Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. This disorder is caused by a mutations in genes encoding cardiac sarcomere protein, resulting in variety of phenotypical expression and clinical course. HCM is the most common cause of sudden death in young people. 

Although HCM was written about and known as idiopathic hypertrophic subaortic stenosis (IHSS) or asymmetrical septal hypertrophy (ASH) decades ago, these terms were replaced by hypertrophic cardiomyopathy because the segmental hypertrophy can occur in any segment of the ventricle, not just the septum. Furthermore, this entity can present without subaortic obstruction to flow yet still carry the same ominous risk of arrhythmogenic sudden death and many of its clinical symptoms.

HCM can be separated into obstructive and nonobstructive types. Obstructive HCM is due to midsystolic obstruction of flow through the left ventricular outflow tract as a result of a Bernoulli effect–induced systolic anterior mitral valve movement toward the septum.

The significance of this obstruction, however, is highly controversial. Some investigators and experts believe the obstruction has less to do with the overall hemodynamic and pathophysiologic manifestations of this entity than it does with the inappropriate segmental hypertrophy, which, with its increased myocardial oxygen consumption and substrate for fatal ventricular arrhythmias, has much more significance in the overall clinical picture of this entity and in the treatment and prognosis of HCM.

Since the initial descriptions of hypertrophic cardiomyopathy (HCM), the feature that has attracted the greatest attention is the dynamic pressure gradient across the LV outflow tract. The pressure gradient appears to be related to further narrowing of an already small outflow tract (already narrowed by the marked asymmetrical septal hypertrophy and possibly by an abnormal location of the mitral valve) by the systolic anterior motion of the mitral valve against the hypertrophied septum.

Three explanations for the systolic anterior motion of the mitral valve have been offered, as follows: (1) the mitral valve is pulled against the septum by contraction of the papillary muscles, which occurs because of the valve's abnormal location and septal hypertrophy altering the orientation of the papillary muscles; (2) the mitral valve is pushed against the septum because of its abnormal position in the outflow tract; (3) the mitral valve is drawn toward the septum because of the lower pressure that occurs as blood is ejected at high velocity through a narrowed outflow tract (Venturi effect).

Most patients with HCM have abnormal diastolic function (whether or not a pressure gradient is present), which impairs ventricular filling and increases filling pressure, despite a normal or small ventricular cavity. These patients have abnormal calcium kinetics and subendocardial ischemia, which are related to the profound hypertrophy and myopathic process.

Abnormal calcium kinetics

Data link abnormal myocardial calcium kinetics to the cause of the inappropriate myocardial hypertrophy and specific features of hypertrophic cardiomyopathy (HCM), particularly in patients with diastolic functional abnormalities. Abnormal myocardial calcium kinetics and abnormal calcium fluxes from an increase in the number of calcium channels result in an increase in intracellular calcium concentration, which, in turn, may produce hypertrophy and cellular disarray.

Genetic causes

Familial HCM occurs as an autosomal dominant Mendelian-inherited disease in approximately 50% of cases. Some, if not all, of the sporadic forms of the disease may be caused by spontaneous mutations.

At least 6 different genes on at least 4 chromosomes are associated with HCM, with more than 50 different mutations discovered thus far. Familial HCM is a genetically heterogenous disease in that it can be caused by genetic defects at more than 1 locus.

In 1989, Seidman and collaborators first reported the genetic basis for HCM. They reported the existence of a disease gene located on the long arm of chromosome 14. Subsequently, they found this to be the gene encoding for beta cardiac myosin heavy chain.

Wide variation exists in the phenotypic expression of a given mutation of a given gene, with variability in clinical symptoms and the degree of hypertrophy expressed. Phenotypic variability is related to the differences in genotype, with specific mutations associated with particular symptoms, the degree of hypertrophy, and the prognosis.[1]

Other possible causes

Other possible causes of HCM include the following:

• Abnormal sympathetic stimulation - Heightened responsiveness of the heart to the excessive production of catecholamines or the reduced neuronal uptake of norepinephrine might cause HCM

• Abnormally thickened intramural coronary arteries - These do not dilate normally, which leads to myocardial ischemia; this progresses to myocardial fibrosis and abnormal compensatory hypertrophy

• Subendocardial ischemia - This is related to abnormalities of the cardiac microcirculation that deplete the energy stores essential for the sequestration of calcium during diastole; subendocardial ischemia results in persistent interaction of the contractile elements during diastole and increased diastolic stiffness

• Cardiac structural abnormalities - These include a catenoid configuration of the septum, which results in myocardial cell hypertrophy and disarray

Hypertrophic cardiomyopathy (HCM) is reported in 0.5% of the outpatient population referred for echocardiography.[2] The overall prevalence of HCM is low and has been estimated to occur in 0.05-0.2% of the population.[3] Morphologic evidence of disease is found by echocardiography in approximately 25% of first-degree relatives of patients with HCM. Genetic testing still is in the early stages of research development but can be used to identify asymptomatic family members with the same mutation as the proband (index case).

Sex-related demographics

HCM is slightly more common in males than in females. However, the genetic inheritance pattern is autosomal dominant, without sex predilection. Modifying genetic, hormonal, and environmental factors may lead to a higher likelihood of identification in males, increased symptomatology, or higher degrees of LV outflow obstruction, with more prominent findings upon physical examination.

HCM usually presents at a younger age in females. Females tend to be more symptomatic and are more likely to be disabled by their symptoms than males.

Age-related demographics

In general, HCM has a bimodal peak of occurrence. The most common presentation is in the third decade of life, but it may present in persons of any age, from newborns to elderly individuals.

In children, inherited cases are found in an age range from newborn (ie, stillborn babies) to adult. The peak incidence is in these cases is in the second decade of life.

In adults, the peak incidence is in the third decade of life, with the vast majority of cases occurring in the age range between the third and sixth decades of life.

Mortality/morbidity

Reported annual mortality rates in patients with hypertrophic cardiomyopathy (HCM) have ranged from less than 1% to 3-6%, and studies suggest that they have significantly improved over the past 40 years.[4]

A study by Elliott et al reported that published sudden death rates over the previous 10 years were lower than were previously published figures (median 1.0% (range 0.1–1.7) v 2.0% (0–3.5)). Nevertheless, HCM still carries a high risk for mortality and morbidity.[5]

One series of 46 patients with midventricular obstruction was found to have an increased risk of apical aneurysm formation, symptoms, and HCM-related death compared with those who did not have midventricular obstruction; the increased risk of symptoms and death was similar to that seen in patients with LV outflow obstruction.[6]

Most patients with HCM are asymptomatic. Unfortunately, the first clinical manifestation of the disease in such individuals may be sudden death, likely from ventricular tachycardia or fibrillation. Younger patients, particularly children, have a much higher mortality rate. Children have a much greater degree of ventricular hypertrophy and are much more symptomatic early on in the disease course, most likely because more malignant genotypes are present earlier in life.

The more benign mutations do not elicit a clinical or echocardiographic phenotype or symptoms in the pediatric population. Death often is sudden, unexpected, and typically is associated with sports or vigorous exertion. Early diagnosis is of prime importance in order to prescribe an appropriate level of safe activity.[1, 7, 8]

Screening of first-degree relatives is useful to identify additional affected family members prior to the onset of significant symptoms or sudden death.

Patients can have a myriad of arrhythmias, including atrial fibrillation, atrial flutter, ventricular ectopy, ventricular tachycardia, and ventricular fibrillation. These patients are among the highest-risk group for ventricular fibrillation and pose difficult therapeutic decisions for risk reduction.

