DEFINITION

Hypertrophic cardiomyopathy (HCM) has classically been defined as hypertrophy of the myocardium greater than 1.5 cm without an identifiable cause (Figures 1 and 2). Other etiologies of left ventricular hypertrophy, such as long-standing hypertension and aortic stenosis, need to be excluded before one can diagnose HCM. The term recommended by the World Health Organization for the disease is HCM. It is also known as muscular subaortic stenosis (MSS), hypertrophic obstructive cardiomyopathy (HOCM), and idiopathic hypertrophic subaortic stenosis (IHSS). As our understanding of the genetics of HCM progresses, HCM will likely be diagnosed in the near future based on genetic testing, with transthoracic echocardiography (TTE) used to assess the phenotypic manifestations and clinical severity of the disease.

HCM is the most common genetic cardiovascular disease.¹ The prevalence in the general adult population for people with phenotypic evidence of HCM is estimated at 1 per 500. In young adults, HCM is the most common etiology for sudden cardiac death.

HCM can be classified as obstructive or nonobstructive depending on whether a significant left ventricular outflow tract (LVOT) gradient is present, either at rest or with provocative maneuvers. Alternatively, HCM can be classified based on location of the hypertrophy (eg, proximal septal versus apical). Finally, there appear to be distinct forms of HCM based on age. Younger patients tend to have reversal of septal curvature and more diffuse hypertrophy (Figure 1), whereas older patients tend to have focal proximal septal hypertrophy (Figure 2).² It has been suggested that these are two different disease processes. Hypertrophy often worsens during adolescence.

Generally, ventricular hypertrophy involves the proximal portion of the interventricular septum. As the septum thickens, it may narrow the outflow tract. In addition, systolic anterior motion of the mitral valve may occur and result in left ventricular outflow tract obstruction and mitral regurgitation (Figures 3 and 4). When systolic anterior motion occurs, the mitral valve leaflets are pulled or dragged anteriorly toward the ventricular septum, producing the obstruction. Consequently, the left ventricle has to generate much higher pressures to overcome the LVOT obstruction and to pump blood to the systemic circulation. Premature closure of the aortic valve may occur and is caused by the decline in pressure distal to the LVOT obstruction.

The obstruction that occurs with HCM is dynamic rather than fixed. Fixed obstructions occur with aortic stenosis and a subvalvular aortic membrane. In dynamic obstruction, the degree of obstruction depends much more on cardiac contractility and loading conditions than it does in fixed obstructions. An underfilled left ventricle results in greater obstruction since there is less separation between the interventricular septum and the mitral valve. Augmenting cardiac contractility also increases LVOT obstruction because a more vigorous contraction is more likely to cause the obstructing components to come together.

Histologically, HCM manifests as hypertrophied, disorganized cardiac myocytes. Cells may take on bizarre shapes, and the connections among cells are often in disarray. Myocardial scarring and growth of the collagen matrix also occur.¹ Scarring and disarray may then form the substrate for arrhythmias. These pathological abnormalities are not necessarily confined to the septum, for areas of the heart that appear grossly normal may have these pathological findings.

The clinical course of HCM is variable. Most patients with HCM are asymptomatic.³ For those HCM patients who do develop symptoms, they do not necessarily correlate with the magnitude of LVOT gradient. For instance, some patients may remain asymptomatic for years with a gradient of 80 mm Hg, whereas others may have severe symptoms with only a 40 mm Hg gradient. However, symptoms may be more related to the severity of mitral regurgitation and diastolic dysfunction.

