image: A: observational links between CD and cardiovascular comorbidities; B: molecular mechanisms by which core clock genes govern physiological homeostasis and drive pathological cascades when dysregulated; C: translational implications for chronotherapy and circadian-targeted drug development.
Credit: Professor Yue Liu from Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences.
Cardiovascular diseases (CVDs) are increasingly multisystem disorders involving cardio-cerebral, cardio-hepatic and cardio-renal comorbidities. A new review from Xiyuan Hospital identifies circadian disruption (CD) as a core mechanism underlying these inter-organ interactions, opening new avenues for chronotherapy and a shift from organ-centric to network-based CVD management.
The suprachiasmatic nucleus (SCN) master clock synchronizes peripheral organ oscillators, coordinating 10%–15% of the transcriptome in 24-hour cycles. CD, caused by sleep disorders, irregular eating or shift work, breaks this synchronization, triggering damage via autonomic imbalance, hormonal fluctuations, metabolic dyshomeostasis, systemic inflammation and gut microbiota dysbiosis. This relationship is bidirectional: end-organ damage from CVDs further disturbs circadian rhythms, creating a vicious cycle.
CD exerts distinct effects on different CVD comorbidities. It amplifies morning blood pressure surges and thrombotic risk in cardio-cerebral comorbidity; impairs lipid metabolism and insulin sensitivity via BMAL1 dysfunction in cardio-hepatic comorbidity; and disrupts renal sodium handling through PER2 dysregulation in cardio-renal comorbidity, with notable sexual dimorphism in disease susceptibility. Central-peripheral circadian regulation also varies by condition, with SCN dominance in cardio-cerebral comorbidity, peripheral clock dysfunction in cardio-hepatic comorbidity, and balanced regulation in cardio-renal comorbidity.
Chronotherapies show promise for re-entraining circadian rhythms. Time-restricted eating (TRE) modulates gut microbiota oscillations to improve metabolic and cardiovascular health; bedtime antihypertensive dosing targets non-dipping blood pressure, though clinical evidence is inconsistent. Preclinical clock-targeted drugs (e.g., REV-ERB agonists) have potential but face bioavailability and off-target challenges.
This review highlights the need to integrate temporal dynamics into CVD care. Future precision medicine for chronotherapy will stratify patients by circadian “chronotype” and tailor interventions to CD-driven inter-organ pathways. Aligning conventional drugs with endogenous circadian rhythms and combining low-dose clock modulators with TRE will optimize multi-organ protection, advancing personalized treatment for CVD comorbidities.