Circulation
· 2026 Jun · PMID 42253052
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BACKGROUND: Global knockout results in vascular defects and early lethality, limiting our knowledge of von Hippel-Lindau/HIF (hypoxia-inducible factor) signaling in coronary vessel formation and homeostasis. The hypoxia...BACKGROUND: Global knockout results in vascular defects and early lethality, limiting our knowledge of von Hippel-Lindau/HIF (hypoxia-inducible factor) signaling in coronary vessel formation and homeostasis. The hypoxia pathway has been implicated in cardiovascular diseases characterized by inflammation and vascular remodeling, such as atherosclerosis, but its involvement in Kawasaki disease (KD) remains unknown. Coronary artery dilation and vessel rupture are the most serious complications of KD. However, the molecular mechanisms underlying these cardiac events are not fully understood. We investigated the role of the von Hippel-Lindau/HIF pathway in cardiovascular pathology and its relevance to KD. METHODS: We generated a novel mouse model with genetic hyperactivation of the hypoxia pathway in progenitors contributing to coronary vessels and cardiac fibroblasts. We characterized the model using echocardiography, magnetic resonance imaging, histology, and molecular profiling. In parallel, we examined cardiac tissues from patients with KD with fatal coronary aneurysms for evidence of HIF signaling and inflammation using immunohistochemistry. RESULTS: Mice with conditional deletion of in Wt1 (Wilms tumor 1)-expressing cells developed normally but exhibited cardiomegaly, vascular abnormalities, progressive coronary artery dilation, pericardial hemorrhage, and systemic inflammation shortly after birth. Histologic analysis revealed coronary arteritis, elastin breaks, vascular remodeling, smooth muscle cell loss, perivascular fibrosis, and frequent intracoronary thrombus formation. In addition, vascular calcification, severe cardiac inflammation, and interstitial hemorrhages were observed, culminating in sudden death between 15 and 20 weeks of age, likely due to vessel rupture. Cardiac transcriptomic profiling identified dysregulated expression of genes involved in extracellular matrix organization, epithelial-mesenchymal transition, angiogenesis, inflammation, coagulation, and calcification, indicating compromised vascular stability and increased remodeling in conditional knockout mice. Simultaneous deletion of rescued both the cardiovascular abnormalities and transcriptomic profile observed in conditional knockout mice, implicating Hif2 (hypoxia-inducible factor 2) as a key mediator. Human KD cardiac samples showed expression of HIF2 in coronary lesions and surrounding inflammatory infiltrates, confirming hypoxia pathway activation in severe KD. CONCLUSIONS: Our findings establish HIF2 as a central driver of coronary inflammation, vascular remodeling, and thrombotic complications resembling those observed in severe KD. The /Wt1 conditional knockout mouse model recapitulates key cardiovascular features of KD and offers a valuable platform for mechanistic studies and therapeutic exploration.
Smith JL, Norland K, Hamed ME
… +5 more, Yu Y, Na J, Dikilitas O, Schaid DJ, Kullo IJ
Circ Genom Precis Med
· 2026 Jun · PMID 42253048
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BACKGROUND: Performance and transferability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease phenotypes may vary across PRS methods, training data, and trait ascertainment. METHODS:...BACKGROUND: Performance and transferability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease phenotypes may vary across PRS methods, training data, and trait ascertainment. METHODS: We aimed to investigate the performance and transferability of contemporary PRS for atherosclerotic cardiovascular disease subtypes: coronary heart disease (CHD), abdominal aortic aneurysm (AAA), ischemic stroke (IS), and peripheral artery disease (PAD), using the All of Us Workbench, which consists of a large, diverse cohort with whole-genome sequence data. We also developed and evaluated a multitrait PRS for each subtype. Performance of PRS for 4 atherosclerotic cardiovascular disease subtypes was compared across genetic similarity groups in 245 388 All of Us participants. Groups genetically similar to European, African, admixed American, and remaining groups (combined as other) were used to assess PRS for CHD, IS, AAA, PAD, and multitrait. RESULTS: PRS for CHD and AAA performed better than IS and PAD. For CHD, CHD performed the best (hazard ratio per SD increase [95% CI]), across genetic ancestry groups, European, and African (1.72 [1.67-1.78], 1.23 [1.17-1.29]), with CHD being best for admixed American (1.91 [1.70-2.15]), and CHD for other (1.75 [1.58-1.95]). The best performing PRS for AAA was AAA for European, other, and admixed American (1.71 [1.52-1.92], 1.59 [1.07-2.37], 1.50 [0.90-2.52]) and AAA for African (1.39 [1.19-1.63]). For IS, IS performed best for other and European (1.49 [1.17-1.89], 1.33 [1.25-1.42]), and IS performed best in admixed American and African (1.17 [1.07-1.27], 1.09 [1.04-1.15]). For PAD, PAD performed best for all groups (other, 1.51 [1.19-1.92]; European, 1.32 [1.24-1.41]; admixed American, 1.23 [1.05-1.45]; and African, 1.18 [1.04-1.34]). CONCLUSIONS: Multitrait and multiancestry PRS performed better than individual trait and/or single ancestry PRS for each atherosclerotic cardiovascular disease phenotype across ancestrally diverse and admixed individuals, with minimal change including adjustment for conventional risk factors.
