Zhang H, Guan C, Jin Z
… +27 more, Yu B, Fu G, Zhou Y, Wang J, Chen Y, Pu J, Chen L, Qu X, Yang J, Liu X, Guo L, Shen C, Zhang Y, Zhang Q, Pan H, Liu J, Zhao Y, Wang Y, Dou K, Kirtane AJ, Wu Y, Yang W, Qiao S, Tu S, Stone GW, Song L, FAVOR III China Study Group
J Am Coll Cardiol
· 2026 Jun · PMID 42268156
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BACKGROUND: The multicenter, randomized, sham-controlled FAVOR III China trial (Comparison of Quantitative Flow Ratio-Guided and Angiography-Guided Percutaneous Intervention in Patients with Coronary Artery Disease) demo...BACKGROUND: The multicenter, randomized, sham-controlled FAVOR III China trial (Comparison of Quantitative Flow Ratio-Guided and Angiography-Guided Percutaneous Intervention in Patients with Coronary Artery Disease) demonstrated that quantitative flow ratio (QFR)-guided percutaneous coronary intervention (PCI) resulted in better outcomes compared with angiographic guidance at 1-year and 2-year follow-up. Whether these benefits are sustained over long-term follow-up remains uncertain. OBJECTIVES: The purpose of this study was to evaluate the long-term effectiveness and safety of a QFR-guided PCI strategy compared with angiography-guided PCI at 5 years. METHODS: Patients with at least 1 angiographically intermediate coronary lesion (50%-90% diameter stenosis) in a vessel ≥2.5 mm diameter were randomized to a QFR-guided (PCI performed only if QFR ≤0.80) or angiography-guided strategy. The primary endpoint was major adverse cardiac events (a composite of all-cause death, myocardial infarction, or ischemia-driven revascularization) at 1 year; 5-year outcomes data are reported herein. RESULTS: At 5 years, major adverse cardiac events composite was lower with QFR guidance than with angiography guidance (17.5% vs 21.1%; HR: 0.80; 95% CI: 0.69-0.92; P = 0.002), driven by fewer myocardial infarctions (5.8% vs 9.0%; HR: 0.63; 95% CI: 0.49-0.80; P < 0.0001) and ischemia-driven revascularizations (9.6% vs 12.0%; HR: 0.78; 95% CI: 0.64-0.95; P = 0.02) in the QFR-guided group. All-cause death did not differ between groups. Landmark analysis showed that the benefit of QFR guidance accrued predominantly within the first 2 years (8.5% vs 12.5%; HR: 0.66; 95% CI: 0.54-0.81; P < 0.0001), with similar outcomes between 2 and 5 years (10.2% vs 11.2%; HR: 0.90; 95% CI: 0.73-1.11; P = 0.32; P for interaction = 0.001). CONCLUSIONS: Compared with angiography guidance, QFR-guided strategy improved 5-year clinical outcomes, with benefits primarily achieved within the first 2 years. (The FAVOR III China Study; NCT03656848).
Ndumele CE, Rodriguez F, Dixon DL
… +33 more, Khan SS, Mukherjee D, Bajaj M, Bangalore S, Bozkurt B, Breathett K, Clarke SL, de Boer IH, Ellison DH, Evangelista LS, Heffron SP, Kazi DS, Kulshreshtha A, Lingvay I, Low Wang CC, Mercado CA, Morton JM, Neeland IJ, Pagidipati N, Powell-Wiley TM, Rangaswami J, Rao G, Reza N, Saeed A, St Peter W, Starks JB, Sterling M, Talbot AW, Tran AH, Tuttle KR, VanWagner LB, Vest AR, Virani SS
J Am Coll Cardiol
· 2026 Jun · PMID 42265997
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AIM: The "2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome" retires, replaces, and expands upon the "2013 AHA/ACC/TOS Guideline for the...AIM: The "2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome" retires, replaces, and expands upon the "2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults." The primary intended audience for this guideline is clinicians who care for patients across the spectrum of cardiovascular-kidney-metabolic syndrome, an interrelated condition characterized by the interconnections among metabolic risk factors (including obesity and type 2 diabetes), chronic kidney disease, and cardiovascular disease. METHODS: A comprehensive literature search was conducted from October 29, 2024, to April 14, 2025, to identify clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human subjects that were published since 2015 in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: The focus of this clinical practice guideline is to create a living, working document that provides current knowledge in the field of cardiovascular-kidney-metabolic syndrome aimed at all practicing cardiologists, endocrinologists, nephrologists, and primary care and specialty clinicians who manage these patients.
