Definition and Etiology

Hypertrophic cardiomyopathy (HCM) is defined as hypertrophy of the myocardium more than 1.5 cm, without an identifiable cause (Figure 1). Other causes of left ventricular (LV) hypertrophy, such as long-standing hypertension, amyloidosis, and aortic stenosis must first be excluded before HCM can be diagnosed. As our understanding of the genetics of HCM continues to progress, the diagnosis of HCM will continue to incorporate information obtained from genetic testing, while also continuing to rely on transthoracic echocardiography (TTE) for the assessment of the phenotypic manifestations and the overall clinical severity of the disease.

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Prevalence and Risk Factors

Epidemiology

HCM is the most common genetic cardiovascular disease.¹ The estimated prevalence in the general adult population with phenotypic evidence of HCM is 1 per 500.²Men are more often affected than women and black patients more so than white. In young adults, HCM is the most common cause of sudden cardiac death (SCD).^3,4

Risk Factors

Any strenuous exercise that increases afterload (i.e., heavy weight lifting/training) can theoretically increase the magnitude of LV hypertrophy over time and thus worsen obstruction in subjects with pre-existing HCM. Risk factors for the development of end-stage HCM (manifesting as LV systolic dysfunction and LV dilation) include younger age of onset/presentation of HCM, a family history of HCM, increased ventricular wall thickness, along with the presence of certain genetic mutations in certain individuals.

Genetics

Many of the mutations associated with HCM involve the cardiac sarcomeric proteins and as a result have an effect on sarcomeric function. The mutations include (but are not limited to) actin, myosin, or troponin component of the sarcomere and are passed in an autosomal dominant fashion.⁵ Other genetic conditions exist which are transmitted in X-linked recessive pattern (Fabry’s disease; GLA gene for alpha-galactosidase A) which is associated with a glycogen storage disorder and HCM; or as an X-linked semidominant pattern (Danon’s disease; LAMP2 gene) which is involved in lysosomal biogenesis and can result in HCM, skeletal myopathy and variable degree of mental retardation.^6,7

Thus far a multitude of mutations in over 27 HCM susceptibility genes have been identified.⁸ The most common dominant myofilament genetic mutations in HCM are associated with 11 genes, with the beta-myosin heavy chain and myosin-binding protein C, accounting for up to 70% of identified mutations thus far.⁹ However at this time due to variable penetrance and heterogeneity in clinical presentations of each of the mutations, it is not possible to prognosticate based on the presence of a certain gene mutation.¹⁰

The suggestion that certain gene mutations were more benign and others were more malignant with a higher likelihood of SCD was studied in a series from the Mayo Clinic. Two hundred ninety-three HCM patients were DNA screened for known “benign” and “malignant” type mutations. Only five patients (1.7%) had one of the eight most common “benign” mutations—however, all had severe HCM requiring myectomy, and three of five had a family history of SCD.¹¹ Of the “malignant” mutations – only three patients in the series tested positive for one of the five mutations, underscoring the low yield of testing as well as the genetic variation in HCM.¹²

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Pathophysiology and Natural History

HCM is a genetic disease that leads to hypertrophy of the left ventricle with or without the presence of LV outflow tract (LVOT) obstruction. The clinical presentation as well as degree of obstruction may vary depending on the location and extent of hypertrophy within the heart as well as the presence of other abnormalities such as mitral regurgitation, diastolic dysfunction, and myocardial ischemia.¹³ Histopathologic evaluation reveals hypertrophied and disorganized myocyte architecture a variable pattern of interstitial fibrosis, as well as abnormalities within the vessel wall of the intramural coronary arterioles preventing compete vasodilation during exercise.¹⁴

The presence of systolic anterior motion (SAM) of the mitral valve may lead to dynamic LVOT obstruction due to impingement of the mitral valve leaflets upon the hypertrophied basal septum. This occurs due to increased flow through an already narrowed LVOT along with drag forces across the mitral valve leaflets, which are pulled anteriorly leading to obstruction which begets itself as the orifice narrows further; LV pressure and flow velocity continue to increase, leading to more anterior “drag” of the mitral leaflets. This process may result in loss of coaptation of the mitral leaflets leading to mitral regurgitation depending on how severe the degree of SAM is. Obstruction can exist at rest or can be brought on with provocative maneuvers (i.e., Valsalva, exercise, sudden upright position, amyl nitrite). It can also occur within the ventricle itself depending on the location and severity of hypertrophy, as a result of mid-systolic contact of the ventricular walls leading to mid-cavitary or apical (Yamaguchi’s disease [Figure 2]) obstruction.^15–17

LVOT obstruction in HCM is dynamic, unlike the fixed obstructive profiles of aortic stenosis and subvalvular aortic membranes. In dynamic obstruction, the degree of obstruction depends more on cardiac contractility and loading conditions than in instances of fixed obstruction. In an underfilled left ventricle there is less separation between the mitral valve and interventricular septum—thus resulting in a greater degree of obstruction since the LVOT orifice is already narrowed prior to onset of systole. Augmentation of cardiac contractility also increases LVOT obstruction, since a more vigorous contraction is more likely to result in contact between the septum and mitral leaflets.

