Excess accumulation of intracellular lipid droplet impairs sinoatrial function in a mouse model of myocardial steatosis

Aims Sinoatrial node (SAN) dysfunction is commonly observed in obesity and diabetes and is associated with increased cardiovascular morbidity and mortality. Cardiac steatosis, characterized by excessive intracellular lipid droplet (LD) accumulation in cardiomyocytes, is common in these metabolic disorders, but its direct contribution to SAN dysfunction remains unclear. We investigated whether intracellular LD accumulation impairs SAN automaticity. Methods and Results Transgenic mice (TG) with cardiomyocyte-specific overexpression of perilipin 2 (PLIN2) and double-transgenic mice (DTG) co-expressing PLIN2 and hormone-sensitive lipase (HSL) were studied. TG mice exhibited marked LD accumulation in SAN myocytes together with prolonged and highly variable R–R intervals on electrocardiography (ECG). Optical Ca²⁺ mapping of SAN–atrial preparations demonstrated displacement of the leading pacemaker site toward peripheral nodal and extranodal regions in TG mice. Isolated TG SAN myocytes exhibited reduced sarcoplasmic reticulum Ca²⁺ content, attenuated local Ca²⁺ releases (LCRs), and elevated intracellular and mitochondrial reactive oxygen species (ROS) levels. In contrast, mitochondrial and SR ultrastructure were unaltered, and global gene expression profiles were preserved, except for PLIN2 overexpression. Normalization of intracellular LD accumulation by HSL co-expression prevented abnormalities in ECG, SAN automaticity, intracellular Ca²⁺ handling, and ROS levels despite persistent PLIN2 overexpression. This study was limited by the use of male mice, and the causal contribution of elevated ROS to the observed SAN dysfunction was not directly tested. Conclusion Intracellular LD accumulation alone was sufficient to alter intracellular Ca²⁺ handling and impair SAN automaticity. Normalization of intracellular LD accumulation by HSL co-expression prevented SAN dysfunction, supporting a causal role for intracellular LD accumulation in pacemaker dysfunction. These findings identify myocardial steatosis as a previously underrecognized contributor to SAN dysfunction.