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Hypertrophic cardiomyopathy (HCM) is a relatively common inherited condition characterized by abnormal asymmetric left ventricular (LV) thickening. This can lead to LV outflow tract (LVOT) obstruction, which has important implications for anesthesia management. This article describes a case of previously undiagnosed HCM discovered during a preoperative physical examination prior to a routine surveillance colonoscopy.

CASE PRESENTATION

A 55-year-old Army veteran with a history of a sessile serrated colon adenoma presented to the preadmission testing clinic prior to planned surveillance colonoscopy under monitored anesthesia care. His medical history included untreated severe obstructive sleep apnea (53 apnea-hypopnea index score), diet-controlled hypertension, prediabetes (6.3% hemoglobin A_1c), hypogonadism, and obesity (41 body mass index). Medications included semaglutide 1.7 mg injected subcutaneously weekly and testosterone 200 mg injected intramuscularly every 2 weeks, as well as lisinopril-hydrochlorothiazide 10 to 12.5 mg daily, which had recently been discontinued because his blood pressure had improved with a low-sodium diet.

A review of systems was unremarkable except for progressive weight gain. The patient had no family history of sudden cardiac death. On physical examination, the patient’s blood pressure was 119/81 mm Hg, pulse was 86 beats/min, and respiratory rate was 18 breaths/min. The patient was clinically euvolemic, with no jugular venous distention or peripheral edema, and his lungs were clear to auscultation. There was, however, a soft, nonradiating grade 2/6 systolic murmur that had not been previously documented. The murmur decreased substantially with the Valsalva maneuver, with no change in hand grip.

Laboratory studies revealed hemoglobin and renal function were within the reference range. A routine 12-lead electrocardiogram (ECG) was unremarkable. A transthoracic echocardiogram revealed moderate pulmonary hypertension (59 mm Hg right ventricular systolic pressure), asymmetric LV hypertrophy (2.1 cm septal thickness), and severe LVOT obstruction (131.8 mm Hg gradient). Severe systolic anterior motion of the mitral valve was also present. The LV ejection fraction was 60% to 65%, with normal cavity size and systolic function. These findings were consistent with severe hypertrophic obstructive cardiomyopathy (HOCM). Upon more detailed questioning, the patient reported that over the previous 5 years he had experienced gradually decreasing exercise tolerance and mild dyspnea on exertion, particularly in hot weather, which he attributed to weight gain. He also reported a presyncopal episode the previous month while working in his garage in hot weather for a prolonged period of time.

The patient’s elective colonoscopy was canceled, and he was referred to cardiology. While awaiting cardiac consultation, he was instructed to maintain good hydration and avoid any heavy physical activity beyond walking. He was told not to resume his use of lisinopril-hydrochlorothiazide. A screening 7-day Holter monitor showed no ventricular or supraventricular ectopy. After cardiology consultation, the patient was referred to a HCM specialty clinic, where a cardiac magnetic resonance imaging confirmed severe asymmetric hypertrophy with resting obstruction (Figures 1-4). Treatment options were discussed with the patient, and he underwent a trial with the Β—blocker metoprolol 50 mg daily, which he could not tolerate. Verapamil extended-release 180 mg orally once daily was then initiated; however, his dyspnea persisted. He was amenable to surgical therapy and underwent septal myectomy, with 12 g of septal myocardium removed. He did well postoperatively, with a follow-up echocardiogram showing normal LV systolic function and no LVOT gradient detectable at rest or with Valsalva maneuver. His fatigue and exertional dyspnea significantly improved. Once the patient underwent septal myectomy and was determined to have no detectable LVOT gradient, he was approved for colonoscopy which has been scheduled but not completed.

DISCUSSION

Once thought rare, HCM is now considered to be a relatively common inherited disorder, occurring in about 1 in 500 persons, with some suggesting that the actual prevalence is closer to 1 in 200 persons.^1,2 Most often caused by mutations in ≥ 1 of 11 genes responsible for encoding cardiac sarcomere proteins, HCM is characterized by abnormal LV thickening without chamber enlargement in the absence of any identifiable cause, such as aortic valve stenosis or uncontrolled hypertension. The hypertrophy is often asymmetric, and in cases of asymmetric septal hypertrophy, dynamic LVOT obstruction can occur (known as HOCM). The condition is inherited in an autosomal dominant pattern with variable expression and is associated with myocardial fiber disarray, which can occur years before symptom onset.³ This myocardial disarray can lead to remodeling and an increased wall-to-lumen ratio of the coronary arteries, resulting in impaired coronary reserve.

Depending on the degree of LVOT obstruction, patients with HCM may be classified as nonobstructive, labile, or obstructive at rest. Patients without obstruction have an outflow gradient ≤ 30 mm Hg that is not provoked with Valsalva maneuver, administration of amyl nitrite, or exercise treadmill testing.³ Patients classified as labile do not have LVOT obstruction at rest, but obstruction may be induced by provocative measures. Finally, about one-third of patients with HCM will have LVOT gradients of > 30 mm Hg at rest. These patients are at increased risk for progression to symptomatic heart failure and may be candidates for surgical myectomy or catheter-based alcohol septal ablation.⁴ The patient in this case had a resting LVOT gradient of 131.8 mm Hg on echocardiography. The magnitude of this gradient placed the patient at a significantly higher risk of ventricular dysrhythmias and sudden cardiac death.⁵

Wall thickness also has prognostic implications. ⁶ Although any area of the myocardium can be affected, the septum is involved in about 90% cases. In their series of 48 patients followed over 6.5 years, Spirito et al found that the risk of sudden death in patients with HCM increased as wall thickness increased. For patients with a wall thickness of < 15 mm, the risk of death was 0 per 1000 person-years; however, this increased to 18.2 per 1000 person-years for patients with a wall thickness of > 30 mm.⁷

While many patients with HCM are asymptomatic, others may report dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, presyncope/ syncope, postural lightheadedness, fatigue, or edema. Symptomatology, however, is quite variable and does not necessarily correlate with the degree of outflow obstruction. Surprisingly, some patients with significant LVOT may have minimal symptoms, such as the patient in this case, while others with a lesser degree of LVOT obstruction may be very symptomatic.^3,4

Physical examination of a patient with HCM may be normal or may reveal nonspecific findings such as a fourth heart sound or a systolic murmur. In general, physical examination abnormalities are related to LVOT obstruction. Those patients without significant outflow obstruction may have a normal cardiac examination. While patients with HCM may have a variety of systolic murmurs, the 2 most common are those related to outflow tract obstruction and mitral regurgitation caused by systolic anterior motion of the mitral valve.⁴ The systolic murmur associated with significant LVOT obstruction has been described as a harsh, crescendo-decrescendo type that begins just after S1 and is heard best at the apex and lower left sternal border.⁴ It may radiate to the axilla and base but not generally into the neck. The murmur usually increases with Valsalva maneuver and decreases with handgrip or going from a standing to a sitting/ squatting position. The initial examination of the patient in this case was not suggestive of HOCM, as confirmed by 2 practitioners (a cardiologist and an internist), each with > 30 years of clinical experience. This may have been related to the patient’s hydration status at the time, with Valsalva maneuver increasing obstruction to the point of reduced flow.

