathing or some other form of biofeedback. Early indications from focus groups are that people will like this.

We have already shown in randomized controlled clinical studies of depression and anxiety that certain video games can improve mood and decrease stress.There is a big movement to get products in people’s hands to help them manage their health.

Question from audience: How much overlap is there between biofeedback methodologies—enhancing heart rate variability, vagal withdrawal, neurofeedback, and electroencephalographic feedback—in the systems you’re targeting and what are the unique contributions of each?

Dr. Gevirtz: We follow a stepped-care model. We start with the simplest and move on to the more complicated technologies. Two published studies with long-term followup showed the effectiveness of a learned breathing technique in alleviating noncardiac chest pain. Simple biofeedback wasn’t even needed. Three years later, the patients were better than they were at the end of the actual training. If you can do it simply, then you do it, and if it doesn’t work, then move on to more and more complicated techniques, with neurofeedback being the last resort.

Question from audience: Has anybody measured the physical impact of stimulating multiple systems on the study subject? In other words, can it be damaging to overstimulate these systems at the same time?

Dr. Gevirtz: We’ve been trying to do that. Recurrent abdominal pain or functional abdominal pain is the most common complaint to pediatric gastroenterologists. We have 1,800 patients a year who make it to the children’s hospital level with this complaint. These are kids who are suffering with very great pain and we we’re pretty sure it’s an autonomically mediated kind of phenomenon. We’re able to measure vagal activity in these kids in ambulatory settings at school and have found very little vagal activity before treatment. After training, they were able to restore vagal activity, and it correlated at the level of 0.63 with a reduction of symptoms. I think it’s important to try to tie the physiology to symptoms. It’s not always easy to do but we’re trying.

Question from audience: I’d like to pick up on two topics that Dr. Duffy raised: the business of medicine and the proposal for informed hope rather than an informed consent before surgery. Something that I see with patients and families at times is this magical expectation promoted by the business side that medicine can do these amazing and wonderful things and doesn’t have any sort of weaknesses. I wonder what role unrealistic expectations promoted by the media, advertising, and others may play in the stress of patients, caregivers, and physicians who need to try to meet the expectations of infallible medicine?

Dr. Duffy: We’ve spun so far the other way with our advanced technology that we’ve lost the human side, especially the concept of a relationship and giving people hope even though they have a terminal condition. It’s a balance between the art and the business of medicine. It’s about setting realistic expectations and realistic hope.

Question from audience: Why does the Cleveland Clinic start its healing services program preoperatively rather than postoperatively?

Dr. Gillinov: We have a fairly well defined preoperative set of medical tests, and during this process nurses present patients with materials that explain the experience, and nurses and doctors make themselves available in special classes to answer patients’ questions. In doing so, we have increasingly identified patients preoperatively who have stress or problems.

Last week I saw a woman who had a leaking mitral valve, but her symptoms were out of proportion to her disease. She had loss of energy and appetite, and she wasn’t eating much. She was depressed and our team picked that up. She actually never had to undergo surgery. We referred her to a psychologist and, according to her son, she started to feel better. By starting preoperatively, we’re sometimes able to pick out things that we should treat instead of heart disease.

We also provide guided imagery and massage preoperatively.

Dr. Duffy: Healing services is on standing preoperative orders at the hospital. The team goes in proactively and asks, “In addition to your open heart surgery on Wednesday, is there anything we can do to support your emotional and spiritual journey here today?”

Terminology also matters. The term “healing services” is a safe umbrella under which we include biofeedback as one of the services, but it encompasses pastoral care, hospice care, and palliative care. The way it’s integrated into a care model is important. If it’s reserved for end of life, it might be viewed as defective or as a death sentence, so we want the healing services team to be proactive.

Question from audience: How does the primary care physician fit into all of this? I believe that if the physicians in the hospital want to gain patient confidence, they’ll show that they’re communicating well with the primary care physician.

Dr. Gevirtz: The primary care physicians are incredibly open to this idea. They have 12 minutes to deal with people with fibromyalgia, irritable bowel syndrome, chronic pain, noncardiac chest pain, etc. What are they going to do in 12 minutes? They’re grateful if they have a handoff, especially if it’s in the Clinic itself.

Question from audience: Are there any thoughts on making biofeedback part of general training rather than using it just for patients who’ve already experienced trauma?

Dr. Gevirtz: We did a study in which we showed that a biofeedback technician in the primary care setting saved the health maintenance system quite a lot of money, but the administration couldn’t decide whose territory to take to give us an office, so it ended the program.

Dr. Russoniello: How we enable greater access to our intervention is an important question. I see people quit the program if they can’t get access to biofeedback. In an effort to enhance compliance, we’ve incorporated biofeedback into video games, working with a couple of private companies to develop them.The idea is that persons playing the video game can accrue points to enhance their overall score if they perform paced breathing or some other form of biofeedback. Early indications from focus groups are that people will like this.

We have already shown in randomized controlled clinical studies of depression and anxiety that certain video games can improve mood and decrease stress.There is a big movement to get products in people’s hands to help them manage their health.

Question from audience: How much overlap is there between biofeedback methodologies—enhancing heart rate variability, vagal withdrawal, neurofeedback, and electroencephalographic feedback—in the systems you’re targeting and what are the unique contributions of each?

Dr. Gevirtz: We follow a stepped-care model. We start with the simplest and move on to the more complicated technologies. Two published studies with long-term followup showed the effectiveness of a learned breathing technique in alleviating noncardiac chest pain. Simple biofeedback wasn’t even needed. Three years later, the patients were better than they were at the end of the actual training. If you can do it simply, then you do it, and if it doesn’t work, then move on to more and more complicated techniques, with neurofeedback being the last resort.

Question from audience: Has anybody measured the physical impact of stimulating multiple systems on the study subject? In other words, can it be damaging to overstimulate these systems at the same time?

Dr. Gevirtz: We’ve been trying to do that. Recurrent abdominal pain or functional abdominal pain is the most common complaint to pediatric gastroenterologists. We have 1,800 patients a year who make it to the children’s hospital level with this complaint. These are kids who are suffering with very great pain and we we’re pretty sure it’s an autonomically mediated kind of phenomenon. We’re able to measure vagal activity in these kids in ambulatory settings at school and have found very little vagal activity before treatment. After training, they were able to restore vagal activity, and it correlated at the level of 0.63 with a reduction of symptoms. I think it’s important to try to tie the physiology to symptoms. It’s not always easy to do but we’re trying.

Question from audience: I’d like to pick up on two topics that Dr. Duffy raised: the business of medicine and the proposal for informed hope rather than an informed consent before surgery. Something that I see with patients and families at times is this magical expectation promoted by the business side that medicine can do these amazing and wonderful things and doesn’t have any sort of weaknesses. I wonder what role unrealistic expectations promoted by the media, advertising, and others may play in the stress of patients, caregivers, and physicians who need to try to meet the expectations of infallible medicine?

Dr. Duffy: We’ve spun so far the other way with our advanced technology that we’ve lost the human side, especially the concept of a relationship and giving people hope even though they have a terminal condition. It’s a balance between the art and the business of medicine. It’s about setting realistic expectations and realistic hope.

The effect of emotion on the heart is not confined to depression, but extends to a variety of mental states; as William Harvey described in 1628, “A mental disturbance provoking pain, excessive joy, hope or anxiety extends to the heart, where it affects its temper and rate, impairing general nutrition and vigor.”

In going beyond the well-established role of depression as a risk factor for heart disease, 2010 delivered several important publications recognizing anxiety, anger, and other forms of distress as key factors in the etiology of coronary heart disease (CHD). Other papers of merit elucidated new and overlooked insights into the pathways linking psychosocial stress and cardiovascular risk, and also considered psychologic states that appear to promote healthy functioning.

IMPACT OF NEGATIVE EMOTIONS ON RISK OF INCIDENT CORONARY HEART DISEASE

In a meta-analysis of 20 prospective studies that included 249,846 persons with a mean follow-up of 11.2 years, Roest et al¹ examined the impact of anxiety characterized by the presence of anxiety symptoms or a diagnosis of anxiety disorder on incident CHD. Most of the studies adjusted for a broad array of relevant potential confounders. Findings suggest the presence of anxiety increases the risk of incident CHD by 26% (P P = .003).

In a meta-analysis of 25 prospective studies of 7,160 persons with a mean follow-up exceeding 10 years, Chida and Steptoe² found that anger increased the risk of incident CHD by 19%, after adjustment for standard coronary risk factors. The effect was less stable than that associated with anxiety and depression, and when stratified by gender, the harmful effects of anger were more evident in men than in women. The effect of anger was attenuated when controlling for behavioral covariates. The association between anger and CHD did not hold for all ways of measuring anger, which suggests that the type of anger or the ability to regulate anger may be relevant to the relationship.

A study that did account for the type of anger expression on the risk of incident CHD was conducted by Davidson and Mostofsky.³ The independent effect of three distinct types of anger expression (constructive anger, destructive anger justification, and destructive anger rumination) on 10-year incident CHD was examined, controlling for other psychosocial factors. In men, higher scores for constructive anger were associated with a lower rate of CHD; in both men and women, higher scores for destructive anger justification were associated with an increased risk of CHD.

Insights gained from these studies are as follows:

• The impact of anxiety appears to be comparable to depression, and the effects of anxiety and depression are largely independent.
• If anxiety and depression co-occur, the effect on CHD is synergistic.
• The effects of anger are less clear; its impact may be independent of or dependent on other forms of psychologic distress.
• Distress in general appears to serve as a signal that something is wrong and needs to be addressed. If ignored, it may become chronic and unremitting; because symptoms of distress may lead to systemic dysregulation and increased CHD risk, they may indicate the need for increased surveillance and intervention.

WHY FOCUS ON THE BIOLOGY OF EMOTIONS?

A clear biologic explanation for the influence of emotional factors on physical health would serve to assuage skeptics who doubt that such a link exists or who attribute a common underlying genetic trait to both negative affect and heart disease. Further, focusing on the biology may help answer key questions with respect to emotions and disease processes: What is the damage incurred by negative emotional states and is it reversible? Can compensatory pathways be activated to bypass the mechanisms causing damage or slow the progression of disease?

Cardiac response to worry and stress

In one study attempting to shed light on relevant emotion-related biologic process, the prolonged physiologic effects of worry were examined. Worry episodes and stressful events were recorded hourly along with ambulatory heart rate and heart rate variability in 73 teachers for 4 days.⁴ Autonomic activity, as reflected by a concurrent elevation in heart rate and a decrease in heart rate variability, was increased up to 2 hours after a worry episode. The findings also suggested that the prolonged cardiac effects of separate worry episodes were independent.

Another study sought to determine whether heightened reactivity or delayed recovery to acute stress increases risk of cardiovascular disease.⁵ This meta-analysis included 36 studies to assess whether acute cardiovascular response to various laboratory stressors (ie, cognitive tasks, stress interviews, public speaking). Findings indicated that heightened cardiovascular reactivity was associated with worse cardiovascular outcomes, such as incident hypertension, coronary calcification, carotid intima-media thickness, and cardiovascular events over time.

Role of aldosterone overlooked

Reprinted from Neuroscience and Biobehavioral Reviews (Kubzansky LD, et al. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav Rev 2010; 34:80–86), © 2010, with permission from Elsevier.

WHY CONSIDER RESILIENCE?

Because the absence of a deficit is not the same as the presence of an asset, greater insight into dysfunction may be gained by explicitly considering what promotes healthy functioning. Ameliorating distress has proven difficult; so, in studying resilience (including the ability to regulate affect), new targets for prevention and intervention may be identified. Although no meta-analysis of resilience factors has been published to date owing to the paucity of data, the studies that have been performed are generally rigorous and have demonstrated consistent findings.