HCM can also be broadly classified based on the location of hypertrophy, with examples such as the proximal septum or the apex. There appear to be distinct forms of HCM at different ages; with younger patients often having more diffuse hypertrophy and reversal of septal curvature (Figure 3), while older patients tend to have more focal proximal septal hypertrophy with a sigmoid septal morphology (Figure 4). 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.^1,18–21 Onset and/or progression of LV hypertrophy usually occurs during the adolescent growth spurt.¹

The natural history of HCM can vary depending on the patient; they can be asymptomatic with no phenotypic features or symptoms or they can manifest a variable level of disease progression.²² Over time, patients can develop subendocardial ischemia due to development of fibrosis, overt hypertrophy with septal thickening and LVOT obstruction, development of restrictive-cardiomyopathy with impaired relaxation and diastolic filling, arrhythmias (ventricular and supra-ventricular), and ultimately end-stage heart failure with LV systolic dysfunction. Again, each patient will have a unique course depending on the presence of risk factors, extent of gene penetrance and phenotypic expression, as well as age of presentation.

The incidence of SCD is estimated to be approximately 0.1% to 0.7% per year across all HCM patients.^23,24

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Signs and Symptoms

For symptomatic patients, the onset and severity of symptoms does not necessarily correlate with the magnitude of the LVOT obstruction. Rather, symptoms appear to be more closely associated with the severity and extent of both mitral regurgitation and diastolic dysfunction.⁴

A majority of patients have minimal to no symptoms, with dyspnea being the most common complaint among symptomatic patients.^23,24 Some patients however will go on to develop progression of symptoms including fatigue, chest discomfort, palpitations, and presyncope/syncope. The spectrum can include development of heart failure due to LV diastolic dysfunction from severe hypertrophy eventually leading to LV dilation and systolic dysfunction with orthopnea, paroxysmal nocturnal dyspnea and leg edema. Diastolic dysfunction can also result in the development of atrial arrhythmias such as atrial fibrillation in addition to possible stroke from cerebral embolism, ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation, chest pain (due to subendocardial ischemia or LVOT obstruction), and even SCD. The post-prandial state may even exacerbate symptoms of HCM due to splanchnic vasodilation, resulting in a decrease in cardiac preload.²⁵

The physical examination can provide several clues suggestive of a diagnosis of HCM. Palpating the carotid pulse can help to distinguish HCM from aortic stenosis or 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 and LVOT obstruction increases, this results in a mid-systolic decrease in the pulse followed by 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 is noted to be the classic parvus et tardus (small amplitude and delayed upstroke) pulse, a carotid pulse with delayed upstroke and amplitude. Therefore, if any patient with a diagnosis of HCM has decreased carotid pulses, one should suspect misdiagnosis and carry out further investigation to rule out the presence of fixed LVOT obstruction.

On auscultation, in the absence of heart failure symptoms, the lungs are usually clear and the jugular venous pressure within normal limits. The point of maximal impulse will be forceful and sustained and laterally displaced, while a palpable or audible S₄ gallop may also be present. The classic auscultatory finding for HCM is a harsh, crescendo–decrescendo systolic murmur along the upper left sternal border that increases with the Valsalva maneuver, which is indicative of dynamic LVOT obstruction. 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). During Valsalva there is decreased venous return to the right side of the heart (due to elevation of intra-thoracic pressures) and hence decreased filling of the left ventricle. An underfilled left ventricle results in an increase in LVOT obstruction as the ventricular cavity is smaller and the septum and mitral leaflets are closer in proximity, leading to narrowing of the LVOT in systole. Standing from a squatting to upright position similarly decreases LV preload and increases the intensity of the murmur as well. Lastly, amyl nitrite (a profound vasodilator), can be used to assess for HCM. It works by decreasing preload and causing a reflex tachycardia, resulting in a louder murmur due to an increase in the degree of obstruction. In addition, it is imperative to auscultate carefully for a mitral regurgitation murmur; since it is possible to have SAM of the mitral valve and LVOT obstruction murmur with (or without) mitral regurgitation. The remainder of the examination is generally unremarkable.

