Imaging

A 76-year-old man whose history included abdominal aortic aneurysm repair, bilateral femoral artery bypass for popliteal artery aneurysm, hypertension, and peptic ulcer disease was admitted to a community hospital with pleuritic chest pain and shortness of breath. Two days earlier, he had undergone repair of a ventral hernia.

At the time of that admission, he reported no fever, chills, night sweats, cough, or history of heart or lung disease. His vital signs were normal, and physical examination had revealed no apparent respiratory distress, no jugular venous distention, normal heart sounds, and no pedal edema; however, decreased air entry was noted in the right lung base. Initial serum levels of troponin and N-terminal pro-B-type natriuretic peptide were normal.

At that time, computed tomographic angiography of the chest showed segmental pulmonary emboli in the left upper and right lower lobes of the lungs and right pleural effusion. Transthoracic echocardiography showed normal atrial and ventricular sizes with no right or left ventricular systolic dysfunction and a left ventricular ejection fraction of 59%.

Treatment with intravenous heparin was started, and the patient was transferred to our hospital.

PLEURAL EFFUSION AND PULMONARY EMBOLISM

1. Which of the following is true about pleural effusion?

• It is rarely, if ever, associated with pulmonary embolism
• Most patients with pleural effusion due to pulmonary embolism do not have pleuritic chest pain
• Pulmonary embolism should be excluded in all cases of pleural effusion without a clear cause

Pulmonary embolism should be excluded in all cases of pleural effusion that do not have a clear cause. As for the other answer choices:

• Pulmonary embolism is the fourth leading cause of pleural effusion in the United States, after heart failure, pneumonia, and malignancy.¹
• About 75% of patients who develop pleural effusion in the setting of pulmonary embolism complain of pleuritic chest pain on the side of the effusion.² Most effusions are unilateral, small, and usually exudative.³

EVALUATION BEGINS: RESULTS OF THORACENTESIS

Our patient continued to receive intravenous heparin.

He underwent thoracentesis on hospital day 3, and 1,000 mL of turbid sanguineous pleural fluid was removed. Analysis of the fluid showed pH 7.27, white blood cell count 3.797 × 10⁹/L with 80% neutrophils, and lactate dehydrogenase (LDH) concentration 736 U/L (a ratio of pleural fluid LDH to a concurrent serum LDH > 0.6 is suggestive of an exudate); the fluid was also sent for culture and cytology. Thoracentesis was terminated early due to cough, and follow-up chest radiography showed a moderate-sized pneumothorax.

Computed tomography (CT) of the chest at this time showed a small wedge-shaped area of lung consolidation in the right lower lobe (also seen on CT done 1 day before admission to our hospital), with an intrinsic air-fluid level suggesting a focal infarct or lung abscess, now obscured by adjacent consolidation and atelectasis. In the interval since the previous CT, the multiloculated right pleural effusion had increased in size (Figure 1).

THE NEXT STEP

2. What is the most appropriate next step for this patient?

• Consult an interventional radiologist for chest tube placement
• Start empiric antibiotic therapy and ask an interventional radiologist to place a chest tube
• Start empiric antibiotic therapy, withhold anticoagulation, and consult a thoracic surgeon
• Start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation

The most appropriate next step is to start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation.

In this patient, it is appropriate to initiate antibiotics empirically on the basis of his significant pleural loculations, a wedge-shaped consolidation, and 80% neutrophils in the pleural fluid, all of which suggest infection. The unmasking of a wedge-shaped consolidation after thoracentesis, with a previously noted air-fluid level and an interval increase in multiloculated pleural fluid, raises suspicion of a necrotic infection that may have ruptured into the pleural space, a possible lung infarct, or a malignancy. Hence, simply placing a chest tube may not be enough.

Blood in the pleural fluid does not necessitate withholding anticoagulation unless the bleeding is heavy. A pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit suggests hemothorax and is an indication to withhold anticoagulation.¹ Our patient’s pleural fluid was qualitatively sanguineous but not frankly bloody, and therefore we judged that it was not necessary to stop his heparin.

HOW DOES PULMONARY INFARCTION PRESENT CLINICALLY?

3. Which of the following statements about pulmonary infarction is incorrect?

• Cavitation and infarction are more common with larger emboli
• Cavitation occurs in fewer than 10% of pulmonary infarctions
• Lung abscess develops in more than 50% of pulmonary infarctions
• Pulmonary thromboembolism is the most common cause of pulmonary infarction

Lung abscess develops in far fewer than 50% of cases of pulmonary infarction. The rest of the statements are correct.

Cavitation complicates about 4% to 7% of infarctions and is more common when the infarction is 4 cm or greater in diameter.⁴ These cavities are usually single and predominantly on the right side in the apical or posterior segment of the upper lobe or the apical segment of the right lower lobe, as in our patient.^5–8 CT demonstrating scalloped inner margins and cross-cavity band shadows suggests a cavitary pulmonary infarction.^9,10

Infection and abscess in pulmonary infarction are poorly understood but have been linked to larger infarctions, coexistent congestion or atelectasis, and dental or oropharyngeal infection. In an early series of 550 cases of pulmonary infarction, 23 patients (4.2%) developed lung abscess and 6 (1.1%) developed empyema.¹¹ The mean time to cavitation for an infected pulmonary infarction has been reported to be 18 days.¹²

A reversed halo sign, generally described as a focal, rounded area of ground-glass opacity surrounded by a nearly complete ring of consolidation, has been reported to be more frequent with pulmonary infarction than with other diseases, especially when in the lower lobes.¹³

CASE CONTINUED: THORACOSCOPY

A cardiothoracic surgeon was consulted, intravenous heparin was discontinued, an inferior vena cava filter was placed, and the patient underwent video-assisted thoracoscopy.

Purulent fluid was noted on the lateral aspect of right lower lobe; this appeared to be the ruptured cavitary lesion functioning like an uncontrolled bronchopleural fistula. Two chest tubes, sizes 32F and 28F, were placed after decortication, resection of the lung abscess, and closure of the bronchopleural fistula. No significant air leak was noted after resection of this segment of lung.

Pathologic study showed acute organizing pneumonia with abscess formation; no malignant cells or granulomas were seen (Figure 2). Pleural fluid cultures grew Streptococcus intermedius, while the tissue culture was negative for any growth, including acid-fast bacilli and fungi.

On 3 different occasions, both chest tubes were shortened, backed out 2 cm, and resecured with sutures and pins, and Heimlich valves were applied before the patient was discharged.

Intravenous piperacillin-tazobactam was started on the fifth hospital day. On discharge, the patient was advised to continue this treatment for 3 weeks at home.

The patient was receiving enoxaparin subcutaneously in prophylactic doses; 72 hours after the thorascopic procedure this was increased to therapeutic doses, continuing after discharge. Bridging to warfarin was not advised in view of his chest tubes.

Our patient appeared to have developed a right lower lobe infarction that cavitated and ruptured into the pleural space, causing a bronchopleural fistula with empyema after a recent pulmonary embolism. Other reported causes of pulmonary infarction in pulmonary embolism are malignancy and heavy clot burden,⁶ but these have not been confirmed in subsequent studies.⁵ Malignancy was ruled out by biopsy of the resected portion of the lung, and our patient did not have a history of heart failure. A clear cavity was not noted (because it ruptured into the pleura), but an air-fluid level was described in a wedge-shaped consolidation, suggesting infarction.

How common is pulmonary infarction after pulmonary embolism?

Pulmonary infarction occurs in few patients with pulmonary embolism.¹³ Since the lungs receive oxygen from the airways and have a dual blood supply from the pulmonary and bronchial arteries, they are not particularly vulnerable to ischemia. However, the reported incidence of pulmonary infarction in patients with pulmonary embolism has ranged from 10% to higher than 30%.^5,14,15

The reasons behind pulmonary infarction with complications after pulmonary embolism have varied in different case series in different eras. CT, biopsy, or autopsy studies reveal pulmonary infarction after pulmonary embolism to be more common than suspected by clinical symptoms.

In a Mayo Clinic series of 43 cases of pulmonary infarction diagnosed over a 6-year period by surgical lung biopsy, 18 (42%) of the patients had underlying pulmonary thromboembolism, which was the most common cause.¹⁶

4. Which statement about risk factors for pulmonary infarction in pulmonary embolism is incorrect?

• Heart failure may be a risk factor for pulmonary infarction
• Pulmonary hemorrhage is a risk factor for pulmonary infarction
• Pulmonary infarction is more common with more proximal sites of pulmonary embolism
• Collateral circulation may protect against pulmonary infarction

Infarction is more common with emboli that are distal rather than proximal.

Dalen et al¹⁵ suggested that after pulmonary embolism, pulmonary hemorrhage is an important contributor to the development of pulmonary infarction independent of the presence or absence of associated cardiac or pulmonary disease, but that the effect depends on the site of obstruction.

This idea was first proposed in 1913, when Karsner and Ghoreyeb¹⁷ showed that when pulmonary arteries are completely obstructed, the bronchial arteries take over, except when the embolism is present in a small branch of the pulmonary artery. This is because the physiologic anastomosis between the pulmonary artery and the bronchial arteries is located at the precapillary level of the pulmonary artery, and the bronchial circulation does not take over until the pulmonary arterial pressure in the area of the embolism drops to zero.

Using CT data, Kirchner et al⁵ confirmed that the risk of pulmonary infarction is higher if the obstruction is peripheral, ie, distal.

Using autopsy data, Tsao et al¹⁸ reported a higher risk of pulmonary infarction in embolic occlusion of pulmonary vessels less than 3 mm in diameter.

Collateral circulation has been shown to protect against pulmonary infarction. For example, Miniati et al¹⁴ showed that healthy young patients with pulmonary embolism were more prone to develop pulmonary infarction, probably because they had less efficient collateral systems in the peripheral lung fields. In lung transplant recipients, it has been shown that the risk of infarction decreased with development of collateral circulation.¹⁹

Dalen et al,¹⁵ however, attributed delayed resolution of pulmonary hemorrhage (as measured by resolution of infiltrate on chest radiography) to higher underlying pulmonary venous pressure in patients with heart failure and consequent pulmonary infarction. In comparison, healthy patients without cardiac or pulmonary disease have faster resolution of pulmonary hemorrhage when present, and less likelihood of pulmonary infarction (and death in submassive pulmonary embolism).

Data on the management of infected pulmonary infarction are limited. Mortality rates have been as high as 41% with noninfected and 73% with infected cavitary infarctions.⁴ Some authors have advocated early surgical resection in view of high rates of failure of medical treatment due to lack of blood supply within the cavity and continued risk of infection.

KEY POINTS

In patients with a recently diagnosed pulmonary embolism and concurrent symptoms of bacterial pneumonia, a diagnosis of cavitary pulmonary infarction should be considered.

Consolidations that are pleural-based with sharp, rounded margins and with focal areas of central hyperlucencies representing hemorrhage on the mediastinal windows on CT are more likely to represent a pulmonary infarct.²⁰

A 76-year-old man whose history included abdominal aortic aneurysm repair, bilateral femoral artery bypass for popliteal artery aneurysm, hypertension, and peptic ulcer disease was admitted to a community hospital with pleuritic chest pain and shortness of breath. Two days earlier, he had undergone repair of a ventral hernia.

At the time of that admission, he reported no fever, chills, night sweats, cough, or history of heart or lung disease. His vital signs were normal, and physical examination had revealed no apparent respiratory distress, no jugular venous distention, normal heart sounds, and no pedal edema; however, decreased air entry was noted in the right lung base. Initial serum levels of troponin and N-terminal pro-B-type natriuretic peptide were normal.

At that time, computed tomographic angiography of the chest showed segmental pulmonary emboli in the left upper and right lower lobes of the lungs and right pleural effusion. Transthoracic echocardiography showed normal atrial and ventricular sizes with no right or left ventricular systolic dysfunction and a left ventricular ejection fraction of 59%.

Treatment with intravenous heparin was started, and the patient was transferred to our hospital.

PLEURAL EFFUSION AND PULMONARY EMBOLISM

1. Which of the following is true about pleural effusion?

• It is rarely, if ever, associated with pulmonary embolism
• Most patients with pleural effusion due to pulmonary embolism do not have pleuritic chest pain
• Pulmonary embolism should be excluded in all cases of pleural effusion without a clear cause

Pulmonary embolism should be excluded in all cases of pleural effusion that do not have a clear cause. As for the other answer choices:

• Pulmonary embolism is the fourth leading cause of pleural effusion in the United States, after heart failure, pneumonia, and malignancy.¹
• About 75% of patients who develop pleural effusion in the setting of pulmonary embolism complain of pleuritic chest pain on the side of the effusion.² Most effusions are unilateral, small, and usually exudative.³

EVALUATION BEGINS: RESULTS OF THORACENTESIS

Our patient continued to receive intravenous heparin.

He underwent thoracentesis on hospital day 3, and 1,000 mL of turbid sanguineous pleural fluid was removed. Analysis of the fluid showed pH 7.27, white blood cell count 3.797 × 10⁹/L with 80% neutrophils, and lactate dehydrogenase (LDH) concentration 736 U/L (a ratio of pleural fluid LDH to a concurrent serum LDH > 0.6 is suggestive of an exudate); the fluid was also sent for culture and cytology. Thoracentesis was terminated early due to cough, and follow-up chest radiography showed a moderate-sized pneumothorax.

Computed tomography (CT) of the chest at this time showed a small wedge-shaped area of lung consolidation in the right lower lobe (also seen on CT done 1 day before admission to our hospital), with an intrinsic air-fluid level suggesting a focal infarct or lung abscess, now obscured by adjacent consolidation and atelectasis. In the interval since the previous CT, the multiloculated right pleural effusion had increased in size (Figure 1).

THE NEXT STEP

2. What is the most appropriate next step for this patient?

• Consult an interventional radiologist for chest tube placement
• Start empiric antibiotic therapy and ask an interventional radiologist to place a chest tube
• Start empiric antibiotic therapy, withhold anticoagulation, and consult a thoracic surgeon
• Start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation

The most appropriate next step is to start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation.

In this patient, it is appropriate to initiate antibiotics empirically on the basis of his significant pleural loculations, a wedge-shaped consolidation, and 80% neutrophils in the pleural fluid, all of which suggest infection. The unmasking of a wedge-shaped consolidation after thoracentesis, with a previously noted air-fluid level and an interval increase in multiloculated pleural fluid, raises suspicion of a necrotic infection that may have ruptured into the pleural space, a possible lung infarct, or a malignancy. Hence, simply placing a chest tube may not be enough.

Blood in the pleural fluid does not necessitate withholding anticoagulation unless the bleeding is heavy. A pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit suggests hemothorax and is an indication to withhold anticoagulation.¹ Our patient’s pleural fluid was qualitatively sanguineous but not frankly bloody, and therefore we judged that it was not necessary to stop his heparin.

HOW DOES PULMONARY INFARCTION PRESENT CLINICALLY?

3. Which of the following statements about pulmonary infarction is incorrect?

• Cavitation and infarction are more common with larger emboli
• Cavitation occurs in fewer than 10% of pulmonary infarctions
• Lung abscess develops in more than 50% of pulmonary infarctions
• Pulmonary thromboembolism is the most common cause of pulmonary infarction

Lung abscess develops in far fewer than 50% of cases of pulmonary infarction. The rest of the statements are correct.

Cavitation complicates about 4% to 7% of infarctions and is more common when the infarction is 4 cm or greater in diameter.⁴ These cavities are usually single and predominantly on the right side in the apical or posterior segment of the upper lobe or the apical segment of the right lower lobe, as in our patient.^5–8 CT demonstrating scalloped inner margins and cross-cavity band shadows suggests a cavitary pulmonary infarction.^9,10

Infection and abscess in pulmonary infarction are poorly understood but have been linked to larger infarctions, coexistent congestion or atelectasis, and dental or oropharyngeal infection. In an early series of 550 cases of pulmonary infarction, 23 patients (4.2%) developed lung abscess and 6 (1.1%) developed empyema.¹¹ The mean time to cavitation for an infected pulmonary infarction has been reported to be 18 days.¹²

A reversed halo sign, generally described as a focal, rounded area of ground-glass opacity surrounded by a nearly complete ring of consolidation, has been reported to be more frequent with pulmonary infarction than with other diseases, especially when in the lower lobes.¹³

CASE CONTINUED: THORACOSCOPY

A cardiothoracic surgeon was consulted, intravenous heparin was discontinued, an inferior vena cava filter was placed, and the patient underwent video-assisted thoracoscopy.

Purulent fluid was noted on the lateral aspect of right lower lobe; this appeared to be the ruptured cavitary lesion functioning like an uncontrolled bronchopleural fistula. Two chest tubes, sizes 32F and 28F, were placed after decortication, resection of the lung abscess, and closure of the bronchopleural fistula. No significant air leak was noted after resection of this segment of lung.

Pathologic study showed acute organizing pneumonia with abscess formation; no malignant cells or granulomas were seen (Figure 2). Pleural fluid cultures grew Streptococcus intermedius, while the tissue culture was negative for any growth, including acid-fast bacilli and fungi.

On 3 different occasions, both chest tubes were shortened, backed out 2 cm, and resecured with sutures and pins, and Heimlich valves were applied before the patient was discharged.

Intravenous piperacillin-tazobactam was started on the fifth hospital day. On discharge, the patient was advised to continue this treatment for 3 weeks at home.