For example, one prospective, well-controlled study of 1,739 men and women demonstrated a protective effect of positive affect (as ascertained by structured interview) against 10-year incident CHD.⁶ The risk of fatal or nonfatal ischemic heart disease events was reduced by 22% (P = .02) for each 1-point increase in positive affect, even after controlling for depression and negative emotions.

Reprinted, with permission, from Archives of General Psychiatry (Kubzansky LD, et al. Arch Gen Psychiatry 2011; 68:400–408), Copyright © 2011 American Medical Association. All rights reserved.

Biology of resilience: Counteracting cellular damage

Genomic changes can be induced by the relaxation response, as evidenced by the differential gene expression profiles of long-term daily practitioners of relaxation (ie, meditation, yoga), short-term (8-week) practitioners of relaxation, and healthy controls.⁸ Alterations in cellular metabolism, oxidative phosphorylation, and generation of reactive oxygen species that counteract proinflammatory responses, indicative of an adaptive response, were observed in both groups that practiced relaxation.

FUTURE DIRECTIONS

Whether and how the sources and effects of psychosocial stress and response to treatment differ across men and women deserves closer examination. A review by Low et al⁹ summarizes the current state of knowledge with respect to psychosocial factors and heart disease in women, noting that the sources of stress associated with increased CHD risk differ across men and women; psychosocial risk factors like depression and anxiety appear to increase risk for both men and women; work-related stress has larger effects in men while stress related to relationships and family responsibilities appear to have larger effects in women.

Although responses to psychosocial stress are not clearly different between men and women, intervention targeted at reducing distress is much less effective in reducing the risk of adverse events in women versus men. The mechanism to explain this difference in effectiveness of intervention urgently requires further exploration.

In conducting this work, several factors are important. The best time to intervene to reduce psychosocial distress is unknown; a key consideration will be, what is the best etiologic window for intervention? Perhaps a life-course approach that targets individuals with chronically high levels of emotional distress who also have multiple coronary risk factors, and that enhances their capacity to regulate emotions would prove superior to waiting until late in the disease process.

Another area that may prove fruitful is to consider in more depth the biology of the placebo effect and whether and how it may inform our understanding of resilience.

More generally, considering why interventions seem to influence outcomes so differently across men and women, applying a life course approach to determine the best etiologic window for prevention and intervention strategies, and conducting a more in-depth exploration of the biology of resilience may lead to improved capacity for population-based approaches to reducing the burden of CHD.

The effect of emotion on the heart is not confined to depression, but extends to a variety of mental states; as William Harvey described in 1628, “A mental disturbance provoking pain, excessive joy, hope or anxiety extends to the heart, where it affects its temper and rate, impairing general nutrition and vigor.”

In going beyond the well-established role of depression as a risk factor for heart disease, 2010 delivered several important publications recognizing anxiety, anger, and other forms of distress as key factors in the etiology of coronary heart disease (CHD). Other papers of merit elucidated new and overlooked insights into the pathways linking psychosocial stress and cardiovascular risk, and also considered psychologic states that appear to promote healthy functioning.

IMPACT OF NEGATIVE EMOTIONS ON RISK OF INCIDENT CORONARY HEART DISEASE

In a meta-analysis of 20 prospective studies that included 249,846 persons with a mean follow-up of 11.2 years, Roest et al¹ examined the impact of anxiety characterized by the presence of anxiety symptoms or a diagnosis of anxiety disorder on incident CHD. Most of the studies adjusted for a broad array of relevant potential confounders. Findings suggest the presence of anxiety increases the risk of incident CHD by 26% (P P = .003).

In a meta-analysis of 25 prospective studies of 7,160 persons with a mean follow-up exceeding 10 years, Chida and Steptoe² found that anger increased the risk of incident CHD by 19%, after adjustment for standard coronary risk factors. The effect was less stable than that associated with anxiety and depression, and when stratified by gender, the harmful effects of anger were more evident in men than in women. The effect of anger was attenuated when controlling for behavioral covariates. The association between anger and CHD did not hold for all ways of measuring anger, which suggests that the type of anger or the ability to regulate anger may be relevant to the relationship.

A study that did account for the type of anger expression on the risk of incident CHD was conducted by Davidson and Mostofsky.³ The independent effect of three distinct types of anger expression (constructive anger, destructive anger justification, and destructive anger rumination) on 10-year incident CHD was examined, controlling for other psychosocial factors. In men, higher scores for constructive anger were associated with a lower rate of CHD; in both men and women, higher scores for destructive anger justification were associated with an increased risk of CHD.

Insights gained from these studies are as follows:

• The impact of anxiety appears to be comparable to depression, and the effects of anxiety and depression are largely independent.
• If anxiety and depression co-occur, the effect on CHD is synergistic.
• The effects of anger are less clear; its impact may be independent of or dependent on other forms of psychologic distress.
• Distress in general appears to serve as a signal that something is wrong and needs to be addressed. If ignored, it may become chronic and unremitting; because symptoms of distress may lead to systemic dysregulation and increased CHD risk, they may indicate the need for increased surveillance and intervention.

WHY FOCUS ON THE BIOLOGY OF EMOTIONS?

A clear biologic explanation for the influence of emotional factors on physical health would serve to assuage skeptics who doubt that such a link exists or who attribute a common underlying genetic trait to both negative affect and heart disease. Further, focusing on the biology may help answer key questions with respect to emotions and disease processes: What is the damage incurred by negative emotional states and is it reversible? Can compensatory pathways be activated to bypass the mechanisms causing damage or slow the progression of disease?

Cardiac response to worry and stress

In one study attempting to shed light on relevant emotion-related biologic process, the prolonged physiologic effects of worry were examined. Worry episodes and stressful events were recorded hourly along with ambulatory heart rate and heart rate variability in 73 teachers for 4 days.⁴ Autonomic activity, as reflected by a concurrent elevation in heart rate and a decrease in heart rate variability, was increased up to 2 hours after a worry episode. The findings also suggested that the prolonged cardiac effects of separate worry episodes were independent.

Another study sought to determine whether heightened reactivity or delayed recovery to acute stress increases risk of cardiovascular disease.⁵ This meta-analysis included 36 studies to assess whether acute cardiovascular response to various laboratory stressors (ie, cognitive tasks, stress interviews, public speaking). Findings indicated that heightened cardiovascular reactivity was associated with worse cardiovascular outcomes, such as incident hypertension, coronary calcification, carotid intima-media thickness, and cardiovascular events over time.

Role of aldosterone overlooked

Reprinted from Neuroscience and Biobehavioral Reviews (Kubzansky LD, et al. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav Rev 2010; 34:80–86), © 2010, with permission from Elsevier.

WHY CONSIDER RESILIENCE?

Because the absence of a deficit is not the same as the presence of an asset, greater insight into dysfunction may be gained by explicitly considering what promotes healthy functioning. Ameliorating distress has proven difficult; so, in studying resilience (including the ability to regulate affect), new targets for prevention and intervention may be identified. Although no meta-analysis of resilience factors has been published to date owing to the paucity of data, the studies that have been performed are generally rigorous and have demonstrated consistent findings.

For example, one prospective, well-controlled study of 1,739 men and women demonstrated a protective effect of positive affect (as ascertained by structured interview) against 10-year incident CHD.⁶ The risk of fatal or nonfatal ischemic heart disease events was reduced by 22% (P = .02) for each 1-point increase in positive affect, even after controlling for depression and negative emotions.

Reprinted, with permission, from Archives of General Psychiatry (Kubzansky LD, et al. Arch Gen Psychiatry 2011; 68:400–408), Copyright © 2011 American Medical Association. All rights reserved.

Biology of resilience: Counteracting cellular damage

Genomic changes can be induced by the relaxation response, as evidenced by the differential gene expression profiles of long-term daily practitioners of relaxation (ie, meditation, yoga), short-term (8-week) practitioners of relaxation, and healthy controls.⁸ Alterations in cellular metabolism, oxidative phosphorylation, and generation of reactive oxygen species that counteract proinflammatory responses, indicative of an adaptive response, were observed in both groups that practiced relaxation.

FUTURE DIRECTIONS

Whether and how the sources and effects of psychosocial stress and response to treatment differ across men and women deserves closer examination. A review by Low et al⁹ summarizes the current state of knowledge with respect to psychosocial factors and heart disease in women, noting that the sources of stress associated with increased CHD risk differ across men and women; psychosocial risk factors like depression and anxiety appear to increase risk for both men and women; work-related stress has larger effects in men while stress related to relationships and family responsibilities appear to have larger effects in women.

Although responses to psychosocial stress are not clearly different between men and women, intervention targeted at reducing distress is much less effective in reducing the risk of adverse events in women versus men. The mechanism to explain this difference in effectiveness of intervention urgently requires further exploration.

In conducting this work, several factors are important. The best time to intervene to reduce psychosocial distress is unknown; a key consideration will be, what is the best etiologic window for intervention? Perhaps a life-course approach that targets individuals with chronically high levels of emotional distress who also have multiple coronary risk factors, and that enhances their capacity to regulate emotions would prove superior to waiting until late in the disease process.

Another area that may prove fruitful is to consider in more depth the biology of the placebo effect and whether and how it may inform our understanding of resilience.

More generally, considering why interventions seem to influence outcomes so differently across men and women, applying a life course approach to determine the best etiologic window for prevention and intervention strategies, and conducting a more in-depth exploration of the biology of resilience may lead to improved capacity for population-based approaches to reducing the burden of CHD.

The effect of emotion on the heart is not confined to depression, but extends to a variety of mental states; as William Harvey described in 1628, “A mental disturbance provoking pain, excessive joy, hope or anxiety extends to the heart, where it affects its temper and rate, impairing general nutrition and vigor.”

In going beyond the well-established role of depression as a risk factor for heart disease, 2010 delivered several important publications recognizing anxiety, anger, and other forms of distress as key factors in the etiology of coronary heart disease (CHD). Other papers of merit elucidated new and overlooked insights into the pathways linking psychosocial stress and cardiovascular risk, and also considered psychologic states that appear to promote healthy functioning.

IMPACT OF NEGATIVE EMOTIONS ON RISK OF INCIDENT CORONARY HEART DISEASE

In a meta-analysis of 20 prospective studies that included 249,846 persons with a mean follow-up of 11.2 years, Roest et al¹ examined the impact of anxiety characterized by the presence of anxiety symptoms or a diagnosis of anxiety disorder on incident CHD. Most of the studies adjusted for a broad array of relevant potential confounders. Findings suggest the presence of anxiety increases the risk of incident CHD by 26% (P P = .003).

In a meta-analysis of 25 prospective studies of 7,160 persons with a mean follow-up exceeding 10 years, Chida and Steptoe² found that anger increased the risk of incident CHD by 19%, after adjustment for standard coronary risk factors. The effect was less stable than that associated with anxiety and depression, and when stratified by gender, the harmful effects of anger were more evident in men than in women. The effect of anger was attenuated when controlling for behavioral covariates. The association between anger and CHD did not hold for all ways of measuring anger, which suggests that the type of anger or the ability to regulate anger may be relevant to the relationship.

A study that did account for the type of anger expression on the risk of incident CHD was conducted by Davidson and Mostofsky.³ The independent effect of three distinct types of anger expression (constructive anger, destructive anger justification, and destructive anger rumination) on 10-year incident CHD was examined, controlling for other psychosocial factors. In men, higher scores for constructive anger were associated with a lower rate of CHD; in both men and women, higher scores for destructive anger justification were associated with an increased risk of CHD.

