BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of death worldwide. While traditional risk factors are well-established, emerging evidence suggests shift work causing circadian rhythm disruption significantly contributes to CVD risk. This systematic review investigated molecular mechanisms linking circadian disruption with cardiovascular pathophysiology through in vivo models.
METHODS: We systematically searched Medline, Embase, and Web of Science through February 2025. Studies employing genetic (clock gene knockouts/mutations) or environmental (light phase shift, sleep deprivation) models of circadian disruption in vivo were included. Meta-analyses were performed for key cardiovascular indicators, and certainty of evidence was evaluated using a modified GRADE approach.
RESULTS: Among 9012 references, 34 studies met inclusion criteria. Following quality assessment for study design and reporting, 32 studies with low or moderate risk of bias were included in the synthesis. Meta-analyses revealed cardiac hypertrophy as the most robust finding, with high-certainty evidence for increased left ventricular mass-to-body weight ratio (LV/BW; SMD: 0.89, 95% CI: 0.38 to 1.39) and moderate-certainty evidence for increased cardiomyocyte size. These convergent organ and cellular-level findings, supported by elevated natriuretic peptides and pro-fibrotic markers, indicate circadian disruption contributes to pathological cardiac remodeling. Sensitivity analyses revealed low-certainty evidence for impaired systolic function, with significant reductions in ejection fraction (SMD: - 1.70, 95% CI: - 3.22 to - 0.17) and fractional shortening (SMD: - 1.60, 95% CI: - 2.71 to - 0.49). Low-certainty evidence was found for impaired endothelium-dependent vasorelaxation (SMD: - 2.72, 95% CI: - 4.90 to - 0.53) based on three genetic model studies with high heterogeneity and elevated triglyceride levels (SMD: 1.64, 95% CI: 0.07 to 3.21). Other markers showed very low-certainty evidence.
CONCLUSIONS: This systematic review improves mechanistic understanding of CVD development following circadian misalignment by demonstrating cardiac hypertrophy as a major pathophysiological consequence in animal models. Cardiac structural changes at organ and cellular levels, supported by biomarkers of pathological remodeling, indicate circadian disruption contributes to adverse cardiac remodeling. Future animal research should prioritize standardized protocols, sex-balanced designs, and environmental models replicating human shiftwork patterns. Substantial epidemiological gaps remain, warranting further investigation in shift workers.