About 90% of patients with HCM will have abnormalities on ECG, most commonly LV hypertrophy with a strain pattern. Other ECG findings include: (1) prominent abnormal Q waves, particularly in the inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6), reflecting depolarization of a hypertrophied septum; (2) left axis deviation; (3) deeply inverted T waves in leads V2 through V4; and (4) P wave abnormalities indicative of left atrial (LA) or biatrial enlargement. ⁸ It is notable that the patient in this case had a normal ECG, given that a minority of patients with HCM have been shown to have a normal ECG.⁹

Echocardiography plays an important role in diagnosing HCM. Diagnostic criteria include the presence of asymmetric hypertrophy (most commonly with anterior septal involvement), systolic anterior motion of the mitral valve, a nondilated LV cavity, septal immobility, and premature closure of the aortic valve. LV thickness is measured at both the septum and free wall; values ≥ 15 mm, with a septal-to-free wall thickness ratio of ≥ 1.3, are suggestive of HCM. Asymmetric LV hypertrophy can also be seen in other segments besides the septum, such as the apex.¹⁰

HCM/HOCM is the most common cause of sudden cardiac death in young people. The condition also contributes to significant functional morbidity due to heart failure and increases the risk of atrial fibrillation and subsequent stroke. Treatments tend to focus on symptom relief and slowing disease progression and include the use of medications such as Β—blockers, nondihydropyridine calcium channel blockers, and the myosin inhibitor mavacamten.¹¹ Select patients, such as those with severe LVOT obstruction and symptoms despite treatment with Β—blockers or nondihydropyridine calcium channel blockers, may be offered septal myectomy or catheter-based alcohol septal ablation, coupled with insertion of an implantable cardiac defibrillator to prevent sudden cardiac death in patients at high arrhythmic risk.^1,12

Patients with HCM, particularly those with LVOT obstruction, pose distinct challenges to the anesthesiologist because they are highly sensitive to decreases in preload and afterload. These patients frequently experience adverse perioperative events such as myocardial ischemia, systemic hypotension, and supraventricular or ventricular arrhythmias. Acute congestive heart failure may also occur, presumably due to concomitant diastolic dysfunction. Patients with previously unrecognized HCM are of particular concern, as they may manifest unexpected and sudden hypotension with the induction of anesthesia. There may then be a paradoxical response to vasoactive drugs and anesthetic agents, which accentuate LVOT obstruction. In these circumstances, undiagnosed HCM should be considered, and intraoperative rescue transesophageal echocardiography be performed.¹³ Once the diagnosis is confirmed, efforts should be made to reduce myocardial contractility and sympathetic discharge (eg, with Β—blockers), increase afterload (eg, with α1 agonists), and improve preload with adequate hydration. Proper resuscitation of hypotensive patients with HCM requires a thorough understanding of disease pathology, as effective interventions may seem to be counterintuitive. Inotropic agents such as epinephrine are contraindicated in HCM because increased inotropy and chronotropy worsen LVOT obstruction. Volume status is often tenuous; while adequate preload is important, overly aggressive fluid resuscitation may promote heart failure. It is important to keep in mind that even patients without resting LVOT obstruction may develop dynamic obstruction with anesthesia induction due to sudden reductions in preload and afterload. It is also important to note that the degree of LV hypertrophy is directly correlated with arrhythmic sudden death. Those patients with LV wall thickness ≥ 30 mm are at increased risk for potentially lethal tachyarrhythmias in the operating room.¹⁴

These considerations reinforce the need for proper preoperative identification of patients with HCM. Heightened awareness is key, given the fact that HCM is relatively common and tends to be underdiagnosed in the general population. These patients are generally young, otherwise healthy, and often undergo minor operative procedures in outpatient settings. It is incumbent upon the preoperative evaluator to take a thorough medical history and perform a careful physical examination. Clues to the diagnosis include exertional dyspnea, fatigue, angina, syncope/presyncope, or a family history of sudden cardiac death or HCM. A systolic ejection murmur, particularly one that increases with standing or Valsalva maneuver, and decreases with squatting or handgrip may also raise clinical suspicion. These patients should undergo a full cardiac evaluation, including echocardiography.

CONCLUSIONS

HCM is a common condition that is important to diagnose in the preoperative clinic. Failure to do so can lead to catastrophic complications during induction of anesthesia due to the sudden reduction in preload and afterload, which may cause a significant increase in LVOT obstruction. A high index of suspicion is essential, as clinical diagnosis can be challenging. The physical examination may be deceiving and symptoms are often subtle and nonspecific. It is imperative to alert the anesthesiologist before surgery so the complex hemodynamic management of patients with HOCM can be appropriately managed.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited condition characterized by abnormal asymmetric left ventricular (LV) thickening. This can lead to LV outflow tract (LVOT) obstruction, which has important implications for anesthesia management. This article describes a case of previously undiagnosed HCM discovered during a preoperative physical examination prior to a routine surveillance colonoscopy.

CASE PRESENTATION

A 55-year-old Army veteran with a history of a sessile serrated colon adenoma presented to the preadmission testing clinic prior to planned surveillance colonoscopy under monitored anesthesia care. His medical history included untreated severe obstructive sleep apnea (53 apnea-hypopnea index score), diet-controlled hypertension, prediabetes (6.3% hemoglobin A_1c), hypogonadism, and obesity (41 body mass index). Medications included semaglutide 1.7 mg injected subcutaneously weekly and testosterone 200 mg injected intramuscularly every 2 weeks, as well as lisinopril-hydrochlorothiazide 10 to 12.5 mg daily, which had recently been discontinued because his blood pressure had improved with a low-sodium diet.

A review of systems was unremarkable except for progressive weight gain. The patient had no family history of sudden cardiac death. On physical examination, the patient’s blood pressure was 119/81 mm Hg, pulse was 86 beats/min, and respiratory rate was 18 breaths/min. The patient was clinically euvolemic, with no jugular venous distention or peripheral edema, and his lungs were clear to auscultation. There was, however, a soft, nonradiating grade 2/6 systolic murmur that had not been previously documented. The murmur decreased substantially with the Valsalva maneuver, with no change in hand grip.

Laboratory studies revealed hemoglobin and renal function were within the reference range. A routine 12-lead electrocardiogram (ECG) was unremarkable. A transthoracic echocardiogram revealed moderate pulmonary hypertension (59 mm Hg right ventricular systolic pressure), asymmetric LV hypertrophy (2.1 cm septal thickness), and severe LVOT obstruction (131.8 mm Hg gradient). Severe systolic anterior motion of the mitral valve was also present. The LV ejection fraction was 60% to 65%, with normal cavity size and systolic function. These findings were consistent with severe hypertrophic obstructive cardiomyopathy (HOCM). Upon more detailed questioning, the patient reported that over the previous 5 years he had experienced gradually decreasing exercise tolerance and mild dyspnea on exertion, particularly in hot weather, which he attributed to weight gain. He also reported a presyncopal episode the previous month while working in his garage in hot weather for a prolonged period of time.

The patient’s elective colonoscopy was canceled, and he was referred to cardiology. While awaiting cardiac consultation, he was instructed to maintain good hydration and avoid any heavy physical activity beyond walking. He was told not to resume his use of lisinopril-hydrochlorothiazide. A screening 7-day Holter monitor showed no ventricular or supraventricular ectopy. After cardiology consultation, the patient was referred to a HCM specialty clinic, where a cardiac magnetic resonance imaging confirmed severe asymmetric hypertrophy with resting obstruction (Figures 1-4). Treatment options were discussed with the patient, and he underwent a trial with the Β—blocker metoprolol 50 mg daily, which he could not tolerate. Verapamil extended-release 180 mg orally once daily was then initiated; however, his dyspnea persisted. He was amenable to surgical therapy and underwent septal myectomy, with 12 g of septal myocardium removed. He did well postoperatively, with a follow-up echocardiogram showing normal LV systolic function and no LVOT gradient detectable at rest or with Valsalva maneuver. His fatigue and exertional dyspnea significantly improved. Once the patient underwent septal myectomy and was determined to have no detectable LVOT gradient, he was approved for colonoscopy which has been scheduled but not completed.

DISCUSSION

Once thought rare, HCM is now considered to be a relatively common inherited disorder, occurring in about 1 in 500 persons, with some suggesting that the actual prevalence is closer to 1 in 200 persons.^1,2 Most often caused by mutations in ≥ 1 of 11 genes responsible for encoding cardiac sarcomere proteins, HCM is characterized by abnormal LV thickening without chamber enlargement in the absence of any identifiable cause, such as aortic valve stenosis or uncontrolled hypertension. The hypertrophy is often asymmetric, and in cases of asymmetric septal hypertrophy, dynamic LVOT obstruction can occur (known as HOCM). The condition is inherited in an autosomal dominant pattern with variable expression and is associated with myocardial fiber disarray, which can occur years before symptom onset.³ This myocardial disarray can lead to remodeling and an increased wall-to-lumen ratio of the coronary arteries, resulting in impaired coronary reserve.