Khan SS, Ndumele CE, Bhave N
… +21 more, Blumenthal RS, Coresh J, Huang X, Joseph JJ, Khera A, Ho JE, Lloyd-Jones DM, Low Wang CC, Lu Y, Morris PB, Nasir K, Natarajan P, Rangaswami J, Rodriguez F, Sperling LS, Virani SS, Zhang S, American Heart Association Council on Lifestyle and Cardiometabolic Health, Council on Clinical Cardiology, Council on Hypertension, Council on Lifelong Congenital Heart Disease and Heart Health in the Young; and the American College of Cardiology
J Am Coll Cardiol
· 2026 Jun · PMID 42263012
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Current clinical practice guidelines for the primary prevention of cardiovascular disease recommend risk assessment to align the type and intensity of preventive efforts with an individual's risk. The 2025 American Heart...Current clinical practice guidelines for the primary prevention of cardiovascular disease recommend risk assessment to align the type and intensity of preventive efforts with an individual's risk. The 2025 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of high blood pressure in adults and the 2026 American Heart Association/American College of Cardiology guideline on the management of dyslipidemia incorporate quantitative risk assessment, recommending the PREVENT (Predicting Risk of Cardiovascular Disease Events) equations to guide initiation and intensification of antihypertensive and lipid-lowering therapies, respectively. Given the growing awareness of the clustering of cardiovascular-kidney-metabolic risk factors along with the expanding armamentarium of cardioprotective therapies for obesity, diabetes, and chronic kidney disease, a harmonized approach that comprehensively assesses and addresses risk across these interconnected conditions is needed. The 2026 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of cardiovascular-kidney-metabolic syndrome provides recommendations for the use of the PREVENT equations with outcome-specific risk thresholds for staging, detection of subclinical cardiovascular disease, and decision-making regarding initiation and intensification of cardiovascular-kidney-metabolic therapies. This approach integrates predicted risk (using PREVENT-CVD [cardiovascular disease], PREVENT-ASCVD [atherosclerotic cardiovascular disease], and PREVENT-HF [heart failure]) with the relative risk reduction expected from treatment for each outcome to estimate the expected benefit (ie, absolute risk reduction) from drug therapy. This scientific statement details the rationale for using outcome-specific PREVENT equations, the evidence base for selected risk thresholds, and the potential population-level impact of these recommendations. This scientific statement also offers practical guidance for applying risk assessment as the first step in shared decision-making and for addressing gaps in awareness, risk communication, and optimal implementation of evidence-based preventive therapies to improve outcomes in individuals with or at risk for cardiovascular-kidney-metabolic syndrome.