The patient was receiving enoxaparin subcutaneously in prophylactic doses; 72 hours after the thorascopic procedure this was increased to therapeutic doses, continuing after discharge. Bridging to warfarin was not advised in view of his chest tubes.

Our patient appeared to have developed a right lower lobe infarction that cavitated and ruptured into the pleural space, causing a bronchopleural fistula with empyema after a recent pulmonary embolism. Other reported causes of pulmonary infarction in pulmonary embolism are malignancy and heavy clot burden,⁶ but these have not been confirmed in subsequent studies.⁵ Malignancy was ruled out by biopsy of the resected portion of the lung, and our patient did not have a history of heart failure. A clear cavity was not noted (because it ruptured into the pleura), but an air-fluid level was described in a wedge-shaped consolidation, suggesting infarction.

How common is pulmonary infarction after pulmonary embolism?

Pulmonary infarction occurs in few patients with pulmonary embolism.¹³ Since the lungs receive oxygen from the airways and have a dual blood supply from the pulmonary and bronchial arteries, they are not particularly vulnerable to ischemia. However, the reported incidence of pulmonary infarction in patients with pulmonary embolism has ranged from 10% to higher than 30%.^5,14,15

The reasons behind pulmonary infarction with complications after pulmonary embolism have varied in different case series in different eras. CT, biopsy, or autopsy studies reveal pulmonary infarction after pulmonary embolism to be more common than suspected by clinical symptoms.

In a Mayo Clinic series of 43 cases of pulmonary infarction diagnosed over a 6-year period by surgical lung biopsy, 18 (42%) of the patients had underlying pulmonary thromboembolism, which was the most common cause.¹⁶

4. Which statement about risk factors for pulmonary infarction in pulmonary embolism is incorrect?

• Heart failure may be a risk factor for pulmonary infarction
• Pulmonary hemorrhage is a risk factor for pulmonary infarction
• Pulmonary infarction is more common with more proximal sites of pulmonary embolism
• Collateral circulation may protect against pulmonary infarction

Infarction is more common with emboli that are distal rather than proximal.

Dalen et al¹⁵ suggested that after pulmonary embolism, pulmonary hemorrhage is an important contributor to the development of pulmonary infarction independent of the presence or absence of associated cardiac or pulmonary disease, but that the effect depends on the site of obstruction.

This idea was first proposed in 1913, when Karsner and Ghoreyeb¹⁷ showed that when pulmonary arteries are completely obstructed, the bronchial arteries take over, except when the embolism is present in a small branch of the pulmonary artery. This is because the physiologic anastomosis between the pulmonary artery and the bronchial arteries is located at the precapillary level of the pulmonary artery, and the bronchial circulation does not take over until the pulmonary arterial pressure in the area of the embolism drops to zero.

Using CT data, Kirchner et al⁵ confirmed that the risk of pulmonary infarction is higher if the obstruction is peripheral, ie, distal.

Using autopsy data, Tsao et al¹⁸ reported a higher risk of pulmonary infarction in embolic occlusion of pulmonary vessels less than 3 mm in diameter.

Collateral circulation has been shown to protect against pulmonary infarction. For example, Miniati et al¹⁴ showed that healthy young patients with pulmonary embolism were more prone to develop pulmonary infarction, probably because they had less efficient collateral systems in the peripheral lung fields. In lung transplant recipients, it has been shown that the risk of infarction decreased with development of collateral circulation.¹⁹

Dalen et al,¹⁵ however, attributed delayed resolution of pulmonary hemorrhage (as measured by resolution of infiltrate on chest radiography) to higher underlying pulmonary venous pressure in patients with heart failure and consequent pulmonary infarction. In comparison, healthy patients without cardiac or pulmonary disease have faster resolution of pulmonary hemorrhage when present, and less likelihood of pulmonary infarction (and death in submassive pulmonary embolism).

Data on the management of infected pulmonary infarction are limited. Mortality rates have been as high as 41% with noninfected and 73% with infected cavitary infarctions.⁴ Some authors have advocated early surgical resection in view of high rates of failure of medical treatment due to lack of blood supply within the cavity and continued risk of infection.

KEY POINTS

In patients with a recently diagnosed pulmonary embolism and concurrent symptoms of bacterial pneumonia, a diagnosis of cavitary pulmonary infarction should be considered.

Consolidations that are pleural-based with sharp, rounded margins and with focal areas of central hyperlucencies representing hemorrhage on the mediastinal windows on CT are more likely to represent a pulmonary infarct.²⁰

A 76-year-old man whose history included abdominal aortic aneurysm repair, bilateral femoral artery bypass for popliteal artery aneurysm, hypertension, and peptic ulcer disease was admitted to a community hospital with pleuritic chest pain and shortness of breath. Two days earlier, he had undergone repair of a ventral hernia.

At the time of that admission, he reported no fever, chills, night sweats, cough, or history of heart or lung disease. His vital signs were normal, and physical examination had revealed no apparent respiratory distress, no jugular venous distention, normal heart sounds, and no pedal edema; however, decreased air entry was noted in the right lung base. Initial serum levels of troponin and N-terminal pro-B-type natriuretic peptide were normal.

At that time, computed tomographic angiography of the chest showed segmental pulmonary emboli in the left upper and right lower lobes of the lungs and right pleural effusion. Transthoracic echocardiography showed normal atrial and ventricular sizes with no right or left ventricular systolic dysfunction and a left ventricular ejection fraction of 59%.

Treatment with intravenous heparin was started, and the patient was transferred to our hospital.

PLEURAL EFFUSION AND PULMONARY EMBOLISM

1. Which of the following is true about pleural effusion?

• It is rarely, if ever, associated with pulmonary embolism
• Most patients with pleural effusion due to pulmonary embolism do not have pleuritic chest pain
• Pulmonary embolism should be excluded in all cases of pleural effusion without a clear cause

Pulmonary embolism should be excluded in all cases of pleural effusion that do not have a clear cause. As for the other answer choices:

• Pulmonary embolism is the fourth leading cause of pleural effusion in the United States, after heart failure, pneumonia, and malignancy.¹
• About 75% of patients who develop pleural effusion in the setting of pulmonary embolism complain of pleuritic chest pain on the side of the effusion.² Most effusions are unilateral, small, and usually exudative.³

EVALUATION BEGINS: RESULTS OF THORACENTESIS

Our patient continued to receive intravenous heparin.

He underwent thoracentesis on hospital day 3, and 1,000 mL of turbid sanguineous pleural fluid was removed. Analysis of the fluid showed pH 7.27, white blood cell count 3.797 × 10⁹/L with 80% neutrophils, and lactate dehydrogenase (LDH) concentration 736 U/L (a ratio of pleural fluid LDH to a concurrent serum LDH > 0.6 is suggestive of an exudate); the fluid was also sent for culture and cytology. Thoracentesis was terminated early due to cough, and follow-up chest radiography showed a moderate-sized pneumothorax.

Computed tomography (CT) of the chest at this time showed a small wedge-shaped area of lung consolidation in the right lower lobe (also seen on CT done 1 day before admission to our hospital), with an intrinsic air-fluid level suggesting a focal infarct or lung abscess, now obscured by adjacent consolidation and atelectasis. In the interval since the previous CT, the multiloculated right pleural effusion had increased in size (Figure 1).

THE NEXT STEP

2. What is the most appropriate next step for this patient?

• Consult an interventional radiologist for chest tube placement
• Start empiric antibiotic therapy and ask an interventional radiologist to place a chest tube
• Start empiric antibiotic therapy, withhold anticoagulation, and consult a thoracic surgeon
• Start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation

The most appropriate next step is to start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation.

In this patient, it is appropriate to initiate antibiotics empirically on the basis of his significant pleural loculations, a wedge-shaped consolidation, and 80% neutrophils in the pleural fluid, all of which suggest infection. The unmasking of a wedge-shaped consolidation after thoracentesis, with a previously noted air-fluid level and an interval increase in multiloculated pleural fluid, raises suspicion of a necrotic infection that may have ruptured into the pleural space, a possible lung infarct, or a malignancy. Hence, simply placing a chest tube may not be enough.

Blood in the pleural fluid does not necessitate withholding anticoagulation unless the bleeding is heavy. A pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit suggests hemothorax and is an indication to withhold anticoagulation.¹ Our patient’s pleural fluid was qualitatively sanguineous but not frankly bloody, and therefore we judged that it was not necessary to stop his heparin.

HOW DOES PULMONARY INFARCTION PRESENT CLINICALLY?

3. Which of the following statements about pulmonary infarction is incorrect?

• Cavitation and infarction are more common with larger emboli
• Cavitation occurs in fewer than 10% of pulmonary infarctions
• Lung abscess develops in more than 50% of pulmonary infarctions
• Pulmonary thromboembolism is the most common cause of pulmonary infarction

Lung abscess develops in far fewer than 50% of cases of pulmonary infarction. The rest of the statements are correct.

Cavitation complicates about 4% to 7% of infarctions and is more common when the infarction is 4 cm or greater in diameter.⁴ These cavities are usually single and predominantly on the right side in the apical or posterior segment of the upper lobe or the apical segment of the right lower lobe, as in our patient.^5–8 CT demonstrating scalloped inner margins and cross-cavity band shadows suggests a cavitary pulmonary infarction.^9,10

Infection and abscess in pulmonary infarction are poorly understood but have been linked to larger infarctions, coexistent congestion or atelectasis, and dental or oropharyngeal infection. In an early series of 550 cases of pulmonary infarction, 23 patients (4.2%) developed lung abscess and 6 (1.1%) developed empyema.¹¹ The mean time to cavitation for an infected pulmonary infarction has been reported to be 18 days.¹²

A reversed halo sign, generally described as a focal, rounded area of ground-glass opacity surrounded by a nearly complete ring of consolidation, has been reported to be more frequent with pulmonary infarction than with other diseases, especially when in the lower lobes.¹³

CASE CONTINUED: THORACOSCOPY

A cardiothoracic surgeon was consulted, intravenous heparin was discontinued, an inferior vena cava filter was placed, and the patient underwent video-assisted thoracoscopy.

Purulent fluid was noted on the lateral aspect of right lower lobe; this appeared to be the ruptured cavitary lesion functioning like an uncontrolled bronchopleural fistula. Two chest tubes, sizes 32F and 28F, were placed after decortication, resection of the lung abscess, and closure of the bronchopleural fistula. No significant air leak was noted after resection of this segment of lung.

Pathologic study showed acute organizing pneumonia with abscess formation; no malignant cells or granulomas were seen (Figure 2). Pleural fluid cultures grew Streptococcus intermedius, while the tissue culture was negative for any growth, including acid-fast bacilli and fungi.

On 3 different occasions, both chest tubes were shortened, backed out 2 cm, and resecured with sutures and pins, and Heimlich valves were applied before the patient was discharged.

Intravenous piperacillin-tazobactam was started on the fifth hospital day. On discharge, the patient was advised to continue this treatment for 3 weeks at home.

The patient was receiving enoxaparin subcutaneously in prophylactic doses; 72 hours after the thorascopic procedure this was increased to therapeutic doses, continuing after discharge. Bridging to warfarin was not advised in view of his chest tubes.

Our patient appeared to have developed a right lower lobe infarction that cavitated and ruptured into the pleural space, causing a bronchopleural fistula with empyema after a recent pulmonary embolism. Other reported causes of pulmonary infarction in pulmonary embolism are malignancy and heavy clot burden,⁶ but these have not been confirmed in subsequent studies.⁵ Malignancy was ruled out by biopsy of the resected portion of the lung, and our patient did not have a history of heart failure. A clear cavity was not noted (because it ruptured into the pleura), but an air-fluid level was described in a wedge-shaped consolidation, suggesting infarction.

How common is pulmonary infarction after pulmonary embolism?

Pulmonary infarction occurs in few patients with pulmonary embolism.¹³ Since the lungs receive oxygen from the airways and have a dual blood supply from the pulmonary and bronchial arteries, they are not particularly vulnerable to ischemia. However, the reported incidence of pulmonary infarction in patients with pulmonary embolism has ranged from 10% to higher than 30%.^5,14,15

The reasons behind pulmonary infarction with complications after pulmonary embolism have varied in different case series in different eras. CT, biopsy, or autopsy studies reveal pulmonary infarction after pulmonary embolism to be more common than suspected by clinical symptoms.

In a Mayo Clinic series of 43 cases of pulmonary infarction diagnosed over a 6-year period by surgical lung biopsy, 18 (42%) of the patients had underlying pulmonary thromboembolism, which was the most common cause.¹⁶

4. Which statement about risk factors for pulmonary infarction in pulmonary embolism is incorrect?

• Heart failure may be a risk factor for pulmonary infarction
• Pulmonary hemorrhage is a risk factor for pulmonary infarction
• Pulmonary infarction is more common with more proximal sites of pulmonary embolism
• Collateral circulation may protect against pulmonary infarction

Infarction is more common with emboli that are distal rather than proximal.

Dalen et al¹⁵ suggested that after pulmonary embolism, pulmonary hemorrhage is an important contributor to the development of pulmonary infarction independent of the presence or absence of associated cardiac or pulmonary disease, but that the effect depends on the site of obstruction.

This idea was first proposed in 1913, when Karsner and Ghoreyeb¹⁷ showed that when pulmonary arteries are completely obstructed, the bronchial arteries take over, except when the embolism is present in a small branch of the pulmonary artery. This is because the physiologic anastomosis between the pulmonary artery and the bronchial arteries is located at the precapillary level of the pulmonary artery, and the bronchial circulation does not take over until the pulmonary arterial pressure in the area of the embolism drops to zero.

Using CT data, Kirchner et al⁵ confirmed that the risk of pulmonary infarction is higher if the obstruction is peripheral, ie, distal.

Using autopsy data, Tsao et al¹⁸ reported a higher risk of pulmonary infarction in embolic occlusion of pulmonary vessels less than 3 mm in diameter.

Collateral circulation has been shown to protect against pulmonary infarction. For example, Miniati et al¹⁴ showed that healthy young patients with pulmonary embolism were more prone to develop pulmonary infarction, probably because they had less efficient collateral systems in the peripheral lung fields. In lung transplant recipients, it has been shown that the risk of infarction decreased with development of collateral circulation.¹⁹

Dalen et al,¹⁵ however, attributed delayed resolution of pulmonary hemorrhage (as measured by resolution of infiltrate on chest radiography) to higher underlying pulmonary venous pressure in patients with heart failure and consequent pulmonary infarction. In comparison, healthy patients without cardiac or pulmonary disease have faster resolution of pulmonary hemorrhage when present, and less likelihood of pulmonary infarction (and death in submassive pulmonary embolism).

Data on the management of infected pulmonary infarction are limited. Mortality rates have been as high as 41% with noninfected and 73% with infected cavitary infarctions.⁴ Some authors have advocated early surgical resection in view of high rates of failure of medical treatment due to lack of blood supply within the cavity and continued risk of infection.

KEY POINTS

In patients with a recently diagnosed pulmonary embolism and concurrent symptoms of bacterial pneumonia, a diagnosis of cavitary pulmonary infarction should be considered.

Consolidations that are pleural-based with sharp, rounded margins and with focal areas of central hyperlucencies representing hemorrhage on the mediastinal windows on CT are more likely to represent a pulmonary infarct.²⁰

SAN DIEGO – A biomarker test based on the presence of two proteins in the blood appears to be suitable for ruling out significant intracranial injuries in patients with a history of mild traumatic brain injury (TBI) without the need for a CT head scan, according to data presented at the annual meeting of the American College of Emergency Physicians.

Ted Bosworth/MDedge News

A biomarker suitable for ruling out significant brain injury could save substantial resources because only about 10% of patients with mild TBI have a positive CT head scan, according to Jeffrey J. Bazarian, MD, professor of emergency medicine, University of Rochester (New York).

In the ALERT-TBI study, which evaluated the biomarker test, 1,959 patients with suspected TBI at 22 participating EDs in the United States and Europe were enrolled and available for analysis. All had mild TBI as defined as a Glasgow Coma Scale (GCS) score of 13-15.

The treating ED physician’s decision to order a head CT scan was the major criterion for study entry. All enrolled patients had their blood drawn within 12 hours in order to quantify two biomarkers, C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP).

The biomarker test for TBI was negative when the UCH-L1 value was less than 327 pg/mL and the GFAP was less than 22 pg/mL; the test was positive if either value was at this threshold or higher. To evaluate the sensitivity and specificity of this dual-biomarker test, results were correlated with head CT scans read by two neurologists blinded to the biomarker values.

The mean age of the study population was 48.8 years and slightly more than half were male. About half of the suspected TBI in these patients was attributed to falls and about one third to motor vehicle accidents.

Typical of TBI with GCS scores in the mild range, only 6% of the patients had a positive CT head scan. Of the 125 positive CT scans, the most common injury detected on CT scan was subarachnoid hemorrhage followed by subdural hematoma.

Of the 671 negative biomarker tests, 668 had normal head CT scans. Of the three false positives, one included a cavernous malformation that may have been present prior to the TBI. The others were a small subarachnoid hemorrhage and a small subdural hematoma. Overall the negative predictive value was 99.6% and the sensitivity was 97.6%.

Although the biomarker specificity was only 36% with an even-lower positive predictive value, the goal of the test was to rule out significant TBI to avoid the need for CT scan. On this basis, the biomarker test, which is being developed under the proprietary name Banyan BTI, appears to be promising. The data, according to Dr. Bazarian, have been submitted to the Food and Drug Administration.

