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Burden of Cardiovascular Outcomes After SARS-CoV-2 Infection in South Korea and Japan: A Binational Population-Based Cohort Study

Circulation, Ahead of Print. BACKGROUND:Despite the significant global impact of the COVID-19 pandemic, limited studies have investigated the long-term cardiovascular sequelae of SARS-CoV-2 infection, particularly among Asian populations. This large-scale, population-based binational cohort study with long-term follow-up aimed to investigate the association between SARS-CoV-2 infection and the risk of cardiovascular events.METHODS:We used binational, large-scale, and population-based cohorts, including a Korean nationwide cohort (K-COV-N; discovery cohort; n=18 989 129) and a Japanese nationwide cohort (Japan Medical Data Center; validation cohort; n=12 218 680). Individuals aged 20 years or older were included from January 1, 2020, to December 31, 2022. We assessed the long-term risk of incident cardiovascular outcomes after SARS-CoV-2 infection. The primary outcome was the risk of cardiovascular diseases based onInternational Classification of Diseases, Tenth Revisioncode diagnosis. After propensity score–based overlap weighting, Cox proportional hazard models were used to estimate adjusted hazard ratios for cardiovascular outcomes. We assessed the time attenuation effect of cardiovascular outcomes after SARS-CoV-2 infection. Multiple subgroup analyses were conducted by 16 cardiovascular outcomes, COVID-19 severity, vaccination, and SARS-CoV-2 strain.RESULTS:In the overlap-weighted discovery cohort, 7 960 357 individuals were included (mean age, 48.52 years [SD, 9.33]; men, 4 283 878 [53.82%]). SARS-CoV-2 infection was associated with a long-term increased risk of overall cardiovascular outcomes (adjusted hazard ratio, 1.62 [95% CI, 1.60–1.64]), particularly ischemic heart disease (1.81 [95% CI, 1.77–1.84]), heart failure (1.79 [95% CI, 1.73–1.85]), cerebrovascular disorders (1.65 [95% CI, 1.60–1.69]), major adverse cardiovascular events (1.65 [95% CI, 1.60–1.70]), inflammatory heart diseases (1.53 [95% CI, 1.31–1.80]), dysrhythmia (1.44 [95% CI, 1.42–1.46]), and thrombotic disorders (1.42 [95% CI, 1.35–1.48]). The increased risk persisted up to 18 months, with the highest association observed for 1 to 6 months after infection. The risk of cardiovascular diseases was pronounced with COVID-19 severity; however, it decreased with the administration of complete vaccination and subsequent booster doses. A similar risk of cardiovascular outcomes existed across every SARS-CoV-2 era (pre-delta, delta, and omicron). Similar patterns were observed in the validation cohort. The absolute risk of cardiovascular disease events after SARS-CoV-2 infection remained remarkably low (2.12% versus 1.31% in the noninfected population), particularly stroke (0.24% versus 0.13%) and ischemic heart disease (0.73% versus 0.39%).CONCLUSIONS:This binational study observed associations between SARS-CoV-2 infection and cardiovascular events during extended follow-up across viral eras. Complete vaccination was linked to lower cardiovascular events. However, the absolute risk of cardiovascular disease events after SARS-CoV-2 infection remained remarkably low, particularly for stroke and ischemic heart disease. Although these findings suggest ongoing vigilance and preventive measures remain crucial, they should be interpreted within the context of these low absolute risks when considering long-term cardiovascular complications.

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Joint Exposure to Ozone and Temperature and Acute Myocardial Infarction Among Adults Aged 18 to 64 Years in the United States

Circulation, Ahead of Print. BACKGROUND:Previous research suggests that exposures to air pollution and nonoptimal temperatures are associated with a higher risk of acute myocardial infarction (AMI), but few studies examined the exposures jointly. Furthermore, moderate exposures were often overlooked. We evaluated short-term exposure to ambient ozone pollution and ambient temperature jointly and over the entire range of exposures, with the occurrence of AMI among adults aged 18 to 64 years (an understudied population) in the contiguous United States.METHODS:We identified eligible individuals with incident AMI insured by a nationwide private insurance company from 2016 to 2020. We designed a time-stratified case-crossover study in which each patient’s ambient exposure to ozone and temperature on the day of their AMI was compared with their exposures on a nearby day. We used a 2-stage model to investigate the associations with joint exposures: (1) fitting climate- and region-specific models with statistical interaction terms between ozone and temperature, and (2) using a multivariate random-effects meta-analysis to pool the region-specific estimates.RESULTS:We included 270 123 adults with incident AMI and observed a significant association between joint ozone-temperature exposures and increased AMI. Compared with the reference of ozone at 35 ppb and temperature at the first percentile, joint exposure to ozone at 60 ppb and temperature at the 95th percentile at lag 0 day was associated with a 33% (95% CI, 16%–51%) increase in incident AMI, and joint exposure to ozone at 50 ppb and temperature at the median was associated with a 15% (95% CI, 4%–28%) increase. There was heterogeneity by sex, with women showing increased odds when both ozone and temperature were high and men showing increased odds when either ozone or temperature was high.CONCLUSIONS:Joint exposure to ozone pollution and high temperature increased the probability of AMI among younger adults, even when 1 of the exposures was moderate. This study highlights the importance of addressing exposures to ozone and nonoptimal temperature simultaneously in AMI prevention strategies.

