Hypertrophic cardiomyopathy

Overview and definition

Picture a ventricle with a thick wall that nothing else explains. ESC 2023 defines HCM as increased LV wall thickness or mass, with or without RV hypertrophy, that abnormal loading conditions do not solely explain.^[2] For AHA/ACC 2024, HCM is a disease state whose morphologic expression is confined solely to the heart. It is characterised predominantly by LVH in the absence of another cardiac, systemic or metabolic disease capable of producing that degree of hypertrophy. It is also a disease for which a disease-causing sarcomere (or sarcomere-related) variant is identified or genetic etiology remains unresolved.^[1]

The two guidelines set almost the same numbers. They differ mainly in how they handle children.^[2][1]

^{[2] [1]}

Older names include idiopathic hypertrophic subaortic stenosis and hypertrophic obstructive cardiomyopathy. AHA/ACC recommends the name "HCM (with or without outflow tract obstruction)" because LVOTO is not always present.^[1] Systolic anterior motion (SAM) of the mitral valve and a hyperdynamic ventricle are common but are neither pathognomonic nor required for diagnosis.^[1] The commonest site of hypertrophy is the basal anterior septum in continuity with the anterior free wall.^[1]

^{[1] [2]}

Population echo screening shows how often HCM goes unnoticed. In CARDIA, 4111 adults aged 23 to 35 selected from the general population of four urban centres had echocardiograms, and probable or definite HCM was found in 0.17%, about 2 in 1000.^[22] Only 1 of the 7 had ever had important cardiac symptoms attributable to HCM, had previously been suspected of having cardiovascular disease, or had LV outflow obstruction.^[22]

Genetics and inheritance

About half of HCM is inherited as a Mendelian trait; in those cases inheritance is mainly autosomal dominant, with a 50% risk of transmission to each child.^[2] MYH7 (beta-myosin heavy chain) and MYBPC3 (myosin-binding protein C3) are the two commonest genes and are found in most variant-positive patients.^[1]

• Yield of testing. ESC 2023 reports a single causal variant in about 40–60% of those tested. AHA/ACC 2024 gives about 30–60%, and an 8-sarcomere-gene panel finds a disease-causing variant in about 30% of sporadic and 60% of familial cases.^[2][1]
• Non-familial HCM. In up to 40% of patients no sarcomere variant is found and there is no family history.^[1]
• Genocopies. Less than 5% of adults but up to 25% of children with HCM carry a variant in a gene known to mimic the HCM phenotype (a causative variant).^[2]
• Penetrance. In a retrospective study of 285 adult and paediatric sarcomere variant carriers identified by family screening and without HCM at first evaluation, estimated penetrance at 15 years of follow-up was 46% (95% CI 38% to 54%). Male sex and an abnormal ECG independently predicted developing HCM.^[18]
• Prognosis by genotype. In SHaRe, pathogenic or likely pathogenic sarcomere variants carried a two-fold greater risk of adverse outcomes than no variant.^[17]

Pathophysiology

^[1]

AHA/ACC 2024 lists the components: dynamic LVOTO, mitral regurgitation, diastolic dysfunction, myocardial ischaemia, arrhythmias, metabolic and energetic abnormalities, and possibly autonomic dysfunction.^[1] One component may dominate in a given patient, or several may interact.^[1]

From gene to stiff ventricle. Sarcomere gene changes lead to hypertrophy and fibrosis. The end result is a small, stiff ventricle with impaired systolic and diastolic performance despite a preserved LVEF.^[1] Impaired relaxation can appear in young variant carriers before the wall thickens.^[1]

Why the gradient moves. LVOTO is mainly caused by SAM and is sensitive to preload, afterload and contractility.^[1] Gradients therefore vary with heart rate, blood pressure, volume status, activity, medications, food and alcohol.^[1] Decreasing preload can augment LVOTO (AHA/ACC), and arterial and venous dilators can exacerbate it (ESC).^[1][2]

Mitral regurgitation. SAM-related MR is typically mid-to-late systolic and directed posteriorly or laterally.^[1] ESC 2023 advises that a central or anteriorly directed jet should raise suspicion of intrinsic mitral valve disease and prompt further assessment.^[2] AHA/ACC notes that central and anterior jets may also result from SAM.^[1]

Ischaemia and autonomic tone. Hypertrophy, microvascular dysfunction with impaired coronary flow reserve, and remodelled intramural arterioles are common in HCM.^[1] About 25% of patients show an abnormal blood pressure response to exercise in AHA/ACC data; ESC 2023 gives about one-third of adults.^[1][2]

The basal anterior septum in continuity with the anterior free wall is the commonest site of hypertrophy.^[1] Mid-cavity obstruction occurs in about 10% of patients, and an apical aneurysm is a discrete thin-walled dyskinetic or akinetic segment of the distal LV.^[2] AHA/ACC considers an EF below 50% to represent significantly reduced systolic function in HCM, because it is associated with worse outcomes, and describes adverse remodelling with cavity enlargement and wall thinning from scarring in these patients.^[1]

Clinical presentation

Most people with HCM are asymptomatic and live a normal lifespan. Some develop symptoms, often many years after ECG or echo evidence of LVH appears.^[2] Ask about chest pain, dyspnoea, palpitations and syncope on exertion, and assess overall fitness and functional capacity.^[1]

In referral cohorts, AHA/ACC 2024 notes that many patients experience adverse events, including:^[1]

1. Sudden death events.
2. Progressive limiting symptoms from LVOTO or diastolic dysfunction.
3. Heart failure symptoms with systolic dysfunction.
4. AF with risk of thromboembolic stroke.