Patients have a high likelihood of recurrent heart failure resulting from mitral regurgitation and profound diastolic dysfunction. HCM is a progressive condition that worsens over time, as does the gradient across the LV outflow tract if left untreated. Systolic function usually is well preserved until the late stages of the disease. Angina is rare in children but common in adults. Syncope and presyncope are common and may identify individuals at high risk for sudden death.

Complications

Complications of HCM may include the following:

• Congestive heart failure

• Ventricular and supraventricular arrhythmias

• Infective mitral endocarditis

• Atrial fibrillation with mural thrombus formation

• Sudden death

Family members should learn cardiopulmonary resuscitation. In addition, refer the patient and family for psychosocial counseling. Refer children of patients with hypertrophic cardiomyopathy (HCM), especially those in the pediatric age range, for urgent echocardiography and genetic testing if an echocardiogram does not yet reveal overt disease.

Impose activity restrictions that include total abstinence from highly competitive athletic activities and very strenuous physical exertion, such as lifting heavy objects, lifting weights, and shoveling snow.

For patient education information, see the Heart Health Center, as well as Palpitations.

Symptoms of hypertrophic cardiomyopathy (HCM) can include dyspnea, syncope and presyncope, angina, palpitations, orthopnea, paroxysmal nocturnal dyspnea, congestive heart failure, dizziness, and sudden cardiac death.

Sudden cardiac death

Sudden cardiac death is the most devastating presenting manifestation of HCM. It has the highest incidence in preadolescent and adolescent children and is particularly related to extreme exertion. The risk of sudden death in children is as high as 6% per year.

In more than 80% of cases, the arrhythmia that causes sudden death is ventricular fibrillation. Many of these cases degenerate into ventricular fibrillation from rapid atrial arrhythmias, such as fibrillation, supraventricular tachycardia, or Wolff-Parkinson-White syndrome, while others result from ventricular tachycardia and low cardiac output hemodynamic collapse.

Dyspnea

This is the most common presenting symptom, occurring in as many as 90% of symptomatic patients. Dyspnea largely is a consequence of elevated LV diastolic filling pressures (and transmission of those elevated pressures back into the pulmonary circulation). The elevated LV filling pressures principally are caused by impaired diastolic compliance as a result of marked hypertrophy of the ventricle.

Syncope

Syncope is a very common symptom, resulting from inadequate cardiac output upon exertion or from cardiac arrhythmia. It occurs more commonly in children and young adults with small LV chamber size and evidence of ventricular tachycardia upon ambulatory monitoring.

Alternatively, syncope may be caused by arrhythmias, either tachycardias or bradycardias. Some patients with HCM have abnormalities in sinus node function, leading to sick sinus syndrome with alternating tachyarrhythmias and bradyarrhythmias or severe bradyarrhythmias.

Syncope and presyncope identify patients at high risk of sudden death and warrant an urgent workup and aggressive treatment.

Presyncope

Presyncope includes "graying-out" spells that occur in the erect posture and can be relieved by immediately lying down. They occur quite commonly and identify patients at high risk for sudden death. These symptoms are exacerbated by vagal stimulation. Presyncope also may occur with nonsustained atrial or ventricular tachyarrhythmias.

Angina

Typical symptoms of angina are quite common in patients with HCM and may occur in the absence of detectable coronary atherosclerosis. Impaired diastolic relaxation and markedly increased myocardial oxygen consumption are caused by ventricular hypertrophy that results in subendocardial ischemia, particularly during exertion.

Palpitations

Palpitations are common. These result from arrhythmias, such as premature atrial and ventricular beats, sinus pauses, atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia.

Orthopnea and paroxysmal nocturnal dyspnea

These are early signs of congestive heart failure and, while relatively uncommon, are observed in patients with severe HCM. They result from impaired diastolic function and elevated LV filling pressure. Orthopnea and paroxysmal nocturnal dyspnea result from pulmonary venous congestion.

Congestive heart failure

This is relatively uncommon but is observed in patients with severe HCM. It may occur as a result of a combination of impaired diastolic function and subendocardial ischemia. Systolic function in these patients almost always is well preserved.

Dizziness

Dizziness is common in patients with HCM with elevated pressure gradients across the LV outflow tract. It is worsened by exertion and may be exacerbated by hypovolemia following high levels of exertion or increased insensible fluid loss (eg, during extreme heat).

Dizziness also may occur as a result of maneuvers, such as rapid standing or Valsalva during defecation, or certain medications, such as diuretics, nitroglycerin, and vasodilating antihypertensive agents, that decrease preload and afterload and increase the pressure gradient across the LV outflow tract.

Dizziness also may be secondary to arrhythmia-related hypotension and decreased cerebral perfusion. Nonsustained arrhythmias often cause symptoms of dizziness, lightheadedness, and presyncope, whereas sustained arrhythmias are more likely to lead to syncope, collapse, and/or sudden cardiac death.

Double apical impulse results from a forceful left atrial contraction against a highly noncompliant left ventricle. This occurs quite commonly in adults. Triple apical impulse results from a late systolic bulge that occurs when the heart is almost empty and is performing near-isometric contraction. This is a highly characteristic finding of hypertrophic cardiomyopathy (HCM); however, it occurs less frequently than does the double apical impulse.

First heart sound is normal. Second heart sound usually is normally split, but in some patients with severe outflow gradients, it is paradoxically split.

An S3 gallop is common in children, but it does not have the same ominous significance as in patients with valvular aortic stenosis. When it occurs in adults, it signifies decompensated congestive heart failure. A fourth heart sound, an S4, frequently is heard and results from atrial systole against a highly noncompliant left ventricle.

Jugular venous pulse reveals a prominent a wave caused by diminished right ventricular compliance secondary to massive hypertrophy of the ventricular septum.

Double carotid arterial pulse is common. The carotid pulse rises quickly because of the increased velocity of blood through the LV outflow tract and into the aorta. The carotid pulse then declines in midsystole as the gradient develops. This is followed by a secondary rise in carotid pulsation during late systole.

Apical precordial impulse frequently is displaced laterally and usually is abnormally forceful and enlarged.

Systolic ejection murmur typically is a systolic ejection crescendo-decrescendo murmur, which is best heard between the apex and left sternal border and radiates to the suprasternal notch but not to the carotid arteries or neck. The murmur and the gradient across the LV outflow tract diminish with any increase in preload (eg, Mueller maneuver, squatting) or increase in afterload (eg, handgrip). The murmur and the gradient increase with any decrease in preload (eg, Valsalva maneuver, nitrate administration, diuretic administration, standing) or with any decrease in afterload (eg, vasodilator administration).

Holosystolic murmur at the apex and axilla of mitral regurgitation is heard in patients with systolic anterior motion of the mitral valve and significant LV outflow gradients. Diastolic decrescendo murmur of aortic regurgitation is heard in 10% of patients, although mild aortic regurgitation can be detected by Doppler echocardiography in 33% of patients.

Approach to hypertrophic cardiomyopathy (HCM) starts with a comprehensive history and physical examination. Multiple tests are used not only in the evaluation of patients with possible HCM but also to determine the diagnosis of HCM, severity of left ventricular (LV) outflow tract gradient, degree of mitral regurgitation, types of arrhythmias, LV function, and prognosis.

First-line laboratory tests are similar in adults and children.[9]  Routine laboratory studies may aid in the evaluation of the etiology and/or exacerbating factors underlying the left ventricular (LV) dysfunction.

• Hemoglobin level: Anemia exacerbates chest pain and dyspnea
• Fasting glucose levels
• Renal function tests: Impaired renal function may be seen with severe LV dysfunction
• Liver function tests (LFT)
• Brain natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP), and troponin T levels: Elevated BNP, NT-proBNP, and troponin T levels are associated with a higher risk of cardiovascular events, heart failure, and death. However, BNP and NT-proBNP do not correlate well with heart failure symptoms in HCM patients.
• Thyroid function tests: In patients on amiodarone, thyroid studies should be obtained at the time of diagnosis and monitored every 6 months 

Additional laboratory tests can be performed after a specialist evaluation, as needed.

