Key result
Ivabradine acutely boosts LVEF by ~11% and enhances calcium handling in DMD models.
Why the study?
Impaired Ca handling causes complications in the dystrophic heart, leading to the hypothesis that ivabradine could improve cardiomyocyte Ca handling and enhance contractile performance.
Does acute administration of ivabradine improve intracellular Ca handling in dystrophic ventricular cardiomyocytes and enhance left ventricular contractile function in a DMD mdx rat model?
Does acute administration of ivabradine improve intracellular Ca handling in dystrophic ventricular cardiomyocytes and enhance left ventricular contractile function in a DMD mdx rat model?
This preclinical study demonstrates that acute ivabradine administration improves systolic function in dystrophin-deficient rats by enhancing sarcoplasmic reticulum calcium release in ventricular cardiomyocytes, providing mechanistic support for its potential therapeutic role in Duchenne muscular dystrophy cardiomyopathy.
Answers are grounded in this paper and cite their sources.
Acute ivabradine benefits in mdx rats warrant human trials; leaves open translation to DMD cardiomyopathy.
The muscular dystrophies caused by dystrophin deficiency, the so‐called dystrophinopathies, are associated with impaired cardiac contractility and arrhythmias, which considerably contribute to disease morbidity and mortality. Impaired Ca handling in ventricular cardiomyocytes has been identified as a causative factor for complications in the dystrophic heart, and restoration of normal Ca handling in myocytes has emerged as a promising new therapeutic strategy. In the present study, we explored the hypothesis that ivabradine, a drug clinically approved for the treatment of heart failure and stable angina pectoris, improves Ca handling in dystrophic cardiomyocytes and thereby enhances contractile performance in the dystrophic heart. Therefore, ventricular cardiomyocytes were isolated from the hearts of adult dystrophin‐deficient DMD mdx rats, and the effects of acutely applied ivabradine on intracellular Ca transients were tested. In addition, the drug's acute impact on cardiac function in DMD mdx rats was assessed by transthoracic echocardiography. We found that administration of ivabradine to DMD mdx rats significantly improved cardiac function. Moreover, the amplitude of electrically induced intracellular Ca transients in ventricular cardiomyocytes isolated from DMD mdx rats was increased by the drug. We conclude that ivabradine enhances Ca release from the sarcoplasmic reticulum in dystrophic cardiomyocytes and thereby improves contractile performance in the dystrophic heart.
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Szabó et al. (2023) studied Duchenne muscular dystrophy (DMD mdx rat model) (n=14). Ivabradine vs. Saline injection prior to ivabradine in vivo; control extracellular solution prior to ivabradine superfusion in vitro was evaluated on Left ventricular ejection fraction (LVEF) and intracellular Ca transient amplitude (p=0.005). Ivabradine acutely increased left ventricular ejection fraction by approximately 10–12% (p=0.005) and enhanced cardiomyocyte Ca transient amplitude (p<0.001) in DMD mdx rats.
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