Tan Z, Qi Y, Chen Y
… +7 more, Zhang L, Li C, Lei B, Xiao Z, Zhang J, Lu L, Wang H
Circulation
· 2026 Jun · PMID 42246060
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BACKGROUND: Congenital heart disease (CHD), the most common birth defect and a leading cause of infant mortality, is frequently linked to dysregulated Notch signaling. However, the role of the Notch transcriptional coact...BACKGROUND: Congenital heart disease (CHD), the most common birth defect and a leading cause of infant mortality, is frequently linked to dysregulated Notch signaling. However, the role of the Notch transcriptional coactivator Mastermind-like 1 (MAML1) in CHD pathogenesis and the underlying molecular mechanism remain unclear. METHODS: We investigated the role of MAML1 in CHD by focusing on a patient-derived Q401K mutation with a knock-in mouse model and an endocardium-specific knockout mouse model, complemented by CRISPR-edited human heart organoids. Cardiac phenotypes were assessed by echocardiography and histological analysis. The underlying molecular mechanisms were dissected through biochemical assays, microscopy to analyze liquid-liquid phase separation (LLPS), and mass spectrometry to identify posttranslational modifications and the upstream kinase of MAML1. RESULTS: In a clinical cohort of patients with CHD, we identified rare missense variants of associated with ventricular septal defects. Modeling a patient-derived variant (Q401K) was sufficient to recapitulate key ventricular septal defect-related phenotypes in both knock-in mice and human heart organoids. To confirm the tissue-specific pathogenicity, we showed that endocardium-specific knockout of in mice and deletion in human heart organoids caused similar septal and valvular defects by disrupting Notch-driven endocardial-to-mesenchymal transition. Mechanistically, we discovered that MAML1 activity depends on LLPS, which forms nuclear condensates, required for efficient interaction with the NOTCH1 intracellular domain and activation of downstream transcriptional targets. Crucially, patient-derived pathogenic variants, including Q401K, function as charge-altering mutations within the intrinsically disordered region 2, a core region for MAML1 LLPS, pathologically abrogating LLPS to downregulate Notch signaling. Furthermore, we identified a regulatory axis in which PKN2 phosphorylates MAML1 at Ser314, which destabilizes MAML1 condensates and consequently attenuates Notch transcriptional output. CONCLUSIONS: These findings support as a candidate gene for CHD and identify MAML1 LLPS as a critical biophysical determinant of Notch transcriptional output in endocardial cells. The electrostatic integrity of MAML1 condensates is essential for proper regulation of Notch signaling during cardiac morphogenesis. Dysregulation of this state, whether through CHD-associated charge-altering variants or aberrant PKN2-mediated phosphorylation, impairs Notch signaling and disrupts endocardial-to-mesenchymal transition, thereby establishing a converged molecular mechanism underlying congenital cardiac malformations.
Han DD, Brooks AC, Baker CD
… +7 more, Dirkx RA, Mickelsen DM, Fisler B, Phadke K, Ashton JM, Delmar M, Small EM
Circ Heart Fail
· 2026 Jun · PMID 42246055
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BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosi...BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosis and inflammation with right ventricle predominance. Most cases of gene-positive ACM are caused by a desmosome protein mutation, with plakophilin-2 () mutations being the most common. We hypothesized that -deficiency in epicardium-derived cells (EPDCs) contributes to fibro-inflammatory signaling and ACM pathogenesis. METHODS: We developed transgenic mice that lack in cardiomyocytes (Pkp2-cKO), in EPDC (Pkp2-eKO), or in both cardiomyocyte and EPDC (Pkp2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Nonmyocyte populations were isolated 21 days posttamoxifen injection for single-cell RNA-sequencing. Immunohistochemistry, flow cytometry, quantitative reverse transcription polymerase chain reaction, and echocardiography were used to interrogate cardiac physiology and cellular composition. RESULTS: We identified a population of epicardium-derived fibroblasts characterized by the expression of , , , and that accumulated on deletion in both cardiomyocytes and EPDC. deletion in cardiomyocytes induced a moderate fibro-inflammatory EPDC phenotype, while deletion in EPDC did not elicit a pathological phenotype, suggesting cardiomyocyte involvement is necessary for ACM pathogenesis. Proinflammatory fibroblasts acquired the senescence-associated secretory phenotype, correlating with elevated senescence associated-βgal staining in the right ventricle. Gene expression, flow cytometry, and histological data also revealed an exaggerated inflammatory response in Pkp2-ceKO mice, which progresses from right to left ventricular predominance. Importantly, macrophages and B cells accumulate in both Pkp2-cKO and Pkp2-ceKO mice compared with controls. Although B-cell depletion delays the early inflammatory and fibrosis response, it did not alter end-stage cardiac physiology. CONCLUSIONS: deletion in EPDC facilitates the emergence of a fibro-inflammatory phenotype that may contribute to ACM pathogenesis.
