The Diagnosis and Treatment of Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) with or without left ventricular outflow tract (LVOT) obstruction is a common primary myocardial disease, with a prevalence of 1:500. It is characterized by thickening of the myocardium. Its diagnostic evaluation includes history-taking and physical examination, genetic studies, transthoracic echocardiography, and cardiac MRI. When optimally treated, it carries a mortality of less than 1% per year.

Methods: This review is based on pertinent publications retrieved by a selective literature search, including the current guidelines.

Results: In symptomatic patients with high LVOT gradients (≥ 50 mm Hg), the treatment of first choice is pharmacotherapy with non-vasodilating beta-blockers or non-dihydropyridine-type calcium channel antagonists. Common side effects include bradycardia and hypotension, and there is a risk of AV nodal blockade. Both substance classes lower the LVOT gradient. Beta-blockers alleviate dyspnea and improve patients’ quality of life. Verapamil can increase physical resilience. A further option is mavacamten, a myosin inhibitor that gained approval in Germany in mid-2023: it, too, lowers the LVOT gradient and improves quality of life. In 7–10% of patients, there is a reversible reduction of the left ventricular ejection fraction to less than 50%. Septal reduction treatments can be considered if drug therapy fails. Attention must also be paid to the management of sequelae such as atrial fibrillation, malignant arrhythmias, and mitral valve insufficiency.

Conclusion: Patients with HCM have a near-normal life expectancy if the disease is diagnosed early and treated according to the guidelines. The treatment of HCM and HOCM (hypertrophic obstructive cardiomyopathy) have been studied in no more than a few clinical trials, and randomized studies with clinical endpoints are needed.

Hypertrophic cardiomyopathy (HCM) is a common primary myocardial disease of genetic transmission but often incomplete penetrance. In around 50% of cases the mutation responsible remains unidentified (e1, e2). HCM is characterized by left ventricular hypertrophy in the absence of any other potentially causative illness (1, 2). The hypertrophy can be found in any part of the ventricle and may even be restricted to a single site. The usual presentation is asymmetric septal hypertrophy (3). In around 70% of cases this causes obstruction of the left ventricular outflow tract (LVOTO) (e3). The disease is then referred to as hypertrophic obstructive cardiomyopathy (HOCM) (4).

HCM is a leading cause of heart failure, sudden cardiac death, atrial fibrillation, and their consequences across all age groups (5, 6), with a prevalence rate of approximately 1:500 (e4, e5, e6, e7). This would correspond to around 167 200 persons with HCM in Germany (e8). Cohort studies have shown an association between appropriate treatment and reduction of mortality. The life expectancy of patients with timely diagnosis and the appropriate treatment matches that of the age-adjusted population without HCM (7, 8).

Etiology

HCM and HOCM are monogenic diseases of mostly autosomal dominant transmission. Cases of X-linked or autosomal recessive transmission represent exceptions (9, 10). Over 2000 causal genetic variants have been identified (11). The most commonly occurring variants affect the sarcomere, the contractile component of cardiac muscle. The genes most frequently involved by variation are those of the heavy myosin chain β (MYH7) and myosin-binding protein C (MYBPC3) (12, 13), as well as the genes TNNT2, TNNI3, and MYL2, coding respectively for cardiac troponin T, troponin I, and the light myosin chain (14). The causal mutation can currently be identified in about half of the cases. Often a variant of (yet) unknown significance is detected, particularly in small families or sporadic cases (e1, e2). At least one third of children with HCM or HOCM are found to have a de novo mutation (e1).

Pathophysiology

Diastolic dysfunction

Thickening of the left—and occasionally also the right—ventricular wall, together with fibrosis and chaotic alignment of muscle fibers, leads to decreased cardiac compliance (15, 16).

Microvascular dysfunction

Myocardial hypertrophy and prolonged contraction are associated with microvascular dysfunction, which may cause myocardial ischemia. The ischemia is aggravated by intracavitary pressure as a consequence of the impaired diastolic compliance and by pathological alterations of myocardial arterioles (17, 18, 19).

