Hypertrophic cardiomyopathy

Article written and reviewed by Dr Luca Moretti

Hypertrophic cardiomyopathy, internationally referred to by the acronym HCM, is defined by increased left ventricular wall thickness, with possible right ventricular involvement, that is not explained solely by loading conditions capable of producing it. The definition describes a phenotype and includes both the inherited sarcomeric form and non-sarcomeric diseases that must be recognized because of their different prognosis and treatment. Diagnosis therefore does not consist of measuring an isolated wall, but of demonstrating that geometry, function, tissue, electrocardiogram and clinical history form a coherent picture. Hypertension and aortic stenosis may coexist with HCM and must be assessed in terms of proportionality, not used as automatic exclusions.

In adults, a maximum wall thickness of at least 15 mm supports the diagnosis in one or more segments, whereas values of 13 or 14 mm may be sufficient in the presence of a causal variant, an affected relative or other strongly suggestive findings. In children, growth makes an absolute threshold inappropriate and requires measurements normalized for body surface area and age. Echocardiographic alignment errors, inclusion of papillary muscles and poorly visualized segments can alter the measurement by several millimeters; magnetic resonance clarifies apical or focal distributions and provides a more complete tissue assessment. The threshold is therefore an operational criterion embedded in clinical reasoning, not an abrupt biological boundary.

HCM affects approximately 0.2% of adults when the phenotype is sought by imaging, equivalent to about one person in five hundred. The frequency of potentially associated genetic variants is higher, but incomplete penetrance and variant classification prevent every molecular finding from being equated with disease. In childhood the condition is much rarer: the ESC correction published in August 2026 revised the incidence to 0.0002-0.0005% and the prevalence to 0.0029%. Differences among studies reflect populations, screening methods, age and inclusion or exclusion of non-sarcomeric causes.

Clinical expression ranges from the carrier without hypertrophy to the patient with severe obstruction, atrial fibrillation, heart failure or ventricular arrhythmias. Many people remain asymptomatic and have a favorable life expectancy when diagnosis, follow-up and treatment are appropriate; older cohorts selected in referral centers overestimated average risk. This does not reduce the importance of identifying vulnerable subgroups, because sudden death may occur before advanced symptoms and hemodynamic progression may gradually impair functional capacity. Assessment must separate arrhythmic risk, heart-failure risk and symptom burden, which do not necessarily progress together.

The monograph on hypertrophic cardiomyopathy systematically addresses etiology, pathology, clinical features, diagnosis and treatment. This page instead introduces the structure of the spectrum and the relationships among its main presentations, because the HCM label alone does not convey the site of hypertrophy, presence of obstruction, systolic function or cause. A complete description must report these elements and update them over time. A patient may move from a non-obstructive form to provocable obstruction or develop a systolic phase without any change in the underlying disease.

Morphologic and hemodynamic spectrum

The most common distribution is asymmetric septal hypertrophy, but involvement may be concentric, apical, midventricular, focal or extend to the right ventricle. Geometry is not a descriptive curiosity: it determines the possibility of obstruction, imaging quality, aneurysm risk and procedural options. Echocardiography may underestimate the apex or a poorly accessible anterolateral wall, whereas magnetic resonance identifies focal segments and measures volumes without geometric assumptions. The same person may show different distributions during growth and remodeling.

Obstructive hypertrophic cardiomyopathy has a dynamic outflow tract gradient, at rest or after provocation, often produced by contact between the anterior mitral leaflet and the septum. Obstruction depends on geometry, contractility, preload, afterload and heart rate and can therefore vary between visits and activities. A maximum gradient of at least 30 mmHg defines obstruction, whereas 50 mmHg becomes relevant when symptoms and response to therapy make septal reduction a possible option. Associated mitral regurgitation must be distinguished from primary leaflet disease because this difference changes the surgical strategy.

The non-obstructive form does not have a significant gradient at rest or with adequate provocation, but this does not make it physiologically normal. Impaired relaxation, stiffness, microvascular ischemia, chronotropic incompetence and increased pressures may limit exercise and cause heart failure with preserved ejection fraction. Treatment cannot simply be copied from the obstructive form because reducing contractility does not resolve an absent gradient and excessive diuresis may reduce output from a small cavity. Cardiopulmonary exercise testing and, in selected cases, exercise hemodynamics help clarify symptoms unexplained by resting data.

