Circulation最新文献

Clonal hematopoiesis (CH), the benign clonal expansion of hematopoietic stem cells, is often caused by somatic sequence variations in genes associated with hematologic malignancies. Over the past decade, CH has emerged as a risk factor for a wide range of cardiovascular diseases (CVDs), including atherosclerosis, heart failure, atrial fibrillation, and thrombosis. The cardiovascular risk associated with CH is heterogeneous; it varies on the basis of specific genes and variants, clone size, and various extrinsic features. Mechanistic studies suggest that CH contributes to CVDs through both gene-specific pathways and broader inflammatory processes. These include aberrant cytokine production, inflammasome activation, and other proinflammatory mechanisms, which can accelerate atherosclerosis, promote thrombogenesis, and impair vascular or myocardial function. These findings underscore the importance of addressing CH as a potential contributor to CVDs. CH is predominantly considered an age-related phenomenon, but lifelong influences on the fitness of genetic variants, including germline predispositions, obesity, chronic inflammation, and exposure to environmental toxins (eg, tobacco, certain cancer treatments), influence CH. A greater understanding of CH risk factors is therefore important for both individual and population-level risk assessments. Incorporating CH-associated risk into existing CVD risk prediction models may inform new personalized preventive or therapeutic approaches. No CH-specific therapies have proven efficacy in CVD treatment or prevention, but multiple molecular-based therapeutic hypotheses are beginning to be tested.

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.