Depending on the degree of LVOT obstruction, patients with HCM may be classified as nonobstructive, labile, or obstructive at rest. Patients without obstruction have an outflow gradient ≤ 30 mm Hg that is not provoked with Valsalva maneuver, administration of amyl nitrite, or exercise treadmill testing.³ Patients classified as labile do not have LVOT obstruction at rest, but obstruction may be induced by provocative measures. Finally, about one-third of patients with HCM will have LVOT gradients of > 30 mm Hg at rest. These patients are at increased risk for progression to symptomatic heart failure and may be candidates for surgical myectomy or catheter-based alcohol septal ablation.⁴ The patient in this case had a resting LVOT gradient of 131.8 mm Hg on echocardiography. The magnitude of this gradient placed the patient at a significantly higher risk of ventricular dysrhythmias and sudden cardiac death.⁵

Wall thickness also has prognostic implications. ⁶ Although any area of the myocardium can be affected, the septum is involved in about 90% cases. In their series of 48 patients followed over 6.5 years, Spirito et al found that the risk of sudden death in patients with HCM increased as wall thickness increased. For patients with a wall thickness of < 15 mm, the risk of death was 0 per 1000 person-years; however, this increased to 18.2 per 1000 person-years for patients with a wall thickness of > 30 mm.⁷

While many patients with HCM are asymptomatic, others may report dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, presyncope/ syncope, postural lightheadedness, fatigue, or edema. Symptomatology, however, is quite variable and does not necessarily correlate with the degree of outflow obstruction. Surprisingly, some patients with significant LVOT may have minimal symptoms, such as the patient in this case, while others with a lesser degree of LVOT obstruction may be very symptomatic.^3,4

Physical examination of a patient with HCM may be normal or may reveal nonspecific findings such as a fourth heart sound or a systolic murmur. In general, physical examination abnormalities are related to LVOT obstruction. Those patients without significant outflow obstruction may have a normal cardiac examination. While patients with HCM may have a variety of systolic murmurs, the 2 most common are those related to outflow tract obstruction and mitral regurgitation caused by systolic anterior motion of the mitral valve.⁴ The systolic murmur associated with significant LVOT obstruction has been described as a harsh, crescendo-decrescendo type that begins just after S1 and is heard best at the apex and lower left sternal border.⁴ It may radiate to the axilla and base but not generally into the neck. The murmur usually increases with Valsalva maneuver and decreases with handgrip or going from a standing to a sitting/ squatting position. The initial examination of the patient in this case was not suggestive of HOCM, as confirmed by 2 practitioners (a cardiologist and an internist), each with > 30 years of clinical experience. This may have been related to the patient’s hydration status at the time, with Valsalva maneuver increasing obstruction to the point of reduced flow.

About 90% of patients with HCM will have abnormalities on ECG, most commonly LV hypertrophy with a strain pattern. Other ECG findings include: (1) prominent abnormal Q waves, particularly in the inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6), reflecting depolarization of a hypertrophied septum; (2) left axis deviation; (3) deeply inverted T waves in leads V2 through V4; and (4) P wave abnormalities indicative of left atrial (LA) or biatrial enlargement. ⁸ It is notable that the patient in this case had a normal ECG, given that a minority of patients with HCM have been shown to have a normal ECG.⁹

Echocardiography plays an important role in diagnosing HCM. Diagnostic criteria include the presence of asymmetric hypertrophy (most commonly with anterior septal involvement), systolic anterior motion of the mitral valve, a nondilated LV cavity, septal immobility, and premature closure of the aortic valve. LV thickness is measured at both the septum and free wall; values ≥ 15 mm, with a septal-to-free wall thickness ratio of ≥ 1.3, are suggestive of HCM. Asymmetric LV hypertrophy can also be seen in other segments besides the septum, such as the apex.¹⁰

HCM/HOCM is the most common cause of sudden cardiac death in young people. The condition also contributes to significant functional morbidity due to heart failure and increases the risk of atrial fibrillation and subsequent stroke. Treatments tend to focus on symptom relief and slowing disease progression and include the use of medications such as Β—blockers, nondihydropyridine calcium channel blockers, and the myosin inhibitor mavacamten.¹¹ Select patients, such as those with severe LVOT obstruction and symptoms despite treatment with Β—blockers or nondihydropyridine calcium channel blockers, may be offered septal myectomy or catheter-based alcohol septal ablation, coupled with insertion of an implantable cardiac defibrillator to prevent sudden cardiac death in patients at high arrhythmic risk.^1,12

Patients with HCM, particularly those with LVOT obstruction, pose distinct challenges to the anesthesiologist because they are highly sensitive to decreases in preload and afterload. These patients frequently experience adverse perioperative events such as myocardial ischemia, systemic hypotension, and supraventricular or ventricular arrhythmias. Acute congestive heart failure may also occur, presumably due to concomitant diastolic dysfunction. Patients with previously unrecognized HCM are of particular concern, as they may manifest unexpected and sudden hypotension with the induction of anesthesia. There may then be a paradoxical response to vasoactive drugs and anesthetic agents, which accentuate LVOT obstruction. In these circumstances, undiagnosed HCM should be considered, and intraoperative rescue transesophageal echocardiography be performed.¹³ Once the diagnosis is confirmed, efforts should be made to reduce myocardial contractility and sympathetic discharge (eg, with Β—blockers), increase afterload (eg, with α1 agonists), and improve preload with adequate hydration. Proper resuscitation of hypotensive patients with HCM requires a thorough understanding of disease pathology, as effective interventions may seem to be counterintuitive. Inotropic agents such as epinephrine are contraindicated in HCM because increased inotropy and chronotropy worsen LVOT obstruction. Volume status is often tenuous; while adequate preload is important, overly aggressive fluid resuscitation may promote heart failure. It is important to keep in mind that even patients without resting LVOT obstruction may develop dynamic obstruction with anesthesia induction due to sudden reductions in preload and afterload. It is also important to note that the degree of LV hypertrophy is directly correlated with arrhythmic sudden death. Those patients with LV wall thickness ≥ 30 mm are at increased risk for potentially lethal tachyarrhythmias in the operating room.¹⁴

These considerations reinforce the need for proper preoperative identification of patients with HCM. Heightened awareness is key, given the fact that HCM is relatively common and tends to be underdiagnosed in the general population. These patients are generally young, otherwise healthy, and often undergo minor operative procedures in outpatient settings. It is incumbent upon the preoperative evaluator to take a thorough medical history and perform a careful physical examination. Clues to the diagnosis include exertional dyspnea, fatigue, angina, syncope/presyncope, or a family history of sudden cardiac death or HCM. A systolic ejection murmur, particularly one that increases with standing or Valsalva maneuver, and decreases with squatting or handgrip may also raise clinical suspicion. These patients should undergo a full cardiac evaluation, including echocardiography.

CONCLUSIONS

HCM is a common condition that is important to diagnose in the preoperative clinic. Failure to do so can lead to catastrophic complications during induction of anesthesia due to the sudden reduction in preload and afterload, which may cause a significant increase in LVOT obstruction. A high index of suspicion is essential, as clinical diagnosis can be challenging. The physical examination may be deceiving and symptoms are often subtle and nonspecific. It is imperative to alert the anesthesiologist before surgery so the complex hemodynamic management of patients with HOCM can be appropriately managed.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited condition characterized by abnormal asymmetric left ventricular (LV) thickening. This can lead to LV outflow tract (LVOT) obstruction, which has important implications for anesthesia management. This article describes a case of previously undiagnosed HCM discovered during a preoperative physical examination prior to a routine surveillance colonoscopy.

CASE PRESENTATION

A 55-year-old Army veteran with a history of a sessile serrated colon adenoma presented to the preadmission testing clinic prior to planned surveillance colonoscopy under monitored anesthesia care. His medical history included untreated severe obstructive sleep apnea (53 apnea-hypopnea index score), diet-controlled hypertension, prediabetes (6.3% hemoglobin A_1c), hypogonadism, and obesity (41 body mass index). Medications included semaglutide 1.7 mg injected subcutaneously weekly and testosterone 200 mg injected intramuscularly every 2 weeks, as well as lisinopril-hydrochlorothiazide 10 to 12.5 mg daily, which had recently been discontinued because his blood pressure had improved with a low-sodium diet.

A review of systems was unremarkable except for progressive weight gain. The patient had no family history of sudden cardiac death. On physical examination, the patient’s blood pressure was 119/81 mm Hg, pulse was 86 beats/min, and respiratory rate was 18 breaths/min. The patient was clinically euvolemic, with no jugular venous distention or peripheral edema, and his lungs were clear to auscultation. There was, however, a soft, nonradiating grade 2/6 systolic murmur that had not been previously documented. The murmur decreased substantially with the Valsalva maneuver, with no change in hand grip.