In apical hypertrophic cardiomyopathy, hypertrophy predominates at the apex and may produce a spade-shaped cavity, systolic obliteration and deep negative T waves. Average prognosis is often favorable, but not uniform: ischemia, scar, atrial fibrillation and apical aneurysm identify higher-risk subgroups. Non-contrast echocardiography may misrepresent or fail to visualize the apex, making magnetic resonance particularly useful. An aneurysm is not merely a geometric variant, because it promotes ventricular tachycardia and thrombosis.

The midventricular form produces an intracavitary narrowing that separates a basal chamber from a high-pressure apical chamber. Persistence of the gradient, ischemia and wall stress may contribute to aneurysm formation, sometimes not evident on echocardiography. This mechanism is distinct from subaortic obstruction and requires accurate anatomic mapping before procedures are considered. Detection of late flow between the chambers and characterization of the apex complete the Doppler assessment.

A minority progresses to the systolic phase, defined by an ejection fraction below 50% in the setting of HCM. Wall thinning, dilation, increasing scar, mitral regurgitation and worsening arrhythmias may appear, but the cavity does not necessarily become very large. The term “dilated phase” is widely used clinically but should not erase the hypertrophic and sarcomeric origin. This phase requires heart-failure therapy, reassessment of negative inotropic drugs and timely referral for advanced therapies when progression continues.

Genetics, histopathology and pathophysiology

Sarcomeric HCM is most often autosomal dominant and results from variants in genes encoding contractile proteins, with MYBPC3 and MYH7 accounting for most genetically resolved cases. MYBPC3 variants are frequently truncating and cause haploinsufficiency, whereas many MYH7 variants alter the protein. Other sarcomeric genes with robust associations account for smaller proportions. Panels that include genes with weak evidence increase variants of uncertain significance without necessarily improving diagnosis.

Transmission of an autosomal dominant variant often entails a 50% probability in each pregnancy, but it does not predict age at onset or severity. Penetrance and expressivity depend on age, sex, blood pressure, body composition, physical activity and genetic background. Within the same family, carriers without hypertrophy, mildly symptomatic adults and individuals with severe disease may coexist. Genetic testing therefore has great value for identifying who inherited the substrate, but limited value for predicting the individual course.

The sarcomeric cardiomyocyte uses energy less efficiently and alters calcium and force regulation, activating growth signals. Cellular hypertrophy is not uniformly distributed and is accompanied by myocyte disarray, interstitial and replacement fibrosis and remodeling of intramural arterioles. These abnormalities explain why a thick wall is only the visible component of a broader disease. Diastolic function, perfusion and electrical stability may be impaired before global systolic function declines.

Ischemia results from the increased demand of a larger myocardial mass, reduced capillary density, arteriolar narrowing and compression during systole and diastole. Obstruction further reduces perfusion pressure and increases stress, while tachycardia and high filling pressures shorten the available time. Repeated episodes may contribute to cell death and fibrosis, creating a link between symptoms, progression and arrhythmic risk. Epicardial coronary artery disease may coexist and should be investigated according to clinical probability.

Diastolic dysfunction includes slowed relaxation, increased stiffness and reduced capacity of the cavity to accommodate volume without a large rise in pressure. The left atrium initially compensates with a more important contraction, but chronic exposure to high pressures causes dilation and fibrosis. Atrial fibrillation removes this contribution and accelerates the heart rate, explaining sudden deterioration in patients who had previously been compensated. Diastolic function cannot be summarized by a single Doppler parameter and must be interpreted in the HCM context.

The main alternative diagnoses include hypertension and aortic stenosis, athlete’s heart, amyloidosis, Fabry, Danon, Pompe, PRKAG2 and mitochondrial diseases. Age, hypertrophy pattern, voltages, conduction, pre-excitation, native T1, LGE and extracardiac findings guide the distinction. The term HCM may describe the phenotype, but the specific cause must be reported when identified because it changes treatment and family management. Calling a disease sarcomeric solely because standard genetic testing is negative is an error: a proportion of clinical HCM remains genetically unresolved.

Clinical manifestations and investigations

Dyspnea is the most frequent symptom and may result from diastolic dysfunction, obstruction, mitral regurgitation, ischemia, chronotropic incompetence or atrial fibrillation. The patient may adapt by gradually reducing activity, making it necessary to quantify concrete performance rather than rely only on subjective perception. Chest pain, fatigue and palpitations complete the picture, whereas syncope and presyncope require detailed reconstruction of the context. No symptom alone identifies the mechanism and therapy must follow the dominant cause of limitation.

Physical examination may be normal in the non-obstructive form. When obstruction is present, the systolic murmur increases with maneuvers that reduce preload, such as standing and Valsalva, and decreases with increased venous return or afterload; these signs do not replace Doppler measurement. The pulse may be bifid and a fourth heart sound reflects atrial contraction against a stiff ventricle. Congestion, hypotension and signs of low output identify advanced disease and require urgent assessment of the mechanism.

