Calcium Homeostasis in HCM
Definition
Calcium homeostasis dysregulation in HCM refers to three interrelated disturbances caused by sarcomere gene mutations: (1) increased myofilament Ca²⁺ sensitivity, (2) decreased sarcoplasmic reticulum (SR) Ca²⁺ reuptake, and (3) cytosolic Ca²⁺ overload. These disturbances collectively promote ventricular arrhythmia through triggered activities (EADs and DADs), triangular AP morphology, shortened ERP, and reentry circuit formation.
Key Concepts
Three Core Disturbances
- ↑Myofilament Ca²⁺ sensitivity: Troponin and other sarcomere mutations (e.g., TNNT2-I79N, TNNT2-R92Q, TNNI-R145G, Tm-D175N) reduce the Ca²⁺ concentration required for contraction; slow diastolic Ca²⁺ dissociation from myofilaments → reduced cytosolic free Ca²⁺ dynamics. (sources/HCM-VA-FCVMed-2022)
- ↓SR Ca²⁺ reuptake: Impaired SERCA2a function reduces the efficiency of Ca²⁺ removal into the SR during diastole → diastolic Ca²⁺ accumulation. (sources/HCM-VA-FCVMed-2022)
- Cytosolic Ca²⁺ overload: Driven by ↑INaL (via NCX impairment), ↑ILTCC, and reduced myofilament release → feeds back into CaMKII activation and RyR2 hyperphosphorylation. (sources/HCM-VA-FCVMed-2022)
Mechanism 1: Triangular AP Morphology and Shortened ERP
- Enhanced myofilament Ca²⁺ binding slows diastolic Ca²⁺ dissociation → ↓Ca²⁺ transient amplitude and dynamics → ↓NCX inward current (third AP phase) → shortened early repolarization (APD70) → triangular AP morphology. (sources/HCM-VA-FCVMed-2022)
- Shortened ERP predisposes to reentry circuit formation. (sources/HCM-VA-FCVMed-2022)
- Demonstrated in: I79N-TnT hiPSC-CMs (myofibril disorder, ↑arrhythmogenic events, ↓Ca²⁺ transient amplitude); human recombinant thin myofilament + I79N(+/-) hiPSC-CMs (Ca²⁺ alternation and AP morphology triangulation). (sources/HCM-VA-FCVMed-2022)
Mechanism 2: SR Ca²⁺ Overload and Triggered Activities
- Under high stimulation frequency: ↑cytosolic Ca²⁺ buffer capacity (from enhanced myofilament sensitivity) → Ca²⁺ transient attenuation + diastolic Ca²⁺ accumulation → SR Ca²⁺ overload → spontaneous SR Ca²⁺ release → EADs and DADs. (sources/HCM-VA-FCVMed-2022)
- CaMKII hyperactivation (secondary to cytosolic Ca²⁺ accumulation) → RyR2 hyperphosphorylation at CaMKII-sensitive sites → ↑RyR2 opening probability → further SR Ca²⁺ leak → positive feedback. (sources/HCM-VA-FCVMed-2022)
- Confirmed in human HCM specimens and mouse HCM models: TnT-I79N cardiomyocytes show slower Ca²⁺ transient kinetics, ↑diastolic Ca²⁺ (especially at high stimulation), ↑SR Ca²⁺ content. (sources/HCM-VA-FCVMed-2022)
- Guinea pig cardiomyocytes transfected with TNT-R92Q, TNI-R145G, Tm-D175N: ↑Ca²⁺ binding → ↑Ca²⁺ buffer capacity → ↑diastolic Ca²⁺ → CaMKII activation → ↑SR Ca²⁺ leakage; targeting myofilament Ca²⁺ sensitivity is an attractive therapeutic strategy. (sources/HCM-VA-FCVMed-2022)
- MYL2-R58Q hiPSC-CMs: ↑myofibrillar disorder, irregular beating, ↓peak Ca²⁺ transients, ↑attenuation time, compensatory ↓ILTCC peak. (sources/HCM-VA-FCVMed-2022)
MYBPC3 and RyR2 Interaction
- MYBPC3 may interact directly with RyR2; MYBPC3 mutation or conformational change disrupts intracellular Ca²⁺ homeostasis via this protein-protein interaction. (sources/HCM-VA-FCVMed-2022)
- Mybpc3-KI mice show ↑myofilament Ca²⁺ sensitivity, faster Ca²⁺ transient decay, and diastolic dysfunction. (sources/HCM-VA-FCVMed-2022)
Oxidative Stress Contribution
- Overactivated oxidative stress → ↑myofilament Ca²⁺ sensitivity → hypertrophy and diastolic dysfunction. (sources/HCM-VA-FCVMed-2022)
- FTY720 (sphingosine-1-phosphate receptor regulator) improves Ca²⁺ hypersensitivity by reducing oxidative stress. (sources/HCM-VA-FCVMed-2022)
- Cardiomyocyte MPO (myeloperoxidase) inhibition alleviates relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. (sources/HCM-VA-FCVMed-2022)
Therapeutic Implications
- Blebbistatin: Non-selective myosin inhibitor; directly reduces myocardial Ca²⁺ sensitivity; anti-arrhythmic in TnT-mutation animal models; research use only. (sources/HCM-VA-FCVMed-2022)
- Mavacamten: Reduces Ca²⁺ sensitivity indirectly by inhibiting myosin ATPase and cross-bridge cycling; preclinical and clinical data support structural benefit; arrhythmia-specific data pending. (sources/HCM-VA-FCVMed-2022)
- Disopyramide: Stabilizes closed state of RyR2 channel; reduces cytosolic Ca²⁺; inhibits Ca²⁺-dependent DADs. (sources/HCM-VA-FCVMed-2022)
- Targeting myofilament Ca²⁺ sensitivity directly (as shown in Tm-E180G hybrid mouse rescue experiments) is a conceptually validated prevention strategy. (sources/HCM-VA-FCVMed-2022)
Contradictions / Open Questions
- Species and model translational gap: Key calcium homeostasis findings (K⁺ current reduction, CaMKII-mediated IK1/Ito downregulation) observed in Mybpc3 knock-in mice were NOT replicated in human MYBPC3-homozygous EHTs or in LV septum samples from HCM patients. Different HCM sarcomere mutations show inconsistent contractility and molecular expression in iPSC-CM models. Extrapolating mechanistic conclusions from mouse models to human disease requires caution. (sources/HCM-VA-FCVMed-2022)
- iPSC-CM immaturity limitation: hiPSC-CM repolarization does not resemble mature adult ventricular myocytes; Ca²⁺ handling in iPSC-CMs may not accurately recapitulate adult HCM phenotypes. Findings from iPSC-CM models may overestimate or underestimate the magnitude of Ca²⁺ dysregulation in vivo. (sources/HCM-VA-FCVMed-2022)
- Mavacamten — Ca²⁺ sensitivity vs. arrhythmia evidence gap: Mavacamten reduces myofilament Ca²⁺ sensitivity indirectly and has been proposed as an anti-arrhythmic strategy in HCM. However, none of the pivotal trials included ventricular arrhythmia or SCD as endpoints. Whether reducing Ca²⁺ sensitivity translates into reduced triggered activity and arrhythmic SCD in humans remains entirely unproven. (sources/HCM-VA-FCVMed-2022)
Connections
- Related to entities/HCM
- Related to concepts/Ion-Channel-Remodeling-in-HCM
- Related to concepts/Cardiac-Action-Potential
- Related to entities/MYBPC3
- Related to entities/MYH7
- Related to entities/RYR2
- Related to entities/Mavacamten
- Related to concepts/Sudden-Cardiac-Death