Ieki H, Zhang S, Koyama S
… +19 more, Kjellberg M, Yoshida H, Kurosawa R, Matsunaga H, Miyazawa K, Enzan N, Kim C, Seo JS, Higasa K, Ozaki K, Onouchi Y, Matsuda K, Kamatani Y, Terao C, Matsuda F, Snyder M, Komuro I, Ito K, Biobank Japan Project
Circ Genom Precis Med
· 2026 Jun · PMID 42237915
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BACKGROUND: GWASs (genome-wide association studies) have advanced our understanding of coronary artery disease (CAD) genetics and enabled the development of polygenic risk scores (PRSs) for estimating genetic risk based...BACKGROUND: GWASs (genome-wide association studies) have advanced our understanding of coronary artery disease (CAD) genetics and enabled the development of polygenic risk scores (PRSs) for estimating genetic risk based on common variant burden. However, GWASs have limitations in analyzing rare variants due to insufficient statistical power, thereby constraining PRS performance. METHODS: We conducted whole-genome sequencing of 1752 Japanese patients with CAD and 3019 controls. A machine learning-based analytical framework was applied to identify and interpret rare genetic variants associated with CAD pathogenesis. RESULTS: This approach identified 59 CAD-related genes, including known causal genes such as and those not previously captured by GWASs. A rare variant-based risk score derived from the framework demonstrated distinct clinical characteristics compared with a conventional common variant-based PRS. The rare variant-based risk score significantly discriminated CAD cases and predicted cardiovascular mortality in an independent cohort. Furthermore, combining the rare variant-based risk score with the traditional PRS improved CAD prediction compared with the PRS alone (area under the curve, 0.66 versus 0.61; =0.007). CONCLUSIONS: These findings underscore the distinct and complementary value of the rare variant-based risk score compared with the conventional PRS, highlighting the enhanced predictive power achieved through their integration. This comprehensive approach proposes broader genetic profiling, offering substantial potential for improved clinical risk stratification and personalized prevention strategies.
Lopez DM, Brown JM, Divakaran S
… +35 more, Huck DM, Weber BN, Hainer J, Carre S, Lemley M, Ramirez G, Shanbhag A, Kavanagh P, Liang JX, Blankstein R, Dorbala S, Dey D, Knight S, Le VT, Mason S, Wopperer S, Chareonthaitawee P, Rosamond TL, Kwiecinski J, Miller RJH, Slipczuk L, Travin MI, Alexanderson E, Carvajal-Juarez I, Packard RRS, Al-Mallah M, Einstein AJ, Feher A, Acampa W, Sanghani R, Buechel RR, deKemp RA, Berman DS, Slomka PJ, Di Carli MF
Circulation
· 2026 Jun · PMID 42237914
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BACKGROUND: Although the prognostic utility of positron emission tomography (PET) myocardial flow reserve (MFR) is well established, emerging data suggest that reduced subendocardial flows also predict adverse outcomes....BACKGROUND: Although the prognostic utility of positron emission tomography (PET) myocardial flow reserve (MFR) is well established, emerging data suggest that reduced subendocardial flows also predict adverse outcomes. However, the incremental value of subendocardial MFR (MFR) beyond transmural MFR (MFR) remains unclear. METHODS: We studied patients in a multicenter PET registry with normal perfusion on stress/rest Rb-82 PET, excluding those with a previous history of coronary artery bypass surgery, heart transplantation, or left ventricular ejection fraction <40%. The optimal MFR cutoff for predicting major adverse cardiovascular events (MACEs; death, myocardial infarction [MI], revascularization, or heart failure [HF] hospitalization) was determined using Youden's index. Patients were stratified into 3 groups: concordant-normal (MFR ≥2.0; MFR ≥2.1), discordant (low-MFR, normal MFR), and abnormal MFR. Clinical outcomes were compared by MFR groups. RESULTS: Among 6603 patients (normal N=4103; discordant N=885; abnormal N=1615) the mean age was 66.3±12.4 years, and 54% were women. Compared with the concordant-normal group, patients with discordant low-MFR were older and more likely to have hypertension, diabetes, peripheral artery disease, and previous percutaneous coronary intervention. The median MFR for normal, discordant, and abnormal groups were 2.86, 2.15, and 1.72, respectively. Over a m edian follow-up of 4.9 years, 1661 MACE events occurred. Discordant low-MFR patients had a higher risk of MACE (hazard ratio [HR], 1.41; 95% CI, 1.22-1.64) and all-cause mortality (HR, 1.36; 95% CI, 1.14-1.61) compared with concordant-normal patients. The discordant group had an intermediate absolute risk of MACE, with an adjusted annualized event rate of 5.79% (95% CI, 5.10-6.49) compared with 3.99% (95% CI, 3.67-4.30; <0.001) in the concordant-normal group and 8.35% (95% CI, 7.71-9.00; <0.001) in the abnormal MFR group. CONCLUSIONS: Subendocardial MFR reveals clinically meaningful risk heterogeneity among patients with preserved transmural flow reserve, helping refine risk stratification beyond traditional PET metrics.
