#hypertrophic-cardiomyopathy #sarcomere #ion-channels #calcium-handling #arrhythmogenesis

HCM: Mechanism

Detail pages. concepts/HCM-Calcium-Homeostasis · concepts/HCM-Ion-Channel-Remodeling

Molecular detail. entities/MYBPC3 — the gene and protein biology of the commonest HCM gene, and itself a sub-hub — with concepts/Sarcomere-Biology and concepts/Haploinsufficiency beneath it.

Definition

Hypertrophic cardiomyopathy begins with a sarcomeric protein that generates too much force. The causal variants converge on increased myofilament calcium sensitivity, so that at any given calcium concentration the sarcomere develops more tension and relaxes more slowly — and the hypertrophy, myocyte disarray and interstitial fibrosis are the myocardium's response to that. The arrhythmic phenotype arises separately. Ion channels and calcium handling are remodelled before hypertrophy is visible, so electrical vulnerability and structural severity are two processes running on different clocks. That dissociation is the reason a drug which corrects contractility can relieve obstruction without preventing sudden death. (sources/HCM-NEJM-2025, rating: very high; sources/membrane-potential-physrev-2021, rating: very high)

Abbreviations: APD, action potential duration; CICR, calcium-induced calcium release; DAD/EAD, delayed/early afterdepolarisation; INaL, late sodium current; Ito, transient outward potassium current; NCX, sodium–calcium exchanger; SR, sarcoplasmic reticulum; VT, ventricular tachycardia.

Key Concepts

The Sarcomere to the Phenotype

The histological signature is myocyte disarray, interstitial fibrosis and thick-walled intramural arteries, with a small LV cavity and a supranormal ejection fraction of 70–75%. (sources/HCM-NEJM-2025, rating: very high)
Increased myofilament calcium sensitivity is the final common pathway. Mutations in different sarcomeric proteins converge on a sarcomere that develops more tension per unit calcium and relaxes more slowly, which is the proximate cause of both the hypercontractile physiology and the impaired filling. See concepts/Sarcomere-Biology. (sources/HCM-NEJM-2025)
Truncating MYBPC3 variants act by haploinsufficiency. Nonsense, frameshift and splice-site variants produce transcripts cleared by nonsense-mediated decay, the ubiquitin–proteasome system or autophagy, leaving roughly half-normal wild-type protein rather than a toxic product. See concepts/Haploinsufficiency. (sources/mybpc3-gene-2015, rating: medium)
The phenotype is an outcome, not a direct effect. The same variant can produce asymmetric septal hypertrophy, apical hypertrophy or no hypertrophy for decades, so the pathway from protein to wall thickness runs through modifiers that are polygenic and environmental rather than through the mutation alone. See concepts/HCM-Genetics-and-Phenotypes.

The cMyBP-C Regulatory Layer

cMyBP-C is a thick-filament brake, not a structural strut. The protein carries eight immunoglobulin-like and three fibronectin-like domains, an N-terminal C0 domain unique to the cardiac isoform, and an M-motif between C1 and C2 that holds the regulatory phosphorylation sites. It sits in the C-zone of the A-band in transverse stripes about 43 nm apart, tethering myosin S1 heads through C1-M-C2 to myosin S2 and thereby limiting loaded shortening velocity and power output. Knockout accelerates crossbridge cycling and raises force redevelopment. (sources/mybpc3-gene-2015, rating: medium)
Phosphorylation releases the brake. PKA — with CaMKII, RSK, PKD and PKC as secondary kinases — phosphorylates Ser273, Ser282 and Ser302, with Ser282 acting as a hierarchical switch that makes the other two accessible. Dephosphorylated protein binds myosin S2 and brakes the crossbridge; phosphorylated protein shifts to actin, accelerating cycling and promoting relaxation, which is what makes the lusitropic response to adrenergic stimulation possible. See concepts/Sarcomere-Biology.
The diastolic consequence arrives before hypertrophy. cMyBP-C prevents residual crossbridge cycling at low diastolic calcium, so reduced or absent protein impairs relaxation directly — diastolic dysfunction is an early consequence of a MYBPC3 mutation and is present independent of wall thickness. This is the mechanism by which a genotype can be electrically and haemodynamically active while the echocardiogram is still normal. (sources/mybpc3-gene-2015)
Phosphorylation is reduced in heart failure, and phosphomimetic protein protects against ischaemia–reperfusion injury and calpain-mediated proteolysis. Other modifications pull in the opposite direction: acetylation of the N-terminal region may promote proteolysis, and S-glutathiolation increases myofilament calcium sensitivity. The net post-translational fingerprint in disease, and which modification to target, have not been established.