When considering a diagnosis of hypertrohic cardiomyopathy (HCM), all patients should undergo complete transthoracic echocardiography (TTE) with two dimensional (2D), color Doppler, spectral Dopler, and tissue Doppler. TTE aids in evaluation of the cardiac morphology, systolic and diastolic function, presence and severity of left venticular outflow tract (LVOT) gradient, and the degree of mitral  regurgitation. 

LV hypertrophy (LVH)

LVH is evaluated primarily in the parasternal short-axis plane during diastole at the level of mitral valve and papillary muscles. Parasternal long-axis and apical 2- and 4- chamber views are also utilized with short-axis images of LVH.

Unexplained LV wall thickness of ≥15 mm anywhere within the LV confirms the diagnosis of HCM.  LV wall thickness ≥13 mm in the presence of a family history of HCM may also be considered diagnostic of HCM. The most common location of LVH is the basal anterior septum. About 10% of patients have LV wall thickening involving one or two LV segments.

Systolic anterior motion (SAM) of the mitral valve

SAM of the mitral valve is positioned in the LVOT. When there is contact between the mitral valve and septum, LVOT obstruction will develop. The greater the duration of the mitral-septum contact, the higher the LVOT obstruction. 

LVOT obstruction

LVOT obstruction gradient can be measured noninvasively using echocardiography continuous-wave Doppler. The best views to determine the LVOT gradient is the apical long-axis window. SAM and mitral regurgitation are often present together, and it can be difficult to distinguish LVOT signal from mitral regurgitation. 

Outflow gradient varies from day to day. It is influenced by myocardial contractility and loading conditions such as dehydration, alcohol, etc. If patients do not have an LVOT gradient at rest, then provoking the gradient is important for patient management. Exercise (stress) echocardiography using the standard Bruce protocol is the preferred method because it represents daily activities. A pharmacologic approach using amyl nitrite, dobutamine, or isoproterenol and the Valsalva maneuver are alternative approaches to provoke the LVOT gradient. However, note that the pharmacologic and nonpharmacologic approaches do not represent true LVOT gradient during daily activities.

Ambulatory electrocardiographic (ECG) monitoring should be performed all patients with hypertrophic cardiomyopathy (HCM) for risk assessment of not only ventricular arrhythmias but also for sudden cardiac death. It should be also be performed in patients with palpitations to assess for atrial fibrillation / atrial flutter. Ambulatory ECG monitoring is performed for 24-48 hours.  

Routine use of extended ambulatory monitoring for longer than 48 hours to detect ventricular arrhythmia for risk stratification is not determined.

Cardiac magnetic resonance imaging (CMRI) provides far more information compared to echocardiography. CMRI should be performed when a diagnosis of hypertrophic cardiomyopathy (HCM) is not certain after echocardiography. 

CMRI can be performed to risk stratify, detect left ventricular hypertrophy that is unrecognized or not well seen on echocardiography, consider septal reduction therapy in those whose mitral valve and papillary muscle anatomy is not well defined by echocardiography, or to determine septal ablation versus surgical myectomy. CMRI also aids in determining the ischemia burden in HCM, which has been associated with morphologic markers of disease severity, fibrosis, arrhythmia, and functional capacity.[10]

Contrast-enhanced CMRI uses intravenous injection of gadolinium for hyperenhancement (late gadolinium enhancement). This hyperenhancement represents myocardial fibrosis. CMRI also provides the following information:

• Assessment of diastolic function
• Assessment of regional myocardial function
• Identification and quantification of right ventricular hypertrophy
• Evidence of microvascular dysfunction
• Subtle structural abnormalities 

Electrocardiography (ECG) should be performed on all patients with possible hypertrophic cardiomyopathy (HCM), although ECG is not specific for HCM.

The ECG is normal in 10% of cases of HCM; thus, it typically abnormal with the most common ECG abnormality being repolarization changes.  Other commmon ECG abnormalities are as follows:

• Left-axis deviation
• P-wave abnormalities, suggesting left and/or right atrial enlargement. Right atrial enlargment with left ventricular hypertrophy strongly suggest HCM.
• Abnormal Q waves in the inferior and lateral leads suggest septal depolarization of the hypertrophied myocardium.
• Deeply inverted T waves in the mid-precordial leads (V2-V4) are seen in the apical variant of HCM.

Although not required for the diagnosis of hypertrophic cardiomyopathy (HCM), a diagnostic cardiac catheterization is useful to determine the degree of outflow obstruction, cardiac hemodynamics, the diastolic characteristics of the left ventricle and LV anatomy, and, of particular importance, the coronary anatomy. Cardiac catheterization is also reserved for situations when invasive modalities of therapy, such as a pacemaker or surgery, are being considered.

Therapeutic cardiac catheterization interventions, utilized in well selected cases of hypertrophic cardiomyopathy, include transcatheter septal alcohol ablation to relieve the LV outflow obstruction by intentional infarction of a portion of the interventricular septum.

Cardiac catheterization frequently reveals diminished diastolic LV compliance and, in cases of obstructive hypertrophic cardiomyopathy, a systolic intracavitary pressure gradient within the body of the left ventricle, related to subaortic systolic anterior motion of the mitral valve abutting the markedly hypertrophied septum. The subaortic pressure gradient may be quite labile and may vary between 0 and 175 mm Hg in the same patient under different conditions.

The arterial pressure tracing found on cardiac catheterization may demonstrate a "spike and dome" configuration similar to the carotid pulse recording. As a consequence of diminished left ventricular compliance, the mean left atrial pressure and, particularly, the a wave, in the left atrial pressure pulse and left ventricular end-diastolic pressures are usually elevated.

Artifactual outflow gradients may occur if the left ventricular catheter becomes entrapped in the trabeculae of a markedly hypertrophied left ventricle.

Cardiac output may be depressed in patients with long-standing severe gradients, but in the majority of patients, it is normal. Occasionally, cardiac output is elevated in patients with markedly hyperdynamic LV systolic function.

Hemodynamic abnormality in hypertrophic cardiomyopathy (HCM) is not limited to the left side of the heart. Approximately one fourth of patients demonstrate pulmonary hypertension. It is usually mild, but in some cases, it can be moderate to severe, due (at least in part) to elevated mean left atrial pressures resulting from diminished LV compliance. A pressure gradient in the right ventricular outflow tract occurs in approximately 15% of patients who have obstruction to LV outflow and appears to result from markedly hypertrophied right ventricular tissue. Right atrial and right ventricular end-diastolic pressures may be slightly elevated.

Outflow gradient variability

A feature characteristic of HCM is the variability and lability of the LV outflow gradient. A patient may demonstrate a large gradient on one occasion and have none at another time. In some patients without a resting gradient, it may be temporarily provoked.

Three basic mechanisms involved in the production of dynamic gradients include increased contractility, decreased preload, and decreased afterload. In many patients with HCM, the gradient is midventricular and may be intensified by increased contractility, which exerts a direct muscular sphincter action.

The stimuli that provoke or intensify LV outflow tract gradients in HCM generally improve myocardial performance in normal subjects and in patients with most other forms of heart disease. Conversely, reductions in contractility or increases in preload or afterload, which increased LV dimensions, reduce or abolish the LV outflow gradient.

One of the most potent stimuli for enhancing the LV outflow gradient is postextrasystolic potentiation, which may occur after a spontaneous premature contraction or be induced by mechanical stimulation with a catheter. The resultant increase in contractility in the beat after the extrasystole is so marked that it produces an increase in the outflow gradient. A characteristic change often occurs in the directly recorded arterial pressure tracing, which, in addition to displacing a more marked spike and dome configuration, exhibits a pulse pressure that fails to increase as expected or actually decreases (the so-called Brockenbrough-Braunwald phenomenon).