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Diagnosis

Clinical Diagnosis

The diagnosis of HCM can be entertained based on the history and physical exam findings. A combination of findings including strong family history of HCM with undifferentiated cardio-pulmonary symptoms (such as dyspnea, palpitations, chest discomfort, dizziness, syncope, etc.) along with the presence of cardinal physical exam findings (harsh upper sternal border murmur that increases with Valsalva and brisk carotid upstroke) and electrocardiogram (ECG) finding of LV hypertrophy are all suggestive features of HCM. Further workup should be initiated to elucidate the diagnosis in these patients.

Differential Diagnosis

The differential diagnosis should include all other causes of LV hypertrophy and LVOT obstruction. HCM should be differentiated from hypertensive heart disease, infiltrative cardiomyopathies (amyloidosis, glycogen storage disorders, hemochromatosis, etc.), aortic stenosis/subvalvular membrane (fixed LVOT obstruction) as well as athlete’s heart. Hypertensive heart disease is the most common cause for LV hypertrophy in older patients; long-standing fixed obstruction can lead to similar findings in severe aortic stenosis patients as well. Athlete’s heart is often seen in younger patients who are exposed to extensive strength training.

Electrocardiographic and Laboratory Studies

Routine labwork is generally unremarkable in HCM patients, except for plasma B-type natriuretic peptide.²⁶ A chest radiograph may the suggestion of LV hypertrophy, but often is normal because the hypertrophy in HCM involves the ventricular septum. The ECG can show LV hypertrophy as well as a pseudoinfarct pattern (Q-waves in the anterolateral leads), despite the absence of coronary artery disease. Patients who have arrhythmias may demonstrate atrial fibrillation as well as non-sustained ventricular tachycardia. The apical form of HCM (Yamaguchi’s disease) may show deep T-wave inversions across the antero-apical leads. Left atrial abnormality may be present if the patient has had long-standing mitral regurgitation due to SAM of the mitral valve.

Imaging

Echocardiography should be the primary imaging modality used in making the diagnosis of HCM (Figures 2-4). With TTE, the septum can be well visualized and measured in the parasternal long, apical long, apical four-chamber, as well as the parasternal short axis views. On TTE, evaluation of 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, along with any change in severity of obstruction with provocation. Continuous-wave Doppler imaging provides a visual representation of blood velocity in a particular direction; it is useful in differentiating patients with HCM from those with fixed obstructions, such as valvular aortic stenosis and subvalvular membrane. Figure 5 illustrates the differences between continuous-wave Doppler signals in patients with HCM and with fixed obstructions. With HCM, the continuous Doppler signal has a late systolic peak with a characteristic “dagger-shaped” profile. This specific profile is seen due to increasing LVOT obstruction through systole. During early systole, blood still flows through the LVOT, however, with continued contraction of the left ventricle, exacerbated by SAM of the mitral valve, the outflow tract area diminishes and an outflow tract gradient develops. In contrast, a fixed obstruction is present during the entirety of systole. Thus, the continuous-wave Doppler signal for fixed obstructions has a smoother contour with an earlier peak. Other modalities that are gaining more widespread use in the evaluation of HCM are tissue Doppler and strain imaging utilizing speckle tracking. Tissue Doppler incorporates Doppler ultrasound imaging principles for the assessment of myocardial motion (systolic and diastolic) using frequency shifts to evaluate myocardial shortening and relaxation velocities, which can be useful in differentiating between athlete’s heart or hypertensive heart disease.^27–29Ongoing research in strain imaging currently is focused on identifying patterns of regional fibrosis and LV dysfunction.^30,31 The role of transesophageal echocardiography (TEE) in HCM is in patients with poor transthoracic images with an inability to accurately assess septal thickness, degree of SAM or MR, as well as unclear papillary muscle attachments.

Cardiac magnetic resonance (CMR) imaging is emerging as an integral tool in the workup and risk-stratification of HCM patients. The use of delayed-enhancement CMR with gadolinium-based contrast agents provides insight into the location, pattern and extent of myocardial fibrosis.^30,31 An active area of current research is the relationship between the extent and location of scar formation with SCD.^32,33 CMR is also a useful tool that provides high-resolution anatomic definition as well as objective assessment of LV function.^34,35 It can be used to identify apical and non-typical variants of HCM, the presence of papillary muscle abnormalities, as well as identifying other etiologies of LV hypertrophy (i.e., Fabry’s disease, amyloidosis).^35–39

