Hypertrophic Cardiomyopathy

Michael S. Chen

Harry Lever

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Definition and causes

Hypertrophic cardiomyopathy (HCM) is defined as hypertrophy of the myocardium more than 1.5 cm, without an identifiable cause (Fig. 1). Other causes of left ventricular hypertrophy, such as long-standing hypertension and aortic stenosis, must be excluded before HCM can be diagnosed. As our understanding of the genetics of HCM progresses, HCM will likely be diagnosed based on genetic testing, with transthoracic echocardiography (TTE) used to assess the phenotypic manifestations and clinical severity of the disease.

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Prevalence and risk factors

HCM is the most common genetic cardiovascular disease. Genetic mutations resulting in HCM primarily involve the cardiac sarcomere but may also involve the connective tissue matrix. The prevalence in the general adult population for people with phenotypic evidence of HCM is 1 per 500. Men are more often affected than women and blacks more often than whites. In young adults, HCM is the most common cause of sudden cardiac death.

Strenuous exercise by increasing afterload, such as heavy weight lifting, could theoretically increase the magnitude of left ventricular hypertrophy and worsen obstruction in subjects with preexisting HCM. Risk factors for the development of end-stage HCM (manifesting as left ventricular [LV] systolic dysfunction and LV dilatation) include younger age at onset of HCM, a family history of HCM, greater ventricular wall thickness, and certain genetic mutations.

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Pathophysiology and natural history

More than 150 mutations in 10 genes, primarily involving the myosin, actin, or troponin components of the cardiac sarcomere, have been identified as causes of HCM. 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 has assessed the prevalence of these malignant mutations and found that only three patients, or approximately 1%, had one of the malignant mutations for HCM. There are varying expressions of mutations for HCM.

HCM can be considered obstructive or nonobstructive, depending on the presence of a left ventricular outflow tract (LVOT) gradient, either at rest or with provocative maneuvers. Alternatively, HCM can be classified based on location of the hypertrophy, such as the proximal septum or the apex. Finally, there appear to be distinct forms of HCM at different ages. Younger patients often have more diffuse hypertrophy and reversal of septal curvature (Fig. 2), whereas older patients tend to have focal proximal septal hypertrophy, with a sigmoid septal morphology (Fig. 3). These may be two different disease processes, because subjects with reversal of septal curvature were found to have an almost 80% yield for screening for HCM-associated mutations but those with a sigmoid septum had less than a 10% yield. Hypertrophy often develops or worsens during the adolescent growth spurt. An apical variant of HCM also exists (Fig. 4).

Left ventricular hypertrophy usually involves thickening of the proximal portion of the interventricular septum, resulting in narrowing of the LVOT. Systolic anterior motion (SAM) of the mitral valve may occur if the mitral valve leaflets are pulled or dragged anteriorly toward the ventricular septum. SAM results in LVOT obstruction and mitral regurgitation. Consequently, the left ventricle has to generate higher pressures to overcome the LVOT obstruction. 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, unlike the fixed obstructions of aortic stenosis and subvalvular aortic membranes. In dynamic obstruction, the degree of obstruction depends more on cardiac contractility and loading conditions than on fixed obstructions. An underfilled left ventricle results in greater obstruction, because there is less separation between the interventricular septum and 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. Most patients with HCM have a favorable prognosis. Complications of HCM include atrial fibrillation, ventricular arrhythmias, congestive heart failure, and sudden cardiac death. End-stage HCM, which occurs in 5% of those with HCM, manifests as systolic left ventricular dysfunction, thinning of the left ventricular wall, and dilation of the ventricular cavity. Sudden cardiac death tends to occur in younger patients and may occur during heavy exertion, light exertion, or even at rest. In an unselect, community-based population with HCM, the estimated incidence of sudden cardiac death is approximately 0.1% to 0.7%/year. Finally, HCM may also result in restrictive cardiomyopathy.

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Signs and symptoms

The clinical course of HCM is variable. Most patients with HCM are asymptomatic. For symptomatic patients, the occurrence and severity of symptoms do not necessarily correlate with the magnitude of the LVOT gradient. Symptoms appear to be associated more with the severity of mitral regurgitation and diastolic dysfunction.