This is one of the more reliable signs of dynamic obstruction of the LV outflow tract. In some patients, the postextrasystolic murmur is attenuated despite an increase in the outflow gradient, apparently because, in this setting, the murmur mirrors to a greater degree changes in the severity of mitral regurgitation than changes in the outflow tract gradient.

Left ventriculography

Left ventriculography typically shows a hypertrophied ventricle and the presence of an outflow gradient. The anterior leaflet of the mitral valve moves anteriorly during systole and encroaches on the outflow tract. Associated with this motion is mitral regurgitation, which is a constant finding in patients with gradients. The LV cavity is often small, and systolic ejection is typically vigorous, resulting in virtual obliteration of the ventricular cavity at end systole. In patients with apical involvement, the extensive hypertrophy may convey a spade-like configuration to the left ventricular angiogram.

Other findings

In patients older than age 45 years, obstructive coronary artery disease may be present, although the symptoms of ischemic pain are indistinguishable from those of patients with normal coronary angiograms and HCM. The left anterior descending and septal perforator coronary arteries may demonstrate phasic narrowing and associated abnormalities of flow during systole

A diagnostic electrophysiology study (EPS) uses programmed electrical stimulation to identify conduction abnormalities, sinus node dysfunction (SND), and the potential for inducible arrhythmias. In hypertrophic cardiomyopathy (HCM), syncope and presyncope are due to arrhythmia, left ventricular outflow tract (LVOT) obstruction, or inappropriate vasodilatation with adequate cardiac output. EPSs rarely discover the mechanism of sudden death, and they are not indicated for decision making on implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden death.

Exercise stress testing should be performed on patients with known or suspected hypertrophic cardiomyopathy (HCM) for risk stratification and evaluation of the left ventricular outflow tract (LVOT) gradient. It is preferred over pharmacologic stress testing. Exercise stress testing provides information on functional capacity, exercise-induced ischemia, arrhythmia, and obstruction.

Echocardiographic images should be utilized with stress testing.

Exercise stress testing should be performed prior to the institution of therapy. Follow-up exercise testing may be helpful to assess treatment. Important findings during exercise testing include the following:

• Symptoms of angina, dyspnea, palpitations, or presyncope
• Hypotension or lack of blood pressure response with exercise
• Arrhythmia (atrial fibrillation or ventricular tachycardia)
• ST-segment depression 
• Increase of or developing LVOT gradient
• Increase of or developing mitral regurgitation

Evaluation usually can be conducted on an outpatient basis. Inpatient studies and surgical treatment also may be necessary. Medical and surgical therapy are used to reduce ventricular contractility or increase ventricular volume, increase ventricular compliance and outflow tract dimensions, and, in the case of obstructive hypertrophic cardiomyopathy (HCM), reduce the pressure gradient across the LV outflow tract. Paramount to any therapy is reduction in the risk of sudden death by identification of these patients early on and effective medical and/or surgical implantation of an automatic defibrillator.[11]

Medications include beta blockers, calcium channel blockers, and, rarely, diltiazem, amiodarone, and disopyramide.[12] Antitussives may be administered as needed to avoid coughing.

Research shows that stepwise therapy can reduce high blood pressure in patients with HCM. In a study of 115 HCM patients, including 94 with obstructive HCM, stepwise antihypertensive therapy effectively controlled both obstructive HCM symptoms and hypertension. Average systolic pressure in the obstructive HCM group was reduced from 137 to 131 mm Hg, and uncontrolled hypertension was reduced from 56% at the first visit to 37% at the last.[13, 14]  

Mavacamten, a first-in-class allosteric inhibitor of cardiac myosin, gained approval form the FDA for adults with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve exercise capacity and symptoms. Mavacamten modulates number of myosin heads that can enter “on actin” (power-generating) states, thus reduces probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM.

Approval of mavacamten was based on results from the multicenter, phase 3 EXPLORER-HCM trial (n = 251). Of 123 patients randomly assigned to mavacamten, 92 (75%) completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and week 30 and of the 128 patients randomly assigned to placebo 88 (69%) completed the KCCQ at baseline and week 30. At 30 weeks, the change in KCCQ-OS score was greater with mavacamten than placebo (mean score 14.9 vs 5·4 13.7; difference +9.1; p < 0.0001), with similar benefits across all KCCQ subscales. The proportion of patients with a very large change (KCCQ-OS 20 points or more) was 36% in the mavacamten group versus 15% in the placebo group, with an estimated absolute difference of 21%. These gains returned to baseline after treatment was stopped.[15]  

Additionally, the EXPLORER long-term extension trial (EXPLORER-LTE) projected mavacamten was associated with an increase of 4.17 additional quality-adjusted life-years compared with placebo (with or without beta-blocker or calcium channel blocker therapies).[16]  

Avoid inotropic drugs if possible; also avoid nitrates and sympathomimetic amines, except in those patients with concomitant coronary artery disease. Avoid digitalis, because glycosides are contraindicated except in patients with uncontrolled atrial fibrillation. Cautious use of diuretics should be exercised because of their potential adverse effect on the LV outflow gradient and ventricular volume.

Transfer

Transfer may be required for further diagnostic evaluation and electrophysiologic device or surgical intervention.

Deterrence/prevention

Patients must abstain from highly strenuous competitive athletic activity and highly strenuous physical exertion, such as shoveling snow or lifting very heavy objects, due to the high risk of arrhythmogenic sudden cardiac death. No acceptable medical recommendation deviates from total abstinence from these activities.

Consultations

Consultations may be indicated with the following specialists:

• Cardiologist

• Cardiothoracic surgeon

• Cardiac electrophysiologist

• Geneticist

Diet

No special diet is required. However, the patient should avoid excessive weight gain.

Left ventricular myomectomy

Left ventricular (LV) myomectomy is used for patients with severe symptoms refractory to therapy and an outflow gradient of more than 50 mmHg, either with provocation or with rest. The procedure typically is successful in abolishing the outflow gradient; most patients have symptomatic improvement for at least 5 years.

The reduction in LV outflow gradient may not correlate with a risk reduction for sudden death or overall mortality. Furthermore, the outflow gradient may increase gradually over time and return to the same level as before, requiring a repeat procedure or additional medical therapy.

Patients who have obstructive hypertrophic cardiomyopathy with low resting gradients and latent obstruction may have limiting symptoms similar to patients with more severe resting gradients. In a series of 749 patients undergoing septal myectomy, 249 had minimal gradients at rest but severe outflow tract obstruction with provocation testing. Symptom relief and survival in these patients was similar to that of patients with severe resting outflow obstruction undergoing myectomy. The authors suggest that septal myectomy may be recommended to patients who have severe outflow obstruction only on provocative testing because survival and symptom relief are excellent, suggesting that dynamic obstruction is the major hemodynamic problem and not diastolic dysfunction.[17]

In a retrospective study (1998-2010) that evaluated data from the Nationwide Inpatient Sample regarding the results of ventricular septal myectomy in patients with hypertrophic cardiomyopathy (HCM) with refractory LV outflow tract (OT) obstruction, Panaich et al found an overall mortality of 5.9%; there was an association between age and severity of comorbidities with higher rates of complications and mortality.[18]

In a prospective observational study (1991-2012) that evaluated the long-term outcomes (8.3 ± 6.1 y) of myectomy combined with anterior mitral leaflet extension in severely symptomatic patients with HCM, Vriesendorp et al reported no operative mortality, with symptomatic relief similar to the general population.[19] Cumulative survival rates at 1 year were 98%; 5 years, 92%; 10 years, 86%; and 15 years, 83%.[19]

In a systematic review and meta-analysis of 10 studies comprising 1824 patients for evaluating the efficacy and short- and long-term mortality of surgical myectomy (n = 1019) compared with alcohol septal ablation (n = 805}, Singh et al found no significant difference in symptomatic relief between the two procedures, and outcomes were similar for sudden cardiac death and short- and long-term mortality.[20]  However, in a more recent study by Cui et al that assessed the long-term mortality of 3859 patients with obstructive HCM who underwent either alcohol septal ablation (n = 585) or septal myectomy (n = 3274), there was an association between alcohol septal ablation and long-term all-cause mortality relative to surgical myectomy, and its impact on survival was independent of other known factors.[21] The investigators suggest that the impact may be influenced by unmeasure confounding patient features.

