Circulation最新文献

Background: Cardiovascular disease (CVD) prevalence is rising among younger women in the United States. Hypertensive disorders of pregnancy (HDP) are early indicators of cardiovascular risk, yet it remains unclear whether HDP independently increase CVD risk or reflect poor prepregnancy health. We aimed to quantify the association between HDP and incident CVD in a diverse, real-world population, with replication of findings across health systems.

Methods: We used data from the All of Us research program, encompassing >50 health systems across the United States, to identify women with longitudinal pregnancy and postpartum data (n=17 357; between 2007 and 2022). Multivariable Cox regression estimated adjusted hazard ratios (aHRs) of HDP with CVD (ischemic heart disease, heart failure, or stroke), overall and stratified by prepregnancy cardiometabolic risk factors (hypertension, obesity, diabetes, hyperlipidemia, or chronic kidney disease). Analyses were replicated in an independent health system (n=56 549; between 2016 and 2025) using the Observational Medical Outcomes Partnership Common Data Model.

Results: Participants had a median [interquartile range] age of 30 [25, 35] years; 2719 (16%) identified as Black or African American, and 7267 (42%) identified as Hispanic or Latino. Among those who reported socioeconomic data, 4306 (35%) reported an income <$25 000, and 6429 (37%) a high school education at most. HDP occurred in 2098 (12%) of pregnancies. Over a median of 4.6 years of follow-up, 701 women developed CVD. Overall, HDP were associated with elevated CVD risk (aHR, 1.82 [95% CI, 1.49-2.22]). Regardless of prepregnancy cardiometabolic risk factors, HDP were independently associated with CVD risk (aHR, 2.06 [95% CI, 1.55-2.74] among women without risk factors, and aHR, 1.33 [95% CI, 1.00-1.77] among women with risk factors). Main findings showed similar effect estimates for the risk of HDP with composite CVD (aHR, 2.62 [95% CI, 2.17-3.16]) in the external replication cohort.

Conclusions: In a diverse, national sample of young US women, HDP were a significant marker of premature CVD risk, even in the absence of prepregnancy cardiometabolic risk factors. Integrating pregnancy complications into CVD risk stratification and promoting cardiometabolic health before, during, and after pregnancy may reduce the growing burden of early-onset CVD among women.

Background: Venous thromboembolism (VTE) is a leading cardiovascular disease, yet its etiology is incompletely understood. This study used large-scale, high-throughput aptamer-based proteomics to identify new circulating protein biomarkers and biological pathways for incident VTE.

Methods: We included 4 longitudinal cohorts (the ARIC study [Atherosclerosis Risk in Communities], CHS [Cardiovascular Health Study], MESA [Multi-Ethnic Study of Atherosclerosis], and the HUNT study [Trøndelag Health]) that identified 1371 incident noncancer VTEs among 20 737 participants followed for a maximum of 10 to 29 years. We used the SomaScan to measure baseline plasma levels of ≈5000 to 7000 proteins and examined the prospective relationships between the protein biomarkers and noncancer VTE. We then conducted an external replication of top VTE proteins in 783 incident noncancer VTEs among 39 097 participants in the UKB study (UK Biobank) based on the Olink proteomics platform. We used Cox proportional hazards regression to estimate the association between each protein biomarker and VTE risk. Mendelian randomization (MR) analysis was used to assess the possible causal associations between identified proteins and VTE risk.

Results: There were 23 proteins that exceeded a false discovery rate-adjusted P<0.05 (unadjusted P<6.5×10^-4) in the discovery meta-analysis of ARIC, CHS, and MESA and were replicated in HUNT at (unadjusted) P<0.05. Of these, 15 are new to VTE, and 3 of the 15 (TAGLN, SVEP1, and TIMP4) exceeded the Bonferroni corrected significance threshold in HUNT. Sixteen of the 23 top VTE proteins were available on the UKB Olink panel, of which 11 were replicated in the UKB study after Bonferroni correction. MR analysis of the 15 new proteins provided significant evidence for a possible causal role of TIMD4 (Bonferroni-corrected P<0.05) and suggestive evidence for TIMP4 and CST3 (unadjusted P<0.05) in VTE risk. The direction of association from the MR analyses was opposite of that from the VTE proteomics analysis for TIMP4 and TIMD4 but was consistent for CST3.

Conclusions: We identified several novel plasma proteins for VTE that reflect biological processes outside established VTE pathophysiology, including extracellular matrix regulation, immunity, immune-vascular endothelium interactions, and vascular senescence. Results may provide new modifiable targets to improve VTE risk stratification, prevention, or treatment.

