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

Hypertrophic Cardiomyopathy (HCM)

Details

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy (prevalence ~0.2% in adults), defined as increased LV wall thickness not solely explained by abnormal loading conditions. It is primarily a disease of the cardiac sarcomere, though metabolic and syndromic phenocopies account for up to 25% of childhood cases. Most patients are asymptomatic and have a normal lifespan; a minority develop symptomatic heart failure, arrhythmias, or sudden cardiac death.

Key Facts

Diagnosis

Adult criteria: LV wall thickness ≥15 mm in any segment (≥13 mm in first-degree relatives of index cases), not explained by loading conditions. (sources/esc-cmp-2023)
Child criteria: LV wall thickness z-score >2 (>2 SD above predicted mean). (sources/esc-cmp-2023)
Initial work-up: history, 3–4-generation pedigree, ECG, echocardiography, CMR, and first-line labs.
CMR is recommended at baseline (Class I, Level B); identifies apical/lateral hypertrophy missed by echo, apical aneurysms, and myocardial fibrosis (LGE present in ~65% of patients). (sources/esc-cmp-2023)

Genetics

~40–60% of HCM patients have a causal sarcomeric variant identified on genetic testing; likelihood highest in young patients with familial disease. (sources/esc-cmp-2023)
Primary sarcomeric genes: MYBPC3 (most common), MYH7, TNNT2, TNNI3, MYL2, MYL3, ACTC1, TPM1.
ClinGen Gene-Disease Validity (2026-05-09): Definitive HCM genes: MYBPC3, MYH7, TNNI3, TNNC1, TPM1, FHOD3, CSRP3 (semidominant), ACTC1, and ALPK3 (AR definitive/AD strong). PLN has definitive evidence for "intrinsic cardiomyopathy" (includes HCM/DCM spectrum). Disputed — these genes should NOT be clinically reported as pathogenic for HCM: CALR3 (disputing 01/11/2023), MYH6 (disputing 07/12/2023), CASQ2 (disputing 05/10/2022), DSP (disputing for HCM 06/22/2022), VCL (disputing 05/10/2023), KCNQ1 (disputing 05/09/2022), ANKRD1 (disputing 02/08/2023). RYR2 has only limited evidence for HCM (12/14/2022). See concepts/ClinGen-Gene-Disease-Validity and sources/clingen-summary-2026-05-09. (sources/clingen-summary-2026-05-09, rating: high)
MYBPC3 mutation burden: >350 individual MYBPC3 mutations identified; >60% are truncating. Most heterozygous mutations have late onset and often benign progression; however, bi-allelic truncating MYBPC3 mutations (homozygotes or compound heterozygotes) produce fatal neonatal cardiomyopathy with heart failure and death within the first year — cardiac transplantation is the only curative option. Gene-dosage effect: 14% of childhood-onset HCM is caused by compound genetic variants. (sources/mybpc3-gene-2015, rating: medium)
South Asian founder variant: A 25-bp MYBPC3 intron 32 deletion is present in 4% of the South Asian population and confers a 6.99-fold increased risk of heart failure — important for pre-test probability in South Asian patients presenting with unexplained cardiomyopathy or HF. (sources/mybpc3-gene-2015)
Founder MYBPC3 mutations: High-frequency founder truncating mutations exist in several populations — Iceland (58% of HCM), Veneto Italy (19.5%), Netherlands/Finland/Japan (~16-17% each), Tuscany (14%), and Center-East France (8.4%); high founder prevalence in these regions elevates the risk of compound heterozygosity. (sources/mybpc3-gene-2015)
Genocopies (clinically resemble HCM but different management): Anderson-Fabry disease (GLA), ATTR amyloidosis (TTR), glycogen storage disorders (LAMP2-Danon, GAA-Pompe, PRKAG2), RASopathies (PTPN11, RAF1), Friedreich ataxia (FXN). These account for <5% of adults but up to 25% of children. (sources/esc-cmp-2023)