Dyspnea on exertion is the most common symptom. Other complaints include chest pain with exertion, syncope or near syncope, or palpitations. Eating may exacerbate symptoms caused by splanchnic vasodilation and the resulting decrease in cardiac preload. Symptoms are often progressive. If patients develop some of the complications of HCM, such as atrial fibrillation or congestive heart failure, symptoms accompanying those particular conditions may occur, such as palpitations and orthopnea, paroxysmal nocturnal dyspnea, or leg edema, respectively.

Physical examination provides several clues suggestive of HCM. Palpation of the carotid pulse aids in distinguishing HCM from aortic stenosis or the presence of a subvalvular aortic membrane. With HCM, the carotid upstroke is brisk, because there is little resistance during early systole in ejecting the blood through the LVOT into the aorta. As systole progresses, LVOT obstruction occurs in HCM, resulting in a collapse in the pulse and then a secondary increase, a finding termed 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 be the classic parvus et tardus pulse (small amplitude and delayed upstroke), a carotid pulse with delayed upstroke and amplitude. Thus, if any patient with a diagnosis of HCM has decreased carotid pulses, one should suspect misdiagnosis and carry out further investigation into fixed obstruction of the LVOT.

The lungs are usually clear and the jugular venous pressure normal. The point of maximal impulse will 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 ( Table 1 ). The Valsalva maneuver decreases preload, which results in decreased filling of the left ventricle. An underfilled left ventricle results in an increase in LVOT obstruction. Similarly, rising from squatting to standing decreases left ventricle preload and increases the intensity of the murmur. Finally, amyl nitrite, a profound vasodilator, decreases preload and causes a reflex tachycardia. This results in a louder murmur because of an increased degree of obstruction. In addition, it is imperative to auscultate carefully for a mitral regurgitation murmur; such a finding may indicate systolic anterior motion of the mitral valve, with accompanying mitral regurgitation. The remainder of the examination is generally unremarkable.

Table 1: Effects of Physiologic and Pharmacologic Maneuvers on Hypertrophic Cardiomyopathy
Maneuver Ventricular Volume Murmur Intensity LVOT Gradient
Hand grip Increase Decrease Decrease
Valsalva Decrease Increase Increase
Amyl nitrite Decrease Increase Increase
Isoproterenol Decrease Increase Increase
Beta blocker Increase Decrease Decrease
Phenylephrine Increase Decrease Decrease

LVOT, left ventricular outflow tract.

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Diagnosis

Laboratory Tests

Blood work generally is unremarkable. A chest radiograph may suggest left ventricular hypertrophy but will often be normal because the hypertrophy in HCM involves the ventricular septum. The electrocardiogram should show left ventricular hypertrophy and occasionally may also have a pseudoinfarct pattern, in which Q waves are present despite the absence of coronary artery disease. Left atrial abnormality may be present if the patient has had long-standing mitral regurgitation from SAM of the mitral valve. Atrial fibrillation also may be present.

Imaging

Echocardiography is the gold standard for diagnosing HCM (see Figs. 2 through 4). With transthoracic echocardiogram (TTE), the septum can be well visualized and measured in the parasternal long, apical long, apical four-chamber, and parasternal short axis views. On TTE, one should note the septal thickness, location and pattern of hypertrophy, site and degree of left LVOT obstruction, presence of SAM of the mitral valve, presence of premature closure of the aortic valve, and any change in severity of obstruction with provocation. If no left ventricular LVOT gradient is present in patients with HCM or suspected HCM, they should undergo provocative testing with squatting, the Valsalva maneuver, or amyl nitrite to determine whether there is latent obstruction. To assess the functional significance of LVOT obstruction further, we often perform stress echocardiography studies in patients with HCM. Some patients have minimal resting gradients but develop large gradients with exercise. In our experience, supervised stress tests in patients with HCM are safe.

