Search Results for: Circulation

Circulation, Volume 152, Issue 1, Page e5-e6, July 8, 2025.

Circulation, Ahead of Print. BACKGROUND:Equal access to care for patients with congenital heart disease (CHD) remains unrealized globally. The ASSIST project (Academic Medical Hospitals–Local Institutions collaboration) is an ongoing national quality initiative implemented in low-resource settings in China attempting to reduce gaps in access to CHD care. This study sought to evaluate its feasibility and effectiveness.METHODS:Shanghai Children’s Medical Center, an academic medical center, has partnered with 4 local hospitals in low-resource regions to enhance local CHD programs since 2021. Comparison was made between patients receiving treatments in these 4 local hospitals before (2013–2020) versus after the ASSIST project (2021–2024). In addition, contemporaneous patients receiving treatments in Shanghai Children’s Medical Center (2021–2024) were compared with the post-ASSIST cohort of patients. The primary outcome was a composite of postoperative mortality and multiorgan dysfunction. A key secondary outcome was delayed treatment, defined as an interval of more than 6 months between the time of surgery and the time when the clinicians recommended surgery at the initial presentation.RESULTS:The analysis cohort included 11 895 pediatric patients (median age, 2.0 years [25th–75th percentile 0.7–5.0]; 5933 female [49.9%]), with 3333 cases in the pre-ASSIST group, 1566 in the post-ASSIST group, and 6996 in the Shanghai Children’s Medical Center group. Lower family educational attainment (odds ratio, 1.50 [95% CI 1.21–1.85];P

Circulation, Ahead of Print. BACKGROUND:Pathological cardiac remodeling after myocardial infarction (MI) is a leading cause of heart failure and sudden death. The detailed mechanisms underlying the transition to heart failure after MI are not fully understood. Disruptions in the endoplasmic reticulum (ER)–mitochondria connectivity, along with mitochondrial dysfunction, are substantial contributors to this remodeling process. In this study, we aimed to explore the impact of mitochondrial tumor suppressor 1A (Mtus1A) on cardiac remodeling subsequent to MI and elucidate its regulatory role in ER-mitochondria interactions.METHODS:Single-nucleus RNA sequencing analysis was performed to delineate the expression patterns of Mtus1 in human cardiomyocytes under ischemic stress. MI models were induced in mice by left coronary artery ligation and replicated in vitro using primary neonatal rat ventricular myocytes exposed to oxygen glucose deprivation. Cardiac-specific deletion of Mtus1 was achieved by crossing floxed Mtus1 mice with the Myh6-MerCreMer mice. The impact of Mtus1A, a mitochondrial isoform of Mtus1, on cardiac function and the molecular mechanisms were investigated in both in vivo and in vitro settings. Mitochondria-associated ER membranes coupling levels were evaluated by transmission electron microscopy and live-cell imaging. Protein interactions involving Mtus1A were explored through immunoprecipitation–mass spectrometry, coimmunoprecipitation, and proximity ligation assay. The roles of Mtus1A and Fbxo7 (F-box protein 7) were validated in a murine MI model using adeno-associated virus serotype 9 (AAV9).RESULTS:Bioinformatics analysis revealed a significant downregulation of Mtus1 expression in human cardiomyocytes under ischemic conditions, indicating its potential role in stress response. The predominant isoform in murine cardiomyocytes, Mtus1A, showed reduced expression in the left ventricle of mice after MI, which is consistent with the decreased levels of its orthologs in heart tissues from patients with MI. Cardiac-specific knockout of Mtus1 in mice exacerbated cardiac dysfunction after MI. Both in vitro and in vivo studies demonstrated the vital role of Mtus1A in modulating mitochondria-associated ER membranes coupling and preserving mitochondrial function. Mechanistically, Mtus1A functions as a scaffold protein that maintains the formation of inositol 1,4,5-trisphosphate receptor 1 (IP3R1)–glucose-regulated protein 75 (Grp75)–voltage-dependent anion channel 1 (VDAC1) complex through its amino acid sequence 189-219. In addition, Mtus1A protein is stabilized by K6-linked ubiquitination through the E3 ubiquitin ligase Fbxo7. Mtus1A overexpression in mice mitigated MI-induced cardiac dysfunction and remodeling by maintaining ER-mitochondria connectivity.CONCLUSIONS:Our study demonstrates that Mtus1A is crucial for modulating MI-induced cardiac remodeling by preserving ER-mitochondria communication and ameliorating mitochondrial function in cardiomyocytes. Mtus1A may serve as a potential therapeutic target for treating heart failure after MI.