Mitral valve replacement

Mitral valve replacement is reserved for patients with severe mitral regurgitation due to systolic anterior movement of the mitral valve, particularly when mitral regurgitation (large regurgitant fraction) is associated with the development of congestive heart failure or severe pulmonary hypertension.

Pacemaker implantation has been a proposed treatment for patients with hypertrophic cardiomyopathy (HCM). Studies have shown that pacing the right ventricular (RV) apex to maintain atrioventricular synchrony results in a decrease of the left ventricular outflow tract (LVOT) gradient, with symptomatic and quality-of-life improvements.[22, 1] A Cochrane review suggested that the benefits of pacing are based on physiologic measures and lacks clinically relevant end-points.[23]

Transvenous catheter ablation of the septal region has been performed using selective arterial ethanol infusion to destroy myocardial tissue.[24] The procedure involves infusing 96% ethanol down the first septal branch of the left anterior descending artery and inducing a therapeutic infarction of the proximal interventricular septal myocardium.

This leads to a remodeling of the septum, which decreases the marked septal thickening characteristic of hypertrophic cardiomyopathy (HCM) and results in a decrease of the gradient across the left ventricular outflow tract (LVOT). In this manner, the procedure is analogous to a surgical myomectomy, in attempting to decrease the amount of septal ventricular myocardium and thereby reducing the LVOT gradient.

The procedure has been used in clinical practice since the early 1990s and the reported results have been excellent, with significant reduction in symptoms, particularly in the incidence of heart failure.[25, 26] In many centers, it is the surgical procedure of choice for HCM.

Alcohol septal ablation

Alcohol septal ablation offers some advantages over surgical myectomy in that (1) it does not require surgical incision and/or general anesthesia, (2) the recovery time is shorter, and (3) its results lead to less discomfort and greater patient satisfaction than are reported with surgical myectomy.[22, 1] In addition, older patients who often have multiple comorbidities may better tolerate alcohol septal ablation than septal myectomy, which has high postoperative risks and complications in this patient population. Note that alcohol septal ablation is not indicated for the pediatric population.[22, 1]

Complications of alcohol septal ablation and comparison to surgical myectomy

The European Society of Cardiology (ESC) indicates that the main nonfatal complication of alcohol septal ablation is atrioventricular block (7-20%); in addition, it is associated with 4-5–fold increased risk for permanent pacemaker, as well as right rather than left bundle branch block, compared to septal myectomy.[9] Moreover, although clinical and hemodynamic effects are seen immediately after setpal myectomy, they may be delayed for up to 3 months following alcohol septal ablation.

There appears to be little benefit to alcohol septal ablation in patients whose septal thickness is 30 mm or more (ie, severe HCM), as compared to septal myectomy.[9] The septal myectomy treatment approach visually assesses the anatomy of the LVOT and the mitral apparatus, whereas the alcohol septal ablation approach indirectly ablates the septal perforator artery distribution.

Overall, the procedural mortality for both procedures are similar.[9]

Sudden cardiac death occurs in approximately 1% of patients with hypertrophic cardiomyopathy (HCM) each year, and pharmacotherapy has not shown protection against sudden cardiac death.[22, 1] However, high-risk individuals in whom prophylactic therapy may be indicated may potentially benefit from placement of an implantable cardioverter defibrillator (ICD), which can effectively terminate life-threatening ventricular tachyarrhythmias in the setting of HCM.[22, 1]

Complications associated with ICD in HCM

There is a 4% reported rate of ICD-associated complications (procedural and over the long term) per year.[22, 1, 27]  Early complications include the possibility of pneumothorax, pericardial effusion, pocket hematoma, acute pocket infection, and/or lead dislodgment. Complications that may arise late include upper extremity deep venous thrombosis, lead dislodgment, infection, a high defibrillation threshold that may require revision of the the lead, and receipt of inappropriate shocks.[22, 1, 27]

Pediatric patients appear to suffer a higher rate of inappropriate shocks and lead fractures than adults adults do, predominantly owing to the strain placed on the leads as the children grow and are active.[22, 1, 27]

Although the procedure to place ICDs is generally safe, defective generators have been known to cause death, high-voltage leads with small diameters have a tendency to fracture, and patients with severe hypertrophy or who are receiving amiodarone may need high-energy output generators or epicardial lead systems.[22, 1, 27]

Heart transplantation is recommended in specific situations for patients with hypertrophic cardiomyopathy (HCM). The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines indications for heart transplantation include advanced heart disease and New York Heart Association (NYHA) functional class III or IV symptoms that are refractory to all other interventions.[22, 1] In addition, transplant referral for refractory symptoms does not require a reduced ejection fraction (EF), and heart transplantation is performed in the presence of preserved EF.[22, 1]

HCM patient outcome after heart transplant is not different from that of other patients with other heart diseases.[22, 1]

Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM). During the clinical course of HCM, approximately 25% of patients will experience AF or atrial flutter. AF is diagnosed by electrocardiography (ECG) during an AF episode, on ambulatory Holter monitoring, or on an event monitor.[22, 1]  AF causes significant worsening of congestive heart failure, especially in patients with left ventricular (LV) outflow tract (OT) obstruction. Amiodarone is most effective in controlling AF recurrence; however, long-term use of this agent is limited due to its side effects. An alternative antiarrhythmic agent to use in this setting is sotalol. 

AF is associated with an increased risk for embolic stroke. Prevalence of AF is 6% and incidence is 0.8% per year. In patients with paroxysmal or chronic AF, prophylactic anticoagulation is recommended. Prior to starting anticoagulation, determine the individual patient's bleeding risk and compliance. The CHADS2 score (Congestive heart failure, Hypertension, Age [>65 y = 1 point, >75 y = 2 points], Diabetes, previous Stroke/transient ischemic attack [2 points]) has not been specifically validated in HCM. Anticoagulants to be considered are warfarin or newer oral agents such as dabigatran or rivaroxaban. 

In patients with symptomatic AF that fails antiarrhythmic therapy, pulmonary vein catheter-based ablation (radiofrequency or cryoablation) should be considered.