Transesophageal echocardiography and magnetic resonance imaging are other potential modalities for diagnosing HCM, particularly in subjects with technically difficult echocardiographic studies. Both modalities have superior resolution to transthoracic echocardiography but are more costly and, in the case of transesophageal echocardiography, more invasive.

Diagnostic Procedures and Differential Diagnosis

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 are 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 5 illustrates the differences between Doppler signals from HCM and from fixed obstructions. With HCM, the continuous Doppler signal has a late systolic dagger shape; the obstruction is late peaking because of 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.

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. 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. A classic sign of HCM is Brockenbrough's sign, in which the left ventricle-to-aortic gradient increases while the aortic pulse pressure decreases post–premature ventricular contraction (PVC) (Fig. 6). Such a phenomenon occurs in HCM because the increased contractility in the post-PVC beat increases the dynamic LVOT obstruction. Patients with HCM often have no obstructive coronary artery disease, although they may have small vessel disease from increased collagen deposition and myocardial ischemia caused by the mismatch between myocardial oxygen supply and demand. This mismatch is driven primarily by the increased myocardial mass.

Currently, genetic testing is expensive and not usually helpful with management. Patients may have a mutation associated with HCM but not display the phenotypic manifestations of HCM. Genetic counseling may be considered for HCM patients and their families. At present, however, we do not recommend widespread genetic testing for HCM for the general population.

Myocardial biopsy is not performed for the purpose of diagnosing HCM. However, 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. Scarring and disarray may form the substrate for arrhythmias. These pathologic abnormalities are not necessarily confined to the septum, because areas of the heart that appear grossly normal may also have these pathologic features.

Summary

  • HCM is hypertrophy of the ventricular septum, generally 1.5 cm, which is not explained by other causes.
  • Currently, transthoracic echocardiography is the gold standard for the diagnosis of HCM.
  • In the future, genetic testing will allow for identification of those possessing mutations associated with HCM; however, diagnosis of HCM as a clinical entity will still require an imaging modality that visualizes myocardial hypertrophy.
  • HCM needs to be differentiated from other causes of LVOT obstruction, primarily aortic stenosis or a subvalvular aortic membrane. Brisk carotid upstrokes, a normal or minimally diseased aortic valve, lack of a subvalvular aortic membrane, and a dagger appearance to the Doppler profile of flow through the LVOT all indicate HCM.
Practice Guidelines

Consensus practice guidelines for HCM were published by a joint task force of the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) in 2003. Overall, these guidelines also recommend transthoracic echocardiography as the best modality to make the clinical diagnosis of HCM, with the standard criteria being a left ventricular wall thickness of at least 15 mm, in the absence of other causes for hypertrophy. These guidelines also emphasize that HCM is the preferred terminology for this disease entity because most HCM subjects do not have obstruction under resting conditions. Finally, subjects may have the HCM genotype without the phenotypic manifestations of HCM.

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Treatment

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.

Lifestyle Modifications

To prevent further disease progression, we recommend that HCM subjects avoid strenuous weight lifting, because weight lifting increases the afterload to the myocardium and can worsen hypertrophy. In addition, because of the risk of sudden cardiac death, subjects should avoid competitive athletics. Finally, patients should always remain well hydrated, so that the left ventricle does not become underfilled and result in worsening obstruction.

Medical Options

Beta blockers are considered first-line therapy for symptomatic HCM. By decreasing contractile force, beta blockers decrease the outflow gradient and decrease oxygen demand. Beta blockers also lengthen diastolic filling by slowing the heart rate. We generally start patients on metoprolol tartrate (Lopressor), 50 mg twice daily, or metoprolol succinate (Toprol-XL), 50 mg daily. If symptoms persist, the dose of metoprolol can be increased by 25-mg increments every few weeks. The peak dose is 400 mg/day. Contraindications to beta blockers include severe bronchospasm, marked bradycardia, and severe conduction system disease. Caution should be exercised with beta blocker use in patients with hepatic impairment. Fatigue is a common side effect of beta blockers.

