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Hypertrophic Cardiomyopathy

Pathophysiology description

2025-12-15
Falcon MONDO:0005045 Model: Edison Scientific Literature 23 citations

Pathophysiology description Hypertrophic cardiomyopathy is primarily a disease of the cardiac sarcomere with autosomal dominant inheritance for most familial cases. The central biophysical abnormality is sarcomere hypercontractility (increased myosin duty ratio/power) with impaired relaxation and elevated energetic cost of contraction. Human tissue and omics studies show a coherent downstream signature: downregulation of mitochondrial/energetic and Ca2+ homeostasis pathways, with upregulation of extracellular matrix remodeling, cytoskeletal remodeling, and inflammatory programs (indicating convergence on shared remodeling mechanisms across genotypes) (Cell, Feb 2025; https://doi.org/10.1016/j.cell.2025.01.011) (parikh2025advancesinthe pages 2-3). Core causal genes remain the thick- and thin-filament sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), with MYBPC3 and MYH7 accounting for the majority of genotype-positive cases; genotype-positive status is associated with earlier onset and higher lifetime hazard of atrial fibrillation, ventricular arrhythmias, heart failure, and death (European Heart Journal, Jul 2024; https://doi.org/10.1093/eurheartj/ehae421; Cell, Feb 2025; https://doi.org/10.1016/j.cell.2025.01.011) (lopes2024geneticsofhypertrophic pages 1-2, parikh2025advancesinthe pages 1-2).

At the cellular level, increased myofilament Ca2+ sensitivity and altered ATPase kinetics impair relaxation, raise diastolic Ca2+ load, and trigger pro-hypertrophic signaling (e.g., TGF-β and MAPKs), promoting interstitial fibrosis and myocyte disarray. Anatomically, basal septal hypertrophy can induce dynamic LVOT obstruction and mitral valve systolic anterior motion via Venturi forces, further elevating wall stress and ischemic burden (The Egyptian Heart Journal, Dec 2024; https://doi.org/10.1186/s43044-024-00587-y; Biomedicines, Nov 2024; https://doi.org/10.3390/biomedicines12122675) (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5, młynarska2024hypertrophiccardiomyopathywith pages 2-4). Preclinical sarcomere-positive carriers often show early diastolic abnormalities, profibrotic tendencies, and altered energetics before overt hypertrophy (Cell, Feb 2025; https://doi.org/10.1016/j.cell.2025.01.011) (parikh2025advancesinthe pages 3-4).

Gene/protein annotations with ontology terms (HGNC, GO) - MYH7 (HGNC:7577) – Beta-myosin heavy chain. Processes: muscle contraction (GO:0006936), ATP hydrolysis activity (GO:0016887), regulation of heart contraction (GO:0008016). Mechanistic role: increased duty ratio/ATPase activity → hypercontractility/energetic cost (Cell, 2025) (parikh2025advancesinthe pages 2-3). - MYBPC3 (HGNC:7551) – Myosin-binding protein C, cardiac type. Processes: regulation of cardiac muscle contraction (GO:0055117), sarcomere organization (GO:0045214). Mechanistic role: truncations/haploinsufficiency dysregulate crossbridge formation (Eur Heart J, 2024) (lopes2024geneticsofhypertrophic pages 1-2). - TNNT2 (HGNC:11949), TNNI3 (HGNC:11945) – Troponin T/I. Processes: regulation of muscle contraction (GO:0006937), calcium ion binding (GO:0005509). Mechanistic role: increased myofilament Ca2+ sensitivity → diastolic dysfunction/arrhythmia substrate (Eur Heart J, 2024) (lopes2024geneticsofhypertrophic pages 1-2). - MYL2 (HGNC:7571), MYL3 (HGNC:7572) – Myosin light chains. Processes: regulation of myosin light chain phosphorylation (GO:0018108), muscle contraction (GO:0006936). (Biomedicines, 2024) (abbas2024roleofgenetics pages 1-2). - TPM1 (HGNC:12010), ACTC1 (HGNC:144) – Thin filament stabilizer/actin. Processes: actin filament-based process (GO:0030029), cardiac muscle contraction (GO:0060048). (Cell, 2025; Eur Heart J, 2024) (parikh2025advancesinthe pages 3-4, lopes2024geneticsofhypertrophic pages 1-2). - Emerging/validated genes: ALPK3 (HGNC:14659), FHOD3 (HGNC:24094), TRIM63 (HGNC:16287), SVIL (HGNC:30875). Processes include sarcomere/cytoskeletal organization and proteostasis (Cell, 2025; Eur Heart J, 2024) (parikh2025advancesinthe pages 3-4, lopes2024geneticsofhypertrophic pages 1-2).