“Head CT scans are the current standard for evaluating intracranial injuries after TBI, but they are overused, based on the high proportion that do not show an injury,” said Dr. Bazarian. Although he does not know the disposition of the FDA application, he said, based on these data, “I would definitely be using this test if it were available.”

SAN DIEGO – A biomarker test based on the presence of two proteins in the blood appears to be suitable for ruling out significant intracranial injuries in patients with a history of mild traumatic brain injury (TBI) without the need for a CT head scan, according to data presented at the annual meeting of the American College of Emergency Physicians.

Ted Bosworth/MDedge News

A biomarker suitable for ruling out significant brain injury could save substantial resources because only about 10% of patients with mild TBI have a positive CT head scan, according to Jeffrey J. Bazarian, MD, professor of emergency medicine, University of Rochester (New York).

In the ALERT-TBI study, which evaluated the biomarker test, 1,959 patients with suspected TBI at 22 participating EDs in the United States and Europe were enrolled and available for analysis. All had mild TBI as defined as a Glasgow Coma Scale (GCS) score of 13-15.

The treating ED physician’s decision to order a head CT scan was the major criterion for study entry. All enrolled patients had their blood drawn within 12 hours in order to quantify two biomarkers, C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP).

The biomarker test for TBI was negative when the UCH-L1 value was less than 327 pg/mL and the GFAP was less than 22 pg/mL; the test was positive if either value was at this threshold or higher. To evaluate the sensitivity and specificity of this dual-biomarker test, results were correlated with head CT scans read by two neurologists blinded to the biomarker values.

The mean age of the study population was 48.8 years and slightly more than half were male. About half of the suspected TBI in these patients was attributed to falls and about one third to motor vehicle accidents.

Typical of TBI with GCS scores in the mild range, only 6% of the patients had a positive CT head scan. Of the 125 positive CT scans, the most common injury detected on CT scan was subarachnoid hemorrhage followed by subdural hematoma.

Of the 671 negative biomarker tests, 668 had normal head CT scans. Of the three false positives, one included a cavernous malformation that may have been present prior to the TBI. The others were a small subarachnoid hemorrhage and a small subdural hematoma. Overall the negative predictive value was 99.6% and the sensitivity was 97.6%.

Although the biomarker specificity was only 36% with an even-lower positive predictive value, the goal of the test was to rule out significant TBI to avoid the need for CT scan. On this basis, the biomarker test, which is being developed under the proprietary name Banyan BTI, appears to be promising. The data, according to Dr. Bazarian, have been submitted to the Food and Drug Administration.

“Head CT scans are the current standard for evaluating intracranial injuries after TBI, but they are overused, based on the high proportion that do not show an injury,” said Dr. Bazarian. Although he does not know the disposition of the FDA application, he said, based on these data, “I would definitely be using this test if it were available.”

SAN DIEGO – A biomarker test based on the presence of two proteins in the blood appears to be suitable for ruling out significant intracranial injuries in patients with a history of mild traumatic brain injury (TBI) without the need for a CT head scan, according to data presented at the annual meeting of the American College of Emergency Physicians.

Ted Bosworth/MDedge News

A biomarker suitable for ruling out significant brain injury could save substantial resources because only about 10% of patients with mild TBI have a positive CT head scan, according to Jeffrey J. Bazarian, MD, professor of emergency medicine, University of Rochester (New York).

In the ALERT-TBI study, which evaluated the biomarker test, 1,959 patients with suspected TBI at 22 participating EDs in the United States and Europe were enrolled and available for analysis. All had mild TBI as defined as a Glasgow Coma Scale (GCS) score of 13-15.

The treating ED physician’s decision to order a head CT scan was the major criterion for study entry. All enrolled patients had their blood drawn within 12 hours in order to quantify two biomarkers, C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP).

The biomarker test for TBI was negative when the UCH-L1 value was less than 327 pg/mL and the GFAP was less than 22 pg/mL; the test was positive if either value was at this threshold or higher. To evaluate the sensitivity and specificity of this dual-biomarker test, results were correlated with head CT scans read by two neurologists blinded to the biomarker values.

The mean age of the study population was 48.8 years and slightly more than half were male. About half of the suspected TBI in these patients was attributed to falls and about one third to motor vehicle accidents.

Typical of TBI with GCS scores in the mild range, only 6% of the patients had a positive CT head scan. Of the 125 positive CT scans, the most common injury detected on CT scan was subarachnoid hemorrhage followed by subdural hematoma.

Of the 671 negative biomarker tests, 668 had normal head CT scans. Of the three false positives, one included a cavernous malformation that may have been present prior to the TBI. The others were a small subarachnoid hemorrhage and a small subdural hematoma. Overall the negative predictive value was 99.6% and the sensitivity was 97.6%.

Although the biomarker specificity was only 36% with an even-lower positive predictive value, the goal of the test was to rule out significant TBI to avoid the need for CT scan. On this basis, the biomarker test, which is being developed under the proprietary name Banyan BTI, appears to be promising. The data, according to Dr. Bazarian, have been submitted to the Food and Drug Administration.

“Head CT scans are the current standard for evaluating intracranial injuries after TBI, but they are overused, based on the high proportion that do not show an injury,” said Dr. Bazarian. Although he does not know the disposition of the FDA application, he said, based on these data, “I would definitely be using this test if it were available.”

MUNICH – The perivascular fat attenuation index, a new measure of coronary plaque inflammation using data collected by a conventional coronary CT scan, identified an elevated risk for future cardiovascular death that was independent of standard risk factors in both derivation and validation studies with prospective data from more than 3,900 patients.

Patients with a high fat attenuation index (FAI) in the perivascular fat surrounding their right coronary artery had a five- to ninefold higher risk of cardiac mortality during 4-6 years of follow-up than did those with lower scores, after adjustment for conventional risk factors and standard findings from the coronary CT, Charalambos Antoniades, MD, said at the annual congress of the European Society of Cardiology.

The FAI is a “powerful, novel technology for cardiovascular disease risk stratification. It has striking prognostic value for cardiac death and nonfatal MI over and above other risk scores and state-of-the-art interpretation of coronary CT angiography,” said Dr. Antoniades, professor of cardiovascular medicine at the University of Oxford (England). He also highlighted that the data he reported suggested a protective effect in patients with a high FAI who received treatment with aspirin or a statin, and he suggested that FAI might be a way to better target an anti-inflammatory agent such as canakinumab (Ilaris), which showed cardiovascular protective effects in the CANTOS trial (N Engl J Med. 2017 Sep 21;377[12]:1119-31).

Another key feature of the FAI analysis is that it uses data collected by “any standard” coronary CT angiogram, Dr. Antoniades said. He is a founder of, shareholder in, and chief scientific officer of Caristo Diagnostics, the company developing the software that uses coronary CT data to calculate the FAI.

Dr. Antoniades and his associates derived the FAI using data collected from 1,872 patients who underwent planned coronary CT angiography at a clinic in Erlangen, Germany, during 2005-2009. The researchers correlated FAI scores with cardiovascular disease outcomes during a median follow-up of 72 months. They then validated the FAI using data collected from 2,040 patients who underwent a planned coronary CT exam at the Cleveland Clinic during 2008-2016 and then had a median follow-up of 54 months. The researchers called this overall post-hoc analysis of prospectively collected CT and outcomes data the Cardiovascular Risk Prediction using Computed Tomography (CRISP-CT) study.

Using the derivation data, FAI measurements taken from fat around the proximal right coronary artery that met or exceeded the specified cutoff value of –70.1 Hounsfield units were tied to a 9.04-fold greater rate of cardiac death during follow-up, compared with patients with a lower FAI, and after adjustment for several demographic, clinical, and CT-angiography variables. When the researchers ran this analysis using data from the validation patients and the same cutoff value they found that an elevated FAI linked with a 5.6-fold higher rate of cardiac death. Concurrently with Dr. Antoniades’ talk the results appeared in an online article that was later published (Lancet. 2018 Sep 15;392[10151]:929-39).

Calculating a patient’s FAI offers the prospect for “better use of CT information,” Dr. Antoniades said during the discussion of his report. After a coronary CT scan and conventional data processing, about half the patients have no finding that warrants intervention, but about 10% of these patients actually have an inflamed coronary plaque that is at high risk for rupture that could trigger a cardiac event. The FAI provides a way to use coronary CT angiography to identify these at-risk patients, he explained.

[email protected]

MUNICH – The perivascular fat attenuation index, a new measure of coronary plaque inflammation using data collected by a conventional coronary CT scan, identified an elevated risk for future cardiovascular death that was independent of standard risk factors in both derivation and validation studies with prospective data from more than 3,900 patients.

Patients with a high fat attenuation index (FAI) in the perivascular fat surrounding their right coronary artery had a five- to ninefold higher risk of cardiac mortality during 4-6 years of follow-up than did those with lower scores, after adjustment for conventional risk factors and standard findings from the coronary CT, Charalambos Antoniades, MD, said at the annual congress of the European Society of Cardiology.

The FAI is a “powerful, novel technology for cardiovascular disease risk stratification. It has striking prognostic value for cardiac death and nonfatal MI over and above other risk scores and state-of-the-art interpretation of coronary CT angiography,” said Dr. Antoniades, professor of cardiovascular medicine at the University of Oxford (England). He also highlighted that the data he reported suggested a protective effect in patients with a high FAI who received treatment with aspirin or a statin, and he suggested that FAI might be a way to better target an anti-inflammatory agent such as canakinumab (Ilaris), which showed cardiovascular protective effects in the CANTOS trial (N Engl J Med. 2017 Sep 21;377[12]:1119-31).

Another key feature of the FAI analysis is that it uses data collected by “any standard” coronary CT angiogram, Dr. Antoniades said. He is a founder of, shareholder in, and chief scientific officer of Caristo Diagnostics, the company developing the software that uses coronary CT data to calculate the FAI.

Dr. Antoniades and his associates derived the FAI using data collected from 1,872 patients who underwent planned coronary CT angiography at a clinic in Erlangen, Germany, during 2005-2009. The researchers correlated FAI scores with cardiovascular disease outcomes during a median follow-up of 72 months. They then validated the FAI using data collected from 2,040 patients who underwent a planned coronary CT exam at the Cleveland Clinic during 2008-2016 and then had a median follow-up of 54 months. The researchers called this overall post-hoc analysis of prospectively collected CT and outcomes data the Cardiovascular Risk Prediction using Computed Tomography (CRISP-CT) study.

Using the derivation data, FAI measurements taken from fat around the proximal right coronary artery that met or exceeded the specified cutoff value of –70.1 Hounsfield units were tied to a 9.04-fold greater rate of cardiac death during follow-up, compared with patients with a lower FAI, and after adjustment for several demographic, clinical, and CT-angiography variables. When the researchers ran this analysis using data from the validation patients and the same cutoff value they found that an elevated FAI linked with a 5.6-fold higher rate of cardiac death. Concurrently with Dr. Antoniades’ talk the results appeared in an online article that was later published (Lancet. 2018 Sep 15;392[10151]:929-39).

Calculating a patient’s FAI offers the prospect for “better use of CT information,” Dr. Antoniades said during the discussion of his report. After a coronary CT scan and conventional data processing, about half the patients have no finding that warrants intervention, but about 10% of these patients actually have an inflamed coronary plaque that is at high risk for rupture that could trigger a cardiac event. The FAI provides a way to use coronary CT angiography to identify these at-risk patients, he explained.

[email protected]

MUNICH – The perivascular fat attenuation index, a new measure of coronary plaque inflammation using data collected by a conventional coronary CT scan, identified an elevated risk for future cardiovascular death that was independent of standard risk factors in both derivation and validation studies with prospective data from more than 3,900 patients.

Patients with a high fat attenuation index (FAI) in the perivascular fat surrounding their right coronary artery had a five- to ninefold higher risk of cardiac mortality during 4-6 years of follow-up than did those with lower scores, after adjustment for conventional risk factors and standard findings from the coronary CT, Charalambos Antoniades, MD, said at the annual congress of the European Society of Cardiology.

The FAI is a “powerful, novel technology for cardiovascular disease risk stratification. It has striking prognostic value for cardiac death and nonfatal MI over and above other risk scores and state-of-the-art interpretation of coronary CT angiography,” said Dr. Antoniades, professor of cardiovascular medicine at the University of Oxford (England). He also highlighted that the data he reported suggested a protective effect in patients with a high FAI who received treatment with aspirin or a statin, and he suggested that FAI might be a way to better target an anti-inflammatory agent such as canakinumab (Ilaris), which showed cardiovascular protective effects in the CANTOS trial (N Engl J Med. 2017 Sep 21;377[12]:1119-31).

Another key feature of the FAI analysis is that it uses data collected by “any standard” coronary CT angiogram, Dr. Antoniades said. He is a founder of, shareholder in, and chief scientific officer of Caristo Diagnostics, the company developing the software that uses coronary CT data to calculate the FAI.

Dr. Antoniades and his associates derived the FAI using data collected from 1,872 patients who underwent planned coronary CT angiography at a clinic in Erlangen, Germany, during 2005-2009. The researchers correlated FAI scores with cardiovascular disease outcomes during a median follow-up of 72 months. They then validated the FAI using data collected from 2,040 patients who underwent a planned coronary CT exam at the Cleveland Clinic during 2008-2016 and then had a median follow-up of 54 months. The researchers called this overall post-hoc analysis of prospectively collected CT and outcomes data the Cardiovascular Risk Prediction using Computed Tomography (CRISP-CT) study.

Using the derivation data, FAI measurements taken from fat around the proximal right coronary artery that met or exceeded the specified cutoff value of –70.1 Hounsfield units were tied to a 9.04-fold greater rate of cardiac death during follow-up, compared with patients with a lower FAI, and after adjustment for several demographic, clinical, and CT-angiography variables. When the researchers ran this analysis using data from the validation patients and the same cutoff value they found that an elevated FAI linked with a 5.6-fold higher rate of cardiac death. Concurrently with Dr. Antoniades’ talk the results appeared in an online article that was later published (Lancet. 2018 Sep 15;392[10151]:929-39).

Calculating a patient’s FAI offers the prospect for “better use of CT information,” Dr. Antoniades said during the discussion of his report. After a coronary CT scan and conventional data processing, about half the patients have no finding that warrants intervention, but about 10% of these patients actually have an inflamed coronary plaque that is at high risk for rupture that could trigger a cardiac event. The FAI provides a way to use coronary CT angiography to identify these at-risk patients, he explained.

[email protected]

ABSTRACT

Improvements in ultrasound technology have increased the popularity and use of ultrasound as a diagnostic and therapeutic modality for many soccer-related musculoskeletal (MSK) injuries. As a dynamic imaging modality, ultrasound offers increased accuracy and efficacy with minimally invasive procedures, such as guided injections, percutaneous tenotomy, and regenerative therapies, in the clinical setting. Emerging evidence indicates that regenerative therapies, such as platelet-rich-plasma (PRP), mesenchymal stem cells, and amniotic products, are a promising treatment for many MSK injuries and are gaining popularity among professional athletes. PRP is a safe treatment for a number of MSK conditions and has been included in the standard of care. However, conflicting evidence on return-to-play timeframes and efficacy in certain MSK conditions have led to inconsistent recommendations on indications for use, dose, and timing of treatment. Mesenchymal stem cell therapy, while promising, lacks high-level evidence of efficacy despite its increasing use among athletes. Currently, no data are available regarding the outcome of the use of amniotic products for the treatment of injuries in athletes. Furthermore, preparation of many regenerative therapies eclipses the concept of minimal manipulation and is subject to US Food and Drug Administration phase I to III trials. High-level research on regenerative medicine therapies should be continuously conducted to establish their clinical efficacy and safety data.

ABSTRACT

Improvements in ultrasound technology have increased the popularity and use of ultrasound as a diagnostic and therapeutic modality for many soccer-related musculoskeletal (MSK) injuries. As a dynamic imaging modality, ultrasound offers increased accuracy and efficacy with minimally invasive procedures, such as guided injections, percutaneous tenotomy, and regenerative therapies, in the clinical setting. Emerging evidence indicates that regenerative therapies, such as platelet-rich-plasma (PRP), mesenchymal stem cells, and amniotic products, are a promising treatment for many MSK injuries and are gaining popularity among professional athletes. PRP is a safe treatment for a number of MSK conditions and has been included in the standard of care. However, conflicting evidence on return-to-play timeframes and efficacy in certain MSK conditions have led to inconsistent recommendations on indications for use, dose, and timing of treatment. Mesenchymal stem cell therapy, while promising, lacks high-level evidence of efficacy despite its increasing use among athletes. Currently, no data are available regarding the outcome of the use of amniotic products for the treatment of injuries in athletes. Furthermore, preparation of many regenerative therapies eclipses the concept of minimal manipulation and is subject to US Food and Drug Administration phase I to III trials. High-level research on regenerative medicine therapies should be continuously conducted to establish their clinical efficacy and safety data.