Left ventricular outflow tract obstruction

Most patients with HCM or HOCM are found to have LVOTO. Pathophysiologically, three factors combine to produce the obstruction: septal hypertrophy, usually in the medial portion of the ventricle; the primary mitral valve anomalies caused by the genetic mutation; and the anterior movement of the anterior mitral valve flap during systole (systolic anterior motion, SAM phenomenon) (20, 21). The SAM phenomenon leads to secondary mitral regurgitation and hence, in time, to atrial dilatation. This explains, among other things, the frequent occurrence of atrial fibrillation (22).

Autonomic dysfunction

Autonomic dysfunction is observed in around a quarter of patients with HCM or HOCM. The dysfunction comprises impaired regulation of heart rate and blood pressure, so that neither increases sufficiently in response to exertion. Activation of the ventricular baroreceptor reflex has been proposed as the cause (23). Studies have shown an association between cardiovascular mortality and autonomic dysfunction (odds ratio 4.5) (24).

Diagnosis

Medical history and physical examination

The most frequently occurring symptoms of HCM and HOCM are shown in Table 1. The disease can manifest at any time of life. Some patients remain entirely asymptomatic. The patients’ average age at diagnosis ranges from 37 to 59 years (25, 26, 27, 28). Special attention needs to be paid to documenting the family medical history over at least three generations (2, 4). Clinical examination should include maneuvers to provoke symptoms (e.g., the Valsalva maneuver and the passive leg raise test). The common findings are a broader and more lateralized apex beat; the presence of a third or fourth heart sound; a crescendo–decrescendo systolic murmur with its maximum over the left sternal margin and increasing in volume during the Valsalva maneuver; and a ribbon-shaped high-frequency systolic murmur reaching its maximum over the mitral valve auscultation site, correlating with functional mitral regurgitation (2). Many patients are oligosymptomatic, particularly when no hemodynamically relevant LVOTO is present (29, 30).

Table 1

The symptoms of patients with HCM and HOCM, including frequency of occurrence*

Instrument-based examinations

Electrocardiography

Every patient should undergo 12-lead electrocardiography (ECG) for detection of cardiac arrhythmia. Around 94% of patients have pathological ECG results (31), but there are no ECG signs that are specific to HCM/HOCM. The typical findings are signs of left ventricular hypertrophy, blocks (e.g., complete left bundle block or left anterior fascicular block), disordered repolarization (e.g., deep, spiky, negative T waves over the chest leads), pathological Q peaks, and cardiac arrhythmias such as atrial fibrillation (29, 30). Long-term ECG should be carried out every 1–2 years for documentation of arrhythmias and stratification of the risk of sudden cardiac death (32).

Transthoracic echocardiography and cardiac MRI

Every patient with suspected HCM should undergo diagnostic transthoracic echocardiography (TTE). HCM can be diagnosed in the presence of either left ventricular (LV) wall thickness ≥ 15 mm or LV wall thickness of 13–14 mm in combination with positive family history or demonstration of one or more genetic variants. Secondary causes of LV hypertrophy such as arterial hypertension, aortic valve stenosis, or amyloidosis must be ruled out (2). Figure 1 shows an example of the TTE findings in a patient with HOCM. The principal differential diagnoses and their discriminating criteria are listed in Table 2. Other factors assessed include the pattern of hypertrophy, the gradients in the LVOT, the left ventricular ejection fraction (LVEF), and mitral valve function (3, 33). All patients with HCM must be specifically evaluated for LVOTO. An LVOT peak gradient ≥ 30 mm Hg shows the presence of obstruction (HOCM). Gradients should be measured at rest and during provocation (Valsalva maneuver, squats, or standing up from a lying position). Gradient-reducing treatment is indicated if an LVOT gradient is found to be ≥ 50 mm Hg (4, 29, 32, 34, 35). Symptomatic patients with LVOT peak gradient ≥ 50 mm Hg should also have the gradient measured under conditions of physiological exertion, e.g., by means of stress ECG with bicycle ergometry (4). Approximately 40% of patients with HOCM exhibit an LVOT gradient < 30 mm Hg at rest, rising to ≥ 30 mm Hg only on exertion (e3). This is sometimes referred to as latent obstruction. The management algorithm for gradients ≥ 50 mm Hg is shown in Figure 2. In addition to TTE, an important role is played by cardiac MRI (CMRI), which helps to distinguish HCM/HOCM from differential diagnoses such as storage disorders. Determination of the myocardial fibrosis burden by means of late gadolinium enhancement (LGE) may be useful in estimating the risk of sudden cardiac death (SCD) (3, 32). For this reason, every patient should undergo CMRI at diagnosis and at intervals of 3–5 years thereafter for evaluation of their SCD risk (4, 32). Whether the patient’s health insurance provider will cover the costs should be established in advance.