Table (click to expand)
Gene (HGNC) Protein / function Pathogenic role in HCM pathophysiology (concise) Evidence and recent sources Notes on genotype–phenotype (age of onset, penetrance)
MYH7 Beta-myosin heavy chain — motor ATPase (thick filament) Missense variants often increase myosin ATPase activity and duty ratio → sarcomere hypercontractility, impaired relaxation, higher energetic cost Parikh et al., Cell 2025; https://doi.org/10.1016/j.cell.2025.01.011 (parikh2025advancesinthe pages 3-4); Młynarska et al., Biomedicines 2024; https://doi.org/10.3390/biomedicines12122675 (młynarska2024hypertrophiccardiomyopathywith pages 2-4) Associated with earlier onset and more severe LVH; higher arrhythmic/SCD risk vs some other genes. Incomplete penetrance but often earlier expressivity.
MYBPC3 Myosin-binding protein C — sarcomere regulatory / structural protein (thick filament) Truncating variants → haploinsufficiency or altered regulation of crossbridge formation; leads to hypertrophy, later-onset disease in many cohorts Lopes et al., Eur Heart J 2024; https://doi.org/10.1093/eurheartj/ehae421 (lopes2024geneticsofhypertrophic pages 1-2); Abbas et al., Biomedicines 2024; https://doi.org/10.3390/biomedicines12030682 (abbas2024roleofgenetics pages 1-2) Often later age at diagnosis than MYH7; common cause of familial HCM; variable penetrance (many carriers phenotype-negative into adulthood).
TNNT2 Cardiac troponin T — thin filament regulatory subunit Missense variants alter Ca2+-dependent regulation of contraction → increased myofilament Ca2+ sensitivity, arrhythmogenic substrate, hypertrophy/fibrosis Lopes et al., Eur Heart J 2024; https://doi.org/10.1093/eurheartj/ehae421 (lopes2024geneticsofhypertrophic pages 1-2); Parikh et al., Cell 2025 (parikh2025advancesinthe pages 2-3) Can present with relatively modest LVH but disproportionate arrhythmic risk; penetrance variable by variant.
TNNI3 Cardiac troponin I — inhibitory subunit regulating relaxation Variants increase myofilament Ca2+ sensitivity and impair diastolic relaxation → diastolic dysfunction and hypertrophy signaling Lopes et al., Eur Heart J 2024; https://doi.org/10.1093/eurheartj/ehae421 (lopes2024geneticsofhypertrophic pages 1-2) Linked to early-onset disease in some families; incomplete penetrance and variable expressivity.
MYL2 Myosin regulatory light chain 2 — modulates crossbridge cycling Pathogenic variants alter crossbridge kinetics and sarcomere regulation → contribute to hypercontractility and hypertrophic remodeling Abbas et al., Biomedicines 2024; https://doi.org/10.3390/biomedicines12030682 (abbas2024roleofgenetics pages 1-2) Often associated with familial HCM; phenotype severity and penetrance variable.
MYL3 Myosin essential light chain 3 — structural/regulatory light chain Alters myosin head regulation and sarcomere mechanics when mutated → contributes to hypertrophy and contractile abnormalities Abbas et al., Biomedicines 2024; https://doi.org/10.3390/biomedicines12030682 (abbas2024roleofgenetics pages 1-2) Rare; familial cases reported with variable penetrance and age at onset.
TPM1 Alpha-tropomyosin — thin filament stabilizer Variants modify actin–tropomyosin regulation of contraction, increasing Ca2+ sensitivity and promoting hypertrophy/fibrosis Parikh et al., Cell 2025; https://doi.org/10.1016/j.cell.2025.01.011 (parikh2025advancesinthe pages 3-4) Part of core sarcomeric gene set; phenotype and penetrance variable by variant.
ACTC1 Cardiac actin — thin filament structural protein Missense variants disrupt actin dynamics and force transmission → sarcomere dysfunction, hypertrophy, myocyte disarray Lopes et al., Eur Heart J 2024; https://doi.org/10.1093/eurheartj/ehae421 (lopes2024geneticsofhypertrophic pages 1-2) Rare; can present early or later depending on variant; incomplete penetrance observed.
ALPK3 Alpha-protein kinase 3 — sarcomere/nuclear signaling (emerging) Biallelic and heterozygous variants implicated in pediatric-onset cardiomyopathy and adult HCM via disrupted sarcomere/nuclear functions Parikh et al., Cell 2025; https://doi.org/10.1016/j.cell.2025.01.011 (parikh2025advancesinthe pages 3-4); Lopes et al., Eur Heart J 2024 (lopes2024geneticsofhypertrophic pages 1-2) Often severe pediatric presentations for biallelic defects; heterozygotes show variable adult-onset HCM; emerging clinical evidence.
FHOD3 Formin homology 2 domain containing 3 — actin cytoskeleton regulator (emerging) Variants perturb myofibrillogenesis and cytoskeletal integrity, contributing to sarcomere/myocyte remodeling and HCM phenotypes Parikh et al., Cell 2025; https://doi.org/10.1016/j.cell.2025.01.011 (parikh2025advancesinthe pages 3-4) Emerging gene with cohort evidence of association; may show variable penetrance and phenotype (some familial clustering).
TRIM63 Muscle-specific RING-finger protein (MuRF1) — proteostasis regulator (emerging) Loss‑ or gain‑of‑function variants may alter sarcomeric protein turnover and stress responses → linked to HCM in some cohorts (including homozygous cases) Lopes et al., Eur Heart J 2024; https://doi.org/10.1093/eurheartj/ehae421 (lopes2024geneticsofhypertrophic pages 1-2); Parikh et al., Cell 2025 (parikh2025advancesinthe pages 3-4) Reported homozygous/compound heterozygous cases with more severe remodeling; evidence population-dependent.
SVIL Supervillin — cytoskeletal–membrane linker (emerging) Rare variants recently reported in HCM cohorts; hypothesized to affect sarcomere–cytoskeleton coupling and signal transduction leading to hypertrophy Parikh et al., Cell 2025; https://doi.org/10.1016/j.cell.2025.01.011 (parikh2025advancesinthe pages 3-4); Sarwer et al., Egyptian Heart J 2024; https://doi.org/10.1186/s43044-024-00587-y (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5) Emerging evidence (cohort studies) suggests association with apical/septal phenotypes in some populations; penetrance and natural history under active study.

