Metabolic Perturbation Exacerbates Sinoatrial Node Dysfunction in Heart Failure
Year: 2026
Type: preprint
Abstract: SUMMARY Heart failure (HF) affects approximately 6.2 million people in the United States, with a 5-year mortality exceeding 50%. Bradyarrhythmia, a known complication in HF due to sinoatrial node (SAN) dysfunction (SAND), increases morbidity and mortality of HF patients. Insights into the mechanistic underpinnings of SAND in HF could therefore uncover vital therapeutic targets to improve clinical outcomes. The SAN is endowed with a dense mitochondrial network crucial for sustaining their pacemaking function on a beat-to-beat basis. We have previously demonstrated significant disruptions in the mitochondrial-sarcoplasmic reticulum connectomics, resulting in abnormal mitochondrial Ca 2+ handling and impaired mitochondrial function in HF. Here, we hypothesize that the metabolic perturbation is one of the critical mechanisms underlying SAND. To this end, we took advantage of a multi-omics approach combined with ultra-resolution imaging and functional analyses to decipher the metabolic shift that transpires in the HF SAN. Our findings revealed significant metabolic remodeling within the SAN mitochondria in HF, associated with altered fatty acid β-oxidation, ketone bodies, and carbohydrate catabolism, together with heightened mitochondrial cristae remodeling. Notably, metabolomics analyses identified pronounced increase of glucosylceramides and ceramides, motivating functional studies in human iPSC-derived SAN cells (iSANCs). Mixed ceramide exposure reduced stimulated oxygen consumption and the ATP-linked respiratory endpoint, increased extracellular acidification, and dose-dependently diminished spontaneous beating frequency. Collectively, our findings support the notion that ceramides are active mediators of mitochondrial and metabolic dysfunction in the SAN. Overall, the study provides evidence that ceramides may be a potential therapeutic target for mitigating SAND in HF.
Authors: Lu Ren, Yu Liu, Daphne A. Diloretto, Mengjie Xie, Yuting Pan, Yang Zheng, Arianne Caudal, Wenshu Zeng, Ryan L. Woltz, Danielle H Shin, Yuanyuan Dai, Rosmery Rodriguez, Richard Q. Ngo, Guy A. Perkins, Gabriela Grigorean, Ebenezer N. Yamoah, Joseph C. Wu, Hao Zhang, Nipavan Chiamvimonvat, Phung N. Thai
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7128466913