Insights gained from these studies are as follows:

• The impact of anxiety appears to be comparable to depression, and the effects of anxiety and depression are largely independent.
• If anxiety and depression co-occur, the effect on CHD is synergistic.
• The effects of anger are less clear; its impact may be independent of or dependent on other forms of psychologic distress.
• Distress in general appears to serve as a signal that something is wrong and needs to be addressed. If ignored, it may become chronic and unremitting; because symptoms of distress may lead to systemic dysregulation and increased CHD risk, they may indicate the need for increased surveillance and intervention.

WHY FOCUS ON THE BIOLOGY OF EMOTIONS?

A clear biologic explanation for the influence of emotional factors on physical health would serve to assuage skeptics who doubt that such a link exists or who attribute a common underlying genetic trait to both negative affect and heart disease. Further, focusing on the biology may help answer key questions with respect to emotions and disease processes: What is the damage incurred by negative emotional states and is it reversible? Can compensatory pathways be activated to bypass the mechanisms causing damage or slow the progression of disease?

Cardiac response to worry and stress

In one study attempting to shed light on relevant emotion-related biologic process, the prolonged physiologic effects of worry were examined. Worry episodes and stressful events were recorded hourly along with ambulatory heart rate and heart rate variability in 73 teachers for 4 days.⁴ Autonomic activity, as reflected by a concurrent elevation in heart rate and a decrease in heart rate variability, was increased up to 2 hours after a worry episode. The findings also suggested that the prolonged cardiac effects of separate worry episodes were independent.

Another study sought to determine whether heightened reactivity or delayed recovery to acute stress increases risk of cardiovascular disease.⁵ This meta-analysis included 36 studies to assess whether acute cardiovascular response to various laboratory stressors (ie, cognitive tasks, stress interviews, public speaking). Findings indicated that heightened cardiovascular reactivity was associated with worse cardiovascular outcomes, such as incident hypertension, coronary calcification, carotid intima-media thickness, and cardiovascular events over time.

Role of aldosterone overlooked

Reprinted from Neuroscience and Biobehavioral Reviews (Kubzansky LD, et al. Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease. Neurosci Biobehav Rev 2010; 34:80–86), © 2010, with permission from Elsevier.

WHY CONSIDER RESILIENCE?

Because the absence of a deficit is not the same as the presence of an asset, greater insight into dysfunction may be gained by explicitly considering what promotes healthy functioning. Ameliorating distress has proven difficult; so, in studying resilience (including the ability to regulate affect), new targets for prevention and intervention may be identified. Although no meta-analysis of resilience factors has been published to date owing to the paucity of data, the studies that have been performed are generally rigorous and have demonstrated consistent findings.

For example, one prospective, well-controlled study of 1,739 men and women demonstrated a protective effect of positive affect (as ascertained by structured interview) against 10-year incident CHD.⁶ The risk of fatal or nonfatal ischemic heart disease events was reduced by 22% (P = .02) for each 1-point increase in positive affect, even after controlling for depression and negative emotions.

Reprinted, with permission, from Archives of General Psychiatry (Kubzansky LD, et al. Arch Gen Psychiatry 2011; 68:400–408), Copyright © 2011 American Medical Association. All rights reserved.

Biology of resilience: Counteracting cellular damage

Genomic changes can be induced by the relaxation response, as evidenced by the differential gene expression profiles of long-term daily practitioners of relaxation (ie, meditation, yoga), short-term (8-week) practitioners of relaxation, and healthy controls.⁸ Alterations in cellular metabolism, oxidative phosphorylation, and generation of reactive oxygen species that counteract proinflammatory responses, indicative of an adaptive response, were observed in both groups that practiced relaxation.

FUTURE DIRECTIONS

Whether and how the sources and effects of psychosocial stress and response to treatment differ across men and women deserves closer examination. A review by Low et al⁹ summarizes the current state of knowledge with respect to psychosocial factors and heart disease in women, noting that the sources of stress associated with increased CHD risk differ across men and women; psychosocial risk factors like depression and anxiety appear to increase risk for both men and women; work-related stress has larger effects in men while stress related to relationships and family responsibilities appear to have larger effects in women.

Although responses to psychosocial stress are not clearly different between men and women, intervention targeted at reducing distress is much less effective in reducing the risk of adverse events in women versus men. The mechanism to explain this difference in effectiveness of intervention urgently requires further exploration.

In conducting this work, several factors are important. The best time to intervene to reduce psychosocial distress is unknown; a key consideration will be, what is the best etiologic window for intervention? Perhaps a life-course approach that targets individuals with chronically high levels of emotional distress who also have multiple coronary risk factors, and that enhances their capacity to regulate emotions would prove superior to waiting until late in the disease process.

Another area that may prove fruitful is to consider in more depth the biology of the placebo effect and whether and how it may inform our understanding of resilience.

More generally, considering why interventions seem to influence outcomes so differently across men and women, applying a life course approach to determine the best etiologic window for prevention and intervention strategies, and conducting a more in-depth exploration of the biology of resilience may lead to improved capacity for population-based approaches to reducing the burden of CHD.

The autonomic nervous system (ANS), composed of the sympathetic and parasympathetic nervous systems, governs our adaptation to changing environments such as physical threats or changes in temperature. It has been difficult to elucidate this process in humans, however, because of limitations in neuroimaging caused by artifacts from cardiorespiratory sources. This article reviews structural and functional imaging that can provide insights into the ANS.

STRUCTURAL IMAGING

The two main subcortical areas of interest for imaging are the lateral hypothalamic area and the paraventricular nucleus, but visualization is difficult. The hypothalamus occupies a volumetric area of the brain no larger than 20 voxels; individual substructures of the hypothalamus therefore cannot easily be viewed by conventional imaging. The larger voxel size of functional MRI (fMRI) mean that fMRI of the hypothalamus can display 1 voxel at most.

Most brainstem nuclei are motor nuclei that affect autonomic responses, either sympathetic or parasympathetic. These nuclei are difficult to visualize on conventional MRI for two reasons: the nuclei are small, and may be the size of only 1 to 2 voxels. More important, MRI contrast between these nuclei and surrounding parenchyma is minimal because these structures “blend in” with the surrounding brain and are difficult to visualize singly. Examples of these major brainstem sympathetic nuclei are the periaqueductal gray substance, parabrachial nuclei, solitary nucleus, and the hypothalamospinal tract; examples of the major brainstem parasympathetic nuclei are the dorsal nucleus of the vagus nerve and the nucleus ambiguus.

The areas of the ANS under cortical control are more integrative, with influence from higher cognitive function—for example, the panic or fear associated with public speaking. Regions of subcortical control involve the basal ganglia and hypothalamus, which regulate primitive, subconscious activity, such as “fight or flight” response, pain reaction, and fear of snakes, all of which affect multiple motor nuclei. Several specific sympathetic and parasympathetic motor nuclei directly affect heart rate and blood pressure and act as relay stations for sensory impulses that reach the cerebral cortex.

NEUROLOGIC PROCESSES AND CARDIAC EFFECTS

MS is classically a disease of white matter, although it can also affect gray matter. Autonomic dysfunction is common, affecting as many as 50% of MS patients with symptoms that include orthostatic dizziness, bladder disturbances, temperature instability, gastrointestinal disturbances, and sweating.^1–4 The effect of autonomic dysfunction on disease activity is unclear. Multiple brainstem lesions are evident on MRI, and may be linked to cardiac autonomic dysfunction. The variability of MS contributes to the difficulty of using imaging to identify culprit lesions.

Stroke causes autonomic dysfunction, with the specific manifestations dependent on the region of the brain involved. In cases of right middle cerebral artery infarct affecting the right insula, an increased incidence of cardiac arrhythmias, cardiac death, and catecholamine production ensues.^5–7 Medullary infarcts have been shown to produce significant autonomic dysfunction.^8,9

Ictal and interictal cardiac manifestations in epilepsy often precede seizure onset.¹ Common cardiac changes are ictal tachycardia or ictal bradycardia, or both, with no clear relationship to the location or type of seizure. Evidence suggests that heart rate variability changes in epilepsy result from interictal autonomic alterations, including sympathetic or parasympathetic dominance. Investigation of baroreflex responses with temporal lobe epilepsy has uncovered decreased baroreflex sensitivity. There is no reliable correlation between sympathetic or parasympathetic upregulation or downregulation and brain MRI findings, however.

Autonomic dysfunction in the form of orthostatic hypotension has been documented in patients with mass effect from tumors, for example posterior fossa epidermoid tumors, wherein tumor resection results in improved autonomic function.¹⁰

FUNCTIONAL BRAIN IMAGING IN GENERAL

Direct visualization of heart-brain interactions is the goal when assessing ANS function. Positron emission tomography (PET) produces quantitative images, but spatial and temporal resolutions are vastly superior with fMRI.¹¹ Further, radiation exposure is low with fMRI, allowing for safe repeat imaging.

Ogawa et al¹² first demonstrated that in vivo images of brain microvasculature are affected by blood oxygen level, and that blood oxygenation reduced vascular signal loss. Therefore, blood oxygenation level–dependent (BOLD) contrast added to MRI could complement PET-like measurements in the study of regional brain activity.

Bilateral finger tapping with intermittent periods of rest is associated with a pattern of increasing and decreasing intensity of fMRI signals in involved brain regions that reflect the periods of activity and rest. This technique has been used to locate brain voxels with similar patterns of activity, enabling the creation of familiar color brain mapping. A challenge posed by autonomic fMRI in such brain mapping is that fMRI is susceptible to artifacts (Figure 3). For example, a movement of the head as little as 1 mm inside the MRI scanner—a distance comparable to the size of autonomic structures—can produce a motion artifact (false activation of brain regions) that can affect statistical significance. In addition, many ANS regions of the brain are near osseous structures (for example the brainstem and skull base) that cause signal distortion and loss.

REQUIREMENTS FOR AUTONOMIC fMRI

The tasks chosen to visualize brain control of autonomic function must naturally elicit an autonomic response. The difficulty is that untrained persons have little or no volitional control over autonomic functions, so the task and its analysis must be designed carefully and be MRI-compatible. Any motion will degrade the image; further, the capacity for the MRI environment to corrupt the measurements can limit the potential tasks for measurement.

Possible stimuli for eliciting a sympathetic response include pain, fear, anticipation, anxiety, concentration or memory, cold pressor, Stroop test, breathing tests, and maximal hand grip. Examples of parasympathetic stimuli are the Valsalva maneuver and paced breathing. The responses to stimuli (ie, heart rate, heart rate variability, blood pressure, galvanic skin response, papillary response) must be monitored to compare the data obtained from fMRI. MRI-compatible equipment is now available for measuring many of these responses.

Identifying areas activated during tasks

Functional neuroimaging with PET and fMRI has shown consistently that the anterior cingulate is activated during multiple tasks designed to elicit an autonomic response (gambling anticipation, emotional response to faces, Stroop test).¹¹

In a study designed to test autonomic interoceptive awareness, subjects underwent fMRI while they were asked to judge the timing of their heartbeats to auditory tones that were either synchronized with their heartbeat or delayed by 500 msec.¹³ Areas of enhanced activity during the task were the right insular cortex, anterior cingulate, parietal lobes, and operculum.

Characterizing brainstem sites

It is difficult to achieve visualization of areas within the brainstem that govern autonomic responses. These regions are small and motion artifacts are common because of brainstem movement with the cardiac pulse. With fMRI, Topolovec et al¹⁴ were able to characterize brainstem sites involved in autonomic control, demonstrating activation of the nucleus of the solitary tract and parabrachial nucleus.

Reprinted from NeuroImage (Napadow V, et al. Brain correlates of autonomic modulation: combining heart rate variability with fMRI. Neuro-Image 2008; 42:169–177), Copyright © 2008, with permission from Elsevier.

