Circadian vulnerability in acute myocardial infarction: from clock-regulated pathways to chrono-individualized therapy

Abstract Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide, and its onset, progression, and prognosis are closely tied to circadian rhythms. Disruption of the biological clock influences susceptibility to AMI as well as the pathophysiological mechanisms and therapeutic responses that follow. This review examines how circadian regulation shapes thrombogenesis, ischemia–reperfusion injury, cardiac metabolism, inflammation, and myocardial repair, spanning the molecular architecture of the cardiomyocyte clock, the early-morning peak in AMI incidence, and the circadian control of platelet function, fibrinolysis, mitochondrial integrity, substrate selection, calcium handling, and the inflammatory response. Building on these mechanisms, we outline chrono-individualized therapy—the alignment of prevention and long-term management with an individual’s measured internal circadian phase, as distinct from fixed-clock-time chronotherapy—and present it deliberately as a research agenda rather than an implementable clinical pathway. In the emergency setting, where reperfusion must never be delayed, we argue that circadian biology should inform risk stratification and the intensity of monitoring rather than the timing of intervention. We set out the principal bottlenecks: no validated point-of-care assay of circadian phase exists, and the correspondence between peripheral blood clock-gene phase and the cardiac clock is unestablished; indirect phase estimation from wearable data is the most tractable workaround. The largest randomized trial of cardiovascular dose timing was neutral, and no event-driven trial has yet shown that aligning therapy to circadian phase improves outcomes after AMI, so the present case for chronotherapy rests principally on mechanistic and observational data.