Mechanical support with a left ventricular assist device improved metabolic and transcriptional defects, including reversing a 2.6-fold increase in pyruvate, in failing human left ventricular tissue.
Observational (n=6)
Does mechanical unloading with an LVAD improve metabolic and transcriptional defects in human heart failure?
Mechanical unloading with an LVAD reverses severe metabolic and transcriptional defects in failing human hearts, demonstrating myocardial metabolic resilience.
BACKGROUND: Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. METHODS AND RESULTS: We compared metabolomic, gene transcript, and protein data from 6 paired samples of failing human left ventricular tissue obtained during left ventricular assist device insertion (heart failure samples) and at heart transplant (post-left ventricular assist device samples). Nonfailing left ventricular wall samples procured from explanted hearts of patients with right heart failure served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in heart failure tissue: 2.6-fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1A, 1.3-fold) and estrogen-related receptor α (ERRA, 1.2-fold) and γ (ERRG, 2.2-fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with left ventricular assist device improved all of these metabolic and transcriptional defects. CONCLUSIONS: These observations underscore an important pathophysiologic role for severely defective metabolism in heart failure, while the reversibility of these defects by left ventricular assist device suggests metabolic resilience of the human heart.
Gupte et al. (Wed,) conducted a observational in Heart failure (n=6). Mechanical support with left ventricular assist device vs. Pre-LVAD failing heart tissue and nonfailing left ventricular wall samples was evaluated on Metabolomic, gene transcript, and protein data. Mechanical support with a left ventricular assist device improved metabolic and transcriptional defects, including reversing a 2.6-fold increase in pyruvate, in failing human left ventricular tissue.
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