#cardiomyopathy #sudden-cardiac-death #genetics #multimodality-imaging #guideline

Hypertrophic Cardiomyopathy (HCM)

Contents. #Details · #Key Facts · #Genetics and Phenotypes · #Diagnosis and Risk Assessment · #Mechanism · #Management · #Contradictions / Open Questions · #Connections · #Sources

Detailed pages. concepts/HCM-Genetics-and-Phenotypes · concepts/HCM-Diagnosis-and-Risk · concepts/HCM-Mechanism · concepts/HCM-Management

Detail pages by spoke.

Genetics and phenotypes — entities/MYBPC3 (sub-hub, with concepts/Sarcomere-Biology and concepts/Haploinsufficiency beneath it), entities/MYH7, concepts/Fabry-Cardiomyopathy, entities/Anderson-Fabry-Disease, concepts/Danon-Disease
Diagnosis and risk — concepts/HCM-Risk-SCD, concepts/HCM-AI-ECG-Scar, concepts/Late-Gadolinium-Enhancement, concepts/ECG-Ventricular-Hypertrophy
Mechanism — concepts/HCM-Calcium-Homeostasis, concepts/HCM-Ion-Channel-Remodeling
Management — concepts/LVOTO, concepts/Septal-Reduction-Therapy, entities/Mavacamten, entities/Aficamten, concepts/HCM-Atrial-Myopathy, concepts/HCM-Exercise

Details

Hypertrophic cardiomyopathy is the most common inherited cardiomyopathy and the most common monogenic cardiac disorder, affecting roughly 1 in 500 adults. It is defined by increased left ventricular wall thickness unexplained by loading conditions, with a small LV cavity and a supranormal ejection fraction. Most patients are asymptomatic and have a normal lifespan; a minority develop symptomatic obstruction, atrial fibrillation, systolic heart failure or sudden cardiac death. (sources/HCM-NEJM-2025, rating: very high)

Definition

Hypertrophic cardiomyopathy is defined as hypertrophy of any LV segment not explained by abnormal loading conditions or infiltration. The LV cavity is small and the ejection fraction supranormal, usually 70–75%. Histology shows myocyte disarray, interstitial fibrosis and thick-walled intramural arteries. Its prevalence is about 0.2%, the highest of the inherited cardiomyopathies. (sources/HCM-NEJM-2025, rating: very high; sources/esc-cmp-2023, rating: very high)

The clinical course is heterogeneous, and annual cardiovascular mortality is 1–2%. Two structural facts organise the whole of management: whether there is a gradient, and whether the ventricle is hypercontractile or fibrotic — because those two questions determine whether therapy relieves obstruction or treats systolic failure. (sources/esc-cmp-2023; sources/HCM-NEJM-2025)

Abbreviations: AF, atrial fibrillation; CMR, cardiac magnetic resonance; ICD, implantable cardioverter-defibrillator; LGE, late gadolinium enhancement; LV, left ventricular; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; LVOTO, left ventricular outflow tract obstruction; MYBPC3, myosin-binding protein C3; MYH7, beta-myosin heavy chain; SCD, sudden cardiac death; SRT, septal reduction therapy.

Key Facts

Headline Facts

Obstruction is present in about 70% and is dynamic — it varies inversely with LV volume, worsening with upright posture, Valsalva, exercise and inotropes. (sources/HCM-NEJM-2025)
A sarcomeric variant is identified in 40–60% of patients, with MYBPC3 and MYH7 dominating; metabolic and syndromic phenocopies account for up to 25% of childhood cases. (sources/esc-cmp-2023, rating: very high)
Sudden cardiac death occurs at 0.5–1% per year, concentrated in the young; prophylactic ICDs have reduced disease-related mortality more than tenfold. (sources/HCM-VA-FCVMed-2022, rating: high)
About one third of overt disease is nonobstructive, and 5–10% eventually progress to a dilated, burned-out phenotype requiring transplantation or mechanical support. (sources/HCM-NEJM-2025)
Atrial fibrillation affects about one quarter of symptomatic patients, and anticoagulation is indicated regardless of CHA₂DS₂-VASc score. (sources/HCM-AHA-2024, rating: very high)
Therapy runs from beta-blockade through cardiac myosin inhibition to septal reduction, with the choice set by the gradient, the symptom class and the physiological stage. (sources/esc-cmp-2023; sources/HCM-AHA-2024)