GWAS and Polygenic Risk

Novel GWAS loci beyond sarcomere genes: HCM GWAS has identified disease-associated common variant loci at genes outside the classical sarcomere: FHOD3 (formin homology domain-containing protein 3; regulates actin filament formation in cardiomyocytes), ALPK3 (alpha-kinase 3; myocardial transcription regulation), PLN (phospholamban; SR calcium handling), ACTN2 (alpha-actinin-2; Z-disc sarcomere anchor), and CSRP3 (cardiac muscle LIM protein; myofibril assembly). These loci implicate calcium handling and actin cytoskeleton organisation as polygenic contributors to HCM beyond myosin/actin gene variants. (sources/gwas-arrhythmias-cmp-genes-2025, rating: high)
HCM PRS — OR 2.34/SD (Zheng 2025): A multi-ancestry HCM GWAS PRS yields OR 2.34 per SD increase for HCM case status. HCM PRS is independent of sarcomeric variant carrier status — individuals lacking an identifiable pathogenic rare variant can still carry a high PRS that substantially elevates risk. HCM PRS also predicts adverse outcomes including death and clinical progression. (sources/gwas-arrhythmias-cmp-genes-2025)
Inverse HCM-DCM risk loci: Several GWAS loci (at MYBPC3, ALPK3, FHOD3) show opposing effect directions for HCM vs. DCM — the same SNP allele elevating HCM risk lowers DCM risk. This is a molecular confirmation that HCM (excess sarcomere stiffness/contractility) and DCM (sarcomere insufficiency) lie at opposing ends of the same genetic contractility axis. The parallel therapeutic implication: mavacamten targets this axis from the HCM (high-contractility) side. See concepts/GWAS-Cardiac-Genetics and entities/DCM. (sources/gwas-arrhythmias-cmp-genes-2025)

Mitochondrial HCM (Phenocopies)

HCM is the most common cardiomyopathy phenotype in mitochondrial diseases; obstructive HCM is rare; may present antenatally; may progress to DCM with systolic dysfunction. (sources/mitochondrial-cv-aha-2025, rating: very high)
Key mitochondrial syndromes presenting as HCM: MELAS (m.3243A>G), MIDD (m.3243A>G at lower VAF), MERRF (m.8344A>G), LHON, Leigh syndrome, Pearson syndrome. See concepts/Mitochondrial-Cardiomyopathy. (sources/mitochondrial-cv-aha-2025)
Standard cardiomyopathy and arrhythmia gene panels do NOT include mitochondrial genes (neither mtDNA nor nuclear-encoded mitochondrial genes); mitochondrial HCM will yield a "gene-elusive" result on standard panels. (sources/mitochondrial-cv-aha-2025)
Suspect mitochondrial disease when HCM presents with: maternal inheritance, multisystemic features (neurological, ophthalmological, hearing loss, diabetes), elevated serum lactate, or no sarcomeric variant identified on standard panels. (sources/mitochondrial-cv-aha-2025)
WGS (not a targeted panel) is recommended as first-line for suspected mitochondrial HCM; involves non-Mendelian inheritance counselling (heteroplasmy, variable penetrance). (sources/mitochondrial-cv-aha-2025)

LVOTO Management

LVOTO ≥30 mmHg on Doppler; treatment threshold is ≥50 mmHg.
Step-wise pharmacological therapy: (1) non-vasodilating beta-blockers (Class I, Level B); (2) verapamil or diltiazem (Class I, Level B); (3) disopyramide added to beta-blockers (Class I, Level B); (4) Mavacamten as addition (Class IIa, Level A). (sources/esc-cmp-2023)
Vasodilators (nitrates, phosphodiesterase inhibitors, digoxin) should be avoided in LVOTO patients. (sources/esc-cmp-2023)
Septal reduction therapy (surgical myectomy or alcohol septal ablation) for LVOTO ≥50 mmHg + NYHA III–IV refractory to maximal therapy (Class I). See concepts/Septal-Reduction-Therapy. (sources/esc-cmp-2023)

