Metabolic Perturbation Exacerbates Sinoatrial Node Dysfunction in Heart Failure.

Area of Science:

• Cardiology
• Mitochondrial Biology
• Metabolic Research

Background:

• Heart failure (HF) affects millions, with high mortality. Sinoatrial node dysfunction (SAND) is a complication increasing HF morbidity and mortality.
• Mitochondrial dysfunction is implicated in HF, but its specific role in SAND remains unclear.
• Understanding SAND mechanisms can reveal therapeutic targets to improve HF patient outcomes.

Purpose of the Study:

• To investigate the metabolic alterations in the sinoatrial node (SAN) during heart failure (HF).
• To determine the role of ceramides in mitochondrial dysfunction and impaired automaticity in HF-related SAND.
• To explore ceramides as potential therapeutic targets for SAND in HF.

Main Methods:

• Multi-omics approach, ultra-resolution imaging, and functional analyses were used to study SAN metabolism in HF.
• Metabolomics identified increased glucosylceramides and ceramides in HF SAN mitochondria.
• Functional assays tested the impact of ceramides on mitochondrial metabolism and SAN automaticity.

Main Results:

• HF SAN mitochondria showed reduced fatty acid oxidation and increased reliance on carbohydrate catabolism and ketone bodies.
• Elevated ceramide levels were identified as a key factor in mitochondrial dysfunction.
• Ceramides induced a dose-dependent shift from oxidative phosphorylation to glycolysis, impairing SAN automaticity.

Conclusions:

• Ceramides are active mediators of mitochondrial and metabolic dysfunction in the heart failure sinoatrial node.
• Metabolic derangements, particularly involving ceramides, contribute significantly to sinoatrial node dysfunction in HF.
• Targeting ceramides may offer a novel therapeutic strategy for mitigating sinoatrial node dysfunction in heart failure patients.