ABSTRACT

Improvements in ultrasound technology have increased the popularity and use of ultrasound as a diagnostic and therapeutic modality for many soccer-related musculoskeletal (MSK) injuries. As a dynamic imaging modality, ultrasound offers increased accuracy and efficacy with minimally invasive procedures, such as guided injections, percutaneous tenotomy, and regenerative therapies, in the clinical setting. Emerging evidence indicates that regenerative therapies, such as platelet-rich-plasma (PRP), mesenchymal stem cells, and amniotic products, are a promising treatment for many MSK injuries and are gaining popularity among professional athletes. PRP is a safe treatment for a number of MSK conditions and has been included in the standard of care. However, conflicting evidence on return-to-play timeframes and efficacy in certain MSK conditions have led to inconsistent recommendations on indications for use, dose, and timing of treatment. Mesenchymal stem cell therapy, while promising, lacks high-level evidence of efficacy despite its increasing use among athletes. Currently, no data are available regarding the outcome of the use of amniotic products for the treatment of injuries in athletes. Furthermore, preparation of many regenerative therapies eclipses the concept of minimal manipulation and is subject to US Food and Drug Administration phase I to III trials. High-level research on regenerative medicine therapies should be continuously conducted to establish their clinical efficacy and safety data.

SAN DIEGO – In the ICU, ultrasound has been shown to reduce the need for CT to evaluate potential pulmonary embolism. But in the ED, this strategy hasn’t worked out so far, according to Joseph Brown, MD, of the department of emergency medicine at the University of California, San Francisco.

Vidyard Video

Based on the data so far, the ED patients were less likely than the ICU patients to have another etiology identified on ultrasound that explained their symptoms. Further, ultrasound alone missed small subsegmental pulmonary emboli that were detected on subsequent CT scans in 2 of 11 patients.

The study is continuing, and Dr. Brown explains in this interview how ultrasound might be combined with other risk stratification measures to safely achieve reductions in CT scans.

SAN DIEGO – In the ICU, ultrasound has been shown to reduce the need for CT to evaluate potential pulmonary embolism. But in the ED, this strategy hasn’t worked out so far, according to Joseph Brown, MD, of the department of emergency medicine at the University of California, San Francisco.

Vidyard Video

Based on the data so far, the ED patients were less likely than the ICU patients to have another etiology identified on ultrasound that explained their symptoms. Further, ultrasound alone missed small subsegmental pulmonary emboli that were detected on subsequent CT scans in 2 of 11 patients.

The study is continuing, and Dr. Brown explains in this interview how ultrasound might be combined with other risk stratification measures to safely achieve reductions in CT scans.

SAN DIEGO – In the ICU, ultrasound has been shown to reduce the need for CT to evaluate potential pulmonary embolism. But in the ED, this strategy hasn’t worked out so far, according to Joseph Brown, MD, of the department of emergency medicine at the University of California, San Francisco.

Vidyard Video

Based on the data so far, the ED patients were less likely than the ICU patients to have another etiology identified on ultrasound that explained their symptoms. Further, ultrasound alone missed small subsegmental pulmonary emboli that were detected on subsequent CT scans in 2 of 11 patients.

The study is continuing, and Dr. Brown explains in this interview how ultrasound might be combined with other risk stratification measures to safely achieve reductions in CT scans.

SAN DIEGO – Clinical outcomes were better when stent placement was guided by intravascular ultrasound rather than angiography, based on the results of a trial conducted in China. Unlike previous comparative studies, which focused on patients with more complex lesions, this trial included all patients undergoing drug-eluting stent (DES) placement.

In the ULTIMATE trial, 1,448 all-comer patients receiving DES were randomized to either intravascular ultrasound (IVUS)–guided or angiography-guided implantation, reported Junjie Zhang, PhD, of Nanjing Medical University in China, and colleagues. The study excluded patients who had a life expectancy shorter than 12 months, who were intolerant of dual antiplatelet therapy, and who had severe calcification needing rotational atherectomy.

At 30 days after stent placement, the incidence of target vessel failure was 0.8% in the IVUS group and 1.9% in the angiography group, a nonsignificant trend. However, outcomes were significantly different at 1 year, with target vessel failure occurring in 2.9% of IVUS patients and 5.4% of angiography patients (hazard ratio, 0.530; 95% confidence interval, 0.312-0.901; P = .019).

The work was simultaneously published in the Journal of the American College of Cardiology (2018 Sept. doi: 10.1016/j.jacc.2018.09.013) .

Despite good results in this and prior studies, uptake of the IVUS procedure is not high in the United States or Europe, according to members of a panel that reviewed the results at the Transcatheter Cardiovascular Therapeutics annual meeting.

“How can people continue to ignore the importance of imaging-guided stent optimization? Even with second-generation DES, the results are consistent across the studies. This is just another piece of irrefutable evidence,” said Gary S. Mintz, MD, chief medical officer at the Cardiovascular Research Foundation, and a discussant at the meeting, sponsored by the Cardiovascular Research Foundation.

Jim Kling/MDedge News

SAN DIEGO – Clinical outcomes were better when stent placement was guided by intravascular ultrasound rather than angiography, based on the results of a trial conducted in China. Unlike previous comparative studies, which focused on patients with more complex lesions, this trial included all patients undergoing drug-eluting stent (DES) placement.

In the ULTIMATE trial, 1,448 all-comer patients receiving DES were randomized to either intravascular ultrasound (IVUS)–guided or angiography-guided implantation, reported Junjie Zhang, PhD, of Nanjing Medical University in China, and colleagues. The study excluded patients who had a life expectancy shorter than 12 months, who were intolerant of dual antiplatelet therapy, and who had severe calcification needing rotational atherectomy.

At 30 days after stent placement, the incidence of target vessel failure was 0.8% in the IVUS group and 1.9% in the angiography group, a nonsignificant trend. However, outcomes were significantly different at 1 year, with target vessel failure occurring in 2.9% of IVUS patients and 5.4% of angiography patients (hazard ratio, 0.530; 95% confidence interval, 0.312-0.901; P = .019).

The work was simultaneously published in the Journal of the American College of Cardiology (2018 Sept. doi: 10.1016/j.jacc.2018.09.013) .

Despite good results in this and prior studies, uptake of the IVUS procedure is not high in the United States or Europe, according to members of a panel that reviewed the results at the Transcatheter Cardiovascular Therapeutics annual meeting.

“How can people continue to ignore the importance of imaging-guided stent optimization? Even with second-generation DES, the results are consistent across the studies. This is just another piece of irrefutable evidence,” said Gary S. Mintz, MD, chief medical officer at the Cardiovascular Research Foundation, and a discussant at the meeting, sponsored by the Cardiovascular Research Foundation.

Jim Kling/MDedge News

SAN DIEGO – Clinical outcomes were better when stent placement was guided by intravascular ultrasound rather than angiography, based on the results of a trial conducted in China. Unlike previous comparative studies, which focused on patients with more complex lesions, this trial included all patients undergoing drug-eluting stent (DES) placement.

In the ULTIMATE trial, 1,448 all-comer patients receiving DES were randomized to either intravascular ultrasound (IVUS)–guided or angiography-guided implantation, reported Junjie Zhang, PhD, of Nanjing Medical University in China, and colleagues. The study excluded patients who had a life expectancy shorter than 12 months, who were intolerant of dual antiplatelet therapy, and who had severe calcification needing rotational atherectomy.

At 30 days after stent placement, the incidence of target vessel failure was 0.8% in the IVUS group and 1.9% in the angiography group, a nonsignificant trend. However, outcomes were significantly different at 1 year, with target vessel failure occurring in 2.9% of IVUS patients and 5.4% of angiography patients (hazard ratio, 0.530; 95% confidence interval, 0.312-0.901; P = .019).

The work was simultaneously published in the Journal of the American College of Cardiology (2018 Sept. doi: 10.1016/j.jacc.2018.09.013) .

Despite good results in this and prior studies, uptake of the IVUS procedure is not high in the United States or Europe, according to members of a panel that reviewed the results at the Transcatheter Cardiovascular Therapeutics annual meeting.

“How can people continue to ignore the importance of imaging-guided stent optimization? Even with second-generation DES, the results are consistent across the studies. This is just another piece of irrefutable evidence,” said Gary S. Mintz, MD, chief medical officer at the Cardiovascular Research Foundation, and a discussant at the meeting, sponsored by the Cardiovascular Research Foundation.

Jim Kling/MDedge News

SAN DIEGO – Don’t be satisfied with a diagnosis of angina with no obstructive coronary artery disease; push for acetylcholine testing, the findings from a trial in Scotland suggest.

M. Alexander Otto/MDedge News

Going a little further with an acetylcholine challenge in the cath lab will usually uncover microvascular or vasospastic heart problems, and this can lead to appropriate treatment. Patients will have less angina and a better quality of life at 6 months, according to investigators from the University of Glasgow (Scotland).

Invasive angiography usually ends on both sides of the Atlantic when no occlusions are found. There are concerns about the safety of going further with acetylcholine challenges, and until now, there had been no grade A evidence from a randomized trial that it improves outcomes. The Glasgow team filled the evidence gap with their presentation of the Coronary Microvascular Angina (CorMicA) trial at the Transcatheter Cardiovascular Therapeutics (TCT) annual meeting, and there wasn’t a single serious adverse event (J Am Coll Cardiol. 2018 Sep 25. doi: 10.1016/j.jacc.2018.09.006).

“This was a proof-of-concept study, which we believe [should] substantiate a large, multicenter trial,” said senior investigator Colin Berry, PhD, a professor of cardiology and imaging at the university.

Acetylcholine was infused down the pressure wire in 151 subjects diagnosed with angina with no obstructive coronary artery diseases before they left the catheter lab. Of these patients, 76 were randomized to have their results shared with their treating cardiologist, and 75 were randomized to not have their results shared. Coronary functional testing is hardly ever done, so the no-share group was considered the standard-of-care control arm. The idea was to see whether it made a difference when treating physicians knew what was causing chest pain when their patients didn’t have occlusive disease.

It turned out to make a huge difference. The diagnosis of “chest pain of noncardiac origin” almost fell off the map. Once cardiologists knew what was going on, they switched up treatment according to European Society of Cardiology guidelines for functional heart pain. Patients with microvascular angina were given beta-blockers and switched off nitrates because these drugs make angina worse in microvascular disease. Subjects with vasospasms were shifted to calcium channel blockers and long-acting nitrates and away from beta-blockers because beta-blockers make vasospasms worse.

Cardiologists who didn’t know the results kept muddling along with what patients came in on at baseline – beta-blockers in two-thirds, long-acting nitrates in half, and calcium channel blockers in a third.

Subjects who got the right treatment because of acetylcholine testing outpaced the standard care group by almost 12 points on the Seattle Angina Questionnaire at 6 months; they could walk farther and didn’t have crushing angina almost every day (P = .001). They reported a statistically significant improvement in quality of life, and they were much happier with their doctors.

“This is the first randomized, sham-controlled trial in this space”; functional testing “was routinely safe and feasible. Therapy guided by the results of physiologic testing improved outcomes” and “treatment satisfaction,” said University of Glasgow interventional cardiologist Tom Ford, MD.

Acetylcholine was infused down the pressure wire into the radial artery, with the left anterior descending coronary artery as the target vessel. A final bolus of less than 100 mcg checked for coronary artery spasms; a symptomatic constriction of greater than 90% was considered positive. Glyceryl trinitrate was used to reverse the effects.

Three-quarters of the subjects were women, which Dr. Ford noted is unusual in an angina study. The mean age was 61 years, and subjects had about a 20% chance of a heart attack within 10 years. The whole procedure, including the angiogram, randomization, and functional testing, took a median of about 60 minutes.

There were no differences in major adverse cardiac events at 6 months, at 2.6% in both groups.

One patient developed persistent atrial fibrillation with acetylcholine testing that was converted to sinus rhythm with intravenous amiodarone, without a night in the hospital.

The work was funded by the British Heart Foundation. No companies were involved. The investigators didn’t have any relevant disclosures. The TCT meeting is sponsored by the Cardiovascular Research Foundation.

[email protected]

SOURCE: Ford TG et al. TCT 2018, Late-Breaking Trial.

SAN DIEGO – Don’t be satisfied with a diagnosis of angina with no obstructive coronary artery disease; push for acetylcholine testing, the findings from a trial in Scotland suggest.

M. Alexander Otto/MDedge News

Going a little further with an acetylcholine challenge in the cath lab will usually uncover microvascular or vasospastic heart problems, and this can lead to appropriate treatment. Patients will have less angina and a better quality of life at 6 months, according to investigators from the University of Glasgow (Scotland).

Invasive angiography usually ends on both sides of the Atlantic when no occlusions are found. There are concerns about the safety of going further with acetylcholine challenges, and until now, there had been no grade A evidence from a randomized trial that it improves outcomes. The Glasgow team filled the evidence gap with their presentation of the Coronary Microvascular Angina (CorMicA) trial at the Transcatheter Cardiovascular Therapeutics (TCT) annual meeting, and there wasn’t a single serious adverse event (J Am Coll Cardiol. 2018 Sep 25. doi: 10.1016/j.jacc.2018.09.006).

“This was a proof-of-concept study, which we believe [should] substantiate a large, multicenter trial,” said senior investigator Colin Berry, PhD, a professor of cardiology and imaging at the university.

Acetylcholine was infused down the pressure wire in 151 subjects diagnosed with angina with no obstructive coronary artery diseases before they left the catheter lab. Of these patients, 76 were randomized to have their results shared with their treating cardiologist, and 75 were randomized to not have their results shared. Coronary functional testing is hardly ever done, so the no-share group was considered the standard-of-care control arm. The idea was to see whether it made a difference when treating physicians knew what was causing chest pain when their patients didn’t have occlusive disease.

It turned out to make a huge difference. The diagnosis of “chest pain of noncardiac origin” almost fell off the map. Once cardiologists knew what was going on, they switched up treatment according to European Society of Cardiology guidelines for functional heart pain. Patients with microvascular angina were given beta-blockers and switched off nitrates because these drugs make angina worse in microvascular disease. Subjects with vasospasms were shifted to calcium channel blockers and long-acting nitrates and away from beta-blockers because beta-blockers make vasospasms worse.

Cardiologists who didn’t know the results kept muddling along with what patients came in on at baseline – beta-blockers in two-thirds, long-acting nitrates in half, and calcium channel blockers in a third.

Subjects who got the right treatment because of acetylcholine testing outpaced the standard care group by almost 12 points on the Seattle Angina Questionnaire at 6 months; they could walk farther and didn’t have crushing angina almost every day (P = .001). They reported a statistically significant improvement in quality of life, and they were much happier with their doctors.

“This is the first randomized, sham-controlled trial in this space”; functional testing “was routinely safe and feasible. Therapy guided by the results of physiologic testing improved outcomes” and “treatment satisfaction,” said University of Glasgow interventional cardiologist Tom Ford, MD.

Acetylcholine was infused down the pressure wire into the radial artery, with the left anterior descending coronary artery as the target vessel. A final bolus of less than 100 mcg checked for coronary artery spasms; a symptomatic constriction of greater than 90% was considered positive. Glyceryl trinitrate was used to reverse the effects.

Three-quarters of the subjects were women, which Dr. Ford noted is unusual in an angina study. The mean age was 61 years, and subjects had about a 20% chance of a heart attack within 10 years. The whole procedure, including the angiogram, randomization, and functional testing, took a median of about 60 minutes.

There were no differences in major adverse cardiac events at 6 months, at 2.6% in both groups.

One patient developed persistent atrial fibrillation with acetylcholine testing that was converted to sinus rhythm with intravenous amiodarone, without a night in the hospital.

The work was funded by the British Heart Foundation. No companies were involved. The investigators didn’t have any relevant disclosures. The TCT meeting is sponsored by the Cardiovascular Research Foundation.

[email protected]

SOURCE: Ford TG et al. TCT 2018, Late-Breaking Trial.

SAN DIEGO – Don’t be satisfied with a diagnosis of angina with no obstructive coronary artery disease; push for acetylcholine testing, the findings from a trial in Scotland suggest.

M. Alexander Otto/MDedge News

Going a little further with an acetylcholine challenge in the cath lab will usually uncover microvascular or vasospastic heart problems, and this can lead to appropriate treatment. Patients will have less angina and a better quality of life at 6 months, according to investigators from the University of Glasgow (Scotland).

Invasive angiography usually ends on both sides of the Atlantic when no occlusions are found. There are concerns about the safety of going further with acetylcholine challenges, and until now, there had been no grade A evidence from a randomized trial that it improves outcomes. The Glasgow team filled the evidence gap with their presentation of the Coronary Microvascular Angina (CorMicA) trial at the Transcatheter Cardiovascular Therapeutics (TCT) annual meeting, and there wasn’t a single serious adverse event (J Am Coll Cardiol. 2018 Sep 25. doi: 10.1016/j.jacc.2018.09.006).

“This was a proof-of-concept study, which we believe [should] substantiate a large, multicenter trial,” said senior investigator Colin Berry, PhD, a professor of cardiology and imaging at the university.

Acetylcholine was infused down the pressure wire in 151 subjects diagnosed with angina with no obstructive coronary artery diseases before they left the catheter lab. Of these patients, 76 were randomized to have their results shared with their treating cardiologist, and 75 were randomized to not have their results shared. Coronary functional testing is hardly ever done, so the no-share group was considered the standard-of-care control arm. The idea was to see whether it made a difference when treating physicians knew what was causing chest pain when their patients didn’t have occlusive disease.

It turned out to make a huge difference. The diagnosis of “chest pain of noncardiac origin” almost fell off the map. Once cardiologists knew what was going on, they switched up treatment according to European Society of Cardiology guidelines for functional heart pain. Patients with microvascular angina were given beta-blockers and switched off nitrates because these drugs make angina worse in microvascular disease. Subjects with vasospasms were shifted to calcium channel blockers and long-acting nitrates and away from beta-blockers because beta-blockers make vasospasms worse.