Ventricular Arrhythmia and SCD Epidemiology

SCD incidence in HCM: 0.5–1% per year; predominantly affects children and young people <30 years. (sources/HCM-VA-FCVMed-2022)
Childhood HCM: Cumulative 5-year SCD incidence ~8–10%; HCM is the leading cause of SCD in young people in North America. (sources/HCM-VA-FCVMed-2022)
SCD may be the first clinical manifestation in some patients. (sources/HCM-VA-FCVMed-2022)
SCD risk decreases with age; rare in patients >60 years. (sources/HCM-VA-FCVMed-2022)
Prophylactic ICD has reduced HCM disease-related mortality >10-fold; HCM-related 5-year and 10-year survival rates are 98% and 94%, comparable to the general US population. (sources/HCM-VA-FCVMed-2022)
Three interlocking cellular arrhythmogenic mechanisms: (1) ion channel remodeling (↑INaL, ↑ILTCC, ↓K⁺ currents), (2) enhanced myofilament Ca²⁺ sensitivity, and (3) SR Ca²⁺ overload → EADs/DADs. See concepts/Ion-Channel-Remodeling-in-HCM and concepts/Calcium-Homeostasis-in-HCM. (sources/HCM-VA-FCVMed-2022)
INaLate upregulation in HCM — mechanistic detail: Coppini et al. (2013) demonstrated ↑INaLate in explanted HCM hearts (both MYBPC3 and MYH7 mutation carriers); INaLate causes Na⁺ overload → Ca²⁺ overload via NCX reverse mode → APD prolongation and EAD generation. Critically, INaLate elevation is detectable in preclinical HCM mutation carriers before hypertrophy is present, confirming electrical remodeling as an early pathological event rather than a consequence of structural disease. Ranolazine (selective INaLate blocker) and mexiletine (INaLate blocker) normalize APD, reduce Ca²⁺ overload, and reverse electromechanical dysfunction in HCM myocyte and animal models — providing a pharmacological rationale for their use in HCM arrhythmia management (off-label, observational evidence only). (sources/membrane-potential-physrev-2021, rating: very high)
↓Ito and asynchronous CICR: Loss of Ito (transient outward K⁺ current) in HCM reduces the Phase 1 "notch" → the AP plateau begins at a more depolarized voltage → L-type Ca²⁺ channel activation is less synchronised across the subendocardial–subepicardial axis → asynchronous calcium-induced calcium release (CICR) from SR → spatial Ca²⁺ gradient within the cell → incomplete systolic relaxation zones → local diastolic Ca²⁺ elevation → DADs under adrenergic stimulation → triggered VT. (sources/membrane-potential-physrev-2021)
Ion channel changes precede structural remodeling in early-stage HCM; supports concept of prophylactic pharmacotherapy in high-risk gene mutation carriers before phenotypic manifestation. (sources/HCM-VA-FCVMed-2022)

SCD Risk Stratification and Prevention

Annual cardiovascular mortality 1–2%; SCD is the most feared complication, especially in the young. (sources/esc-cmp-2023)
HCM Risk-SCD calculator (adults ≥16 years, Class I, Level B): Calculates 5-year SCD probability using: age, NSVT, unexplained syncope, maximum LV wall thickness, family history of SCD, left atrial diameter, LVOT gradient. See concepts/HCM-Risk-SCD. (sources/esc-cmp-2023)
HCM Risk-Kids (children <16 years, Class I, Level B): validated paediatric-specific tool. (sources/esc-cmp-2023)
ICD implantation: Class IIa for 5-year risk ≥6%; Class IIb for 4–6% with clinical risk factors; Class IIb for low-risk with extensive LGE (≥15%) or LVEF <50%. (sources/esc-cmp-2023)
Secondary prevention ICD: Class I for cardiac arrest survivors or sustained VT with haemodynamic compromise. (sources/esc-cmp-2023)
LV apical aneurysm: ESC 2023 does NOT recommend as sole indication for ICD (insufficient evidence); contrasts with AHA/ACC 2020 position. (sources/esc-cmp-2023)
Sarcomeric variants alone do NOT guide ICD decisions independent of validated risk tools. (sources/esc-cmp-2023)
HCM Risk-SCD and HCM Risk-Kids should NOT be used in elite athletes or in metabolic/infiltrative diseases (Fabry, Noonan). (sources/esc-cmp-2023)