Diagnostic Procedures

The use of other diagnostic procedures in patients with HCM is required if the diagnosis is not evident from the clinical history and initial imaging testing. In the presence of a normal LVOT gradient at rest, provocation testing may be required to initiate the cascade leading to the onset of dynamic LVOT obstruction. Patients may squat or perform the Valsalva maneuver in an attempt to elicit latent obstruction. If that is not successful, inhalation of amyl nitrite (potent venodilator) will cause a reduction in preload followed by a compensatory increase in heart rate. However, in some patients severe obstruction may only occur with exertion and thus patients may need to be referred for exercise (treadmill) echocardiographic stress testing. The safety of treadmill testing has been evaluated, with a single center study showing a major complication rate of 0.04% with the appropriate monitoring and pre-screening of patients.⁴⁰

Although the role of cardiac catheterization has decreased with the advances in noninvasive imaging, it has a specific role in patients being evaluated for septal ablation. Catheterization allows for the evaluation of coronary artery disease along with coronary anatomy in the evaluation for possible alcohol septal ablation (ASA) as well as direct LV pressure and LVOT gradient measurement. The utility of ventriculogram is greatly diminished in these patients since CMR and echocardiography provide such a high-yield LV assessment.

The LVOT gradient can be measured by positioning a catheter near the apex of the left ventricle and recording pressures during a slow catheter pullback. A classic finding in HCM is the Brockenbrough-Braunwald-Morrow sign, in which the left ventricle-to-aortic gradient increases while the aortic pulse pressure decreases following premature ventricular contraction (PVC) (Figure 6).⁴¹ Such a phenomenon occurs in HCM due to increased contractility in the post-PVC beat, which can cause an increase in 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 resultant sub-endocardial or myocardial ischemia caused by the mismatch between myocardial oxygen supply and demand. This mismatch is driven primarily by the increased myocardial mass and is often associated with worse clinical outcomes in this population.⁴²

Genetic testing currently has a class I indication in patients with familial inheritance of HCM as well as patients who have unexplained LV hypertrophy. The use of genetic testing must be performed in tandem with genetic counseling to appropriately interpret and evaluate the results.⁴

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, as areas of the heart that appear grossly normal may also have these pathologic features.

Summary

• HCM is defined as hypertrophy of the left ventricular myocardium, generally 1.5 cm or more, which is not explained by another cause.
• Currently, transthoracic echocardiography is the diagnostic test of choice for the diagnosis of HCM. Cardiac MRI and genetic testing are increasingly being used as adjunctive testing modalities.
• Genetic testing allows for the 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.
• In the presence of LVOT obstruction, the diagnosis of HCM needs to be differentiated from other causes of obstruction, primarily aortic stenosis or subvalvular aortic membrane. With brisk carotid upstrokes, a normal or minimally diseased aortic valve, lack of a subvalvular aortic membrane on imaging, as well as the presence of dynamic LVOT obstructive profile (dagger-shaped appearance) of flow through the LVOT all indicative of HCM.

Practice Guidelines

Consensus practice guidelines for HCM were revised in 2011 by the American College of Cardiology (ACC) and the American Heart Association (AHA). Overall, these guidelines also recommend TTE as the best modality to make the clinical diagnosis of HCM, and the standard criterion is a LV wall thickness of at least 15 mm in the absence of other causes for hypertrophy.⁴ These guidelines also emphasize that hypertrophic cardiomyopathy 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

Management

Treatment options for HCM include medical therapy and lifestyle modification, ASA, and septal myectomy (for obstruction), as well as heart transplantation for end-stage HCM patients with heart failure. Additionally, the use of dual chamber pacing was postulated to help improve LV contraction mechanics and decrease LVOT obstruction. Results have indeed shown that this is not the case and patients who received pacemakers did not have improvements in LVOT gradient or symptoms compared with those who did not.^43,44

Lifestyle Modifications

Patients with a diagnosis of HCM are recommended to avoid strenuous activity (endurance training, heavy weight lifting, etc.), since this activity increases the afterload seen by the heart and can subsequently worsen LV hypertrophy. In the case of heavy lifting resulting in Valsalva, preload also can decrease significantly, resulting in increased LVOT obstruction and syncope. Additionally, due to the risk of SCD, subjects should avoid competitive athletics. Lastly, HCM patients should remain well hydrated to prevent LV under-filling and worsening LVOT obstruction.

Medical Options

Beta-blockers are considered first-line therapy for symptomatic HCM. By decreasing contractile force, beta-blockers decrease the LVOT gradient as well as decrease overall myocardial workload and oxygen demand. Beta-blockers increase diastolic filling by slowing the heart rate and allowing for more passive filling of the LV. Patients are generally started on metoprolol tartrate (Lopressor), 25 mg twice daily, or metoprolol succinate (Toprol-XL), 50 mg daily and titrated to a goal resting heart rate of 60 bpm as tolerated. If symptoms persist, the dose of metoprolol can be increased by 25-mg increments every few weeks, with the peak dose being 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 dysfunction due to primary hepatic metabolism of metoprolol. Fatigue and loss of libido are common side effects of beta-blockers.

