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Electrocontractile remodeling of isolated cardiomyocytes induced during early-stage hypercholesterolemia
Artur Santos-Miranda1,2, Julliane V Joviano-Santos3,4, Ivan Lobo Sousa Marques5
1Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Minas Gerais, Brazil. artursm@ufmg.br.
Insights
High cholesterol (hypercholesterolemia) directly impacts heart cells, altering electrical activity and contraction. This study reveals early cellular cholesterol changes affect cardiomyocyte function and overall heart performance.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Hypercholesterolemia is a major cardiovascular disease risk factor, primarily linked to vascular issues.
- Direct effects of hypercholesterolemia on cardiomyocytes and heart function remain incompletely understood.
Purpose of the Study:
- To investigate the direct impact of hypercholesterolemia on heart function.
- To analyze the electro-contractile properties of isolated cardiomyocytes in hypercholesterolemic mice.
Main Methods:
- Male Swiss mice were fed a cholesterol-enriched diet (1.25% cholesterol) for 5 weeks.
- Serum cholesterol and cardiomyocyte cholesterol levels were measured.
- Electrocardiography, isolated cardiomyocyte electrophysiology, and isolated heart contractility were assessed.
Main Results:
- Cholesterol-fed mice showed increased serum and cardiomyocyte cholesterol, shortened QT intervals, and altered action potentials in cardiomyocytes.
- Key ion channel currents (IK, ICa.L, INa) were modulated, affecting cardiomyocyte excitability.
- Reduced diastolic intracellular calcium ([Ca2+]i) was observed, with preserved cellular contraction but impaired isolated heart function, though reduced arrhythmia susceptibility.
Conclusions:
- Early hypercholesterolemia directly alters cardiomyocyte cholesterol content.
- These changes modulate cardiac electrophysiology, calcium handling, and contractility.
- Hypercholesterolemia impacts heart function beyond vascular effects, influencing cardiomyocyte excitability and contractility.
Abstract:
Hypercholesterolemia is one of the most important risk factors for cardiovascular diseases. However, it is mostly associated with vascular dysfunction and atherosclerotic lesions, while evidence of direct effects of hypercholesterolemia on cardiomyocytes and heart function is still incomplete and controversial. In this study, we assessed the direct effects of hypercholesterolemia on heart function and the electro-contractile properties of isolated cardiomyocytes. After 5 weeks, male Swiss mice fed with AIN-93 diet added with 1.25% cholesterol (CHO), developed an increase in total serum cholesterol levels and cardiomyocytes cholesterol content. These changes led to altered electrocardiographic records, with a shortening of the QT interval. Isolated cardiomyocytes displayed a shortening of the action potential duration with increased rate of depolarization, which was explained by increased IK, reduced ICa.L and altered INa voltage-dependent inactivation. Also, reduced diastolic [Ca2+]i was found with preserved adrenergic response and cellular contraction function. However, contraction of isolated hearts is impaired in isolated CHO hearts, before and after ischemia/reperfusion, although CHO heart was less susceptible to arrhythmic contractions. Overall, our results demonstrate that early hypercholesterolemia-driven increase in cellular cholesterol content is associated with direct modulation of the heart and cardiomyocytes' excitability, Ca2+ handling, and contraction.