Risk assessment frequency (Class I): 5-year SCD risk must be assessed at first evaluation AND at 1–3-year intervals or when clinical status changes (new explicit requirement). (sources/VA-SCD-ESC-2022)
ICD at 5-year risk ≥6% (Class I, Level B): explicit ESC 2022 upgrade from previous Class IIa. (sources/VA-SCD-ESC-2022)
ICD at intermediate risk (4–6%) with additional risk modifiers (Class IIa): significant LGE (≥15% LV mass), LVEF <50%, abnormal BP response to exercise (failure to increase ≥20 mmHg or fall >20 mmHg from peak), LV apical aneurysm, or sarcomeric pathogenic mutation. (sources/VA-SCD-ESC-2022)
Children <16 years: HCM Risk-Kids score ≥6% → ICD Class IIa. (sources/VA-SCD-ESC-2022)
ICD even at low risk (<4%) with significant LGE (≥15% LV mass), LVEF <50%, or LV apical aneurysm: Class IIb. (sources/VA-SCD-ESC-2022)
Catheter ablation in specialized centres for recurrent symptomatic SMVT or ICD shocks refractory to AADs: Class IIb. (sources/VA-SCD-ESC-2022)
High-intensity exercise may be considered for asymptomatic adult HCM patients without risk markers: Class IIb (nuanced — not universal restriction). (sources/VA-SCD-ESC-2022)

Sports and Lifestyle

Patients should have individualized exercise risk assessment. High-intensity exercise and competitive sports should be discouraged in high-risk patients. Genotype-positive/phenotype-negative patients with no symptoms or risk factors may participate in competitive sports. (sources/esc-cmp-2023)
AHA 2024 paradigm shift: Universal restriction from vigorous physical activity or competitive sports is not indicated for most patients (Class III: No Benefit). Vigorous recreational activity is reasonable after annual expert evaluation (Class IIa); competitive sports may be considered by HCM-experienced providers (Class IIb). See concepts/Exercise-in-HCM. (sources/HCM-AHA-2024)

AHA/ACC 2025 Sports Statement — HCM-Specific Guidance

Genotype+/phenotype-: Can participate in competitive sports — low arrhythmic risk is well-established. (sources/competitive-sports-aha-2025, rating: very high)
Clinical HCM: Competitive sports participation reasonable to consider after comprehensive expert assessment with SDM in which risks (including SCD) and benefits are explicitly discussed. This is supported by LIVE-HCM (no increased malignant VA in HCM with vigorous exercise compared with less active patients) and multicenter SDM registry data showing low breakthrough event rates. (sources/competitive-sports-aha-2025)
ICD should NOT be implanted solely to enable competitive sports participation in HCM athletes — ~5%/year inappropriate shock risk and ~4%/year ICD-related complications. (sources/competitive-sports-aha-2025)
Athletes who discontinue competitive sports should be counselled that recreational physical activity remains important for health and longevity. (sources/competitive-sports-aha-2025)
See concepts/Sports-Cardiology-SDM for the full SDM framework and preparticipation evaluation approach.

Pregnancy

Mavacamten is absolutely contraindicated in pregnancy due to potential teratogenic effects (Class III: Harm — AHA 2024 new recommendation). (sources/HCM-AHA-2024)
Pregnant women with HCM should be managed at comprehensive HCM centers with appropriate expertise. (sources/HCM-AHA-2024)

Nonobstructive HCM — Disease Modification

Valsartan (NEW AHA 2024, Class IIb, Level B-R): For patients ≤45 years with nonobstructive HCM due to a pathogenic/likely pathogenic sarcomeric variant and mild phenotype (NYHA I–II, max wall 13–25 mm, no secondary prevention ICD, no AF) — may slow adverse cardiac remodeling. Based on one RCT (n=178, 8–45 years of age). (sources/HCM-AHA-2024)