Laboratory studies revealed hemoglobin and renal function were within the reference range. A routine 12-lead electrocardiogram (ECG) was unremarkable. A transthoracic echocardiogram revealed moderate pulmonary hypertension (59 mm Hg right ventricular systolic pressure), asymmetric LV hypertrophy (2.1 cm septal thickness), and severe LVOT obstruction (131.8 mm Hg gradient). Severe systolic anterior motion of the mitral valve was also present. The LV ejection fraction was 60% to 65%, with normal cavity size and systolic function. These findings were consistent with severe hypertrophic obstructive cardiomyopathy (HOCM). Upon more detailed questioning, the patient reported that over the previous 5 years he had experienced gradually decreasing exercise tolerance and mild dyspnea on exertion, particularly in hot weather, which he attributed to weight gain. He also reported a presyncopal episode the previous month while working in his garage in hot weather for a prolonged period of time.

The patient’s elective colonoscopy was canceled, and he was referred to cardiology. While awaiting cardiac consultation, he was instructed to maintain good hydration and avoid any heavy physical activity beyond walking. He was told not to resume his use of lisinopril-hydrochlorothiazide. A screening 7-day Holter monitor showed no ventricular or supraventricular ectopy. After cardiology consultation, the patient was referred to a HCM specialty clinic, where a cardiac magnetic resonance imaging confirmed severe asymmetric hypertrophy with resting obstruction (Figures 1-4). Treatment options were discussed with the patient, and he underwent a trial with the Β—blocker metoprolol 50 mg daily, which he could not tolerate. Verapamil extended-release 180 mg orally once daily was then initiated; however, his dyspnea persisted. He was amenable to surgical therapy and underwent septal myectomy, with 12 g of septal myocardium removed. He did well postoperatively, with a follow-up echocardiogram showing normal LV systolic function and no LVOT gradient detectable at rest or with Valsalva maneuver. His fatigue and exertional dyspnea significantly improved. Once the patient underwent septal myectomy and was determined to have no detectable LVOT gradient, he was approved for colonoscopy which has been scheduled but not completed.

DISCUSSION

Once thought rare, HCM is now considered to be a relatively common inherited disorder, occurring in about 1 in 500 persons, with some suggesting that the actual prevalence is closer to 1 in 200 persons.^1,2 Most often caused by mutations in ≥ 1 of 11 genes responsible for encoding cardiac sarcomere proteins, HCM is characterized by abnormal LV thickening without chamber enlargement in the absence of any identifiable cause, such as aortic valve stenosis or uncontrolled hypertension. The hypertrophy is often asymmetric, and in cases of asymmetric septal hypertrophy, dynamic LVOT obstruction can occur (known as HOCM). The condition is inherited in an autosomal dominant pattern with variable expression and is associated with myocardial fiber disarray, which can occur years before symptom onset.³ This myocardial disarray can lead to remodeling and an increased wall-to-lumen ratio of the coronary arteries, resulting in impaired coronary reserve.

Depending on the degree of LVOT obstruction, patients with HCM may be classified as nonobstructive, labile, or obstructive at rest. Patients without obstruction have an outflow gradient ≤ 30 mm Hg that is not provoked with Valsalva maneuver, administration of amyl nitrite, or exercise treadmill testing.³ Patients classified as labile do not have LVOT obstruction at rest, but obstruction may be induced by provocative measures. Finally, about one-third of patients with HCM will have LVOT gradients of > 30 mm Hg at rest. These patients are at increased risk for progression to symptomatic heart failure and may be candidates for surgical myectomy or catheter-based alcohol septal ablation.⁴ The patient in this case had a resting LVOT gradient of 131.8 mm Hg on echocardiography. The magnitude of this gradient placed the patient at a significantly higher risk of ventricular dysrhythmias and sudden cardiac death.⁵

Wall thickness also has prognostic implications. ⁶ Although any area of the myocardium can be affected, the septum is involved in about 90% cases. In their series of 48 patients followed over 6.5 years, Spirito et al found that the risk of sudden death in patients with HCM increased as wall thickness increased. For patients with a wall thickness of < 15 mm, the risk of death was 0 per 1000 person-years; however, this increased to 18.2 per 1000 person-years for patients with a wall thickness of > 30 mm.⁷

While many patients with HCM are asymptomatic, others may report dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, presyncope/ syncope, postural lightheadedness, fatigue, or edema. Symptomatology, however, is quite variable and does not necessarily correlate with the degree of outflow obstruction. Surprisingly, some patients with significant LVOT may have minimal symptoms, such as the patient in this case, while others with a lesser degree of LVOT obstruction may be very symptomatic.^3,4

Physical examination of a patient with HCM may be normal or may reveal nonspecific findings such as a fourth heart sound or a systolic murmur. In general, physical examination abnormalities are related to LVOT obstruction. Those patients without significant outflow obstruction may have a normal cardiac examination. While patients with HCM may have a variety of systolic murmurs, the 2 most common are those related to outflow tract obstruction and mitral regurgitation caused by systolic anterior motion of the mitral valve.⁴ The systolic murmur associated with significant LVOT obstruction has been described as a harsh, crescendo-decrescendo type that begins just after S1 and is heard best at the apex and lower left sternal border.⁴ It may radiate to the axilla and base but not generally into the neck. The murmur usually increases with Valsalva maneuver and decreases with handgrip or going from a standing to a sitting/ squatting position. The initial examination of the patient in this case was not suggestive of HOCM, as confirmed by 2 practitioners (a cardiologist and an internist), each with > 30 years of clinical experience. This may have been related to the patient’s hydration status at the time, with Valsalva maneuver increasing obstruction to the point of reduced flow.

About 90% of patients with HCM will have abnormalities on ECG, most commonly LV hypertrophy with a strain pattern. Other ECG findings include: (1) prominent abnormal Q waves, particularly in the inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6), reflecting depolarization of a hypertrophied septum; (2) left axis deviation; (3) deeply inverted T waves in leads V2 through V4; and (4) P wave abnormalities indicative of left atrial (LA) or biatrial enlargement. ⁸ It is notable that the patient in this case had a normal ECG, given that a minority of patients with HCM have been shown to have a normal ECG.⁹

Echocardiography plays an important role in diagnosing HCM. Diagnostic criteria include the presence of asymmetric hypertrophy (most commonly with anterior septal involvement), systolic anterior motion of the mitral valve, a nondilated LV cavity, septal immobility, and premature closure of the aortic valve. LV thickness is measured at both the septum and free wall; values ≥ 15 mm, with a septal-to-free wall thickness ratio of ≥ 1.3, are suggestive of HCM. Asymmetric LV hypertrophy can also be seen in other segments besides the septum, such as the apex.¹⁰

HCM/HOCM is the most common cause of sudden cardiac death in young people. The condition also contributes to significant functional morbidity due to heart failure and increases the risk of atrial fibrillation and subsequent stroke. Treatments tend to focus on symptom relief and slowing disease progression and include the use of medications such as Β—blockers, nondihydropyridine calcium channel blockers, and the myosin inhibitor mavacamten.¹¹ Select patients, such as those with severe LVOT obstruction and symptoms despite treatment with Β—blockers or nondihydropyridine calcium channel blockers, may be offered septal myectomy or catheter-based alcohol septal ablation, coupled with insertion of an implantable cardiac defibrillator to prevent sudden cardiac death in patients at high arrhythmic risk.^1,12

Patients with HCM, particularly those with LVOT obstruction, pose distinct challenges to the anesthesiologist because they are highly sensitive to decreases in preload and afterload. These patients frequently experience adverse perioperative events such as myocardial ischemia, systemic hypotension, and supraventricular or ventricular arrhythmias. Acute congestive heart failure may also occur, presumably due to concomitant diastolic dysfunction. Patients with previously unrecognized HCM are of particular concern, as they may manifest unexpected and sudden hypotension with the induction of anesthesia. There may then be a paradoxical response to vasoactive drugs and anesthetic agents, which accentuate LVOT obstruction. In these circumstances, undiagnosed HCM should be considered, and intraoperative rescue transesophageal echocardiography be performed.¹³ Once the diagnosis is confirmed, efforts should be made to reduce myocardial contractility and sympathetic discharge (eg, with Β—blockers), increase afterload (eg, with α1 agonists), and improve preload with adequate hydration. Proper resuscitation of hypotensive patients with HCM requires a thorough understanding of disease pathology, as effective interventions may seem to be counterintuitive. Inotropic agents such as epinephrine are contraindicated in HCM because increased inotropy and chronotropy worsen LVOT obstruction. Volume status is often tenuous; while adequate preload is important, overly aggressive fluid resuscitation may promote heart failure. It is important to keep in mind that even patients without resting LVOT obstruction may develop dynamic obstruction with anesthesia induction due to sudden reductions in preload and afterload. It is also important to note that the degree of LV hypertrophy is directly correlated with arrhythmic sudden death. Those patients with LV wall thickness ≥ 30 mm are at increased risk for potentially lethal tachyarrhythmias in the operating room.¹⁴

