# Pleiotropic Effects of Cardiac Resynchronization Therapy on Cardiometabolic Modulation in Heart Failure

## TL;DR

Cardiac resynchronization therapy improves heart failure by enhancing mechanical and metabolic functions, including energy metabolism and gut-related inflammation.

## Contribution

This review highlights novel cardiometabolic effects of CRT, including systemic and myocardial metabolic adaptations and gut-derived pathway modulation.

## Key findings

- CRT improves mechanical efficiency and shifts substrate utilization toward fatty acid and ketone oxidation.
- CRT normalizes energy metabolites and improves Krebs cycle intermediates, correlating with cardiac reverse remodeling.
- CRT may reduce gut dysbiosis and endotoxemia, mitigating systemic inflammation in heart failure.

## Abstract

Cardiac resynchronization therapy (CRT) is a cornerstone intervention for patients with heart failure (HF) and electrical dyssynchrony, improving quality of life, functional capacity, and survival. Beyond mechanical synchrony, mounting evidence suggests CRT exerts systemic and myocardial cardiometabolic benefits. CRT acutely enhances mechanical efficiency and shifts substrate utilization toward greater oxidation of fatty acids and ketones, effects that correlate with long-term reverse remodeling on cardiac magnetic resonance imaging. Earlier metabolomic profiling demonstrated that CRT normalizes circulating energy metabolites, improving Krebs cycle intermediates and substrate balance between glucose and lipids, while baseline metabolite patterns may differentiate responders from non-responders. These metabolic adaptations accompany favorable changes in diastolic performance, right ventricular function, and ventriculo-arterial coupling. In parallel, improved splanchnic perfusion and reduced congestion may ameliorate gut dysbiosis and endotoxemia, mitigating systemic inflammation. Collectively, these findings position CRT as a therapy capable of both mechanical and metabolic restoration in advanced HF. In this review, we discuss the emerging data on how CRT reconditions myocardial energy metabolism, influences ventricular–arterial interactions, and modulates peripheral and gut-derived metabolic pathways.