In general, women with HCM can safely undergo pregnancy and labor with minimal risks.[22, 1] However, preconception genetic counseling is advised, and it is essential that the expectant mothers receive careful prepregnancy and pregnancy evaluation and functional assessment. Cesarean delivery is usually not required.[22, 1]

If the patient's HCM is controlled with medical therapy, then such management should be continued with careful maternal-fetal monitoring. In setting of advanced disease (eg, progressive heart failure, severe diastolic dysfunction, ventricular tachycardia, supraventricular tachycardia, marked left ventricular outflow tract obstruction [LVOT]), management with a multidisciplinary team that includes a materal-fetal specialist and cardiologist is crucial.[22, 1]

Pillarisetti et al reported that predictors of improvement in left ventricular dysfunction in patients with peripartum cardiomyopathy appear to include postpartum diagnosis and white/Hispanic race.[28]

Data spanning 2 decades and 160,000 deliveries from an institutional review of pregnant women with hypertrophic cardiomyopathy showed a small number of completed pregnancies (23 completed in 14 patients) and no maternofetal deaths.[29] The overall morbidity was 26%, with a 13% incidence of peripartum congestive heart failure.[29]

Federal Motor Carrier Safety Administration recommendations

The Federal Motor Carrier Safety Administration (FMCSA) sets medical standards and guidelines for commerical motor vehicle drivers. Current guidelines state that individuals with hypertrophic cardiomyopathy (HCM) should not be certified to drive CMV. However, the Medical Expert Panel (MEP) recommends that the guidelines be changed to reflect the fact that not all individuals with HCM are at risk for sudden incapacitation or death. Specifically, the panel recommends that individuals who meet all the following criteria are at low risk and may be certified to drive[30] :

• No history of cardiac arrest
• No spontaneous sustained ventricular tachycardia (VT)
• Normal exercise blood pressure (BP) (eg, no decrease in BP at maximal exercise)
• No nonsustained VT
• No family history or premature sudden death
• No syncope
• Has an left ventricular (LV) septum thickness of less than 30 mm

However, low-risk individuals must be closely monitored for changes in their risk status.[30]

Federal Aviation Administration standards

The Federal Aviation Administration (FAA) sets the criteria for aircraft pilots with medical conditions, including cardiovascular diseases.[31] Currently, HCM is incompatible with the highest grade aviation license for commercial pilots due to its unpredictable risk for impairment in the cockpit.[32, 33, 34]

Avoid strenuous exercise. Competitive-level sports should not be permitted if any of the following is present:

• Significant outflow gradient

• Significant ventricular or supraventricular arrhythmia

• Marked LV hypertrophy

• History of sudden death in relatives with hypertrophic cardiomyopathy (HCM)

• Identified malignant genotype

• Young age (< 30 years)

• Abnormal blood pressure response to exercise

• History of syncope, particularly in children

Although avoidance of intense physical exertion is probably appropriate, participation in noncompetitive-level recreational sports activities is not believed to be contraindicated.

Cardiovascular screening before participation in competitive sports appears to reduce the frequency of unexpected sudden death from HCM, although whether large-scale screening of athletes is administratively feasible or cost-effective remains to be determined.[35, 36]

Sudden death often occurs during exercise, but it also demonstrates a circadian distribution, with clustering of deaths in the morning and early evening.

The following organizations have released guidelines for the managment of hypertrophic cardiomyopathy:

• American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)
• European Society of Cardiology(ESC)
• Heart Rhythm Society(HRS)/American College of Cardiology Foundation (ACCF)

Invasive Therapies

The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommendations regarding invasive therapies in patients with hypertrophic cardiomyopathy (HCM) are summarized below.[22, 1]

Class I recommendations

Only experienced operators should perform septal reduction therapy, in the setting of a dedicated HCM. Moreover, septal reduction therapy should be reserved for treatment-eligible patients with severe drug-refractory symptoms and left ventricular outlet tract (LVOT) obstruction. (Level of evidence: C)

Class IIa recommendations

It is reasonable to consult with centers experienced in performing surgical septal myectomy and alcohol septal ablation for treatment-eligible patients with HCM with severe drug-refractory symptoms and LVOT obstruction. At these centers, surgical septal myomectomy may be of benefit in symptomatic pediatric patients in whom traditional medical therapy has been ineffective. (Level of evidence: C)

Surgical septal myectomy performed in experienced centers is the first-line option for most treatment-eligible patients with HCM and severe drug-refractory symptoms and LVOT obstruction. Moreover, at these centers, adult patients with HCM and severe drug-refractory symptoms and LVOT obstruction who are not surgical candidates but who are eligible for alcohol septal ablation may benefit from this procedure (usually New York Heart Association [NYHA] class III or IV). (Level of evidence: B)

Class IIb recommendations

In experienced centers, following a detailed discussion with eligible adult patients with HCM and severe drug-refractory symptoms and LVOT obstruction, alcohol septal ablation may be a treatment option to surgical myectomy when the patient indicates a preference for septal ablation. (Level of evidence: B)

In general, alcohol septal ablation is discouraged in patients with HCM and marked (ie, >30 mm) septal hypertrophy owing to uncertainty regarding its efficacy in these patients. (Level of evidence: C)

Precautions (class III recommendations)

Note the following to prevent harm to patients with HCM (C level of evidence for all)[22, 1] :

• Septal reduction therapy should only be performed as part of a dedicated HCM program.
• Avoid septal reduction therapy in asymptomatic adults with HCM who have normal exercise tolerance or whose symptoms are controlled/minimized on medical therapy.
• When septal reduction therapy is a feasible treatment option to relieve LVOT obstruction in eligible patients, do not perform mitral valve replacement as an alternative therapy.
• Avoid performing alcohol septal ablation in (1) patients with HCM and comorbid conditions that also require surgical repair, in whom myectomy can be performed concomitantly; (2) pediatric patients with HCM (age < 21 years); and (3) adults younger than 40 years in whom myectomy is a feasible alternative therapy.

The 2014 ESC guidelines recommendations for septal reduction therapy are summarized below.[9]

Class I recommendations

Septal reduction therapies be performed by experienced operators, working as part of a multidisciplinary team expert in the management of HCM.(Level of evidence: C)

Septal reduction therapy to improve symptoms in patients with a resting or maximum provoked LVOT gradient of ≥50 mm Hg, who are in NYHA functional Class III–IV, despite maximum tolerated medical therapy. (Level of evidence: B)

Septal myectomy, rather than alcohol septal ablationis in patients with an indication for septal reduction therapy and other lesions requiring surgical intervention (e.g. mitral valve repair/replacement, papillary muscle intervention).(Level of evidence: C)

Class IIa recommendations

Septal reduction therapy should be considered in patients with recurrent exertional syncope caused by a resting or maximum provoked LVOTO gradient ≥50 mm Hg despite optimal medical therapy. (Level of evidence: C)

Mitral valve repair or replacement should be considered in symptomatic patients with a resting or maximum provoked LVOTO gradient ≥50 mm Hg and moderate-to-severe mitral regurgitation not caused by systolic anterior motion of the mitral valve alone. (Level of evidence: C)

Class IIb recommendation

Mitral valve repair or replacement may be considered in patients with a resting or maximum provoked LVOTO gradient ≥50 mm Hg and a maximum septal thickness 16 mm at the point of the mitral leaflet–septal contact or when there is moderate-to-severe mitral regurgitation following isolated myectomy. 

Pacemaker Implemenation

The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommendations regarding pacing in patients with HCM are summarized below.[22, 1]

Class IIa recommendation

For patients with HCM who previously underwent dual-chamber device implantation for non–HCM-related causes, the ACCF/AHA believe a trial of dual-chamber atrial-ventricular pacing (from the right ventricular apex) for symptomatic relief from LVOT obstruction can be considered. (Level of evidence: B)

Class IIb recommendation

Permanent pacing is an option in symptomatic patients with medically refractory obstructive HCM who are not good candidates for septal reduction therapy. (Level of evidence: B)

Select patients in whom permanent pacemaker implantation is of no benefit (class III recommendations)

The 2011 ACCF/AHA guidelines indicate pacemaker implantation is not beneficial in the following scenarios for patients with HCM[22, 1] :

• For reduction of the gradient in those who are asymptomatic or whose symptoms are medically-controlled (Level of evidence: C)
• For first-line treatment of symptomatic relief in candidates eligible for septal reduction who have medically refractory disease and LVOT obstruction (Level of evidence: B)

The 2012 HRS/ACCF expert consensus statement on pacemaker device and mode selection offer the following guidance[37] :