The electrocardiogram is abnormal in most patients and may show criteria for hypertrophy, narrow deep Q waves, repolarization abnormalities, giant T-wave inversions in apical forms, atrial enlargement or conduction disturbances. The pattern is not specific and electrical severity does not necessarily track wall thickness in millimeters. A markedly abnormal ECG with an apparently normal echocardiogram may indicate an unvisualized location or an early phase. Pre-excitation and major conduction blocks should prompt consideration of non-sarcomeric diagnoses.

Echocardiography defines distribution and maximum wall thickness, function, atrial size, mitral apparatus and gradients. If the resting gradient is below 50 mmHg, Valsalva, standing and exercise are used according to symptoms and context to search for provocable obstruction. Dobutamine does not reproduce everyday physiology and is not the standard modality for this purpose. Exercise echocardiography links symptoms, blood pressure, regurgitation and gradient and may explain limitation that is absent at rest.

Magnetic resonance is indicated when echocardiography is incomplete, the diagnosis is uncertain, an apical form or aneurysm is suspected and when tissue characterization contributes to prognosis. LGE documents replacement fibrosis and its extent, particularly when approximately 15% or more of ventricular mass, may modify the ICD discussion in the appropriate context. T1 and extracellular volume provide information on diffuse fibrosis and help differential diagnosis. Quantification must use validated acquisitions and should not be treated as an autonomous threshold disconnected from other risks.

ECG monitoring searches for nonsustained ventricular tachycardia and atrial fibrillation, with duration tailored to symptoms and risk. Frequency, duration and rate of NSVT episodes modify their weight, especially in younger patients, whereas subclinical atrial fibrillation requires a decision based on duration and context. Exercise testing assesses capacity, blood-pressure response and arrhythmias; cardiopulmonary testing quantifies limitation and may contribute to assessment of advanced heart failure. For rare symptoms, a loop recorder may provide a correlation that short-term monitors cannot obtain.

Genetic diagnosis begins with the patient who has a defined phenotype and must be accompanied by counseling. A pathogenic or likely pathogenic variant enables cascade testing, whereas a VUS must not be used for predictive decisions in relatives. A negative result does not exclude HCM, because genes and mechanisms are not completely resolved and a proportion may have a complex architecture. Relatives remain subject to clinical assessment when the molecular cause is not identified.

Treatment, arrhythmic risk and procedures

An asymptomatic patient without major risk factors does not require treatment aimed at reducing wall thickness as such, but rather surveillance, control of cardiovascular factors and individualized exercise prescription. Dehydration, fever, vasodilation and tachycardia may worsen obstruction, whereas generic restrictions on fluids or exercise may be harmful. Symptoms must be attributed to obstruction, congestion, ischemia, arrhythmia or comorbidity before treatment is chosen. This approach avoids pharmacologic escalation based on findings rather than mechanisms.

In symptomatic obstructive disease, nonvasodilating beta-blockers often represent first-line therapy; verapamil or diltiazem may be used when appropriate, with caution in hypotension and very severe obstruction. Disopyramide adds a negative inotropic effect but requires monitoring of the QT interval and anticholinergic effects. Mavacamten inhibits cardiac myosin and reduces gradient and symptoms in eligible patients, requiring echocardiographic monitoring of ejection fraction and attention to interactions. Response should be measured in terms of symptoms, function and safety, not the gradient alone.

Septal reduction is considered when limiting symptoms attributable to obstruction persist with a maximum gradient of at least 50 mmHg despite adequate therapy or when therapy is not tolerated. Myectomy provides direct correction of the septum and allows associated mitral or subvalvular abnormalities to be treated; alcohol ablation produces a controlled septal infarction and requires favorable coronary anatomy. Age, comorbidities, wall thickness, mitral apparatus, risk of block and local expertise guide the choice. The best results depend on high-volume centers and multidisciplinary assessment.

In the non-obstructive form, therapy controls heart rate, ischemia, congestion and comorbidities, but specific options are more limited. Low-dose diuretics may reduce pressures and symptoms while avoiding excessive reduction in filling. If ejection fraction falls below 50%, therapy for systolic heart failure is applied and drugs with marked negative inotropic effects are reassessed. Severe unexplained limitation requires cardiopulmonary exercise testing and transplant evaluation before organ damage develops.