These considerations reinforce the need for proper preoperative identification of patients with HCM. Heightened awareness is key, given the fact that HCM is relatively common and tends to be underdiagnosed in the general population. These patients are generally young, otherwise healthy, and often undergo minor operative procedures in outpatient settings. It is incumbent upon the preoperative evaluator to take a thorough medical history and perform a careful physical examination. Clues to the diagnosis include exertional dyspnea, fatigue, angina, syncope/presyncope, or a family history of sudden cardiac death or HCM. A systolic ejection murmur, particularly one that increases with standing or Valsalva maneuver, and decreases with squatting or handgrip may also raise clinical suspicion. These patients should undergo a full cardiac evaluation, including echocardiography.

CONCLUSIONS

HCM is a common condition that is important to diagnose in the preoperative clinic. Failure to do so can lead to catastrophic complications during induction of anesthesia due to the sudden reduction in preload and afterload, which may cause a significant increase in LVOT obstruction. A high index of suspicion is essential, as clinical diagnosis can be challenging. The physical examination may be deceiving and symptoms are often subtle and nonspecific. It is imperative to alert the anesthesiologist before surgery so the complex hemodynamic management of patients with HOCM can be appropriately managed.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

Muscle-related complaints occur in 7% to 25% of patients taking statin medications.¹ In most instances, these adverse effects are quickly resolved when the medication is discontinued, but in rare occurrences, the statin can trigger an autoimmune response that progresses even after stopping use. This uncommon condition is typically accompanied by symmetrical proximal muscle weakness and an elevated CPK leading to a necrotizing myopathy requiring treatment with immunosuppressive therapy. Although less common, some patients may also present with dysphagia, myalgia, weight loss, and/or skin rash.¹

Statin medications have been the cornerstone of lipid-lowering therapy due to their mechanism of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which is the rate-limiting step within the cholesterol synthesis pathway to produce mevalonic acid. There is a proven genetic association with human leukocyte antigen (HLA)-DRB1*11:01 in adults and anti-HMGCR–associated myopathy.¹ The incidence of statin-induced necrotizing autoimmune myopathy (SINAM) in relation to each specific statin agent remains unknown; however, a systematic review of case reports found higher correlations for atorvastatin and simvastatin.²

There are 2 ways to confirm a SINAM diagnosis. The first and simplest includes checking for the presence of antibodies against HMGCR. The anti-HMGCR antibody test is typically used as a definitive diagnosis because it has a high specificity for SINAM.³ The second and more invasive diagnosis method involves a muscle biopsy, which is identified as positive if the biopsy shows the presence of necrotic muscle fibers.^1,3

The anti-HMGCR antibody test can serve as a marker for disease activity because the antibodies are strongly correlated with CPK levels.¹ CPK levels indicate the severity of muscle injury and is often used in addition to either of the confirmatory tests because it is faster and less expensive. Anti-HMGCR titers may remain positive while CPK returns to baseline when SINAM is dormant. In addition, clinicians may use an electromyography (EMG) test to measure the muscle response in association to nerve stimulation. ¹ This test can show potential features of myopathic lesions such as positive sharp waves, spontaneous fibrillations, or myotonic repetitive potentials.

Typical treatment includes glucocorticoids as first-line agents, but SINAM can be difficult to treat due to its complicated pathophysiology processes.³ Escalation of therapy is sometimes required beyond a single agent; in these complex scenarios, methotrexate and/or intravenous (IV) immunoglobulin (IVIG) therapy are frequently added to the steroid therapy. There have been concerns with steroid use in specific patient populations due to the undesired adverse effect (AE) profile, and as a result IVIG has been used as monotherapy at a dose of 2 g/kg per month.³ Studies looking at IVIG monotherapy showed a reduction in CPK levels and improvement in strength after just 2 to 3 rounds of monthly treatment.³ Some patients receiving IVIG monotherapy even achieved baseline strength and no longer reported muscle-related symptoms, although the total treatment duration varied. A systematic review of 39 articles where glucocorticoids, IVIG, methotrexate and/or a combination were used to treat SINAM found an average time to remission of 8.6 months. Additionally, this systematic review observed more patients returned to baseline or experienced improvement in symptoms when being treated with a combination of glucocorticoid plus IVIG plus methotrexate.² Suggested dosing recommendations are available in Table 1.

Patients diagnosed with HMGCR antibody myopathy are contraindicated for future statin therapy.¹ Rechallenge of statins in this patient population has led to worsening of disease and therefore these patients should have a severe statin allergy listed in their medical documentation record.

CASE PRESENTATION

A 59-year-old male patient with a medical history including atrial fibrillation, peripheral vascular disease, type 2 diabetes mellitus (T2DM), hypertension, and peripheral neuropathy was referred by his primary care clinical pharmacist practitioner for an outpatient neurology consult. The patient reported a 4-month history of fatigue, lower extremity paresthesia, and progressive proximal muscle weakness which began in his legs, mostly noticeable when walking upstairs but quickly developed into bilateral arm weakness. The patient reported significant impact on his quality of life: he could no longer lift his arms above his head and had difficulty with daily activities such as brushing his hair or getting up from a chair. He reported multiple falls at home, and began to use a cane for assistance with ambulation. He confirmed adherence to atorvastatin over the past year. Laboratory testing on the day of the visit revealed an elevated CPK level at 9729 mcg/L (reference range for men, 30-300 mcg/L).

The patient was urged to go to the emergency department where his CPK level had increased to 12,990 mcg/L (Figure 1). The workup began to find the source of rhabdomyolysis and elevated liver enzymes differentiating autoimmune vs medication-induced myopathy. Upon admission atorvastatin was discontinued, anti-HMGCR antibody level was ordered, and IV fluids were started.

After 8 days of hospital admission with minimal improvement, Rheumatology and Neurology services were consulted in the setting of persistent CPK elevation and the potential neuropathic component of muscle weakness. Both consulting services agreed to consider muscle biopsy and EMG if the patient did not begin to show signs of improvement. The patient’s CPK levels remained elevated with minimal change in muscle weakness. The next step was a right quadricep muscle biopsy performed on Day 14 of admission. Sixteen days after admission, the anti-HMGCR antibody test (originally obtained upon admission) was positive and elevated at 249 CU/mL (reference range, < 20 CU/mL negative; reference range, ≥ 60 CU/mL strong positive), which confirmed the SINAM diagnosis (Table 2).

On Day 17 of hospitalization, the Neurology service initiated IVIG monotherapy to avoid the undesired glycemic AEs associated with glucocorticoids. The patient had a history of T2DM that was difficult to manage and his hemoglobin A_1c level was the best it had ever been (6.2%) relative to a peak A_1c of 11.0% 9 months prior. The patient was treated with a total IVIG dose of 2 g/kg divided into 3 daily doses while still obtaining CPK levels with daily laboratory tests to assist with trending the extent of disease severity improvement (Figures 2-4). After a 20-day hospital stay, the patient was discharged home with rehabilitation services and a scheduled outpatient EMG the following week.

The patient continued to report generalized body weakness, pain, and deconditioning upon discharge and was unable to attend the EMG neurology appointment. The patient did eventually attend a follow-up appointment about 6 weeks after hospital discharge and reported continued weakness. The Neurology service prescribed a 2-day IVIG regimen (total dose = 2 g/kg) monthly for the next 2 months. The patient returned to the neurology clinic 8 weeks later following 2 rounds of IVIG posthospitalization and reported that his muscle strength was returning, and he was able to slowly reintroduce exercise into his daily routine. During a follow-up appointment about 11 months after the initial hospitalization, the patient’s primary care clinical pharmacist provided education of effective management of cholesterol without statins, including use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as recommended by the Neurology service. At this time, the patient’s calculated low-density lipoprotein (LDL) was 110 mg/dL (reference range, 0-99 mg/dL). The patient preferred to work on a healthy diet and positive lifestyle choices before trialing any lipid lowering therapies.