Figure 1

Echocardiogram showing the thickened cardiac septum of a patient with HCOM in end-diastole

Figure 2

Flow chart for management of patients with maximal LVOT gradient = 50 mm Hg as measured by Doppler sonography LVOT, Left ventricular outflow tract; max., maximal; SM, surgical myectomy; SRT, invasive septal reduction treatment; TASH, transarterial alcohol ablation of septal hypertrophy

Table 2

The most commonly occurring differential diagnoses for hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy

Clinical management

The goal of treatment is to reduce the symptoms and manage the after-effects. Recent randomized trials have shown that mild to moderate sport improves resilience (maximal oxygen uptake + 1.35 mL/kg/min in the exercise group versus + 0.08 mL/kg/min with no specific exercise) with no negative events (36). Mild to moderate sporting activity is hence recommended for all patients after cardiological examination (4, 32, 37, 38).

Assessment of the risk of sudden cardiac death and placement of an implantable cardioverter–defibrillator

Patients with HCM or HOCM are at elevated risk of SCD. In mixed HCM and HOCM cohorts, the annual SCD-related mortality is around 1–2% (8). An implantable cardioverter–defibrillator (ICD) can be inserted for prevention of SCD. An observational study showed an annual appropriate ICD shock rate of 3.7% (39).

Primary prevention

The risk of SCD should be evaluated at diagnosis and then every 1–2 years by means of questioning, 24- to 48-hour ECG, and TTE and every 3–5 years by CMRI (4, 32). The major SCD risk factors are presented in the eTable. According to the recommendations of both the European Society of Cardiology (ESC) and the American Heart Association (AHA), the 5-year risk should be assessed on an individual basis and the decision regarding primary prophylactic ICD placement should be taken in consultation with the patient. The AHA has defined the major risk factors (eTable). If two or more of these factors are present, ICD placement should be considered (class of recommendation [COR] 2a, “can be useful”). If no major risk factors are present but there is NSVT on long-term ECG or marked LGE on CMRI, ICD placement can be considered (COR 2b, “unknown usefulness”).

eTable

The risk factors for sudden cardiac death

The ESC recommendations are based on calculation of the 5-year SCD-related mortality risk using the HCM Risk-SCD score. With low risk (5-year mortality < 4%) and ≥ 1 further risk factor, or with intermediate risk (5-year mortality 4–6%), ICD placement can be considered (COR IIb). With high 5-year mortality risk (≥ 6%), ICD placement should be considered (COR IIa) (4).

Secondary prevention

Both sets of guidelines recommend secondary preventive ICD placement for patients with persisting ventricular tachycardia (VT) and for those who have survived SCD.

Options for pharmacotherapy

HCM and HOCM with low LVOT gradients (30–50 mm Hg)

The management of patients with a low LVOT gradient (< 50 mm Hg) principally addresses after-effects such as atrial fibrillation, angina pectoris, or SCD. Treatment comprises administration of non-vasodilating beta blockers or calcium channel blockers of non-dihydropyridine type and low-dose diuretics. These lower the heart rate, the elevated ventricular filling pressures, and myocardial oxygen consumption (32). In a study of 32 patients, verapamil increased exercise duration on spiroergometry from 12.8 ± 3.8 min to 14.8 ± 4.2 min and maximal oxygen uptake from 22.6 ± 3.9 mL/kg/min to 25.6 ± 6.1 mL/kg/min (40). Administration of propranolol also significantly increased the maximal exercise time on treadmill ergometry from an initial 4.9 ± 3.2 min to 6.6 ± 3.1 min (e37). With LVEF reduction < 50% the standard pharmacotherapeutics for heart failure with (moderately) reduced LVEF are used (4).