Background: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg.

Methods: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization).

Results: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy (P<0.0002), left ventricular strain impairment (P<0.0001), and decreased left ventricular compliance (P<0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction (P<0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P<0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P<0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively.

Conclusions: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Background: Tissue-specific regulatory T cells (Tregs) accumulate in the heart after myocardial infarction (MI) and play a vital role in limiting inflammation and promoting tissue repair. However, the developmental trajectory of heart Tregs and the molecular cues that guide their recruitment to the heart remain poorly understood, impeding therapeutic strategies that leverage Treg-mediated cardiac protection.

Methods: We used single-cell and bulk RNA sequencing in a murine MI model to delineate the differentiation trajectory of Tregs from mediastinal lymph nodes to the heart. Functional validation was performed using Treg-specific CCR8 (CC motif chemokine receptor 8) knockout mice (Ccr8^flox/floxFoxp3^Cre), CCL1 (CC motif chemokine ligand 1) knockout mice (Ccl1^-/-), macrophage-targeted CCL1 knockdown mice, CCL1-overexpressing mice, and DEREG mice. The CCL1-CCR8 axis was evaluated in cardiac tissues and circulating blood from patients with MI.

Results: Single-cell RNA sequencing revealed a stepwise differentiation of mediastinal lymph node-derived naive Tregs into cardiac resident Tregs, marked by the progressive acquisition of CCR8 expression and reparative capacity. CCR8⁺ Tregs in the heart exhibited enhanced immunosuppressive and tissue-repair signatures. Treg-specific CCR8 deletion led to reduced Treg accumulation and worsened cardiac function after MI, along with increased proinflammatory macrophage features and number of CD8⁺ T cells and natural killer cells. In addition, Tregs promoted a shift of macrophages toward an anti-inflammatory phenotype by secreting IL-1R2 (interleukin 1 receptor, type 2). We identified cardiac macrophages as the main source of CCL1, which was essential for CCR8⁺ Treg recruitment. CCL1 deficiency or macrophage-specific CCL1 knockdown impaired Treg infiltration and aggravated ventricular remodeling; CCL1 overexpression promoted Treg recruitment and improved cardiac outcomes. Moreover, the cardioprotective effects of CCL1 were abolished in DEREG mice upon Treg depletion and Ccr8^flox/floxFoxp3^Cre mice, establishing a CCR8⁺ Treg-dependent mechanism. Furthermore, circulating CCR8⁺ Tregs and cardiac CCL1 were elevated in humans with MI, and the presence of CCR8⁺ Tregs and CCL1-expressing macrophages was confirmed in the hearts of patients with MI, suggesting important clinical relevance.

Conclusions: Our findings reveal a 2-phase Treg specialization process and establish the CCL1-CCR8 axis as a crucial pathway for Treg recruitment and function in the infarcted heart. Therapeutic targeting of this axis may improve immune-regulated cardiac repair after MI.

Background: BCR-ABL tyrosine kinase inhibitors (TKIs) have been increasingly linked to pulmonary arterial hypertension (PAH) since 2009, although supporting evidence is limited. Our objective was to evaluate the risk of PAH associated with second- and third-generation BCR-ABL TKIs compared with imatinib in adults.

Methods: We employed a prevalent new-user design that emulates a randomized trial within the French national health care database population between 2008 and 2024. Thus, subjects initiating a second- and third-generation BCR-ABL TKI were matched on time and propensity score with users of the first-generation BCR-ABL TKI, imatinib. Patients were followed to occurrence of the primary outcome (ie, new onset of PAH), switch to another BCR-ABL TKI, death from any cause, end of registration within the database, or end of the study period, whichever came first. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression models, and incidence rates and corresponding 95% CIs were calculated using the Poisson distribution.

Results: Six thousand six hundred twenty-five dasatinib (age 59.7±15.2 years, 44.0% women), 5205 nilotinib (age 55.4±15.0 years, 44.2% women), 2421 bosutinib (age 63.8±14.2 years, 42.1% women),1358 ponatinib (age 57.3±14.9 years, 46.1% women), and 922 asciminib (age 64.3±13.8 years, 43.7% female) new users were each matched with the maximum of available imatinib users on time-conditional propensity score and on duration of prior imatinib use (prevalent users). Dasatinib use was associated with a 9-fold increased risk of PAH compared with imatinib (1829 versus 43 events per million persons per year; HR=8.89 [95% CI, 5.30-14.92]). Bosutinib and ponatinib were associated with HRs of 10.76 (95% CI, 4.68-24.73) and 7.74 (95% CI, 2.33-25.70) respectively, with most cases occurring in patients previously exposed to dasatinib. Nilotinib and asciminib were not associated with an increased risk of PAH.