^[1]

In adults, lower sudden death rates appear to have shifted the focus to heart failure and AF complications as the predominant cause of disease-related morbidity and mortality.^[1] In SHaRe, heart failure and AF were the most prevalent adverse events, usually emerging several years after diagnosis.^[17]

Bedside assessment

The classic findings are a harsh crescendo-decrescendo systolic murmur (often from SAM with LVOTO), a prominent apical impulse, an abnormal carotid pulse and a fourth heart sound.^[1] Look for obstruction at rest and, when possible, with provocation: Valsalva and standing from squatting.^[1] A patient without resting or provocable LVOTO may have a normal examination.^[1]

Take a family history across three generations to find relatives with HCM or unexpected or sudden death.^[1] Exclude alternative causes, including athletic remodelling, uncontrolled hypertension, renal disease or infiltrative disease.^[1]

Differential diagnosis

The question at every new thick ventricle is whether a systemic disease or a loading condition explains it. AHA/ACC names metabolic and multiorgan syndromes such as RASopathies, mitochondrial myopathies and glycogen and lysosomal storage diseases in children, and Fabry, amyloid, sarcoid and Danon cardiomyopathies.^[1] Secondary LVH from athletic training or long-standing hypertension can also overlap with HCM.^[1]

^{[2] [1]}

Athlete or HCM? On CMR, absence of fibrosis may help separate HCM from physiological adaptation. LGE may still be absent in HCM, particularly in young people and mild disease.^[2]

When genetics changes treatment. With an atypical presentation, or when another genetic condition is suspected, a workup including genetic testing for HCM and phenocopy genes is recommended (AHA/ACC COR 1).^[28] AHA/ACC adds that phenocopy genes (including PRKAG2, LAMP2, GLA, transthyretin and RASopathy genes) may be included in first-tier testing if phenotype evaluation raises clinical suspicion of a systemic disorder.^[1] In some circumstances a result may alter management, such as enzyme replacement in Fabry disease or more aggressive management of Danon disease.^[1]

Investigations

ECG and ambulatory monitoring

The 12-lead ECG is abnormal in 75% to 95% of patients with phenotypic HCM, including LVH and repolarisation change, but it does not reliably track the severity or pattern of hypertrophy.^[1] In child gene carriers, ECG changes can precede LVH, so the ECG is considered more sensitive than echo as a family screening tool.^[1]

AHA/ACC recommends 24- to 48-hour ambulatory ECG monitoring at initial evaluation and every 1 to 2 years (COR 1).^[28] Extended monitoring to screen for AF in patients at high risk of AF (by risk factors or a validated score such as HCM-AF) who are eligible for anticoagulation is recommended as part of initial evaluation and annual follow-up (AHA/ACC COR 1).^[1][28] Predictors of clinically important AF include left atrial dilatation, increasing age, duration of disease and NYHA class III to IV heart failure.^[1]

Echocardiography and the hunt for obstruction

ESC 2023 advises that hypertrophy be documented with a standardised protocol from several projections, because thickening can occur anywhere, including the RV.^[2] Ejection fraction is a suboptimal measure of systolic performance when hypertrophy is present.^[2]

Resting recumbent echo tends to underestimate the presence and severity of ambulatory LVOTO. AHA/ACC notes that LVOT gradients can be dynamic and can be missed on resting echocardiography in up to 50% of patients with obstructive physiology.^[1]

^{[2] [1]}

To attribute effort symptoms to LVOTO, the resting or provoked gradient generally needs to exceed 50 mm Hg (AHA/ACC).^[1] In one cohort, Valsalva underestimated the presence and size of exercise-induced obstruction.^[16]

AHA/ACC recommends repeat TTE every 1 to 2 years when there is no change in clinical status or events (COR 1).^[28] Its supportive text notes the interval may be extended in patients who remain clinically stable after multiple evaluations.^[1]

Cardiac magnetic resonance

ESC 2023 recommends CMR at baseline assessment in HCM. It can be particularly helpful when apical or lateral wall hypertrophy or an apical aneurysm is suspected.^[2] AHA/ACC adds that CMR clarifies the diagnosis when the echo is nondiagnostic or inconclusive.^[1]

LGE is present in 65% of patients (range 33–84%), usually patchy mid-wall in hypertrophied segments and at the RV insertion points.^[2] Studies have promoted extensive LGE of 15% or more of LV mass as a significant (2-fold) increase in SCD risk, though no consensus exists on the best quantification technique. In the Chan cohort (1293 patients), that 2-fold increase was in patients otherwise considered at lower risk.^[14] Absent or minimal LGE is associated with lower risk.^[1] In 1293 HCM patients referred for CMR and followed for a median of 3.3 years, each 10% increase in LGE carried an adjusted hazard ratio of 1.46 for SCD events.^[14]

Exercise testing and genetics

Exercise testing shows the severity and mechanism of limitation. In more than 9000 patients, reduced peak oxygen consumption and submaximal exercise parameters, such as ventilatory efficiency and anaerobic threshold, were associated with a higher rate of ventricular arrhythmias, progression to advanced heart failure and higher all-cause mortality.^[1] In children with HCM, exercise testing regardless of symptoms, to determine functional capacity and provide prognostic information, carries COR 1 (AHA/ACC 2024).^[28] Exercise testing is only useful in older children, typically over 7 to 8 years of age, or when able to cooperate with the testing protocol.^[1]

Genetic testing starts in a family member with clear phenotypic evidence of HCM, usually the proband. A variant of uncertain significance (VUS) identified in a proband is not a clinically actionable result.^[1] Variants get reclassified: in one report, 11% of HCM variants moved over 6 years into a category that would change cascade screening of family members. Because family screening hinges on variant pathogenicity, AHA/ACC states that the reported pathogenicity should be reconfirmed every 2 to 3 years.^[1]

Sudden cardiac death risk

The most commonly recorded fatal arrhythmic event is spontaneous VF, but asystole, AV block and pulseless electrical activity are described.^[2] ESC recommends an ICD for survivors of cardiac arrest due to VT or VF and for spontaneous sustained VT with haemodynamic compromise (Class I), when the intent is to increase survival.^[2] The decision should consider the patient's view and quality of life, and the absence of other diseases likely to cause death within the following year.^[2] AHA/ACC recommends an ICD after previous documented cardiac arrest or sustained VT (COR 1).^[28] The guidelines differ on primary prevention.

