Unlocking the Clock: Optimal Physical Activity Timing for Cardiovascular Disease Prevention

BACKGROUND: This study aims to elucidate the causal effect of physical activity (PA) at different times of day on the risk of cardiovascular diseases, including subtypes of stroke, heart failure, atherosclerosis (AS), myocardial infarction, hypertension, and peripheral artery disease. METHODS: Two-sample univariable and multivariable Mendelian randomization were conducted. Genetic instruments for total PA and PA across twelve 2-hour intervals were derived from UK Biobank. Summary-level data for outcomes were obtained from large consortia. We estimated causal effects using inverse variance weighted, MR-Egger, and weighted median methods. Sensitivity analyses were also conducted. RESULTS: Multivariable Mendelian randomization revealed independent protective effects of PA during 6 AM to 8 AM, 10 AM to 12 PM, and 4 PM to 6 PM on total and ischemic stroke. In contrast, the effect in protecting total, ischemic and large artery stroke were detected for PA during 6 PM to 8 PM in univariable MR. PA during 2 AM to 4 AM and 10 AM to 12 PM had directly protective effect of total AS, and PA during 2 PM to 4 PM for coronary AS, while univariable MR results indicated PA during 8 PM to 10 PM and 6 PM to 8 PM decreased the risk of cerebral and coronary AS, respectively. PA during 2 PM to 4 PM exhibited a total but not a direct effect of reducing risk of total and essential hypertension. No robust causal associations were observed for heart failure, myocardial infarction, or peripheral artery disease. CONCLUSION: This study provides evidence that PA during specific periods is causally associated with the risk of stroke, AS, and hypertension. These findings suggest that the timing of PA should be considered for the prevention of cardiovascular diseases.