A review of four fMRI studies of stressor-evoked blood pressure reactivity demonstrated activation in corticolimbic areas, including the cingulate cortex, insula, amygdala, and cortical and subcortical areas that are involved in hemodynamic and metabolic support for stress-related behavioral responses.¹⁶

FUNCTIONAL BRAIN IMAGING IN DISEASE STATES

There are few studies of functional brain imaging in patients with disease because of the challenges involved. The studies are difficult to perform on sick patients because of the unfriendly MRI environment, with struct requirements for attention and participation. Furthermore, autonomic responses may be blunted, making physiologic comparisons difficult. In addition, there is evidence that BOLD may be intrinsically impaired in disease states. Unlike fMRI studies to locate brain regions involved in simple tasks such as finger tapping, which can be performed in a single subject, detecting changes in autonomic responses in disease states requires averaging over studies of multiple patients.

Woo et al¹⁷ used fMRI to compare brain regions of activation in six patients with heart failure and 16 controls upon a forehead cold pressor challenge. Increases in heart rate were measured in the patients with heart failure with application of the cold stimulus. Larger neural fMRI signal responses in patients with heart failure were observed in 14 brain regions, whereas reduced fMRI activity was observed in 15 other brain regions in the heart failure patients. Based on the results, the investigators suggested that heart failure may be associated with altered sympathetic and parasympathetic activity, and that these dysfunctions might contribute to the progression of heart failure.

Gianaros et al¹⁸ found fMRI evidence for a correlation between carotid artery intima-media thickness, a surrogate measure for carotid artery or coronary artery disease, and altered ANS reaction to fear using a fearful faces paradigm.

CONCLUSION

Functional MRI of heart-brain interactions has strong potential for normal subjects, in whom the BOLD effect is small, within the limits of motion and susceptibility artifacts. Typically, such applications require averaging results over multiple subjects. Its potential utility in disease states is less significant because of the additional limitations of MRI with sick patients (the MRI environment, blunting of autonomic response in disease, possible impairment of BOLD), but continued investigation is warranted.

The autonomic nervous system (ANS), composed of the sympathetic and parasympathetic nervous systems, governs our adaptation to changing environments such as physical threats or changes in temperature. It has been difficult to elucidate this process in humans, however, because of limitations in neuroimaging caused by artifacts from cardiorespiratory sources. This article reviews structural and functional imaging that can provide insights into the ANS.

STRUCTURAL IMAGING

The two main subcortical areas of interest for imaging are the lateral hypothalamic area and the paraventricular nucleus, but visualization is difficult. The hypothalamus occupies a volumetric area of the brain no larger than 20 voxels; individual substructures of the hypothalamus therefore cannot easily be viewed by conventional imaging. The larger voxel size of functional MRI (fMRI) mean that fMRI of the hypothalamus can display 1 voxel at most.

Most brainstem nuclei are motor nuclei that affect autonomic responses, either sympathetic or parasympathetic. These nuclei are difficult to visualize on conventional MRI for two reasons: the nuclei are small, and may be the size of only 1 to 2 voxels. More important, MRI contrast between these nuclei and surrounding parenchyma is minimal because these structures “blend in” with the surrounding brain and are difficult to visualize singly. Examples of these major brainstem sympathetic nuclei are the periaqueductal gray substance, parabrachial nuclei, solitary nucleus, and the hypothalamospinal tract; examples of the major brainstem parasympathetic nuclei are the dorsal nucleus of the vagus nerve and the nucleus ambiguus.

The areas of the ANS under cortical control are more integrative, with influence from higher cognitive function—for example, the panic or fear associated with public speaking. Regions of subcortical control involve the basal ganglia and hypothalamus, which regulate primitive, subconscious activity, such as “fight or flight” response, pain reaction, and fear of snakes, all of which affect multiple motor nuclei. Several specific sympathetic and parasympathetic motor nuclei directly affect heart rate and blood pressure and act as relay stations for sensory impulses that reach the cerebral cortex.

NEUROLOGIC PROCESSES AND CARDIAC EFFECTS

MS is classically a disease of white matter, although it can also affect gray matter. Autonomic dysfunction is common, affecting as many as 50% of MS patients with symptoms that include orthostatic dizziness, bladder disturbances, temperature instability, gastrointestinal disturbances, and sweating.^1–4 The effect of autonomic dysfunction on disease activity is unclear. Multiple brainstem lesions are evident on MRI, and may be linked to cardiac autonomic dysfunction. The variability of MS contributes to the difficulty of using imaging to identify culprit lesions.

Stroke causes autonomic dysfunction, with the specific manifestations dependent on the region of the brain involved. In cases of right middle cerebral artery infarct affecting the right insula, an increased incidence of cardiac arrhythmias, cardiac death, and catecholamine production ensues.^5–7 Medullary infarcts have been shown to produce significant autonomic dysfunction.^8,9

Ictal and interictal cardiac manifestations in epilepsy often precede seizure onset.¹ Common cardiac changes are ictal tachycardia or ictal bradycardia, or both, with no clear relationship to the location or type of seizure. Evidence suggests that heart rate variability changes in epilepsy result from interictal autonomic alterations, including sympathetic or parasympathetic dominance. Investigation of baroreflex responses with temporal lobe epilepsy has uncovered decreased baroreflex sensitivity. There is no reliable correlation between sympathetic or parasympathetic upregulation or downregulation and brain MRI findings, however.

Autonomic dysfunction in the form of orthostatic hypotension has been documented in patients with mass effect from tumors, for example posterior fossa epidermoid tumors, wherein tumor resection results in improved autonomic function.¹⁰

FUNCTIONAL BRAIN IMAGING IN GENERAL

Direct visualization of heart-brain interactions is the goal when assessing ANS function. Positron emission tomography (PET) produces quantitative images, but spatial and temporal resolutions are vastly superior with fMRI.¹¹ Further, radiation exposure is low with fMRI, allowing for safe repeat imaging.

Ogawa et al¹² first demonstrated that in vivo images of brain microvasculature are affected by blood oxygen level, and that blood oxygenation reduced vascular signal loss. Therefore, blood oxygenation level–dependent (BOLD) contrast added to MRI could complement PET-like measurements in the study of regional brain activity.

Bilateral finger tapping with intermittent periods of rest is associated with a pattern of increasing and decreasing intensity of fMRI signals in involved brain regions that reflect the periods of activity and rest. This technique has been used to locate brain voxels with similar patterns of activity, enabling the creation of familiar color brain mapping. A challenge posed by autonomic fMRI in such brain mapping is that fMRI is susceptible to artifacts (Figure 3). For example, a movement of the head as little as 1 mm inside the MRI scanner—a distance comparable to the size of autonomic structures—can produce a motion artifact (false activation of brain regions) that can affect statistical significance. In addition, many ANS regions of the brain are near osseous structures (for example the brainstem and skull base) that cause signal distortion and loss.

REQUIREMENTS FOR AUTONOMIC fMRI

The tasks chosen to visualize brain control of autonomic function must naturally elicit an autonomic response. The difficulty is that untrained persons have little or no volitional control over autonomic functions, so the task and its analysis must be designed carefully and be MRI-compatible. Any motion will degrade the image; further, the capacity for the MRI environment to corrupt the measurements can limit the potential tasks for measurement.

Possible stimuli for eliciting a sympathetic response include pain, fear, anticipation, anxiety, concentration or memory, cold pressor, Stroop test, breathing tests, and maximal hand grip. Examples of parasympathetic stimuli are the Valsalva maneuver and paced breathing. The responses to stimuli (ie, heart rate, heart rate variability, blood pressure, galvanic skin response, papillary response) must be monitored to compare the data obtained from fMRI. MRI-compatible equipment is now available for measuring many of these responses.

Identifying areas activated during tasks

Functional neuroimaging with PET and fMRI has shown consistently that the anterior cingulate is activated during multiple tasks designed to elicit an autonomic response (gambling anticipation, emotional response to faces, Stroop test).¹¹

In a study designed to test autonomic interoceptive awareness, subjects underwent fMRI while they were asked to judge the timing of their heartbeats to auditory tones that were either synchronized with their heartbeat or delayed by 500 msec.¹³ Areas of enhanced activity during the task were the right insular cortex, anterior cingulate, parietal lobes, and operculum.

Characterizing brainstem sites

It is difficult to achieve visualization of areas within the brainstem that govern autonomic responses. These regions are small and motion artifacts are common because of brainstem movement with the cardiac pulse. With fMRI, Topolovec et al¹⁴ were able to characterize brainstem sites involved in autonomic control, demonstrating activation of the nucleus of the solitary tract and parabrachial nucleus.

Reprinted from NeuroImage (Napadow V, et al. Brain correlates of autonomic modulation: combining heart rate variability with fMRI. Neuro-Image 2008; 42:169–177), Copyright © 2008, with permission from Elsevier.

A review of four fMRI studies of stressor-evoked blood pressure reactivity demonstrated activation in corticolimbic areas, including the cingulate cortex, insula, amygdala, and cortical and subcortical areas that are involved in hemodynamic and metabolic support for stress-related behavioral responses.¹⁶

FUNCTIONAL BRAIN IMAGING IN DISEASE STATES

There are few studies of functional brain imaging in patients with disease because of the challenges involved. The studies are difficult to perform on sick patients because of the unfriendly MRI environment, with struct requirements for attention and participation. Furthermore, autonomic responses may be blunted, making physiologic comparisons difficult. In addition, there is evidence that BOLD may be intrinsically impaired in disease states. Unlike fMRI studies to locate brain regions involved in simple tasks such as finger tapping, which can be performed in a single subject, detecting changes in autonomic responses in disease states requires averaging over studies of multiple patients.

Woo et al¹⁷ used fMRI to compare brain regions of activation in six patients with heart failure and 16 controls upon a forehead cold pressor challenge. Increases in heart rate were measured in the patients with heart failure with application of the cold stimulus. Larger neural fMRI signal responses in patients with heart failure were observed in 14 brain regions, whereas reduced fMRI activity was observed in 15 other brain regions in the heart failure patients. Based on the results, the investigators suggested that heart failure may be associated with altered sympathetic and parasympathetic activity, and that these dysfunctions might contribute to the progression of heart failure.

Gianaros et al¹⁸ found fMRI evidence for a correlation between carotid artery intima-media thickness, a surrogate measure for carotid artery or coronary artery disease, and altered ANS reaction to fear using a fearful faces paradigm.

CONCLUSION

Functional MRI of heart-brain interactions has strong potential for normal subjects, in whom the BOLD effect is small, within the limits of motion and susceptibility artifacts. Typically, such applications require averaging results over multiple subjects. Its potential utility in disease states is less significant because of the additional limitations of MRI with sick patients (the MRI environment, blunting of autonomic response in disease, possible impairment of BOLD), but continued investigation is warranted.

The autonomic nervous system (ANS), composed of the sympathetic and parasympathetic nervous systems, governs our adaptation to changing environments such as physical threats or changes in temperature. It has been difficult to elucidate this process in humans, however, because of limitations in neuroimaging caused by artifacts from cardiorespiratory sources. This article reviews structural and functional imaging that can provide insights into the ANS.

STRUCTURAL IMAGING

The two main subcortical areas of interest for imaging are the lateral hypothalamic area and the paraventricular nucleus, but visualization is difficult. The hypothalamus occupies a volumetric area of the brain no larger than 20 voxels; individual substructures of the hypothalamus therefore cannot easily be viewed by conventional imaging. The larger voxel size of functional MRI (fMRI) mean that fMRI of the hypothalamus can display 1 voxel at most.