Circulation, Ahead of Print. The postacute sequelae of SARS-CoV-2, also known as Long COVID, may affect 10% to 25% of individuals diagnosed with SARS-CoV-2. More than 100 symptoms have been reported among patients with Long COVID, but almost all patients report severe fatigue, orthostatic intolerance, shortness of breath, and reductions in exercise tolerance. Emerging data suggest that cardiovascular deconditioning plays a major role in the development of this syndrome and that reductions in functional capacity among patients with Long COVID are comparable to reductions seen among individuals with cardiovascular deconditioning resulting from bed rest. Concern has been raised about the use of exercise training as part of the management strategy for patients with Long COVID. However, exercise training appropriately tailored to the patient with cardiovascular deconditioning may be an effective strategy to facilitate improvement in symptoms. This American Heart Association scientific statement provides a concise yet comprehensive overview of mechanisms contributing to development of Long COVID and methods by which exercise training may be applied to this unique patient population to alleviate symptoms and improve quality of life. In addition, methods of reintroducing exercise and return to play among athletes affected by COVID-19 are discussed.

Circulation, Ahead of Print. BACKGROUND:Evaluation of whether dyspnea has a cardiac cause is essential. Guidelines from 2016 were reported to result in a high incidence of indeterminate left ventricular (LV) filling pressure. We sought to validate a new algorithm for the estimation of LV filling pressure (LVFP) in a multicenter study, with the objective of decreasing the yield of indeterminate filling pressure and increasing accuracy.METHODS:In an observational study, echocardiography was performed in 951 patients referred for cardiac catheterization. Echocardiographic measurements included mitral inflow, pulmonary vein and tissue Doppler mitral annulus velocities, tricuspid regurgitation velocity, assessment of mean right atrial pressure, biplane LV and left atrial volumes, and LV and left atrial strain. A stepwise approach was applied in a new algorithm for estimation of LVFP, whereby pressure >15 mm Hg was considered abnormally elevated. The first step included mitral annulus early diastolic velocity (e′), the ratio of mitral early flow velocity to e′, and pulmonary artery systolic pressure. With concordant findings in all 3 variables, conclusions about LVFP could be reached. In case of discordant or incomplete variables, left atrial reservoir strain, left atrial maximum volume index, isovolumic relaxation time, and pulmonary vein flow were analyzed in a second step. In the presence of ≥1 abnormal measurement in the second step, the conclusion of elevated LVFP could be reached.RESULTS:Only 2 patients had indeterminate LVFP as per the new algorithm versus 38 applying 2016 guidelines (P

Stroke, Ahead of Print. Recently, 6 randomized controlled trials of endovascular treatment (EVT) versus medical management in anterior circulation large vessel occlusion with large-core documented significant benefit of EVT on functional outcome. Moreover, one trial reported the benefit of EVT in the large-core category (Alberta Stroke Program Early Computed Tomography Score, 0–2). These results are considered paradoxical by some as they contradict the prevailing view that the presence of a large core precludes the possibility of good outcomes following reperfusion. They, in turn, led some investigators to question the applicability of the core/penumbra model in the case of large-core stroke and even its overall validity, specifically regarding the notion that the core reliably predicts tissue infarction. Here, we discuss the trial results and propose alternative explanations for the large-core paradox. First, although EVT does improve outcomes as compared with medical management, overall outcomes remain poor in ≈80% of the treated population. Second, the assessment of core extent on imaging, particularly with computed tomography, is potentially inaccurate, especially in the early time window. Third, consistent with observational studies, some randomized controlled trial substudies suggest that the benefit of EVT in this population derives at least in part from the salvage of penumbra, which appears to have been present in a large percentage of enrolled patients. Fourth, the markedly reduced perfusion that prevails within large cores facilitates the early development of vasogenic edema. This heterogeneity of tissue injury may, in turn, lead to an overestimation of true core/neuronal death as estimated with computed tomography and magnetic resonance imaging. Assessing patients with apparent large core should consider these notions when discussing eligibility for EVT. Early reperfusion of large-core patients is expected to both target any residual penumbra and prevent the development of vasogenic edema within the severely hypoperfused areas. These considerations underscore the need for more reliable methods to identify irreversible neuronal injury inside the imaging-based estimated core.

