Ventricular arrhythmia and sudden cardiac death in hypertrophic cardiomyopathy: From bench to bedside

Authors, Journal, Affiliations, Type, DOI

• Authors: Hua Shen, Shi-Yong Dong, Ming-Shi Ren, Rong Wang
• Journal: Frontiers in Cardiovascular Medicine
• Affiliations: Division of Adult Cardiac Surgery and Department of Cardiovascular Medicine / Surgery, The Sixth and First Medical Centers, Chinese PLA General Hospital, Beijing, China
• Type: Review article
• DOI: https://doi.org/10.3389/fcvm.2022.949294

Overview

This review summarizes bench-to-bedside knowledge on ventricular arrhythmia and SCD in HCM, integrating data from human surgical specimens, transgenic animal models, and hiPSC-CM platforms. Three interrelated cellular arrhythmogenic mechanisms are identified: ion channel remodeling (↑INaL, ↑ILTCC, ↓K⁺ currents), Ca²⁺ homeostasis dysregulation (SR overload, EADs/DADs), and enhanced myofilament Ca²⁺ sensitivity — all converging through CaMKII hyperactivation. The review also evaluates the current SCD risk stratification discrepancies between ACC/AHA and ESC guidelines, discusses INaL inhibitors and myosin inhibitors as emerging anti-arrhythmic strategies, and argues for individualized prevention combining gene screening, hiPSC-CM testing, machine learning, and advanced ECG analysis.

Keywords

hypertrophic cardiomyopathy (HCM), sudden cardiac death (SCD), ion channel, reentry, calcium homeostasis, sarcomere, gene screening

Key Takeaways

Hypertrophic Cardiomyopathy: Overview and Genetics

• HCM prevalence is 1:200–1:500 in the general population; inherited as autosomal dominant with variable penetrance.

• 2000 variants in >20 genes have been identified; eight genes have high-level pathogenic evidence: MYBPC3, MYH7, TNNT2, TNNI3, MYL2, MYL3, ACTC1, TPM1.

• MYBPC3 is the most common mutation (~50% of identified cases); MYH7 second (~25–40%).
• Up to 5% of patients have multiple mutations; most patients do NOT carry sarcomere gene variants.
• ~40% of HCM cases remain genetically unexplained, suggesting oligogenic or polygenic mechanisms.
• Polygenic common variants (GWAS by Watkins et al.) substantially influence phenotypic severity, especially in sarcomere-negative HCM.

Gene Screening

• Gene screening identifies preclinical HCM: genotype-positive/phenotype-negative relatives requiring longitudinal monitoring.
• Also distinguishes true HCM from phenocopies (Danon disease, PRKAG2 cardiomyopathy, Fabry disease, cardiac amyloidosis).
• Incomplete penetrance and variable expressivity complicate genotype-phenotype correlation.

Epidemiology of SCD in HCM

• SCD incidence 0.5–1% per year; predominantly affects children and young people <30 years old.
• Cumulative childhood HCM SCD incidence over 5 years: ~8–10%; HCM is the leading cause of SCD in young people in North America.
• SCD risk decreases with age; rare in patients >60 years.
• SCD may be the first clinical manifestation in some patients.
• Prophylactic ICDs have reduced disease-related mortality >10-fold to ~0.5%/year; 5-year and 10-year HCM-related survival rates are 98% and 94%, comparable to the general US population.

SCD Risk Stratification

• Well-recognized risk factors (ACC/AHA + ESC consensus): Prior cardiac arrest or sustained VT, SCD in first-degree relatives <50 years, syncope suspected arrhythmic, severe LVH (≥30 mm wall thickness), apical aneurysm, end-stage HCM (LVEF <50%).
• Risk-modifying factors: Genetic mutations, LGE on CMR, patient age, multiple NSVT episodes, myocardial ischemia, LVOT pressure gradient.
• Major discrepancy exists between ACC/AHA and ESC guidelines on SCD risk classification and ICD indications; real-world decision-making requires integrating both frameworks.
• Existing SCD risk scoring systems have limited accuracy for early-stage HCM patients with mild structural remodeling; young asymptomatic patients can suffer SCD even without advanced fibrosis or microvascular dysfunction.

Research Models and Their Limitations

• Human myocardial specimens: High translational value (patch-clamp, isometric contraction studies) but scarce, heterogeneous, and represent late-stage HCM (surgical myectomy specimens).
• Transgenic animal models: Rodents (α-MyHC R403Q mouse) replicate pathological changes but have short ERP (fast heart rate) and hearts too small for sustained reentry — poor models for ventricular arrhythmogenesis. Transgenic pigs are more comparable to humans.
• hiPSC-CMs: Overcome sample scarcity; replicate patient's complete gene map; suitable for drug screening and CRISPR editing. Key limitation: electrophysiological immaturity (fetal-like phenotype); uncertain whether immature iPSC-CMs recapitulate adult HCM phenotype vs. predict it. Engineered heart tissue (EHT) systems improve maturity.