Most brainstem nuclei are motor nuclei that affect autonomic responses, either sympathetic or parasympathetic. These nuclei are difficult to visualize on conventional MRI for two reasons: the nuclei are small, and may be the size of only 1 to 2 voxels. More important, MRI contrast between these nuclei and surrounding parenchyma is minimal because these structures “blend in” with the surrounding brain and are difficult to visualize singly. Examples of these major brainstem sympathetic nuclei are the periaqueductal gray substance, parabrachial nuclei, solitary nucleus, and the hypothalamospinal tract; examples of the major brainstem parasympathetic nuclei are the dorsal nucleus of the vagus nerve and the nucleus ambiguus.

The areas of the ANS under cortical control are more integrative, with influence from higher cognitive function—for example, the panic or fear associated with public speaking. Regions of subcortical control involve the basal ganglia and hypothalamus, which regulate primitive, subconscious activity, such as “fight or flight” response, pain reaction, and fear of snakes, all of which affect multiple motor nuclei. Several specific sympathetic and parasympathetic motor nuclei directly affect heart rate and blood pressure and act as relay stations for sensory impulses that reach the cerebral cortex.

NEUROLOGIC PROCESSES AND CARDIAC EFFECTS

MS is classically a disease of white matter, although it can also affect gray matter. Autonomic dysfunction is common, affecting as many as 50% of MS patients with symptoms that include orthostatic dizziness, bladder disturbances, temperature instability, gastrointestinal disturbances, and sweating.^1–4 The effect of autonomic dysfunction on disease activity is unclear. Multiple brainstem lesions are evident on MRI, and may be linked to cardiac autonomic dysfunction. The variability of MS contributes to the difficulty of using imaging to identify culprit lesions.

Stroke causes autonomic dysfunction, with the specific manifestations dependent on the region of the brain involved. In cases of right middle cerebral artery infarct affecting the right insula, an increased incidence of cardiac arrhythmias, cardiac death, and catecholamine production ensues.^5–7 Medullary infarcts have been shown to produce significant autonomic dysfunction.^8,9

Ictal and interictal cardiac manifestations in epilepsy often precede seizure onset.¹ Common cardiac changes are ictal tachycardia or ictal bradycardia, or both, with no clear relationship to the location or type of seizure. Evidence suggests that heart rate variability changes in epilepsy result from interictal autonomic alterations, including sympathetic or parasympathetic dominance. Investigation of baroreflex responses with temporal lobe epilepsy has uncovered decreased baroreflex sensitivity. There is no reliable correlation between sympathetic or parasympathetic upregulation or downregulation and brain MRI findings, however.

Autonomic dysfunction in the form of orthostatic hypotension has been documented in patients with mass effect from tumors, for example posterior fossa epidermoid tumors, wherein tumor resection results in improved autonomic function.¹⁰

FUNCTIONAL BRAIN IMAGING IN GENERAL

Direct visualization of heart-brain interactions is the goal when assessing ANS function. Positron emission tomography (PET) produces quantitative images, but spatial and temporal resolutions are vastly superior with fMRI.¹¹ Further, radiation exposure is low with fMRI, allowing for safe repeat imaging.

Ogawa et al¹² first demonstrated that in vivo images of brain microvasculature are affected by blood oxygen level, and that blood oxygenation reduced vascular signal loss. Therefore, blood oxygenation level–dependent (BOLD) contrast added to MRI could complement PET-like measurements in the study of regional brain activity.

Bilateral finger tapping with intermittent periods of rest is associated with a pattern of increasing and decreasing intensity of fMRI signals in involved brain regions that reflect the periods of activity and rest. This technique has been used to locate brain voxels with similar patterns of activity, enabling the creation of familiar color brain mapping. A challenge posed by autonomic fMRI in such brain mapping is that fMRI is susceptible to artifacts (Figure 3). For example, a movement of the head as little as 1 mm inside the MRI scanner—a distance comparable to the size of autonomic structures—can produce a motion artifact (false activation of brain regions) that can affect statistical significance. In addition, many ANS regions of the brain are near osseous structures (for example the brainstem and skull base) that cause signal distortion and loss.

REQUIREMENTS FOR AUTONOMIC fMRI

The tasks chosen to visualize brain control of autonomic function must naturally elicit an autonomic response. The difficulty is that untrained persons have little or no volitional control over autonomic functions, so the task and its analysis must be designed carefully and be MRI-compatible. Any motion will degrade the image; further, the capacity for the MRI environment to corrupt the measurements can limit the potential tasks for measurement.

Possible stimuli for eliciting a sympathetic response include pain, fear, anticipation, anxiety, concentration or memory, cold pressor, Stroop test, breathing tests, and maximal hand grip. Examples of parasympathetic stimuli are the Valsalva maneuver and paced breathing. The responses to stimuli (ie, heart rate, heart rate variability, blood pressure, galvanic skin response, papillary response) must be monitored to compare the data obtained from fMRI. MRI-compatible equipment is now available for measuring many of these responses.

Identifying areas activated during tasks

Functional neuroimaging with PET and fMRI has shown consistently that the anterior cingulate is activated during multiple tasks designed to elicit an autonomic response (gambling anticipation, emotional response to faces, Stroop test).¹¹

In a study designed to test autonomic interoceptive awareness, subjects underwent fMRI while they were asked to judge the timing of their heartbeats to auditory tones that were either synchronized with their heartbeat or delayed by 500 msec.¹³ Areas of enhanced activity during the task were the right insular cortex, anterior cingulate, parietal lobes, and operculum.

Characterizing brainstem sites

It is difficult to achieve visualization of areas within the brainstem that govern autonomic responses. These regions are small and motion artifacts are common because of brainstem movement with the cardiac pulse. With fMRI, Topolovec et al¹⁴ were able to characterize brainstem sites involved in autonomic control, demonstrating activation of the nucleus of the solitary tract and parabrachial nucleus.

Reprinted from NeuroImage (Napadow V, et al. Brain correlates of autonomic modulation: combining heart rate variability with fMRI. Neuro-Image 2008; 42:169–177), Copyright © 2008, with permission from Elsevier.

A review of four fMRI studies of stressor-evoked blood pressure reactivity demonstrated activation in corticolimbic areas, including the cingulate cortex, insula, amygdala, and cortical and subcortical areas that are involved in hemodynamic and metabolic support for stress-related behavioral responses.¹⁶

FUNCTIONAL BRAIN IMAGING IN DISEASE STATES

There are few studies of functional brain imaging in patients with disease because of the challenges involved. The studies are difficult to perform on sick patients because of the unfriendly MRI environment, with struct requirements for attention and participation. Furthermore, autonomic responses may be blunted, making physiologic comparisons difficult. In addition, there is evidence that BOLD may be intrinsically impaired in disease states. Unlike fMRI studies to locate brain regions involved in simple tasks such as finger tapping, which can be performed in a single subject, detecting changes in autonomic responses in disease states requires averaging over studies of multiple patients.

Woo et al¹⁷ used fMRI to compare brain regions of activation in six patients with heart failure and 16 controls upon a forehead cold pressor challenge. Increases in heart rate were measured in the patients with heart failure with application of the cold stimulus. Larger neural fMRI signal responses in patients with heart failure were observed in 14 brain regions, whereas reduced fMRI activity was observed in 15 other brain regions in the heart failure patients. Based on the results, the investigators suggested that heart failure may be associated with altered sympathetic and parasympathetic activity, and that these dysfunctions might contribute to the progression of heart failure.

Gianaros et al¹⁸ found fMRI evidence for a correlation between carotid artery intima-media thickness, a surrogate measure for carotid artery or coronary artery disease, and altered ANS reaction to fear using a fearful faces paradigm.

CONCLUSION

Functional MRI of heart-brain interactions has strong potential for normal subjects, in whom the BOLD effect is small, within the limits of motion and susceptibility artifacts. Typically, such applications require averaging results over multiple subjects. Its potential utility in disease states is less significant because of the additional limitations of MRI with sick patients (the MRI environment, blunting of autonomic response in disease, possible impairment of BOLD), but continued investigation is warranted.

We have known for more than 100 years that heart failure is characterized by excessive sympathetic nervous system (SNS) activity. Thanks to refinement of this concept in the 1980s and 1990s, we now have a good understanding of SNS activity in both experimental and clinical heart failure. During those two decades, we also realized the pathophysiologic importance of the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure.¹ By 2000, it was obvious that heart failure was inextricably intertwined with excessive neurohormonal activity.^2,3 This understanding of the pathophysiology of heart failure took on greater importance with the ability to pharmacologically block these neurohormonal systems, thereby demonstrating the detrimental role of neurohormones in the onset and progression of heart failure.

This article is a brief historical and personal description of the study of neurohormonal control mechanisms as they relate to the clinical syndrome of heart failure. The article includes a personal account of how the story unfolded in the cardiology research laboratories at the University of Minnesota.

THE EARLY YEARS: NEUROHORMONAL HYPOTHESIS

A hypothesis emerged gradually in the 1980s suggesting that progression of heart failure was in part a product of excessive SNS and RAAS activity. Many believed that pharmacologic inhibition of these systems might mitigate against progressive cardiac remodeling and thereby reduce symptoms and extend life—the so called neurohormonal hypothesis.⁴ SNS blockers and RAAS blockers are now widely used in tandem as first-line therapy to treat patients with heart failure,^5–11 but in 1980 we were just beginning to consider their therapeutic effects.

This major shift in thinking about neurohormonal systems and heart failure did not come about quickly. Early success was driven by the ability to quickly and precisely measure neurohormones in the laboratory coupled with the availability of drugs specifically designed to block the SNS and RAAS. It was also critically important to embrace the power of randomized controlled trials to test new therapies. Investigators, research nurses, and patients from many medical centers and laboratories should be credited with this astonishing success. I am proud to have been a part of this activity at the University of Minnesota.

THE COHN LABORATORY

Early work done in the 1960s by numerous investigators noted that the failing left ventricle (LV) was exquisitely sensitive to afterload conditions.^12–15 John Ross and Eugene Braunwald explored this observation in patients in 1964.¹⁵ Jay Cohn, with his unique background in hypertension and hemodynamics, brought the concept back into the laboratory in the early 1970s, where he explored the mechanisms responsible for increased sensitivity to afterload in patients with heart failure.¹⁶

I had the good fortune to join Cohn’s laboratory in 1979, when this avenue of heart failure research was in full bloom. A team of investigators was gradually assembled that included Maria Teresa Olivari, who relocated from the Cardiovascular Research Institute in Milan, Italy, directed by Maurizio D. Guazzi. Also joining the group were T. Barry Levine from the University of Michigan, Ann Arbor; Steven Goldsmith from Ohio State University, Columbus; Susan Ziesche from the Minneapolis Veterans Affairs (VA) Medical Center; Thomas Rector, an expert statistician and pharmacologist at the University of Minnesota; and many research fellows, visitors, students, biochemists, statisticians, and research nurses. Joseph Franciosa joined the University of Minnesota group in 1974 and, after completing several important trials, left in 1979 to lead the cardiology group at the Philadelphia VA Medical Center.

The Cohn group developed a working hypothesis that activation of the SNS and RAAS in heart failure was most likely an adaptive mechanism intended for short-term circulatory support, such as in the setting of blood loss, dehydration, shock, volume depletion, or flight response. In patients with heart failure, according to the hypothesis, the SNS and RAAS activity persisted beyond that needed for adaptation, with chronic release of norepinephrine (NE), renin, angiotensin II, aldosterone, and other neurohormones. The neurohormones ultimately became “maladaptive.” Thanks to the assaying skills of Ada Simon, we had the early advantage of precise and rapid radioenzyme measurement of plasma norepinephrine and renin activity in the blood of patients and animals.