Stroke, Ahead of Print. BACKGROUND:In acute ischemic stroke, infarcted tissue gradually becomes detectable on noncontrast computed tomography (NCCT) as a hypodensity representing vasogenic edema. We studied whether subtle NCCT density changes are also present in penumbral tissue.METHODS:This observational cohort study included patients with stroke with anterior circulation occlusions from the CRISP2 study (CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project 2) who were transferred from a primary to a comprehensive stroke center for consideration of endovascular thrombectomy. Patients received baseline NCCT and computed tomography perfusion at the referring hospital and magnetic resonance imaging at the receiving hospital. We created baseline relative NCCT images, which compare voxel density to the corresponding area in the contralateral hemisphere. We analyzed the relative density of rNCCT in the core and penumbra (based on computed tomography perfusion in referring hospitals). We also assessed the correlation between relative density and the degree of hypoperfusion in the penumbra, defined as the time-to-maximum of the tissue residue function. We studied the association between penumbral changes and functional outcomes on the full distribution of the modified Rankin Scale score at 90 days.RESULTS:From the 314 patients, 162 met inclusion criteria with a median (interquartile range) age of 73 (61–83) years, penumbra volume of 78 (52–113) mL, and core volume of 0.6 (0–13.0) mL; 54% were men. The relative density was reduced by a median of 1.8% (P

Stroke, Ahead of Print. BACKGROUND:Multiple recent randomized trials have demonstrated the benefit of thrombectomy over medical management alone in adult patients with large vessel occlusion (LVO) stroke and large infarct on baseline imaging. Cohort studies have also identified improved functional outcomes in pediatric patients who received thrombectomy. However, the role of thrombectomy in pediatric stroke with large baseline infarct remains uncertain.METHODS:A case-control study was undertaken using pooled data from 3 cohort studies of pediatric stroke (Save ChildS, Save ChildS Pro, Pediatric LVO Stroke Study). Pediatric patients of age 1 to 18 years with acute anterior circulation LVO stroke presenting within 24 hours since last seen well with an Alberta Stroke Program Early Computed Tomography (CT) Score of 0 to 5 on CT or magnetic resonance imaging were included. Isolated M2 occlusion or focal cerebral arteriopathy–inflammatory subtype cases were excluded. Thrombectomy-treated patients were compared with patients who received medical management alone. The primary clinical outcome was the pediatric modified Rankin Scale score at 90 days, compared between groups using ordinal logistic regression.RESULTS:Of 56 pediatric patients with anterior circulation LVO and low Alberta Stroke Program Early CT Score presenting between January 1, 2000 and August 31, 2023 from 45 centers across Europe, North America, and Australia, 40 patients were eligible for inclusion (female: n=14, 35.0%; mean age, 9.1 years; range, 1.5–17; SD, 5.27). Thrombectomy-treated patients (n=24) had significantly better pediatric modified Rankin Scale scores at 90 days than medical management alone patients (n=16; odds ratio, 3.68 [95% CI, 1.11–12.21];P=0.034). There was no significant difference between groups in the rate of symptomatic intracranial hemorrhage (P=0.806).CONCLUSIONS:In this multicentre case-control study, pediatric patients (age, 1–18 years) with anterior circulation LVO stroke and low Alberta Stroke Program Early CT Score who received thrombectomy had significantly better functional outcomes than those treated with medical management alone. Exclusion of pediatric patients from thrombectomy based on low Alberta Stroke Program Early CT Score alone may not be appropriate.