Organising Principles

Diagnosis rests on phenotype, not genotype. A maximum wall thickness of ≥15 mm (≥13 mm in a first-degree relative), unexplained by loading conditions, establishes the diagnosis; CMR is recommended at baseline to detect apical and lateral hypertrophy, apical aneurysm and fibrosis. A negative genetic test does not exclude disease, and a positive one does not establish risk. (sources/esc-cmp-2023, rating: very high)
Genotype and phenotype dissociate in both directions. Up to 60% of patients have a causal sarcomeric variant, yet a polygenic score independent of rare variants also predicts case status and outcome; conversely, carriers can remain phenotype-negative for decades while showing electrical remodelling before hypertrophy appears. (sources/gwas-arrhythmias-cmp-genes-2025, rating: high; sources/membrane-potential-physrev-2021, rating: very high)
Risk is a continuous estimate, not a threshold. HCM Risk-SCD and HCM Risk-Kids produce five-year probabilities, and the two major guidelines disagree about how binding that number should be — a disagreement that changes which patients receive an ICD. (sources/esc-cmp-2023; sources/HCM-AHA-2024)
Obstruction is volume-dependent, and every drug rule follows from that. Preload-reducing and inotropic agents worsen the gradient; vasopressors and volume correct it. This governs anaesthesia, pregnancy, and the choice between medical and interventional therapy. (sources/periop-aha-2024, rating: very high)
Myosin inhibition works only where contractility is the problem. It relieves obstruction and improves exercise capacity in obstructive disease, but fails in nonobstructive disease, where symptoms arise from diastolic dysfunction, ischaemia and microvascular disease rather than excess contractility. (sources/aficamten-maplehcm-nejm-2025, rating: very high; sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)
Comorbidity is not incidental. Obesity, hypertension, diabetes and sleep apnoea are highly prevalent and worsen prognosis, making their treatment part of disease management rather than an adjunct to it. (sources/HCM-AHA-2024)

Genetics and Phenotypes

Full detail: concepts/HCM-Genetics-and-Phenotypes.

This spoke covers the sarcomeric and polygenic architecture, gene-disease curation, and the phenocopies that mimic HCM but demand different treatment. Its detail pages are entities/MYBPC3 — itself a sub-hub for the molecular biology of the commonest gene — entities/MYH7, and the three phenocopies whose management diverges most: concepts/Fabry-Cardiomyopathy, concepts/Danon-Disease and entities/Anderson-Fabry-Disease.

Definitive HCM genes are MYBPC3, MYH7, TNNI3, TNNC1, TPM1, FHOD3, CSRP3, ACTC1 and ALPK3; seven genes long reported as HCM genes are now disputed by ClinGen. (sources/clingen-summary-2026-05-09, rating: high)
Mitochondrial HCM is the commonest cardiomyopathy phenotype in mitochondrial disease — and is invisible to standard gene panels. (sources/mitochondrial-cv-aha-2025, rating: very high)
A polygenic score confers an odds ratio of 2.34 per standard deviation, independent of rare-variant status. (sources/gwas-arrhythmias-cmp-genes-2025)

Diagnosis and Risk Assessment

Full detail: concepts/HCM-Diagnosis-and-Risk.

This spoke covers the diagnostic criteria, CMR and ECG imaging, the invasive haemodynamic assessment of the gradient, the epidemiology of sudden death, and the competing frameworks for ICD selection. Its detail pages are concepts/HCM-Risk-SCD for calculator mechanics and validation, and concepts/HCM-AI-ECG-Scar for the emerging ECG-based scar model.

ESC 2022 grades an ICD at five-year risk ≥6% as Class I; ESC 2023 grades the same threshold Class IIa. (sources/VA-SCD-ESC-2022, rating: very high; sources/esc-cmp-2023)
Invasive assessment is required when non-invasive data are inconclusive, with provocation by Valsalva, post-extrasystolic potentiation and then isoproterenol. (sources/hemodynamics-circ-2012, rating: high)
In the Maron registry, 15.6% of patients with a risk marker and a primary-prevention ICD received device-terminated ventricular arrhythmia, against 0.3% sudden death among those without markers and without devices. (sources/HCM-NEJM-2025)

Mechanism

Full detail: concepts/HCM-Mechanism.