The most common symptom of HCM is dyspnea on exertion. Patients may also complain of chest pain with exertion, syncope or near syncope, or palpitations. Eating may make symptoms worse because of splanchnic vasodilation and the resulting decrease in cardiac preload. Patients often describe a progressive course. Congestive heart failure and atrial fibrillation, along with their accompanying symptoms, may be part of the natural history of HCM. Unfortunately, HCM can also present as sudden cardiac death (SCD). SCD tends to occur in younger patients and may occur during heavy exertion, light exertion, or even while the patient is sedentary. In an unselected, community-based population with HCM (as opposed to a tertiary hospital referral population of HCM), the estimated incidence of SCD is approximately 0.1% to 0.7% per year.^4,5

The physical examination may provide several clues that point to HCM. Palpation of the carotid pulse aids in distinguishing HCM from aortic stenosis or the presence of a subvalvular aortic membrane. With HCM, little or no difficulty exists during early systole in ejecting the blood through the LVOT into the aorta; therefore, the carotid upstroke is brisk. As systole progresses, LVOT obstruction may occur, resulting in a collapse in the pulse and then a secondary rise. This is called a bisferiens pulse. In contrast, because the fixed obstruction of aortic stenosis or subvalvular aortic membranes is present during the entire cardiac cycle, the carotid upstroke in these entities will often be the classic parvus et tardus pulse, a carotid pulse with delayed upstroke and amplitude. Therefore, if any patient with a diagnosis of HCM has decreased carotid pulses, this should prompt thoughts of a mistaken diagnosis and further investigation into a fixed obstruction of the LVOT.

Unless congestive heart failure has developed, the lungs are usually clear and the jugular venous pressure normal. The point of maximal impulse will often be forceful and sustained, and a palpable S4 gallop may be present. The classic auscultatory finding for HCM is a crescendo-decrescendo systolic murmur along the left sternal border that increases with the Valsalva maneuver. Almost all cardiac murmurs decrease in intensity during Valsalva with the exception of HCM, so this maneuver is a crucial part of the cardiac examination if HCM is suspected. The Valsalva maneuver decreases preload, which results in decreased filling of the left ventricle. An underfilled left ventricle increases the obstruction. Similarly, arising from squatting to standing decreases left ventricle preload and increases the intensity of the murmur. Finally, amyl nitrite results in vasodilation, decreased preload and a reflex tachycardia, all of which result in a louder murmur because of greater obstruction. During the cardiac examination, it is imperative to listen carefully for a mitral regurgitation murmur; such a finding may indicate systolic anterior motion of the mitral valve. The remainder of the examination is generally unremarkable.

Laboratory studies generally will be unremarkable. Chest radiograph may suggest left ventricular hypertrophy but will often be normal because the hypertrophy in HCM involves the ventricular septum. The electrocardiogram often shows left ventricular hypertrophy and occasionally may also have a pseudoinfarct pattern. Figure 5 illustrates this pseudoinfarct pattern (with Q waves in the anterolateral leads) in a patient with HCM, normal LV systolic function and no known coronary artery disease. Left atrial abnormality may be present if the patient has had long-standing mitral regurgitation from systolic anterior motion of the mitral valve. Atrial fibrillation also may be present as one of the complications of HCM.

Echocardiography is the gold standard for diagnosing HCM. Figures 1 and 2 are echocardiographic images from patients with HCM that depict marked hypertrophy of the interventricular septum. Figures 3 and 4 are video clips illustrating LVOT obstruction during systole. With transthoracic echocardiography, the septum can be well-visualized and measured in the parasternal long, apical long, apical 4-chamber, and parasternal short axis views. On transthoracic echocardiography, the clinician should note the thickness of the septum; location and pattern of hypertrophy; site and degree of left ventricular outflow tract obstruction; presence of systolic anterior motion of the mitral valve; presence of premature closure of the aortic valve; and any change in severity of obstruction with amyl nitrite. All patients with HCM or suspected HCM should undergo provocative testing with amyl nitrite to determine whether there is latent obstruction if no resting obstruction is present. The resulting decrease in preload to the left ventricle combined with the increased heart rate results in an increase in LVOT gradient. To further assess the functional significance of any LVOT obstruction, we often perform stress echocardiogram studies in patients with HCM. Some patients have minimal resting gradients but develop large gradients with exercise. In our experience, supervised stress tests under controlled conditions in patients with HCM are safe.