From Truncating Variant to Arrhythmic Substrate

Truncating variants cause haploinsufficiency, not a toxic fragment. The truncated protein is undetectable in human myocardium and in heterozygous knock-in mice because it is cleared by nonsense-mediated mRNA decay, the ubiquitin–proteasome system and the autophagy–lysosome pathway. What remains is a reduced total level of cMyBP-C rather than a stable poison. See concepts/Haploinsufficiency. (sources/mybpc3-gene-2015, rating: medium)
Missense variants may instead poison the sarcomere. Stable mutant protein can be incorporated, disrupting structure and function. Homozygous c.772G>A knock-in mice produce three mutant species at low levels, which suggests combined haploinsufficiency and polypeptide poisoning in the homozygous state. The distinction matters therapeutically: gene replacement treats haploinsufficiency, whereas silencing or exon skipping is needed for a dominant-negative allele. See entities/MYBPC3.
Reduced cMyBP-C raises myofilament calcium sensitivity. This has been shown in human HCM samples, in heterozygous and homozygous knock-in mice, and in engineered heart tissue. The mechanism linking the two is not fully elucidated but probably reflects relief of the diastolic braking role, and it makes calcium sensitivity the point at which a protein-level defect becomes a contractile one.
The calcium leak reaches the arrhythmia through RyR2. cMyBP-C may interact directly with RyR2, and a conformational change can disrupt intracellular calcium homeostasis through that interaction, contributing to spontaneous sarcoplasmic reticulum calcium release and the DADs that trigger ventricular tachycardia. See concepts/HCM-Calcium-Homeostasis. (sources/HCM-VA-FCVMed-2022, rating: high)
Proteostasis fails as the disease progresses. Neurohumoral stress and ageing impair proteasomal activity in Mybpc3 mutant mice, and proteasomal activity is depressed in human HCM myocardium — a second hit that turns a compensated haploinsufficiency into a decompensating one. (sources/mybpc3-gene-2015)

Ion Channel Remodelling

Three interlocking mechanisms generate arrhythmia: ion channel remodelling — increased INaL and L-type calcium current with reduced potassium currents — enhanced myofilament calcium sensitivity, and sarcoplasmic reticulum calcium overload generating early and delayed afterdepolarisations. (sources/HCM-VA-FCVMed-2022, rating: high)
INaL upregulation is an early event, not a consequence of hypertrophy. Increased late sodium current is demonstrable in explanted hearts from both MYBPC3 and MYH7 carriers and causes sodium overload, reverse-mode NCX calcium overload, action potential prolongation and EADs. Critically it is detectable in preclinical mutation carriers before hypertrophy appears, so electrical remodelling precedes structural disease. Ranolazine and mexiletine normalise the action potential and reverse electromechanical dysfunction in myocyte and animal models, but the clinical evidence in HCM remains observational and off-label. (sources/membrane-potential-physrev-2021, rating: very high)
Loss of Ito desynchronises calcium release. A reduced phase 1 notch depolarises the start of the plateau, so L-type channel activation is less synchronised across the subendocardial–subepicardial axis. The result is asynchronous calcium-induced calcium release, local diastolic calcium elevation and DAD-triggered VT under adrenergic stimulation. (sources/membrane-potential-physrev-2021)
The consequence for risk assessment is that the substrate exists before the risk model can see it: HCM Risk-SCD requires wall thickness, left atrial size and NSVT, none of which is abnormal in the preclinical carrier. See concepts/HCM-Diagnosis-and-Risk and concepts/HCM-Calcium-Homeostasis. (sources/HCM-VA-FCVMed-2022)