In patients with highly symptomatic HOCM and low LVOT gradient, treatment to reduce the LVOT gradient may be appropriate in individual cases. The decision should be taken at a specialized HCM center.

HOCM with LVOT gradients ≥ 50 mm Hg

The management of symptomatic patients with LVOT gradient ≥ 50 mm Hg aims at reducing the LVOTO and the severity of the sequelae. The initial treatment comprises cardioselective beta blockers, with verapamil/diltiazem-type calcium channel blockers as second line (4). A recent double-blind, placebo-controlled randomized study investigated the action of metoprolol compared with placebo in 29 patients. After administration of metoprolol the LVOT gradient was 25 mm Hg versus 72 mm Hg in the placebo group at rest and 45 mm Hg versus 115 mm Hg on exertion. Metoprolol improved the quality of life (KCCQ-OSS questionnaire 76.2 ± 16.2 versus 73.8 ± 19.5), decreased respiratory distress (proportion of patients ≥ NYHA III 14% versus 38%), and reduced angina pectoris (proportion of patients ≥ CCS III 0% versus 10%) (e38). A study of 62 patients with LVOTO showed that intravenous administration of verapamil in the cardiac catheterization laboratory reduced the LVOT gradient from 62 ± 34 mm Hg to 29 ± 34 mm Hg (e39). Another study observed 126 patients and found that 12 and 24 months of verapamil treatment increased exercise capacity compared with baseline (exercise time before discontinuation 6.5 ± 3.8 min versus 9.2 ± 4.5 min versus 9.1 ± 4.6 min) (e39). In patients with LVOTO and LVOT gradient ≥ 50 mm Hg one should not attempt to alter the preload and afterload, e.g., by giving medications such as ACE inhibitors, angiotensin II receptor blockers, and SGLT2 inhibitors or mineralocorticoid receptor antagonists, because these may drastically worsen the gradient and the symptoms (4). Digitoxin should also be avoided, because an existing calcium metabolism disorder can be aggravated. Moreover, it is important to avoid physiological states that affect preload or afterload, e.g., volume fluctuations brought about by heat (dehydration/hyperhydration) and the consumption of alcohol, which aggravates the LVOTO by causing vasodilation (e40).

Cardiac myosin inhibitors

In June 2023 mavacamten was licensed as a new treatment option for LVOT gradient reduction in symptomatic HOCM patients (NYHA II–III) in Germany. The ESC and AHA have differing recommendations for the use of mavacamten. The ESC recommends administration of mavacamten in addition to first-line treatment with non-vasodilating beta blockers or non-dihydropyridine calcium channel antagonists or, if contraindications or intolerance prevent use of these first-line approaches, as monotherapy (COR IIa, “can be useful”) (4). The AHA recommends additional use of a myosin inhibitor only if the symptoms persist despite administration of the first-line substances (COR I, “recommended”; LOE B-R [evidence from ≥ 1 randomized controlled trial])(32). Mavacamten acts via selective blockade of the myosin ATPase of the heavy chain of cardiac myosin and thus reduces the pathological formation of cross-bridges between actin and myosin in cardiac muscle that occurs in HOCM (Figure 3) (e41). In the randomized, multicenter, placebo-controlled EXPLORER-HCM study, symptomatic (NYHA I and II) patients with HOCM, LVEF ≥ 55%, and peak LVOT gradient ≥ 50 mm Hg were treated for 30 weeks with mavacamten versus placebo. Pre-existing treatment with beta blockers or calcium channel antagonists was continued. Mavacamten decreased the LVOT gradient by 47 mm Hg versus 10 mm Hg in the placebo group. The symptoms were reduced by ≥ 1 NYHA class in 65% of the mavacamten patients versus 31% of the placebo group. Physical resilience, defined by peak VO₂, and quality of life, as assessed using the KCCQ-CSS and HCMSQ questionnaires, improved significantly (e42). In seven patients from the mavacamten group (circa 6%) there was reduction of the LVEF to < 50%. After discontinuation, the LVEF increased to ≥ 50% in all patients. In one patient this LVEF increase was only partial (baseline LVEF 80%, LVEF after recovery 50%) (e42). For this reason, use of mavacamten in the USA must always be preceded by preparation of a risk assessment and reduction strategy for the individual patient (32). The number needed to treat (NNT) is 5.2 (e43). Administration of mavacamten must be preceded by genotyping of the CYP2C19 allele, because in “slow metabolizers” the dosage has to be increased gradually to avoid accumulation. Preconditions for use of mavacamten are LVEF ≥ 55 % and monitoring for a possible decrease in LV function. Mavacamten bears the potential risk of embryofetal toxicity.