Cardiologists who didn’t know the results kept muddling along with what patients came in on at baseline – beta-blockers in two-thirds, long-acting nitrates in half, and calcium channel blockers in a third.

Subjects who got the right treatment because of acetylcholine testing outpaced the standard care group by almost 12 points on the Seattle Angina Questionnaire at 6 months; they could walk farther and didn’t have crushing angina almost every day (P = .001). They reported a statistically significant improvement in quality of life, and they were much happier with their doctors.

“This is the first randomized, sham-controlled trial in this space”; functional testing “was routinely safe and feasible. Therapy guided by the results of physiologic testing improved outcomes” and “treatment satisfaction,” said University of Glasgow interventional cardiologist Tom Ford, MD.

Acetylcholine was infused down the pressure wire into the radial artery, with the left anterior descending coronary artery as the target vessel. A final bolus of less than 100 mcg checked for coronary artery spasms; a symptomatic constriction of greater than 90% was considered positive. Glyceryl trinitrate was used to reverse the effects.

Three-quarters of the subjects were women, which Dr. Ford noted is unusual in an angina study. The mean age was 61 years, and subjects had about a 20% chance of a heart attack within 10 years. The whole procedure, including the angiogram, randomization, and functional testing, took a median of about 60 minutes.

There were no differences in major adverse cardiac events at 6 months, at 2.6% in both groups.

One patient developed persistent atrial fibrillation with acetylcholine testing that was converted to sinus rhythm with intravenous amiodarone, without a night in the hospital.

The work was funded by the British Heart Foundation. No companies were involved. The investigators didn’t have any relevant disclosures. The TCT meeting is sponsored by the Cardiovascular Research Foundation.

[email protected]

SOURCE: Ford TG et al. TCT 2018, Late-Breaking Trial.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

Bicuspid aortic valve may initially be asymptomatic, but it is associated with progressive valvular and aortic abnormalities that can lead to chronic heart failure and sudden death. Regular monitoring is required with an eye toward surgery when indicated.

See related editorial

This article reviews inheritance patterns and conditions associated with bicuspid aortic valve. We discuss diagnosis, management, and monitoring, and offer surgical recommendations. Special guidance for dental procedures, pregnancy, and athletes is also provided.

A YOUNG MAN WITH PALPITATIONS AND A MURMUR

A 34-year-old man presented to an outpatient clinic with occasional palpitations over the past several months. He reported that he had been diagnosed with a murmur as a child but had received no further testing.

Physical examination at this time revealed a faint systolic crescendo-decrescendo murmur along the right sternal border without radiation to the carotid arteries or to the apex. Transthoracic echocardiography (TTE) showed a bicuspid aortic valve with fusion of the right and left coronary cusps, with no aortic valve stenosis or insufficiency. There was mild dilation of the aortic root, but the mid-ascending aorta could not be evaluated because of limited acoustic windows.

Is further diagnostic testing needed, and if so, what? May he participate in exertional physical activity? Does his newborn son need evaluation?

ABNORMALITIES OCCUR DURING EMBRYOGENESIS

Bicuspid aortic valve develops because of abnormal valvulogenesis. Adjacent cusps fail to separate from each other, resulting in only 2 cusps, with 1 usually larger than the other. Morphology varies according to which commissures are fused.¹

Bicuspid aortic valve is associated with abnormalities in the coronary artery anatomy in about 2% of patients, including anomalous origins of the coronary arteries and upwardly displaced coronary ostia.² Such features need to be considered before surgical intervention.

Bicuspid aortic valve can be found in 1% to 2% of the general population, with a male-to-female predominance of 3:1.^1,3,4 It is one of the most common congenital cardiac malformations and is the leading congenital cause of aortic valve stenosis.^1,3 However, routine screening of newborns for the condition is not recommended, and most cases are diagnosed incidentally.

GENETIC FACTORS PROMINENT

Bicuspid aortic valve is thought to be primarily inherited in an autosomal-dominant pattern, but there is evidence of genetic heterogeneity, and the pattern may be variable.^5,6

No single gene responsible for bicuspid aortic valve has been identified. The condition may occur as a component of different pleiotropic genetic syndromes such as Loeys-Dietz, DiGeorge, and Marfan syndromes,^7,8 as well as in patients with Turner syndrome and Williams syndrome.^8–11 It also commonly coexists with other congenital heart diseases, including ventricular septal defect, isolated aortic arch obstruction, and patent ductus arteriosus.⁹

Studies have found a 15% rate of familial clustering.^6,12 In a study of 142 patients with bicuspid aortic valve, 20% of first-degree relatives had some cardiac abnormality found by screening, of whom 68% had bicuspid aortic valve. Of these, 71% were newly detected abnormalities.¹³

CHARACTERISTIC CLICK AND MURMUR

Physical examination findings of a functionally normal bicuspid aortic valve include a systolic ejection click followed by an early peaking systolic murmur at the apex or left lower sternal border. With progression of aortic stenosis, the ejection murmur has a harsher sound, with later peaking, and the S2 sound diminishes or becomes inaudible.¹⁴ If aortic regurgitation is present, a diastolic decrescendo murmur is heard best at the left lower sternal border.

DISEASE PROGRESSION

Although bicuspid aortic valve is typically asymp­tomatic at first, it is commonly associated with progressive valvulopathy and thoracic aortic disease.^1,3,4,15 It can lead to chronic heart failure and increase the risk of acute aortic syndromes and sudden cardiac death.¹⁵

Michelena et al¹⁶ studied 212 cases of asymp­tomatic bicuspid aortic valve. Although the survival rate 20 years after diagnosis was the same as for an age-matched cohort in the general population, the frequency of adverse cardiovascular events and surgical interventions was higher.

Aortic stenosis progresses rapidly

Aortic stenosis associated with a bicuspid aortic valve tends to affect younger patients and progress more rapidly than when associated with a tricuspid valve.¹⁷

In a study of 542 patients with congenital bicuspid aortic valve undergoing aortic valve replacement,³ 75% had isolated aortic stenosis, 10% had aortic stenosis with some degree of aortic insufficiency, and 13% had isolated aortic insufficiency. Given the tendency of aortic stenosis to progress rapidly, early surgery is often pursued.^17,18

Aneurysmal disease is common

The thoracic aorta is at increased risk of aneurysmal disease, coarctation, and dissection in patients with a bicuspid aortic valve.^1,6,15

Michelena et al¹⁶ reported that in patients without an aneurysm at the time of bicuspid aortic valve diagnosis, the 25-year risk of aneurysm formation was approximately 26%. In patients with an aneurysm at the time of diagnosis, the 15-year risk of aortic surgery after the diagnosis of aneurysm was about 46% and the risk of aortic dissection after aneurysm diagnosis was 7%.¹⁵ Compared with the general population, the age-adjusted relative risk of aortic aneurysm in patients with bicuspid aortic valve was 86.2, and that of aortic dissection was 8.4. Although the absolute incidence of dissection is low in these patients, it is markedly higher than in the general population, particularly in older patients (age > 50) and those with an aneurysm at the time of diagnosis.¹⁵

The risk of infective endocarditis

Patients with bicuspid aortic valve are highly prone to infective endocarditis for reasons that remain poorly understood. The pathogens in most cases are staphylococci or viridans streptococci.¹⁹ Patients with infective endocarditis typically require emergency surgery. Complications including valvular abscess, myocardial abscess, and overt heart failure are common.¹⁹

Lamas and Eykyn²⁰ studied 408 cases of native valve endocarditis; in 12.3%, the patient had a bicuspid aortic valve. In this subset, all were male, the mean age was 39 at diagnosis, 82% needed surgery, and the death rate was 14%.

Patients with bicuspid aortic valve do not routinely need antibiotics before dental and surgical procedures, but if they have had endocarditis in the past, they need antibiotics to prevent a recurrence.²¹

REGULAR MONITORING NEEDED

Because complications may be life-threatening, early detection of progressive disease by regular screening is critical. Echocardiographic evaluation of valvular function, ventricular dimensions and function, and diameter of the aortic root and ascending aorta should be performed in every patient with bicuspid aortic valve. If initial imaging is normal and there is no aortic dilation, imaging should be repeated every 5 to 10 years. If any abnormality is found, repeat imaging is needed every year.²²

Magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be required to better assess the aorta for patients requiring a surgical intervention, or when aortic dimensions are not clearly visualized on TTE. MRI has 2 advantages over CT angiography: it poses no radiation risk, and it provides more information on left ventricular function and dimensions, in addition to valve assessment.^23,24

No published study has compared MRI or CT angiography and transesophageal echocardiography (TEE), but in a study of 174 patients with dilated aortic root, combined TTE and TEE detected aortic valve morphology accurately in 98% of cases. As TEE is more invasive, it is not recommended for regular surveillance (Figures 1 and 2).²⁵

FAMILY SCREENING RECOMMENDED

Close relatives should be evaluated for aortic valve and thoracic aortic disease.^12,13,23,26

The American College of Cardiology (ACC) and the American Heart Association (AHA), backed by radiologic and cardiovascular associations, concur in recommending echocardiographic screening and routine screening of the thoracic aorta for aortic root dilation in first-degree relatives (ie, siblings, parents, and children) of patients with bicuspid aortic valve (class I recommendation).^22,27,28

A comprehensive physical examination is recommended for family members in addition to TTE, with careful assessment of the aortic valve in short and long axes, and of the aortic root.¹⁴ If the aorta cannot be adequately evaluated with TTE, further assessment should be pursued with CT angiography or MRI.

EXERCISE RESTRICTIONS

The 2015 ACC/AHA guidelines for competitive athletes with cardiovascular abnormalities recommend annual screening with TTE or MRI angiography for athletes with bicuspid aortic valve and coexisting dilation of the ascending aorta (aortic diameter 40–42 mm in men and 36–39 mm in women) (class I recommendation, level of evidence C).²⁹

Athletes with a bicuspid aortic valve and a normal aortic root and ascending aorta may participate in all competitive activities.²⁹ However, those with a dilated aorta should avoid strenuous activities because of the increased risk of rupture.³⁰ The ACC/AHA recommendations²⁹ depend on the diameter of the ascending aorta and the nature of the sport:

• For an aortic diameter 40 to 42 mm in men or 36 to 39 mm in women, and no features of connective tissue disease or familial thoracic ascending aortic syndrome, low- and moderate-intensity sports with a low likelihood of significant body contact may be considered; consider avoiding intense weight training (class IIb, level of evidence C)
• For an aortic diameter 43 to 45 mm, low-intensity sports with a low likelihood of body contact may be considered (class IIb, level of evidence C)
• For an aortic diameter greater than 43 mm in men or greater than 40 mm in women, sports involving body collision should be avoided (class III, level of evidence C)
• For an aortic diameter greater than 45 mm, sports activities should be avoided (class III, level of evidence C).

PREGNANCY CONSIDERATIONS

Bicuspid aortic valve is associated with aortic dissection, mainly in the third trimester.³¹ Patients should ideally undergo echocardiographic screening before conception. The 2010 ACC/AHA guidelines for managing thoracic aortic disease recommend monthly or bimonthly echocardiography until delivery in pregnant women with a dilated thoracic aorta.²²

Patients with bicuspid aortic valve and aortic root enlargement of more than 40 mm should have preconception counseling about surgery for aortic root replacement before becoming pregnant. If the diagnosis of enlarged aortic root is made during pregnancy, echocardiographic surveillance at 4- to 6-week intervals is indicated.³²

SURGICAL MANAGEMENT

In the past, beta-blockers and angiotensin-converting enzyme inhibitors were recommended to minimize shear stress, with the goal of slowing progression of aortic dilation. However, evidence to support their use is inadequate.^33,34

The only definitive treatment is surgery, with various procedures that lower the risk of death or dissection.^24,35

The dimensions of the aortic root or ascending aorta should be examined vigilantly, according to the 2014 ACC/AHA guidelines²⁷:

• Repairing the aortic sinuses or replacing the ascending aorta is indicated if the diameter of the aortic sinuses or ascending aorta is greater than 5.5 cm (class I, level of evidence B)
• Repairing the aortic sinuses or replacing the ascending aorta is reasonable if the diameter of the aortic sinuses or ascending aorta is greater than 5.0 cm and the patient has a risk factor for dissection such as a family history of aortic dissection or an increase in diameter of 0.5 cm or greater per year (class IIa, level of evidence C)
• Replacement of the ascending aorta is reasonable if the diameter of the ascending aorta is greater than 4.5 cm and the patient is undergoing aortic valve surgery for severe aortic stenosis or regurgitation.

Valve repair or replacement

Aortic valve repair or replacement is sometimes done separately from aortic root repair.

The value of aortic valve repair is debatable, but a series of 728 patients at Cleveland Clinic showed a very low mortality rate (0.41%) and an annual reoperation rate of 2.6% during up to 15 years of follow-up.³⁶

Aortic valve replacement is usually considered for patients with severe valve dysfunction, abnormal left ventricular dimensions, or symptoms. It is important to determine if the patient is a good surgical candidate and to refer early for surgical evaluation to avoid the higher risk of death associated with emergency surgery.³⁶

Transcatheter aortic valve replacement has been studied in patients deemed to be at too high a risk for surgical replacement. Short- and intermediate-term outcomes have been good in these patients, but long-term data are lacking.³⁷

Surveillance after surgery

The type of operation determines postoperative surveillance.

After isolated aortic valve repair or replacement, patients should continue with surveillance at least annually to monitor for progressive aortopathy, as they remain at increased risk of dissection or rupture after isolated valve surgery, especially if they had aortic insufficiency preoperatively.³⁸

After definitive surgery with replacement or repair of the ascending aorta, no clear recommendations have been established for continued surveillance. However, it is reasonable to image these patients with either MRI or CT angiography 3 to 5 years after their surgery to monitor for anastomotic complications.

CASE QUESTIONS ANSWERED

Our patient should undergo repeat TTE in 1 year. He should also undergo CT angiography of the ascending aorta if it is not seen by TTE. He can participate in low-intensity sports but should avoid intense weight training. His parents, siblings, and children should be screened for bicuspid aortic valve or associated aortopathies.

A 64-year-old man with hypertension but  without known structural heart disease presents for a second opinion on management of his atrial fibrillation. The condition was first diagnosed at age 38, when he experienced palpitations and shortness of breath on exertion; at times he also experienced decreased endurance and fatigue without overt palpitations. At first, these episodes occurred about twice a year, and the patient was managed with a beta-blocker for rate control and an oral anticoagulant.

Over the past 10 years, the episodes have become more frequent and longer-lasting and have required frequent cardioversions. He was given flecainide for rhythm control but continued to have frequent episodes, and so about 1 year ago he was switched to amiodarone, which controlled his rhythm better. However, after reading about side effects of amiodarone, he decided to seek a second opinion.

He was evaluated by our team and eventually underwent radiofrequency ablation. During the procedure, he was noted to have diffuse scarring and fibrosis of his left atrium, and afterward he continued to require antiarrhythmic drugs to maintain sinus rhythm.

Should he have been referred sooner? What factors should primary care physicians consider when referring a patient with atrial fibrillation for ablation?

THE EPIDEMIC OF ATRIAL FIBRILLATION

Atrial fibrillation is a large and growing public health problem. In 2010, it was estimated to affect 2.7 to 6.1 million people in the United States, and with the rapid aging of our population, its prevalence is expected to rise to between 5.6 and 12 million by 2050.^1–3 It is associated with significant morbidity, poor quality of life, and increased risk of death, heart failure, stroke, and cognitive impairment.

The number of new cases per year has increased over the years despite research and preventive measures, which may reflect aging of the population and increased survival rates in patients with cardiovascular or comorbid conditions.^1,4

Thus, atrial fibrillation is one of the most common cardiovascular conditions encountered by primary care physicians and cardiologists, putting them at the forefront of its management. Proper treatment in its early stages and referral to a specialist for advanced management may alter its natural history and improve clinical outcomes.

HOW DOES ATRIAL FIBRILLATION ARISE AND PERSIST?

Much is still unknown about the pathogenesis of atrial fibrillation, but considerable progress has been made in the past few decades, opening the door for clinical ablative strategies.

Multiple wavelet hypothesis

Until the late 1980s, the most widely accepted conceptual mechanism of atrial fibrillation was the multiple wavelet hypothesis developed by Moe et al.⁵ According to this hypothesis, atrial fibrillation begins with multiple independent wavelets occurring simultaneously and spreading randomly throughout both atria, and it persists if there are a minimum number of coexisting wavelets, increased atrial mass, and heterogeneous conduction delays across the atrial tissue.

The surgical maze procedure, in which a series of incisions arranged in a maze-like pattern is created in the left atrium, was predicated on this model. The theory was that these surgical lesions would compartmentalize the atria into discrete electrical segments and thereby reduce  the number of circulating random wavelets.^6,7

However, experimental and clinical studies suggest that although randomly propagating wavelets can contribute to maintaining atrial fibrillation, focal triggers are noted in most cases.

Focal triggers

In 1997, Jaïs et al⁸ observed that atrial fibrillation is often triggered by a rapidly firing ectopic focus and that ablation of that focus can eliminate it. These ectopic foci are often found at or near the ostia of the pulmonary veins or near the superior vena cava.^8,9 It is now well established that ectopic foci in the pulmonary veins are crucial triggers that initiate atrial fibrillation.

