Search Results for: Circulation

Circulation, Volume 151, Issue 22, Page e1043-e1044, June 3, 2025.

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.

Circulation, Volume 151, Issue 22, Page 1547-1549, June 3, 2025.

Circulation, Volume 151, Issue 22, Page e1045-e1046, June 3, 2025.

Circulation, Volume 151, Issue 22, Page 1622-1625, June 3, 2025.

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.

Circulation, Volume 151, Issue 21, Page 1544-1546, May 27, 2025.

Circulation, Volume 151, Issue 21, Page e1027-e1027, May 27, 2025.

Circulation, Volume 151, Issue 21, Page 1508-1511, May 27, 2025.

Circulation, Volume 151, Issue 21, Page 1495-1497, May 27, 2025.

Circulation, Volume 151, Issue 21, Page 1541-1543, May 27, 2025.

Circulation, Volume 151, Issue 21, Page e1028-e1029, May 27, 2025.

Circulation, Ahead of Print. BACKGROUND:Desmosomal gene variants (DGVs) have been associated with a diverse spectrum of phenotypic manifestations within arrhythmogenic cardiomyopathy, but data on genotype-specific outcomes are lacking. We investigated genotype-specific arrhythmic and heart failure (HF) outcomes in DGV carriers.METHODS:This cohort study included consecutive patients referred for screening for desmosomal genes. Carriers of pathogenic and rare (allele frequency

Circulation, Ahead of Print. BACKGROUND:Proteomic signatures might improve disease prediction and enable targeted disease prevention and management. We explored whether a protein risk score derived from large-scale proteomics data improves risk prediction of atrial fibrillation (AF).METHODS:A total of 51 680 individuals with 1459 unique plasma protein measurements and without a history of AF were included from the UKB-PPP (UK Biobank Pharma Proteomics Project). A protein risk score was developed with lasso-penalized Cox regression from a random subset of 70% (36 176 individuals, 54.4% women, 2155 events) and was tested on the remaining 30% (15 504 individuals, 54.4% women, 910 events). The protein risk score was externally replicated with the ARIC study (Atherosclerosis Risk in Communities; 11 012 individuals, 54.8% women, 1260 events).RESULTS:The protein risk score formula developed from the UKB-PPP derivation set was composed of 165 unique plasma proteins, and 15 of them were associated with atrial remodeling. In the UKB-PPP test set, a 1-SD increase in protein risk score was associated with a hazard ratio of 2.20 (95% CI, 2.05–2.41) for incident AF. The C index for a model including CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation), NT-proBNP (N-terminal B-type natriuretic peptide), polygenic risk score, and protein risk score was 0.816 (95% CI, 0.802–0.829) compared with 0.771 (95% CI, 0.755–0.787) for a model including CHARGE-AF, NT-proBNP, and polygenic risk score (C-index change, 0.044 [95% CI, 0.039–0.055]). Protein risk score added to CHARGE-AF, NT-proBNP, and polygenic risk score resulted in a risk reclassification of 5.4% (95% CI, 2.9%–7.9%) with a 5-year risk threshold of 5%. In the decision curve, the predicted net benefit before and after the addition of protein risk score to a model including CHARGE-AF, NT-proBNP, and polygenic risk score was 3.8 and 5.4 per 1000 people, respectively, at a 5-year risk threshold of 5%. External replication of a protein risk score in the ARIC study showed consistent improvement in risk stratification of AF.CONCLUSIONS:Protein risk score derived from a single plasma sample improved risk prediction of AF. Further research using proteomic signatures in AF screening and prevention is needed.

Circulation, Ahead of Print. BACKGROUND:Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury.METHODS:The profiling of AA metabolic enzymes was analyzed with the RNA sequencing transcriptome data from the mouse heart tissues with I/R injury. Cultured neonatal and adult rat ventricular myocytes, human embryonic stem cell–derived cardiomyocytes, and in vivo mouse I/R models were used to confirm the role of L-PGDS (lipocalin-type prostaglandin D2 synthase)/15d-PGJ2 in I/R injury. A biotin-tagged 15d-PGJ2 analog combined with liquid chromatography–tandem mass spectrometry was used to identify the downstream signaling of L-PGDS/15d-PGJ2.RESULTS:Based on the transcriptome data and experimental validations, L-PGDS, together with its downstream metabolite 15d-PGJ2, was downregulated in cardiac tissue with I/R injury. Functionally, L-PGDS overexpression mitigates myocardial I/R injury, whereas knockdown exacerbates the damage. Supplementation of 15d-PGJ2 alleviated I/R injury. Mechanistically, 15d-PGJ2 covalently bound to the Ca2+/CaMKII (calmodulin protein kinase II) and induced lipoxidation of its cysteine 495 (CaMKII-δ9) to dampen the formation of CaMKII oligomers and alleviate its overactivation, consequently ameliorating cardiomyocyte death and cardiac injury.CONCLUSIONS:Our study uncovered L-PGDS/15d-PGJ2/CaMKII signaling as a new mechanism underlying I/R-induced cardiomyocyte death. This provides new mechanistic insights and therapeutic targets for myocardial I/R injury and subsequent heart failure. We also showed that lipoxidation is a new post-translational modification type for CaMKII, deepening our understanding of the regulation of its activity.

Stroke, Ahead of Print. BACKGROUND:For patients with acute ischemic stroke due to a large vessel occlusion admitted in primary stroke centers, helicopter transfer to comprehensive stroke centers is often used to expedite access to mechanical thrombectomy. Some studies have suggested that vibrations generated during helicopter transport might enhance intravenous thrombolysis (IVT) efficacy. We aimed to evaluate the impact of helicopter transfer, compared with ground transportation, on interhospital recanalization and functional outcomes.METHODS:We conducted a retrospective analysis of 2 prospectively collected cohorts of anterior circulation acute ischemic stroke due to a large vessel occlusion patients transferred to 2 comprehensive stroke centers (Stanford, CA, November 2019 to January 2023, and Montpellier, France, January 2015 to January 2017) for mechanical thrombectomy consideration with arterial imaging both at the primary stroke center and on comprehensive stroke center arrival. The primary outcome was interhospital recanalization, determined by comparison of the baseline and posttransfer arterial imaging and defined as revised arterial occlusive lesion scores of 2b to 3. The association between transportation mode (helicopter versus ground) and interhospital recanalization was studied in logistic regression analysis, adjusting for pretransfer IVT use, occlusion site, and transfer duration.RESULTS:Among 520 included patients, 315 (61%) were transferred by helicopter and 259 (50%) received IVT before transfer. Interhospital recanalization rates were similar between helicopter and ground transfers in both the overall cohort (23% versus 19%;P=0.30) and the IVT subgroup (36% versus 33%;P=0.61). Adjusted analyses confirmed no association between helicopter transport and interhospital recanalization (adjusted odds ratio, 1.23 [95% CI, 0.72–2.11];P=0.44). Favorable 3-month functional outcome (modified Rankin Scale score, 0–2) rates were also similar between helicopter and ground transfers in both unadjusted (35% versus 40%;P=0.29) and adjusted analyses (adjusted odds ratio, 1.12 [95% CI, 0.67–1.88];P=0.67).CONCLUSIONS:In this multicenter observational cohort study, helicopter transfer was not associated with improved interhospital recanalization or favorable functional outcomes compared with ground transport. These findings do not support the hypothesis that vibrations during helicopter transport enhance IVT efficacy.