Search Results for: Circulation

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 e1093-e1094, 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 e1095-e1095, June 24, 2025.

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

Circulation, Volume 151, Issue 25, Page 1755-1757, 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.

Circulation, Volume 151, Issue 25, Page e1097-e1097, June 24, 2025.

Circulation, Ahead of Print. Poor diet quality is a leading risk factor for cardiometabolic disease (ie, diabetes and diseases associated with metabolism and inflammation), which is present in about half of American adults. Support has grown for incorporating the provision of healthy food as a complement to or a component of clinical care. Such “Food Is Medicine” programs provide free or subsidized healthy food directly to patients in close coordination with the health care system. In this review, we systematically examined published randomized controlled trials examining Food Is Medicine programs in the United States, categorizing them into different stages of development using the National Institutes of Health Model for Behavioral Intervention Development. This review identified a total of 14 randomized controlled trials of Food Is Medicine interventions in the United States with noncommunicable disease outcomes, more than one-third of which were early-stage smaller-scale trials (stage 1 randomized controlled trials). Broad variations in populations enrolled; intervention design, duration, and intensity; and outcomes precluded many direct comparisons between studies. Randomized controlled trial data were generally consistent with findings in the observational literature, indicating that common Food Is Medicine approaches often positively influence diet quality and food security, which are theorized to be key mediators for clinical outcomes. However, the impact on clinical outcomes was inconsistent and often failed to reach statistical significance. These observations highlight the need for larger, higher-quality Food Is Medicine studies focusing on the measurement of clinical outcomes within well-designed programs and the need for additional randomized controlled trials that more systematically map out the relationship between participation in different types of Food Is Medicine programs and health outcomes.

Circulation, Ahead of Print. BACKGROUND:Penetrance and risk of ventricular arrhythmias (VAs) in arrhythmogenic right ventricular cardiomyopathy (ARVC) are increasingly recognized as being genotype specific. Therefore, genotype-informed family screening protocols may lead to safer and more personalized recommendations than the current one-size-fits-all screening recommendations. We aimed to develop a safe, evidence-based plakophilin-2 (PKP2)–specific longitudinal screening algorithm.METHODS:We included 295 relatives (41% male; age 30.9 years [18.0–47.7 years]) with a pathogenic or likely pathogenicPKP2variant from 145 families. Phenotype was ascertained with ECG, Holter monitoring, and cardiac imaging and classified by the 2010 Task Force Criteria. VA was defined as a composite of sudden cardiac arrest or death, spontaneous sustained ventricular tachycardia, ventricular fibrillation, or appropriate implantable cardioverter defibrillator intervention. We performed Cox regression to determine predictors of ARVC development and multistate modeling to assess the probability of ARVC development and occurrence of VA.RESULTS:At baseline, 110 relatives (37%) had definite ARVC. During 8.5 years (4.2–12.9 years) of follow-up, 62 of 185 relatives (34%) without definite ARVC at baseline progressed to definite ARVC diagnosis, and 35 of 295 of all relatives (12%) had VA. VAs occurred only in relatives who previously fulfilled definite ARVC diagnosis. Relatives with borderline ARVC (fulfillment of one minor criterion plus the major family history criterion) progressed 5 times faster in the multistate model to definite ARVC diagnosis and compared with genotype-positive/phenotype-negative (G+/P−) relatives (ie, major family history criterion alone). Relatives 20 to 40 years of age had increased risk for developing definite ARVC (hazard ratio, 2.23;P=0.012) compared with those ≥40 years of age. New Task Force Criteria fulfillment most commonly occurred first on ECGs, followed by Holter monitoring and cardiac imaging. Consequently, 3 risk profiles were identified, and appropriate screening protocols were derived: relatives with borderline ARVC (annual ECG and Holter monitoring; complete evaluation [ie, ECGs, Holter monitoring, and imaging] every 2 years), younger (

Circulation, Ahead of Print. BACKGROUND:The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the RhoA signaling pathway are limited in hypertension treatment, suffering from poor efficacy, insufficient specificity, and developmental challenges.METHODS:Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation. VSMC, hypertensive animal models,Trpv4-/-andArhgdiaf/fMyh11-CREERT2(smooth muscle–specific RhoGDI1 knockout) mice were used to investigate the role of the TRPV4 (transient receptor potential cation channel subfamily V member 4)–RhoA–RhoGDI1 (Rho GDP dissociation inhibitor 1) axis in hypertension.RESULTS:AH001 ((R)-1-(3-ethylphenyl) ethane-1,2-diol) was identified as a novel inhibitor of the RhoA signaling pathway. It targets the TRPV4–RhoA–RhoGDI1 axis to effectively sequester inactive RhoA–GDP in the plasma membrane and cytoplasm, which is distinct from typical RhoA inhibition modes. The cryo-EM structure of the TRPV4AH001–RhoA complex showed that AH001-bound TRPV4 adopts a closed state with RhoA in an inactive GDP-bound state. Functional studies further revealed that AH001 reduced the pool of active RhoA by enhancing TRPV4–RhoA binding and facilitating RhoGDI1–RhoA interaction in VSMC. This inhibition notably decreased both acute and long-term blood pressure and prevented vascular remodeling in Ang II–induced hypertensive mice and spontaneously hypertensive rats. However, these antihypertensive effects were weakened inTrpv4-/-andArhgdiaf/fMyh11-CREERT2mice. Additionally, AH001 effectively inhibited VSMC contraction via the RhoA/ROCK (Rho-associated protein kinase)/MYPT1 (myosin phosphatase target subunit 1)/MLC (myosin light chain 2) signaling pathway and suppressed VSMC phenotype switching to myofibroblasts through the RhoA/ROCK/LIMK1 (LIM domain kinase)/cofilin/MRTF-A (myocardin-related transcription factor A)/SRF (serum response factor) signaling cascade. TRPV4 and RhoGDI1 knockdown attenuated AH001’s inhibition of VSMC contraction and phenotypic switching to myofibroblasts.CONCLUSIONS:This study revealed a novel mode of RhoA signaling inhibition targeting the TRPV4–RhoA–RhoGDI1 axis, offering new insights for future antihypertensive drug development and proposing innovative strategies for targeting challenging Rho GTPases.

Circulation, Volume 151, Issue 24, Page e1073-e1074, June 17, 2025.