HCM should be differentiated from valvular aortic stenosis and a subvalvular aortic membrane. In aortic stenosis, the aortic valve is calcified and has restricted mobility. In HCM, the obstruction occurs below the aortic valve, and the valve structure and function is preserved. However, with aging, degenerative calcific disease of the aortic valve may make it difficult to distinguish between the two entities. A subvalvular aortic membrane sometimes may be difficult to visualize on transthoracic echocardiography.

Continuous wave Doppler imaging is useful in differentiating HCM from fixed obstructions such as valvular aortic stenosis and a subvalvular membrane. Doppler imaging measures the velocity of blood over time. Figure 6 illustrates the difference between Doppler signals from HCM and from fixed obstructions. With HCM, the continuous Doppler signal classically is described as having a late systolic dagger shape because the obstruction is late-peaking due to its dynamic nature. During early systole, blood still flows through the LVOT; however, with continued contraction of the left ventricle, exacerbated by systolic anterior motion of the mitral valve, the outflow tract area diminishes and an outflow tract gradient then develops. In contrast, a fixed obstruction is present during all of systole. Thus, the continuous-wave Doppler signal for fixed obstructions is a smoother contour that peaks earlier.

Transesophageal echocardiography may be necessary if transthoracic windows are inadequate. If echocardiographic images are difficult to obtain or interpret, MRI may be used to diagnose HCM.

Cardiac catheterization has some value in diagnosing HCM, but advances in echocardiography have made the latter method the predominant means by which HCM is diagnosed. Patients with HCM often have no obstructive coronary artery disease, although they may have small vessel disease from increased collagen deposition and myocardial ischemia due to the mismatch between myocardial oxygen supply and demand. This mismatch is driven primarily by the increased myocardial mass. The left ventriculogram demonstrates cavity obliteration and a hyperdynamic left ventricle. LVOT gradients can be assessed by positioning a catheter near the left ventricle apex and recording ventricular pressures during slow catheter pullback.

In patients with HCM, genetic heterogeneity exists. More than 150 mutations in 10 genes have been identified as causes of HCM. These mutations primarily involve the myosin, actin or troponin components of the cardiac sarcomere. Five of these mutations are considered especially malignant in light of their propensity for sudden cardiac death. However, a recent study of 293 HCM patients at the Mayo Clinic assessed the prevalence of these malignant mutations and found that only three patients, or approximately 1%, had one of the malignant mutations for HCM.⁶ Therefore, genetic testing appears to have high specificity but low sensitivity for HCM. Currently, genetic testing is expensive and not usually helpful with management. However, genetic counseling may be considered for HCM patients and their families. We presently do not recommend widespread genetic testing for HCM.

Treatment options for HCM include medical therapy, alcohol ablation, septal myectomy and heart transplantation. Additionally, pacemaker implantation has been attempted but results have indicated a substantial placebo effect.

Medical Therapy
Treatment with ß-blockers is considered first-line therapy. By decreasing contractile force, ß-blockers decrease the outflow gradient and decrease oxygen demand. ß-blockers also lengthen diastolic filling by slowing the heart rate. We generally start patients on metoprolol 50 mg twice a day or Toprol XL 50 mg daily. If the patient continues to be symptomatic, the dose of metoprolol or Toprol XL can be increased further by 25 mg increments every few weeks. Second-line therapy includes the calcium channel blocker verapamil and the class I antiarrhythmic agent disopyramide. Both calcium channel blockers and disopyramide exert a negative inotropic effect. The extended release formulation of verapamil can be started at 240 mg daily and increased by 60 mg every few weeks. Verapamil should not be used in patients with severe pulmonary hypertension because they may develop excessive vasodilation that worsens LVOT obstruction and cardiac output, resulting in pulmonary edema. The extended release formulation of disopyramide may be started at 150 mg twice per day. Diltiazem has been used in HCM patients, but there is little data on its effectiveness. Nifedipine, amlodipine and felodipine should be avoided because they cause peripheral vasodilation, which may result in decreased left ventricular filling and worsening of outflow tract obstruction.

