Remodelling of potassium currents underlies arrhythmic action potential prolongation under beta-adrenergic stimulation in hypertrophic cardiomyopathy

Doste, Rubén; Coppini, Raffaele; Bueno‐Orovio, Alfonso

doi:10.1016/j.yjmcc.2022.08.361

Cited by 6 publications

(4 citation statements)

References 60 publications

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“…These results suggest a preserved adrenergic reserve in the MYBPC3 +/- μHM. Together with evidence for cellular hypertrophy in the absence of gross sarcomere disarray, our model appears to reflect an early stage HCM phenotype(40, 41).…”

Section: Resultssupporting

confidence: 62%

“…To test whether the structural abnormalities we observed were linked to differential adrenergic tone, as suggested by previous HCM studies, we stressed the µHMs with beta-adrenergic stimulation(37–39). Acute treatment with isoproterenol revealed a significant increase in spontaneous beat rate and calcium intake for both control and MYBPC3 +/- tissues ( Fig.…”

Section: Resultsmentioning

confidence: 93%

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Mechanical Resistance to Micro-Heart Tissue Contractility unveils early Structural and Functional Pathology in iPSC Models of Hypertrophic Cardiomyopathy

Guo,

Jiang,

Schuftan

et al. 2023

Preprint

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Hypertrophic cardiomyopathy is the most common cause of sudden death in the young. Because the disease exhibits variable penetrance, there are likely nongenetic factors that contribute to the manifestation of the disease phenotype. Clinically, hypertension is a major cause of morbidity and mortality in patients with HCM, suggesting a potential synergistic role for the sarcomeric mutations associated with HCM and mechanical stress on the heart. We developed anin vitrophysiological model to investigate how the afterload that the heart muscle works against during contraction acts together with HCM-linked MYBPC3 mutations to trigger a disease phenotype. Micro-heart muscle arrays (μHM) were engineered from iPSC-derived cardiomyocytes bearing MYBPC3 loss-of-function mutations and challenged to contract against mechanical resistance with substrates stiffnesses ranging from the of embryonic hearts (0.4 kPa) up to the stiffness of fibrotic adult hearts (114 kPa). Whereas MYBPC3+/-iPSC-cardiomyocytes showed little signs of disease pathology in standard 2D culture, μHMs that included components of afterload revealed several hallmarks of HCM, including cellular hypertrophy, impaired contractile energetics, and maladaptive calcium handling. Remarkably, we discovered changes in troponin C and T localization in the MYBPC3+/-μHM that were entirely absent in 2D culture. Pharmacologic studies suggested that excessive Ca2+intake through membrane-embedded channels, rather than sarcoplasmic reticulum Ca2+ATPase (SERCA) dysfunction or Ca2+buffering at myofilaments underlie the observed electrophysiological abnormalities. These results illustrate the power of physiologically relevant engineered tissue models to study inherited disease mechanisms with iPSC technology.

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Section: Resultssupporting

confidence: 62%

Section: Resultsmentioning

confidence: 93%

Mechanical Resistance to Micro-Heart Tissue Contractility unveils early Structural and Functional Pathology in iPSC Models of Hypertrophic Cardiomyopathy

Guo,

Jiang,

Schuftan

et al. 2023

Preprint

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“…Cardiomyocyte electrophysiology was simulated using the ToR-ORd action potential (AP) model, which is a computational tool that uses biophysically detailed ion channel behaviours to produce APs and Ca 2+ transients representative of human cardiac electrophysiology ( Tomek et al, 2019 ). The model has been previously validated to reproduce AP behaviours under diseased conditions, including repolarisation impairment in HCM ( Doste et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

“…Repolarisation impairment in HCM occurs secondary to ionic remodelling (primarily upregulation of late Na + and downregulation of K + channels), as measured in vitro in septal hypertrophy samples from HCM patients undergoing surgical myectomy ( Coppini et al, 2013 ). This experimentally reported ionic remodelling was introduced to the AP model by remodelling ion channel maximal conductances, as in previous works ( Passini et al, 2016 ; Doste et al, 2022 ). Three patterns of ionic remodelling were considered ( Supplementary Table S1 ): moderate–where only late Na + was upregulated, as reported early in murine HCM ( Coppini et al, 2017 ); severe–where all ionic remodelling components were included, but with K + channel remodelling at half-maximal severity; and extreme–where all ionic remodelling components were included at full severity ( Coppini et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy

Coleman,

Doste,

Beltrami

et al. 2024

Front. Pharmacol.

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Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM.Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects.Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment.Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.

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Electrophysiological mechanisms underlying T wave pseudonormalisation on stress ECGs in hypertrophic cardiomyopathy

Coleman,

Doste,

Beltrami

et al. 2024

Computers in Biology and Medicine

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Remodelling of potassium currents underlies arrhythmic action potential prolongation under beta-adrenergic stimulation in hypertrophic cardiomyopathy

Cited by 6 publications

References 60 publications

Mechanical Resistance to Micro-Heart Tissue Contractility unveils early Structural and Functional Pathology in iPSC Models of Hypertrophic Cardiomyopathy

Mechanical Resistance to Micro-Heart Tissue Contractility unveils early Structural and Functional Pathology in iPSC Models of Hypertrophic Cardiomyopathy

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy

Electrophysiological mechanisms underlying T wave pseudonormalisation on stress ECGs in hypertrophic cardiomyopathy

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