Modulation of cardiac fatty acid or glucose oxidation to treat heart failure in preclinical models: a systematic review and meta-analysis.

Background: Current expert opinion on cardiac metabolism in heart failure (HF) suggests that inhibiting cardiac fatty acid oxidation (FAO) or stimulating cardiac glucose oxidation (GO) can improve heart function. However, systematic evidence is lacking, and contradictory data exist. Therefore, we conducted a comprehensive meta-analysis to assess the effects of modulating myocardial GO or FAO on heart function.

Methods: We screened MEDLINE via Ovid, Scopus, and Web of Science until March 02, 2024 for interventional studies reporting significant changes in cardiac GO or FAO in established animal models of HF, such as ischemia-reperfusion, pressure overload, rapid pacing, and diabetic cardiomyopathy. We employed multivariate analysis (four-level random-effects model) to enclose all measures of heart function. Additionally, we used meta-regression to explore heterogeneity and contour-enhanced funnel plots to assess publication bias. The protocol is registered on PROSPERO (CRD42023456359).

Results: Of a total of 10,628 studies screened, 103 studies are included. Multivariate meta-analysis reveals that enhancing cardiac GO considerably restores cardiac function (Hedges' g = 1.03; 95% CI: 0.79-1.26; p < 0.001). Interestingly, interventions associated with reduced myocardial FAO show neutral effects (Hedges' g = 0.24; 95% CI: -0.57-1.05; p = 0.557), while those augmenting myocardial FAO markedly improve function (Hedges' g = 1.17; 95% CI: 0.58-1.76; p < 0.001).

Conclusions: Our data underscore the role of cardiac metabolism in treating HF. Specifically, these results suggest that stimulating either myocardial FAO or GO may considerably improve cardiac function. Furthermore, these results question the current notion that inhibition of cardiac FAO is protective.