Background: Cold exposure has been considered an essential risk factor for the global disease burden, while its role in cardiovascular diseases is still underappreciated. The increase in frequency and duration of extreme cold weather events like cold spells makes it an urgent task to evaluate the effects of ambient cold on different types of cardiovascular disease and to understand the factors contributing to the population's vulnerability.Methods: In the present systematic review and meta-analysis, we searched PubMed, Scopus, and Cochrane. We included original research that explored the association between cold exposure (low temperature and cold spell) and cardiovascular disease outcomes (mortality and morbidity). We did a random-effects meta-analysis to pool the relative risk (RR) of the association between a 1°C decrease in temperature or cold spells and cardiovascular disease outcomes.Results: In total, we included 159 studies in the meta-analysis. As a result, every 1°C decrease in temperature increased cardiovascular disease-related mortality by 1.6% (RR 1.016; [95% CI 1.015–1.018]) and morbidity by 1.2% (RR 1.012; [95% CI 1.010–1.014]). The most pronounced effects of low temperatures were observed in the mortality of coronary heart disease (RR 1.015; [95% CI 1.011–1.019]) and the morbidity of aortic aneurysm and dissection (RR 1.026; [95% CI 1.021–1.031]), while the effects were not significant in hypertensive disease outcomes. Notably, we identified climate zone, country income level and age as crucial influential factors in the impact of ambient cold exposure on cardiovascular disease. Moreover, the impact of cold spells on cardiovascular disease outcomes is significant, which increased mortality by 32.4% (RR 1.324; [95% CI 1.2341.421]) and morbidity by 13.8% (RR 1.138; [95% CI 1.015–1.276]).Conclusion: Cold exposure could be a critical risk factor for cardiovascular diseases, and the cold effect varies between disease types and climate zones.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42022347247.

Background: Prostaglandin E ₂ (PGE ₂ ) in the rostral ventrolateral medulla (RVLM) has been recognized as a pivotal pressor substance in hypertension, yet understanding of its effects and origins in the RVLM remains largely elusive. This study aimed to elucidate the pivotal enzymes and molecular mechanisms underlying PGE ₂ synthesis induced by central Ang II (angiotensin II) and its implications in the heightened oxidative stress and sympathetic outflow in hypertension. Methods and Results: RVLM microinjections of PGE ₂ and Tempol were administered in Wistar‐Kyoto rats. Intracisternal drug delivery and adeno‐associated viral vectors microinjection were used in both Wistar‐Kyoto rats and spontaneous hypertensive rats to modulate the function of Ang II, PGE ₂ receptor 3, and expression of COX2 (cyclooxygenase 2). Microinjection of PGE ₂ into the RVLM significantly augmented sympathetic activity (25.380±1.566%) and oxidative stress level, whereas intracisternal infusion of a prostaglandin E receptor 3 antagonist attenuated sympathetic activity in both spontaneous hypertensive rats and Ang II‐induced hypertensive rats. Furthermore, Ang II treatment upregulated COX2 expression in RVLM neurons (1.000±0.112 versus 1.506±0.370 fold change), with no significant effect on other enzymes involved in PGE ₂ synthesis. Additionally, inhibition of the JAK2/STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathway nullified Ang II‐mediated elevation of COX2 expression, as evidenced by phosphorylated STAT3 binding to the COX2 sequence in PC12 cells. Conclusions: Central Ang II induces the accumulation of RVLM PGE ₂ through the neuronal AT1R (angiotensin type 1 receptor)/JAK2/STAT3/COX2 pathway, thereby promoting oxidative stress, augmenting sympathetic outflow, and contributing to essential hypertension.

Heart failure (HF) is known as the final manifestation of cardiovascular diseases. Although cellular heterogeneity of the heart is well understood, the phenotypic transformation of cardiac cells in progress of HF remains obscure. This study aimed to analyze phenotypic transformation of cardiac cells in HF through human single-cell RNA transcriptome profile. Here, phenotypic transformation of cardiomyocytes (CMs), endothelial cells (ECs), and fibroblasts was identified by data analysis and animal experiments. Abnormal myosin subunits including the decrease in Myosin Heavy Chain 6, Myosin Light Chain 7 and the increase in Myosin Heavy Chain 7 were found in CMs. Two disease phenotypes of ECs named inflammatory ECs and muscularized ECs were identified. In addition, myofibroblast was increased in HF and highly associated with abnormal extracellular matrix. Our study proposed an integrated map of phenotypic transformation of cardiac cells and highlighted the intercellular communication in HF. This detailed definition of cellular transformation will facilitate cell-based mapping of novel interventional targets for the treatment of HF.

Objective: Cyclooxygenase (COX) is critical in regulating cardiovascular function, but its role involved in the central control of blood pressure (BP) is uncovered. The tonic glutamatergic inputs to the rostral ventrolateral medulla (RVLM) are enhanced in hypertension. Here, the present study was designed to investigate the effect and mechanism of central COX on tonic glutamatergic inputs to the RVLM and BP regulation. Methods: Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) received RVLM microinjection of adeno-associated viral vectors to promote or inhibit the COX2 expression were subjected to subsequent experiments. Glutamate level and glutaminase expression were detected by ELISA and western blot, respectively. The function of tonic glutamatergic inputs was assessed by BP response to microinjection of the glutamate receptor antagonist into the RVLM. PC12 cells were used to detect the underlying signal pathway. Results: The RVLM COX2 expression and prostaglandin E2 level were significant higher in SHRs than in WKY rats. Overexpression of COX2 in the RVLM produced an increase in basal BP, RVLM glutamate level, and glutaminase expression in WKY rats, while they were significantly reduced by interfering with COX2 expression in SHRs. Microinjections of the glutamate receptor antagonist into the RVLM produced a significant BP decrease in WKY rats with COX2 overexpression pretreatment. Furthermore, the increased levels of BP, glutamate content, and glutaminase activity in the RVLM evoked by central infusion of angiotensin II were attenuated in COX2 knockout mice. It was also found that prostaglandin E2 increased supernatant glutamate level and phosphorylation of signal transducer and activator of transcription 3 in PC12 cells. Conclusion: Our findings suggest that upregulated COX2 expression enhances the tonically active glutamatergic inputs to the RVLM, which is associated with cardiovascular regulation in hypertension.