Conclusion: This study, designed to emulate a randomized trial, suggests that, in French patients with chronic myeloid leukemia treated with BCR-ABL TKIs, dasatinib use is associated with a higher risk of PAH compared with imatinib, while bosutinib and ponatinib exposure may aggravate or trigger a recurrence of PAH in patients with preexisting dasatinib exposure. Whether bosutinib and ponatinib could induce PAH without preexposure to dasatinib remains to be explored.

Background: Obesity is an established risk factor for cardiovascular disease (CVD); however, the overall and sex-specific relationships across the full spectrum of body mass index (BMI), particularly severe obesity defined as class 2 (BMI 35 to <40.0 kg/m²) and class 3 (BMI ≥40 kg/m²), and long-term CVD outcomes remain incompletely described.

Methods: We included 289 875 participants (mean age, 60.3 years; 79.2% women) from 21 cohorts of the Cross-Cohort Collaboration enrolled between 1948 and 2015 with harmonized BMI data, a BMI ≥18.5 kg/m², and at least one of nine adjudicated outcomes: time to first fatal and non-fatal myocardial infarction (MI), fatal and nonfatal stroke, heart failure (HF), atrial fibrillation (AF), total coronary heart disease (CHD), total CVD, CHD mortality, CVD mortality, and all-cause mortality. Multivariable Cox proportional hazard models with restricted cubic splines were used to estimate the hazard ratio (HR) of BMI for each outcome, adjusting for demographic and clinical risk factors.

Results: Over 19.2 median years (25th, 11.6; 75th, 23.5 percentile) of follow-up, there were a total of 15 542 incident MI events, 15 467 incident stroke events, 14 172 incident HF events, 9066 diagnosed AF, and 113 918 total deaths, of which 14 647 were CHD-related and 28 879 were CVD-related. Overall, compared with individuals with normal weight, those with class 2 and class 3 obesity had the highest risk of HF (HR, 2.1, 95% CI, 2.0-2.3, and HR, 3.0, 95% CI, 2.7-3.2, respectively) and AF (HR, 1.8, 95% CI 1.7-2.0, and HR, 2.8, 95% CI, 2.5-3.1, respectively). Compared with men, women experienced higher relative increases in the risk associated with severe obesity for outcomes stroke, CVD, and all-cause mortality (P for interaction: <0.001, 0.003, and <0.001, respectively). Furthermore, in men, no increase in stroke risk was observed with higher BMI categories (P trend=0.49), whereas in women, the risk of stroke plateaued across obesity subclasses (compared with normal weight) yet remained significantly increased.

Conclusions: Higher BMI was robustly associated with increased risk for most outcomes, particularly HF and AF, even after adjusting for traditional risk factors. Observed sex differences in the relative hazard of higher BMI categories and stroke, total CVD, and all-cause mortality suggest potential differences in underlying biological mechanisms.

Background: During myocardial infarction (MI), M1-like macrophages exacerbate myocardial injury by excessively secreting inflammatory cytokines. Therefore, modulating the activity of M1-like macrophages may represent a novel therapeutic strategy for MI. PRMTs (protein arginine methyltransferases) primarily regulate protein function via asymmetric dimethylation, but PRMT9 does so through symmetric dimethylation. However, its role in cardiovascular diseases has yet to be established. In this study, we investigated the role of PRMT9 in macrophage polarization in the context of MI and explored its therapeutic effect for MI.

Methods: The correlation between PRMT9 in monocytes/macrophages and MI was investigated using the MI dataset GSE166780. Peripheral blood mononuclear cells were obtained from healthy individuals and patients with MI and analyzed to assess PRMT9 expression. We elucidated the functional role of PRMT9 in MI using macrophage-specific Prmt9 knockout mice and macrophage-specific overexpression adeno-associated virus vectors. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments.

Results: We discovered that PRMT9 was highly expressed in murine and human peripheral blood mononuclear cells in the early stages of MI. PRMT9 deficiency enhanced M1-like polarization and exacerbated cardiac damage in murine models of MI. Conversely, PRMT9 overexpression in macrophages reduced infarct size, accelerated inflammation resolution, and improved cardiac function after MI. Our findings established that PRMT9-catalyzed methylation played an important role in STAT1 (signal transducer and activator of transcription 1)-mediated macrophage polarization. Mechanistically, PRMT9 directly binds to STAT1 and facilitates its symmetric dimethylation at R588 and R736. Further analysis revealed that PRMT9-mediated symmetric dimethylation facilitated STAT1 ubiquitination, which promoted STAT1 recognition by SQSTM1/p62 (sequestosome-1) and NDP52/CALCOCO2 (nuclear dot protein 52), facilitating STAT1-selective autophagic degradation and suppressing excessive M1-like macrophage responses. Moreover, we demonstrated that the STAT1 inhibitor fludarabine, a clinically used chemotherapeutic agent, mitigated the exacerbation of post-MI myocardial injury induced by PRMT9 deletion in macrophages.

