Milind Y. Desai, MD

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Physical findings are nonspecific

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

To try to identify and treat people who are at highest risk of cardiovascular events, including death, we use comprehensive risk-prediction models. Unfortunately, these models have limited accuracy and precision and do not predict very well.

See related article

Attractive, then, is the idea of using a noninvasive imaging test to measure coronary atherosclerosis before it causes trouble and thereby individualize the risk assessment. Noncontrast computed tomography (CT) can measure the amount of calcification in the coronary arteries, and therefore it can estimate the coronary atherosclerotic burden. It seems like an ideal test, and calcification as a marker of subclinical atherosclerosis has been extensively investigated.

However, despite more than 2 decades of use and data from hundreds of thousands of patients, the test remains poorly understood. Many physicians seem to use it solely as a means of placating “worried well” patients and do not truly appreciate its implications. Others proceed to ordering CT angiography, a more expensive test that involves the added risks of using higher x-ray doses and iodinated contrast, even when a correctly interpreted calcification score would provide ample information.

In this issue of the Cleveland Clinic Journal of Medicine, Chauffe and Winchester review the utility of coronary artery calcification scoring in current practice. We wish to supplement their review by suggesting some considerations to take into account before ordering this test:

• Does the patient have symptoms of coronary artery disease, and what is his or her risk-factor profile? Baseline patient characteristics are important to consider if we are to use this test appropriately.
• How should the result be interpreted, and does the ordering physician have the confidence to accept the result?

BEST USED IN ASYMPTOMATIC PATIENTS AT INTERMEDIATE RISK

Many large retrospective and prospective registries have demonstrated the predictive value of coronary artery calcification in diverse cohorts of patients without symptoms.

In three prospective registries—the Multi-Ethnic Study of Atherosclerosis¹ (MESA) with 6,722 patients, the Coronary CT Angiography Evaluation for Clinical Outcomes² (CONFIRM) with 7,590 patients, and the Heinz Nixdorf Recall (NHR) study³ with 4,129 patients—most of the patients who had heart attacks had a calcification score greater than 100. And conversely, data from more than 100,000 people show that the absence of calcification (ie, a score of 0) denotes a very low risk (< 1% over 5 years).^1–6

The pretest probability of coronary artery disease needs to be considered. The data clearly indicate that a Bayesian approach is warranted and that coronary artery calcification scoring should mainly be done in patients at intermediate or low-intermediate risk. Trials have shown that calcification scoring will reclassify more than 50% of intermediate-risk patients into the high-risk or low-risk category.³

The implications of these findings were eloquently assessed in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). In this trial, it was estimated that for patients with no calcification who would otherwise fulfill the criteria for treatment with a statin, 549 patients would need to be treated to prevent one coronary event, compared with 24 similar patients with a calcification score greater than 100.⁷

Although such analyses have potential shortcomings, in this era of greater concern about how to allocate finite resources, using a simple, inexpensive test to individualize long-term treatment is an attractive idea. Further, measuring calcification does not appear to increase testing “downstream” and indeed reduces it as compared with no calcification scoring. It also results in better adherence to drug therapy and lifestyle changes.

Because calcification scoring provides additional prognostic data and accurately discriminates and reclassifies risk, the American College of Cardiology and the American Heart Association have awarded it a class IIa recommendation for asymptomatic patients at intermediate risk, meaning that there is conflicting evidence or a divergence of opinion about its usefulness, but the weight of evidence or opinion favors it.⁸

ITS ROLE IS MORE CONTROVERSIAL IN SYMPTOMATIC PATIENTS

Perhaps a less established and more controversial use of coronary artery calcification scoring is in patients who are having coronary symptoms. In patients at high cardiovascular risk, this test by itself may miss an unacceptable number of those who truly have significant stenoses.⁹ However, when the appropriate population is selected, there is substantial evidence that it can be an important means of risk stratification.

In patients at low to intermediate risk, the absence of calcification indicates a very low likelihood of significant coronary artery stenosis, as demonstrated in the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry.¹⁰ In the 10,037 symptomatic patients evaluated, a score of 0 had a 99% negative predictive value for excluding stenosis greater than 70% and was associated with a 2-year event rate less than 1%. These data were supported by a meta-analysis of nearly 1,000 symptomatic patients with a score of 0, in whom the 2-year event rate was less than 2%.⁴

Taken together, these data suggest that the absence of coronary calcification in people at low to intermediate risk indicates a very low likelihood of significant stenotic coronary artery disease and foretells an excellent prognosis.

These data have already been incorporated into the British National Institute for Health and Clinical Excellence (NICE) guidelines, in which calcification scoring is an integral part of the management algorithm in patients with chest pain who are at low risk.

WHY NOT JUST DO CT ANGIOGRAPHY?