Circulation, Ahead of Print. BACKGROUND:Allograft arteriosclerosis, a significant cause of graft failure, is linked to the formation of tertiary lymphoid organs. T follicular helper (Tfh) cells are a vital subset of helper T cells that control the formation of the germinal center in tertiary lymphoid organs. Thus, understanding the origins and regulatory mechanisms of Tfh cells in allograft arteriosclerosis is essential for developing targeted therapies.METHODS:We used a lineage-tracing strategy to track Tfh cell fate in mouse models. Single-cell RNA sequencing, flow cytometry, and immunofluorescence staining were employed to analyze cell populations in remodeled arteries 2 and 4 weeks after transplantation. Additionally, we used VEGFR-3 inhibitors and lymph node dissection to suppress lymphatic vessel formation. Metabolic signatures and flux in different cell types were investigated using ultrahigh-performance liquid chromatography and high-resolution mass spectrometry–based metabolomics. CD4+T cell–specific MTHFD2 knockout mice were used to corroborate our hypothesis about the role of mitochondrial 1-carbon metabolism in Tfh cell differentiation. Mechanisms discovered in vivo were also tested ex vivo.RESULTS:CD34-lineage cells were found to be the major source of cells differentiating into T cell populations in allograft arteries. CD34-lineage cells mainly originated from the thymus, with drainage through lymphatic vessels, and differentiated into effective T cells around grafting arteries. Using CD34 lineage-tracing mice and single-cell RNA sequencing, we identified a Tfh cell population derived from CD34-lineage CD4+T cells. Untargeted and targeted metabolomics revealed distinct upregulation of 1-carbon metabolism during CD4+T-to-Tfh cell differentiation. Supplementation of amino acids essential for 1-carbon metabolism, such as serine, methionine or glycine, facilitated differentiation from CD4+T to Tfh cells. Using deuterium-labeled serine, we found that the mitochondrial 1-carbon pathway is predominant. Inhibition of the mitochondrial 1-carbon metabolic enzyme MTHFD2 by administration of DS18561882 or generating CD4+T cell–specific MTHFD2 knockout mice, significantly inhibited the numbers of Tfh cells and tertiary lymphoid organ formation as well as vascular remodeling.CONCLUSIONS:This study provides insights into the critical role of mitochondrial 1-carbon metabolism and MTHFD2 in governing the differentiation of CD34-lineage cells into Tfh cells, which contributes to tertiary lymphoid organ formation in transplant vasculopathy, offering potential therapeutic targets to enhance transplant outcomes.

Circulation, Ahead of Print. BACKGROUND:Combining antiplatelet therapy (APT) with conventional anticoagulants increases the risk of bleeding. In the AZALEA-TIMI 71 trial (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation), the novel factor XI inhibitor abelacimab significantly reduced the risk of bleeding compared with rivaroxaban in patients with atrial fibrillation. Whether the safety of combination antithrombotic therapy differs in the context of factor XI inhibition has not been well characterized.METHODS:This prespecified analysis of AZALEA-TIMI 71 includes patients randomized between March and December of 2021 to 1 of 2 subcutaneous monthly abelacimab doses (90 or 150 mg) or oral rivaroxaban (20 mg daily, dose reduced to 15 mg in patients with creatinine clearance ≤50 mL/min), stratified by planned use of concomitant APT. The primary composite of major or clinically relevant nonmajor bleeding and other safety and efficacy outcomes were examined by concomitant APT and randomized treatment.RESULTS:Of 1287 patients (44% female; median age, 74 years [interquartile range, 69–78]), 318 (24.7%) were on APT at baseline with planned continuation (15.5% aspirin only, 7.5% P2Y12inhibitor only, and 1.6% dual APT). In the rivaroxaban arm, the rate of major or clinically relevant nonmajor bleeding was 10.6% per 100 patient-years with concomitant APT versus 7.7% per 100 patient-years without. In the abelacimab arms, the rates were 2.5% and 3.5% per 100 patient-years for the 90-mg and 150-mg doses, respectively, with concomitant APT and 2.7% and 3.1% per 100 patient-years without. Each abelacimab dose significantly reduced major or clinically relevant nonmajor bleeding compared with rivaroxaban, both in those with concomitant APT (adjusted hazard ratio, 0.26 [95% CI, 0.10–0.70] and hazard ratio, 0.30 [95% CI, 0.12–0.74] for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) and in those without concomitant APT (adjusted hazard ratio, 0.34 [95% CI, 0.19–0.60] and hazard ratio, 0.40 [95% CI, 0.23–0.68] for 90 mg and 150 mg of abelacimab, respectively;Pinteractions=0.56 and 0.60, respectively). Patients with concomitant APT tended to derive greater absolute risk reductions with abelacimab (8.1% and 7.1% for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) than those without concomitant APT (5.0% and 4.6%, respectively).CONCLUSIONS:Inhibition of factor XI with abelacimab consistently reduced bleeding compared with rivaroxaban regardless of concomitant APT use, with greater absolute reductions in bleeding in those requiring concomitant APT. These data suggest that factor XI inhibition may be a safe anticoagulant option in patients with atrial fibrillation requiring concomitant APT.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT04755283.