Atrial fibrillation is a common complication of HCM. Treatment of persistent atrial fibrillation in HCM includes anticoagulation and rate control, preferably with ß-blockers. One should attempt to restore normal sinus rhythm with direct current cardioversion and/or antiarrhythmic agents. If atrial fibrillation has been present for over 48 hours or the duration of atrial fibrillation is uncertain, then either transesophageal echocardiogram (TEE) to ensure that there is no left atrial or left atrial appendage clot (with therapeutic anticoagulation) or anticoagulation for at least four weeks should be performed prior to any electrical or chemical attempts at restoration of sinus rhythm. However, HCM patients often tolerate atrial fibrillation poorly, and TEE followed by electrical cardioversion is generally the preferred approach. Amiodarone or sotalol is the preferred therapy for pharmacologic conversion to sinus rhythm or maintenance of sinus rhythm in HCM patients. Digoxin should be avoided in HCM patients, particularly in those with resting or latent obstruction, because of its positive inotropic effect. Atrial fibrillation ablation or a maze procedure may be considered for those with refractory, highly symptomatic atrial fibrillation. In a small number of patients with severe HCM and atrial fibrillation, we have performed combined maze-myectomy procedures.

Patients with HCM should receive prophylactic antibiotics for endocarditis prevention before dental or invasive procedures.⁷ Turbulent flow through the LVOT striking the aortic valve as well as mitral regurgitation from systolic anterior motion of the mitral valve predispose to endocarditis.

Septal Myectomy
Some patients do not respond well to medical therapy. If a patient remains symptomatic despite medical therapy and has a resting or latent gradient of 50 mm Hg or more, septal myectomy should be considered. This operation involves resecting part of the proximal septum so that the outflow tract obstruction is lessened (Figures 7 and 8). Sometimes myectomy may be combined with mitral valve repair or replacement if mitral regurgitation persists on intraoperative transesophageal echocardiography after myectomy has been performed. If the patient is young or in good health, septal myectomy is recommended as the most definitive treatment for HCM.

At the Cleveland Clinic, in a group of 194 consecutive patients from 1994 to 1999, operative mortality was 1%.⁸ 105 of these patients underwent pure myectomy and had 0% mortality and a 3.8% rate of permanent pacemaker implantation. 30 patients underwent combined myectomy and coronary artery bypass graft surgery, and had 0% mortality and a 6.7% rate of permanent pacemaker implantation. The remaining 59 patients underwent combined myectomy and valve surgery, and this group had a 3.4% operative mortality and a 24% rate of requiring permanent pacemakers. In another study from the Cleveland Clinic which analyzed 51 patients with HCM who underwent either myectomy or alcohol ablation, of the 25 patients who underwent alcohol ablation, LVOT gradient was significantly reduced from 62 mm Hg pre-alcohol ablation to 7 mm Hg post-alcohol ablation, and New York Heart Association class improved significantly from 3.3 to 1.5.⁹ Another group reported long-term follow-up in myectomy patients and found that of 175 HCM patients undergoing myectomy, 5-year survival was 93% and 10-year survival 87% for patients undergoing isolated myectomy, while for patients undergoing a myectomy, combined with other cardiac surgery, primarily coronary artery bypass graft surgery or valve surgery, 5-year survival was 80% and 10-year survival 80%.¹⁰

Alcohol Ablation
For patients who are poor surgical candidates or those who choose not to undergo open-heart surgery, alcohol ablation is another option. Septal ablation is performed in the catheterization laboratory. Alcohol is instilled into the first septal perforator or the perforator that supplies the proximal septum, resulting in a controlled myocardial infarction. Alcohol acts as a toxic agent to the coronary artery and surrounding myocardium, effectively infarcting the cardiac muscle supplied by the septal perforator. Consequently, the muscle shrinks and the LVOT obstruction lessens.