Ion Channel Remodeling (Mechanism 1)

• In HCM cardiomyocytes vs. control: ↑ILTCC, ↑INaL; ↓Kir2.1/IK1, ↓Kv4.3/Ito, ↓IKs, ↓IKr.
• INaL increases precede hypertrophy and diastolic dysfunction in early-stage HCM (confirmed in TNNT-R92Q mice at 4 weeks, before phenotypic changes at 6 months).
• CaMKII bridges gene variants → ion channel remodeling: autophosphorylation → LTCC β-subunit phosphorylation (↑Ca²⁺ entry) + Nav1.5 phosphorylation (↑INaL) → NCX impairment → diastolic Ca²⁺ accumulation → further CaMKII activation (positive feedback loop).
• Result: APD prolongation → EADs and DADs → ventricular arrhythmia.
• MYH7-R442G hiPSC-CMs confirmed these changes: prolonged APD50/90, ↑Ca²⁺ current, ↑INaL, K⁺ current abnormality.

Myofilament Ca²⁺ Sensitivity (Mechanism 2)

• Troponin mutations that increase myofilament Ca²⁺ sensitivity are associated with familial HCM and high SCD risk.
• TNNT2-I79N mutation: HCM patients susceptible to SCD even without extensive fibrosis or LVH; direct effect on cytosolic Ca²⁺ buffer and Ca²⁺ transient amplitude.
• Enhanced Ca²⁺ sensitivity → slower diastolic Ca²⁺ dissociation → reduced Ca²⁺ transient dynamics → reduced NCX current → shortening of early repolarization (APD70) → triangular AP morphology.
• Under high stimulation: ↑cytosolic Ca²⁺ buffer → Ca²⁺ transient attenuation + diastolic Ca²⁺ accumulation → SR Ca²⁺ overload → spontaneous SR Ca²⁺ release → EADs/DADs.
• Rescue of abnormal Ca²⁺ sensitivity: hybridization of Tm-E180G HCM mouse model with low-myofilament-Ca²⁺-sensitivity mice → significant HCM phenotype improvement.

SR Ca²⁺ Overload and Trigger Activities (Mechanism 3)

• ↑Cytosolic Ca²⁺ + SR Ca²⁺ overload + CaMKII-mediated RyR2 hyperphosphorylation jointly increase RyR2 opening probability → spontaneous Ca²⁺ release → EADs/DADs.
• Confirmed in both human HCM specimens and mouse HCM models.
• TnT-I79N cardiomyocytes: slower Ca²⁺ transient kinetics, ↑diastolic Ca²⁺ (especially at high stimulation rate), ↑SR Ca²⁺ content → SR overload + spontaneous Ca²⁺ release events.
• RyR2 may interact directly with MYBPC3 — MYBPC3 mutation or conformational change affects intracellular Ca²⁺ homeostasis.

Other Arrhythmogenic Mechanisms

• Heterogeneous ion channel remodeling across LV: ↑dispersion of repolarization → substrate for persistent VT.
• Transverse tubule (TT) destruction: Impairs synchronous SR Ca²⁺ release → APD increases + ERP alternation → reentry circuit formation (confirmed in Δ160E cTnT HCM mouse model).
• Oxidative stress: Overactivated oxidative stress → ↑myofilament Ca²⁺ sensitivity; FTY720 (sphingosine-1-phosphate receptor regulator) and MPO inhibition may attenuate this.
• Genotype-negative HCM: mutations in RyR2-P1124L may increase RyR2 Ca²⁺ sensitivity → arrhythmia + secondary structural remodeling.

Drugs Against HCM Arrhythmia

INaL Inhibitors

• Ranolazine: Reduces intracellular Ca²⁺ in HCM cardiomyocytes; reduces PVC frequency on 24-h ECG (confirmed in RESTYLE-HCM and RHYME trials) — does NOT improve exercise capacity; low selectivity limits interpretation.
• Eleclazine (GS-6615): Novel selective INaL inhibitor; LIBERTY-HCM trial failed to show ICD shock reduction vs. placebo; trials in HCM and LQT3 halted.
• GS-967: Abolishes isoprenaline-induced arrhythmias in HCM specimens; selectivity questioned (may be class I/B antiarrhythmic).
• Disopyramide: Stabilizes closed state of RyR2; inhibits Ca²⁺-dependent arrhythmias and DADs by reducing cytosolic Ca²⁺.