But why bother with coronary artery calcification scoring when we can do CT angiography instead? The angiography scanners we have today can cover the entire heart in a single gantry rotation. Dual-source scanners provide temporal resolution as low as 75 ms, and sequential, prospective electrocardiographic gating and iterative reconstruction can routinely achieve scans with doses of radiation as low as 3 mSv that provide coronary artery images of exquisite quality.

On the other hand, calcification scoring is fast and easy to perform and poses less potential harm to the patient, since it uses lower doses of radiation and no contrast agents. In addition, the quantification is semi-automated, so the results can be interpreted quickly and are reproducible.

In the CONFIRM trial, prediction by CT angiography was no better than calcification scoring in asymptomatic patients, so it is not recommended in this population.² In symptomatic patients, the CONFIRM trial data suggest that almost 1,000 additional CT angiography procedures would need to be done to identify one myocardial infarction and more than 1,500 procedures to identify one patient at risk of death missed by calcification scoring of 0 in patients at low to intermediate risk.¹¹

Chauffe and Winchester nicely summarize the limitations of calcification scoring. However, we would emphasize the potential implications of the above findings. Appropriately utilized, calcification scoring is safe, reproducible, and inexpensive and helps individualize treatment in asymptomatic patients at low to intermediate risk, thereby avoiding under- and overtreatment and potentially reducing downstream costs while improving compliance.

In patients at low to intermediate risk who present with chest pain, documenting the absence of calcification can rationalize downstream testing and reliably, quickly, and safely permit patient discharge from emergency departments. In a time of increasing costs and patient demands and finite resources, clinicians should remain cognizant of the usefulness of evaluating coronary artery calcification.

To try to identify and treat people who are at highest risk of cardiovascular events, including death, we use comprehensive risk-prediction models. Unfortunately, these models have limited accuracy and precision and do not predict very well.

See related article

Attractive, then, is the idea of using a noninvasive imaging test to measure coronary atherosclerosis before it causes trouble and thereby individualize the risk assessment. Noncontrast computed tomography (CT) can measure the amount of calcification in the coronary arteries, and therefore it can estimate the coronary atherosclerotic burden. It seems like an ideal test, and calcification as a marker of subclinical atherosclerosis has been extensively investigated.

However, despite more than 2 decades of use and data from hundreds of thousands of patients, the test remains poorly understood. Many physicians seem to use it solely as a means of placating “worried well” patients and do not truly appreciate its implications. Others proceed to ordering CT angiography, a more expensive test that involves the added risks of using higher x-ray doses and iodinated contrast, even when a correctly interpreted calcification score would provide ample information.

In this issue of the Cleveland Clinic Journal of Medicine, Chauffe and Winchester review the utility of coronary artery calcification scoring in current practice. We wish to supplement their review by suggesting some considerations to take into account before ordering this test:

• Does the patient have symptoms of coronary artery disease, and what is his or her risk-factor profile? Baseline patient characteristics are important to consider if we are to use this test appropriately.
• How should the result be interpreted, and does the ordering physician have the confidence to accept the result?

BEST USED IN ASYMPTOMATIC PATIENTS AT INTERMEDIATE RISK

Many large retrospective and prospective registries have demonstrated the predictive value of coronary artery calcification in diverse cohorts of patients without symptoms.

In three prospective registries—the Multi-Ethnic Study of Atherosclerosis¹ (MESA) with 6,722 patients, the Coronary CT Angiography Evaluation for Clinical Outcomes² (CONFIRM) with 7,590 patients, and the Heinz Nixdorf Recall (NHR) study³ with 4,129 patients—most of the patients who had heart attacks had a calcification score greater than 100. And conversely, data from more than 100,000 people show that the absence of calcification (ie, a score of 0) denotes a very low risk (< 1% over 5 years).^1–6

The pretest probability of coronary artery disease needs to be considered. The data clearly indicate that a Bayesian approach is warranted and that coronary artery calcification scoring should mainly be done in patients at intermediate or low-intermediate risk. Trials have shown that calcification scoring will reclassify more than 50% of intermediate-risk patients into the high-risk or low-risk category.³

The implications of these findings were eloquently assessed in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). In this trial, it was estimated that for patients with no calcification who would otherwise fulfill the criteria for treatment with a statin, 549 patients would need to be treated to prevent one coronary event, compared with 24 similar patients with a calcification score greater than 100.⁷

Although such analyses have potential shortcomings, in this era of greater concern about how to allocate finite resources, using a simple, inexpensive test to individualize long-term treatment is an attractive idea. Further, measuring calcification does not appear to increase testing “downstream” and indeed reduces it as compared with no calcification scoring. It also results in better adherence to drug therapy and lifestyle changes.