This spoke explains how a sarcomeric variant becomes hypertrophy, fibrosis and ventricular arrhythmia, and why the two phenotypes respond differently to therapy. Its detail pages are concepts/HCM-Calcium-Homeostasis and concepts/HCM-Ion-Channel-Remodeling for the cellular electrophysiology; the molecular layer beneath them runs through entities/MYBPC3 to concepts/Sarcomere-Biology and concepts/Haploinsufficiency.

Increased myofilament calcium sensitivity is the final common pathway; truncating MYBPC3 variants act by haploinsufficiency rather than a toxic product. (sources/HCM-NEJM-2025; sources/mybpc3-gene-2015, rating: medium)
Increased late sodium current is detectable in preclinical carriers before hypertrophy, so electrical remodelling precedes structural disease. (sources/membrane-potential-physrev-2021, rating: very high)
Nonobstructive symptoms arise from diastolic dysfunction, ischaemia and microvascular disease, which myosin inhibition does not correct. (sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)

Management

Full detail: concepts/HCM-Management.

This spoke covers the treatment of obstruction — the drug ladder, cardiac myosin inhibitors and septal reduction — and then the management of the nonobstructive phenotype, systolic heart failure, atrial fibrillation, pregnancy, exercise, the perioperative period and cardiometabolic comorbidity.

Aficamten added to background therapy improved peak oxygen consumption by 1.7 ml/kg/min and met all ten secondary endpoints in SEQUOIA-HCM. (sources/aficamten-sequoiahcm-nejm-2024, rating: very high)
Aficamten monotherapy outperformed metoprolol monotherapy on every objective endpoint in MAPLE-HCM, despite beta-blockade remaining Class I first-line. (sources/aficamten-maplehcm-nejm-2025)
Mavacamten failed on both primary endpoints in nonobstructive HCM while lowering NT-proBNP by 59%, and no approved pharmacotherapy exists for that phenotype. (sources/mavacamten-odysseyhcm-nejm-2025)
Anticoagulation for AF is mandatory irrespective of CHA₂DS₂-VASc, and mavacamten is absolutely contraindicated in pregnancy. (sources/HCM-AHA-2024)
Universal exercise restriction is no longer indicated; competitive sport may be considered after expert shared decision-making. (sources/competitive-sports-aha-2025, rating: very high)