Second-line therapy includes the calcium channel blocker verapamil because of its negative inotropic effect. The extended-release formulation of verapamil (Calan SR, Verelan, Isoptin SR) can be started at 240 mg daily and increased by 60 mg every few weeks. The maximum dose is approximately 480 mg daily. The dose should be decreased and the use of shorter acting agents considered for subjects with hepatic dysfunction. Verapamil should not be used in patients with severe pulmonary hypertension because they may develop excessive vasodilation, which worsens LVOT obstruction and cardiac output, resulting in pulmonary edema. Other contraindications to verapamil use include severe LV systolic dysfunction, conduction system disease, and hypotension. Diltiazem has been used in HCM patients, but there are 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.

Another second-line agent is disopyramide, a Class IA antiarrhythmic agent that has negative inotropic effects. The extended-release formulation of disopyramide (Norpace CR) may be started at 150 mg twice daily. This can then be increased to 300 mg twice daily in a few weeks if symptoms remain. The maximum dosage is 800 mg/day. The dose of disopyramide should be decreased if there is renal or hepatic dysfunction. Relative contraindications to disopyramide include decompensated congestive heart failure, baseline prolonged QTc interval, or severe conduction system disease. Disopyramide is also used as an antiarrhythmic, and as such has both antiarrhythmic and proarrhythmic properties. Common side effects of disopyramide include anticholinergic effects, such as dry mouth, urinary retention, and blurred vision.

Atrial fibrillation is a common complication of HCM. In new-onset atrial fibrillation, the clinician should attempt to restore normal sinus rhythm with direct current cardioversion, antiarrhythmic agents, or both. If atrial fibrillation has been present for longer than 48 hours or the duration of atrial fibrillation is uncertain, transesophageal echocardiography (TEE) should be performed to ensure that there is no left atrial or left atrial appendage clot or an anticoagulant should be given for at least 4 weeks 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 or maintenance of sinus rhythm in HCM patients. Digoxin should be avoided in HCM patients, particularly those with resting or latent obstruction, because of its positive inotropic effect. Treatment of persistent atrial fibrillation in HCM includes anticoagulation with warfarin and rate control, preferably with beta blockers. 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. 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.

Percutaneous and Surgical Options

 
Septal Myectomy

Septal myectomy involves resection of part of the proximal septum through an aortotomy (Fig. 7). Pre- and postmyectomy echocardiography images demonstrate a marked reduction in septal thickness after myectomy (Figs. 8 and 9). Abnormalities of the mitral valve, such as redundancy of the anterior or posterior mitral valve leaflet, may predispose to systolic anterior motion of the mitral valve. Thus, myectomy may sometimes be combined with mitral valve repair or replacement if mitral regurgitation or outflow tract obstruction persists on intraoperative TEE after myectomy has been performed. Myectomy may also be combined with coronary artery bypass grafting (CABG).

We recommend septal myectomy as first-line therapy for medically refractory HCM, particularly in young subjects who are otherwise in good health. If a patient remains symptomatic despite optimum medical therapy and has a resting or provocable gradient of 50 mm Hg or higher, septal myectomy should be considered. In contrast, we generally recommend continued aggressive medical management for subjects with gradients above 50 mm Hg if they remain asymptomatic or have only mild symptoms. Myectomy would then be performed for progression of symptoms. One exception is young, otherwise healthy subjects with gradients higher than 75 mm Hg. The low operative risk of these subjects tilts the balance in favor of earlier intervention. Septal myectomy is not indicated in apical hypertrophy.

Operative mortality for isolated myectomy is less than 2%. In one study from the Cleveland Clinic of 323 consecutive myectomy subjects from 1994 to 2004, subjects who underwent myectomy had 0% in-hospital mortality.

Septal myectomy decreases LVOT gradients, improves symptoms, and increases exercise capacity. Both the decrease in LVOT gradient and the decrease in any associated mitral regurgitation are responsible for symptom improvement. It is rare to require reoperation caused by recurrence of LVOT obstruction.

