Structural and functional adaptations of human cardiomyocytes in metabolic disease and heart failure

Abstract

Heart failure (HF), obesity, and diabetes are associated with structural and functional changes that affect the heart at both the organ and cellular levels. Studying isolated adult single cardiomyocytes provides valuable mechanistic insights. However, isolating single cardiomyocytes from human tissue is particularly challenging. This study presents an optimized multiple-step digestion protocol to isolate viable cardiomyocytes from atrial and ventricular human tissue obtained perioperatively or through myocardial biopsies. Using this method and resource, we analyzed calcium-signaling during excitation-contraction coupling and structural features such as t-tubules and mitochondria using confocal microscopy in patients with or without HF, obesity, or diabetes. In a subset of patients undergoing open heart surgery, tissue samples and serum from the great cardiac vein were obtained either under control conditions or upon cardiac volume challenge (VC). We isolated viable cells and observed distinct structural differences between atrial and ventricular cardiomyocytes, including variations in t-tubular and cell size. In atrial cardiomyocytes, when comparing control with patients with HF, the t-tubular networks were unchanged. However, patients with obesity exhibited significantly more t-tubules associated with larger cell sizes. Furthermore, mitochondrial density appeared higher in patients with overweight and diabetes, suggesting that the metabolic status influences cardiomyocyte structure. Finally, when exposing isolated cardiomyocytes with VC serum from the respective patients, excitation-contraction coupling was markedly enhanced, indicating a distention-related alteration of the cardiac secretome with immediate effects on cardiomyocytes. In summary, an optimized protocol for isolating human cardiomyocytes confirmed structural features, identified disease-related changes, and allowed studying the dynamic impact of cardiac distention on secretome-related cardiomyocyte function.NEW & NOTEWORTHY This study presents a novel protocol for isolating human cardiomyocytes, uncovering atrial-ventricular structural differences, obesity-related increases in t-tubules and mitochondria, and metabolic influences on cell architecture. It highlights the dynamic effects of cardiac volume challenge on excitation-contraction coupling through secretome alterations. These advancements provide insights into how conditions like obesity and diabetes reshape cardiomyocyte structure and function, advancing our understanding of heart disease mechanisms.

Keywords: cardiac physiology; excitation-contraction coupling; heart failure; human cardiomyocytes; metabolic disease.