BACKGROUND: The EARLY TAVR trial demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS) in asymptomatic severe aortic stenosis. The relative impact of early TAVR...BACKGROUND: The EARLY TAVR trial demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS) in asymptomatic severe aortic stenosis. The relative impact of early TAVR versus a CS strategy by age is unknown. METHODS: The study population of the EARLY TAVR trial was stratified into 4 age groups: 65 to 69 years (n=141), 70 to 74 years (n=263), 75 to 79 years (n=250), and ≥80 years (n=247). Associations between age and the trial primary end point of death, stroke, or unplanned cardiovascular hospitalization; the composite end point of death, stroke, or heart failure hospitalization; and its individual components were examined. Interaction tests evaluated whether the treatment effect of early TAVR versus CS differed by age. RESULTS: No interaction was detected between age and the treatment effect of early TAVR versus CS for the composite or individual outcomes. We observed lower stroke rates with early TAVR compared with CS in the youngest (65-69 years, absolute risk reduction, 13%; =0.008) and oldest (≥80 years; absolute risk reduction, 12.3%; =0.029) age groups. The absolute difference in heart failure hospitalization rates between the early TAVR and CS arms at 2 years was greatest in the oldest patients (≥80 years, 9.1%; 75-79 years, 5.9%; 70-74 years, 5.1%; 65-69 years, 4.4%). In the CS group, time to conversion to AVR was similar across all age groups (median, 11 months; =0.73). Approximately one-third of younger patients (65-69 years) in the CS arm presented with acute valve syndrome at the time of conversion, and the frequency tended to increase with age (=0.06). CONCLUSIONS: In the EARLY TAVR trial, the relative benefit of early TAVR over CS was consistent among all age groups. The greatest absolute reduction in stroke rate with early TAVR compared with CS appeared in the youngest and oldest groups, whereas reduction in heart failure hospitalization was most pronounced in the oldest patients. These data suggest that early TAVR should be considered in all age groups above 65 years. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03042104.
BACKGROUND: Complete revascularization is superior to culprit lesion-only percutaneous coronary intervention (PCI) in reducing ischemic events in patients with ST-segment-elevation myocardial infarction and multivessel d...BACKGROUND: Complete revascularization is superior to culprit lesion-only percutaneous coronary intervention (PCI) in reducing ischemic events in patients with ST-segment-elevation myocardial infarction and multivessel disease. However, the relationship between the extent of revascularization and the benefits of a complete revascularization strategy remains unclear. The aim of this substudy of the COMPLETE trial was to evaluate how the degree of anatomic completeness of revascularization, measured by the core laboratory-derived modified residual SYNTAX score (R'SS), relates to major cardiovascular events. METHODS: We conducted an exploratory post hoc analysis of the COMPLETE trial (n=3738), stratifying patients randomized in the complete revascularization group based on the R'SS assessed after staged nonculprit lesion-PCI. Complete revascularization was defined by an R'SS=0, whereas incomplete revascularization was defined by an R'SS>0. A stratified Cox proportional hazards model was used, with the culprit-only PCI arm designated as the reference group for comparison. The first coprimary outcome was a composite of cardiovascular death or new myocardial infarction. The second coprimary outcome was a composite of cardiovascular death, new myocardial infarction, or ischemia-driven revascularization. RESULTS: Among patients randomized to a complete revascularization strategy, 90% achieved complete revascularization (R'SS=0), whereas 10% did not (R'SS>0). In patients with R'SS=0, the first coprimary outcome occurred less frequently (6.6%) compared with those randomized to the culprit lesion-only PCI strategy (10.7%; adjusted hazard ratio, 0.61 [95% CI, 0.47-0.78]). Among patients with an R'SS>0, the first coprimary outcome was similar (10.7%) to those in the culprit lesion-only PCI group (10.7%; adjusted hazard ratio, 1.01 [95% CI, 0.61-1.67]). A similar result was observed for the second coprimary outcome. CONCLUSIONS: This exploratory analysis of the COMPLETE trial suggests that the benefit of a complete revascularization strategy in patients with ST-segment-elevation myocardial infarction and multivessel disease may be related to the extent of anatomic completeness of revascularization. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01740479.
