Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy

Szappanos, Henrietta Cserné; Viola, Helena M.; Ito, Danica W.; Lim, Seakcheng; Mangala, Melissa; Holliday, Mira; Ross, Samantha Barratt; Semsarian, Christopher; Hill, Adam P.; Dixon, Rose E.; Hool, Livia C.

doi:10.1038/s41598-023-38296-2

Cited by 4 publications

References 37 publications

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Slow conduction and spatial dispersion of repolarization are intrinsic properties of cardiomyocyte electrophysiology that contribute to proarrhythmia in an iPSC model of hypertrophic cardiomyopathy

Lim¹,

Mangala²,

Holliday³

et al. 2023

Preprint

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Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease; characterised by left ventricular wall thickening, cardiomyocyte disarray, and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to the structural changes in the myocardium, or as a result of intrinsic properties of the HCM cardiomyocyte. In this study, we used an induced pluripotent stem cell model of the Arg403Gln variant in myosin heavy chain 7 (MYH7) to study ′tissue level′ electrophysiological properties of HCM cardiomyocytes. For the first time, we show significant slowing of conduction velocity and an increase in local spatial dispersion of repolarisation – both well established substrates for arrhythmia – in monolayers of HCM cardiomyocytes. Analysis of rhythmonome protein expression in R403Q cardiomyocytes revealed dramatically reduced connexin-43, sodium channels, and inward rectifier channels, a three-way hit that combines to reduce electrotonic coupling between HCM cardiomyocytes and slow cardiac conduction. Our data therefore represent a novel, biophysical basis for arrhythmia in HCM, that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic electrical phenotypes may be accentuated by fibrosis and myocyte disarray to contribute to sudden death in HCM patients.

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Slow conduction and spatial dispersion of repolarization are intrinsic properties of cardiomyocyte electrophysiology that contribute to proarrhythmia in an iPSC model of hypertrophic cardiomyopathy

Lim¹,

Mangala²,

Holliday³

et al. 2023

Preprint

Self Cite

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Recreational and occupational physical activity and risk of adverse events in truncatingMYBPC3founder variant carriers

Hassanzada,

Jansen,

van Lint

et al. 2024

Preprint

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Background: MYBPC3 founder variants cause hypertrophic cardiomyopathy (HCM) leading to heart failure (HF) and malignant ventricular arrhythmias (MVA). Exercise is typically regarded a risk factor for disease expression, although evidence is conflicting. Stratifying by type of exercise may discriminate low- from high-risk activities in these patients. Objective(s): Evaluate effects of exercise, stratified by high-static and high-dynamic component, on risk of major cardiomyopathy-related events (MCE) and cardiomyopathy penetrance among MYBPC3 founder variant carriers. Methods: We interviewed 188 carriers (57% male, 43.4±14.8 years) on exercise participation since age ten. Exercise was quantified as metabolic equivalent task (MET)-hours/week before presentation. MCE was defined as a composite of MVA (sustained ventricular tachycardia/fibrillation), HF (HF hospitalizations or transplantation), and septal reduction therapy. Static and dynamic exercise were defined per Bethesda classification. Associations of exercise with MCE and cardiomyopathy penetrance were adjusted for sex and assessed using Cox regression. Results: Overall, 40 (21%) subjects experienced MCE and 139 (74%) were diagnosed with cardiomyopathy. No association was found for overall physical activity and high-static activity with MCE (p=0.900 overall; p=0.274 high-static) or cardiomyopathy penetrance (p=0.787 overall; p=0.774 high-static). In contrast, high-dynamic activity was associated with MVA (dichotomized at 75th percentile: adjusted hazard ratio 2.70, 95% confidence interval 1.01-7.24, p=0.049). Conclusions: Overall exercise participation does not generally increase the risk of adverse events among MYBPC3 founder variant carriers. Nonetheless, an increased risk of MVA was observed among those engaged in the highest quartile of high-dynamic-sports, suggesting that high-level high-intensity exercise activities should be entertained with caution.

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Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers

Hassanzada,

Jansen,

van Lint

et al. 2024

Circ: Genomic and Precision Medicine

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BACKGROUND: MYBPC3 founder variants cause hypertrophic cardiomyopathy leading to heart failure and malignant ventricular arrhythmias. Exercise is typically regarded as a risk factor for disease expression although evidence is conflicting. Stratifying by type of exercise may discriminate low- from high-risk activities in these patients. Here, we evaluate the effects of exercise, stratified by high-static and high-dynamic components, on the risk of major cardiomyopathy-related events (MCEs) and cardiomyopathy penetrance among MYBPC3 founder variant carriers. METHODS: We interviewed 188 carriers (57.4% male; aged 43.0±15.0 years) on exercise participation since the age of 10 years. The exercise was quantified as the metabolic equivalent of task-h/wk before the presentation. MCE was defined as a composite of malignant ventricular arrhythmia (sustained ventricular tachycardia/fibrillation), heart failure (heart failure hospitalizations or transplantation), and septal reduction therapy. Static and dynamic exercises were defined per the Bethesda classification. Associations of exercise with MCE and cardiomyopathy penetrance were adjusted for sex and assessed using Cox regression. RESULTS: Overall, 43 (22.9%) subjects experienced MCE and 139 (73.9%) were diagnosed with cardiomyopathy. No association was found between overall physical activity and high-static activity with MCE ( P =0.587 overall; P =0.322 high static) or cardiomyopathy penetrance ( P =0.317 overall; P =0.623 high static). In contrast, high-dynamic activity was associated with malignant ventricular arrhythmia (dichotomized at the 75th percentile: adjusted hazard ratio, 3.26 [95% CI, 1.26–8.44]; P =0.015). CONCLUSIONS: Overall exercise participation does not generally increase the risk of adverse events among MYBPC3 founder variant carriers. Nonetheless, an increased risk of malignant ventricular arrhythmia was observed among those engaged in the highest quartile of high-dynamic sports, suggesting that high-level high-intensity exercise activities should be entertained with caution.

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Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy

Cited by 4 publications

References 37 publications

Slow conduction and spatial dispersion of repolarization are intrinsic properties of cardiomyocyte electrophysiology that contribute to proarrhythmia in an iPSC model of hypertrophic cardiomyopathy

Slow conduction and spatial dispersion of repolarization are intrinsic properties of cardiomyocyte electrophysiology that contribute to proarrhythmia in an iPSC model of hypertrophic cardiomyopathy

Recreational and occupational physical activity and risk of adverse events in truncatingMYBPC3founder variant carriers

Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers

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