#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)
SEQUOIA-HCM (NEJM 2024) — aficamten vs placebo on background therapy: Phase 3 RCT (N=282; 24 weeks) demonstrated aficamten added to background therapy (beta-blockers in 61%) improved peak VO2 by +1.7 ml/kg/min vs placebo (P<0.001) and hit all 10 secondary endpoints — NYHA improvement 58.5% vs 24.3%, Valsalva LVOTO −50 mmHg, KCCQ-CSS +7 points, NT-proBNP ~80% reduction, SRT eligibility 78 fewer days. Benefit was consistent regardless of background beta-blocker use. See entities/Aficamten. (sources/aficamten-sequoiahcm-nejm-2024, rating: very high)
MAPLE-HCM (NEJM 2025) — aficamten monotherapy superior to metoprolol monotherapy: Phase 3 double-blind double-dummy RCT (N=175; 24 weeks) showed aficamten outperforms metoprolol on peak VO2 (+2.3 ml/kg/min difference; P<0.001), Valsalva LVOTO gradient (−40.7 vs −3.8 mmHg), NT-proBNP (81% relative difference favoring aficamten), and LAVi. Metoprolol, despite reducing HR by 23.4 bpm, did NOT improve LVOTO gradient, NT-proBNP, or LAVi — and peak VO2 actually decreased. This is the first RCT establishing cardiac myosin inhibitor superiority over beta-blockers as monotherapy for obstructive HCM. See entities/Aficamten. (sources/aficamten-maplehcm-nejm-2025, rating: very high)

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 and Treatment

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)
Mavacamten — NOT effective in nonobstructive HCM (ODYSSEY-HCM, NEJM 2025): Phase 3 RCT (N=580; 201 centers; 22 countries; 48 weeks) showed mavacamten did NOT improve peak VO2 (P=0.07) or KCCQ-CSS (P=0.06) vs placebo in symptomatic nonobstructive HCM. Despite robust NT-proBNP reduction (geometric mean ratio 0.41), there was no clinical benefit — demonstrating that biomarker improvements do not reliably predict clinical efficacy in nonobstructive HCM. Safety concerns were significant: LVEF <50% in 21.5% vs 1.7% placebo; serious CHF events in 6.6% vs 1.7%. The dominant contributors to symptoms in nonobstructive HCM (diastolic dysfunction, subendocardial ischemia, LV noncompliance, microvascular disease) are not corrected by cardiac myosin inhibition. No approved pharmacotherapy exists for symptomatic nonobstructive HCM. See entities/Mavacamten. (sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)

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)
Mavacamten biomarker-clinical dissociation in nonobstructive HCM (ODYSSEY-HCM, 2025): ODYSSEY-HCM showed NT-proBNP reduction of 59% (geometric mean ratio 0.41) with mavacamten vs placebo in nonobstructive HCM — a large biomarker benefit — yet neither primary clinical endpoint (peak VO2, KCCQ-CSS) was significantly improved. This challenges the assumption that NT-proBNP reduction in HCM predicts clinical benefit, and contrasts with obstructive HCM trials where biomarker and clinical endpoints tracked together. The mechanism is that NT-proBNP reduction (reflecting reduced myocardial wall stress/filling pressures) does not address the non-hemodynamic contributors to symptoms in nonobstructive HCM (diastolic dysfunction, microvascular ischemia, chronotropic incompetence). (sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)
Beta-blockers as first-line Class I but inferior to cardiac myosin inhibitor on objective endpoints (MAPLE-HCM, 2025): Both AHA 2024 and ESC 2023 position beta-blockers as Class I step-1 therapy for obstructive HCM; cardiac myosin inhibitors are step-3 (AHA) or step-4 (ESC). However, MAPLE-HCM (2025) showed aficamten monotherapy is superior to metoprolol monotherapy on all objective endpoints — peak VO2, LVOTO gradient, NT-proBNP, LAVi — while metoprolol failed to improve any objective hemodynamic parameter despite robust heart rate reduction. This is the first RCT evidence that the current step-care paradigm may be suboptimal for obstructive HCM. Guidelines have not yet been updated. (sources/aficamten-maplehcm-nejm-2025, rating: very 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 entities/Aficamten
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