Contradictions / Open Questions

ESC 2022 and ESC 2023 grade the same ICD threshold differently. The 2022 ventricular arrhythmia guideline makes an ICD at five-year SCD risk ≥6% Class I; the 2023 cardiomyopathy guideline makes the same threshold Class IIa. A European physician following the cardiomyopathy guideline will implant fewer devices than one following the arrhythmia guideline, with no reconciling trial. Both grades are recorded faithfully on the spokes, which means the conflict is visible but unresolved. (sources/VA-SCD-ESC-2022, rating: very high; sources/esc-cmp-2023, rating: very high)
AHA 2024 and ESC 2023 disagree on the LV apical aneurysm. AHA 2024 treats apical aneurysm with transmural scar as a major SCD risk factor warranting an ICD (Class IIa). ESC 2023 explicitly declines to accept it as a sole indication for want of evidence. A patient whose only risk factor is an apical aneurysm receives an ICD in the United States and not in Europe. (sources/HCM-AHA-2024, rating: very high; sources/esc-cmp-2023)
AHA 2024 and ESC 2023 place mavacamten on different rungs. AHA 2024 makes it Class I at step 3, equal to disopyramide and septal reduction. ESC 2023 makes it Class IIa at step 4, below disopyramide. No head-to-head trial against disopyramide exists, and MAPLE-HCM's comparison was against metoprolol, so the ordering is contested by inference rather than settled by evidence. (sources/HCM-AHA-2024; sources/esc-cmp-2023)
Exercise advice is opposite in the two guidelines. AHA 2024 states that universal restriction from vigorous activity and competitive sport is not indicated (Class III: No Benefit) and allows competitive sport after expert assessment. ESC 2023 still discourages high-intensity and competitive sport in high-risk patients. LIVE-HCM supports the American position, but no randomised data support either. (sources/HCM-AHA-2024; sources/esc-cmp-2023)
The risk calculator is either a threshold or a conversation starter. ESC 2023 mandates HCM Risk-SCD with a 6% threshold (Class I). AHA 2024 treats it as one element of shared decision-making (Class IIa) and states that prespecified thresholds should not be the sole arbiter. The two represent fundamentally different positions on whether a five-year probability can be acted on mechanically. (sources/esc-cmp-2023; sources/HCM-AHA-2024)
Nonobstructive disease is described as both benign and progressive. Long-term mortality in nonobstructive HCM does not differ significantly from obstructive disease, yet 5–10% progress to cavity dilatation and loss of obstruction requiring transplantation or mechanical support. A phenotype that is prognostically equivalent at the group level contains a subgroup that reaches end-stage disease, and no marker currently identifies that subgroup at diagnosis. (sources/HCM-NEJM-2025, rating: very high)
Mitochondrial HCM is systematically missed by standard testing. Standard cardiomyopathy and arrhythmia panels include neither mitochondrial DNA nor nuclear-encoded mitochondrial genes, so mitochondrial HCM returns a "gene-elusive" result that is indistinguishable from true negative. Whole-genome sequencing on clinical suspicion is the only route, and no guideline defines how hard to pursue it. (sources/mitochondrial-cv-aha-2025, rating: very high)
The principal 2025 review predates the trial that settled nonobstructive disease. Braunwald's NEJM review describes phase 3 trials of myosin inhibitors in nonobstructive HCM as fully enrolled with favourable phase 2 signals, whereas ODYSSEY-HCM found no clinical benefit with LVEF <50% in 21.5% versus 1.7% on placebo. A current state-of-the-art review is materially out of date on the one randomised trial that answered its own question. (sources/HCM-NEJM-2025; sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)

Connections

concepts/HCM-Genetics-and-Phenotypes — genetic architecture, polygenic risk and phenocopies
concepts/HCM-Diagnosis-and-Risk — diagnostic criteria, imaging and ICD selection
concepts/HCM-Mechanism — sarcomere biology, ion channel remodelling and the arrhythmogenic substrate
concepts/HCM-Management — obstruction, myosin inhibition, septal reduction and comorbidity
concepts/HCM-Risk-SCD — calculator mechanics and validation
concepts/LVOTO — obstruction physiology and gradients
concepts/Septal-Reduction-Therapy — myectomy and alcohol ablation
entities/Mavacamten and entities/Aficamten — cardiac myosin inhibitors
entities/MYBPC3 and entities/MYH7 — the two dominant sarcomeric genes
concepts/ClinGen-Gene-Disease-Validity — gene curation and disputed genes
concepts/GWAS-Cardiac-Genetics and concepts/Polygenic-Risk-Score — common-variant architecture
concepts/Mitochondrial-Cardiomyopathy and concepts/Heteroplasmy — mitochondrial phenocopy
entities/Anderson-Fabry-Disease and entities/ATTR-Amyloidosis — other phenocopies
concepts/HCM-Atrial-Myopathy — atrial substrate in sarcomeric disease
concepts/HCM-Exercise and concepts/Sports-Cardiology-SDM — athletic participation
concepts/Pregnancy-in-Genetic-Cardiomyopathy and concepts/mWHO-Classification — pregnancy
concepts/Perioperative-Cardiovascular-Assessment — non-cardiac surgery
concepts/Sarcomere-Biology — myofilament physiology
concepts/Late-Gadolinium-Enhancement — fibrosis imaging
concepts/Sudden-Cardiac-Death and concepts/Phenotypic-Approach-to-Cardiomyopathy — wider context
concepts/Cascade-Family-Screening — family testing

Sources

Guidelines and consensus statements

Reviews and synthesis

Genetics and genomics

Diagnostic imaging and AI

sources/lvh-scar-aiecg-naturesr-2025

Randomised trials

Special populations

sources/cmp-pregnancy-jaccadv-2026