Lalani C, Butala N, Dong H
… +8 more, Song Y, Stone GW, Mack MJ, Shahim B, Kazi DS, Cohen DJ, Dahabreh IJ, Yeh RW
J Am Coll Cardiol
· 2026 Jun · PMID 42233929
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BACKGROUND: Although mitral transcatheter edge-to-edge repair (MTEER) was approved for secondary mitral regurgitation after the COAPT trial, findings of other MTEER trials have been mixed, raising questions about the app...BACKGROUND: Although mitral transcatheter edge-to-edge repair (MTEER) was approved for secondary mitral regurgitation after the COAPT trial, findings of other MTEER trials have been mixed, raising questions about the applicability of the COAPT results to contemporary clinical practice. OBJECTIVES: We used transportability methods to estimate the treatment effects of COAPT trial interventions applied to 2 target populations: 1) trial-eligible patients representative of U.S. clinical practice; and 2) treatment-candidate patients with secondary mitral regurgitation representative of U.S. clinical practice, regardless of trial eligibility. METHODS: We identified patients from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (TVT) Registry who were treated with MTEER for secondary mitral regurgitation from March 14, 2019 to September 30, 2023. To select trial-eligible individuals, we applied COAPT trial eligibility criteria to the TVT Registry sample. We used inverse odds of participation weighting to standardize patient-level COAPT data to the data distribution of each target population sample and estimated treatment-specific outcomes. The primary outcome was heart failure hospitalization at 2 years. We also examined 10 secondary outcomes, including all-cause death. RESULTS: Our analyses included 614 COAPT trial patients and 15,275 TVT Registry patients, of which 7,289 were COAPT trial-eligible. Trial-eligible TVT Registry patients were less likely to have ischemic cardiomyopathy (34.1% vs 60.8%) and more likely to have 4+ mitral regurgitation (79.4% vs 47.9%) compared with trial patients. We estimated that compared with medical therapy alone, MTEER in conjunction with other COAPT interventions (eg, optimization of medical therapy) in the trial-eligible population would result in 2-year absolute risk reductions of 17.0% for heart failure hospitalizations (95% CI: -28.7% to -5.7%) and 15.4% for all-cause death (95% CI: -26.6% to -5.2%), effect sizes similar to those estimated in the trial (P for difference between the trial and target populations >0.05 for both outcomes). The estimated treatment effect for heart failure hospitalizations in the broader treatment-candidate target population was also similar to that in the COAPT trial (P for difference = 0.90). CONCLUSIONS: Although COAPT trial patients had different baseline characteristics than patients undergoing MTEER in contemporary U.S. practice, we estimated that treatment effects would be similar had real-world patients received COAPT trial interventions, under the assumptions required for transportability (eg, conditional exchangeability across data sources, positivity of trial participation).
Foà A, Pabon MA, Filippatos G
… +22 more, Claggett BL, Miao ZM, Jhund PS, Henderson A, Brinker M, Lage A, Hofmeister L, De Sanctis Y, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Rossing P, Ruilope LM, Anker SD, Pitt B, Agarwal R, McMurray JJV, Solomon SD, Vaduganathan M, Desai AS
J Am Coll Cardiol
· 2026 Jun · PMID 42233928
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BACKGROUND: The nonsteroidal mineralocorticoid receptor antagonist finerenone has been shown to improve cardiovascular and kidney outcomes in patients with cardio-kidney-metabolic (CKM) syndrome, but its effects on sudde...BACKGROUND: The nonsteroidal mineralocorticoid receptor antagonist finerenone has been shown to improve cardiovascular and kidney outcomes in patients with cardio-kidney-metabolic (CKM) syndrome, but its effects on sudden death (SD) are uncertain. OBJECTIVES: We investigated independent predictors of SD and treatment effects of finerenone on SD. METHODS: In this prespecified FINE-HEART analysis, we pooled participant-level data from 3 placebo-controlled trials of finerenone in CKM syndrome, including 2 trials of chronic kidney disease with type 2 diabetes (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]) and a trial of heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction (FINEARTS-HF [FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure]). SD in each trial was centrally adjudicated by a blinded clinical endpoint committee. We identified clinical predictors of SD in multivariable Cox regression models and examined treatment effects of finerenone on SD in Cox models stratified by region and trial. RESULTS: Of the 18,991 participants, 418 (2.2%) (0.77 per 100 patient-years) experienced SD during a median follow-up of 2.9 years. Overall, rates of SD were higher in FINEARTS-HF than in the chronic kidney disease trials (1.5 vs 0.5 per 100 patient-years). For the pooled population, higher risk of SD was associated with older age, history of heart failure, atrial fibrillation, prior myocardial infarction, higher urine albumin-to-creatinine ratio, and lower baseline systolic blood pressure. Randomization to finerenone reduced the risk of SD compared with placebo (HR: 0.81; 95% CI: 0.67-0.98; P = 0.034). Relative risk reductions were consistent across subgroups defined by number of baseline CKM conditions (P = 0.93) and trial (P = 0.71). CONCLUSIONS: The nonsteroidal mineralocorticoid receptor antagonist finerenone was associated with a lower risk of SD across the CKM spectrum. (FINE-HEART: An Integrated Pooled Analysis of Finerenone across 3 Phase III Trials of Heart Failure and Chronic Kidney Disease and Type 2 Diabetes; CRD42024570467).
