Insomnia-Associated Circadian and Thrombotic Alterations Coincide with Morning Cardiac Vulnerability

Abstract

Cardiovascular events such as myocardial infarction (MI) show an early morning peak, suggesting circadian regulation of cardiac vulnerability. However, the mechanisms through which sleep loss may contribute to time-of-day myocardial risk remain unclear. We examined whether insomnia-associated circadian and thrombotic alterations are associated with morning cardiac vulnerability. Rats were subjected to pharmacologically induced insomnia using para-chlorophenylalanine (PCPA), isoproterenol-induced myocardial stress, and their combination. Temporal profiling across zeitgeber times (ZTs) assessed locomotor activity, biochemical markers (melatonin, serotonin, and cardiac troponin I), cardiac electrophysiology, and coagulation parameters. Integrative transcriptomic analysis was performed using human insomnia and MI data sets. Experimentally, insomnia and myocardial stress altered rest–activity, temporal electrophysiology, biochemical, and coagulation circadian profiles, and the combined condition showed the most pronounced alterations. These included changes in cardiac conduction and repolarization indices, altered melatonin rhythmicity, altered serotonin levels, elevated troponin I, reduced clotting time, and increased platelet aggregation, predominantly during ZT6–ZT12, corresponding to the light–dark transition, analogous to the human early morning phase. PCPA effects were restricted to the light phase, whereas ISO-containing groups showed sustained alterations. Integrative transcriptomic analysis identified a candidate circadian–thrombotic molecular signature involving CRY1, F2R, LEP, SSTR2, and IL7R, with mRNA profiling in rats showing altered Cry1 expression in heart and Lep expression in both SCN and the heart, suggesting altered SCN–heart coordination under combined insomnia and MI. These findings suggest a shift toward a pro-thrombotic cardiac profile during the early day window with insomnia-associated circadian alterations, supporting future investigation of circadian-informed chronotherapeutic approaches for morning cardiac vulnerability.