Shourya Kashyap

Background: Hypertrophic Cardiomyopathy (HCM) is a monogenic inherited cardiac disease that has a prevalence of 1/500 and is present in over 60 countries in all continents.^1,2The disease is caused by a genetic mutation (mostly missense) that disrupts the genetic coding of cardiac sarcomeres.¹While advanced cases are clinically diagnosable with the available risk-assessment algorithms, there is a lack of appropriate assessment of younger patients without significant disease expression.¹This is an issue because a significant cause of sudden cardiac death (SCD) is the ventricular tachycardia/fibrillation that results from HCM, especially in children and young adults (age < 30 years).^1,2As it pertains to identifying the risk of SCD for patients with HCM there are various risk markers that are used but no other diagnostic test.³

Objective: In this narrative review, we explored HCM as a channelopathy to understand the mechanisms behind the Ca²⁺ dysregulation.

Search Methods: An online search in the PubMed database was conducted from 2017-2023 using the following keywords: “hypertrophic cardiomyopathy”, “sudden cardiac death”, “ion channel”, “troponin T”, “channelopathy”, “calcium”.

Results: Studies showed the diastolic [Ca²⁺] was elevated in the HCM mutated iPSC-CM cells when compared to the control cells. Additionally, the HCM cells and a longer decay time compared to the control cells.⁴ To determine the mechanism behind the [Ca²⁺] irregularities, qPCR profiling was done, alongside store-operated Ca²⁺ entry (SOCE) measurements.⁴ Downstream effects of increased calcium retention in disease states showed a significant increase in phosphorylation of phospholamban (PLN) and CaMKIIδ when compared to the wild type iPSC-CMs.⁵ Mutation in troponin T (TnT), specifically the TnT-I79N mutation, causes ventricular irregularities that can lead to SCD and ventricular arrythmias.⁶ Using hiPSC-CMs that were heterozygous for the I79N mutation, alongside a wild type control, Ca²⁺ sensitivity was measured using different frequncies.⁶ The wild type cells had a significant decrease in action potential duration when the frequency went from 55 bpm to 75 bpm, something that did not happen for the I79N mutated cells.⁶ Optical mapping showed the I79N cell lines showed arrhythmogenicity at frequencies from 75 bpm to 150 bpm.⁶ TnT-I79N mutated (HCM) mice were crossed with TnT-R141W (DCM) knock-in mice were and resulting cardiac measurements were made to examine this potential therapy for each disease state.⁷ Ca²⁺ sensitivity tests, echocardiography results and fibrosis levels all showed that the I79N/HET crossed samples were closer to the wild type sample.⁷

Conclusion: Results showed that the HCM cell populations have an upregulation in activity and expression of L-type Ca²⁺ channels and transient receptor potential cation channels.⁴ The excessive phosphorylation of CaMKIIδ in HCM iPSC-CMs suggest that HCM pathogenesis is caused by the calcium disturbance that is further accentuated by CaMKIIδ.⁵ The increased Ca²⁺ sensitivity, altered Ca²⁺ control and arrhythmogenic effects that are displayed by the I79N mutated hiPSC-CMs match up with the complex cellular mechanisms that induce SCD.⁶The combination of TnT mutations at different ends of the spectrum provide a potential mechanism for eliminating HCM and the associated SCD risk that can be explored further.⁷

Works Cited:

1. Santini L, Coppini R, Cerbai E. Ion Channel Impairment and Myofilament Ca²⁺Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy. Cells. 2021;10(10):2789. Published 2021 Oct 18. doi:10.3390/cells10102789
2. Coppini R, Santini L, Olivotto I, Ackerman MJ, Cerbai E. Abnormalities in sodium current and calcium homoeostasis as drivers of arrhythmogenesis in hypertrophic cardiomyopathy. Cardiovasc Res. 2020;116(9):1585-1599. doi:10.1093/cvr/cvaa124
3. Makavos G, Κairis C, Tselegkidi ME, et al. Hypertrophic cardiomyopathy: an updated review on diagnosis, prognosis, and treatment. Heart Fail Rev. 2019;24(4):439-459. doi:10.1007/s10741-019-09775-4
4. Wu H, Yang H, Rhee JW, et al. Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients. Eur Heart J. 2019;40(45):3685-3695. doi:10.1093/eurheartj/ehz326
5. Kondo T, Higo S, Shiba M, et al. Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for TNNT2Δ160E-Induced Cardiomyopathy. Circ Genom Precis Med. 2022;15(5):e003522. doi:10.1161/CIRCGEN.121.003522
6. Shafaattalab S, Li AY, Gunawan MG, et al. Mechanisms of Arrhythmogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant I79N. Front Cell Dev Biol. 2021;9:787581. Published 2021 Dec 17. doi:10.3389/fcell.2021.787581
7. Dieseldorff Jones KM, Koh Y, Weller RS, et al. Pathogenic troponin T mutants with opposing effects on myofilament Ca²⁺sensitivity attenuate cardiomyopathy phenotypes in mice. Arch Biochem Biophys. 2019;661:125-131. doi:10.1016/j.abb.2018.11.006