Calcium Homeostasis Agents

• Blebbistatin: Non-selective myosin inhibitor; reduces myocardial Ca²⁺ sensitivity in vitro; anti-arrhythmic in TnT-mutation HCM animal models; research use only.
• Mavacamten (MYK-461): Selective allosteric myosin ATPase inhibitor; prevents LVH and fibrosis in transgenic HCM mice; proven effective and safe in PIONEER-HCM, EXPLORER-HCM, MAVERICK-HCM, VALOR-HCM trials; first-in-class agent expected to become the first myosin inhibitor approved for HCM. Its preventive effect on ventricular arrhythmia and SCD has not been directly studied but is worthy of attention given improved functional status.

Future Direction: Individualized SCD Prevention

• Early ion channel abnormalities (↑INaL, ↑ILTCC) precede structural changes → preventive medication in young HCM patients with high-risk gene mutations and negative clinical phenotype is a rational strategy.
• Ideal individualized prevention: gene screening + hiPSC-CM phenotyping + machine learning (Ca²⁺ transient analysis) + high-resolution ECG + whole-heart computerized simulation with MRI-guided anatomy.
• Polygenic modifiers increasingly expected to dominate SCD risk determination as large patient databases mature.

Key Concepts Mentioned

• concepts/Ion-Channel-Remodeling-in-HCM — three-ion-channel mechanism: ↑INaL, ↑ILTCC, ↓K⁺ currents; CaMKII-mediated link to gene mutations
• concepts/Calcium-Homeostasis-in-HCM — myofilament Ca²⁺ sensitivity, SR Ca²⁺ overload, EADs/DADs
• concepts/HCM-Risk-SCD — limitations of existing risk models for early-stage HCM
• concepts/iPSC-Derived-Cardiomyocytes — HCM-specific applications including CRISPR Ca²⁺ reporter lines
• concepts/CRISPR-Cas9-in-Channelopathies — CRISPR Ca²⁺ indicator knock-in; platform for HCM functional genomics
• concepts/Sudden-Cardiac-Death — HCM-specific SCD epidemiology; young patients; first manifestation
• concepts/Cardiac-Action-Potential — APD prolongation, EADs, DADs, triangular AP morphology

Key Entities Mentioned

• entities/HCM — central subject of the review
• entities/MYBPC3 — most common HCM mutation gene; 50% of identified cases
• entities/MYH7 — second most common; high-risk mutations (R403Q, R453C, G716R, R719W) for SCD
• entities/Mavacamten — myosin ATPase inhibitor; PIONEER-, EXPLORER-, MAVERICK-, VALOR-HCM trials
• entities/RYR2 — RyR2-MYBPC3 interaction in HCM; RyR hyperphosphorylation; CaMKII

Limitations of the Document

• Species translational gap: Mybpc3-KI mouse studies show reduced K⁺ currents as proarrhythmic trigger, but this was NOT confirmed in human EHT or LV septum specimens from HCM patients — rodent findings may not translate to humans.
• iPSC-CM maturity: Repolarization in hiPSC-CMs resembles fetal rather than adult ventricular myocytes; it is unclear whether immature iPSC-CMs genuinely recapitulate or predict adult HCM phenotype.
• Ranolazine paradox: In Mybpc3-KI mice, ranolazine improved high-workload tolerance not via INaL blockade but via β-adrenoceptor antagonism + Ca²⁺ desensitization; chronic ranolazine had no translatory effects on cardiac phenotype in vivo — calls into question the mechanism assumed in clinical trials.
• Mavacamten and arrhythmia: No direct data on mavacamten's effect on ventricular arrhythmia or SCD in HCM; postulated benefit is indirect (improved functional status, hemodynamics).
• Eleclazine failure: Despite strong preclinical rationale for selective INaL inhibition, eleclazine failed in clinical trials — gap between bench and bedside remains.

Wiki Pages Updated

• wiki/sources/HCM-VA-FCVMed-2022.md (created)
• wiki/entities/MYBPC3.md (created)
• wiki/concepts/Ion-Channel-Remodeling-in-HCM.md (created)
• wiki/concepts/Calcium-Homeostasis-in-HCM.md (created)
• wiki/entities/HCM.md (updated)
• wiki/concepts/HCM-Risk-SCD.md (updated)
• wiki/entities/Mavacamten.md (updated)
• wiki/concepts/iPSC-Derived-Cardiomyocytes.md (updated)
• wiki/concepts/Sudden-Cardiac-Death.md (updated)
• wiki/entities/MYH7.md (updated)
• wiki/entities/RYR2.md (updated)
• wiki/index.md (updated)
• wiki/log.md (updated)