The patient appeared to tolerate this treatment regimen following 7 rounds of IVIG. He noted fatigue for about 24 hours after his infusion sessions but otherwise reported no additional AEs. He has continued to attend weekly physical therapy sessions and is able to walk without the assistance of a cane. He can now walk a mile before he begins to feel fatigued or experience bilateral lower leg pain. The pain appears neuropathic in nature, as the patient reports ongoing “pins and needles” sensation in his legs and feet. The patient has noticed a major improvement in his overall function, strength, and exercise tolerance since starting IVIG treatments and although he is not yet back to his baseline, he is motivated to continue his recovery. Neurology is considering ongoing treatment with IVIG monthly infusions given his continued clinical improvement.

DISCUSSION

There is limited evidence on the use of IVIG monotherapy for SINAM, although it may be a viable option for patients deemed poor candidates for glucocorticoid or methotrexate therapy. This particularly applies to patients with DM for which there may be concerns for managing blood glucose levels with steroid use. The Johns Hopkins Myositis Center evaluated 3 patients with SINAM who declined glucocorticoid therapy and had documented DM and weakness in the proximal arms and legs. Following 2 to 3 monthly rounds of IVIG 2 g/kg monotherapy, these patients had reduced CPK levels and had improvement in both arm and hip-flexion strength. Two patients reported no muscle-related symptoms after completing IVIG monotherapy treatment for 9 and 19 months.³

The optimal treatment duration for IVIG monotherapy for SINAM is still uncertain given the limited available data. The patient in this case report showed clinically significant muscle-related improvement following 7 monthly rounds of 2 g/kg IVIG treatments. The mechanism of action for IVIG in this setting is still unknown, although the medication may allow muscle regeneration to surpass muscle destruction, thus leading to resolution of the muscle-related symptoms.³

There are numerous concerns with IVIG use to consider prior to initiating treatment, including expense, AEs, patient response, and comorbidities. IVIG is considerably more expensive than glucocorticoid and methotrexate alternatives. Systemic reactions have been shown to occur in 5% to 15% of patients receiving IVIG infusion.⁴ The majority of these infusion reactions occur early during infusion or within a few hours after administration is complete.⁵ Early AEs to monitor for include injection site reactions, flu-like symptoms, dermatologic reactions, anaphylaxis, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Additional AEs may be delayed, including thromboembolic events, acute kidney injury, aseptic meningitis, hemolysis, neutropenia, and blood-borne infection.⁶ IVIG has a boxed warning for thrombosis, renal dysfunction, and acute renal failure risk.⁷ There are multiple strategies documented to reduce the risk of IVIG reactions including slowing the infusion rate, ensuring adequate hydration, and/or giving analgesics, antihistamines, or steroids prior to infusion.⁶ The patient in this case had monthly IVIG infusions without the need of any pretreatment medications and only reported fatigue for about 24 hours following the infusion.

An essential question is how to provide safe cholesterol management for patients with SINAM. Some evidence has suggested that other lipid-lowering medications that avoid the mevalonate pathway, such as fenofibrate or ezetimibe, may be used cautiously initially at lower doses.¹ Due to the severity of SINAM, it is crucial to closely monitor and ensure tolerability as new lipid-lowering agents are introduced. More evidence suggests that PCSK9 inhibitors are a safer option.⁸ PCSK9 inhibitors avoid the mevalonate pathway and block PCSK9 from binding to LDL receptors, allowing LDL to be removed from circulation.

Tiniakou et al followed 8 individuals for a mean 1.5 years who had anti-HMGCR immune-mediated myopathy at high cardiovascular risk. Muscle strength, CPK levels, and serum anti-HMGCR antibody titers were assessed at baseline and again after initiation of PCSK9 inhibitor. None of the patients experienced a decline in their muscle strength. CPK, anti-HMGCR antibody levels, and LDL trended down in all participants and 2 patients were able to reduce their immunosuppression treatment while still achieving clinical improvement. Tiniakou et al suggest that PCSK9 inhibitors are a safe and effective option to lower cholesterol in patients with SINAM.⁸

Alirocumab is the preferred PCSK9 inhibitor for patients at the US Department of Veterans Affairs (VA). The VA Pharmacy Benefits Management (PBM) Service guidance recommends alirocumab for patients with a history of atherosclerotic cardiovascular disease (ASCVD) or severe hypercholesterolemia.⁹ PBM guidance suggests alirocumab use for patients with a contraindication, intolerance, or insufficient LDL reduction with a maximally tolerated dose of statin and ezetimibe with a desire to reduce ASCVD risk by lowering LDL. Per the PBM Criteria for Use guidance, patients should follow the stepwise approach and trial ezetimibe prior to being considered for PCSK9 inhibitor therapy. Given the patient’s contraindication to future statin use and severity of myopathy, in this case the Neurology Service felt that the safest option to reach goal LDL reduction would be a PCSK9 inhibitor. Consideration can be made for alirocumab use when considering an alternative lipid lowering therapy.

CONCLUSIONS

This report demonstrates a case of SINAM caused by atorvastatin therapy. Patients presenting with proximal muscle weakness and elevated CPK even after statin discontinuation should be considered for a full workup to determine whether SINAM may be involved. This uncommon form of myopathy can be diagnosed based on the detection of anti-HMGCR antibodies and/or presence of necrosis on muscle biopsy. A combination of glucocorticoid, methotrexate, and IVIG is recommended for a patient’s best chance of muscle symptom improvement. IVIG monotherapy should be considered for patients with glycemic control concerns.

The US Department of Veterans Affairs (VA) delivers care to > 9 million veterans, including primary and specialty care.¹ While clinical duties remain important across the health system, proposed productivity models have included clinician research activity, given that many hold roles in academia.² Within this framework, research plays a pivotal role in advancing clinical practices and outcomes. Studies have found that physicians who participated in research report higher job satisfaction.³

As a specialty within the VA, podiatrists diagnose, treat, and prevent foot and ankle disorders. In addition to clinical practice, various scholarly activities are shared among these physicians.⁴ Reasons for scholarly pursuits among podiatrists vary, including participation in research for academic promotion or to establish expertise in a given area.^4-7 Although research remains a component associated with promotion within the VA, little is known about the scholarly activity of VA podiatrists. Specifically, there remains a paucity of data concerning their expertise, as evidenced through peer-reviewed publications, among these physicians and surgeons. To date, no analysis of scholarly activity among VA podiatrists has been conducted.

The primary aim of this investigation was to describe the scholarly productivity among podiatrists employed by the VA through an analysis of the number of peer-reviewed publications and the respective h-index of each physician. The secondary aim of this investigation was to assess the effect of academic productivity on compensation. This study describes research activities pursued by VA physicians and provides the veteran patient population with the confidence that their foot health care remains in the hands of experts within the field.

MATERIALS AND METHODS

The Feds Data Center (www.fedsdatacenter.com) online database of employees was used to identify VA podiatrists on June 17, 2024. All GS-15 physicians and their respective salaries in fiscal year 2023 were recorded. Administratively determined employees, including residents, were excluded. The h-index and number of published documents from any point during a physician’s training or career were reported for each podiatrist using Scopus; podiatrists without an h-index or publication were excluded. ⁸ Among podiatrists with scholarly activity, this analysis collected academic appointment, sex, and region of practice.

Statistical Analysis

Descriptive statistics, presented as counts and frequencies, were used. The median and IQR were used to describe the number of publications and h-index due to their nonnormal distribution. A Kruskal-Wallis test was used to compare median publication counts and h-index values among for junior faculty (JF), which includes instructors and assistant professors; senior faculty (SF), which includes associate professors and professors; and those with no academic affiliation (NF). Salary was reported as mean (SD) as it remained normally distributed and was compared using analysis of variance with posthoc Tukey test to increase statistical power. Additionally, this analysis used linear regression to investigate the relationship between scholarly activity and salary. The threshold for statistical significance was set at P < .05.