Because calcification scoring provides additional prognostic data and accurately discriminates and reclassifies risk, the American College of Cardiology and the American Heart Association have awarded it a class IIa recommendation for asymptomatic patients at intermediate risk, meaning that there is conflicting evidence or a divergence of opinion about its usefulness, but the weight of evidence or opinion favors it.⁸

ITS ROLE IS MORE CONTROVERSIAL IN SYMPTOMATIC PATIENTS

Perhaps a less established and more controversial use of coronary artery calcification scoring is in patients who are having coronary symptoms. In patients at high cardiovascular risk, this test by itself may miss an unacceptable number of those who truly have significant stenoses.⁹ However, when the appropriate population is selected, there is substantial evidence that it can be an important means of risk stratification.

In patients at low to intermediate risk, the absence of calcification indicates a very low likelihood of significant coronary artery stenosis, as demonstrated in the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry.¹⁰ In the 10,037 symptomatic patients evaluated, a score of 0 had a 99% negative predictive value for excluding stenosis greater than 70% and was associated with a 2-year event rate less than 1%. These data were supported by a meta-analysis of nearly 1,000 symptomatic patients with a score of 0, in whom the 2-year event rate was less than 2%.⁴

Taken together, these data suggest that the absence of coronary calcification in people at low to intermediate risk indicates a very low likelihood of significant stenotic coronary artery disease and foretells an excellent prognosis.

These data have already been incorporated into the British National Institute for Health and Clinical Excellence (NICE) guidelines, in which calcification scoring is an integral part of the management algorithm in patients with chest pain who are at low risk.

WHY NOT JUST DO CT ANGIOGRAPHY?

But why bother with coronary artery calcification scoring when we can do CT angiography instead? The angiography scanners we have today can cover the entire heart in a single gantry rotation. Dual-source scanners provide temporal resolution as low as 75 ms, and sequential, prospective electrocardiographic gating and iterative reconstruction can routinely achieve scans with doses of radiation as low as 3 mSv that provide coronary artery images of exquisite quality.

On the other hand, calcification scoring is fast and easy to perform and poses less potential harm to the patient, since it uses lower doses of radiation and no contrast agents. In addition, the quantification is semi-automated, so the results can be interpreted quickly and are reproducible.

In the CONFIRM trial, prediction by CT angiography was no better than calcification scoring in asymptomatic patients, so it is not recommended in this population.² In symptomatic patients, the CONFIRM trial data suggest that almost 1,000 additional CT angiography procedures would need to be done to identify one myocardial infarction and more than 1,500 procedures to identify one patient at risk of death missed by calcification scoring of 0 in patients at low to intermediate risk.¹¹

Chauffe and Winchester nicely summarize the limitations of calcification scoring. However, we would emphasize the potential implications of the above findings. Appropriately utilized, calcification scoring is safe, reproducible, and inexpensive and helps individualize treatment in asymptomatic patients at low to intermediate risk, thereby avoiding under- and overtreatment and potentially reducing downstream costs while improving compliance.

In patients at low to intermediate risk who present with chest pain, documenting the absence of calcification can rationalize downstream testing and reliably, quickly, and safely permit patient discharge from emergency departments. In a time of increasing costs and patient demands and finite resources, clinicians should remain cognizant of the usefulness of evaluating coronary artery calcification.

To try to identify and treat people who are at highest risk of cardiovascular events, including death, we use comprehensive risk-prediction models. Unfortunately, these models have limited accuracy and precision and do not predict very well.

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Attractive, then, is the idea of using a noninvasive imaging test to measure coronary atherosclerosis before it causes trouble and thereby individualize the risk assessment. Noncontrast computed tomography (CT) can measure the amount of calcification in the coronary arteries, and therefore it can estimate the coronary atherosclerotic burden. It seems like an ideal test, and calcification as a marker of subclinical atherosclerosis has been extensively investigated.

However, despite more than 2 decades of use and data from hundreds of thousands of patients, the test remains poorly understood. Many physicians seem to use it solely as a means of placating “worried well” patients and do not truly appreciate its implications. Others proceed to ordering CT angiography, a more expensive test that involves the added risks of using higher x-ray doses and iodinated contrast, even when a correctly interpreted calcification score would provide ample information.

In this issue of the Cleveland Clinic Journal of Medicine, Chauffe and Winchester review the utility of coronary artery calcification scoring in current practice. We wish to supplement their review by suggesting some considerations to take into account before ordering this test:

• Does the patient have symptoms of coronary artery disease, and what is his or her risk-factor profile? Baseline patient characteristics are important to consider if we are to use this test appropriately.
• How should the result be interpreted, and does the ordering physician have the confidence to accept the result?

BEST USED IN ASYMPTOMATIC PATIENTS AT INTERMEDIATE RISK

Many large retrospective and prospective registries have demonstrated the predictive value of coronary artery calcification in diverse cohorts of patients without symptoms.

