Circulation最新文献

Background: Limited data are available regarding the relative rates, etiology, and long-term prognostic implications of spontaneous myocardial infarction (MI) after percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery for left main coronary artery disease (LMCAD).

Methods: MIs after PCI and CABG for LMCAD were adjudicated from the EXCEL trial (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization). Cox proportional hazards regression was performed to assess the association between spontaneous (and procedural) MI and cardiovascular and all-cause mortality at 5 years.

Results: Among 1882 patients who underwent LMCAD revascularization, spontaneous MI during 5-year follow-up occurred in 60 (6.8%) patients after PCI and in 29 (3.4%) patients after CABG (adjusted hazard ratio [adjHR], 2.01; 95 CI, 1.29-3.15; P=0.002). By multivariable analysis, spontaneous MI (as a time-adjusted covariate) was a strong independent predictor of subsequent cardiovascular mortality (adjHR, 9.39; 95% CI, 5.22-16.87) and all-cause mortality (adjHR, 4.77; 95% CI, 2.92-7.80) within 5 years, with consistent effects after PCI and CABG (P_interaction=0.60 and 0.78, respectively). In the same models, procedural MI as defined by extensive myonecrosis was associated with 5-year cardiovascular (adjHR, 3.02; 95% CI, 1.64-5.56) and all-cause mortality (adjHR, 2.38; 95% CI, 1.48-3.80), with consistent effects after PCI and CABG (P_interaction=0.23 and 0.34, respectively).

Conclusions: In the EXCEL trial, spontaneous MI occurred relatively infrequently within 5 years after LMCAD revascularization but at a higher rate after PCI compared with CABG. Spontaneous MI after revascularization was strongly related to subsequent cardiovascular and all-cause mortality, consistently after PCI and CABG, and was more strongly associated with mortality than was large procedural MI.

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.

There is an emerging convergence between atherosclerotic cardiovascular disease and cancer, driven by shared risk factors and overlapping pathophysiologic mechanisms. Traditional factors, such as smoking, aging, obesity, hypertension, and diabetes, alongside novel markers, such as clonal hematopoiesis of indeterminate potential, not only predispose individuals to both malignancies and coronary atherosclerosis but also amplify the risk of cardiotoxicity from cancer therapies. Inflammatory processes play a central role in atherogenesis, a process further accelerated by oncologic treatments-including chemotherapy (eg, anthracyclines, 5-fluorouracil), targeted and hormone therapies (eg, tyrosine kinase inhibitors, androgen deprivation, aromatase inhibitors), immune checkpoint inhibitors, and radiation therapy (RT)-that contribute to endothelial dysfunction and plaque instability. This scientific statement synthesizes the evidence on the interplay between cancer and coronary atherosclerosis, highlighting advances in noninvasive imaging modalities (ie, cardiac CT, nuclear imaging, cardiac magnetic resonance, echocardiography) for early detection, risk stratification, and surveillance of coronary artery disease in oncologic populations, and examines the role of invasive imaging techniques in guiding revascularization decisions. Given the elevated bleeding and thrombotic risks in these patients, individualized management of post-percutaneous coronary intervention medications and abbreviated dual antiplatelet therapy regimens is emphasized. This scientific statement also addresses knowledge gaps and reinforces the need for more evidence to improve risk stratification for atherosclerotic cardiovascular disease in patients with cancer. The shared pathobiology between coronary atherosclerosis and cancer necessitates an integrated, multidisciplinary approach to screening, diagnosis, and management.

Background: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need.

Methods: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included.

Results: Median age at presentation was 48 years (quartile 1-3, 34-59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (quartile 1-3, 25%-48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.3% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis-associated form (13.1%) at 3 years (P=0.15).

Conclusions: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes.

Registration: https://www.clinicaltrials.gov; Unique identifier: NCT06447935.

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.