Trigger-and-substrate theory

The substrate for maintaining atrial fibrillation consists of an abnormal left atrium with heterogeneous fibrosis (scarring) and conduction delays. Any heart disease that increases left atrial pressure could lead to atrial dilation and remodeling, which could be substrates for atrial fibrillation. Extensive atrial remodeling and scarring are associated with progression and persistence of atrial fibrillation and make rhythm control more challenging.

Atrial fibrillation begets atrial fibrillation

As shown in the case above, over time, paroxysmal atrial fibrillation often progresses to persistent and long-standing atrial fibrillation if not aggressively managed initially.

In 1972, Davies and Pomerance¹⁰ performed 100 autopsies and found that the people who had had atrial fibrillation for longer than 1 month had lost muscle mass in the sinus node and internodal tract, and their atria were dilated. The study introduced the concept that atrial fibrillation itself causes pathologic changes in the atrium.

Wijffels et al,¹¹ in an experiment in goats, showed that atrial fibrillation produced by rapid bursts of atrial pacing was initially paroxysmal. However, as they continued to induce atrial fibrillation over and over again, it lasted progressively longer until it would persist for more than 24 hours. Thus, in a relatively short time, the atria went from supporting paroxysmal fibrillation to supporting persistent fibrillation.

Atrial fibrillation leads to electrophysiologic and anatomic remodeling in the atrium, which leads to a shorter action potential duration and a shorter refractory period. This in turn makes it easier for atrial fibrillation to persist.¹²

Because atrial fibrillation tends to progress, intervening early may improve its outcomes. Early ablation has been shown to improve the chances of staying in sinus rhythm in both paroxysmal and persistent atrial fibrillation.^13–15

The goal of ablation is to prevent atrial fibrillation by eliminating the trigger that initiates it, altering the arrhythmogenic substrate, or both.

Pulmonary vein isolation

The most common ablation strategy is to electrically isolate the pulmonary veins by creating circumferential lesions around their antra. This creates a nonconducting rim of scar tissue, electrically disconnecting the pulmonary veins from the atrium.

Ablation outside of the pulmonary veins

Because recurrence rates are high in patients with persistent atrial fibrillation who undergo pulmonary vein ablation alone, the search continues for adjunctive strategies to improve outcomes. Although these strategies have a sound rationale based on experimental data and anecdotal evidence in humans, they have not yet been convincingly shown to be helpful in large clinical studies. Nonetheless, it is possible that more extensive substrate ablation—atrial “debulking”—could improve outcomes by reducing the amount of tissue that can fibrillate.

Linear ablation. Creating lines of ablation (as in the maze procedure) isolates different segments of the left atrium. Often, these lines are created along the roof of the left atrium between the right and left upper pulmonary veins and from the mitral valve to the left inferior pulmonary vein. The benefit of linear ablation has not been proven, and gaps in such lines may introduce atrial flutter.

Triggers not in the pulmonary veins. Common sites of nonpulmonary vein triggers include the posterior wall of the left atrium, the superior vena cava, the coronary sinus, and along the ligament of Marshall. Provocative maneuvers such as isoproterenol infusion can help find those triggers, which can then be ablated. A limitation is that there is no protocol proven to reproducibly elicit triggers.

Complex fractionated atrial electrograms are areas in the atrium with highly fractionated, low voltage potentials. They may be critical sites of substrate for atrial fibrillation, and many electrophysiologists target them in patients with persistent atrial fibrillation. But despite initial enthusiasm, doing so has not resulted in better outcomes in persistent atrial fibrillation.

Rotors. Animal studies have shown that atrial fibrillation can be triggered or maintained by localized sources of organized reentrant circuits (rotors) or focal impulses. Recent studies have shown that these electrical rotors and focal sources could potentially be mapped and ablated in humans. But positive results in initial reports have not been reproduced, and this remains an area of controversy.

Our practice. We isolate the pulmonary veins with antral ablations, ablate the posterior wall, and extend the ablation toward the septum and inferior to the right pulmonary veins, with good long-term outcomes.¹⁴ The rationale behind ablating the posterior wall is that it shares embryologic origins with the pulmonary veins and may be a common source of triggers in atrial fibrillation.

We do not routinely create empiric ablation lines in the left or right atrium unless the patient has atrial flutter. Empiric ablation lines have not been convincingly shown to provide additional benefit compared with our extensive ablation approach, which involves the posterior wall. Empiric ablation of the appendage or coronary sinus is typically reserved for repeat ablation in patients with recurrent persistent atrial fibrillation.

RATIONALE FOR TREATING ATRIAL FIBRILLATION WITH ABLATION

To control symptoms

At this time, the primary aim of atrial fibrillation ablation is to reduce symptoms and improve quality of life. In theory, ablation could also decrease the risk of stroke, heart failure, and death. However, these outcomes have not been systematically evaluated in any large randomized controlled trial.

To control rhythm and improve survival

Randomized controlled trials of rhythm vs rate control of atrial fibrillation^16–18 have failed to demonstrate that restoring sinus rhythm is associated with better survival. All of these trials used antiarrhythmic drugs for rhythm control. However, nonrandomized studies^19,20 showed that maintaining sinus rhythm is associated with a significant reduction in mortality rates, whereas the use of antiarrhythmic drugs increased mortality risk.

This suggests that the beneficial effect of restoring sinus rhythm may be offset by adverse effects of antiarrhythmic drugs, and if rhythm control could be achieved by a method other than antiarrhythmic drug therapy, it may be superior to rate control. On the other hand, these data may be affected by residual confounding. This topic deserves further research, but maintaining sinus rhythm is typically preferred whenever possible.

Discontinuing anticoagulation is not a goal at this time

Retrospective studies have reported a low risk of stroke in patients who discontinue anticoagulation several months after undergoing atrial fibrillation ablation.^21–23 However, atrial fibrillation can recur, and risk of stroke increases with age.

Therefore, guidelines²⁴ still recommend continuing anticoagulation after ablation. Generally, we do not offer ablation with a goal of discontinuing anticoagulation. That said, stopping anticoagulation may be considered after long-term suppression of paroxysmal atrial fibrillation on a case-by-case basis in patients deemed to be at low risk. Left atrial appendage closure devices may eventually allow concomitant atrial fibrillation ablation and closure of the appendage, so that anticoagulation could then be stopped. This remains a topic of investigation.

Who should be considered for ablation?

There are no absolute age or comorbidity contraindications to ablation. Everyone who has atrial fibrillation deserves, in our opinion, a referral to the electrophysiology clinic.

Atrial fibrillation ablation is most often performed by electrophysiologists using a minimally invasive endovascular approach. The patient can be under either moderate sedation or general anesthesia; we prefer general anesthesia for patient comfort, safety, and efficacy.

We use an electrogram-based technique to target and eliminate electrical potentials and ensure continuity of ablation sets, with additional guidance by 3-dimensional cardiac mapping systems and intracardiac echocardiography. We also use contact force-sensing catheters to ensure catheter-tissue contact during ablation and to avoid excessive contact, which may enhance the safety of the procedure.

Energy: Hot or cold

Two types of energy can be used for ablation:

Radiofrequency energy (low voltage, high frequency—30 kHz to 1.5 mHz) is delivered to the endocardial surface via a point-source catheter. The radiofrequency energy produces controlled, focal thermal ablation.

In a randomized trial,²⁵ these ablation technologies were shown to be equivalent for preventing recurrences of atrial fibrillation. We use both in our practice. The choice depends primarily on the planned ablation set, given that balloon cryoablation can achieve antral isolation of the pulmonary veins but allows little or no substrate modification.

Improved ablation technology

Contact force-sensing catheters. Radio­frequency ablation catheters are now equipped with a pressure sensor at the tip that measures how hard the catheter is pressing on the heart wall.^26,27 In our experience, this has improved the outcomes of ablation procedures, primarily in persistent atrial fibrillation.²⁸

Complications of ablation

Although catheter ablation for atrial fibrillation is safe, it is still one of the most complex electrophysiologic procedures. Improvements in technology and techniques and accumulated experience over the past 15 years have made ablation safer, especially in tertiary care centers. But adverse outcomes are more frequent in low-volume centers.²⁹

Minor procedural complications include pericarditis, complications at the site of vascular access, and anesthesia-related complications. While they do not affect the long-term outcome for the patient, they may increase hospital length of stay and cause temporary inconvenience.

Major complications include cardiac perforation and tamponade, periprocedural stroke, pulmonary vein stenosis, atrioesophageal fistula, phrenic nerve paralysis, major bleeding, myocardial infarction, and death. In a worldwide survey published in 2005, when atrial fibrillation ablation was still novel, the rate of major complications was 6%.³⁰ By 2010, this had declined to 4.5%,³¹ and the rates of major complications may be significantly lower in more experienced centers.²⁹ In our practice, in 2015, the rate of major complications was 1.3% (unpublished data).

Outcomes of catheter ablation

Clinical outcomes depend on many factors including the type of atrial fibrillation (paroxysmal vs nonparoxysmal), overall health of the atria (atrial size and scarring), patient age and comorbidities, and most importantly, the center’s and operator’s experience.

In randomized controlled trials comparing ablation and antiarrhythmic drug therapy, the efficacy of ablation in maintaining sinus rhythm has been in the range of 66% to 86% vs 16% to 22% for drug therapy,^32,33 but these trials have been predominantly in middle-aged white men with paroxysmal atrial fibrillation. These trials also showed that catheter ablation reduced symptoms and improved quality of life. Ablation is less effective in persistent than in paroxysmal atrial fibrillation.³⁴

In a long-term study from our group,¹⁴ 660 (79.4%) of 831 patients who underwent ablation in 2005 were arrhythmia-free and not on antiarrhythmic drug therapy after a total of 1,019 ablations (an average of 1.2 ablations per patient) at a median of 55 months; 125 patients (15%, 41 with more than 1 ablation) continued to have atrial arrhythmia, controlled with drugs in 87 patients (69.6%). Only 38 patients (4.6%) continued to have drug-resistant atrial fibrillation and were treated with rate control with negative dromotropic agents.

Recent evidence

The largest randomized controlled trial of catheter ablation vs drug therapy for atrial fibrillation (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation [CABANA]) was completed recently, and the results were presented at a national meeting, although they have not yet been published in a peer-reviewed journal.³⁵

A total of 2,204 patients with atrial fibrillation (42.4% paroxysmal, 47.3% persistent, and 10.3% long-standing persistent) were randomized to either ablation or drug therapy. Median follow-up was 4 years. The crossover rate was high—9.2% of those randomized to ablation did not undergo it, and 27.5% of those randomized to drug therapy underwent ablation.

The incidence of the primary end point (a composite of death, disabling stroke, serious bleeding, and cardiac arrest) was not significantly different between the 2 groups in the intention-to-treat analysis; however, given the high crossover rates, the as-treated and per-protocol analyses become important, and as-treated and per-protocol analyses revealed a significant benefit of ablation compared with drug therapy. The hazard ratio (HR) for the primary composite outcome was 0.67 (P = .006) on as-treated analysis and 0.73 (P = .05) on per-protocol analysis. The HR for all-cause mortality was 0.60 (P = .005) on as-treated analysis.

PERIPROCEDURAL CONSIDERATIONS

Periprocedural anticoagulation

The risk of thromboembolism is increased during, immediately following, and for several weeks to months after atrial fibrillation ablation.^36,37

During the procedure, the risk is related to transseptal sheath placement, electrode catheters in the left atrium, and char formation on ablation catheters. These risks are mitigated with proper and careful sheath and catheter manipulation, maintenance of bubble-free irrigation through lines and sheaths, use of irrigated catheters, and initiation of heparin before transseptal access. Heparin is also infused during the procedure, with close monitoring of activated clotting time.

Postprocedurally, the transiently increased clotting risk could be due to damaged endothelium from the ablation itself and stunning of atrial tissue, which results in impaired contraction. Damaged endothelium improves as the tissue heals, and the stunning resolves by electrical reverse remodeling with sinus rhythm maintenance.

In view of these risks, the referring physician and electrophysiologist must pay careful attention to anticoagulation before and after ablation.

Before the procedure. It is safe to continue anticoagulation uninterrupted through the procedure.^38,39 If the patient is on warfarin, we want the international normalized ratio to be in the therapeutic range when we perform atrial fibrillation ablation, and the patient takes his or her usual dose on the day of the procedure. If taking a direct oral anticoagulant, patients typically skip a dose the day before ablation and again on the morning of the procedure, and resume taking it immediately afterward while in the anesthesia recovery room.

During the procedure, we start heparin before transseptal puncture, adjust it to achieve an activated clotting time of 300 to 400 seconds, and keep it in this range as long as there are sheaths or catheters in the left atrium.

After the procedure. The current guidelines²⁴ recommend that oral anticoagulation be continued without interruption for at least 2 months after the procedure, and in most cases indefinitely, depending on age and comorbidities. The decision to stop anticoagulation after 2 months is typically based on the stroke risk as assessed by the CHA₂DS₂-VASc score (www.chadsvasc.org) and not on the success of the ablation procedure.

ANTIARRHYTHMIC DRUGS AFTER THE PROCEDURE

Some patients actually experience more atrial fibrillation in the first weeks to months after the procedure. The mechanism in this setting may be different from that causing the arrhythmia in the first place. The causes of early recurrence of atrial arrhythmias include postablation inflammation, temporary autonomic imbalance, and delay of atrial radio­frequency lesion formation.^40,41 These arrhythmias may completely resolve as the ablation lesions heal and scars mature.

It has been hypothesized that short-term use of antiarrhythmic drugs after atrial fibrillation ablation is effective in preventing arrhythmias because it alters atrial electrophysiologic characteristics induced by the above transient factors. A recent systematic review of 6 clinical trials showed that short-term use of antiarrhythmic drugs reduces the risk of early arrhythmia recurrence but does not reduce recurrence in the long term.⁴²

In terms of outcomes, any arrhythmias that occur in the first 3 months do not necessarily affect long-term success. This is referred to as the “blanking period.” However, generally speaking, it is preferable to maintain sinus rhythm during that time to avoid further anatomic or electrical left atrial adverse remodeling. In many situations, patients continue taking the same antiarrhythmic agent or start on antiarrhythmic therapy in the first few months after ablation.^43,44

The mechanisms of late recurrence of atrial arrhythmias after ablation are thought to be different from those in early recurrence. Late recurrence has been ascribed to incomplete pulmonary vein isolation, recovery of pulmonary vein-left atrium connections, or recovery of any other lines of ablation created in the procedure.^45,46 For late recurrence of atrial arrhythmia, studies and guidelines suggest that repeat ablation may be an option.^24,47

PRACTICAL CONSIDERATIONS FOR PROCEDURAL PLANNING

Before the procedure, some electrophysiologists use cardiac computed tomography or magnetic resonance imaging to evaluate the pulmonary vein anatomy. This helps in planning and in selecting the appropriate tools for the procedure.

The patient is asked to fast on the day of the procedure. The procedure can take 3 to 6 hours, depending on the patient’s anatomy and the operator’s technique and experience. It can be performed with the patient under general anesthesia or conscious sedation. Currently, we use general anesthesia most of the time to maximize patient comfort.

After the procedure, our patients must stay in bed for 4 hours and stay overnight for observation. If no complications arise, they are discharged the next day.

A 64-year-old man with hypertension but  without known structural heart disease presents for a second opinion on management of his atrial fibrillation. The condition was first diagnosed at age 38, when he experienced palpitations and shortness of breath on exertion; at times he also experienced decreased endurance and fatigue without overt palpitations. At first, these episodes occurred about twice a year, and the patient was managed with a beta-blocker for rate control and an oral anticoagulant.

Over the past 10 years, the episodes have become more frequent and longer-lasting and have required frequent cardioversions. He was given flecainide for rhythm control but continued to have frequent episodes, and so about 1 year ago he was switched to amiodarone, which controlled his rhythm better. However, after reading about side effects of amiodarone, he decided to seek a second opinion.

He was evaluated by our team and eventually underwent radiofrequency ablation. During the procedure, he was noted to have diffuse scarring and fibrosis of his left atrium, and afterward he continued to require antiarrhythmic drugs to maintain sinus rhythm.

Should he have been referred sooner? What factors should primary care physicians consider when referring a patient with atrial fibrillation for ablation?

THE EPIDEMIC OF ATRIAL FIBRILLATION

Atrial fibrillation is a large and growing public health problem. In 2010, it was estimated to affect 2.7 to 6.1 million people in the United States, and with the rapid aging of our population, its prevalence is expected to rise to between 5.6 and 12 million by 2050.^1–3 It is associated with significant morbidity, poor quality of life, and increased risk of death, heart failure, stroke, and cognitive impairment.

The number of new cases per year has increased over the years despite research and preventive measures, which may reflect aging of the population and increased survival rates in patients with cardiovascular or comorbid conditions.^1,4

Thus, atrial fibrillation is one of the most common cardiovascular conditions encountered by primary care physicians and cardiologists, putting them at the forefront of its management. Proper treatment in its early stages and referral to a specialist for advanced management may alter its natural history and improve clinical outcomes.

HOW DOES ATRIAL FIBRILLATION ARISE AND PERSIST?

Much is still unknown about the pathogenesis of atrial fibrillation, but considerable progress has been made in the past few decades, opening the door for clinical ablative strategies.