The ESC approach: estimate first

ESC 2023 uses the HCM Risk-SCD tool as the first step in patients aged 16 or more, and a validated paediatric score (such as HCM Risk-Kids) under 16.^[2] The model was built from 3675 patients. Seven predictors entered it: age, maximal LV wall thickness, left atrial diameter, LVOT gradient, family history of SCD, non-sustained VT and unexplained syncope.^[4] It estimates 5-year SCD probability; in the 3675-patient derivation cohort the C-index was 0.70.^[4] In the derivation paper, implanting 16 ICDs in patients with a 5-year risk of 4% or more would potentially save one patient from SCD at 5 years.^[4]

Risk categories and ICD thresholds. ESC 2023 Recommendation Table 23 sets the cut-offs. An ICD should be considered at an estimated 5-year risk of 6% or more (Class IIa), after detailed clinical assessment of lifelong complication risk, competing mortality from the disease and comorbidities, and the impact on lifestyle, socio-economic status and psychological health. It may be considered in individual patients at 4% to below 6% (Class IIb), after detailed assessment of lifelong complication risk and the impact on lifestyle, socio-economic status and psychological health. Below 4% is the low-risk category.^[2] The same cut-offs defined the 2014 ESC categories.^[20]

• External validation (EVIDENCE-HCM). In 3703 patients the C-index was 0.70. In the complete-case analysis (n=2147), a predicted risk below 4% carried an observed 5-year SCD incidence of 1.4%; 6% or more carried 8.9%.^[19] In that analysis, for every 13 ICDs implanted at an estimated 5-year risk of 6% or more, one patient could potentially be saved.^[19]
• Meta-analysis. Across 7291 unselected adults without prior cardiac arrest, pooled prevalence of SCD endpoints within 5 years of baseline evaluation was 1.01% (low), 2.43% (intermediate) and 8.4% (high risk). Most of these 5-year SCD endpoints (68%) occurred in the 30% of patients with an estimated 5-year risk of 4% or more.^[20] ESC 2023 notes that pooled estimates were concordant with the observed SCD risk in patients designated high or low risk.^[2]
• Children (HCM Risk-Kids). Built from 1024 patients aged 16 or under, it uses unexplained syncope, maximal wall thickness, LA diameter, LVOT gradient and NSVT. In internal (bootstrap) validation, its C statistic for 5-year prediction was 0.69. The authors report that for every 10 ICDs implanted at an estimated 5-year risk of 6% or more, one patient may potentially be saved from SCD at 5 years.^[21]

^[2]

Do not use the models in elite athletes, in metabolic or infiltrative disease (such as Anderson–Fabry) or in syndromes (such as Noonan). They do not use exercise-induced gradients and are not validated before and after myectomy.^[2]

ESC also addresses further markers:^[2]

• Extensive LGE (15% or more) may be considered in shared decision-making about a prophylactic ICD in the low-risk category (below 4%), acknowledging the lack of robust data (Class IIb).^[2]
• LVEF below 50% may likewise be considered in shared decision-making in the low-risk category (Class IIb).^[2]
• Apical aneurysm. Basing primary-prevention ICD decisions on HCM Risk-SCD (or a validated paediatric model such as HCM Risk-Kids), and not solely on the aneurysm, should be considered (Class IIa).^[2]
• Abnormal exercise blood pressure response (failure of systolic pressure to rise by at least 20 mm Hg from rest to peak, or a fall of more than 20 mm Hg from peak) is not recommended as an indication for a primary prevention ICD in patients in the low or intermediate risk category.^[2]
• Sarcomeric variants are not recommended to guide primary prevention ICD decisions in individuals with a low or intermediate SCD risk score.^[2]

The AHA/ACC approach: risk markers first

In adults, AHA/ACC 2024 recommends a comprehensive, systematic noninvasive SCD risk assessment at initial evaluation and every 1 to 2 years thereafter (COR 1).^[1][28] For adults with one or more major risk factors, it is reasonable to offer an ICD (COR 2a). The major risk factors the COR 2a row lists include sudden death judged definitively or likely due to HCM in a first-degree or close relative aged 50 or under. They also include massive LVH of 30 mm or more; recent syncope suspected to be arrhythmic; apical aneurysm with transmural scar or LGE; and EF below 50%.^[28] In select adults without a major risk factor after clinical assessment, or when the ICD decision otherwise remains uncertain, an ICD may be considered for extensive LGE on CMR or NSVT on ambulatory monitoring (COR 2b).^[28] Table 8 defines each marker.^[1]

^[1]