Why the Two Phenotypes Respond to Different Therapy

Hypercontractile and fibrotic physiology are different diseases sharing a name. Where the sarcomere generates excess force, relieving obstruction works; where fibrosis and reduced compliance have replaced hypercontractility, the patient is treated as classic systolic heart failure. (sources/HCM-NEJM-2025, rating: very high)
Nonobstructive symptoms are not contractility-driven. They arise from diastolic dysfunction, subendocardial ischaemia, reduced LV compliance and microvascular disease — none of which myosin inhibition corrects, which is why the drug reduced NT-proBNP by 59% in nonobstructive disease without improving peak oxygen consumption or symptom score. See concepts/HCM-Management. (sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)

Contradictions / Open Questions

Electrical remodelling precedes the phenotype, but every therapeutic decision requires the phenotype. INaL elevation and reduced Ito are present in mutation carriers with normal wall thickness, yet diagnosis needs 15 mm, risk assessment needs structural variables, and ICD indications need a calculated five-year probability. A mechanism that is known to be active has no route into a clinical decision. (sources/membrane-potential-physrev-2021, rating: very high; sources/HCM-VA-FCVMed-2022, rating: high)
INaL blockade has a coherent rationale and no clinical trial. Ranolazine and mexiletine normalise the action potential and reverse electromechanical dysfunction in myocyte and animal models, and the mechanism is demonstrated in human explanted hearts — but the clinical evidence in HCM is observational and the agents are off-label. A mechanism this well characterised has never been tested against an arrhythmic endpoint in this population. (sources/membrane-potential-physrev-2021)
The failure of myosin inhibition in nonobstructive disease is explained by assertion rather than measurement. The trial result is unambiguous, but the account that diastolic dysfunction, ischaemia and microvascular disease dominate symptoms is a mechanistic inference, not something the trial measured. If it is right, it predicts that a therapy targeting fibrosis or microvascular disease should work in the same patients, and that prediction is untested. (sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)
Fibrosis is used as a risk marker but has never been shown to be a causal target. LGE burden feeds directly into ICD decisions, and annual mortality is about 2% in patients with extensive fibrosis. No therapy that reduces fibrosis in HCM has been shown to reduce sudden death, so it is unclear whether fibrosis generates arrhythmia or merely marks the myocardium that does. (sources/HCM-NEJM-2025, rating: very high)
The post-translational modifications of cMyBP-C pull in opposite directions. M-motif phosphorylation is broadly protective — reduced in heart failure, with phosphomimetic protein cardioprotective — while S-glutathiolation raises myofilament calcium sensitivity and acetylation appears to promote calpain-mediated proteolysis. The net fingerprint under disease conditions, and therefore which modification a therapy should target, has never been systematically established. (sources/mybpc3-gene-2015, rating: medium)

Connections

Part of entities/HCM — the parent overview
The variants that initiate the mechanism — concepts/HCM-Genetics-and-Phenotypes
How the mechanism is measured and risk estimated — concepts/HCM-Diagnosis-and-Risk
Where the mechanism is or is not therapeutically addressable — concepts/HCM-Management
Molecular and cellular detail — concepts/Sarcomere-Biology, concepts/Haploinsufficiency, concepts/HCM-Calcium-Homeostasis and concepts/HCM-Ion-Channel-Remodeling
Gene page — entities/MYBPC3
Electrophysiology background — concepts/Electrical-Remodeling and concepts/Cardiac-Action-Potential
Fibrosis imaging — concepts/Late-Gadolinium-Enhancement
Disease modelling — concepts/iPSC-Derived-Cardiomyocytes