Intermittent fasting and cardiometabolic responses under cardiac stress: a systematic review of preclinical studies

Intermittent fasting (IF) has emerged as a dietary strategy with benefits that extend beyond weight management and glycemic control. Although growing evidence supports its favorable effects on cardiometabolic health, the impact of IF under conditions of cardiac stress remains poorly characterized. Since clinical trials cannot ethically expose patients to acute cardiac stress during IF protocols, preclinical models are essential to elucidate its potential cardioprotective mechanisms. This systematic review aimed to synthesize the preclinical evidence on the effects of IF in models of cardiac stress. Following a registered protocol (PROSPERO:#CRD42023466215), we searched databases for preclinical studies evaluating IF under cardiac stress. Models included atherosclerosis induction, diet modulation, hypercholesterolemic mice, doxorubicin-induced cardiotoxicity, pulmonary arterial hypertension, myocardial infarction, ischemia-reperfusion injury, among others. All IF regimens, encompassing variations in timing, frequency, and type, were considered. Clinical trials, observational studies, reviews, meta-analyses, updates, guidelines were excluded. Thirty-two studies involving 451 predominantly male animals were included. Approximately 80% reported that IF improved cardiovascular outcomes, reducing blood pressure, cardiac hypertrophy, fibrosis, and ischemic injury while enhancing vascular and metabolic function. Mechanistically, IF protects the heart under stress by downregulating NF-κB, IL-1β, and TNF, and activating SIRT3 and AMPK pathways, improving mitochondrial function, lipid metabolism, and cardiac energy homeostasis. Cardioprotective benefits were dependent on fasting duration and regimen, emphasizing the importance of metabolic context. In conclusion, IF appears to enhance cardiovascular resilience under stress through multiple metabolic and molecular pathways. These findings support further clinical investigation of IF as a potential adjunct strategy for cardiometabolic protection under stress.