At the Cleveland Clinic, most alcohol ablations have been performed on elderly, suboptimal surgical candidates. We generally prefer that the septum be between 1.8 cm and 3.0 cm to provide a safety margin; if the septum is too thick, favorable ablation results may be difficult to attain. Complications of alcohol ablation include complete heart block (requiring a permanent pacemaker), a large anterior wall myocardial infarction, ventricular tachycardia or fibrillation, and pericarditis. The risk of alcohol ablation include a 2%-4% procedural mortality rate and a 9%-27% incidence of patients requiring permanent pacemakers.^11-14 Like septal myectomy, alcohol ablation has not been shown to improve survival due to the lack of randomized controlled trials and a suitable control population. However, septal myectomy does result in both short-term and long-term significant decreases in the LVOT gradient as well as a significant improvement in New York Heart Association classification.^9,12 In 3-month follow-up data, Qin et al reported a decrease in LVOT gradient from 64 mm Hg to 28 mm Hg and an improvement in NYHA class from 3.5 to 1.9 after alcohol ablation.⁹

Permanent Pacemaker Implantation
Pacemaker implantation has been used to alleviate the symptoms of HCM, but this procedure has fallen out of favor. It was hypothesized that initiating the ventricular contraction at the right ventricular apex would alter the sequence of ventricular contraction such that the outflow gradient would be decreased and symptoms alleviated. Although initial non-randomized, unblinded studies reported symptomatic improvement, subsequent double-blind, randomized cross-over trials with dual chamber pacing demonstrated no significant change in exercise capacity but a small decrease in the LVOT gradient.^15,16 In addition, patients both with and without active pacing noted subjective improvement in exercise capacity. Thus, a significant placebo effect accounts for the improvement in symptoms attributed to pacemakers. American College of Cardiology/American Heart Association guidelines¹⁷ consider pacemaker implantation for medically refractory, symptomatic HCM with a significant LVOT gradient to be a IIb indication. Class IIb means there is conflicting evidence for the particular intervention, and its usefulness and efficacy is less well-established by the available evidence and expert opinion. We do not recommend a permanent pacemaker specifically for treatment of HCM.

Sudden Cardiac Death
The most serious complication of HCM is sudden cardiac death, with an incidence of 0.1% to 0.7% per year.^4,5 A survivor of an episode of SCD warrants an implantable cardioverter-defibrillator. Primary prevention of SCD in HCM patients is not as well defined. Antiarrhythmic therapy for primary prevention generally is not recommended in asymptomatic patients. HCM patients at higher risk for sudden cardiac death include those with a left ventricular wall thickness greater than 30 mm; prolonged or repetitive episodes of nonsustained ventricular tachycardia on Holter monitor; family history of SCD; hypotensive blood pressure response to exercise; and syncope or near syncope.¹⁸ Patients with these risk factors may benefit from automatic cardioverter-defibrillator implantation for primary prevention of SCD. Assessing genotype may one day help ascertain SCD risk, but presently, genetic testing will generally not alter management in the prevention of SCD. Electrophysiologic testing has not been shown to be predictive of SCD in HCM.

Nonobstructive Hypertrophic Cardiomyopathy
The treatment of patients with nonobstructive hypertrophic cardiomyopathy is difficult and less effective than in those with obstructive disease. ß-blockers may be used to control heart rate and calcium channel blockers may improve diastolic function. Over time, hypertrophic cardiomyopathy may become "burned out" and evolve into a picture similar to a dilated cardiomyopathy, with decreased left ventricular systolic function and a dilated left ventricle. In patients with symptoms and signs of congestive heart failure, diuretics, ACE-inhibitors, and digoxin may be necessary. Heart transplantation is an option for end-stage nonobstructive HCM.

Surgical outcomes for HCM are excellent; operative mortality is generally less than 2% for septal myectomy. As described previously, most patients report improvement in their symptoms. Outcomes for alcohol ablation are more limited, with follow-up averaging three to five years, as compared with decades for myectomy. At three-month follow-up, both myectomy and alcohol ablation are effective in improving symptoms and reducing LVOT gradients, but myectomy results in larger improvements in LVOT gradients.⁹ Alcohol ablation is a promising therapeutic option for HCM, with a major advantage being its less invasive nature. However, presently, septal myectomy remains the preferred treatment of choice for most HCM patients.

Many questions remain unanswered about the pathogenesis and treatment of HCM; however, tremendous strides have been made in decreasing mortality and morbidity. Further research is needed to enhance our understanding of HCM.

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