Circulation, Volume 151, Issue 25, Page 1814-1817, June 24, 2025.

Circulation, Volume 151, Issue 25, Page e1096-e1096, June 24, 2025.

Circulation, Volume 151, Issue 25, Page 1767-1779, June 24, 2025. BACKGROUND:Clinical guidelines recommend different revascularization strategies for nonculprit lesions in patients with ST-segment–elevation myocardial infarction (STEMI) versus non-STEMI (NSTEMI). Whether the prevalence of untreated high-risk vulnerable plaques differs in STEMI and NSTEMI and affects their outcomes is unknown.METHODS:In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree II), a multicenter, prospective natural history study, patients with recent myocardial infarction underwent 3-vessel coronary angiography with coregistered near-infrared spectroscopy and intravascular ultrasound after successful percutaneous coronary intervention of obstructive lesions from 2014 through 2017. Two-feature high-risk plaques were defined as those with both plaque burden ≥70% and maximum lipid core burden index over any 4-mm segment ≥324.7. The primary end point was major adverse cardiovascular events arising from untreated nonculprit lesions during a median 3.7-year follow-up.RESULTS:Of 898 patients, 199 (22.2%) with 849 nonculprit lesions had STEMI and 699 (77.8%) with 2784 nonculprit lesions had NSTEMI. By intravascular ultrasound, the median nonculprit lesion length was 17.4 mm (interquartile range, 16.3–18.5) in STEMI and 17.7 mm (interquartile range, 17.1–18.4) in NSTEMI (P=0.63), and the median minimal lumen area was 5.5 mm2(interquartile range, 5.3–5.7 mm2) in STEMI and 5.5 mm2(interquartile range, 5.3–5.6 mm2) in NSTEMI (P=0.99). At the lesion level, the prevalence of 2-feature high-risk nonobstructive nonculprit plaques was slightly higher in patients with STEMI than in patients with NSTEMI (12.8% versus 10.1%;P=0.03). At the patient level, however, the prevalence of 2-feature high-risk plaques was similar in STEMI versus NSTEMI (38.8% versus 32.7%;P=0.11). The prevalence of patients with 1 or more lesions meeting at least 1 high-risk plaque criterion was also similar (plaque burden ≥70%, 63.3% versus 57.8% [P=0.16]; maximum lipid core burden index over any 4-mm segment ≥324.7, 63.3% versus 57.6% [P=0.15]). The 4-year rates of nonculprit lesion–related major adverse cardiovascular events were similar in STEMI versus NSTEMI (8.6% versus 7.8%; hazard ratio, 1.02 [95% CI, 0.57–1.81];P=0.95), as were the rates of all major adverse cardiovascular events (14.2% versus 13.0%; hazard ratio, 1.06 [95% CI, 0.68–1.64];P=0.80).CONCLUSIONS:In the PROSPECT II study, the per-patient prevalence of high-risk vulnerable plaques was comparable in STEMI versus NSTEMI, as was the overall long-term incidence of nonculprit lesion–related and all major adverse cardiovascular events. These results support a similar revascularization strategy for nonculprit lesions in patients with STEMI or NSTEMI after culprit lesion management.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT02171065.

Circulation, Volume 151, Issue 25, Page e1093-e1094, June 24, 2025.

Circulation, Volume 151, Issue 25, Page e1098-e1098, June 24, 2025.

Circulation, Volume 151, Issue 25, Page e1091-e1092, June 24, 2025.