The risk that a myectomy patient will require a permanent pacemaker postmyectomy depends on the health of the conduction system. In subjects with normal conduction systems, as noted on the electrocardiogram (ECG), there was a 2% rate of permanent pacemaker implantation postmyectomy, whereas for patients with preexisting conduction abnormalities, there was a 10% incidence of permanent pacemaker implantation. The patient subset at highest risk for requiring a permanent pacemaker are those with preexisting right bundle branch block, because left bundle branch block occurs in over 90% of patients after myectomy.

Long-term isolated myectomy has had excellent results, with survival rates of 93% to 96% at 5 years and 83% to 87% at 10 years. Factors portending to higher mortality rates include age 50 years or older at time of surgery, female gender, concomitant CABG, history of preoperative atrial fibrillation, and left atrial diameter of at least 46 mm. Concomitant open heart procedures at the time of myectomy are associated with higher long-term mortality rates. Patients undergoing myectomy in conjunction with CABG or valve surgery have demonstrated 5-year survival rates of 80%.

No randomized data exist assessing long-term survival in HCM patients undergoing medical management versus myectomy. However, retrospective, nonrandomized data suggest that HCM patients undergoing myectomy have lower mortality rates than HCM patients with obstruction who did not undergo surgery. It has further been suggested that long-term survival for HCM subjects who have undergone myectomy becomes equivalent to that of the age- and gender-matched general population.

Percutaneous Alcohol Septal Ablation

Alcohol ablation was first reported in 1995, and its popularity subsequently surged. By 2000, more than 3000 alcohol ablations had been performed, more than the number of myectomies performed over 40 years. At the Cleveland Clinic, most alcohol ablations have been performed on older or suboptimal surgical candidates, or both. We prefer that the septum be between 1.8 and 2.5 cm to provide a safety margin; if the septum is too thick, favorable ablation results may be difficult to attain, whereas if it is too thin, the patient is at higher risk for developing a ventricular septal defect. A septum less than 1.8 cm thick in a patient with the clinical picture of HCM suggests that mitral valve abnormalities, such as long leaflets, abnormal insertion of the papillary muscles, or anterior displacement of the mitral valve apparatus, may be the primary cause for the LVOT obstruction. Such mitral valve abnormalities would contraindicate alcohol septal ablation, because the primary cause for LVOT obstruction in these cases would be mitral valve abnormalities rather than a thick septum.

We consider alcohol septal ablation as second-line therapy for medically refractory HCM, in part because of concerns about the formation of scar tissue in the myocardium that occurs with ablation, with the accompanying potential arrhythmogenic substrate. In HCM patients with symptoms refractory to optimum medical management and a resting or provocative gradient of 50 mm Hg who are poor surgical candidates or those who refuse open heart surgery, percutaneous alcohol septal ablation is another option. For the most definitive treatment of HCM, we generally do not recommend alcohol septal ablation for reasonable surgical candidates but instead recommend myectomy.

Alcohol septal ablation is performed in the catheterization laboratory. Diagnostic coronary angiography is first performed to assess whether septal ablation is possible, based on the vessel size and area of myocardium subtended by the septal perforators. Echocardiography must also be reviewed to ensure that the LVOT obstruction is a result of contact of the mitral valve with the proximal septum. Because the goal of alcohol ablation is necrosis of part of the proximal septum, alcohol ablation will not benefit the patient if the LVOT obstruction occurs in the mid or distal LV cavity.

First, a temporary pacing wire is placed in the right ventricle to provide protection against complete heart block, which may occur during ablation. Next, through a guide catheter, a coronary guidewire is directed into the first major septal perforator (or the perforator that supplies the proximal septum) of the left anterior descending artery. Rarely, the major septal perforator may arise off a diagonal branch of the left anterior descending artery or left circumflex artery. An over-the-wire balloon is then inflated in the septal perforator (Fig. 10). Myocardial contrast echocardiography is performed by injecting contrast through the distal lumen of the coronary balloon into the septal perforator to visualize the size and location of myocardium supplied by the chosen septal perforator. This contrast injection also verifies that no leakage has occurred proximal to the inflated balloon in the septal perforator. Any leakage could be disastrous, because it would result in alcohol flowing antegrade into the left anterior descending artery, causing a myocardial infarction.