For adults, the 5-year risk calculator needs left atrial diameter and the maximal instantaneous LVOT gradient by continuous-wave Doppler.^[1] It does not include LVEF below 50%, apical aneurysm or LGE, so their effect on the estimate is undetermined.^[1] In patients with at least one major risk factor, discussing the estimated 5-year sudden death risk and mortality rates can be useful in shared decision-making for ICD placement (COR 2a).^[1] AHA/ACC adds that prespecified risk thresholds should not be the sole arbiter of an ICD.^[1]

• Age over 60. The marker strategy applies mostly to young and middle-aged adults, because SCD rates are very low after 60.^[1]
• No risk marker, no ICD. Device therapy should not be offered without evidence of increased risk; in patients without risk factors, ICD placement should not be performed (COR 3: Harm).^[1][28]
• Genetics alone. A genetic result in isolation does not influence ICD decisions in adults.^[1]
• Children. With one or more conventional risk factors, including unexplained syncope, massive LVH, NSVT or family history of early HCM-related SCD, ICD placement is reasonable after weighing the relatively high complication rates of long-term ICDs in young patients (COR 2a).^[28]

^{[2] [20] [1] [28]}

In an international series of 3387 high-risk patients with ICDs followed for a mean of 7 years (up to 32), 16% received appropriate therapy (2.6% per year; 2.2% per year after primary prevention implants).^[25] Unexplained syncope, apical aneurysm, systolic dysfunction and NSVT independently predicted it. Of primary prevention patients with appropriate therapy, 16% had their first one 10 years or more after implantation.^[25]

Device choice. Patients with a subcutaneous ICD should be screened for oversensing after exercise.^[1] In smaller children, usually under 30 kg, epicardial leads will often be necessary.^[1]

Management of obstructive HCM

^{[1] [28] [2]}

Drug therapy treats symptoms. AHA/ACC notes that no convincing data show it alters natural history, and success is judged by symptom response rather than the measured gradient.^[1]

General measures

• Avoid dehydration and excess alcohol, and encourage weight loss (ESC).^[2]
• Avoidance of digoxin and arterial and venous dilators, including nitrates and phosphodiesterase inhibitors, should be considered if possible with resting or provocable LVOTO (ESC Class IIa).^[2]
• AHA/ACC: in obstructive HCM, discontinuing vasodilators (eg, ACE inhibitors, ARBs, dihydropyridine calcium channel blockers) or digoxin may be reasonable (COR 2b).^[28] High-dose diuretics can be considered relatively contraindicated in symptomatic obstructive HCM.^[1]
• New or poorly controlled AF can exacerbate LVOTO symptoms and should be managed by prompt restoration of sinus rhythm or rate control (ESC). Doing so should be considered before invasive management of LVOTO (Class IIa).^[2]

Stepwise drug therapy

^{[2] [1] [28] [6] [8] [9]}

AHA/ACC regards calcium channel blockers combined with beta-blockers, as HCM-directed therapy, as unsupported by evidence.^[1] AHA/ACC notes that in some patients verapamil and diltiazem have been reported to have a more prominent vasodilatory action; this afterload-reducing effect can be particularly dangerous with very high resting gradients (above 80–100 mm Hg) and signs of congestive heart failure.^[1] Several reports describe life-threatening bradycardia and hypotension in newborns under 6 weeks given intravenous verapamil for supraventricular tachycardia.^[1] AHA/ACC rates verapamil potentially harmful in obstructive HCM with severe dyspnoea at rest, hypotension or very high resting gradients (eg, above 100 mm Hg), and in all children under 6 weeks (COR 3: Harm).^[1][28]

Disopyramide safety. Dose-limiting anticholinergic effects include dry eyes and mouth, urinary hesitancy or retention, and constipation.^[2] Avoid it in glaucoma, in men with prostatism, and with other QT-prolonging drugs such as amiodarone and sotalol.^[2]

Cardiac myosin inhibitors

Mavacamten inhibits cardiac myosin ATPase. It reduces actin–myosin cross-bridge formation, lowering contractility and improving myocardial energetics.^[2] AHA/ACC describes the class as decreasing contractility and so reducing LVOT obstruction.^[1]

How each guideline places it:^[2][1]

• ESC 2023. Without a head-to-head comparison, the Task Force did not recommend myosin inhibitors first line. In adults with resting or provoked LVOTO, mavacamten titrated to the maximum tolerated dose with echocardiographic surveillance of LVEF should be considered in addition to a beta-blocker, or to verapamil or diltiazem if a beta-blocker is not possible, to improve symptoms (Class IIa).^[2] In the absence of evidence to the contrary, ESC advises that it should not be used with disopyramide; adding disopyramide is the Class I alternative at the same step (Figure 14).^[2] In symptomatic adults with resting or provoked LVOTO (exercise or Valsalva) who are intolerant of, or have contraindications to, beta-blockers, verapamil/diltiazem or disopyramide, mavacamten monotherapy titrated to the maximum tolerated dose with echocardiographic surveillance of LVEF should be considered (Class IIa).^[2]
• AHA/ACC 2024. For persistent symptoms from LVOTO that interfere with everyday activity or quality of life despite a beta-blocker or non-dihydropyridine calcium channel blocker, adding a myosin inhibitor (adults only), disopyramide (with an AV nodal blocker) or SRT at an experienced centre is recommended (COR 1).^[1][28]
• LVEF rule (AHA/ACC). If persistent systolic dysfunction develops (LVEF below 50%), myosin inhibitors should be discontinued (COR 1).^[1][28] Interrupt, then resume at a lower dose if LVEF improves, or stop if it does not return above 50%, regardless of symptoms.^[1]

Trial evidence on cardiac myosin inhibitors:

