The Diagnosis and Treatment of Hypertrophic Cardiomyopathy

Abstract

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.

CME plus⁺

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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–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 (17–19).

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 (25–28). 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*.

Symptom	Frequency
Tiredness/fatigue	89% (e9)
Dyspnea > NYHA I	16–52% (e10–e12)
Asymptomatic at time of diagnosis	34–47% (e10–e12)
Angina pectoris	30–43% (e10–e12)
Palpitations	28–47% (e10, e12)
Syncopes	6–12% (e10–e12)

* Note that 34–47% of patients are asymptomatic at the time of diagnosis. These cases come to light, for example, when a heart sound is discovered during routine or mandatory investigations or because the person concerned is related to someone with HCM/HOCM.

HCM, Hypertrophic cardiomyopathy;

HCOM, hypertrophic obstructive cardiomyopathy

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.

AMVL, Anterior mitral valve leaflet; Ao, ascending aorta; LA, left atrium; LV, left ventricle; NCC, non-coronary cusp (of the aortic valve); PMVL, posterior mitral valve leaflet; IVS, interventricular septum; RCC, right coronary cusp; RVOT, right ventricular outflow tract

*1 LVOT (left ventricular outflow tract)

*2 IVST (interventicular septal thickness).

The thickening of the cardiac septum (26 mm) is clear to see.

Table 2. The most commonly occurring differential diagnoses for hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy.

Diagnosis	Distinguishing characteristics
Hypertensive heart disease	• Frequently coexistent, hence differentiation is very difficult • Elevated LV mass index on CMRI • Less LGE on CMRI • Absence of SAM phenomenon (e14)
Aortic valve stenosis	• Jet directly over aortic valve in aortic valve stenosis, subaortic in the LVOT in HCM (e15) • In some cases TEE can be used to assess the aortic valve • Concentric hypertrophy
Cardiac amyloidosis	• Apical sparing (reduction of myocardial muscle shortening on contraction except at apex) and echo-rich septal myocardium (so-called granular sparkling phenomenon), thickening of the cardiac valves and interatrial septum, minor pericardial effusion on echocardiography • Concentric hypertrophy • The most frequently occurring forms are AL and ATTR amyloidosis • Typical subendocardial LGE on CMRI (e16) • Specific diagnostic work-up for amyloidosis: technetium99m skeletal scintigraphy, determination of free light chains, protein electrophoresis, immunofixation in serum/urine, and possibly bone marrow aspiration (e17)
Athlete’s heart	• Concentric hypertrophy • Normal ratio of ventricular diameter and myocardial wall thickness (e18) • Absence of diastolic dysfunction • LV wall thickness very rarely ≥ 13 mm (e19) • Regression of hypertrophy after deconditioning phase of 9–12 weeks (e20, e21)
Cardiac sarcoidosis	• Cardiac septum often involved, later frequently septal thinning (e22, e23) • Multifocal LGE on CMRI, particularly in the septum • FDG-PET-CT with tracer enhancement in heart as correlate of autoinflammation (e24)
Left ventricular thrombus, non-compaction cardiomyopathy, Löffler syndrome	• LV thrombus and non-compaction cardiomyopathy usually apical • Löffler syndrome is associated with hypereosinophilia • Thrombus typically echo-poor on TTE, centrally echo-richer without movement in relation to rest of heart wall • Contrast-enhanced TTE and CMRI aid differential diagnosis if 2D-TTE is not adequate • Thrombi usually located at apex
Storage disorders, e.g., Anderson–Fabry disease, Pompe disease, Danon disease, particular forms of mucopolysaccharidosis, and glycogen storage disorder types II, IIa, III, IV	• Well over 1000 known • May also manifest in adulthood • Usually manifest in several organ systems, hence thorough history and physical examination (e25, e26)

The most commonly occurring differential diagnoses for hypertrophic cardiomyopathy (HCM) and hypertrophic obstructive cardiomyopathy (HOCM) with the respective distinguishing characteristics

AL amyloidosis, amyloid light chain amyloidosis; ATTR amyloidosis, amyloid transthyretin amyloidosis; CMRI, cardiac magnetic resonance imaging; FDG-PET-CT, fluorodeoxyglucose positron emission tomography; LGE, late gadolinium enhancement; LV, left ventricular; LVOT, left ventricular outflow tract; SAM phenomenon, systolic anterior motion phenomenon; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography,

2D, two-dimensional

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

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.

