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Sustained high-fat diet increases ventricular susceptibility to arrhythmias and impairs myocardial calcium cycling

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Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Medizinische Fakultät, Heinrich Heine Universität Düsseldorf Background – Obesity is one of the most relevant factors for cardiovascular… Click to show full abstract

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Medizinische Fakultät, Heinrich Heine Universität Düsseldorf Background – Obesity is one of the most relevant factors for cardiovascular disease in western societies. Independent of coronary heart disease, obesity promotes a multimodal arrhythmic substrate and increases the susceptibility to ventricular arrhythmias (VA) eventually leading to sudden cardiac death. Purpose – Aim of the present study was to develop an ex vivo mouse model to characterize obesity-mediated VAs and left ventricular (LV) myocardial disruption of calcium homeostasis. Methods – All experiments were performed ex vivo in retrogradely perfused hearts from 32 – 36 week-old C57Bl/6J mice (n=14). Five mice received a normal chow diet (NCD), 9 mice were fed a sustained high-fat diet (HFD) over a 6-month period to generate diet-induced-obesity (DIO). We combined an endocardial catheter-based technique to assess VA susceptibility with an epicardial dual fluorescence imaging approach employing a potentiometric (Rh237) and a calcium sensitive (Rhod2) dye to assess action potential and calcium cycling characteristics. Optical mapping data was analysed using a MATLAB-based algorithm. VA susceptibility was quantified by an established scoring system. Results – Mice receiving a sustained HFD were significantly heavier than those receiving NCD (NCD: 34.8±2.1g, HFD: 53.3±3.2g, P<0.0001). The number of induced VAs and VA susceptibility were increased in HFD compared to NCD (number of induced VAs: NCD: 1.4±0.7, HFD: 6.3±0.8, P=0.005, Figure 1A; VA susceptibility: NCD: 1.4±0.7, HFD: 18.1±2.3, P=0.001, Figure 1B). Ventricular tachycardias (VT) were only inducible in HFD, additionally, those hearts presented mostly polymorphic VTs (VT inducibility: NCD: 0.0 %, HFD: 88.9 %, P=0.003, Figure 1C; VT morphology: monomorphic VT: 25 %, polymorphic VT: 75 %). Epicardial optical mapping of the anterior LV wall showed a prolonged action potential duration (APD) and prolonged calcium transient duration (CaTD) in HFD (APD90 at CL 100 ms: NCD: 45.1±1.5 ms, HFD: 50.8±1.8 ms, P=0.03; CaTD90 at 100 ms pacing cycle length (PCL): NCD: 61.0±2.3 ms, HFD: 66.6±0.6 ms, P=0.02, Figure 2A). Furthermore, CaT alternans (ALT) threshold defined as amplitude alternans > 10 % of two consecutive beats was decreased (PCL ALT threshold: NCD: 60.0±1.6 ms, DIO: 67.8±1.2 ms, P=0.006, Figure 2B), with mean ALT being increased in HFD (mean ATL at 60 ms PCL: NCD: 15.4±2.4 %, HFD: 25.7±3.0 %, P=0.04). Conclusions – Our findings show that sustained HFD in mice increases ventricular susceptibility to VTs, especially polymorphic VTs indicating heterogeneity in wave propagation. DIO leads to disruption of LV myocardial calcium homeostasis as demonstrated by a decreased ALT threshold and increased mean ALT. Our data suggest that LV calcium mishandling may be a driver for arrhythmogenesis in DIO and modulation may present a perspective therapeutical approach. Further experiments will address molecular mechanisms and identify potential targets of modulation.

Keywords: calcium; ncd hfd; sustained high; susceptibility; figure

Journal Title: Europace
Year Published: 2023

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