Figure 3

Schematic diagrams of the structure of cardiac myosin and the mechanism of action of mavacamten

Mavacamten is classified as a prescribable substance by the German National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung, KBV). As of September 2024, the cost of treatment was € 2163 per month (e44). No studies directly comparing mavacamten to beta blockers and/or calcium channel antagonists have yet been published. To date there are no robust data on younger patients or those with NYHA class III and IV. Data on clinical endpoints—with the exception of quality of life—and long-term data on efficacy, risks, and adverse effects, especially with regard to LV function, are absent. It remains open whether mavacamten is beneficial for HCM patients without LVOTO or whether the prognosis can be expected to improve together with amelioration of the symptoms.

Invasive treatment options for LVOT gradient reduction

After exhaustion of the pharmacotherapeutic options for LVOT gradient reduction, one can resort to invasive septal reduction treatment (SRT). The choice is between surgical myectomy (SM) (e46) and transarterial alcohol ablation of septal hypertrophy (TASH), in which local myocardial necrosis is achieved by cardiac catheter-guided injection of ethanol into a septal branch of the left anterior descending artery (LAD) (e49). Which method is more appropriate for each individual patient should be discussed by the members of an interdisciplinary cardiac team at an HOCM center. Further information can be found in the eBox.

eBox

Concise description of the options for septal reduction treatment

Conclusion

HCM and HOCM are commonly occurring genetic disorders. Patients with an LVOT gradient ≥ 50 mm Hg and symptoms should be treated primarily with medication and secondarily by means of septal reduction procedures. Because of the low number of studies and the sparseness of the evidence available, many decisions are left to expert assessment. We therefore recommend that H(O)CM be diagnosed and managed at specialized centers.

Conflict of interest statement
UL has received payments for lectures and advisory board activities, reimbursement of travel costs and congress attendance fees, and/or research funding from the following companies: Amgen, AstraZeneca, Bayer, Boehringer, Daiichi-Sankyo, Lilly, MSD, Novartis, NovoNordisk, Pfizer, Roche, Sanofi, and Synlab. He is a committee member of the German Cardiology Association (Deutsche Gesellschaft für Kardiologie, DGK) and chair of the Society for Prevention of Cardiovascular Diseases (Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen, DACH).

KL has received lecture fees, payments for advisory board activities, and travel costs from the following companies: Bristol Myers Squibb, Astra Zeneca, and Boston Scientific.

MNMW declares that no conflict of interest exists.

Manuscript received on 22 March 2024, revised version accepted on 19 September 2024

Translated from the original German by David Roseveare

Corresponding author
Dr. med. Maximilian Möbius-Winkler
Universitätsklinikum Leipzig AöR
Liebigstr. 20
04103 Leipzig, Germany

Cite this as:
Möbius-Winkler MN, Laufs U, Lenk K: The diagnosis and treatment of hypertrophic cardiomyopathy. Dtsch Arztebl Int 2024; 121: 805–11. DOI: 10.3238/arztebl.m2024.0196

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