We believed that neurohormonal activation contributed in part to the excessive afterload conditions observed in heart failure. We also thought that excessive neurohormonal activation directly impaired cardiac systolic function. The obvious next step was to explore whether neurohormonal antagonists would improve myocardial performance.

Under the leadership of Steven Goldsmith, many studies were performed to investigate reflex control mechanisms and their pathogenic role in patients with heart failure. The accumulating data suggested that persistent, excessive neurohormonal activity was characteristic of heart failure and that it was associated with a poor prognosis.¹⁷ The precise mechanism that drives activation of the SNS remained elusive, however, and is poorly defined even today. In that era, when β-adrenergic blockers were believed to be contraindicated, we inhibited the central SNS with bromocriptine, clonidine, and guanfacine with modestly favorable responses. We inhibited circulating arginine vasopressin antibody (thanks to Prof. Alan Cowley for noting an acute favorable response).

THE PHARMACOLOGIC ERA

The 1980s and 1990s saw the availability of several pharmacologic tools for assessing the roles of the SNS and RAAS in heart failure. The hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors and, later, angiotensin-receptor blockers (ARBs) were sources of concern, since many patients with advanced heart failure had low- to normal-range blood pressures before they received RAAS blockers. However, our group as well as others observed that abrupt blood pressure reduction occurred primarily in patients with very hyperreninemic responses to intravenous diuretics (ie, volume-depleted patients). Eventually, we learned that low baseline blood pressure did not adversely affect outcomes when vasodilators were used in patients with heart failure,^18,19 leading us to titrate these drugs upward over days to weeks.

Several different combinations of vasodilators were used successfully to treat heart failure, including hydralazine, isosorbide dinitrate,²⁰ ACE inhibitors,^21,22 and ARBs.^8,23–28 Direct-acting calcium channel blocking vasodilators, such as amlodipine, did not improve survival in patients with systolic heart failure, although they appeared to be safe in this setting.²⁹ The aldosterone receptor blockers spironolactone³⁰ and eplerenone³¹ were later demonstrated to improve survival of patients with advanced systolic heart failure when added to vasodilator therapy.

By the end of the 1990s, it was evident that drugs that blocked the SNS and RAAS were not just vasodilators or “afterload reducers,” similar to α-blockers, hydralazine, nitrates, and amlodipine. Neurohormonal blockers were doing something profoundly beneficial not observed with more direct-acting vasodilators.^32–37 Simple afterload reduction was not enough in patients with systolic heart failure.

Neurohormonal antagonists were acting more directly on the myocardium. They were preventing the progression of LV remodeling and, in some cases, promoting reverse remodeling, thus improving myocardial function and favorably influencing the natural history of heart failure.^31–39 We were astonished to discover that the failing, dilated heart could revert to normal size in response to neurohormone blockade with ACE inhibitors and β-adrenergic blockers; these findings were soon reported by other laboratories as well.

Contrary to our concept of heart failure in the 1970s, we now understood that the heart has inherent plasticity. It can dilate in response to abnormal loading conditions or myocardial injury, and it can restore itself to normal size when neurohormones are blocked and perverse loading conditions are improved. This reversal can occur spontaneously if an offending agent such as chronic alcohol use or inflammation is removed, but it is likely facilitated by SNS and RAAS blockers.

THE REMODELING ERA

Ken McDonald joined the University of Minnesota lab in 1989 as a research fellow. His skill in conducting both animal and clinical mechanistic studies was pivotal to our achieving our research goals. The inspired animal work by Boston-based Marc and Janice Pfeffer revealed the significance of the LV remodeling concept in the development of heart failure³⁶: ventricular remodeling was a hallmark of systolic heart failure, and pharmacologic inhibition of LV remodeling by blocking neurohormones had profound clinical implications.

Under the direction of Wenda Carlyle, a molecular biology laboratory was established at the University of Minnesota whose work was dedicated solely to exploration of remodeling at a very basic level. Alan Hirsch was recruited from Victor Dzau’s laboratory at Brigham and Women’s Hospital in Boston to extend our efforts to understand the molecular basis of cardiac remodeling. Ken McDonald guided the use of magnetic resonance imaging to study remodeling in dogs.

The late 1970s saw the initiation and eventual execution of several important clinical trials, including the Vasodilator Heart Failure Trials (V-HeFT I and V-HeFT II)^40,41 under our leadership, and Studies of Left Ventricular Dysfunction (SOLVD)^5,6 under the leadership of Salim Yusuf and others at the National Heart Lung and Blood Institute (NHLBI). Many neuro hormonal and remodeling substudies sprang from these large clinical trials. Spencer Kubo joined our group from the Medical College of Cornell University in the mid-1980s, and he immediately demonstrated his prowess in clinical research. He also recruited Alan Bank to study the endothelium in both experimental and human heart failure.

Integrating the molecular, animal, and clinical laboratories allowed us to pursue many mechanistic studies. Laboratory meetings, often held on Saturday mornings, generated ideas for program projects that were subsequently funded by NHLBI. Birthday parties and other social events with laboratory staff and their families were part of our fabric. Late-night trips to the Post Office to send off abstracts for national meetings before the midnight deadline were a regular feature.

Our coordination of and participation in the large clinical trials allowed us to meet frequently in Bethesda with colleagues from other major centers, fostering many collaborations and friendships that continue to thrive. Susan Ziesche deserves much of the credit for coordinating many groups that were part of these large, complex trials. Cheryl Yano, our administrator, also played a key role. All National Institutes of Health (NIH) grants passed through Cheryl, and she worked tirelessly to ensure that the proposals were in the best possible shape before we submitted them. Inder Anand joined our group in the early 1990s and became a major analytical force. Jay Cohn was the intellectual leader of the group, as well as our soul and inspiration. People worked hard for him, and he taught us much in a setting that valued creativity and new ideas above all.

THE LATER YEARS

By 1997, the face of heart failure had changed. New treatments were effective, but there were new challenges to face. I moved that year to the Cleveland Clinic, where I spent 11 enjoyable and productive years. I returned to Minnesota in 2008 to help build a new cardiovascular division.

It is gratifying to look back and see what has become of the “neurohormonal hypothesis.” Today, nearly all major medical centers have heart failure programs, and certification in advanced heart failure/heart transplantation is a reality. Training programs in advanced heart failure and heart transplant are common. The Heart Failure Society of America sprang up in the early 1990s, dedicated to patients with heart failure. Jay Cohn founded the Journal of Cardiac Failure, which flourished under his leadership. Neurohormonal blockers are now considered standard, conventional therapy and are widely used throughout the world.

CONCLUSIONS

Still, there is much work to do. An increasing number of devices are being developed, largely for patients with more advanced heart failure, but attention is also being directed to prevention of heart failure. Identification and possible treatment of patients at risk for the development of heart failure, and identification of those who already have some early structural and functional perturbation without advanced symptoms, are critically important. Since event rates are so low in these patients, we need to create new strategies for studying interventions. In the long term, the best treatment for nearly any condition is early diagnosis and perhaps early treatment with a goal of prevention.

One consequence of our progress over the years may be that heart failure now primarily affects a more elderly group—patients who often have many associated comorbidities. The consequences include more frequent readmissions, large numbers of patients with intractable signs and symptoms, and the emergence of difficult end-of-life decisions. If we could truly prevent heart failure rather than forestall its emergence to a later point in life, perhaps we could do more good.

For me, the study of neurohormonal mechanisms in the setting of heart failure was the centerpiece of my early career. Jay Cohn had asked several of us early in our laboratory experience to choose a neurohormonal system and learn about it in great depth and detail. My assignment was the SNS. Since then, I have never tired of learning about its control mechanisms, how it achieves circulatory homeostasis, how its excess quantities can be directly toxic to the heart, and the variety of pharmacologic ways that we can control it. I am indeed fortunate to have been part of this amazing study group.

We have known for more than 100 years that heart failure is characterized by excessive sympathetic nervous system (SNS) activity. Thanks to refinement of this concept in the 1980s and 1990s, we now have a good understanding of SNS activity in both experimental and clinical heart failure. During those two decades, we also realized the pathophysiologic importance of the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure.¹ By 2000, it was obvious that heart failure was inextricably intertwined with excessive neurohormonal activity.^2,3 This understanding of the pathophysiology of heart failure took on greater importance with the ability to pharmacologically block these neurohormonal systems, thereby demonstrating the detrimental role of neurohormones in the onset and progression of heart failure.

This article is a brief historical and personal description of the study of neurohormonal control mechanisms as they relate to the clinical syndrome of heart failure. The article includes a personal account of how the story unfolded in the cardiology research laboratories at the University of Minnesota.

THE EARLY YEARS: NEUROHORMONAL HYPOTHESIS

A hypothesis emerged gradually in the 1980s suggesting that progression of heart failure was in part a product of excessive SNS and RAAS activity. Many believed that pharmacologic inhibition of these systems might mitigate against progressive cardiac remodeling and thereby reduce symptoms and extend life—the so called neurohormonal hypothesis.⁴ SNS blockers and RAAS blockers are now widely used in tandem as first-line therapy to treat patients with heart failure,^5–11 but in 1980 we were just beginning to consider their therapeutic effects.

This major shift in thinking about neurohormonal systems and heart failure did not come about quickly. Early success was driven by the ability to quickly and precisely measure neurohormones in the laboratory coupled with the availability of drugs specifically designed to block the SNS and RAAS. It was also critically important to embrace the power of randomized controlled trials to test new therapies. Investigators, research nurses, and patients from many medical centers and laboratories should be credited with this astonishing success. I am proud to have been a part of this activity at the University of Minnesota.

THE COHN LABORATORY

Early work done in the 1960s by numerous investigators noted that the failing left ventricle (LV) was exquisitely sensitive to afterload conditions.^12–15 John Ross and Eugene Braunwald explored this observation in patients in 1964.¹⁵ Jay Cohn, with his unique background in hypertension and hemodynamics, brought the concept back into the laboratory in the early 1970s, where he explored the mechanisms responsible for increased sensitivity to afterload in patients with heart failure.¹⁶

I had the good fortune to join Cohn’s laboratory in 1979, when this avenue of heart failure research was in full bloom. A team of investigators was gradually assembled that included Maria Teresa Olivari, who relocated from the Cardiovascular Research Institute in Milan, Italy, directed by Maurizio D. Guazzi. Also joining the group were T. Barry Levine from the University of Michigan, Ann Arbor; Steven Goldsmith from Ohio State University, Columbus; Susan Ziesche from the Minneapolis Veterans Affairs (VA) Medical Center; Thomas Rector, an expert statistician and pharmacologist at the University of Minnesota; and many research fellows, visitors, students, biochemists, statisticians, and research nurses. Joseph Franciosa joined the University of Minnesota group in 1974 and, after completing several important trials, left in 1979 to lead the cardiology group at the Philadelphia VA Medical Center.

The Cohn group developed a working hypothesis that activation of the SNS and RAAS in heart failure was most likely an adaptive mechanism intended for short-term circulatory support, such as in the setting of blood loss, dehydration, shock, volume depletion, or flight response. In patients with heart failure, according to the hypothesis, the SNS and RAAS activity persisted beyond that needed for adaptation, with chronic release of norepinephrine (NE), renin, angiotensin II, aldosterone, and other neurohormones. The neurohormones ultimately became “maladaptive.” Thanks to the assaying skills of Ada Simon, we had the early advantage of precise and rapid radioenzyme measurement of plasma norepinephrine and renin activity in the blood of patients and animals.

We believed that neurohormonal activation contributed in part to the excessive afterload conditions observed in heart failure. We also thought that excessive neurohormonal activation directly impaired cardiac systolic function. The obvious next step was to explore whether neurohormonal antagonists would improve myocardial performance.