After verification of the territory supplied by the septal perforator and ruling out any leaks retrograde in the septal perforator, 1 to 3 mL of desiccated ethanol is instilled into the septal perforator through the distal lumen of the balloon. Alcohol acts as a toxic agent to the coronary artery and surrounding myocardium, resulting in a controlled myocardial infarction of the cardiac muscle supplied by the septal perforator. Consequently, the proximal septum shrinks, LVOT obstruction lessens, and any associated systolic anterior motion is also decreased. In comparison with the effects of septal myectomy on LVOT obstruction, which are instantaneous, the effects of alcohol ablation on LVOT obstruction take longer to manifest because necrosis of the proximal septum needs to occur. After alcohol ablation, the patient is observed in the cardiac intensive care unit for two days. Creatine kinase (CK) and CK-MB levels are measured; CK level increases generally range from 400 to 2500 U (3% to 10% of the left ventricle or 20% of the septum). Despite the myocardial infarction, global LV function is usually not impaired.

Complications of alcohol ablation include right bundle branch block or complete heart block, anterior myocardial infarction from an incomplete balloon seal in the septal perforator, ventricular tachycardia or fibrillation, and pericarditis. The risks of alcohol ablation include a 2% to 4% procedural mortality rate and a 9% to 27% incidence of patients requiring permanent pacemakers.

Alcohol ablation has not been shown to improve survival because of the lack of randomized controlled trials and a suitable control population. However, alcohol ablation 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 (NYHA) classification. For example, at 3-month follow-up, we have noted a decrease in LVOT gradient from 64 to 28 mm Hg and an improvement in NYHA class from 3.5 to 1.9. Decreased LV filling pressures and a decrease in septal thickness have also been reported after alcohol ablation. Predictors of suboptimal outcomes after ablation include a residual LVOT gradient of more than 25 mm Hg, measured in the catheterization laboratory, and a peak CK level lower than 1300 U/L.

Unlike septal myectomy, alcohol ablation results in a myocardial scar. Thus, there is a theoretical risk that alcohol ablation may increase the risk of sudden cardiac death, especially because an arrhythmogenic substrate is already present with HCM. One study of 71 HCM patients who already had an implantable cardioverter-defibrillator (ICD) for the primary prevention of sudden cardiac death and were undergoing alcohol ablation reported an 8% appropriate ICD firing rate at almost 2 years after alcohol ablation. Sudden cardiac death has been reported several months after successful alcohol ablation.

Comparison of Septal Myectomy and Alcohol Ablation—Treatment Outcomes

Both myectomy and alcohol ablation reduce LVOT gradient and improve symptoms, but septal myectomy is slightly more efficacious ( Table 2 ). A nonrandomized comparison from the Cleveland Clinic of 51 HCM patients who underwent myectomy or alcohol ablation has found larger and more consistent reductions in LVOT gradient with myectomy. Of the 26 patients who underwent septal myectomy, resting LVOT gradient was significantly reduced from 62 mm Hg premyectomy to 7 mm Hg postmyectomy. In the 25 alcohol ablation subjects, resting LVOT gradient was significantly reduced from 64 mm Hg preablation to 28 mm Hg postablation. Myectomy also demonstrated a more favorable effect in lowering provocable gradients. In those with a resting peak gradient lower than 50 mm Hg, myectomy decreased the amyl nitrite–induced provocable gradient from 86 mm Hg preoperatively to 28 mm Hg at follow-up, whereas alcohol ablation decreased this provocable gradient from 92 mm Hg before ablation to 55 mm Hg at follow-up. NYHA class improved significantly from 3.3 to 1.5 in the myectomy group and from 3.5 to 1.9 in the alcohol ablation group. Additionally, in this study, five patients in the alcohol ablation group later required myectomy secondary to persistent gradients.