Table: A compact table of core sarcomeric and emerging HCM-associated genes (2023–2025 evidence), their molecular functions, concise pathogenic mechanisms, source citations (journal, year, DOI + context ID), and short genotype–phenotype notes to support knowledge‑base annotation and curation.

Phenotype associations (HP terms) - Left ventricular hypertrophy (HP:0001712) with asymmetric septal hypertrophy (HP:0009124) and apical variants; diastolic dysfunction (HP:0005150); dynamic LVOT obstruction (HP:0030880); systolic anterior motion of the mitral valve (HP:0034026); atrial fibrillation (HP:0005110); ventricular arrhythmia (HP:0004307); syncope (HP:0001279); sudden cardiac death (HP:0001645). Mechanistic linkage: sarcomeric hypercontractility → diastolic dysfunction; mitral–septal geometry → LVOT obstruction; fibrosis/disarray → arrhythmic substrate (Cell, 2025; Egyptian Heart J, 2024) (parikh2025advancesinthe pages 1-2, sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5).

Cell type involvement (CL terms) - Ventricular cardiomyocyte (CL:0000746): primary locus of sarcomeric dysfunction, Ca2+ handling/energetics remodeling (Cell, 2025) (parikh2025advancesinthe pages 2-3). - Cardiac fibroblast/myofibroblast (CL:0002553): ECM deposition and interstitial fibrosis downstream of stress signaling (Biomedicines, 2024; Cell, 2025) (młynarska2024hypertrophiccardiomyopathywith pages 2-4, parikh2025advancesinthe pages 2-3). - Vascular endothelial cells and smooth muscle (CL:0000115; CL:0000192): microvascular dysfunction and ischemic contribution in hypertrophied myocardium (Biomedicines, 2024) (młynarska2024hypertrophiccardiomyopathywith pages 2-4). - Immune cells (macrophages/lymphocytes): contribute to inflammatory signaling noted in omics (Cell, 2025) (parikh2025advancesinthe pages 2-3).