Conclusions: This study discovered a novel PRMT9-driven symmetric dimethylation of STAT1, resulting in its ubiquitination and lysosomal degradation, which suppresses the proinflammatory polarization of macrophages and mitigates myocardial damage following MI.

Risk prediction has been used in the primary prevention of cardiovascular disease for >3 decades. Contemporary cardiovascular risk assessment relies on multivariable models, which integrate established cardiovascular risk factors and have evolved over time from the Framingham Risk Model to the pooled cohort equations to the PREVENT (Predicting Risk of CVD Events) equations. Recent scientific (ie, genomics, proteomics, metabolomics) and methodologic (ie, artificial intelligence) advances have led to a proliferation of novel models, biomarkers, and tools for potential use in risk prediction. In parallel, the growing armamentarium of preventive therapies, some with considerable cost, underscores the need for more accurate and precise risk assessment to prioritize those at highest risk who will derive the greatest absolute benefit. Accompanying the considerable enthusiasm for the potential of newer approaches to improve risk prediction is the need for rigorous evaluation and assessment of their performance (ie, accuracy, precision, incremental performance when added to contemporary multivariable risk models or established risk factors) and clinical utility (ie, actionability, scalability, generalizability) before adoption in clinical practice. Additional considerations in risk tool evaluation include reproducibility, cost-value considerations (including impact on downstream health care costs), and implications for health equity. This scientific statement defines a standardized framework for general considerations in risk prediction, statistical assessment of predictive utility, and critical appraisal of clinical utility and readiness. This scientific statement is intended to support clinicians, researchers, and policymakers in how best to evaluate current and emerging risk prediction tools and ultimately improve the prevention of cardiovascular disease in diverse populations.

Background: Stressor-associated atrial fibrillation (AF), defined as newly diagnosed AF in the setting of a reversible physiological stressor, is common. However, risk factors, outcomes, and current management practices remain poorly understood.

Methods: We analyzed data from VITAL-AF, a pragmatic, cluster-randomized AF screening trial conducted in 2018 and 2019 comprising adults ≥65 years of age across 16 primary care practices affiliated with Massachusetts General Hospital. All participants had longitudinal follow-up for adjudicated incident AF (including whether stressor-associated versus nonstressor-associated ["primary"]) and clinical outcomes. We compared associations between clinical AF risk factors and incident AF group (stressor-associated versus primary) using Fine-Gray models handling death and each AF group as competing risks. We also quantified oral anticoagulant initiation rates after AF diagnosis. We then fit Cox proportional hazards models to quantify associations between incident AF group (as a time-varying covariate) and a composite end point of major bleeding, stroke, and all-cause mortality, with adjustment for CHA₂DS₂-VASc (congestive heart failure, hypertension, age >74, diabetes, stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74, sex category; stroke) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation; bleeding) scores and time-varying oral anticoagulant exposure.

Results: We analyzed 30 265 patients (41% men, 83% White, and mean age 74 years). Of 988 incident AF events, 290 (29%) were stressor associated. Clinical risk factors, including age, hypertension, and heart failure, showed similar associations with both primary and stressor-associated AF. Oral anticoagulant initiation within 90 days of new AF diagnosis was lower for stressor-associated versus primary AF (56% versus 75%, P<0.001). The incidence of the composite end point was 2.30 per 100 person-years (95% CI, 2.17-2.44) for no AF, 15.09 (95% CI, 12.22-18.42) for primary AF, and 22.71 (95% CI, 16.91-29.87) for stressor-associated AF. In adjusted models and using no AF as the referent, both primary AF (hazard ratio [HR], 3.91 [95% CI, 2.89-5.28]) and stressor-associated AF (HR, 6.13 [95% CI, 4.31-8.72]) were associated with substantially higher risk of the composite end point.

Conclusions: Among >30 000 primary care patients with adjudicated AF events, nearly one-third of incident AF cases were stressor associated. Despite similar risk factor profiles and comparably high rates of adverse outcomes, oral anticoagulant initiation is lower when AF is stressor associated. Future work is needed to define optimal approaches to prevention, surveillance, and management of stressor-associated AF.