Under the leadership of Steven Goldsmith, many studies were performed to investigate reflex control mechanisms and their pathogenic role in patients with heart failure. The accumulating data suggested that persistent, excessive neurohormonal activity was characteristic of heart failure and that it was associated with a poor prognosis.¹⁷ The precise mechanism that drives activation of the SNS remained elusive, however, and is poorly defined even today. In that era, when β-adrenergic blockers were believed to be contraindicated, we inhibited the central SNS with bromocriptine, clonidine, and guanfacine with modestly favorable responses. We inhibited circulating arginine vasopressin antibody (thanks to Prof. Alan Cowley for noting an acute favorable response).

THE PHARMACOLOGIC ERA

The 1980s and 1990s saw the availability of several pharmacologic tools for assessing the roles of the SNS and RAAS in heart failure. The hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors and, later, angiotensin-receptor blockers (ARBs) were sources of concern, since many patients with advanced heart failure had low- to normal-range blood pressures before they received RAAS blockers. However, our group as well as others observed that abrupt blood pressure reduction occurred primarily in patients with very hyperreninemic responses to intravenous diuretics (ie, volume-depleted patients). Eventually, we learned that low baseline blood pressure did not adversely affect outcomes when vasodilators were used in patients with heart failure,^18,19 leading us to titrate these drugs upward over days to weeks.

Several different combinations of vasodilators were used successfully to treat heart failure, including hydralazine, isosorbide dinitrate,²⁰ ACE inhibitors,^21,22 and ARBs.^8,23–28 Direct-acting calcium channel blocking vasodilators, such as amlodipine, did not improve survival in patients with systolic heart failure, although they appeared to be safe in this setting.²⁹ The aldosterone receptor blockers spironolactone³⁰ and eplerenone³¹ were later demonstrated to improve survival of patients with advanced systolic heart failure when added to vasodilator therapy.

By the end of the 1990s, it was evident that drugs that blocked the SNS and RAAS were not just vasodilators or “afterload reducers,” similar to α-blockers, hydralazine, nitrates, and amlodipine. Neurohormonal blockers were doing something profoundly beneficial not observed with more direct-acting vasodilators.^32–37 Simple afterload reduction was not enough in patients with systolic heart failure.

Neurohormonal antagonists were acting more directly on the myocardium. They were preventing the progression of LV remodeling and, in some cases, promoting reverse remodeling, thus improving myocardial function and favorably influencing the natural history of heart failure.^31–39 We were astonished to discover that the failing, dilated heart could revert to normal size in response to neurohormone blockade with ACE inhibitors and β-adrenergic blockers; these findings were soon reported by other laboratories as well.

Contrary to our concept of heart failure in the 1970s, we now understood that the heart has inherent plasticity. It can dilate in response to abnormal loading conditions or myocardial injury, and it can restore itself to normal size when neurohormones are blocked and perverse loading conditions are improved. This reversal can occur spontaneously if an offending agent such as chronic alcohol use or inflammation is removed, but it is likely facilitated by SNS and RAAS blockers.

THE REMODELING ERA

Ken McDonald joined the University of Minnesota lab in 1989 as a research fellow. His skill in conducting both animal and clinical mechanistic studies was pivotal to our achieving our research goals. The inspired animal work by Boston-based Marc and Janice Pfeffer revealed the significance of the LV remodeling concept in the development of heart failure³⁶: ventricular remodeling was a hallmark of systolic heart failure, and pharmacologic inhibition of LV remodeling by blocking neurohormones had profound clinical implications.

Under the direction of Wenda Carlyle, a molecular biology laboratory was established at the University of Minnesota whose work was dedicated solely to exploration of remodeling at a very basic level. Alan Hirsch was recruited from Victor Dzau’s laboratory at Brigham and Women’s Hospital in Boston to extend our efforts to understand the molecular basis of cardiac remodeling. Ken McDonald guided the use of magnetic resonance imaging to study remodeling in dogs.

The late 1970s saw the initiation and eventual execution of several important clinical trials, including the Vasodilator Heart Failure Trials (V-HeFT I and V-HeFT II)^40,41 under our leadership, and Studies of Left Ventricular Dysfunction (SOLVD)^5,6 under the leadership of Salim Yusuf and others at the National Heart Lung and Blood Institute (NHLBI). Many neuro hormonal and remodeling substudies sprang from these large clinical trials. Spencer Kubo joined our group from the Medical College of Cornell University in the mid-1980s, and he immediately demonstrated his prowess in clinical research. He also recruited Alan Bank to study the endothelium in both experimental and human heart failure.

Integrating the molecular, animal, and clinical laboratories allowed us to pursue many mechanistic studies. Laboratory meetings, often held on Saturday mornings, generated ideas for program projects that were subsequently funded by NHLBI. Birthday parties and other social events with laboratory staff and their families were part of our fabric. Late-night trips to the Post Office to send off abstracts for national meetings before the midnight deadline were a regular feature.

Our coordination of and participation in the large clinical trials allowed us to meet frequently in Bethesda with colleagues from other major centers, fostering many collaborations and friendships that continue to thrive. Susan Ziesche deserves much of the credit for coordinating many groups that were part of these large, complex trials. Cheryl Yano, our administrator, also played a key role. All National Institutes of Health (NIH) grants passed through Cheryl, and she worked tirelessly to ensure that the proposals were in the best possible shape before we submitted them. Inder Anand joined our group in the early 1990s and became a major analytical force. Jay Cohn was the intellectual leader of the group, as well as our soul and inspiration. People worked hard for him, and he taught us much in a setting that valued creativity and new ideas above all.

THE LATER YEARS

By 1997, the face of heart failure had changed. New treatments were effective, but there were new challenges to face. I moved that year to the Cleveland Clinic, where I spent 11 enjoyable and productive years. I returned to Minnesota in 2008 to help build a new cardiovascular division.

It is gratifying to look back and see what has become of the “neurohormonal hypothesis.” Today, nearly all major medical centers have heart failure programs, and certification in advanced heart failure/heart transplantation is a reality. Training programs in advanced heart failure and heart transplant are common. The Heart Failure Society of America sprang up in the early 1990s, dedicated to patients with heart failure. Jay Cohn founded the Journal of Cardiac Failure, which flourished under his leadership. Neurohormonal blockers are now considered standard, conventional therapy and are widely used throughout the world.

CONCLUSIONS

Still, there is much work to do. An increasing number of devices are being developed, largely for patients with more advanced heart failure, but attention is also being directed to prevention of heart failure. Identification and possible treatment of patients at risk for the development of heart failure, and identification of those who already have some early structural and functional perturbation without advanced symptoms, are critically important. Since event rates are so low in these patients, we need to create new strategies for studying interventions. In the long term, the best treatment for nearly any condition is early diagnosis and perhaps early treatment with a goal of prevention.

One consequence of our progress over the years may be that heart failure now primarily affects a more elderly group—patients who often have many associated comorbidities. The consequences include more frequent readmissions, large numbers of patients with intractable signs and symptoms, and the emergence of difficult end-of-life decisions. If we could truly prevent heart failure rather than forestall its emergence to a later point in life, perhaps we could do more good.

For me, the study of neurohormonal mechanisms in the setting of heart failure was the centerpiece of my early career. Jay Cohn had asked several of us early in our laboratory experience to choose a neurohormonal system and learn about it in great depth and detail. My assignment was the SNS. Since then, I have never tired of learning about its control mechanisms, how it achieves circulatory homeostasis, how its excess quantities can be directly toxic to the heart, and the variety of pharmacologic ways that we can control it. I am indeed fortunate to have been part of this amazing study group.

We have known for more than 100 years that heart failure is characterized by excessive sympathetic nervous system (SNS) activity. Thanks to refinement of this concept in the 1980s and 1990s, we now have a good understanding of SNS activity in both experimental and clinical heart failure. During those two decades, we also realized the pathophysiologic importance of the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure.¹ By 2000, it was obvious that heart failure was inextricably intertwined with excessive neurohormonal activity.^2,3 This understanding of the pathophysiology of heart failure took on greater importance with the ability to pharmacologically block these neurohormonal systems, thereby demonstrating the detrimental role of neurohormones in the onset and progression of heart failure.

This article is a brief historical and personal description of the study of neurohormonal control mechanisms as they relate to the clinical syndrome of heart failure. The article includes a personal account of how the story unfolded in the cardiology research laboratories at the University of Minnesota.

THE EARLY YEARS: NEUROHORMONAL HYPOTHESIS

A hypothesis emerged gradually in the 1980s suggesting that progression of heart failure was in part a product of excessive SNS and RAAS activity. Many believed that pharmacologic inhibition of these systems might mitigate against progressive cardiac remodeling and thereby reduce symptoms and extend life—the so called neurohormonal hypothesis.⁴ SNS blockers and RAAS blockers are now widely used in tandem as first-line therapy to treat patients with heart failure,^5–11 but in 1980 we were just beginning to consider their therapeutic effects.

This major shift in thinking about neurohormonal systems and heart failure did not come about quickly. Early success was driven by the ability to quickly and precisely measure neurohormones in the laboratory coupled with the availability of drugs specifically designed to block the SNS and RAAS. It was also critically important to embrace the power of randomized controlled trials to test new therapies. Investigators, research nurses, and patients from many medical centers and laboratories should be credited with this astonishing success. I am proud to have been a part of this activity at the University of Minnesota.

THE COHN LABORATORY

Early work done in the 1960s by numerous investigators noted that the failing left ventricle (LV) was exquisitely sensitive to afterload conditions.^12–15 John Ross and Eugene Braunwald explored this observation in patients in 1964.¹⁵ Jay Cohn, with his unique background in hypertension and hemodynamics, brought the concept back into the laboratory in the early 1970s, where he explored the mechanisms responsible for increased sensitivity to afterload in patients with heart failure.¹⁶

I had the good fortune to join Cohn’s laboratory in 1979, when this avenue of heart failure research was in full bloom. A team of investigators was gradually assembled that included Maria Teresa Olivari, who relocated from the Cardiovascular Research Institute in Milan, Italy, directed by Maurizio D. Guazzi. Also joining the group were T. Barry Levine from the University of Michigan, Ann Arbor; Steven Goldsmith from Ohio State University, Columbus; Susan Ziesche from the Minneapolis Veterans Affairs (VA) Medical Center; Thomas Rector, an expert statistician and pharmacologist at the University of Minnesota; and many research fellows, visitors, students, biochemists, statisticians, and research nurses. Joseph Franciosa joined the University of Minnesota group in 1974 and, after completing several important trials, left in 1979 to lead the cardiology group at the Philadelphia VA Medical Center.

The Cohn group developed a working hypothesis that activation of the SNS and RAAS in heart failure was most likely an adaptive mechanism intended for short-term circulatory support, such as in the setting of blood loss, dehydration, shock, volume depletion, or flight response. In patients with heart failure, according to the hypothesis, the SNS and RAAS activity persisted beyond that needed for adaptation, with chronic release of norepinephrine (NE), renin, angiotensin II, aldosterone, and other neurohormones. The neurohormones ultimately became “maladaptive.” Thanks to the assaying skills of Ada Simon, we had the early advantage of precise and rapid radioenzyme measurement of plasma norepinephrine and renin activity in the blood of patients and animals.

We believed that neurohormonal activation contributed in part to the excessive afterload conditions observed in heart failure. We also thought that excessive neurohormonal activation directly impaired cardiac systolic function. The obvious next step was to explore whether neurohormonal antagonists would improve myocardial performance.

