Alterations in myocardial mitochondrial function and metabolism have been implicated in the pathophysiology of heart failure with reduced ejection fraction (HFrEF). The impact of mechanical dyssynchrony and its alleviation through cardiac resynchronization therapy (CRT) on myocardial mitochondrial function and metabolism remain poorly understood.
HFrEF patients with an indication for CRT underwent targeted metabolomic analysis of 84 energetic substrates at baseline (coronary sinus and peripheral venous blood). Mitochondrial membrane potential (Ψ) as an indicator of mitochondrial function was assessed non-invasively through TC-sestamibi myocardial washout. Changes in peripheral metabolism and Ψ were assessed 6-months after CRT and their association with left ventricular remodeling and peakVO was assessed. Principle component analysis (PCA) was used as dimension reduction strategy for metabolic analysis.
Forty-five HFrEF-patients underwent CRT-implant (76% male, ejection fraction 29±6%). At baseline, PCA of coronary (CS) vs peripheral blood (PB) illustrated preferred cardiac uptake of β-hydroxybutyrate (CS vs PB-ratio=-78%; p<0.005) together with anaplerotic amino-acids, and glycolytic pyruvate breakdown to lactate. Baseline Ψdysfunction was associated with shift away from free fatty acids oxidation (FAO). Myocardial β-hydroxybutyrate extraction strongly associated with peakV (-0.836; p<0.001). CRT improved Ψ (25±5% vs 18±6%; p=0.002), in parallel with metabolic remodeling, with increased reliance on FAO, and less reliance on β-hydroxybutyrate and glycolytic pyruvate breakdown to lactate. Changes in myocardial mitochondrial function and metabolism were associated with left ventricular reverse remodeling.
HFrEF-patients exhibit baseline mitochondrial dysfunction, which is associated with alterations in myocardial substrate utilization, including less FAO, more reliance on ketone bodies, anaplerotic amino-acids and the breakdown of glycolytic pyruvate to lactate. CRT is capable of inducing mitochondrial and metabolic reverse remodeling which is associated with cardiac morphology changes.

Copyright © 2021. Published by Elsevier Inc.
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