Second-line therapy includes the use of calcium-channel blockers (specifically nondihydropyridine, i.e., verapamil) due to their negative chronotropic effect, which leads to increased diastolic relaxation time (thus increasing preload). 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 shorter-acting agents should be considered for subjects with hepatic dysfunction. Verapamil should not be used in patients with severe pulmonary hypertension since they may develop excessive vasodilation, which could worsen LVOT obstruction and decrease cardiac output, resulting in pulmonary edema.⁴⁵ Other contraindications to verapamil use include the presence of severe LV systolic dysfunction, conduction system disease, and hypotension. Diltiazem has been used in select HCM patients, but there is little data available on its effectiveness. Nondihydropyridine calcium-channel blockers, such as nifedipine, amlodipine, and felodipine should be avoided since they may cause peripheral vasodilation, which can result in decreased LV filling and worsening of LVOT obstruction.

Another second-line agent is disopyramide, a Class IA antiarrhythmic drug that has negative inotropic effects and can improve diastolic function and affect a decrease in LVOT gradient.⁴⁶ The extended-release formulation of disopyramide (Norpace CR) may be started at 150 mg twice daily—however, due to concerns for QT prolongation, patients should be monitored in the hospital during initiation of drug therapy. 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 it has both antiarrhythmic and proarrhythmic properties. Common side effects of disopyramide include anticholinergic effects such as dry mouth, urinary retention, and blurred vision.

Drugs that should be avoided in patients with HCM are angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and nitrates since they all decrease afterload and can worsen LVOT obstruction. Agents such as digoxin and IV medications such as dopamine, dobutamine, and norepinephrine should be avoided due to their positive inotropic effect and resultant increase the LVOT gradient. In patients with hypotension that is refractory to IV fluid boluses, IV phenylephrine (alpha agonist) should be the drug of choice for use as a vasoconstrictor.

Atrial fibrillation is a common complication of HCM. In HCM patients with new-onset atrial fibrillation, the clinician should attempt to restore normal sinus rhythm with the use of 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, TEE should be performed to ensure that there is no thrombus formation in the left atrium or left atrial appendage; alternatively, a systemic anticoagulant can be given for at least 4 to 6 weeks before any electrical or chemical attempts at restoration of sinus rhythm. However, HCM patients often tolerate atrial fibrillation poorly (due to the loss of their atrial “kick” as well as the variations in their heart rate) so TEE followed by electrical cardioversion is generally the preferred approach. Amiodarone or sotalol are the preferred therapies in HCM patients for pharmacologic conversion to or maintenance of sinus rhythm.

Treatment of persistent atrial fibrillation in HCM includes systemic anticoagulation with warfarin and rate control, preferably with a beta-blocker. Anti-coagulation with the newer agents (factor Xa and direct thrombin inhibitors) has not been studied in a randomized controlled fashion and as of yet do not have an indication for systemic anticoagulation to prevent embolic stroke in HCM patients with atrial fibrillation. Ablation of atrial fibrillation (pulmonary vein isolation) or surgical 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, a combined MAZE and myectomy procedure has been performed safely with symptomatic improvement.⁴⁷

The most recent guidelines from ACC/AHA have reversed the recommendation that patients with HCM should not receive prophylactic antibiotics for endocarditis prevention.⁴⁸ In the past, it was postulated that turbulent flow through the LVOT would damage the aortic valve and that SAM of the MV would predispose both valves to endocarditis in the setting of transient bacteremia; there still exists some HCM expert opinion that states prophylaxis may still be of benefit to these patients.⁴⁹

Surgical and Percutaneous Considerations

Surgical Options

Referral for surgical intervention has been reserved for patients with recalcitrant symptoms despite maximal medical therapy and a resting or latent gradient of 50 mm Hg or more. Septal myectomy has been considered the treatment of choice in these patients, and particularly in young patients who are healthy and have no associated cardiac risk factors.⁴ There is data to suggest that the degree of dynamic LVOT obstruction (>30 mm Hg) has prognostic significance in this group of patients; thus providing a rationale for surgical intervention.⁵⁰ In contrast, patients who remain asymptomatic with LVOT gradients >50 mm Hg should continue medical management and regular followup, with a progression to surgery once they become symptomatic.

Abnormalities of the mitral valve, such as lengthy, redundant anterior and/or posterior mitral valve leaflet(s), may lead to SAM of the mitral valve resulting in mitral regurgitation.^51,52 Apically displaced, bifid, hypermobile, thickened or hypertrophied papillary muscles may also demonstrate SAM, leading to obstruction and/or symptoms.^36,53 A growing number of patients are requiring additional procedures (mitral valve repair/replacement, and/or papillary muscle reorientation) in addition to a septal myectomy in order to adequately relieve LVOT obstruction.⁵⁴ Myectomy may also be combined with coronary artery bypass grafting.