RESULTS

Among 819 VA podiatrists, 150 were administratively determined and excluded, and 512 were excluded for no history of publications, leaving 157 eligible for analysis (Table). A statistically significant difference was found in median (IQR) publication count by faculty appointment. JF had 6.0 (9.5), SF had 12.5 (22.3), and NF had 1.0 (2.0) publication(s) (P < .001) (Figure 1A). There was a statistically significant difference in h-index by faculty appointment. The median (IQR) h-index for JF was 2.0 (3.5), for SF was 5.5 (4.25), and for NF was 1.0 (2.0) (P = .002) (Figure 1B). Salary was not significantly associated with publication count (P = .20) or h-index (P = .62) (Figure 2). No statistically significant difference was found between academic appointment and mean (SD) salary. JF had a median (IQR) salary of $224,063 (27,989), SF of $234,260 (42,963), and NF of $219,811 (P = .35).

DISCUSSION

Focused on providing high-quality care, VA physicians use their expertise to practice comprehensive and specialized care.^9,10 A cornerstone to this expertise is scholarly activity that contributes to the body of knowledge and, ultimately, the evidence-based medicine by which these physicians practice.¹¹ With veterans considering VA care, it is important to highlight the commitment and dedication to the science and the practice of medicine. This analysis describes the scholarly activity of VA podiatrists and underscores the expertise veterans will receive for the diagnosis and treatment of their foot and ankle pathology.

were not part of an academic facility, a finding that may encourage further action to increase academic productivity in this specialty. For example, collaboration through academic affiliations has been seen throughout VA medical and surgical specialties and provides many benefits. Beginning with graduate medical education, the VA serves as a tremendous resource for resident training.¹² Additionally, veterans who sought emergency care at the VA had a lower risk of death than those treated at non-VA hospitals.¹³ In podiatric medicine and surgery, scholarly activity has been linked to improved outcomes, particularly in the study of ulceration development and its role in either prolonging or preventing amputation.¹⁴

Beyond improving clinical outcomes and patient care, engagement in research and inquiry offers other benefits. A cross-sectional study of 7734 physicians within the VA found that research involvement was associated with more favorable job characteristics and job satisfaction perceptions. ³ While this analysis found that about 19% of podiatrists have published once in their career, it remains likely that more may continue to engage in research during their VA tenure. Although this finding shows that an appreciable number of VA podiatrists have published in their field of study, it also encourages departments to provide resources to engage in research. Similar to previous research among foot and ankle surgeons, this analysis also found an increase in publications and h-index as tenure increased.⁴ Unlike previous research, which found h-index and academic appointment to be contributors to VA dermatologists’ salaries, no significant difference in salary was found in this study associated with publications, h-index, or academic role.¹⁵ Although the increase was not statistically significant, salary tended to rise as these variables increased.

Limitations

This analysis was confined to the most recent year of available data, which may not fully capture the longitudinal academic contributions and trends of individual podiatrists. Academic productivity can fluctuate significantly over time due to various factors, including changes in research focus and administrative responsibilities. The study also relied on Scopus to identify and quantify academic productivity. This database may not include all publications relevant to podiatrists, particularly those in niche or nonindexed journals. Additionally, name variations and potential misspellings could lead to missing data for individual podiatrists’ publications. Furthermore, this study did not account for other significant contributors to salary and career advancement within the federal system. Factors such as clinical performance, administrative duties, patient satisfaction, and contributions to teaching and mentoring are critical elements that also influence career progression and compensation but were not captured in this analysis. The retrospective design of this study inherently limits the ability to establish causal relationships. While associations between academic productivity and certain outcomes may be identified, it is not possible to definitively determine the direction or causality of these relationships. Future research may examine how scholarly activity continues once a clinician is part of VA.

CONCLUSIONS

This study highlights the significant academic contributions of VA podiatrists to research and the medical literature. By fostering an active research environment, the VA can ensure veterans receive the highest quality of care from knowledgeable and expert clinicians. Future research should aim to provide a more comprehensive analysis, capturing long-term trends and considering all factors influencing career advancement in VA.

The US Department of Veterans Affairs (VA) delivers care to > 9 million veterans, including primary and specialty care.¹ While clinical duties remain important across the health system, proposed productivity models have included clinician research activity, given that many hold roles in academia.² Within this framework, research plays a pivotal role in advancing clinical practices and outcomes. Studies have found that physicians who participated in research report higher job satisfaction.³

As a specialty within the VA, podiatrists diagnose, treat, and prevent foot and ankle disorders. In addition to clinical practice, various scholarly activities are shared among these physicians.⁴ Reasons for scholarly pursuits among podiatrists vary, including participation in research for academic promotion or to establish expertise in a given area.^4-7 Although research remains a component associated with promotion within the VA, little is known about the scholarly activity of VA podiatrists. Specifically, there remains a paucity of data concerning their expertise, as evidenced through peer-reviewed publications, among these physicians and surgeons. To date, no analysis of scholarly activity among VA podiatrists has been conducted.

The primary aim of this investigation was to describe the scholarly productivity among podiatrists employed by the VA through an analysis of the number of peer-reviewed publications and the respective h-index of each physician. The secondary aim of this investigation was to assess the effect of academic productivity on compensation. This study describes research activities pursued by VA physicians and provides the veteran patient population with the confidence that their foot health care remains in the hands of experts within the field.

MATERIALS AND METHODS

The Feds Data Center (www.fedsdatacenter.com) online database of employees was used to identify VA podiatrists on June 17, 2024. All GS-15 physicians and their respective salaries in fiscal year 2023 were recorded. Administratively determined employees, including residents, were excluded. The h-index and number of published documents from any point during a physician’s training or career were reported for each podiatrist using Scopus; podiatrists without an h-index or publication were excluded. ⁸ Among podiatrists with scholarly activity, this analysis collected academic appointment, sex, and region of practice.

Statistical Analysis

Descriptive statistics, presented as counts and frequencies, were used. The median and IQR were used to describe the number of publications and h-index due to their nonnormal distribution. A Kruskal-Wallis test was used to compare median publication counts and h-index values among for junior faculty (JF), which includes instructors and assistant professors; senior faculty (SF), which includes associate professors and professors; and those with no academic affiliation (NF). Salary was reported as mean (SD) as it remained normally distributed and was compared using analysis of variance with posthoc Tukey test to increase statistical power. Additionally, this analysis used linear regression to investigate the relationship between scholarly activity and salary. The threshold for statistical significance was set at P < .05.

RESULTS

Among 819 VA podiatrists, 150 were administratively determined and excluded, and 512 were excluded for no history of publications, leaving 157 eligible for analysis (Table). A statistically significant difference was found in median (IQR) publication count by faculty appointment. JF had 6.0 (9.5), SF had 12.5 (22.3), and NF had 1.0 (2.0) publication(s) (P < .001) (Figure 1A). There was a statistically significant difference in h-index by faculty appointment. The median (IQR) h-index for JF was 2.0 (3.5), for SF was 5.5 (4.25), and for NF was 1.0 (2.0) (P = .002) (Figure 1B). Salary was not significantly associated with publication count (P = .20) or h-index (P = .62) (Figure 2). No statistically significant difference was found between academic appointment and mean (SD) salary. JF had a median (IQR) salary of $224,063 (27,989), SF of $234,260 (42,963), and NF of $219,811 (P = .35).

DISCUSSION

Focused on providing high-quality care, VA physicians use their expertise to practice comprehensive and specialized care.^9,10 A cornerstone to this expertise is scholarly activity that contributes to the body of knowledge and, ultimately, the evidence-based medicine by which these physicians practice.¹¹ With veterans considering VA care, it is important to highlight the commitment and dedication to the science and the practice of medicine. This analysis describes the scholarly activity of VA podiatrists and underscores the expertise veterans will receive for the diagnosis and treatment of their foot and ankle pathology.

were not part of an academic facility, a finding that may encourage further action to increase academic productivity in this specialty. For example, collaboration through academic affiliations has been seen throughout VA medical and surgical specialties and provides many benefits. Beginning with graduate medical education, the VA serves as a tremendous resource for resident training.¹² Additionally, veterans who sought emergency care at the VA had a lower risk of death than those treated at non-VA hospitals.¹³ In podiatric medicine and surgery, scholarly activity has been linked to improved outcomes, particularly in the study of ulceration development and its role in either prolonging or preventing amputation.¹⁴

Beyond improving clinical outcomes and patient care, engagement in research and inquiry offers other benefits. A cross-sectional study of 7734 physicians within the VA found that research involvement was associated with more favorable job characteristics and job satisfaction perceptions. ³ While this analysis found that about 19% of podiatrists have published once in their career, it remains likely that more may continue to engage in research during their VA tenure. Although this finding shows that an appreciable number of VA podiatrists have published in their field of study, it also encourages departments to provide resources to engage in research. Similar to previous research among foot and ankle surgeons, this analysis also found an increase in publications and h-index as tenure increased.⁴ Unlike previous research, which found h-index and academic appointment to be contributors to VA dermatologists’ salaries, no significant difference in salary was found in this study associated with publications, h-index, or academic role.¹⁵ Although the increase was not statistically significant, salary tended to rise as these variables increased.