Table 2: Comparison of Septal Myectomy and Percutaneous Alcohol Septal Ablation
Parameter Percutaneous Alcohol Septal Ablation Surgical Myectomy
Invasiveness Percutaneous groin access Sternotomy
Onset of reduction in LVOT gradient Some decrease in gradient instantly, but 6-12 mo for full effect Instantaneous
Success rate (%) >80 >95
Procedural mortality (%) 1-2 0-2
Recovery time 2-4 days 1 wk
Effect on LVOT gradient Decreases to <25 mm Hg Decreases to <10 mm Hg
Postprocedure conduction abnormality Right bundle branch block Left bundle branch block
Need for permanent pacemaker—all patients (%) 12-27 3-10
Need for permanent pacemaker if no preexisting conduction abnormalities (%) 13% 2%
Length of follow-up (yr) 6-8 30-40

LVOT, left ventricular outflow tract.

Another nonrandomized cohort study of 44 patients found similar improvements in LVOT gradients and NYHA classification after myectomy or ablation, but superior results in the myectomy group with respect to exercise parameters, including peak oxygen consumption and peak work rate achieved. A third nonrandomized study compared 41 alcohol ablation patients from Baylor with an age- and gradient-matched cohort of myectomy patients studied at the Mayo Clinic. The functional and hemodynamic changes after 1 year were similar, although alcohol ablation subjects had a significantly higher incidence of permanent pacing.

Practice Guidelines

ACC/ESC guidelines address both medical and surgical treatments for HCM. These guidelines state that the efficacy of medical therapy for asymptomatic subjects with HCM is currently unresolved. For those with obstruction with exercise, beta blockers are the preferred therapy. However, little evidence exists for benefit with beta blockers in patients with resting obstruction. The guidelines also state that verapamil is often used as a second-line agent, particularly in those who do not benefit from beta blockers or cannot tolerate them. No evidence exists that combined therapy with beta blockers and verapamil is more advantageous than monotherapy. Finally, disopyramide is regarded as third-line therapy, following beta blockers and verapamil in the guidelines.

In the guidelines, septal myectomy is considered the gold standard for subjects with drug-refractory HCM. Myectomy is not recommended in asymptomatic or mildly symptomatic patients. One exception to this recommendation is the consideration of myectomy for young patients (who are low-risk surgical candidates) with severe (more than 75 mm Hg) outflow tract obstruction, regardless of whether they are symptomatic. The guidelines regard alcohol septal ablation as second-line therapy for drug-refractory HCM, behind myectomy. It is recommended that septal ablation be confined to older adults.

Our approach to therapy for HCM is similar to that advocated by the guidelines. One slight difference is that although we also favor beta blockers as first-line therapy, we are slightly more aggressive in starting them. For example, we would consider starting beta blockers in patients with resting obstruction, a category for which the guidelines state that benefit is uncertain. We concur that verapamil and disopyramide are second- and third-line therapies, respectively. With respect to interventional therapy for HCM, we absolutely agree that septal myectomy is first-line therapy. We reserve septal ablation for suboptimal surgical candidates, in part because of the scar created by septal ablation and thus the potential for arrhythmias.

Permanent Pacemaker Implantation

Pacemaker implantation has been used historically to alleviate the symptoms of HCM, but this procedure has fallen out of favor. It has been hypothesized that initiating ventricular contraction at the right ventricular apex and distal septum would alter the sequence of ventricular contraction, such that the outflow gradient would be decreased and symptoms improved.

Although initial, nonrandomized, unblinded studies have reported symptomatic improvement, subsequent double-blind, randomized, crossover trials with dual-chamber pacing have demonstrated no significant change in exercise capacity but a small decrease in LVOT gradient. In addition, patients with and without active pacing have noted subjective improvement in exercise capacity. Thus, a notable placebo effect accounts for the improvement in symptoms attributed to pacemakers. Furthermore, in a nonrandomized, concurrent, cohort study, 39 patients underwent surgical myectomy or received permanent pacemakers. Surgical myectomy was unquestionably superior in this study, with larger decreases in LVOT gradient (76 to 9 mm Hg vs. 77 to 55 mm Hg) and larger improvements in symptoms and exercise duration than permanent pacing.