Septal myectomy is performed by resecting a small portion of the proximal septum through an aortotomy (Figure 7). The pre- and post-myectomy echocardiography images will demonstrate a reduction in septal thickness (depending on the amount of excised myocardium) after myectomy (Figures 8 and 9). In addition, mitral valve surgery (repair or replacement) and/or papillary muscle re-orientation may be performed if severe mitral regurgitation or outflow tract obstruction persists despite an adequate septal myectomy. Septal myectomy is usually not indicated in HCM patients who present with mid-cavitary or apical hypertrophy; however, a limited series has shown some benefit of an apical myectomy procedure in those patients with apical hypertrophy for symptomatic relief.⁵⁵

Septal myectomy (and associated MV and papillary muscle procedures) decrease LVOT obstruction, improve symptoms, and increase exercise capacity.^56–59 Both the decrease in LVOT gradient as well as any associated mitral regurgitation is responsible for improvement in symptoms. It is rare to require reoperation for recurrence of LVOT obstruction.⁴ Isolated septal myectomy is a relatively safe procedure, with operative mortality being reported between 0% and 4%.^60–62 Long-term survival with 5- and 10-year survival rates of 93% to 96%, and 83% to 87% (respectively); those undergoing additional procedure (such as valve or bypass surgery) have a 5-year survival of 80%.^54,62,63 Many patients have good outcomes after surgery, with some recent data to suggest that those with advanced age (>50 years) or presence of atrial fibrillation post-procedure have worse long-term outcomes.^64,65

The risk that a myectomy patient will require a permanent pacemaker after myectomy depends on the health of the conduction system prior to the procedure. In subjects with normal conduction systems, as noted on the ECG, there was a 2% to 3% rate of permanent pacemaker implantation after myectomy, whereas for patients with preexisting conduction abnormalities, there was a 10% incidence of permanent pacemaker implantation.^66,67 Patients at the highest risk for requiring a permanent pacemaker are those with a preexisting right bundle branch block, since left bundle branch blocks occur in more than 90% of patients after septal reduction procedures.⁶⁶

No randomized studies assessing long-term survival in HCM patients undergoing medical management versus myectomy exist currently. However, retrospective, nonrandomized data suggest that HCM patients undergoing myectomy have lower mortality rates than patients with obstruction who do not undergo surgery, and that long-term survival for HCM subjects who have undergone myectomy becomes equivalent to that of the age- and gender-matched general population.⁶³

Percutaneous Alcohol Septal Ablation

ASA was first reported as an alternate treatment for HCM in 1995. Subsequently over 5,000 procedures have been performed and even outpacing the number of septal myectomy procedures performed over the last 45 years.^4,68

ASAs should be reserved for older patients and/or those who are suboptimal surgical candidates. The septum should be between 1.8 and 2.5 cm to provide an adequate safety margin; if the septum is too thick, favorable ablation results may be difficult to attain, alternatively if it is too thin, the patient is at higher risk for (theoretically) 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, redundant leaflets, abnormal insertion of the papillary muscles, or anterior displacement of the mitral valve apparatus may be the primary cause for the LVOT obstruction. As such, the presence of these mitral valve abnormalities is a contraindication for ASA, since the LVOT obstruction in these situations may not be alleviated by ASA alone.

ASA should be considered as a second-line therapy for medically refractory HCM, due to concerns about the formation of scar tissue that occurs after ablation, as well as the accompanying risk of potential arrhythmogenic substrate and SCD.⁶⁹ Data is conflicting in this area as one study of 123 HCM patients who already had an implantable cardioverter-defibrillator (ICD) in place did not show an increase in pro-arrhythmogenicity after ablation.⁷⁰ However, other studies have shown ICD therapy is four-fold more likely after ASA than following septal myectomy.⁴ In HCM patients with symptoms refractory to optimum medical management and a resting or provocative gradient of >50 mm Hg who refuse open heart surgery or are poor surgical candidates, percutaneous ASA can be considered. For definitive treatment of HCM, septal myectomy is still the preferred therapy in reasonable surgical candidates as the treatment of choice for relief of LVOT obstruction.

ASA should be performed in the catheterization laboratory or in a hybrid-OR setting. Diagnostic coronary angiography should be first performed to assess whether septal ablation is feasible. Key features that need to be assessed are the presence of co-existing unrevascularized coronary disease and also whether based on the vessel size an area of myocardium subtended by the septal perforators exists. Echocardiography must also be reviewed prior to the procedure to ensure that the LVOT obstruction is a result of contact between the mitral valve leaflets and the proximal septum. Since the goal of an ASA is to cause a controlled infarction resulting in necrosis involving a portion of the proximal septum, it will not benefit the patient if the LVOT obstruction exists predominantly in the mid- or distal-LV cavity.