• EXPLORER-HCM (Lancet 2020). Patients with an LVOT gradient of 50 mm Hg or more and NYHA II–III symptoms received mavacamten (starting at 5 mg) or placebo for 30 weeks. Over the 30-week treatment period, the primary composite pVO2-plus-NYHA endpoint was met by 37% on mavacamten versus 17% on placebo, and post-exercise gradient fell 36 mm Hg more than with placebo.^[5] Safety and tolerability were similar to placebo.^[5]
• VALOR-HCM (JACC 2022). In patients meeting guideline criteria for SRT, 17.9% on mavacamten versus 76.8% on placebo met guideline criteria or underwent SRT at 16 weeks.^[6]
• Long-term extension (MAVA-LTE, EHJ 2024). In this open-label extension of EXPLORER-HCM (231 patients enrolled; 99 had reached week 180), mean LVEF fell from 73.9% at baseline to 63.9% at week 180. Over 739 patient-years of exposure, 20 of the 231 (8.7%) had transient LVEF falls below 50% that led to temporary interruption.^[7]
• SEQUOIA-HCM (NEJM 2024). In adults with symptomatic obstructive HCM, aficamten (starting 5 mg, maximum 20 mg, dose adjusted by echocardiography) raised peak oxygen uptake by 1.7 ml/kg/min more than placebo at 24 weeks. All 10 secondary end points (assessed at week 12 or 24) were significantly improved with aficamten compared with placebo.^[8]
• MAPLE-HCM (NEJM 2025). In adults with symptomatic obstructive HCM, aficamten monotherapy (5–20 mg daily) was superior to metoprolol monotherapy (50–200 mg daily) on change in peak oxygen uptake at 24 weeks, with a 2.3 ml/kg/min difference, and improved symptoms and haemodynamics.^[9]
• ODYSSEY-HCM (NEJM 2025). In nonobstructive HCM, mavacamten did not improve peak oxygen uptake (P = 0.07) or symptoms significantly more than placebo at 48 weeks.^[10]

AHA/ACC 2024 noted that a US risk evaluation and mitigation strategy was required because of the observed decrease in LVEF below 50% in 5.7% of patients attributable solely to the drug.^[1] Mavacamten is contraindicated in pregnancy (COR 3: Harm).^[1][28]

Septal reduction therapy

Who qualifies. ESC 2023 recommends that SRT be performed by experienced operators in a multidisciplinary HCM team (Class I). It recommends SRT to improve symptoms for a resting or maximum provoked gradient of 50 mm Hg or more in NYHA/Ross class III–IV despite maximum tolerated medical therapy (Class I).^[2] SRT should be considered for recurrent exertional syncope caused by a resting or maximum provoked gradient of 50 mm Hg or more despite optimal medical therapy (Class IIa).^[2] It may be considered in NYHA II refractory to medical therapy (Class IIb), with a resting or maximum provoked gradient of 50 mm Hg or more plus moderate-to-severe SAM-related MR, AF or moderate-to-severe left atrial dilatation, at expert centres with low complication rates.^[2] No data support SRT in asymptomatic patients, whatever the gradient.^[2]

In obstructive HCM, AHA/ACC 2024 recommends SRT to relieve LVOTO in eligible patients who remain symptomatic despite guideline-directed medical therapy, performed at experienced HCM centres (COR 1).^[28] For symptomatic patients with obstructive HCM, SRT in eligible patients at experienced centres may be considered as an alternative to escalating medical therapy after shared decision-making (COR 2b).^[28] AHA/ACC 2024 judged the evidence then available insufficient to recommend SRT purely to improve survival.^[1] If either procedure is unavailable at the patient's primary cardiology practice, AHA/ACC encourages referral to more comprehensive HCM centres because the literature shows a volume-outcome relationship.^[1]

^{[2] [1]}

• Head to head. No randomised trial compares the two. Meta-analyses show that both improve functional status, with similar procedural mortality. ESC adds that ablation carries a higher risk of AV block requiring a permanent pacemaker, and larger residual LVOT gradients.^[2] Repeat procedures follow ablation in 7–20%.^[2] AHA/ACC notes lower survival at 10 years after ablation than after myectomy.^[1]
• Myectomy outcomes. In a series of 289 myectomy patients, procedural mortality was 0.8% and 10-year survival 83%, matching the age- and sex-matched population. Myectomy was independently associated with survival (HR 0.43).^[11]
• Ablation outcomes. In Euro-ASA (1275 highly symptomatic patients, median follow-up 5.7 years), 30-day mortality was 1% and survival 98%, 89% and 77% at 1, 5 and 10 years.^[12]
• Long-term meta-analysis. Across 16 myectomy cohorts (mean follow-up 7.4 years) and 11 ablation cohorts (mean follow-up 6.2 years), all with at least 3 years of follow-up, mortality was similarly low after ablation (1.5% per year) and myectomy (1.4% per year). Pacemakers followed 10% of ablations versus 4.4% of myectomies, and reintervention 7.7% versus 1.6%.^[26]
• Larger meta-analysis. In 27 observational studies (15 968 patients), overall mortality was similar. Higher mortality after ablation with follow-up of 5 years or more came from a subgroup analysis and is hypothesis-generating only.^[27]
• SHaRe after SRT. Of 1832 patients (75% myectomy) at 13 high-volume HCM centres, 30-day mortality was 0.4%, and 1499 of 1565 (92%) had a maximal LVOT gradient below 50 mm Hg at 1 year. De novo AF occurred after SRT in 387 patients (21%). After 6.8 years of follow-up (range 3.4–9.8; 12,565 person-years) from SRT, HCM-related death had occurred in 4% (0.6% per year), and the authors conclude that event-free survival at 10 years was 83%.^[24]
• Mitral surgery. Mitral valve replacement, with or without myectomy, raises hospital mortality more than ten-fold compared with isolated septal myectomy (AHA/ACC).^[1]
• Children. Alcohol ablation should not be used in children outside experimental settings.^[2]