Class IIa recommendation

Dual-chamber pacing can be useful for patients with medically refractory, symptomatic hypertrophic, cardiomyopathy with significant resting, or provoked left ventricular outflow obstruction. (Level of evidence: C)

Class III recommendation

Single-chamber (VVI or AAI) pacing is not recommended for patients with medically refractory, symptomatic hypertrophic cardiomyopathy. (Level of evidence: C)

In its 2013 guidelines for cardiac pacing and cardiac resynchronization therapy[38] and its 2014 guidelines for management of hypertrophic cardiomyopathy[9] , the European Society of Cardiology (ESC) recommends considering sequential AV pacing, with optimal AV interval to reduce the LV outflow tract gradient or to facilitate medical treatment with ß-blockers and/or verapamil in selected patients who have contraindications for septal alcohol ablation or septal myectomy. (Class IIb; Level of evidence: C)[9]

Alcohol Septal Ablation

The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommendations regarding alcohol septal ablation in patients with HCM are summarized below.[22, 1]

Class I recommendations

As discussed earlier, it is reasonable to consult with centers experienced in performing alcohol septal ablation and surgical septal myectomy for treatment-eligible patients with HCM with severe drug-refractory symptoms and LVOT obstruction.

Use transthoracic (TTE) or transesophageal (TTE) echocardiography for intraoperative guidance of alcohol septal ablation (level of evidence: B) and TTE for assessing the outcomes of alcohol septal ablation (or surgical myectomy) in patients with obstruct HCM (level of evidence: C).

Class IIa recommendations

For clinical decision making and evaluation for the feasibility of alcohol septal ablation, use TEE when TTE findings are unclear.

Class IIb recommendations

In experienced centers, following a detailed discussion with eligible adult patients with HCM and severe drug-refractory symptoms and LVOT obstruction, alcohol septal ablation may be a treatment option to surgical myectomy when the patient indicates a preference for septal ablation. (Level of evidence: B)

In general, alcohol septal ablation is discouraged in patients with HCM and marked (ie, >30 mm) septal hypertrophy owing to uncertainty regarding its efficacy in these patients. (Level of evidence: C)

Class III recommendations

To prevent harm, avoid performing alcohol septal ablation in (1) patients with HCM and comorbid conditions that also require surgical repair, in whom myectomy can be performed concomitantly; (2) pediatric patients with HCM (age < 21 years); and (3) adults younger than 40 years in whom myectomy is a feasible alternative therapy. (Level of evidence: C)

ICD Placement

The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommendations regarding ICD placement in patients with HCM are summarized below.[22, 1]

Class I recommendations

ICD placement decision making in patients with HCM should involve a comprehensive discussion between clinicians and patients. (Level of evidence: C)

This procedure is recommended for patients with HCM who have documentation of having suffered cardiac arrest, ventricular fibrillation, or hemodynamically significant VT. (Level of evidence: B)

Class IIa recommendations

ICD placement is a reasonable intervention for patients with HCM who also have (1) one or more first-degree relatives who suffered sudden cardiac death likely related to HCM, (2) an LV wall thickness of 30 mm or more, and (3) one or more recent unexplained syncopal events, as well as for (4) high-risk pediatric patients with HCM and a history of unexplained syncope or massive LV hypertrophy, or a family history of sudden cardiac death, with consideration of long-term ICD complication rates. (Level of evidence: C)

ICD placement is an option for select patients with other risk factors for other sudden cardiac death in addition to having (1) nonsustained VT (eg, age < 30 y) or (2) HCM plus exercise-induced blood pressure anomalies. (Level of evidence: C)

For ICD-eligible patients with HCM, it is reasonable to place a single-chamber device in younger patients who do not require atrial or ventricular pacing, or a dual-chamber device (1) in patients with sinus bradycardia and/or paroxysmal atrial fibrillation or (2) predominantly in older patients with high resting outflow gradients (>50 mm Hg) and significant heart failure symptoms in whom right ventricular pacing has the potential beneficial effects. (Level of evidence: C)

Class IIb recommendations

ICD effectiveness remains unclear in patients with HCM who do not have other risk factors for sudden cardiac death but do have either (1) isolated bursts of nonsustained VT or (2) exercise-induced blood pressure anomalies, especially in the setting of significant LVOT. (Level of evidence: C)

Precautions (class III recommendations)

To prevent harm to patients with HCM, do not use ICD placement as either (1) a routine strategy in the absence of high-risk factors or (2) a strategy to allow participation in competitive athletic events. Do not place an ICD in those with a known HCM genotype but who are asymptomatic. (Level of evidence: C)

In its 2013 guidelines for cardiac pacing and cardiac resynchronization therapy[38] and its 2014 guidelines for management of hypertrophic cardiomyopathy[9] , the European Society of Cardiology (ESC) recommends  considering a dual-chamber ICD (instead of a single-lead device) to reduce the LV outflow tract gradient or to facilitate medical treatment with ß-blockers and/or verapamil in patients with resting or provocable LVOTO ≥50 mm Hg, sinus rhythm and drug refractory symptoms. (Class IIb; Level of evidence: C)[9]

Heart Transplantation

The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommendations regarding heart transplantation in patients with HCM are summarized below.[22, 1]

Class I recommendations

Heart transplantion should not be considered in the setting of advanced heart failure (end stage) and nonobstructive HCM not otherwise amenable to other treatment intervention, in the presence of an ejection fraction (EF)  that is at or below 50% (or, occasionally, with preserved EF). (Level of evidence: B)

Pediatric heart transplant candidates include those with symptomatic HCM with a restrictive physiology who are not responsive to or appropriate candidates for other therapeutic interventions. (Level of evidence: C)

Precautions (class III recommendations)

To prevent harm, do not perform heart transplantation in mildy symptomatic patients of any age with HCM. (Level of evidence: C)

The 2014 ESC guidelines recommendations regarding heart transplantation in patients with HCM are summarized below.[9]

Class I recommendation

For severely symptomatic patients with systolic and/or diastolic LV dysfunction being evaluated for heart transplantation or mechanical support, cardiopulmonary exercise testing, with simultaneous measurement of respiratory gases should be performed. (Level of evidence: B)

Class IIa recommendation

Orthotopic cardiac transplantation should be considered in eligible patients who have an LVEF < 50% and NYHA functional Class III–IV symptoms despite optimal medical therapy or intractable ventricular arrhythmia.(Level of evidence: B)

Class IIb recommendation

Orthotopic cardiac transplantation may be considered in eligible patients with normal LVEF ( 50%) and severe drug refractory symptoms (NYHA functional Class III–IV) caused by diastolic dysfunction.(Level of evidence: B)

Management of Atrial Fibrillation

The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommendations regarding management of atrial fibrillation in patients with HCM are summarized below.[22, 1]

Class I recommendations

Use vitamin K antagonis (ie, warfarin, to an international normalized ratio [INR] of 2-3) for anticoagulation in patients with paroxysmal, persistent, or chronic atrial fibrillation AF and HCM. (Data are not available in the setting of HCM for anticoagulation with direct thrombin inhibitors such as dabigatran in reducing the risk of thromboembolism). (Level of evidence: C)

Control the ventricular rate in patients with HCM and atrial fibrillation who have rapid ventricular rates. High doses of beta antagonists and nondihydropyridine calcium channel blockers may need to be administered. (Level of evidence: C)

Class IIa recommendations

The ACCF/AHA indicates it is reasonable to use disopyramide (with ventricular rate–controlling agents) and amiodarone for atrial fibrillation in patients with HCM. (Level of evidence: B)

Radiofrequency ablation can be beneficial in the setting of HCM with refractory atrial fibrillation or patients unable to take antiarrhythmic agents. (Level of evidence: B)