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Hierarchical Composite Outcomes and Win Ratio Methods in Cardiovascular Trials: A Review and Consequent Guidance

Circulation, Volume 151, Issue 22, Page 1606-1619, June 3, 2025. The win ratio is a method for analyzing a hierarchical composite outcome. It has been most widely used in randomized clinical trials (RCTs) in cardiovascular disease. We performed a review of cardiovascular RCTs using the win ratio published between January 2022 and July 2024. The aims were to summarize current use and to provide examples to illustrate effective use and communication. We identified 36 eligible RCTs, mainly in heart failure and ischemic heart disease. Intervention was pharmaceutical in 26, a procedure in 7, and treatment strategy in 3 trials. When outcomes were analyzed with both conventional composite end points or hierarchical analysis, the conclusions tended to be similar. The win ratio was often used to combine evidence from event outcomes and quantitative measures together in a hierarchical composite, as was done in 23 RCTs. It was also used to create a clinically more relevant measure in RCTs by recognizing the clinical priorities among event outcomes. Selected example RCTs illustrate how the clarity of win ratio findings can be improved by (1) complementing the win ratio (a relative measure) with the win difference, (2) identifying which components of a hierarchical composite drive the overall results, and (3) clearly prespecifying the outcomes and win ratio analysis to be used. We conclude with a set of recommendations for future use of hierarchical composite outcomes and the win ratio. When used wisely, the win ratio is a valuable tool in the analysis of RCTs.

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Disruption of cTnT-Mediated Sarcomere–Mitochondrial Communication Results in Dilated Cardiomyopathy

Circulation, Ahead of Print. BACKGROUND:Dilated cardiomyopathy (DCM) is substantially influenced by genetic factors. Sarcomere function is intricately associated with other organelles, particularly the reciprocal regulation between sarcomeres and mitochondria. Mitochondrial stress dysregulation is linked to DCM progression, yet mechanisms remain unclear. In this study, we investigated the effects of cTnT (cardiac troponin T) dysregulation on sarcomere–mitochondrial communication in DCM.METHODS:Induced pluripotent stem cells (iPSCs) derived from a DCM family cohort were used in this study, and CRISPR-Cas9 genome editing was used to rectify theTNNT2(c.A553G) sequence variation in iPSCs. A knock-in mouse model harboring the (p.K192E) sequence variation, equivalent to the human cTnT (p.K185E) sequence variation, was subsequently established. The pathological phenotypes were analyzed in iPSC-derived cardiomyocytes, iPSC-derived cardiac organoids, and mice. RNA sequencing, metabolite profiling, and coimmunoprecipitation mass spectrometry were used to elucidate the molecular mechanisms.RESULTS:Through whole exome sequencing, we identified a novel pathogenic variant in cTnT (p.K185E) as the causal sequence variation in a familial DCM cohort. In iPSC-derived cardiomyocytes from patients with DCM, we observed sarcomere disarray and mitochondrial fragmentation accompanied by severe mitochondrial dysfunction. The diminished interaction between cTnT (p.K185E) and 14-3-3 proteins resulted in the dissociation of 14-3-3 proteins from sarcomeric structures. The free 14-3-3 proteins aberrantly engaged in the RAS/RAF1 signaling axis, driving aberrant p44/42 kinase activation that culminated in the phosphorylation of mitochondrial fission regulators DRP1 (dynamin-related protein 1) and MFF (mitochondrial fission factor). These observations were replicated in iPSC-derived cardiac organoids. The knock-in mice bearing the orthologous cTnT sequence variation faithfully recapitulated the hallmark features of human DCM, including cardiac dysfunction, ventricular dilatation, sarcomeric disarray, and mitochondrial fragmentation. Mdivi-1, a mitochondrial fission inhibitor, alleviated DCM phenotypes in vivo.CONCLUSIONS:Our findings delineate a novel pathogenic mechanism underlying DCM, demonstrating that cTnT (p.K185E) sequence variation disrupts sarcomere–mitochondrial communication by weakening the interaction between cTnT and 14-3-3 proteins, thereby accelerating mitochondrial fragmentation through excessive activation of the 14-3-3 protein–mediated RAS/RAF1-p44/42-DRP1/MFF signaling axis. Therefore, therapeutic targeting of 14-3-3 proteins and p44/42 kinase activity may represent a promising strategy for DCM and other cardiac diseases associated with aberrant mitochondrial dynamics.

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