Multiple wavelet hypothesis

Until the late 1980s, the most widely accepted conceptual mechanism of atrial fibrillation was the multiple wavelet hypothesis developed by Moe et al.⁵ According to this hypothesis, atrial fibrillation begins with multiple independent wavelets occurring simultaneously and spreading randomly throughout both atria, and it persists if there are a minimum number of coexisting wavelets, increased atrial mass, and heterogeneous conduction delays across the atrial tissue.

The surgical maze procedure, in which a series of incisions arranged in a maze-like pattern is created in the left atrium, was predicated on this model. The theory was that these surgical lesions would compartmentalize the atria into discrete electrical segments and thereby reduce  the number of circulating random wavelets.^6,7

However, experimental and clinical studies suggest that although randomly propagating wavelets can contribute to maintaining atrial fibrillation, focal triggers are noted in most cases.

Focal triggers

In 1997, Jaïs et al⁸ observed that atrial fibrillation is often triggered by a rapidly firing ectopic focus and that ablation of that focus can eliminate it. These ectopic foci are often found at or near the ostia of the pulmonary veins or near the superior vena cava.^8,9 It is now well established that ectopic foci in the pulmonary veins are crucial triggers that initiate atrial fibrillation.

Trigger-and-substrate theory

The substrate for maintaining atrial fibrillation consists of an abnormal left atrium with heterogeneous fibrosis (scarring) and conduction delays. Any heart disease that increases left atrial pressure could lead to atrial dilation and remodeling, which could be substrates for atrial fibrillation. Extensive atrial remodeling and scarring are associated with progression and persistence of atrial fibrillation and make rhythm control more challenging.

Atrial fibrillation begets atrial fibrillation

As shown in the case above, over time, paroxysmal atrial fibrillation often progresses to persistent and long-standing atrial fibrillation if not aggressively managed initially.

In 1972, Davies and Pomerance¹⁰ performed 100 autopsies and found that the people who had had atrial fibrillation for longer than 1 month had lost muscle mass in the sinus node and internodal tract, and their atria were dilated. The study introduced the concept that atrial fibrillation itself causes pathologic changes in the atrium.

Wijffels et al,¹¹ in an experiment in goats, showed that atrial fibrillation produced by rapid bursts of atrial pacing was initially paroxysmal. However, as they continued to induce atrial fibrillation over and over again, it lasted progressively longer until it would persist for more than 24 hours. Thus, in a relatively short time, the atria went from supporting paroxysmal fibrillation to supporting persistent fibrillation.

Atrial fibrillation leads to electrophysiologic and anatomic remodeling in the atrium, which leads to a shorter action potential duration and a shorter refractory period. This in turn makes it easier for atrial fibrillation to persist.¹²

Because atrial fibrillation tends to progress, intervening early may improve its outcomes. Early ablation has been shown to improve the chances of staying in sinus rhythm in both paroxysmal and persistent atrial fibrillation.^13–15

The goal of ablation is to prevent atrial fibrillation by eliminating the trigger that initiates it, altering the arrhythmogenic substrate, or both.

Pulmonary vein isolation

The most common ablation strategy is to electrically isolate the pulmonary veins by creating circumferential lesions around their antra. This creates a nonconducting rim of scar tissue, electrically disconnecting the pulmonary veins from the atrium.

Ablation outside of the pulmonary veins

Because recurrence rates are high in patients with persistent atrial fibrillation who undergo pulmonary vein ablation alone, the search continues for adjunctive strategies to improve outcomes. Although these strategies have a sound rationale based on experimental data and anecdotal evidence in humans, they have not yet been convincingly shown to be helpful in large clinical studies. Nonetheless, it is possible that more extensive substrate ablation—atrial “debulking”—could improve outcomes by reducing the amount of tissue that can fibrillate.

Linear ablation. Creating lines of ablation (as in the maze procedure) isolates different segments of the left atrium. Often, these lines are created along the roof of the left atrium between the right and left upper pulmonary veins and from the mitral valve to the left inferior pulmonary vein. The benefit of linear ablation has not been proven, and gaps in such lines may introduce atrial flutter.

Triggers not in the pulmonary veins. Common sites of nonpulmonary vein triggers include the posterior wall of the left atrium, the superior vena cava, the coronary sinus, and along the ligament of Marshall. Provocative maneuvers such as isoproterenol infusion can help find those triggers, which can then be ablated. A limitation is that there is no protocol proven to reproducibly elicit triggers.

Complex fractionated atrial electrograms are areas in the atrium with highly fractionated, low voltage potentials. They may be critical sites of substrate for atrial fibrillation, and many electrophysiologists target them in patients with persistent atrial fibrillation. But despite initial enthusiasm, doing so has not resulted in better outcomes in persistent atrial fibrillation.

Rotors. Animal studies have shown that atrial fibrillation can be triggered or maintained by localized sources of organized reentrant circuits (rotors) or focal impulses. Recent studies have shown that these electrical rotors and focal sources could potentially be mapped and ablated in humans. But positive results in initial reports have not been reproduced, and this remains an area of controversy.

Our practice. We isolate the pulmonary veins with antral ablations, ablate the posterior wall, and extend the ablation toward the septum and inferior to the right pulmonary veins, with good long-term outcomes.¹⁴ The rationale behind ablating the posterior wall is that it shares embryologic origins with the pulmonary veins and may be a common source of triggers in atrial fibrillation.

We do not routinely create empiric ablation lines in the left or right atrium unless the patient has atrial flutter. Empiric ablation lines have not been convincingly shown to provide additional benefit compared with our extensive ablation approach, which involves the posterior wall. Empiric ablation of the appendage or coronary sinus is typically reserved for repeat ablation in patients with recurrent persistent atrial fibrillation.

RATIONALE FOR TREATING ATRIAL FIBRILLATION WITH ABLATION

To control symptoms

At this time, the primary aim of atrial fibrillation ablation is to reduce symptoms and improve quality of life. In theory, ablation could also decrease the risk of stroke, heart failure, and death. However, these outcomes have not been systematically evaluated in any large randomized controlled trial.

To control rhythm and improve survival

Randomized controlled trials of rhythm vs rate control of atrial fibrillation^16–18 have failed to demonstrate that restoring sinus rhythm is associated with better survival. All of these trials used antiarrhythmic drugs for rhythm control. However, nonrandomized studies^19,20 showed that maintaining sinus rhythm is associated with a significant reduction in mortality rates, whereas the use of antiarrhythmic drugs increased mortality risk.

This suggests that the beneficial effect of restoring sinus rhythm may be offset by adverse effects of antiarrhythmic drugs, and if rhythm control could be achieved by a method other than antiarrhythmic drug therapy, it may be superior to rate control. On the other hand, these data may be affected by residual confounding. This topic deserves further research, but maintaining sinus rhythm is typically preferred whenever possible.

Discontinuing anticoagulation is not a goal at this time

Retrospective studies have reported a low risk of stroke in patients who discontinue anticoagulation several months after undergoing atrial fibrillation ablation.^21–23 However, atrial fibrillation can recur, and risk of stroke increases with age.

Therefore, guidelines²⁴ still recommend continuing anticoagulation after ablation. Generally, we do not offer ablation with a goal of discontinuing anticoagulation. That said, stopping anticoagulation may be considered after long-term suppression of paroxysmal atrial fibrillation on a case-by-case basis in patients deemed to be at low risk. Left atrial appendage closure devices may eventually allow concomitant atrial fibrillation ablation and closure of the appendage, so that anticoagulation could then be stopped. This remains a topic of investigation.

Who should be considered for ablation?

There are no absolute age or comorbidity contraindications to ablation. Everyone who has atrial fibrillation deserves, in our opinion, a referral to the electrophysiology clinic.

Atrial fibrillation ablation is most often performed by electrophysiologists using a minimally invasive endovascular approach. The patient can be under either moderate sedation or general anesthesia; we prefer general anesthesia for patient comfort, safety, and efficacy.

We use an electrogram-based technique to target and eliminate electrical potentials and ensure continuity of ablation sets, with additional guidance by 3-dimensional cardiac mapping systems and intracardiac echocardiography. We also use contact force-sensing catheters to ensure catheter-tissue contact during ablation and to avoid excessive contact, which may enhance the safety of the procedure.

Energy: Hot or cold

Two types of energy can be used for ablation:

Radiofrequency energy (low voltage, high frequency—30 kHz to 1.5 mHz) is delivered to the endocardial surface via a point-source catheter. The radiofrequency energy produces controlled, focal thermal ablation.

In a randomized trial,²⁵ these ablation technologies were shown to be equivalent for preventing recurrences of atrial fibrillation. We use both in our practice. The choice depends primarily on the planned ablation set, given that balloon cryoablation can achieve antral isolation of the pulmonary veins but allows little or no substrate modification.

Improved ablation technology

Contact force-sensing catheters. Radio­frequency ablation catheters are now equipped with a pressure sensor at the tip that measures how hard the catheter is pressing on the heart wall.^26,27 In our experience, this has improved the outcomes of ablation procedures, primarily in persistent atrial fibrillation.²⁸

Complications of ablation

Although catheter ablation for atrial fibrillation is safe, it is still one of the most complex electrophysiologic procedures. Improvements in technology and techniques and accumulated experience over the past 15 years have made ablation safer, especially in tertiary care centers. But adverse outcomes are more frequent in low-volume centers.²⁹

Minor procedural complications include pericarditis, complications at the site of vascular access, and anesthesia-related complications. While they do not affect the long-term outcome for the patient, they may increase hospital length of stay and cause temporary inconvenience.

Major complications include cardiac perforation and tamponade, periprocedural stroke, pulmonary vein stenosis, atrioesophageal fistula, phrenic nerve paralysis, major bleeding, myocardial infarction, and death. In a worldwide survey published in 2005, when atrial fibrillation ablation was still novel, the rate of major complications was 6%.³⁰ By 2010, this had declined to 4.5%,³¹ and the rates of major complications may be significantly lower in more experienced centers.²⁹ In our practice, in 2015, the rate of major complications was 1.3% (unpublished data).

Outcomes of catheter ablation

Clinical outcomes depend on many factors including the type of atrial fibrillation (paroxysmal vs nonparoxysmal), overall health of the atria (atrial size and scarring), patient age and comorbidities, and most importantly, the center’s and operator’s experience.

In randomized controlled trials comparing ablation and antiarrhythmic drug therapy, the efficacy of ablation in maintaining sinus rhythm has been in the range of 66% to 86% vs 16% to 22% for drug therapy,^32,33 but these trials have been predominantly in middle-aged white men with paroxysmal atrial fibrillation. These trials also showed that catheter ablation reduced symptoms and improved quality of life. Ablation is less effective in persistent than in paroxysmal atrial fibrillation.³⁴

In a long-term study from our group,¹⁴ 660 (79.4%) of 831 patients who underwent ablation in 2005 were arrhythmia-free and not on antiarrhythmic drug therapy after a total of 1,019 ablations (an average of 1.2 ablations per patient) at a median of 55 months; 125 patients (15%, 41 with more than 1 ablation) continued to have atrial arrhythmia, controlled with drugs in 87 patients (69.6%). Only 38 patients (4.6%) continued to have drug-resistant atrial fibrillation and were treated with rate control with negative dromotropic agents.

Recent evidence

The largest randomized controlled trial of catheter ablation vs drug therapy for atrial fibrillation (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation [CABANA]) was completed recently, and the results were presented at a national meeting, although they have not yet been published in a peer-reviewed journal.³⁵

A total of 2,204 patients with atrial fibrillation (42.4% paroxysmal, 47.3% persistent, and 10.3% long-standing persistent) were randomized to either ablation or drug therapy. Median follow-up was 4 years. The crossover rate was high—9.2% of those randomized to ablation did not undergo it, and 27.5% of those randomized to drug therapy underwent ablation.

The incidence of the primary end point (a composite of death, disabling stroke, serious bleeding, and cardiac arrest) was not significantly different between the 2 groups in the intention-to-treat analysis; however, given the high crossover rates, the as-treated and per-protocol analyses become important, and as-treated and per-protocol analyses revealed a significant benefit of ablation compared with drug therapy. The hazard ratio (HR) for the primary composite outcome was 0.67 (P = .006) on as-treated analysis and 0.73 (P = .05) on per-protocol analysis. The HR for all-cause mortality was 0.60 (P = .005) on as-treated analysis.

PERIPROCEDURAL CONSIDERATIONS

Periprocedural anticoagulation

The risk of thromboembolism is increased during, immediately following, and for several weeks to months after atrial fibrillation ablation.^36,37

During the procedure, the risk is related to transseptal sheath placement, electrode catheters in the left atrium, and char formation on ablation catheters. These risks are mitigated with proper and careful sheath and catheter manipulation, maintenance of bubble-free irrigation through lines and sheaths, use of irrigated catheters, and initiation of heparin before transseptal access. Heparin is also infused during the procedure, with close monitoring of activated clotting time.

Postprocedurally, the transiently increased clotting risk could be due to damaged endothelium from the ablation itself and stunning of atrial tissue, which results in impaired contraction. Damaged endothelium improves as the tissue heals, and the stunning resolves by electrical reverse remodeling with sinus rhythm maintenance.

In view of these risks, the referring physician and electrophysiologist must pay careful attention to anticoagulation before and after ablation.

Before the procedure. It is safe to continue anticoagulation uninterrupted through the procedure.^38,39 If the patient is on warfarin, we want the international normalized ratio to be in the therapeutic range when we perform atrial fibrillation ablation, and the patient takes his or her usual dose on the day of the procedure. If taking a direct oral anticoagulant, patients typically skip a dose the day before ablation and again on the morning of the procedure, and resume taking it immediately afterward while in the anesthesia recovery room.

During the procedure, we start heparin before transseptal puncture, adjust it to achieve an activated clotting time of 300 to 400 seconds, and keep it in this range as long as there are sheaths or catheters in the left atrium.

After the procedure. The current guidelines²⁴ recommend that oral anticoagulation be continued without interruption for at least 2 months after the procedure, and in most cases indefinitely, depending on age and comorbidities. The decision to stop anticoagulation after 2 months is typically based on the stroke risk as assessed by the CHA₂DS₂-VASc score (www.chadsvasc.org) and not on the success of the ablation procedure.

ANTIARRHYTHMIC DRUGS AFTER THE PROCEDURE

Some patients actually experience more atrial fibrillation in the first weeks to months after the procedure. The mechanism in this setting may be different from that causing the arrhythmia in the first place. The causes of early recurrence of atrial arrhythmias include postablation inflammation, temporary autonomic imbalance, and delay of atrial radio­frequency lesion formation.^40,41 These arrhythmias may completely resolve as the ablation lesions heal and scars mature.

It has been hypothesized that short-term use of antiarrhythmic drugs after atrial fibrillation ablation is effective in preventing arrhythmias because it alters atrial electrophysiologic characteristics induced by the above transient factors. A recent systematic review of 6 clinical trials showed that short-term use of antiarrhythmic drugs reduces the risk of early arrhythmia recurrence but does not reduce recurrence in the long term.⁴²

In terms of outcomes, any arrhythmias that occur in the first 3 months do not necessarily affect long-term success. This is referred to as the “blanking period.” However, generally speaking, it is preferable to maintain sinus rhythm during that time to avoid further anatomic or electrical left atrial adverse remodeling. In many situations, patients continue taking the same antiarrhythmic agent or start on antiarrhythmic therapy in the first few months after ablation.^43,44

The mechanisms of late recurrence of atrial arrhythmias after ablation are thought to be different from those in early recurrence. Late recurrence has been ascribed to incomplete pulmonary vein isolation, recovery of pulmonary vein-left atrium connections, or recovery of any other lines of ablation created in the procedure.^45,46 For late recurrence of atrial arrhythmia, studies and guidelines suggest that repeat ablation may be an option.^24,47

PRACTICAL CONSIDERATIONS FOR PROCEDURAL PLANNING

Before the procedure, some electrophysiologists use cardiac computed tomography or magnetic resonance imaging to evaluate the pulmonary vein anatomy. This helps in planning and in selecting the appropriate tools for the procedure.

The patient is asked to fast on the day of the procedure. The procedure can take 3 to 6 hours, depending on the patient’s anatomy and the operator’s technique and experience. It can be performed with the patient under general anesthesia or conscious sedation. Currently, we use general anesthesia most of the time to maximize patient comfort.

After the procedure, our patients must stay in bed for 4 hours and stay overnight for observation. If no complications arise, they are discharged the next day.

A 64-year-old man with hypertension but  without known structural heart disease presents for a second opinion on management of his atrial fibrillation. The condition was first diagnosed at age 38, when he experienced palpitations and shortness of breath on exertion; at times he also experienced decreased endurance and fatigue without overt palpitations. At first, these episodes occurred about twice a year, and the patient was managed with a beta-blocker for rate control and an oral anticoagulant.

Over the past 10 years, the episodes have become more frequent and longer-lasting and have required frequent cardioversions. He was given flecainide for rhythm control but continued to have frequent episodes, and so about 1 year ago he was switched to amiodarone, which controlled his rhythm better. However, after reading about side effects of amiodarone, he decided to seek a second opinion.

He was evaluated by our team and eventually underwent radiofrequency ablation. During the procedure, he was noted to have diffuse scarring and fibrosis of his left atrium, and afterward he continued to require antiarrhythmic drugs to maintain sinus rhythm.

Should he have been referred sooner? What factors should primary care physicians consider when referring a patient with atrial fibrillation for ablation?