^[1]

Nonobstructive HCM and systolic dysfunction

For heart failure without LVOTO, ESC 2023 says the aim of drug therapy is to lower LV diastolic pressure and improve filling by slowing the heart rate with beta-blockers, verapamil or diltiazem (ideally monitored by ambulatory ECG recording), with cautious use of loop diuretics.^[2] For exertional angina or dyspnoea in nonobstructive HCM with preserved EF, AHA/ACC recommends beta-blockers or non-dihydropyridine calcium channel blockers (COR 1).^[28] Its supportive text makes beta-blockers the primary therapy in neonates and children.^[1] The overall risk of HCM-related death appears similar with and without obstruction.^[1]

• Angina-like chest pain. Beta-blockers and calcium antagonists (verapamil or diltiazem) should be considered even without LVOTO or obstructive CAD (ESC Class IIa). Oral nitrates may be considered if there is no LVOTO (ESC Class IIb).^[2]
• Valsartan. For younger patients (eg, 45 years or under) with nonobstructive HCM due to a pathogenic or likely pathogenic sarcomere variant and a mild phenotype (NYHA I–II, maximal LV wall thickness 13–25 mm, no secondary-prevention ICD, no appropriate ICD shocks and no AF), valsartan may slow adverse remodelling (AHA/ACC COR 2b).^[1][28] In a 12-month placebo-controlled trial of 124 patients with nonobstructive and obstructive HCM, losartan showed no benefit over placebo on LV mass, fibrosis or functional class.^[1]
• Myosin inhibitors. In ODYSSEY-HCM, mavacamten did not improve peak oxygen uptake or symptoms in nonobstructive disease significantly more than placebo.^[10]
• Very small cavities. Extensive apical hypertrophy extending to the midventricle may severely reduce LV end-diastolic volume. Transapical myectomy has been safe and reduced symptoms in this group, though only single-centre experience is published. AHA/ACC says it may be an option for this rare subgroup of severely symptomatic patients with nonobstructive HCM and a small LV cavity refractory to routine therapy, limited to centres of excellence with the highest volumes and expertise.^[1]

When LVEF falls below 50%. AHA/ACC considers an EF below 50% significantly reduced systolic function because it is associated with worse outcomes.^[1] Reduced EF is uncommon (about 5%) and should prompt a search for other causes.^[1] For LVEF below 50%, AHA/ACC recommends guideline-directed therapy for HF with reduced EF (COR 1). The 2026 ESC heart failure guideline also advises that patients with HCM who develop HFrEF should in general be treated as other patients with HFrEF.^[28][3] With LVEF below 50%, it is reasonable to discontinue previously indicated verapamil, diltiazem or disopyramide (AHA/ACC COR 2a).^[28] With persistent LVEF below 50%, ICD placement can be beneficial (AHA/ACC COR 2a).^[28]

Advanced heart failure. It develops in 3–8% of patients. Between 20% and 50% of those have preserved EF with restrictive physiology, so transplant referral does not require a reduced EF.^[1]

Atrial fibrillation

AF is common in HCM and badly tolerated. In a community cohort of 480 consecutive patients, AF occurred in 107 (22%) over a mean follow-up of 9.1 years (incidence 2% per year) and carried a stroke odds ratio of 17.7.^[13] A meta-analysis of 33 studies (7381 patients) found an overall thromboembolism prevalence of 27.09% in HCM with AF.^[1]

• Rhythm first. Because AF is poorly tolerated, rhythm control is often preferred.^[1]
• Rate control. AHA/ACC prefers a non-dihydropyridine calcium channel blocker, a beta-blocker or both. AHA/ACC advises avoiding verapamil in patients with hypotension, dyspnoea at rest and very high resting gradients (eg, above 100 mm Hg), and rates verapamil potentially harmful in obstructive HCM with severe dyspnoea at rest, hypotension or very high resting gradients (eg, above 100 mm Hg), and in all children under 6 weeks of age (COR 3: Harm). AHA/ACC notes a theoretical concern that digoxin could exacerbate LVOTO through its positive inotropic effect; without a gradient, digoxin is a potential option, although efficacy data are lacking.^[1][28]
• Antiarrhythmics. Amiodarone is generally a favoured option. AHA/ACC does not generally recommend flecainide or propafenone without an ICD.^[1]
• Ablation. Catheter ablation results seem less favourable than in AF without HCM, with a 2-fold higher relapse risk, more repeat procedures and higher use of concomitant antiarrhythmic drugs.^[1] In cardiomyopathy registries (mainly HCM), ESC 2023 reports maintenance of sinus rhythm after catheter ablation in up to two-thirds, although repeat procedures or continued antiarrhythmic drugs are often necessary.^[2] Surgical AF ablation can be added at myectomy.^[1]

Ventricular arrhythmias

ESC 2023 finds no randomised data supporting antiarrhythmic drugs to prevent SCD in HCM.^[2] In ICD patients who continue to have symptomatic ventricular arrhythmias, paroxysmal AF or recurrent shocks despite optimal treatment and device reprogramming, ESC recommends beta-blockers and/or amiodarone.^[2] No drug trial has targeted ICD shocks in HCM, so AHA/ACC extrapolates from other populations.^[1] In OPTIC, a trial of 412 patients with documented ventricular arrhythmias (not specific to HCM), shocks at 1 year occurred in 38.5% on a beta-blocker alone and 10.3% on amiodarone plus a beta-blocker.^[1] Among 71 patients with HCM and ICDs who received appropriate therapies, antitachycardia pacing, when available, succeeded in 74% of episodes.^[1] AHA/ACC cites ablation reports of 9 to 22 patients, with findings confirmed by a recent meta-analysis of 6 studies. It concludes that in selected patients combined epicardial and endocardial ablation appears to be a reasonably safe and effective option for monomorphic VT refractory to antiarrhythmic drugs and optimal ICD programming.^[1]