Anatomical locations (UBERON terms) - Heart (UBERON:0000948); Left ventricle (UBERON:0002084); Interventricular septum (UBERON:0002094); Mitral valve apparatus (UBERON:0002135); Coronary microvasculature (UBERON:0001982). Septal hypertrophy and mitral–septal interaction drive LVOT obstruction; diffuse/interstitial fibrosis remodels LV wall mechanics (Egyptian Heart J, 2024; Biomedicines, 2024) (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5, młynarska2024hypertrophiccardiomyopathywith pages 2-4).

Chemical entities (CHEBI terms) - Calcium ion (CHEBI:29108): increased myofilament Ca2+ sensitivity; diastolic Ca2+ load. - ATP (CHEBI:15422): elevated energetic cost of contraction. - cAMP (CHEBI:17489): relevant to β-adrenergic signaling and downstream kinase pathways. - Therapeutics (not CHEBI-coded here): mavacamten, aficamten as selective cardiac myosin inhibitors that reduce crossbridge formation (Nature Cardiovascular Research, Jul 2024; https://doi.org/10.1038/s44161-024-00505-0; Cell, 2025) (parikh2025advancesinthe pages 2-3).

Evidence items with PMIDs/DOIs/URLs (selected, 2023–2025) - Parikh et al., Advances in the study and treatment of genetic cardiomyopathies. Cell, Feb 2025. DOI: 10.1016/j.cell.2025.01.011. URL: https://doi.org/10.1016/j.cell.2025.01.011 (core mechanisms, genetics, progression, VANISH trial insights) (parikh2025advancesinthe pages 3-4, parikh2025advancesinthe pages 2-3, parikh2025advancesinthe pages 1-2). - Lopes, Ho, Elliott. Genetics of hypertrophic cardiomyopathy: established and emerging implications for clinical practice. European Heart Journal, Jul 2024. DOI: 10.1093/eurheartj/ehae421. URL: https://doi.org/10.1093/eurheartj/ehae421 (gene curation, testing yields, penetrance) (lopes2024geneticsofhypertrophic pages 1-2). - Sarwer et al. Obstructive HCM: genetic insights and therapeutic approach with myosin inhibitors. The Egyptian Heart Journal, Dec 2024. DOI: 10.1186/s43044-024-00587-y. URL: https://doi.org/10.1186/s43044-024-00587-y (LVOT/SAM mechanisms; inhibitors) (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5). - Abbas et al. Role of Genetics in Diagnosis and Management of HCM. Biomedicines, Mar 2024. DOI: 10.3390/biomedicines12030682. URL: https://doi.org/10.3390/biomedicines12030682 (prevalence, testing yields, gene list) (abbas2024roleofgenetics pages 1-2). - Młynarska et al. HCM with Special Focus on Mavacamten. Biomedicines, Nov 2024. DOI: 10.3390/biomedicines12122675. URL: https://doi.org/10.3390/biomedicines12122675 (Ca2+ sensitivity, signaling, AF) (młynarska2024hypertrophiccardiomyopathywith pages 2-4). - Ogieuhi et al. Cardiac myosin inhibitors: aficamten in HOCM. The Egyptian Heart Journal, Jun 2025. DOI: 10.1186/s43044-025-00652-0. URL: https://doi.org/10.1186/s43044-025-00652-0 (clinical developments in CMIs) (ogieuhi2025cardiacmyosininhibitors pages 14-14).

1) Core Pathophysiology - Primary mechanisms: sarcomere hypercontractility with impaired relaxation; increased energetic cost; altered Ca2+ handling and myofilament Ca2+ sensitivity; activation of TGF-β/MAPK and other stress pathways; interstitial and replacement fibrosis; cytoskeletal remodeling; inflammation (Cell, 2025) (parikh2025advancesinthe pages 2-3). Microvascular dysfunction and ischemia further exacerbate hypertrophy and fibrosis, especially with LVOT obstruction (Biomedicines, 2024; Egyptian Heart J, 2024) (młynarska2024hypertrophiccardiomyopathywith pages 2-4, sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5). - Dysregulated pathways: downregulation of energy metabolism and Ca2+ homeostasis; upregulation of ECM/inflammation/cytoskeleton; evidence for genotype-independent late-stage remodeling across HCM tissues (Cell, 2025) (parikh2025advancesinthe pages 2-3). - Affected cellular processes: crossbridge cycling kinetics, diastolic Ca2+ removal, mitochondrial energetics, proteostasis, ECM deposition, and electrophysiologic remodeling (AF/ventricular arrhythmia substrate) (Cell, 2025; Biomedicines, 2024) (parikh2025advancesinthe pages 2-3, młynarska2024hypertrophiccardiomyopathywith pages 2-4).

2) Key Molecular Players - Genes/proteins (HGNC): core sarcomere genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1); emerging (ALPK3, FHOD3, TRIM63, SVIL). MYBPC3 and MYH7 account for most genotype-positive cases in many cohorts (Eur Heart J, 2024; Cell, 2025) (lopes2024geneticsofhypertrophic pages 1-2, parikh2025advancesinthe pages 1-2). See table above for concise roles and genotype–phenotype notes (parikh2025advancesinthe pages 3-4). - Chemical entities (CHEBI): calcium ion (CHEBI:29108), ATP (CHEBI:15422), cAMP (CHEBI:17489). Pharmacologic agents targeting the sarcomere include mavacamten and aficamten (mechanistic: reduction of strongly bound myosin heads/crossbridges) (Cell, 2025) (parikh2025advancesinthe pages 2-3). - Cell types: ventricular cardiomyocytes (contractile deficit/energetics), cardiac fibroblasts (fibrosis), endothelium/smooth muscle of microvasculature (ischemia), immune cells (inflammatory milieu) (Cell, 2025; Biomedicines, 2024) (parikh2025advancesinthe pages 2-3, młynarska2024hypertrophiccardiomyopathywith pages 2-4). - Anatomical locations (UBERON): left ventricle, interventricular septum, mitral apparatus, coronary microvasculature; asymmetric septal hypertrophy and mitral–septal interactions drive LVOT obstruction (Egyptian Heart J, 2024) (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5).

3) Biological Processes (GO) disrupted - Cardiac muscle contraction/relaxation (GO:0060048, GO:0008016); regulation of myofilament Ca2+ sensitivity (part of GO:0006937); ATP metabolic process/oxidative phosphorylation (GO:0006091/GO:0006119); calcium ion transport (GO:0006816); extracellular matrix organization (GO:0030198); response to TGF-β (GO:0071559) and MAPK cascade (GO:0000165); inflammatory response (GO:0006954) (Cell, 2025; Biomedicines, 2024) (parikh2025advancesinthe pages 2-3, młynarska2024hypertrophiccardiomyopathywith pages 2-4).

4) Cellular Components (GO) - Sarcomere/thick and thin filament (GO:0030017, GO:0005865); Z-disc (GO:0030018); sarcoplasmic reticulum (GO:0016529); mitochondrion (GO:0005739); intercalated disc (GO:0014704); extracellular matrix (GO:0031012) (Cell, 2025) (parikh2025advancesinthe pages 2-3).

5) Disease Progression - Sequence: pathogenic variant → hypercontractility/energetic inefficiency and Ca2+ dysregulation → activation of stress signaling and ECM programs → hypertrophy (often septal), diastolic dysfunction, microvascular dysfunction/ischemia → interstitial/replacement fibrosis and myocyte disarray → clinical phenotypes (dyspnea, syncope, arrhythmias; sudden death risk) → a subset (~8%) progresses to LV systolic dysfunction (LVEF <50%), commonly with extensive fibrosis (Cell, 2025) (parikh2025advancesinthe pages 3-4). Preclinical sarcomere-positive carriers show early diastolic/energetic abnormalities; valsartan stabilized/improved early remodeling in VANISH, particularly in less-hypertrophied individuals (Cell, 2025) (parikh2025advancesinthe pages 3-4).

6) Phenotypic Manifestations (HP) and mechanistic links - LV hypertrophy with asymmetric septal predominance (HP:0001712/HP:0009124), diastolic dysfunction (HP:0005150) from Ca2+ sensitivity/relaxation deficit; dynamic LVOT obstruction (HP:0030880) and SAM-related MR (HP:0034026) from mitral–septal geometry; atrial fibrillation (HP:0005110) and ventricular arrhythmias (HP:0004307) from fibrosis/disarray/electrical remodeling; syncope (HP:0001279) and sudden cardiac death (HP:0001645) as major clinical risks (Cell, 2025; Egyptian Heart J, 2024; Biomedicines, 2024) (parikh2025advancesinthe pages 1-2, sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5, młynarska2024hypertrophiccardiomyopathywith pages 2-4).

Recent developments and latest research (2023–2025) - Genetics and penetrance: Reappraisal of gene lists confirms a core set of sarcomeric genes account for most genotype-positive HCM; many previously proposed genes lack sufficient evidence. GWAS (~4,500 cases) shows common variants contribute polygenic risk independent of rare sarcomere variants; polygenic/monogenic factors jointly shape risk (Cell, Feb 2025) (parikh2025advancesinthe pages 2-3). Penetrance is incomplete; among carriers, about 60% convert to overt HCM within the first four decades, with earlier disease and worse outcomes in sarcomere-positive individuals (Cell, 2025) (parikh2025advancesinthe pages 3-4). - Mechanistic omics: HCM tissues demonstrate downregulated energetics/Ca2+ homeostasis and upregulated ECM/inflammation/cytoskeletal remodeling, indicating convergence of late remodeling pathways cross-cutting genotypes (Cell, 2025) (parikh2025advancesinthe pages 2-3). - Early-stage intervention: VANISH trial data indicate valsartan can stabilize/improve composite remodeling in early sarcomeric HCM, especially in patients with less LVH (Cell, 2025) (parikh2025advancesinthe pages 3-4). - Therapeutics targeting the sarcomere: Myosin inhibitors (mavacamten, aficamten) reduce the number of force-generating myosin heads to directly counter hypercontractility; aficamten binds a distinct allosteric site and stabilizes a weak actin-binding state (mechanistic class summary) (Cell, 2025) (parikh2025advancesinthe pages 2-3). Clinical reviews in 2024–2025 report consistent improvements in LVOT gradients, symptoms, and functional capacity in obstructive HCM (Egyptian Heart J, 2024; Biomedicines, 2024; Egyptian Heart J, 2025) (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5, młynarska2024hypertrophiccardiomyopathywith pages 2-4, ogieuhi2025cardiacmyosininhibitors pages 14-14).

Current applications and real-world implementations - Genetic testing: Recommended for all HCM patients to identify causal variants, enable cascade testing, refine diagnosis, and exclude phenocopies; yields ~30% in sporadic cases and up to ~60% in familial/younger patients with typical asymmetric septal hypertrophy. Periodic reclassification of variants is necessary (Biomedicines, Mar 2024; https://doi.org/10.3390/biomedicines12030682; Eur Heart J, Jul 2024; https://doi.org/10.1093/eurheartj/ehae421) (abbas2024roleofgenetics pages 1-2, lopes2024geneticsofhypertrophic pages 1-2). - Imaging and physiology: Diagnosis integrates wall thickness, diastolic function, and fibrosis assessment; LVOT physiology and mitral–septal geometry guide management in obstructive disease (Egyptian Heart J, 2024) (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5). - Myosin inhibitors: Mavacamten (approved) and aficamten (advanced development) are used/being evaluated for symptomatic obstructive HCM, with documented reductions in LVOT gradients and symptomatic/functional improvements; ongoing studies are defining long-term outcomes and roles across subgroups (Egyptian Heart J, 2024; Biomedicines, 2024; Egyptian Heart J, 2025) (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5, młynarska2024hypertrophiccardiomyopathywith pages 2-4, ogieuhi2025cardiacmyosininhibitors pages 14-14).

Expert opinions and analysis from authoritative sources - Cell (2025) synthesis emphasizes that sarcomere hypercontractility and impaired relaxation are upstream in HCM, with shared downstream remodeling (ECM/inflammation/energy/Ca2+) across genetic backgrounds; genotype-positive status portends earlier and more adverse outcomes and supports mechanistically targeted therapy (Cell, Feb 2025) (parikh2025advancesinthe pages 2-3, parikh2025advancesinthe pages 1-2). - European Heart Journal (2024) clarifies established vs emerging HCM genes, the clinical utility and limits of genetic testing, and the importance of rigorous gene curation to avoid over-attribution beyond core sarcomeric genes (Eur Heart J, Jul 2024) (lopes2024geneticsofhypertrophic pages 1-2).

Relevant statistics and data from recent studies - Prevalence: ~1:500 adults (range up to ~1:200 reported in recent literature) (Cell, Feb 2025; Biomedicines, Mar 2024) (parikh2025advancesinthe pages 2-3, abbas2024roleofgenetics pages 1-2). - Genetic architecture: >80% of sarcomeric HCM attributable to MYBPC3 and MYH7 among genotype-positive patients; overall genotype-positive yields ~30–60% depending on cohort (Eur Heart J, Jul 2024; Biomedicines, Mar 2024; Cell, Feb 2025) (lopes2024geneticsofhypertrophic pages 1-2, abbas2024roleofgenetics pages 1-2, parikh2025advancesinthe pages 1-2). - Penetrance and progression: Approximately 60% of sarcomere variant carriers convert to overt HCM (often within first four decades). About 8% of HCM patients progress to LV systolic dysfunction (LVEF <50%), frequently in the setting of extensive fibrosis (Cell, Feb 2025) (parikh2025advancesinthe pages 3-4). - Arrhythmic risk: Sudden arrhythmic death risk is highest in young patients (≈2%/yr in children, ≈1%/yr in adults until later decades) and is higher overall in sarcomere-positive disease (Cell, Feb 2025) (parikh2025advancesinthe pages 3-4).

Directly relevant quotes (contextual) - “Upstream HCM biology reflects sarcomere hypercontractility and impaired relaxation with increased energetic cost; downstream, omics identify downregulation of energy metabolism and Ca2+ homeostasis and upregulation of ECM, inflammation, and cytoskeletal remodeling.” (paraphrased summary with details from Cell, Feb 2025) (parikh2025advancesinthe pages 2-3). - “Diagnostic and management strategies should integrate genetic testing with advanced imaging and clinical profiles; genotype-positive patients show earlier onset and worse outcomes.” (Eur Heart J, Jul 2024; Cell, Feb 2025) (lopes2024geneticsofhypertrophic pages 1-2, parikh2025advancesinthe pages 1-2).

Notes and limitations - Imaging biomarkers (CMR LGE/T1 mapping, PET perfusion/metabolism) are central to risk stratification and phenotyping in HCM, but specific quantitative metrics and PET studies were beyond the directly retrieved, citable context here; the mechanistic and clinical statements above are anchored to 2023–2025 Cell/Eur Heart J and contemporary clinical reviews (parikh2025advancesinthe pages 3-4, ogieuhi2025cardiacmyosininhibitors pages 14-14).

References (with URLs/dates) - Parikh et al. Cell, Feb 2025. https://doi.org/10.1016/j.cell.2025.01.011 (parikh2025advancesinthe pages 3-4, parikh2025advancesinthe pages 2-3, parikh2025advancesinthe pages 1-2). - Lopes, Ho, Elliott. European Heart Journal, Jul 2024. https://doi.org/10.1093/eurheartj/ehae421 (lopes2024geneticsofhypertrophic pages 1-2). - Sarwer et al. The Egyptian Heart Journal, Dec 2024. https://doi.org/10.1186/s43044-024-00587-y (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5). - Abbas et al. Biomedicines, Mar 2024. https://doi.org/10.3390/biomedicines12030682 (abbas2024roleofgenetics pages 1-2). - Młynarska et al. Biomedicines, Nov 2024. https://doi.org/10.3390/biomedicines12122675 (młynarska2024hypertrophiccardiomyopathywith pages 2-4). - Ogieuhi et al. The Egyptian Heart Journal, Jun 2025. https://doi.org/10.1186/s43044-025-00652-0 (ogieuhi2025cardiacmyosininhibitors pages 14-14).

References

  1. (parikh2025advancesinthe pages 2-3): Victoria N. Parikh, Sharlene M. Day, Neal K. Lakdawala, Eric D. Adler, Iacopo Olivotto, Christine E. Seidman, and Carolyn Y. Ho. Advances in the study and treatment of genetic cardiomyopathies. Cell, 188:901-918, Feb 2025. URL: https://doi.org/10.1016/j.cell.2025.01.011, doi:10.1016/j.cell.2025.01.011. This article has 14 citations and is from a highest quality peer-reviewed journal.

  2. (lopes2024geneticsofhypertrophic pages 1-2): Luis R Lopes, Carolyn Y Ho, and Perry M Elliott. Genetics of hypertrophic cardiomyopathy: established and emerging implications for clinical practice. European Heart Journal, 45:2727-2734, Jul 2024. URL: https://doi.org/10.1093/eurheartj/ehae421, doi:10.1093/eurheartj/ehae421. This article has 70 citations and is from a highest quality peer-reviewed journal.

  3. (parikh2025advancesinthe pages 1-2): Victoria N. Parikh, Sharlene M. Day, Neal K. Lakdawala, Eric D. Adler, Iacopo Olivotto, Christine E. Seidman, and Carolyn Y. Ho. Advances in the study and treatment of genetic cardiomyopathies. Cell, 188:901-918, Feb 2025. URL: https://doi.org/10.1016/j.cell.2025.01.011, doi:10.1016/j.cell.2025.01.011. This article has 14 citations and is from a highest quality peer-reviewed journal.

  4. (sarwer2024obstructivehypertrophiccardiomyopathy pages 4-5): Khadija Sarwer, Saeeda Lashari, Nida Rafaqat, Maher, Abdul Raheem, Muneeb Ur Rehman, and Syed Muhammad Iraj Abbas. Obstructive hypertrophic cardiomyopathy: from genetic insights to a multimodal therapeutic approach with mavacamten, aficamten, and beyond. The Egyptian Heart Journal, Dec 2024. URL: https://doi.org/10.1186/s43044-024-00587-y, doi:10.1186/s43044-024-00587-y. This article has 1 citations.

  5. (młynarska2024hypertrophiccardiomyopathywith pages 2-4): Ewelina Młynarska, Ewa Radzioch, Bartłomiej Dąbek, Klaudia Leszto, Alicja Witkowska, Witold Czarnik, Weronika Jędraszak, Jacek Rysz, and Beata Franczyk. Hypertrophic cardiomyopathy with special focus on mavacamten and its future in cardiology. Biomedicines, 12:2675, Nov 2024. URL: https://doi.org/10.3390/biomedicines12122675, doi:10.3390/biomedicines12122675. This article has 1 citations and is from a poor quality or predatory journal.

  6. (parikh2025advancesinthe pages 3-4): Victoria N. Parikh, Sharlene M. Day, Neal K. Lakdawala, Eric D. Adler, Iacopo Olivotto, Christine E. Seidman, and Carolyn Y. Ho. Advances in the study and treatment of genetic cardiomyopathies. Cell, 188:901-918, Feb 2025. URL: https://doi.org/10.1016/j.cell.2025.01.011, doi:10.1016/j.cell.2025.01.011. This article has 14 citations and is from a highest quality peer-reviewed journal.

  7. (abbas2024roleofgenetics pages 1-2): Mohammed Tiseer Abbas, Nima Baba Ali, Juan M. Farina, Ahmed K. Mahmoud, Milagros Pereyra, Isabel G. Scalia, Moaz A. Kamel, Timothy Barry, Steven J. Lester, Charles R. Cannan, Rohit Mital, Susan Wilansky, William K. Freeman, Chieh-Ju Chao, Said Alsidawi, Chadi Ayoub, and Reza Arsanjani. Role of genetics in diagnosis and management of hypertrophic cardiomyopathy: a glimpse into the future. Biomedicines, 12:682, Mar 2024. URL: https://doi.org/10.3390/biomedicines12030682, doi:10.3390/biomedicines12030682. This article has 19 citations and is from a poor quality or predatory journal.

  8. (ogieuhi2025cardiacmyosininhibitors pages 14-14): Ikponmwosa Jude Ogieuhi, Victor Oluwatomiwa Ajekiigbe, Boluwaduro Abasiekem Adeyemi, Bright Nwatamole, Komolafe Babajide Ayodeji, Oshomoh Mark-Anthony Ugiomoh, Temiloluwa Adebayo Odeniyi, Adewunmi Akingbola, Efosa Peace Iyawe, Olabode Olawale Oladejo, Motunrayo Oluwatoyosi Lawal, Nathnael Abera Woldehana, Ifeoluwa Sandra Bakare, Adejumo Temilade Patience, and Grace Chinenye Okoro. Cardiac myosin inhibitors: efficacy, safety and future directions of aficamten in hypertrophic obstructive cardiomyopathy. The Egyptian Heart Journal, Jun 2025. URL: https://doi.org/10.1186/s43044-025-00652-0, doi:10.1186/s43044-025-00652-0. This article has 2 citations.