Klein H, Alufer L, Goldberg Toren DT
… +20 more, Pachter D, Kamer O, Ebstein Karamani N, Chassidim Y, Shelef I, Rudich A, Yoel U, Ben-Arie G, Zelicha H, Yaskolka Meir A, Tsaban G, Bartal C, Blüher M, Stumvoll M, Ceglarek U, Isermann B, Qi L, Stampfer MJ, Hu FB, Shai I
Circulation
· 2026 Jun · PMID 42227111
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BACKGROUND: During the 18-month CENTRAL (Effect of Weight-Loss Diet Strategies and Exercise on Dynamics of Body Fat Depots and Metabolic Rate) and DIRECT-PLUS (Effects of Green-Mediterranean Diet via the Gut-Fat-Brain Ax...BACKGROUND: During the 18-month CENTRAL (Effect of Weight-Loss Diet Strategies and Exercise on Dynamics of Body Fat Depots and Metabolic Rate) and DIRECT-PLUS (Effects of Green-Mediterranean Diet via the Gut-Fat-Brain Axis) randomized controlled trials, participants achieved considerable reductions in abdominal and ectopic fat. We examined the long-term postintervention cardiometabolic profile associated with these changes. METHODS: We invited participants from CENTRAL (2012-2014) and DIRECT-PLUS (2017-2018), which evaluated dietary patterns (low-fat, healthy dietary guidelines and Mediterranean diet variants, including standard, low-carbohydrate, and polyphenol-enriched "green" Mediterranean diets) combined with structured physical activity. Participants underwent additional magnetic resonance imaging of visceral adipose tissue, deep subcutaneous adipose tissue (SAT), superficial SAT, intrahepatic fat, and intrapancreatic fat, along with clinical follow-up measurements, 5 and 10 years after completion of the trials. RESULTS: We reached 366 out of 381 eligible participants (96%) for follow-up. Despite complete weight regain, waist circumference and abdominal fat depots, including visceral adipose tissue, deep SAT, and superficial SAT, partially preserved their intervention-induced achievements at long-term follow-up (false discovery rate ≤0.01 for all). In contrast, postintervention reductions of intrahepatic fat and intrapancreatic fat were fully and excessively gained during follow-up, respectively (false discovery rate ≤0.01 for both). Each 10% intervention-induced loss of visceral adipose tissue, superficial SAT, and intrapancreatic fat were associated with long-term postintervention improvements in Metabolic Score for Insulin Resistance, composite risk score, and Metabolic Syndrome Severity Score (meta-analysis models adjusted to weight change, Mediterranean diet adherence, and physical activity scores at follow-up, and further measures; all <0.05). Only 10% visceral adipose tissue loss, however, was independently associated with a 28% lower risk of incident type 2 diabetes (hazard ratio, 0.72 [95% CI, 0.54-0.94]; multivariable model) during follow-up. CONCLUSIONS: This 5- and 10-year follow-up of 18-month clinical trials suggests that diet and physical activity lifestyle interventions may yield long-term improvements in cardiometabolic measures despite weight regain. A 10% reduction in visceral fat due to lifestyle interventions may reduce future type 2 diabetes risk by nearly 30%. Visceral fat loss rather than weight loss emerges as a key target for durable cardiometabolic health. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01530724; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03020186.
Stewart N, Henden N, Smith-Díaz CC
… +21 more, Rigby J, Butters A, Baker A, Catto L, Subasinghe I, Yeates L, Geraghty L, Follett J, Sillence D, Kemp L, Deveson IW, Alasady M, Wilson S, Simons C, MacArthur DG, Gray B, Duflou J, Freckmann ML, Richardson E, Zankl A, Ingles J
Circ Genom Precis Med
· 2026 Jun · PMID 42227110
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