Practice Guidelines

American College of Cardiology–American Heart Association (ACC/AHA) guidelines consider pacemaker implantation for medically refractory, symptomatic HCM with a significant LVOT gradient to be a Class IIb indication. Class IIb means that there is conflicting evidence for the particular intervention, and its usefulness and efficacy are less well established by the available evidence and expert opinion. We do not recommend a permanent pacemaker specifically for treatment of HCM.

Outcomes

Surgical outcomes for HCM are excellent; operative mortality is lower than 2% for septal myectomy and there is durable symptomatic improvement. Outcomes for alcohol ablation are more limited, with follow-up averaging 3 to 5 years, as compared with decades for myectomy. At 3-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.

Summary

  • Beta blockers are first-line therapy for symptomatic HCM, with alternate therapies including verapamil and disopyramide.
  • For drug-refractory HCM with severe symptoms (NYHA Class III or IV), septal myectomy is the favored therapeutic approach, with durable improvements in symptoms and exercise capacity.
  • Alcohol septal ablation, although also effective for HCM, should be reserved for suboptimal surgical candidates, partly because of the scar formation that accompanies ablation, which increases the potential for malignant arrhythmias.
  • Permanent pacemakers are not recommended as therapy for HCM, because randomized controlled trials have demonstrated that their purported benefit in HCM is actually a placebo effect.

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Prevention and screening

HCM is a genetic disease. However, given the varying phenotypic expressions of the known HCM mutations, if those with a genetic predisposition for HCM were to limit vigorous exercise, the manifestations of HCM might theoretically be attenuated. Because HCM is the leading cause of death in young athletes, it is recommended in this country that all competitive athletes undergo a history and physical examination before athletic clearance, with consideration for an echocardiogram if a history of syncope is present, a systolic murmur is heard on physical examination, or any other clinical indicator is present that suggests the diagnosis of HCM. Electrocardiographic screening for cardiac disease in competitive athletes is required in Italy, but not at this time in the United States. This remains controversial. We do not recommend screening the general population for HCM with transthoracic echocardiography. We do recommend clinical and genetic screening for first-degree relatives of those with HCM. Because HCM is the leading cause of death in young athletes, all competitive athletes should undergo history and physical examination before athletic clearance, with consideration for an echocardiogram if a history of syncope is present, a harsh systolic murmur is heard on physical examination, or any other clinical indicator is present that suggests the diagnosis of HCM.

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Considerations in special populations

Pregnancy

Patients with HCM generally tolerate pregnancy well. The maternal mortality rate for HCM patients during pregnancy is 1%, which is increased as compared with that of the general population. Maternal morbidity from HCM, generally manifests as atrial fibrillation, syncope, or congestive heart failure, appears to occur primarily in women who already had similar symptoms and complications of HCM before pregnancy.

Sudden Cardiac Death and Defibrillator Implantation

The most serious complication of HCM is sudden cardiac death (SCD), with an incidence of 0.1% to 0.7%/year. A survivor of an episode of SCD warrants consideration for an ICD. Primary prevention of SCD in HCM patients is not as well defined. Antiarrhythmic therapy for primary prevention is not recommended for asymptomatic patients. HCM patients at higher risk for sudden cardiac death include those with a left ventricular wall thickness more than 30 mm, prolonged or repetitive episodes of nonsustained ventricular tachycardia on Holter monitoring, family history of SCD, hypotensive blood pressure response to exercise, and syncope or near syncope. Patients with these risk factors may benefit from automatic ICD implantation for primary prevention of SCD. Assessing the genotype may help ascertain SCD risk in the future, but, at present, genetic testing will generally not alter management in regard to the prevention of SCD. Electrophysiologic testing has not been shown to be predictive of SCD in those with HCM.

Nonobstructive Hypertrophic Cardiomyopathy

The treatment of patients with nonobstructive hypertrophic cardiomyopathy is difficult and less effective than those with obstructive disease. Beta 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 that of 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, angiotensin-converting enzyme inhibitors, and digoxin may be necessary. Heart transplantation is an option for those with end-stage nonobstructive HCM.

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Suggested Readings

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