Atrial fibrillation is treated promptly because the stiff ventricle poorly tolerates loss of atrial contraction and tachycardia. Rhythm control, cardioversion, drugs and ablation are selected according to duration, symptoms and atrial remodeling, recognizing a higher recurrence risk than in the general population. Anticoagulation for clinical atrial fibrillation is recommended regardless of CHA2DS2-VASc, unless contraindicated, and direct oral anticoagulants are generally preferred in eligible patients. Monitoring searches for silent episodes when atrial features and the clinical profile make risk plausible.

Prevention of sudden death clearly distinguishes secondary from primary prevention. Cardiac arrest or nonreversible sustained ventricular tachycardia are strong indications for an ICD; in primary prevention, family history, suspicious syncope, maximum wall thickness of at least 30 mm, apical aneurysm, ejection fraction below 50%, NSVT and extensive LGE are integrated. The ESC HCM Risk-SCD model estimates five-year risk in adults for whom it has been validated, whereas HCM Risk-Kids supports pediatric assessment. No score replaces judgment when the patient is outside the relevant population or has modifiers not included in the model.

Physical activity is no longer governed by a universal prohibition. Moderate-intensity recreational exercise is generally encouraged and controlled studies have shown functional benefits without a signal of harm, whereas competition requires shared decision-making based on phenotype, arrhythmias, symptoms, obstruction and preferences. Risk cannot be reduced to zero and changes as the disease evolves, making reassessment necessary. Imposed sedentary behavior without indication increases metabolic risk and worsens quality of life.

Complications, family, follow-up and prognosis

Chronic obstruction increases systolic and diastolic pressures, worsens mitral regurgitation and may cause progressive limitation. Its severity varies with loading conditions and does not perfectly match symptoms; a high gradient in an asymptomatic patient does not automatically mandate a procedure, whereas a provocable gradient may explain apparently disproportionate dyspnea. Follow-up assesses the appearance of symptoms, valvular changes and response to therapy. Correction of obstruction improves hemodynamics but does not eliminate the sarcomeric or arrhythmic substrate.

Atrial fibrillation is promoted by atrial pressure, dilation and fibrosis and may cause acute heart failure and thromboembolism. Risk rises with age and disease duration, but episodes may also occur in young people without a massively enlarged atrium. Stroke can be prevented by timely diagnosis and anticoagulation, making it important to investigate palpitations and monitor selected patients. A rate-control-only strategy may be insufficient when loss of sinus rhythm causes substantial hemodynamic impairment.

Apical aneurysm occurs especially in apical or midventricular forms and concentrates three risks: ventricular arrhythmias, thrombosis and hemodynamic progression. Magnetic resonance and contrast echocardiography improve recognition when the apex is not visible. The presence of an aneurysm modifies ICD risk stratification, whereas the anticoagulation decision in the absence of thrombus or atrial fibrillation must be individualized because the evidence is less definitive. Size, wall motion and scar are followed over time.

The systolic phase with ejection fraction below 50% is associated with higher risk of heart failure, arrhythmias and death. Progression may be preceded by increasing fibrosis, reduced longitudinal function and dilation, but no intervention is capable of preventing it in every case. Heart-failure therapy is introduced early and transplant candidacy is assessed when symptoms and capacity worsen. Ventricular assist support may be technically difficult if the cavity remains small, making timely referral particularly important.

First-degree relatives should receive clinical screening with electrocardiography and echocardiography at intervals defined by age and context, or cascade testing when a causal variant is known. A relative who tests negative for the familial pathogenic variant can generally be released from surveillance related to that variant, whereas a carrier without a phenotype continues follow-up because penetrance is age dependent. In children, growth and puberty may rapidly modify the phenotype. Reproductive counseling explains transmission, prognostic uncertainty and available options without exerting pressure on the choice.

Follow-up includes symptoms, examination, ECG, echocardiography and periodic rhythm monitoring, with magnetic resonance and functional testing repeated according to findings and clinical questions. A normal check does not make the next one unnecessary, but frequency should be proportionate to avoid redundant testing. Development of syncope, persistent palpitations, worsening exercise tolerance, pregnancy or therapeutic changes requires earlier reassessment. Sudden-death risk stratification is repeated because age, wall thickness, function, arrhythmias and scar change.

Modern prognosis is more favorable than historical descriptions, especially in patients diagnosed before complications and followed in expert centers. Residual risk is not homogeneous, however: sarcomeric genotype, early age at onset, obstruction, atrial fibrillation, aneurysm, fibrosis and dysfunction identify different trajectories. Communication must separate the possibility of a long and active life from the need for surveillance, avoiding both alarmism and absolute reassurance. Quality of care derives from the ability to adapt arrhythmic prevention, symptom control and family management over time.