Circulation最新文献

Premenopausal women presenting with acute coronary syndrome (ACS) are a unique and often underrecognized patient population. Although they are traditionally considered at lower cardiovascular risk than other groups, we have begun to appreciate the potential risk for ACS in this younger subset of women. Whereas atherosclerotic disease (obstructive or nonobstructive) accounts for most presentations, a substantial number are attributable to nonatherosclerotic causes, including spontaneous coronary artery dissection, epicardial coronary artery spasm, and coronary embolism. A major challenge at present is the lack of specific data and evidence for the diagnosis and management of these women. Unfortunately, as a result of several factors, diagnostic delays, misclassification, and mistreatment appear to be more frequent than for other patient groups. Of great concern, younger women less often receive guideline-directed therapies after ACS, and younger women with ACS have been shown to have worse outcomes than young men with ACS. Management should be tailored to the unique pathophysiology in premenopausal women, emphasizing early diagnosis, a low threshold for invasive angiography if appropriate, and special consideration in the pregnant patient. Secondary prevention must address traditional cardiovascular and disease-specific risk factors, with consideration of current or future pregnancies and lactation. Participation in cardiac rehabilitation is associated with improved outcomes and must be strongly encouraged, whereas attention to potential post-ACS depression and anxiety is an important aspect of holistic care. Increased patient and health care professional awareness and improved representation in research are critical to closing the knowledge and outcome gaps in premenopausal women with ACS.

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: 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: 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: 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.