Atrial Fibrillation Management

Anticoagulation with DOACs (or warfarin) is required for all patients with HCM and clinical AF, independent of CHA2DS2-VASc score (Class I, Level B-NR). The HCM stroke risk from AF is not predicted by CHA2DS2-VASc — strokes occur even in patients with score of 0. (sources/HCM-AHA-2024)
Extended ambulatory monitoring for AF screening is Class I (upgraded from IIa) annually in high-risk patients (based on HCM-AF score or risk factors). (sources/HCM-AHA-2024)
Rhythm control preferred over rate control given poor AF tolerance in HCM. (sources/HCM-AHA-2024)
AF ablation in genotype-positive HCM (MYBPC3/MYH7): A 2024 single-center retrospective study (n=27; 12 gene-positive, 15 controls) found that MYBPC3/MYH7 variant–positive patients had appreciably more LA fibrosis by electroanatomical mapping (12.3% abnormal voltage vs. 5.7% in gene-negative HCM controls), despite similar LA pressures. Freedom from AF at 12 months was similar (~75% vs. 73%), but gene-positive patients required significantly more ablation procedures (mean 1.67 vs. 1.20; P=0.03) and all remained on AADs post-ablation. Progressive atrial fibrosis was observed in redo procedures, suggesting ongoing atrial myopathy. See concepts/Atrial-Myopathy-in-HCM. (sources/MYBPC3-MYH7-JACCEP-2024, rating: medium)

Invasive Hemodynamic Assessment in HCM

Cardiac catheterization is required when noninvasive data are inconclusive to document a resting or provoked LVOT gradient ≥50 mmHg before septal reduction therapy sources/hemodynamics-circ-2012 high
Catheter entrapment is a major hazard in the small, hypertrophied, hyperdynamic HCM ventricle — results in erroneous pressure tracings; must be identified by continuous pressure contour analysis and small hand injections of contrast sources/hemodynamics-circ-2012 high
Transseptal catheterization preferred for LV inflow pressure measurement — avoids entrapment; allows accurate assessment of true LV diastolic pressure without retrograde catheter interference sources/hemodynamics-circ-2012 high
If retrograde approach is used: multipurpose or Rodriquez catheter (side holes at the distal end) preferred; pigtail catheters with long side-hole sections should be avoided as they may straddle the LVOT and artificially fuse LV and Ao pressures sources/hemodynamics-circ-2012 high
Provocative maneuvers if resting gradient <50 mmHg: (1) Valsalva maneuver, (2) PVC induction; if still insufficient, (3) isoproterenol infusion (β1+β2 stimulation) to simulate exercise — most sensitive in uncovering labile obstruction sources/hemodynamics-circ-2012 high
Post-septal ablation assessment must include both resting AND provoked gradients; residual provokable gradient ≥50 mmHg indicates incomplete procedural result sources/hemodynamics-circ-2012 high

Cardiometabolic Risk

Cardiometabolic risk factors (obesity, hypertension, diabetes, obstructive sleep apnea) are highly prevalent in HCM and worsen prognosis; intensive modification is a core management component. (sources/HCM-AHA-2024)

Perioperative Management of HCM

LVOT aggravating factors (COR 3: Harm): Inotropic agents (dobutamine, milrinone), tachycardia, excessive preload reduction, and peripheral vasodilation all worsen LVOT obstruction and must be avoided in obstructive HCM patients undergoing NCS. (sources/periop-aha-2024, rating: very high)
Vasopressors preferred over inotropes: For perioperative hypotension in HCM, phenylephrine or norepinephrine (vasopressors) are recommended to restore SVR; inotropes worsen dynamic LVOT obstruction and are contraindicated. (sources/periop-aha-2024, rating: very high)
Intraoperative TEE (COR 2a): Indicated for haemodynamically unstable HCM patients and for monitoring unexplained haemodynamic deterioration; allows real-time assessment of LVOT obstruction severity and volume status. (sources/periop-aha-2024, rating: very high)
Maintain adequate preload and afterload: IV fluid administration and vasopressors to maintain intravascular volume; avoid spinal/epidural anaesthesia that causes abrupt sympatholytic vasodilation in patients with obstructive physiology. (sources/periop-aha-2024, rating: very high)