The procedure is performed by inserting a temporary pacemaker in case the patient develops complete heart block after the procedure. A coronary guidewire is advanced into an appropriate septal branch that supplies the proximal septum, and an over-the-wire balloon is inflated in the artery to isolate it and prevent any antegrade flow into the branch (Figure 10). Myocardial contrast echocardiography is performed by injecting contrast through the distal lumen into the septal perforator and imaging the location and extent of the supplied myocardium. Also it is important to confirm that a good seal exists between the balloon and the septal branch; retrograde extravasation of the alcohol could be catastrophic, possibly leading to extensive LAD damage and infarction.

If an appropriate septal perforator exists and has been localized, a small amount (1-3 mL) of desiccated ethanol is instilled into the artery. The alcohol is a profound endothelial irritant and causes closure of the vessel and subsequent myocardial infarction in the supplied territory. Unlike surgical myectomy, the clinical improvements are not immediate and may occur over weeks as the infarction reaches completion, the myocardium shrinks and eventually scars. As the septum shrinks, this can lead to decreases in LVOT obstruction and associated SAM and septal contact. A small septal infarct will cause the creatinine kinase (CK) to peak <1,300 U/L which portends a less favorable outcome⁷¹; increases above 2,500 U/L should alert the physician to the possibility of larger infarct or damage to LAD. The patient should be monitored in the intensive care unit for 1 to 2 days and CK as well as CK-MB levels are measured to gain information on the extent of infarction, while also monitoring for the onset of new conduction abnormalities (such as complete heart block). Despite the myocardial infarction, global LV function is usually not impaired.

Complications noted with ASA include onset of a right bundle branch block or complete heart block,^66,67 anterior myocardial infarction, 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.^67,72–74

Due to the absence of any randomized control trials, ASA has not been shown to improve survival thus far. It has still been extensively utilized in this group of patients as an alternate therapy to surgical myectomy. In both short- and long-term follow-up, improvement was seen in both the LVOT gradient as well as the New York Heart Association (NYHA) heart failure symptom classification; at 3-month follow-up, a decrease in LVOT gradient from 64 to 28 mm Hg and an improvement in NYHA class from 3.5 to 1.9 was noted.⁷⁵ Accordingly, decreased LV filling pressures and septal thicknesses have also been reported after alcohol ablation.^73–75

Comparison of Septal Myectomy and Alcohol Ablation Treatment Outcomes

Both myectomy and alcohol ablation are able to reduce LVOT gradient and improve symptoms, but septal myectomy has been shown to be more efficacious with a lower procedural complication rate (Table 2).⁷⁶ A non-randomized comparison of 51 HCM patients who underwent either myectomy or ablation showed that those undergoing myectomy had larger and more consistent reductions in LVOT gradient; of the 26 patients undergoing myectomy, an average reduction from 62 to 7 mm Hg was observed after surgery.⁷⁵ In the 25 alcohol ablation subjects, resting LVOT gradient was significantly reduced from 64 to 28 mm Hg after ablation; however, 5 of the patients in the ablation group required myectomy due to persistent LVOT gradient after the ablation.⁷⁵ 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.⁷⁵

A meta-analysis from 2010 of HCM patients undergoing septal myectomy versus ASA reported that there was a similar mortality and functional class between both groups, with older patients and those with pre-existing conduction abnormalities faring worse with septal ablation.⁷⁷ HCM patients being evaluated for possible intervention to relieve LVOT obstruction merit a thorough workup prior to surgery. The presence of severe coronary disease and/or surgical grade valvular disease should cue the physician to a surgical approach rather than ablation, since bypass, surgical MAZE, and/or valve repair/replacements can be performed at the time of surgery. Although many patients with HCM have mitral regurgitation due to SAM, in a certain group of patients (approximately 20%) the MR is due to intrinsic valvular abnormalities (such as elongated, redundant leaflets or abnormal papillary muscles). It is important to recognize these patients prior to intervention and appropriately refer them for surgical evaluation, as a reducing septal thickness with septal ablation alone will not alleviate the mitral regurgitation.

Practice Guidelines

ACC and the European Society of Cardiology 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 who have 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 can be 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, after 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, however is the consideration of myectomy for young patients (who are low-risk surgical candidates) with severe (>75 mm Hg) resting or latent outflow tract obstruction, regardless of whether they are symptomatic. The guidelines consider ASA as a second-line therapy for drug-refractory HCM, behind myectomy. It is recommended that septal ablation be confined to older adults, and to those without concomitant coronary disease, or mitral valve/papillary muscle abnormalities.