Special situations

Mid-cavity obstruction and apical aneurysm. Mid-cavity obstruction affects about 10% of patients. ESC treats it with high-dose beta-blockers, verapamil or diltiazem, but response is often suboptimal.^[2] ESC defines an apical aneurysm as a discrete thin-walled dyskinetic or akinetic distal LV segment, often with a mid-cavity gradient.^[2] Thrombus within an aneurysm should be treated with long-term oral anticoagulation.^[2]

Pregnancy. Most women with HCM tolerate pregnancy well, with complications concentrated in women who had symptoms, arrhythmias or impaired LV function beforehand.^[2][1]

• Symptoms or complications occur in about 25% of pregnant women with HCM, mostly in those symptomatic before pregnancy.^[1]
• Anticoagulate AF with LMWH or a VKA according to pregnancy stage (ESC). AHA/ACC notes insufficient DOAC safety data.^[2][1]
• Most beta-blockers are generally considered safe in pregnancy; atenolol has some evidence of potential fetal risk.^[1]
• Mode of delivery: ESC recommends vaginal delivery for most women (Class I), unless there are obstetric indications for caesarean section, severe heart failure (EF below 30% or NYHA III–IV), severe outflow tract obstruction, or labour while on oral anticoagulants.^[2] AHA/ACC recommends vaginal delivery as the first choice in most pregnant women with HCM (COR 1).^[28]
• Anaesthesia: avoid hypotension (AHA/ACC). ESC advises applying epidural and spinal anaesthesia cautiously, especially with severe LVOTO, and avoiding single-shot spinal anaesthesia.^[1][2]
• Mavacamten is contraindicated in pregnancy (AHA/ACC COR 3: Harm).^[1][28]

Exercise and sport. Regular low- to moderate-intensity exercise is recommended in all able individuals with cardiomyopathy (ESC Class I).^[2] Mild- to moderate-intensity recreational exercise is beneficial (AHA/ACC COR 1).^[28] In a randomised trial in adults with HCM, 4 months of moderate-intensity exercise improved peak oxygen consumption compared with usual activity.^[1] AHA/ACC grades intensity as light (under 3 METs), moderate (3 to 6 METs) and vigorous (over 6 METs).^[1]

^{[1] [28] [2]}

ICD decisions follow the risk algorithm, independent of sports participation (AHA/ACC).^[1] Avoid dehydration and extreme environmental conditions such as heat or humidity, particularly with obstruction.^[1]

Family screening. ESC 2023 says all first-degree relatives should be offered ECG and cardiac imaging. ESC recommends that cascade genetic testing, with pre- and post-test counselling, is offered to adult at-risk relatives once a pathogenic or likely pathogenic (P/LP) variant is established in the family (Class I). In at-risk children it should be considered (Class IIa), considering the underlying cardiomyopathy, expected age of onset, presentation in the family and clinical or legal consequences.^[2] First-degree relatives without a phenotype who do not carry the familial variant are discharged from follow-up, with advice to seek re-assessment if symptoms develop or new clinically relevant family data emerge (Class I).^[2] Where testing was not done or found no actionable variant, relatives still need regular clinical screening (AHA/ACC).^[1]

^[1]

AHA/ACC adds that the screening interval may be modified, for example at onset of new symptoms or in families with a malignant clinical course or late-onset HCM.^[1] In 2 large paediatric studies, echocardiographic screening of first-degree relatives found clinical HCM in 10% to 15% throughout childhood and adolescence.^[1]

Genotype-positive, phenotype-negative. These carriers are at risk of developing HCM but do not yet have it.^[1] Large studies suggest that clinical HCM can develop in younger family members: 5% to 10% were phenotype-positive at first screening and another 3% to 5% before 18 years of age.^[1] They are not offered primary prevention ICDs or preemptive drugs.^[1] Although systematic evidence is lacking, most physicians continue clinical screening of these carriers until midlife (about 50 years of age).^[1]

Comorbidities. Hypertension affects about 35% to 50% of adults with HCM, and sleep-disordered breathing affects 55% to 70% of patients with HCM.^[1] In data cited by ESC, hypertension and obesity were associated with higher provocable LVOT gradients and LVH.^[2]

Prognosis

Most contemporary adult series report annual cardiovascular mortality of 1–2%, mainly from SCD, heart failure and thrombo-embolism.^[2] HCM can be compatible with normal life expectancy without limiting symptoms or major treatment in most patients, but many can experience significant consequences attributable to the disease.^[1] In SHaRe, patients aged 20–29 had 4-fold higher mortality than the US population of similar age.^[17] In children, recent population studies show SCD rates of about 1.2–1.5% per year, and SCD appears to be very rare under 6 years.^[2]

A pooled analysis of 98 studies (70,510 patients) found an overall HCM SCD rate of 0.43% per year, with more than 2-fold higher risk under 18 years than in adults aged 18–60 (1.09% vs 0.43% per year).^[23] Contemporary rates since 2015 were 0.32% per year, against 0.73% per year in 2000 or earlier.^[23]