In three prospective registries—the Multi-Ethnic Study of Atherosclerosis¹ (MESA) with 6,722 patients, the Coronary CT Angiography Evaluation for Clinical Outcomes² (CONFIRM) with 7,590 patients, and the Heinz Nixdorf Recall (NHR) study³ with 4,129 patients—most of the patients who had heart attacks had a calcification score greater than 100. And conversely, data from more than 100,000 people show that the absence of calcification (ie, a score of 0) denotes a very low risk (< 1% over 5 years).^1–6

The pretest probability of coronary artery disease needs to be considered. The data clearly indicate that a Bayesian approach is warranted and that coronary artery calcification scoring should mainly be done in patients at intermediate or low-intermediate risk. Trials have shown that calcification scoring will reclassify more than 50% of intermediate-risk patients into the high-risk or low-risk category.³

The implications of these findings were eloquently assessed in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). In this trial, it was estimated that for patients with no calcification who would otherwise fulfill the criteria for treatment with a statin, 549 patients would need to be treated to prevent one coronary event, compared with 24 similar patients with a calcification score greater than 100.⁷

Although such analyses have potential shortcomings, in this era of greater concern about how to allocate finite resources, using a simple, inexpensive test to individualize long-term treatment is an attractive idea. Further, measuring calcification does not appear to increase testing “downstream” and indeed reduces it as compared with no calcification scoring. It also results in better adherence to drug therapy and lifestyle changes.

Because calcification scoring provides additional prognostic data and accurately discriminates and reclassifies risk, the American College of Cardiology and the American Heart Association have awarded it a class IIa recommendation for asymptomatic patients at intermediate risk, meaning that there is conflicting evidence or a divergence of opinion about its usefulness, but the weight of evidence or opinion favors it.⁸

ITS ROLE IS MORE CONTROVERSIAL IN SYMPTOMATIC PATIENTS

Perhaps a less established and more controversial use of coronary artery calcification scoring is in patients who are having coronary symptoms. In patients at high cardiovascular risk, this test by itself may miss an unacceptable number of those who truly have significant stenoses.⁹ However, when the appropriate population is selected, there is substantial evidence that it can be an important means of risk stratification.

In patients at low to intermediate risk, the absence of calcification indicates a very low likelihood of significant coronary artery stenosis, as demonstrated in the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry.¹⁰ In the 10,037 symptomatic patients evaluated, a score of 0 had a 99% negative predictive value for excluding stenosis greater than 70% and was associated with a 2-year event rate less than 1%. These data were supported by a meta-analysis of nearly 1,000 symptomatic patients with a score of 0, in whom the 2-year event rate was less than 2%.⁴

Taken together, these data suggest that the absence of coronary calcification in people at low to intermediate risk indicates a very low likelihood of significant stenotic coronary artery disease and foretells an excellent prognosis.

These data have already been incorporated into the British National Institute for Health and Clinical Excellence (NICE) guidelines, in which calcification scoring is an integral part of the management algorithm in patients with chest pain who are at low risk.

WHY NOT JUST DO CT ANGIOGRAPHY?

But why bother with coronary artery calcification scoring when we can do CT angiography instead? The angiography scanners we have today can cover the entire heart in a single gantry rotation. Dual-source scanners provide temporal resolution as low as 75 ms, and sequential, prospective electrocardiographic gating and iterative reconstruction can routinely achieve scans with doses of radiation as low as 3 mSv that provide coronary artery images of exquisite quality.

On the other hand, calcification scoring is fast and easy to perform and poses less potential harm to the patient, since it uses lower doses of radiation and no contrast agents. In addition, the quantification is semi-automated, so the results can be interpreted quickly and are reproducible.

In the CONFIRM trial, prediction by CT angiography was no better than calcification scoring in asymptomatic patients, so it is not recommended in this population.² In symptomatic patients, the CONFIRM trial data suggest that almost 1,000 additional CT angiography procedures would need to be done to identify one myocardial infarction and more than 1,500 procedures to identify one patient at risk of death missed by calcification scoring of 0 in patients at low to intermediate risk.¹¹

Chauffe and Winchester nicely summarize the limitations of calcification scoring. However, we would emphasize the potential implications of the above findings. Appropriately utilized, calcification scoring is safe, reproducible, and inexpensive and helps individualize treatment in asymptomatic patients at low to intermediate risk, thereby avoiding under- and overtreatment and potentially reducing downstream costs while improving compliance.

In patients at low to intermediate risk who present with chest pain, documenting the absence of calcification can rationalize downstream testing and reliably, quickly, and safely permit patient discharge from emergency departments. In a time of increasing costs and patient demands and finite resources, clinicians should remain cognizant of the usefulness of evaluating coronary artery calcification.