Hypertension is the most common cardiovascular condition in clinical practice and a major risk factor for stroke and cardiovascular events. There are more than 270 million hypertension patients in China, and the prevalence of hypertension in the high-latitude cold areas is significantly higher than in the low-latitude warm areas. The unique epidemiological characteristics and risk factors of hypertension in the cold regions of China urge for establishment of the prevention and control system for targeted and more effective management of the condition.

  Objective  Myocardial ischemia-reperfusion (I/R) injury remains a major contributor to cardiac morbidity and mortality, and accumulating evidence suggests that epitranscriptomic regulation may critically influence cardiac stress responses. N6-methyladenosine (m6A) modification and circular RNAs (circRNAs) have emerged as important regulators of cardiovascular pathology; however, their integrated roles in myocardial I/R injury, particularly under chronic cold stress, remain poorly defined.  Methods  A mouse model of myocardial I/R injury was established under room-temperature or chronic cold exposure conditions. Cardiac function, infarct size, histopathology, and serum injury markers were assessed. Global m6A levels were quantified, and m6A-modified circRNA profiles were analyzed using epitranscriptomic microarrays and bioinformatics approaches. Differentially expressed circRNAs were validated in vivo and in hypoxia-reoxygenation-treated neonatal cardiomyocytes. Circular structures and stability were confirmed by Sanger sequencing, divergent/convergent PCR, and actinomycin D assays. Competing endogenous RNA (ceRNA) networks were constructed to identify downstream regulatory pathways.  Results  Myocardial I/R injury resulted in significant cardiac dysfunction, increased infarct size, histological damage, and elevated serum CK-MB and LDH levels, accompanied by a marked increase in global m6A methylation. Epitranscriptomic profiling identified 391 circRNAs with altered m6A modification following I/R injury, involving pathways related to molecular binding, cellular processes, and kinase signaling. Multiple circRNAs exhibited consistent dysregulation in both in vivo and in vitro I/R models and displayed high structural stability. Importantly, chronic cold exposure significantly exacerbated I/R-induced cardiac dysfunction and infarct severity while further modulating the expression of specific m6A-modified circRNAs. ceRNA network analysis revealed that cold-responsive circRNAs potentially regulate myocardial injury through miRNA-mediated signaling pathways.  Conclusion  This study identifies m6A-modified circRNAs as key epitranscriptomic regulators of myocardial I/R injury and demonstrates that chronic cold stress amplifies circRNA-mediated regulatory networks. These findings provide novel mechanistic insight into temperature-dependent epigenetic regulation in ischemic heart disease and highlight m6A-circRNAs as potential therapeutic targets.