Risk factor for sudden cardiac death (SCD)	Description
Massive left ventricular (LV) hypertrophy (LV wall thickness ≥ 30 mm)*1,*3	• The SCD risk rises with increasing LV wall thickness. Data expressed as SCD risk per 1000 person years [95% confidence interval]. The SCD risk is 0 [0; 14.4] for a maximal LV wall thickness of ≤ 15 mm, 2.6 [0.3; 9.6] for LV wall thickness 16–19 mm, 7.4 [3.5; 13.6] for LV wall thickness 20–24 mm, 11.0 [3.0; 28.2] for LV wall thickness 25–29 mm, and 18.2 [7.3; 37.6] for LV wall thickness of ≥ 30 mm (e27). • Extreme LV wall thickness of ≥ 30 mm was observed mainly in younger patients (in an observational study with 480 patients the mean age of the whole cohort was 47 years and the mean age of the patients with extreme LV wall thickness was 31 years; of 12 patients < 18 years with extreme lv hypertrophy, 5 died from scd [e27]).
Positive family history of SCD*1, *3	• There are various definitions of a positive family history: • ESC definition: SCD in ≥ 1 first-degree relative < 40 years, independent of whether hcm/hocm was diagnosed, or scd in a first-degree relative of any age if hcm/hocm was diagnosed (4). • AHA definition: SCD in ≥ 1 first-degree relative independent of age or in second-degree relatives < 50 years or ≥ 2 scd in third-degree relatives (32). • Hazard ratio (HR) 1.76 [1.32; 2.4] for SCD-related 5-year mortality with positive family history (e28)
Unexplained, most likely arrhythmogenic syncope*1, *3	• Assessment is often difficult because of the large number of potential causes. • Syncope in the previous 6 months is associated with a particularly high risk of SCD (HR 4.89 [2.19; 10.94]), while unexplained syncopes > 5 years earlier in older patient (≥ 40 years) are not associated with an elevated SCD risk (HR 0.38 [0.05; 2.74] (e29). • An unexplained syncope in a young patient is a strong risk factor for SCD. In patients < 18 years with unexplained syncope the hr for scd is 8.01 [2.07; 31.45] (e29). • In an observational study with 3675 HCM/HOCM patients the HR was 2.33 [1.69; 3.2] for SCD-related 5-year mortality in the presence of unexplained syncopes (e28)
Left ventricular ejection fraction (LVEF) < 50%*1	• One study observed 2447 HCM/HOCM patients, of whom 118 had LVEF ≤ 49%. The SCD rate per year was 2.4% versus 0.5% in the remaining 2329 patients with LVEF > 50% (e30).
Apical LV aneurysm*1	• Only a small proportion of patients form an apical aneurysm (ca. 4.8%) with transmural fibrosis (detectable on MRI) (e31). • The risk of SCD is greatly increased. A study that followed 1940 HCM/HOCM patients, of whom 93 (4.8%) had an apical aneurysm, observed an annual SCD rate of 4.7% in patients with apical aneurysm vs. 0.9% in the remaining 1847 patients without apical aneurysm (e31).
Pronounced late gadolinium enhancement (LGE) on cardiac MRI (≥ 15%)*2	• LGE is a marker of fibrosis and can be detected on cardiac MRI. The extent of LGE in relation to LV mass can be expressed in %. • Around 50% of patients with HCM/HOCM have LGE (e32) • A meta-analysis of 5 studies and 2993 HCM/HOCM patients concluded that the SCD risk rises with increasing LGE. HR of 1.56 [1.33; 1.82] per 10% LGE reported (e33). • One study explored the risk of SCD depending on the extent of LGE over an observation period of 7 years. Patients with ≤ 15% LGE had an elevated SCD risk (HR 1.4). In patients with LGE > 15% the HR for the occurrence of SCD was 2.84 [1.27; 6.34] for those with HCM and 3.04 [1.48; 6.10] for HOCM (e32).
Non-sustained ventricular tachycardia (NSVT) on long-term ECG*2, 3	• Definition: ventricular tachycardia ≥ 3 consecutive ventricular beats with heart rate ≥ 120 bpm and duration < 30 s (4, 32) • Approximately 20% of HCM/HOCM patients have NSVT on long-term ECG. • HR 2.29 [1.64; 3.18] for SCD-related 5-year mortality when NSVT are found on long-term ECG (e28) • NSVT in young patients shows a greatly increased risk of SCD. In one study with 104 patients the OR for SCD was 4.35 [1.54; 12.28] in patients with NSVT ≤ 30 years and 2.16 [0.82; 5.69] for patients > 30 years (e34).
Age (higher risk at younger age)*3	• Younger patients are at higher risk of SCD. NSVT (e34), extreme LV hypertrophy (e27), or unexplained syncope (e29) indicate particularly high risk.
Size of left atrium*3	• In a study that explored the link between syncopes and SCD by observing 1511 patients, multimodal regression analysis was carried out. The identified independent risk factors for SCD included enlargement of the left atrium (relative risk 1.03 [1.00; 1.06]). Another study also associated left atrial enlargement with a significantly increased risk of SCD, HR 1.035 [1.018; 1.052] (e28).
Left ventricular outflow tract (LVOT) obstruction*3	• An LVOT obstruction with LVOT gradient ≥ 30 mm Hg increases the risk of SCD with a HR of 1.84 [1.14; 2.98] (e35). • Another observational study with 917 patients showed that LVOT obstruction increases the risk of SCD 2.4-fold compared with patients without LVO obstruction (e36).

*¹ Classified as a major risk factor by the AHA (if ≥ 1 risk factor is present, ICD placement should be considered [class of recommendation (COR) IIa (“can be useful”)], level of evidence [LOE] B-NR (evidence from ≥ 1 non-randomized study, observational study, or registry study)

*² Classified as an important risk factor by the AHA,but with a weaker recommendation for ICD placement (if ≥ 1 risk factor is present, ICD placement can be considered [COR IIb (“unknown usefulness”)], LOE B-NR),

*³ Is considered in the ESC’s HCM Risk-SCD score and influences the ESC recommendation concerning ICD placement. If the HCM Risk-SCD score indicates low risk (5-year mortality < 4%) with ≥ 1 further clinical risk factor or intermediate risk (5-year mortality 4–6%), ICD placement can be considered (COR IIb [“unknown usefulness”]), LOE B [evidence from one randomized clinical trial or > 1 large non-randomized study]). In the case of high risk (5-year mortality ≥ 6%), ICD placement should be considered (COR IIa [“can be useful”], LOE B).

ECG, Electrocardiogram; HCM, hypertrophic cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; MRI, magnetic resonance imaging

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.

One mechanism for the development of HOCM is excessive formation of cross-bridges between the actin filament and the myosin head (shown in blue). Mavacamten reduces cross-bridge formation (gray myosin heads) via blockade of myosin ATPase and thus counters the mechanism behind the development of HOCM.

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.

• After exhaustion of the pharmacotherapeutic treatment options, and in the presence of persisting symptoms, two forms of septal reduction treatment (SRT) are available:

• Surgical myectomy (SM)

  • Normalization of the LVOT gradient in > 90% of cases and reduction of the burden of symptoms (e45, e46)

  • Very good long-term outcome in circa 80% of cases and survival similar to that of the normal population (e47)

  • Advantage: possible combination with bypass or mitral valve surgery

  • Negative predictive factors: postoperative atrial fibrillation, high age (e48)

  • Higher perioperative risk of mortality than with TASH (SM 2.0% versus TASH 1.2%, P 0.009) (e50)

  • Higher risk of stroke than with TASH (SM 1.5% versus TASH 0.8%, P < 0.013) (e50)