Where ESC and AHA/ACC differ

^{[2] [1] [28]}

Australia and New Zealand

High-yield summary

• Diagnosis: unexplained wall thickness ≥15 mm in an adult (not explained solely by loading conditions, ESC; without another cause, AHA/ACC); ≥13 mm in an adult first-degree relative of a patient with unequivocal disease (ESC); children by z-score (above 2, ESC; AHA/ACC: above 2.5 may be appropriate in asymptomatic children without a family history, above 2 may suffice with a definitive family history or positive genetic test).^[2][1]
• Obstruction: ≥30 mm Hg defines LVOTO; ≥50 mm Hg is usually considered the threshold for invasive treatment (ESC); provocation with a resting gradient below 50 mm Hg (AHA/ACC COR 1) and Valsalva echo (sitting and semi-supine, then standing if no gradient is provoked) in all at initial evaluation (ESC Class I); no dobutamine.^[2][1]
• HCM Risk-SCD inputs: age, maximal wall thickness, LA diameter, LVOT gradient, family history of SCD, NSVT, unexplained syncope; ESC notes the models do not use exercise-induced gradients.^[4][2]
• ESC ICD thresholds (estimated 5-year SCD risk from HCM Risk-SCD at age 16 or more, or a validated paediatric model such as HCM Risk-Kids under 16; ESC says these models should not be used in elite athletes or in metabolic or infiltrative diseases and syndromes, and they have not been validated before and after myectomy): 6% or more, ICD should be considered after detailed clinical assessment (Class IIa); 4% to below 6%, may be considered in individual patients after detailed clinical assessment (Class IIb); below 4%, low risk, where extensive LGE (15% or more) or LVEF below 50% may be considered in shared decisions, acknowledging the lack of robust data (Class IIb).^[2]
• AHA/ACC adult major risk factors (with one or more, an ICD is reasonable, COR 2a) include sudden death judged definitively or likely due to HCM in a first-degree or close relative aged 50 or under, massive LVH of 30 mm or more, recent syncope suspected to be arrhythmic, apical aneurysm with transmural scar or LGE, EF below 50%. In select adults without a major factor after clinical assessment (or when the ICD decision remains otherwise uncertain), extensive LGE on CMR or NSVT on ambulatory monitoring: ICD may be considered (COR 2b).^[28]
• Drugs for symptomatic LVOTO: non-vasodilating beta-blocker first, titrated to maximum tolerated dose (ESC Class I) or to effectiveness or maximally tolerated doses (AHA/ACC COR 1). Verapamil or diltiazem: titrated to maximum tolerated dose if beta-blockers are not tolerated or contraindicated (ESC Class I); substituted when beta-blockers are ineffective or not tolerated (AHA/ACC COR 1). Disopyramide titrated to maximum tolerated dose, usually 400–600 mg/day, with QTc monitoring during up-titration (reduce the dose if QTc exceeds 500 ms), added to a beta-blocker or, if that is not possible, to verapamil or diltiazem (ESC Class I), with an AV nodal blocker (AHA/ACC). Without a direct head-to-head comparison, the ESC Task Force could not recommend myosin inhibitors as first-line therapy, but said second-line use should be considered when optimal medical therapy with beta-blockers, calcium antagonists and/or disopyramide is ineffective or poorly tolerated. Its Class IIa row: in adults with resting or provoked LVOTO, mavacamten titrated to the maximum tolerated dose with echocardiographic LVEF surveillance should be considered in addition to a beta-blocker (or, if that is not possible, with verapamil or diltiazem) to improve symptoms. The VALOR-HCM regimen was 5 mg daily, titrated up to 15 mg based on LVOT gradient and LVEF; ESC caps up-titration at 15 mg, monitored with echocardiography in accordance with licensed recommendations. AHA/ACC text says that at LVEF below 50%, myosin inhibitors must be interrupted regardless of symptoms and resumed at a lower dose if LVEF improves; its COR 1 row says to discontinue them for persistent systolic dysfunction (LVEF below 50%).^{[2][1][28][6]}
• SRT: ESC recommends it, by experienced operators in a multidisciplinary HCM team, for a resting or maximum provoked gradient ≥50 mm Hg in NYHA/Ross III–IV despite maximum tolerated medical therapy (Class I) and says it should be considered for recurrent exertional syncope caused by a resting or maximum provoked gradient ≥50 mm Hg despite optimal medical therapy (Class IIa); AHA/ACC recommends SRT to relieve LVOTO in eligible patients with obstructive HCM who remain symptomatic despite GDMT, at experienced HCM centres (COR 1). Eligibility means severe dyspnoea or chest pain (usually NYHA III or IV), or occasionally other exertional symptoms (eg, syncope, near syncope), attributable to LVOTO and interfering with everyday activity or quality of life despite optimal medical therapy; a dynamic LVOT gradient at rest or with physiologic provocation with an approximate peak gradient of 50 mm Hg or more, with septal hypertrophy and SAM; and anterior septal thickness sufficient for a safe, effective procedure in the operator's judgment.^[2][28]
• AF: oral anticoagulation recommended in all patients with AF or atrial flutter unless contraindicated (ESC 2023 Class I); for clinical AF, a DOAC first line and a vitamin K antagonist second line, independent of CHA2DS2-VASc (AHA/ACC 2024 COR 1).^[2][28]
• Family: ECG and imaging for all first-degree relatives; cascade genetic testing with counselling once a P/LP variant is established (ESC Class I for adult relatives; IIa for at-risk children, considering the underlying cardiomyopathy, expected age of onset, presentation in the family and clinical or legal consequences).^[2]

References30ShowHide

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