Under the leadership of Steven Goldsmith, many studies were performed to investigate reflex control mechanisms and their pathogenic role in patients with heart failure. The accumulating data suggested that persistent, excessive neurohormonal activity was characteristic of heart failure and that it was associated with a poor prognosis.¹⁷ The precise mechanism that drives activation of the SNS remained elusive, however, and is poorly defined even today. In that era, when β-adrenergic blockers were believed to be contraindicated, we inhibited the central SNS with bromocriptine, clonidine, and guanfacine with modestly favorable responses. We inhibited circulating arginine vasopressin antibody (thanks to Prof. Alan Cowley for noting an acute favorable response).

THE PHARMACOLOGIC ERA

The 1980s and 1990s saw the availability of several pharmacologic tools for assessing the roles of the SNS and RAAS in heart failure. The hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors and, later, angiotensin-receptor blockers (ARBs) were sources of concern, since many patients with advanced heart failure had low- to normal-range blood pressures before they received RAAS blockers. However, our group as well as others observed that abrupt blood pressure reduction occurred primarily in patients with very hyperreninemic responses to intravenous diuretics (ie, volume-depleted patients). Eventually, we learned that low baseline blood pressure did not adversely affect outcomes when vasodilators were used in patients with heart failure,^18,19 leading us to titrate these drugs upward over days to weeks.

Several different combinations of vasodilators were used successfully to treat heart failure, including hydralazine, isosorbide dinitrate,²⁰ ACE inhibitors,^21,22 and ARBs.^8,23–28 Direct-acting calcium channel blocking vasodilators, such as amlodipine, did not improve survival in patients with systolic heart failure, although they appeared to be safe in this setting.²⁹ The aldosterone receptor blockers spironolactone³⁰ and eplerenone³¹ were later demonstrated to improve survival of patients with advanced systolic heart failure when added to vasodilator therapy.

By the end of the 1990s, it was evident that drugs that blocked the SNS and RAAS were not just vasodilators or “afterload reducers,” similar to α-blockers, hydralazine, nitrates, and amlodipine. Neurohormonal blockers were doing something profoundly beneficial not observed with more direct-acting vasodilators.^32–37 Simple afterload reduction was not enough in patients with systolic heart failure.

Neurohormonal antagonists were acting more directly on the myocardium. They were preventing the progression of LV remodeling and, in some cases, promoting reverse remodeling, thus improving myocardial function and favorably influencing the natural history of heart failure.^31–39 We were astonished to discover that the failing, dilated heart could revert to normal size in response to neurohormone blockade with ACE inhibitors and β-adrenergic blockers; these findings were soon reported by other laboratories as well.

Contrary to our concept of heart failure in the 1970s, we now understood that the heart has inherent plasticity. It can dilate in response to abnormal loading conditions or myocardial injury, and it can restore itself to normal size when neurohormones are blocked and perverse loading conditions are improved. This reversal can occur spontaneously if an offending agent such as chronic alcohol use or inflammation is removed, but it is likely facilitated by SNS and RAAS blockers.

THE REMODELING ERA

Ken McDonald joined the University of Minnesota lab in 1989 as a research fellow. His skill in conducting both animal and clinical mechanistic studies was pivotal to our achieving our research goals. The inspired animal work by Boston-based Marc and Janice Pfeffer revealed the significance of the LV remodeling concept in the development of heart failure³⁶: ventricular remodeling was a hallmark of systolic heart failure, and pharmacologic inhibition of LV remodeling by blocking neurohormones had profound clinical implications.

Under the direction of Wenda Carlyle, a molecular biology laboratory was established at the University of Minnesota whose work was dedicated solely to exploration of remodeling at a very basic level. Alan Hirsch was recruited from Victor Dzau’s laboratory at Brigham and Women’s Hospital in Boston to extend our efforts to understand the molecular basis of cardiac remodeling. Ken McDonald guided the use of magnetic resonance imaging to study remodeling in dogs.

The late 1970s saw the initiation and eventual execution of several important clinical trials, including the Vasodilator Heart Failure Trials (V-HeFT I and V-HeFT II)^40,41 under our leadership, and Studies of Left Ventricular Dysfunction (SOLVD)^5,6 under the leadership of Salim Yusuf and others at the National Heart Lung and Blood Institute (NHLBI). Many neuro hormonal and remodeling substudies sprang from these large clinical trials. Spencer Kubo joined our group from the Medical College of Cornell University in the mid-1980s, and he immediately demonstrated his prowess in clinical research. He also recruited Alan Bank to study the endothelium in both experimental and human heart failure.

Integrating the molecular, animal, and clinical laboratories allowed us to pursue many mechanistic studies. Laboratory meetings, often held on Saturday mornings, generated ideas for program projects that were subsequently funded by NHLBI. Birthday parties and other social events with laboratory staff and their families were part of our fabric. Late-night trips to the Post Office to send off abstracts for national meetings before the midnight deadline were a regular feature.

Our coordination of and participation in the large clinical trials allowed us to meet frequently in Bethesda with colleagues from other major centers, fostering many collaborations and friendships that continue to thrive. Susan Ziesche deserves much of the credit for coordinating many groups that were part of these large, complex trials. Cheryl Yano, our administrator, also played a key role. All National Institutes of Health (NIH) grants passed through Cheryl, and she worked tirelessly to ensure that the proposals were in the best possible shape before we submitted them. Inder Anand joined our group in the early 1990s and became a major analytical force. Jay Cohn was the intellectual leader of the group, as well as our soul and inspiration. People worked hard for him, and he taught us much in a setting that valued creativity and new ideas above all.

THE LATER YEARS

By 1997, the face of heart failure had changed. New treatments were effective, but there were new challenges to face. I moved that year to the Cleveland Clinic, where I spent 11 enjoyable and productive years. I returned to Minnesota in 2008 to help build a new cardiovascular division.

It is gratifying to look back and see what has become of the “neurohormonal hypothesis.” Today, nearly all major medical centers have heart failure programs, and certification in advanced heart failure/heart transplantation is a reality. Training programs in advanced heart failure and heart transplant are common. The Heart Failure Society of America sprang up in the early 1990s, dedicated to patients with heart failure. Jay Cohn founded the Journal of Cardiac Failure, which flourished under his leadership. Neurohormonal blockers are now considered standard, conventional therapy and are widely used throughout the world.

CONCLUSIONS

Still, there is much work to do. An increasing number of devices are being developed, largely for patients with more advanced heart failure, but attention is also being directed to prevention of heart failure. Identification and possible treatment of patients at risk for the development of heart failure, and identification of those who already have some early structural and functional perturbation without advanced symptoms, are critically important. Since event rates are so low in these patients, we need to create new strategies for studying interventions. In the long term, the best treatment for nearly any condition is early diagnosis and perhaps early treatment with a goal of prevention.

One consequence of our progress over the years may be that heart failure now primarily affects a more elderly group—patients who often have many associated comorbidities. The consequences include more frequent readmissions, large numbers of patients with intractable signs and symptoms, and the emergence of difficult end-of-life decisions. If we could truly prevent heart failure rather than forestall its emergence to a later point in life, perhaps we could do more good.

For me, the study of neurohormonal mechanisms in the setting of heart failure was the centerpiece of my early career. Jay Cohn had asked several of us early in our laboratory experience to choose a neurohormonal system and learn about it in great depth and detail. My assignment was the SNS. Since then, I have never tired of learning about its control mechanisms, how it achieves circulatory homeostasis, how its excess quantities can be directly toxic to the heart, and the variety of pharmacologic ways that we can control it. I am indeed fortunate to have been part of this amazing study group.

Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.

Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.

Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.

In this article, we review the current clinical management of small renal masses.

SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP

Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.^1,2

With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.³

This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.⁴

Small renal masses vary in biologic aggressiveness

Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.^5–7

A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.⁵ Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.⁸

Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.⁹

In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.

CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES

In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.¹⁰

Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”¹¹

High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.

Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.

Differential diagnosis

By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.

With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.

Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.

RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT

Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.

Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.

Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.¹² In addition, false-negative rates are now consistently less than 1%.¹³

Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.¹²

Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.

However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.

The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.

For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.

Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.

Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.¹⁴ This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).

TREATMENT OPTIONS

Radical nephrectomy: Still the most common treatment

In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.

Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al¹⁵ reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.

One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.¹⁶ However, total removal of the kidney comes at a great price—loss of renal function.

Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.¹⁷

In a landmark study, Huang et al¹⁸ evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.

The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.¹⁹ However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.

The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.⁴

Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).

Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.

The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.¹⁷ After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).

Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.

Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.^20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.²²

Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.^23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.²⁵

Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.¹⁷ Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.

Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.

Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.

A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.

Thermal ablation: Another minimally invasive option

Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.

Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.^26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.²⁸ Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.

Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.

Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.²⁹ In a more robust single-institution experience,³⁰ renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.

Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell³¹ reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.

Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.³² One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.

Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.^17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).³⁴ Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.

Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).

Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.

Active surveillance for select patients

In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.

A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).^17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.³⁵

Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.³⁶

Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.^5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.^37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).

Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).

In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).

Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.

Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.

Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.

In this article, we review the current clinical management of small renal masses.

SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP

Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.^1,2

With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.³

This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.⁴

Small renal masses vary in biologic aggressiveness

Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.^5–7

A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.⁵ Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.⁸

Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.⁹

In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.

CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES

In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.¹⁰

Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”¹¹

High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.

Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.

Differential diagnosis

By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.

With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.

Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.

RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT

Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.

Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.

Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.¹² In addition, false-negative rates are now consistently less than 1%.¹³

Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.¹²

Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.

However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.

The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.

For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.

Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.

Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.¹⁴ This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).

TREATMENT OPTIONS

Radical nephrectomy: Still the most common treatment

In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.

Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al¹⁵ reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.

One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.¹⁶ However, total removal of the kidney comes at a great price—loss of renal function.

Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.¹⁷

In a landmark study, Huang et al¹⁸ evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.

The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.¹⁹ However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.

The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.⁴

Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).

Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.

The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.¹⁷ After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).

Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.

Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.^20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.²²

Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.^23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.²⁵

Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.¹⁷ Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.

Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.

Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.

A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.

Thermal ablation: Another minimally invasive option

Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.

Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.^26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.²⁸ Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.

Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.

Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.²⁹ In a more robust single-institution experience,³⁰ renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.

Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell³¹ reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.

Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.³² One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.

Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.^17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).³⁴ Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.

Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).

Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.

Active surveillance for select patients

In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.

A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).^17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.³⁵

Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.³⁶

Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.^5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.^37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).

Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).

In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).

Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.

Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.

Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.

In this article, we review the current clinical management of small renal masses.

SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP

Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.^1,2

With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.³

This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.⁴

Small renal masses vary in biologic aggressiveness

Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.^5–7

A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.⁵ Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.⁸

Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.⁹

In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.

CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES

In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.¹⁰

Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”¹¹

High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.

Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.

Differential diagnosis

By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.

With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.

Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.

RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT

Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.

Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.

Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.¹² In addition, false-negative rates are now consistently less than 1%.¹³

Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.¹²

Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.

However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.

The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.

For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.

Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.

Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.¹⁴ This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).

TREATMENT OPTIONS

Radical nephrectomy: Still the most common treatment

In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.

Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al¹⁵ reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.

One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.¹⁶ However, total removal of the kidney comes at a great price—loss of renal function.

Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.¹⁷

In a landmark study, Huang et al¹⁸ evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.

The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.¹⁹ However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.

The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.⁴

Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).

Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.

The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.¹⁷ After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).

Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.

Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.^20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.²²

Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.^23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.²⁵

Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.¹⁷ Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.

Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.

Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.

A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.

Thermal ablation: Another minimally invasive option

Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.

Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.^26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.²⁸ Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.

Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.

Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.²⁹ In a more robust single-institution experience,³⁰ renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.

Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell³¹ reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.

Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.³² One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.

Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.^17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).³⁴ Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.

Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).

Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.

Active surveillance for select patients

In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.

A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).^17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.³⁵

Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.³⁶

Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.^5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.^37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).

Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).

In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.