• TASH, or alcoholic septal ablation (ASA)

  • Injection of ethanol by means of a cardiac catheter into a septal branch of the LAD (first described by Ulrich Sigwart in 1994) with consecutive myocardial necrosis and LVOT gradient reduction (e49)

  • Reintervention necessary more often than with SM (TASH 11% versus SM 1.5%, P < 0.001) (e50)

  • Postoperative pacemaker implantation necessary more often than with SM (TASH 10% versus SM 5%, P < 0.001) (e50)

• In the long term (defined as follow-up > 3 years) overall mortality (TASH 1.5% versus SM 1.1%, P 0.21), cardiovascular mortality (TASH 0.4% versus SM 0.5%, P 0.53) and the rate of sudden cardiac death (TASH 0.3% versus SM 0.3%, P 0.43) did not differ significantly (e50).

LAD, Left anterior descending artery; LVOT, left ventricular outflow tract; TASH, transarterial alcohol ablation of septal hypertrophy

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.

Questions on the article from issue 24/2024:

The Diagnosis and Treatment of Hypertrophic Cardiomyopathy

CME credit for this unit can be obtained via cme.aerzteblatt.de until 28.11.2025. Only one answer is possible per question. Please choose the most appropriate answer.

Question 1

How many persons living in Germany are affected by hypertrophic cardiomyopathy?

1. Around 1670

2. Around 16 700

3. Around 67 000

4. Around 167 000

5. Around 367 000

Question 2

Which form of genetic transmission accounts for most cases of hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy?

1. Autosomal recessive

2. X-linked recessive

3. Autosomal dominant

4. X-linked dominant

5. Mitochondrial

Question 3

What proportion of patients with hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy have a pathological ECG?

1. Around 14%

2. Around 24%

3. Around 54%

4. Around 74%

5. Around 94%

Question 4

Which of the following examinations is recommended for every patient suspected of having hypertrophic cardiomyopathy?

1. Transthoracic echocardiography

2. Chest computed tomography

3. Chest radiography

4. Transesophageal echocardiography

5. Chest magnetic resonance imaging

Question 5

What is the number needed to treat (NNT) for mavacamten?

1. 1.2

2. 3.2

3. 5.2

4. 7.2

5. 9.2

Question 6

From which of the following thresholds is treatment to reduce the LVOT gradient in symptomatic patients generally indicated?

1. LVOT gradient ≥ 10 mm Hg

2. LVOT gradient ≥ 30 mm Hg

3. LVOT gradient ≥ 50 mm Hg

4. LVOT gradient ≥ 70 mm Hg

5. LVOT gradient ≥ 100 mm Hg

Question 7

After diagnosis of hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy, how often should each patient undergo CMRI to assess the risk of sudden cardiac death?

1. Every 3–4 months

2. Every 1–2 years

3. Every 6–9 months

4. Every 6–8 weeks

5. Every 3–5 years

Question 8

Which of the following medications can be used to increase the resilience of symptomatic patients with LVOT gradient ≥ 50 mm Hg?

1. Angiotensin-II receptor blockers

2. SGLT2 inhibitors

3. Verapamil

4. ACE inhibitors

5. Digitoxin

Question 9

What is the mechanism of action of the new drug mavacamten, licensed for use in 2023?

1. It reduces the formation of cross-bridges between actin and myosin by blocking myosin ATPase.

2. It reduces myosin activity by means of a blockade in the myosin heavy chains.

3. It weakens myocardial contractions by inhibiting mitochondrial activity in the myocardium.

4. It reduces the formation of cross-bridges between actin and myosin by intercalation into the actin filaments.

5. It reduces the formation of cross-bridges between actin and myosin by selective enzymatic depletion of actin filaments.

Question 10

Which of the following is an invasive treatment option for reduction of the LVOT gradient?

1. Transmural septal radiofrequency ablation

2. Transepicardial septal cryoablation

3. Transmural septal laser ablation

4. Transarterial septal alcohol ablation

5. Transatrial septal ultrasound ablation