Maze procedure with closure of the left atrial appendage is a reasonable intervention in patients with HCM and a histroy of atrial fibrillation. The procedure may be performed during septal myectomy or as an isolated procedure in selected patients. (Level of evidence: C)

Class IIb recommendations

Alternative antiarrhthmic agents for patients with HCM and atrial fibrillation include sotalol, dofetilide, and dronedarone, particularly in those with an implantable cardioverter defibrillator. (Level of evidence: C)

Management of Pregnancy

The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommendations regarding management of pregnancy and/or delivery in women with HCM are summarized below.[22, 1]

Class I recommendations

Pregnancy is not contraindicated in asymptomatic women with HCM; perform a careful evaluation for pregnancy risks. Asymptomatic women or those whose symptoms are controlled with beta-blocking drugs should continue pharmacotherapy during their pregnancy, and close monitoring for fetal bradycardia or other complications is important. (Level of evidence: C)

Male and female patients with HCM should receive genetic counseling before planned conception. (Level of evidence: C)

Management by a high-risk obstetric team is essential for women with HCM and resting or provocable LVOT obstruction of 50 mm Hg or greater and/or cardic symptoms not controlled by medical therapy alone. (Level of evidence: C)

Class IIa recommendations

Management by an expert materal-fetal team is advised for women with HCM whose symptoms are controlled (mild to moderate). Such specialist care includes cardiovascular and prenatal monitoring. (Level of evidence: C)

Precautions (class III recommendations)

Women with advanced heart failure symptoms and HCM have an increased risk of  excess morbidity/mortality in pregnancy. (Level of evidence: C)

The 2014 ESC guidelines recommendations are summarized below.[9]

Class I recommendations (Level of evidence C for all)

• Pre-pregnancy risk assessment and counselling is indicated in all women.
• Counselling on safe and effective contraception is indicated in all women of fertile age. 
• Counselling on the risk of disease transmission is recommended for all men and women before conception.
• β-Blockers (preferably metoprolol) should be started in women who develop symptoms during pregnancy.
• Whenever β-blockers are prescribed, monitoring of fetal growth and of the condition of the neonate is recommended.
• Scheduled (induced) vaginal delivery is recommended as first choice in most patients.
• For atrial fibrillation, therapeutic anticoagulation with LMWH or vitamin K antagonists depending on the stage of pregnancy.

Class IIa recommendations

• β-Blockers (preferably metoprolol) should be continued in women who used them before pregnancy.
• Cardioversion should be considered for persistent atrial fibrillation.

Competitive Athletes

In 2015, the American Heart Association(AHA) and American College of Cardiology (ACC) released a scientific statement containing eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities. The recommendations for athlestes with HCM are summarized below.[39]

Class IIa recommendation

Participation in competitive athletics for asymptomatic, genotype-positive HCM patients without evidence of LV hypertrophy by 2-dimensional echocardiography and CMR is reasonable, particularly in the absence of a family history of HCM-related sudden death (Level of evidence C).

Class III recommendations

Athletes with a probable or confirmed diagnosis of HCM should not participate in most competitive sports, with the exception of those of low intensity (class IA sports). (Level of evidence C).

Pharmacological agents (eg, β-blockers) to control cardiac-related symptoms or ventricular tachyarrhythmias should not be administered for the sole purpose of permitting participation in high-intensity sports. (Level of evidence C).

Prophylactic ICDs should not be placed in athlete-patients with HCM for the sole or primary purpose of permitting participation in high-intensity sports competition because of the possibility of device-related complications. ICD indications for competitive athletes with HCM should not differ from those in nonathlete patients with HCM.(Level of evidence B).

 

 

 

The purpose of pharmacologic therapy is to reduce the pressure gradient across the LV outflow tract by reducing the inotropic state of the left ventricle, improving compliance of the left ventricle, and reducing diastolic dysfunction. Mavacamten, a first-in-class allosteric inhibitor of cardiac myosin, has gained FDA approval for adults with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve exercise capacity and symptoms. Amiodarone has been shown to reduce the incidence of arrhythmogenic sudden cardiac death.[40, 41]

Class Summary

These reduce the inotropic state of the left ventricle. They decrease diastolic dysfunction and increase LV compliance, thereby reducing the pressure gradient across LV outflow tract. Beta-adrenergic blocking agents decrease heart rate, thus lowering myocardial oxygen consumption and reducing the potential for myocardial ischemia.

Metoprolol (Lopressor, Toprol XL)

This is a first-line therapy in the treatment of obstructive and nonobstructive hypertrophic cardiomyopathy (HCM). Rarely, patients may require up to 200 mg orally twice daily to achieve the desired effect. The dose is titrated to a heart rate of between 50 and 60 bpm.

Atenolol (Tenormin)

Atenolol selectively blocks beta1 receptors, with little or no effect on beta2 types.

Sotalol (Betapace, Sorine)

This is a class III antiarrhythmic agent that blocks K+ channels, prolongs action potential duration, and lengthens the QT interval. Sotalol is a noncardiac selective beta-adrenergic blocker that may be helpful in the conversion of atrial fibrillation and flutter to normal rhythm. It may also suppress the recurrence of atrial fibrillation and flutter.

Propranolol (Inderal LA, InnoPran XL)

Propranolol is a class II antiarrhythmic nonselective beta-adrenergic receptor blocker with membrane-stabilizing activity that decreases the automaticity of contractions. The

dose is titrated to a heart rate of between 50 and 60 bpm.

Class Summary

These agents alter the electrophysiologic mechanisms responsible for arrhythmia.

Disopyramide (Norpace, Norpace CR)

Disopyramide decreases the inotropic state of the left ventricle. It decreases ventricular and supraventricular arrhythmias. The drug decreases diastolic dysfunction and increases LV compliance, thereby reducing the pressure gradient across the LV outflow tract. Disopyramide raises the threshold for atrial and ventricular ectopy.

Amiodarone (Cordarone, Pacerone)

Amiodarone is the only agent proven to reduce the incidence and risk of cardiac sudden death, with or without obstruction to LV outflow. It is very effective at converting atrial fibrillation and flutter to sinus rhythm and at suppressing the recurrence of these arrhythmias.

Class Summary

An alternative to beta blockers, calcium channel blockers decrease the inotropic state of the left ventricle, decrease the gradient across the LV outflow tract, decrease diastolic dysfunction, and increase diastolic filling of the left ventricle by improving LV diastolic relaxation. These agents may have a better effect on exercise performance.

Verapamil (Calan, Isoptin, Verelan)

During depolarization, verapamil inhibits calcium ions from entering slow channels or voltage-sensitive areas of the vascular smooth muscle and myocardium. The drug provides an alternative to beta-blocker therapy. It is useful in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

The use of short-acting calcium channel blockers is being discouraged because of numerous reports of adverse cardiac and hemodynamic events associated with their use, particularly in patients with known coronary artery disease.

Class Summary

Anticoagulants are used to prevent thromboembolic complications.

Warfarin (Coumadin, Jantoven)

Warfarin is a competitive, direct thrombin inhibitor. Thrombin enables fibrinogen conversion to fibrin during the coagulation cascade, thereby preventing thrombus development. It inhibits both free and clot-bound thrombin and thrombin-induced platelet aggregation. Warfarin is indicated for the prevention of stroke and thromboembolism associated with nonvalvular atrial fibrillation.

Class Summary

Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. 

Mavacamten (Camzyos)

Indicated for symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve exercise capacity and symptoms in adults. Mavacamten is a selective allosteric inhibitor of cardiac myosin. Modulates number of myosin heads that can enter “on actin” (power-generating) states, thus reduces probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Mavacamten shifts overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In patients with HCM, myosin inhibition with mavacamten reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures.