Table 1.

Diverse landscape of HCM endophenotypes

HCM Endophenotype³⁰	Relevance to HCM	Selected Supporting References
Autoimmunity	Association studies linking HCM with Anti-HLA-17 and β1-receptors and Muscarin-2-receptors; Prevalence studies linking HCM with autoimmune connective tissue disease including systemic sclerosis, systemic lupus erythematosus, others.	39-45
Cell transformation	Endothelial-to-mesenchymal transition and cardiac fibrosis; TGF-β-associated fibrosis in noncardio-myocyte cell types	46,47
DNA damage	Cardiomyocyte-specific telomere shortening and heart failure in hypertrophic hearts	48
DNA repair deficiency	G:C base excision repair editing ameliorates HCM phenotype	49
Fibrosis	Left ventricular thickening due to interstitial collagen deposition, and replacement fibrosis from microvascular ischemia	50-53
Hyperplasia	Junctophilin-2-mediated cardiomyocyte hyperplasia ex vivo, and hyperplastic remodeling in zebra fish model of HCM in vivo	54-57
Hypertension	Polygenic risk for HCM associates positively with diastolic blood pressure	27
Immunological derangement	Tacrolimus use associated with HCM in a pediatric cohort and in other case series in adults	37, 58, 59
Metabolic derangement	Dysregulated mitochondrial Ca²⁺ handling linked to abnormal LV contractility; ↑ plasma branched chain amino acids, triglycerides and ether phospholipids in HCM; ↓ phosphocreatine:ATP in HCM vs. control	60-65
Inflammation	↑circulating IL-6, IL-1β, IL-1RA, IL-10	66, 67
Metaplasia	Juxtaglomerular metaplasia in feline HCM, linked to renin-angiotensin axis overactivation	68
Mitochondrial dysfunction	↓cardioplipin à lipotoxicity in HCM	69,70
Neoplastic signaling	Dysregulated RAS-RAF-MEK-ERK MAPK pathway	71-73
Neovascularization	Abnormal diastolic coronary vascular reserve related to vasculopathy of microcirculation	74
Thromboembolism	Impaired von Willebrand factor ↑thrombin generation ↑platelet reactivity	75-77
Senescence	Leukocyte telomere length correlates with HCM phenotypic parameters (e.g., inversely with LVOT gradient)	78
Vasculitis	HCM incidence in associations with mixed cryoglobulinemia vasculitis, hepatitis C virus, polyarteritis nodosa	79-82
Hypoxia	HIF1-α-PPARgamma axis regulates glycolytic and lipid metabolism pathways in hypertrophic cardiomyopathies	83
Oxidant stress	Disruption to redox potential of cardiomyocytes slinked to fibrosis and LV thickening in HCM	31, 84-86

ATP = adenosine triphosphate; ERK = extracellular signal-regulated kinase; HCM = hypertrophic cardiomyopathy; HIF = hypoxia inducible factor; HLA = human leukocyte antigen; IL = interleukin; LV = left ventricle; LVOT = left ventricular outflow tract; MAPK = mitogen-activated protein kinase; PPAR = peroxisome proliferator-activated receptor; TGF = transforming growth factor.

Endophenotypes that are implicated as a cause of HCM or a response to HCM.