Contradictions / Open Questions

AHA 2024 vs. ESC 2023 — LV apical aneurysm as ICD indication: AHA 2024 lists apical aneurysm with transmural scar/LGE as a major SCD risk factor warranting ICD (Class IIa). ESC 2023 explicitly does NOT recommend apical aneurysm as a sole ICD indication due to insufficient evidence. A patient with apical aneurysm as their only risk factor would receive an ICD in the US but not in Europe. (sources/HCM-AHA-2024, sources/esc-cmp-2023)
AHA 2024 vs. ESC 2023 — mavacamten treatment tier: AHA 2024 elevates mavacamten to Class I, equivalent to disopyramide or SRT at step 3. ESC 2023 positions mavacamten as Class IIa, step 4 — below disopyramide — with no direct head-to-head trial evidence. (sources/HCM-AHA-2024, sources/esc-cmp-2023)
AHA 2024 vs. ESC 2023 — exercise restriction: AHA 2024 explicitly states universal exercise restriction is NOT indicated for most HCM patients (Class III: No Benefit), while ESC 2023 retains the recommendation to discourage high-intensity and competitive sport in high-risk patients. ESC 2023 is more conservative, but neither approach is backed by prospective RCT data. (sources/HCM-AHA-2024, sources/esc-cmp-2023)
AHA 2024 vs. ESC 2023 — SCD risk tool as threshold vs. decision aid: ESC 2023 mandates the HCM Risk-SCD calculator with a 6% threshold (Class I); AHA 2024 treats it as one element of shared decision-making (Class IIa), explicitly stating prespecified thresholds should NOT be the sole arbiter. This reflects fundamentally different philosophies on quantitative vs. qualitative risk assessment. (sources/HCM-AHA-2024, sources/esc-cmp-2023)
Early-stage HCM risk stratification gap: Current risk tools (HCM Risk-SCD, Risk-Kids) have limited accuracy for patients with early-stage or mild structural disease. Ion channel remodeling (↑INaL, ↑ILTCC) precedes structural changes — young asymptomatic patients can suffer SCD without the traditional risk markers. No validated tool captures pre-structural arrhythmic vulnerability. (sources/HCM-VA-FCVMed-2022)
ClinGen disputes multiple published "HCM genes" (2026): The following genes previously attributed to HCM in publications or on older panels have been reclassified as "Disputing" by ClinGen expert curation (2026-05-09 report): CALR3 (01/2023), MYH6 (07/2023), CASQ2 (05/2022), DSP for HCM specifically (06/2022), VCL (05/2023), KCNQ1 (05/2022), ANKRD1 (02/2023). Clinicians using broad legacy panels may receive false-positive results for these genes. Note that DSP has definitive evidence for ACM/arrhythmogenic cardiomyopathy (with wooly hair/keratoderma phenotype) — the dispute applies specifically to isolated HCM without the skin phenotype. (sources/clingen-summary-2026-05-09, rating: high)

Connections

Related to concepts/Electrical-Remodeling
Related to sources/membrane-potential-physrev-2021
Related to concepts/Atrial-Myopathy-in-HCM
Related to concepts/Exercise-in-HCM
Related to concepts/Ion-Channel-Remodeling-in-HCM
Related to concepts/Calcium-Homeostasis-in-HCM
Related to entities/MYBPC3
Related to concepts/HCM-Risk-SCD
Related to concepts/LVOTO
Related to concepts/Septal-Reduction-Therapy
Related to concepts/Late-Gadolinium-Enhancement
Related to concepts/Phenotypic-Approach-to-Cardiomyopathy
Related to entities/Mavacamten
Related to entities/Anderson-Fabry-Disease
Related to entities/ATTR-Amyloidosis
Related to entities/MYH7
Related to concepts/Sudden-Cardiac-Death
Related to concepts/Cascade-Family-Screening
Related to concepts/Perioperative-Cardiovascular-Assessment
Related to sources/periop-aha-2024
Related to concepts/Sports-Cardiology-SDM
Related to sources/competitive-sports-aha-2025
Related to concepts/Mitochondrial-Cardiomyopathy
Related to concepts/Heteroplasmy
Related to sources/mybpc3-gene-2015
Related to concepts/GWAS-Cardiac-Genetics
Related to concepts/Polygenic-Risk-Score
Related to sources/gwas-arrhythmias-cmp-genes-2025
Related to concepts/ClinGen-Gene-Disease-Validity
Related to sources/clingen-summary-2026-05-09