THE EPIDEMIC OF ATRIAL FIBRILLATION

Atrial fibrillation is a large and growing public health problem. In 2010, it was estimated to affect 2.7 to 6.1 million people in the United States, and with the rapid aging of our population, its prevalence is expected to rise to between 5.6 and 12 million by 2050.^1–3 It is associated with significant morbidity, poor quality of life, and increased risk of death, heart failure, stroke, and cognitive impairment.

The number of new cases per year has increased over the years despite research and preventive measures, which may reflect aging of the population and increased survival rates in patients with cardiovascular or comorbid conditions.^1,4

Thus, atrial fibrillation is one of the most common cardiovascular conditions encountered by primary care physicians and cardiologists, putting them at the forefront of its management. Proper treatment in its early stages and referral to a specialist for advanced management may alter its natural history and improve clinical outcomes.

HOW DOES ATRIAL FIBRILLATION ARISE AND PERSIST?

Much is still unknown about the pathogenesis of atrial fibrillation, but considerable progress has been made in the past few decades, opening the door for clinical ablative strategies.

Multiple wavelet hypothesis

Until the late 1980s, the most widely accepted conceptual mechanism of atrial fibrillation was the multiple wavelet hypothesis developed by Moe et al.⁵ According to this hypothesis, atrial fibrillation begins with multiple independent wavelets occurring simultaneously and spreading randomly throughout both atria, and it persists if there are a minimum number of coexisting wavelets, increased atrial mass, and heterogeneous conduction delays across the atrial tissue.

The surgical maze procedure, in which a series of incisions arranged in a maze-like pattern is created in the left atrium, was predicated on this model. The theory was that these surgical lesions would compartmentalize the atria into discrete electrical segments and thereby reduce  the number of circulating random wavelets.^6,7

However, experimental and clinical studies suggest that although randomly propagating wavelets can contribute to maintaining atrial fibrillation, focal triggers are noted in most cases.

Focal triggers

In 1997, Jaïs et al⁸ observed that atrial fibrillation is often triggered by a rapidly firing ectopic focus and that ablation of that focus can eliminate it. These ectopic foci are often found at or near the ostia of the pulmonary veins or near the superior vena cava.^8,9 It is now well established that ectopic foci in the pulmonary veins are crucial triggers that initiate atrial fibrillation.

Trigger-and-substrate theory

The substrate for maintaining atrial fibrillation consists of an abnormal left atrium with heterogeneous fibrosis (scarring) and conduction delays. Any heart disease that increases left atrial pressure could lead to atrial dilation and remodeling, which could be substrates for atrial fibrillation. Extensive atrial remodeling and scarring are associated with progression and persistence of atrial fibrillation and make rhythm control more challenging.

Atrial fibrillation begets atrial fibrillation

As shown in the case above, over time, paroxysmal atrial fibrillation often progresses to persistent and long-standing atrial fibrillation if not aggressively managed initially.

In 1972, Davies and Pomerance¹⁰ performed 100 autopsies and found that the people who had had atrial fibrillation for longer than 1 month had lost muscle mass in the sinus node and internodal tract, and their atria were dilated. The study introduced the concept that atrial fibrillation itself causes pathologic changes in the atrium.

Wijffels et al,¹¹ in an experiment in goats, showed that atrial fibrillation produced by rapid bursts of atrial pacing was initially paroxysmal. However, as they continued to induce atrial fibrillation over and over again, it lasted progressively longer until it would persist for more than 24 hours. Thus, in a relatively short time, the atria went from supporting paroxysmal fibrillation to supporting persistent fibrillation.

Atrial fibrillation leads to electrophysiologic and anatomic remodeling in the atrium, which leads to a shorter action potential duration and a shorter refractory period. This in turn makes it easier for atrial fibrillation to persist.¹²

Because atrial fibrillation tends to progress, intervening early may improve its outcomes. Early ablation has been shown to improve the chances of staying in sinus rhythm in both paroxysmal and persistent atrial fibrillation.^13–15

The goal of ablation is to prevent atrial fibrillation by eliminating the trigger that initiates it, altering the arrhythmogenic substrate, or both.

Pulmonary vein isolation

The most common ablation strategy is to electrically isolate the pulmonary veins by creating circumferential lesions around their antra. This creates a nonconducting rim of scar tissue, electrically disconnecting the pulmonary veins from the atrium.

Ablation outside of the pulmonary veins

Because recurrence rates are high in patients with persistent atrial fibrillation who undergo pulmonary vein ablation alone, the search continues for adjunctive strategies to improve outcomes. Although these strategies have a sound rationale based on experimental data and anecdotal evidence in humans, they have not yet been convincingly shown to be helpful in large clinical studies. Nonetheless, it is possible that more extensive substrate ablation—atrial “debulking”—could improve outcomes by reducing the amount of tissue that can fibrillate.

Linear ablation. Creating lines of ablation (as in the maze procedure) isolates different segments of the left atrium. Often, these lines are created along the roof of the left atrium between the right and left upper pulmonary veins and from the mitral valve to the left inferior pulmonary vein. The benefit of linear ablation has not been proven, and gaps in such lines may introduce atrial flutter.

Triggers not in the pulmonary veins. Common sites of nonpulmonary vein triggers include the posterior wall of the left atrium, the superior vena cava, the coronary sinus, and along the ligament of Marshall. Provocative maneuvers such as isoproterenol infusion can help find those triggers, which can then be ablated. A limitation is that there is no protocol proven to reproducibly elicit triggers.

Complex fractionated atrial electrograms are areas in the atrium with highly fractionated, low voltage potentials. They may be critical sites of substrate for atrial fibrillation, and many electrophysiologists target them in patients with persistent atrial fibrillation. But despite initial enthusiasm, doing so has not resulted in better outcomes in persistent atrial fibrillation.

Rotors. Animal studies have shown that atrial fibrillation can be triggered or maintained by localized sources of organized reentrant circuits (rotors) or focal impulses. Recent studies have shown that these electrical rotors and focal sources could potentially be mapped and ablated in humans. But positive results in initial reports have not been reproduced, and this remains an area of controversy.

Our practice. We isolate the pulmonary veins with antral ablations, ablate the posterior wall, and extend the ablation toward the septum and inferior to the right pulmonary veins, with good long-term outcomes.¹⁴ The rationale behind ablating the posterior wall is that it shares embryologic origins with the pulmonary veins and may be a common source of triggers in atrial fibrillation.

We do not routinely create empiric ablation lines in the left or right atrium unless the patient has atrial flutter. Empiric ablation lines have not been convincingly shown to provide additional benefit compared with our extensive ablation approach, which involves the posterior wall. Empiric ablation of the appendage or coronary sinus is typically reserved for repeat ablation in patients with recurrent persistent atrial fibrillation.

RATIONALE FOR TREATING ATRIAL FIBRILLATION WITH ABLATION

To control symptoms

At this time, the primary aim of atrial fibrillation ablation is to reduce symptoms and improve quality of life. In theory, ablation could also decrease the risk of stroke, heart failure, and death. However, these outcomes have not been systematically evaluated in any large randomized controlled trial.

To control rhythm and improve survival

Randomized controlled trials of rhythm vs rate control of atrial fibrillation^16–18 have failed to demonstrate that restoring sinus rhythm is associated with better survival. All of these trials used antiarrhythmic drugs for rhythm control. However, nonrandomized studies^19,20 showed that maintaining sinus rhythm is associated with a significant reduction in mortality rates, whereas the use of antiarrhythmic drugs increased mortality risk.

This suggests that the beneficial effect of restoring sinus rhythm may be offset by adverse effects of antiarrhythmic drugs, and if rhythm control could be achieved by a method other than antiarrhythmic drug therapy, it may be superior to rate control. On the other hand, these data may be affected by residual confounding. This topic deserves further research, but maintaining sinus rhythm is typically preferred whenever possible.

Discontinuing anticoagulation is not a goal at this time

Retrospective studies have reported a low risk of stroke in patients who discontinue anticoagulation several months after undergoing atrial fibrillation ablation.^21–23 However, atrial fibrillation can recur, and risk of stroke increases with age.

Therefore, guidelines²⁴ still recommend continuing anticoagulation after ablation. Generally, we do not offer ablation with a goal of discontinuing anticoagulation. That said, stopping anticoagulation may be considered after long-term suppression of paroxysmal atrial fibrillation on a case-by-case basis in patients deemed to be at low risk. Left atrial appendage closure devices may eventually allow concomitant atrial fibrillation ablation and closure of the appendage, so that anticoagulation could then be stopped. This remains a topic of investigation.

Who should be considered for ablation?

There are no absolute age or comorbidity contraindications to ablation. Everyone who has atrial fibrillation deserves, in our opinion, a referral to the electrophysiology clinic.

Atrial fibrillation ablation is most often performed by electrophysiologists using a minimally invasive endovascular approach. The patient can be under either moderate sedation or general anesthesia; we prefer general anesthesia for patient comfort, safety, and efficacy.

We use an electrogram-based technique to target and eliminate electrical potentials and ensure continuity of ablation sets, with additional guidance by 3-dimensional cardiac mapping systems and intracardiac echocardiography. We also use contact force-sensing catheters to ensure catheter-tissue contact during ablation and to avoid excessive contact, which may enhance the safety of the procedure.

Energy: Hot or cold

Two types of energy can be used for ablation:

Radiofrequency energy (low voltage, high frequency—30 kHz to 1.5 mHz) is delivered to the endocardial surface via a point-source catheter. The radiofrequency energy produces controlled, focal thermal ablation.

In a randomized trial,²⁵ these ablation technologies were shown to be equivalent for preventing recurrences of atrial fibrillation. We use both in our practice. The choice depends primarily on the planned ablation set, given that balloon cryoablation can achieve antral isolation of the pulmonary veins but allows little or no substrate modification.

Improved ablation technology

Contact force-sensing catheters. Radio­frequency ablation catheters are now equipped with a pressure sensor at the tip that measures how hard the catheter is pressing on the heart wall.^26,27 In our experience, this has improved the outcomes of ablation procedures, primarily in persistent atrial fibrillation.²⁸

Complications of ablation

Although catheter ablation for atrial fibrillation is safe, it is still one of the most complex electrophysiologic procedures. Improvements in technology and techniques and accumulated experience over the past 15 years have made ablation safer, especially in tertiary care centers. But adverse outcomes are more frequent in low-volume centers.²⁹

Minor procedural complications include pericarditis, complications at the site of vascular access, and anesthesia-related complications. While they do not affect the long-term outcome for the patient, they may increase hospital length of stay and cause temporary inconvenience.

Major complications include cardiac perforation and tamponade, periprocedural stroke, pulmonary vein stenosis, atrioesophageal fistula, phrenic nerve paralysis, major bleeding, myocardial infarction, and death. In a worldwide survey published in 2005, when atrial fibrillation ablation was still novel, the rate of major complications was 6%.³⁰ By 2010, this had declined to 4.5%,³¹ and the rates of major complications may be significantly lower in more experienced centers.²⁹ In our practice, in 2015, the rate of major complications was 1.3% (unpublished data).

Outcomes of catheter ablation

Clinical outcomes depend on many factors including the type of atrial fibrillation (paroxysmal vs nonparoxysmal), overall health of the atria (atrial size and scarring), patient age and comorbidities, and most importantly, the center’s and operator’s experience.

In randomized controlled trials comparing ablation and antiarrhythmic drug therapy, the efficacy of ablation in maintaining sinus rhythm has been in the range of 66% to 86% vs 16% to 22% for drug therapy,^32,33 but these trials have been predominantly in middle-aged white men with paroxysmal atrial fibrillation. These trials also showed that catheter ablation reduced symptoms and improved quality of life. Ablation is less effective in persistent than in paroxysmal atrial fibrillation.³⁴

In a long-term study from our group,¹⁴ 660 (79.4%) of 831 patients who underwent ablation in 2005 were arrhythmia-free and not on antiarrhythmic drug therapy after a total of 1,019 ablations (an average of 1.2 ablations per patient) at a median of 55 months; 125 patients (15%, 41 with more than 1 ablation) continued to have atrial arrhythmia, controlled with drugs in 87 patients (69.6%). Only 38 patients (4.6%) continued to have drug-resistant atrial fibrillation and were treated with rate control with negative dromotropic agents.

Recent evidence

The largest randomized controlled trial of catheter ablation vs drug therapy for atrial fibrillation (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation [CABANA]) was completed recently, and the results were presented at a national meeting, although they have not yet been published in a peer-reviewed journal.³⁵

A total of 2,204 patients with atrial fibrillation (42.4% paroxysmal, 47.3% persistent, and 10.3% long-standing persistent) were randomized to either ablation or drug therapy. Median follow-up was 4 years. The crossover rate was high—9.2% of those randomized to ablation did not undergo it, and 27.5% of those randomized to drug therapy underwent ablation.

The incidence of the primary end point (a composite of death, disabling stroke, serious bleeding, and cardiac arrest) was not significantly different between the 2 groups in the intention-to-treat analysis; however, given the high crossover rates, the as-treated and per-protocol analyses become important, and as-treated and per-protocol analyses revealed a significant benefit of ablation compared with drug therapy. The hazard ratio (HR) for the primary composite outcome was 0.67 (P = .006) on as-treated analysis and 0.73 (P = .05) on per-protocol analysis. The HR for all-cause mortality was 0.60 (P = .005) on as-treated analysis.

PERIPROCEDURAL CONSIDERATIONS

Periprocedural anticoagulation

The risk of thromboembolism is increased during, immediately following, and for several weeks to months after atrial fibrillation ablation.^36,37

During the procedure, the risk is related to transseptal sheath placement, electrode catheters in the left atrium, and char formation on ablation catheters. These risks are mitigated with proper and careful sheath and catheter manipulation, maintenance of bubble-free irrigation through lines and sheaths, use of irrigated catheters, and initiation of heparin before transseptal access. Heparin is also infused during the procedure, with close monitoring of activated clotting time.

Postprocedurally, the transiently increased clotting risk could be due to damaged endothelium from the ablation itself and stunning of atrial tissue, which results in impaired contraction. Damaged endothelium improves as the tissue heals, and the stunning resolves by electrical reverse remodeling with sinus rhythm maintenance.

In view of these risks, the referring physician and electrophysiologist must pay careful attention to anticoagulation before and after ablation.

Before the procedure. It is safe to continue anticoagulation uninterrupted through the procedure.^38,39 If the patient is on warfarin, we want the international normalized ratio to be in the therapeutic range when we perform atrial fibrillation ablation, and the patient takes his or her usual dose on the day of the procedure. If taking a direct oral anticoagulant, patients typically skip a dose the day before ablation and again on the morning of the procedure, and resume taking it immediately afterward while in the anesthesia recovery room.

During the procedure, we start heparin before transseptal puncture, adjust it to achieve an activated clotting time of 300 to 400 seconds, and keep it in this range as long as there are sheaths or catheters in the left atrium.

After the procedure. The current guidelines²⁴ recommend that oral anticoagulation be continued without interruption for at least 2 months after the procedure, and in most cases indefinitely, depending on age and comorbidities. The decision to stop anticoagulation after 2 months is typically based on the stroke risk as assessed by the CHA₂DS₂-VASc score (www.chadsvasc.org) and not on the success of the ablation procedure.

ANTIARRHYTHMIC DRUGS AFTER THE PROCEDURE

Some patients actually experience more atrial fibrillation in the first weeks to months after the procedure. The mechanism in this setting may be different from that causing the arrhythmia in the first place. The causes of early recurrence of atrial arrhythmias include postablation inflammation, temporary autonomic imbalance, and delay of atrial radio­frequency lesion formation.^40,41 These arrhythmias may completely resolve as the ablation lesions heal and scars mature.

It has been hypothesized that short-term use of antiarrhythmic drugs after atrial fibrillation ablation is effective in preventing arrhythmias because it alters atrial electrophysiologic characteristics induced by the above transient factors. A recent systematic review of 6 clinical trials showed that short-term use of antiarrhythmic drugs reduces the risk of early arrhythmia recurrence but does not reduce recurrence in the long term.⁴²

In terms of outcomes, any arrhythmias that occur in the first 3 months do not necessarily affect long-term success. This is referred to as the “blanking period.” However, generally speaking, it is preferable to maintain sinus rhythm during that time to avoid further anatomic or electrical left atrial adverse remodeling. In many situations, patients continue taking the same antiarrhythmic agent or start on antiarrhythmic therapy in the first few months after ablation.^43,44

The mechanisms of late recurrence of atrial arrhythmias after ablation are thought to be different from those in early recurrence. Late recurrence has been ascribed to incomplete pulmonary vein isolation, recovery of pulmonary vein-left atrium connections, or recovery of any other lines of ablation created in the procedure.^45,46 For late recurrence of atrial arrhythmia, studies and guidelines suggest that repeat ablation may be an option.^24,47

PRACTICAL CONSIDERATIONS FOR PROCEDURAL PLANNING

Before the procedure, some electrophysiologists use cardiac computed tomography or magnetic resonance imaging to evaluate the pulmonary vein anatomy. This helps in planning and in selecting the appropriate tools for the procedure.

The patient is asked to fast on the day of the procedure. The procedure can take 3 to 6 hours, depending on the patient’s anatomy and the operator’s technique and experience. It can be performed with the patient under general anesthesia or conscious sedation. Currently, we use general anesthesia most of the time to maximize patient comfort.

After the procedure, our patients must stay in bed for 4 hours and stay overnight for observation. If no complications arise, they are discharged the next day.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.