Limitations

This analysis was confined to the most recent year of available data, which may not fully capture the longitudinal academic contributions and trends of individual podiatrists. Academic productivity can fluctuate significantly over time due to various factors, including changes in research focus and administrative responsibilities. The study also relied on Scopus to identify and quantify academic productivity. This database may not include all publications relevant to podiatrists, particularly those in niche or nonindexed journals. Additionally, name variations and potential misspellings could lead to missing data for individual podiatrists’ publications. Furthermore, this study did not account for other significant contributors to salary and career advancement within the federal system. Factors such as clinical performance, administrative duties, patient satisfaction, and contributions to teaching and mentoring are critical elements that also influence career progression and compensation but were not captured in this analysis. The retrospective design of this study inherently limits the ability to establish causal relationships. While associations between academic productivity and certain outcomes may be identified, it is not possible to definitively determine the direction or causality of these relationships. Future research may examine how scholarly activity continues once a clinician is part of VA.

CONCLUSIONS

This study highlights the significant academic contributions of VA podiatrists to research and the medical literature. By fostering an active research environment, the VA can ensure veterans receive the highest quality of care from knowledgeable and expert clinicians. Future research should aim to provide a more comprehensive analysis, capturing long-term trends and considering all factors influencing career advancement in VA.

The US Department of Veterans Affairs (VA) delivers care to > 9 million veterans, including primary and specialty care.¹ While clinical duties remain important across the health system, proposed productivity models have included clinician research activity, given that many hold roles in academia.² Within this framework, research plays a pivotal role in advancing clinical practices and outcomes. Studies have found that physicians who participated in research report higher job satisfaction.³

As a specialty within the VA, podiatrists diagnose, treat, and prevent foot and ankle disorders. In addition to clinical practice, various scholarly activities are shared among these physicians.⁴ Reasons for scholarly pursuits among podiatrists vary, including participation in research for academic promotion or to establish expertise in a given area.^4-7 Although research remains a component associated with promotion within the VA, little is known about the scholarly activity of VA podiatrists. Specifically, there remains a paucity of data concerning their expertise, as evidenced through peer-reviewed publications, among these physicians and surgeons. To date, no analysis of scholarly activity among VA podiatrists has been conducted.

The primary aim of this investigation was to describe the scholarly productivity among podiatrists employed by the VA through an analysis of the number of peer-reviewed publications and the respective h-index of each physician. The secondary aim of this investigation was to assess the effect of academic productivity on compensation. This study describes research activities pursued by VA physicians and provides the veteran patient population with the confidence that their foot health care remains in the hands of experts within the field.

MATERIALS AND METHODS

The Feds Data Center (www.fedsdatacenter.com) online database of employees was used to identify VA podiatrists on June 17, 2024. All GS-15 physicians and their respective salaries in fiscal year 2023 were recorded. Administratively determined employees, including residents, were excluded. The h-index and number of published documents from any point during a physician’s training or career were reported for each podiatrist using Scopus; podiatrists without an h-index or publication were excluded. ⁸ Among podiatrists with scholarly activity, this analysis collected academic appointment, sex, and region of practice.

Statistical Analysis

Descriptive statistics, presented as counts and frequencies, were used. The median and IQR were used to describe the number of publications and h-index due to their nonnormal distribution. A Kruskal-Wallis test was used to compare median publication counts and h-index values among for junior faculty (JF), which includes instructors and assistant professors; senior faculty (SF), which includes associate professors and professors; and those with no academic affiliation (NF). Salary was reported as mean (SD) as it remained normally distributed and was compared using analysis of variance with posthoc Tukey test to increase statistical power. Additionally, this analysis used linear regression to investigate the relationship between scholarly activity and salary. The threshold for statistical significance was set at P < .05.

RESULTS

Among 819 VA podiatrists, 150 were administratively determined and excluded, and 512 were excluded for no history of publications, leaving 157 eligible for analysis (Table). A statistically significant difference was found in median (IQR) publication count by faculty appointment. JF had 6.0 (9.5), SF had 12.5 (22.3), and NF had 1.0 (2.0) publication(s) (P < .001) (Figure 1A). There was a statistically significant difference in h-index by faculty appointment. The median (IQR) h-index for JF was 2.0 (3.5), for SF was 5.5 (4.25), and for NF was 1.0 (2.0) (P = .002) (Figure 1B). Salary was not significantly associated with publication count (P = .20) or h-index (P = .62) (Figure 2). No statistically significant difference was found between academic appointment and mean (SD) salary. JF had a median (IQR) salary of $224,063 (27,989), SF of $234,260 (42,963), and NF of $219,811 (P = .35).

DISCUSSION

Focused on providing high-quality care, VA physicians use their expertise to practice comprehensive and specialized care.^9,10 A cornerstone to this expertise is scholarly activity that contributes to the body of knowledge and, ultimately, the evidence-based medicine by which these physicians practice.¹¹ With veterans considering VA care, it is important to highlight the commitment and dedication to the science and the practice of medicine. This analysis describes the scholarly activity of VA podiatrists and underscores the expertise veterans will receive for the diagnosis and treatment of their foot and ankle pathology.

were not part of an academic facility, a finding that may encourage further action to increase academic productivity in this specialty. For example, collaboration through academic affiliations has been seen throughout VA medical and surgical specialties and provides many benefits. Beginning with graduate medical education, the VA serves as a tremendous resource for resident training.¹² Additionally, veterans who sought emergency care at the VA had a lower risk of death than those treated at non-VA hospitals.¹³ In podiatric medicine and surgery, scholarly activity has been linked to improved outcomes, particularly in the study of ulceration development and its role in either prolonging or preventing amputation.¹⁴

Beyond improving clinical outcomes and patient care, engagement in research and inquiry offers other benefits. A cross-sectional study of 7734 physicians within the VA found that research involvement was associated with more favorable job characteristics and job satisfaction perceptions. ³ While this analysis found that about 19% of podiatrists have published once in their career, it remains likely that more may continue to engage in research during their VA tenure. Although this finding shows that an appreciable number of VA podiatrists have published in their field of study, it also encourages departments to provide resources to engage in research. Similar to previous research among foot and ankle surgeons, this analysis also found an increase in publications and h-index as tenure increased.⁴ Unlike previous research, which found h-index and academic appointment to be contributors to VA dermatologists’ salaries, no significant difference in salary was found in this study associated with publications, h-index, or academic role.¹⁵ Although the increase was not statistically significant, salary tended to rise as these variables increased.

Limitations

This analysis was confined to the most recent year of available data, which may not fully capture the longitudinal academic contributions and trends of individual podiatrists. Academic productivity can fluctuate significantly over time due to various factors, including changes in research focus and administrative responsibilities. The study also relied on Scopus to identify and quantify academic productivity. This database may not include all publications relevant to podiatrists, particularly those in niche or nonindexed journals. Additionally, name variations and potential misspellings could lead to missing data for individual podiatrists’ publications. Furthermore, this study did not account for other significant contributors to salary and career advancement within the federal system. Factors such as clinical performance, administrative duties, patient satisfaction, and contributions to teaching and mentoring are critical elements that also influence career progression and compensation but were not captured in this analysis. The retrospective design of this study inherently limits the ability to establish causal relationships. While associations between academic productivity and certain outcomes may be identified, it is not possible to definitively determine the direction or causality of these relationships. Future research may examine how scholarly activity continues once a clinician is part of VA.

CONCLUSIONS

This study highlights the significant academic contributions of VA podiatrists to research and the medical literature. By fostering an active research environment, the VA can ensure veterans receive the highest quality of care from knowledgeable and expert clinicians. Future research should aim to provide a more comprehensive analysis, capturing long-term trends and considering all factors influencing career advancement in VA.