Permanent Pacemaker Implantation

Pacemaker implantation has been used to alleviate the symptoms of HCM in the past, but this procedure has fallen out of favor. It was 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 and only 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.^43,44 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->9 mm Hg vs. 77->55 mm Hg) with larger improvements in symptoms and exercise duration than permanent pacing.⁷⁸

Practice Guidelines

ACC/AHA guidelines consider pacemaker implantation for medically refractory, symptomatic HCM with a significant LVOT gradient to be a Class IIb indication. Class IIb recommendation is given when there is conflicting evidence for the particular intervention, and its usefulness and efficacy are less well established by the available evidence and expert opinion. A permanent pacemaker specifically for the treatment of HCM is not recommended.

Outcomes

Surgical outcomes for HCM are excellent; operative mortality is lower than 2% for septal myectomy and there is durable symptomatic improvement.^{54,60,61,63–65}Outcomes for alcohol ablation are more limited, with follow-up averaging 3 to 5 years, as compared with decades or myectomy. At 3-month follow-up, both myectomy and alcohol ablation are effective in improving symptoms and reducing LVOT gradients, however myectomy results in larger incremental decrease in LVOT gradients.⁷⁵

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 effective for HCM, should be reserved for suboptimal surgical candidates without concomitant CAD and with MR due solely to SAM, and also due to 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 disease with genetic basis. Because HCM is the leading cause of death in young athletes, it is recommended that all competitive athletes undergo a history and physical examination before clearance to participate in athletic activities, with referral for an ECG and echocardiogram if a prior history of syncope is present, if a systolic murmur is heard on physical examination, or if any other clinical indicator is present that is suggestive of HCM. ECG screening for cardiac disease in competitive athletes is required in Italy, but not at this time in the United States. Although this remains controversial, there is limited cost-to-benefit ratio for generalized screening with ECG and echocardiogram.⁴ However, it is recommended to have clinical and genetic screening for first-degree relatives of those with 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.⁷⁹ Maternal morbidity from HCM, generally manifesting 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.⁸⁰ Patients with resting or provocable gradient should be followed closely by a high-risk obstetrician with regular cardiology followup as well. Recommendations during pregnancy should be aimed at avoiding dehydration and maintaining beta-blockade for heart rate control. Beta-blockers can be continued during pregnancy; however, this requires extra monitoring for fetal bradycardia. Of note, patients should only receive metoprolol since atenolol is hydrophilic and freely crosses the placental barrier and has elevated concentrations in breast milk.

Sudden Cardiac Death and Defibrillator Implantation

The most serious complication of HCM is SCD, with an incidence of 0.1% to 0.7% per year.²³ A patient with a prior history of SCD warrants evaluation for an ICD. Primary prevention of SCD in HCM patients is not as well defined. Anti-arrhythmic therapy for primary prevention is not recommended for asymptomatic patients. HCM patients at higher risk for SCD include those with LV wall thickness more than 30 mm,²² 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.⁸¹ Patients with these risk factors may benefit from ICD implantation for primary prevention of SCD. Assessing the genotype may help ascertain SCD risk in the future, but at present, genetic testing generally does 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 HCM is difficult and less effective than those with obstructive disease. Beta-blockers and/or calcium-channel blockers may be used to control heart rate and improve diastolic function. Over time, HCM may reach a stage colloquially known as “burned out” as the hypertrophy and small cavity regress and evolves into a picture similar to that of a dilated cardiomyopathy, with decreased LV systolic function and a dilated left ventricle. In patients with signs and symptoms of congestive heart failure, diuretics, angiotensin-converting enzyme inhibitors, and digoxin may be necessary. Heart transplantation may be considered in those with end-stage nonobstructive HCM who require advanced heart-failure therapy.

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Suggested Readings

• Crawford FA, Killip D, Franklin J, et al. Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in patients with hypertrophic obstructive cardiomyopathy after alcohol ablation. Circulation 2003; 108:386–387.
• Firoozi S, Elliott PM, Sharma S, et al. Septal myotomy-myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy: a comparison of clinical, haemodynamic and exercise outcomes. Eur Heart J 2002; 23:1617–1624.
• Maron BJ, McKenna WJ, Danielson GK, et al; Task Force on Clinical Expert Consensus Documents; American College of Cardiology; Committee for Practice Guidelines; European Society of Cardiology. American College of Cardiology/ European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003; 42:1687–1713.
• Nishimura RA, Holmes DR Jr. Clinical practice: hypertrophic obstructive cardiomyopathy. N Engl J Med 2004; 350:1320–1327.

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