Circulation最新文献

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.

Btk (Bruton's tyrosine kinase), a Tec-family kinase initially recognized for its role in B-cell signaling, has emerged as a critical player in thrombosis and cardiovascular disease. Beyond the established therapeutic effects of Btk inhibitors in B-cell malignancies, its expression in platelets, macrophages, and neutrophils implicates Btk in platelet activation, atherothrombosis, and innate immunity. This state-of-the-art review synthesizes the current understanding of Btk's mechanistic contributions to thrombosis and cardiovascular disease, evaluates the evolution of Btk inhibitors (BTKi), and explores their therapeutic potential. Patients with X-linked agammaglobulinemia who lack Btk do not have a bleeding diathesis, indicating that platelet-selective Btk inhibition would be a safe antithrombotic strategy. In platelets, Btk mediates immunoreceptor tyrosine-based activation motif-dependent and -independent signaling, driving atherothrombosis, venous thrombosis, and immunothrombosis without affecting hemostatic platelet functions. In myeloid cells, Btk amplifies inflammation via NLRP3 inflammasome activation and neutrophil extracellular trap formation, linking it to thromboinflammation and atherosclerosis. First-generation BTKi such as ibrutinib demonstrate antithrombotic efficacy but are limited by off-target effects, including bleeding and atrial fibrillation. Second- and third-generation inhibitors (eg, acalabrutinib, zanubrutinib, and pirtobrutinib) show enhanced selectivity, reducing cardiovascular toxicity in patients with B-cell malignancies. Highly selective BTKi (fenebrutinib and remibrutinib) do not show bleeding in clinical trials of various autoimmune disorders, and covalent selective BTKi applied at low dosage are expected to selectively inhibit Btk in platelets without bleeding side effects. Preclinical data and early observations from compassionate use in patients with atypical autoimmune thrombosis highlight the potential of BTKi as selective antithrombotic agents beyond traditional therapies. This review conceptualizes and underscores Btk's pivotal role at immune-thrombosis interfaces in atherothrombosis, advocating for precision medicine approaches and innovative platforms to unlock its full therapeutic potential in cardiovascular disease management.

Background: End-stage heart failure (HF) remains a major global health challenge, and left ventricular assist devices (LVADs) represent an important therapeutic option. LVAD-mediated mechanical unloading improves cardiac function and promotes myocardial recovery in many patients with HF. How cardiac unloading by LVADs leads to myocardial recovery and whether impairment of these processes underlies the limited myocardial recovery benefit in obese patients remain poorly understood.

Methods: Patients with HF with LVADs were recruited for an investigation of the correlation between patients' body mass index and their response to LVAD-mediated myocardial recovery. Moreover, a mouse model of heterotopic cervical heart transplantation was used to simulate LVAD unloading. Single-nucleus RNA sequencing and stable-isotope tracing metabolomics were performed to explore the changes of signaling pathways and metabolic processes in unloaded hearts. In vitro cyclic stretch assays were used to evaluate how reduced mechanical load regulates cardiomyocyte metabolic pathways. Unloaded hearts from HF mice were used to determine whether the identified metabolic process contributed to unloading-induced myocardial recovery. Furthermore, the unloaded hearts from obese HF mice were used to evaluate whether the identified metabolic process was attenuated by obesity.

Results: HF patients with a higher body mass index (≥28.0) and greater insulin resistance tended to have poorer LVAD-mediated myocardial recovery. Single-nucleus RNA sequencing demonstrated that mechanical unloading activated myocardial insulin signaling and increased glucose uptake. Stable-isotope tracing metabolomics revealed that glucose taken up by unloaded hearts was preferentially diverted into the pentose phosphate pathway. Mechanistically, reduced mechanical stress attenuated Hippo pathway activation in cardiomyocytes, facilitating insulin signaling and enhancing pentose phosphate pathway flux. The unloaded hearts from HF mice revealed that an increase in pentose phosphate pathway flux could reduce oxidative stress and exert cardioprotective effects. However, these benefits were blunted by insulin resistance in obese mice, whereas treatment with insulin sensitizers alleviated insulin resistance and restored unloading-mediated cardioprotection.

Conclusions: In failing hearts, unloading leads to activation of insulin signaling, resulting in increased glucose uptake and an enhanced pentose phosphate pathway to protect cardiomyocytes against oxidative stress. However, this cardioprotective effect is attenuated by obesity-induced insulin resistance. Administration of insulin sensitizers has the potential to improve LVAD-mediated myocardial recovery in obese patients with HF.

Background: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV.

Methods: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals).

Results: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes (WNT4, LEF1, STRN, and KANK2) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90-2.25; P=5.43×10^-62) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank.

Conclusions: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.