Sattar N, Linetzky B, Ruotolo G
… +8 more, Verma S, Sourij H, Wang H, Vanderman K, Wilson JM, Griffin RM, Stefanski A, Ridker PM
J Am Coll Cardiol
· 2026 Jun · PMID 42233927
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BACKGROUND: Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes and obesity. The effect of tirzepatide on cardi...BACKGROUND: Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes and obesity. The effect of tirzepatide on cardiovascular risk biomarkers in people with overweight or obesity remains uncertain. OBJECTIVES: The purpose of this study was to evaluate the association of tirzepatide compared to placebo on biomarkers that reflect inflammation (high-sensitivity C-reactive protein, interleukin-6, fibrinogen, leukocytes), metabolic/adiposity/hepatic stress (homeostatic model assessment of insulin resistance, leptin, gamma-glutamyl transferase, fibroblast growth factor-21, adiponectin, free fatty acids), endothelial dysfunction (soluble intercellular adhesion molecule-1, E-selectin), and hemostasis/thrombosis (plasminogen activator inhibitor-1:antigen [Ag], tissue plasminogen activator:Ag, thrombomodulin, platelets) in people with obesity. METHODS: The aforementioned biomarkers were assayed from plasma samples, collected at baseline, 24 weeks, and 72 weeks, from 100 randomly selected participants from each group of the SURMOUNT-1 trial who completed treatment with once-weekly placebo or tirzepatide 5, 10, or 15 mg (n = 392 after low sample volumes excluded). The change in each log-transformed biomarker level over time was evaluated by a mixed model for repeated measures, with change at 72 weeks the primary outcome of interest. Model estimates were back-transformed to the original (geometric mean ratio) scale and expressed as percent change in geometric means. Pearson correlations between log change in biomarker levels and weight were done on pooled tirzepatide doses. RESULTS: At week 72, tirzepatide was associated with significantly greater reductions (negative values) or increases (positive values) in biomarker geometric means compared with placebo. For the 5-, 10-, or 15-mg doses, respectively, these included high-sensitivity C-reactive protein (-36.9%, -46.9%, -54.6%), interleukin-6 (-25.4%, -27.8%, -30.2%), leukocytes (not significant [NS], -8.6%, -10.0%), homeostatic model assessment of insulin resistance (-26.4%, -35.5%, -39.1%), leptin (-44.4%, -59.3%, -61.4%), gamma-glutamyl transferase (-18.6%, -21.6%, -32.7%), fibroblast growth factor-21 (-27.4%, -27.6%, -39.9%), adiponectin (21.1%, 35.1%, 47.7%), free fatty acids (NS, NS, -17.1%), soluble intercellular adhesion molecule-1 (NS, -9.7%, -11.1%), E-selectin (-12.6%, -20.0%, -26.4%), plasminogen activator inhibitor-1:Ag (-41.4%, -35.6%, -44.3%), and platelets (NS, NS, -6.0%) (all adjusted P < 0.05). No consistent associations were observed between tirzepatide and changes in fibrinogen, tissue plasminogen activator:Ag, or thrombomodulin. CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with improvements in biomarkers of metabolic/adiposity/hepatic stress and endothelial dysfunction, as well as selected biomarkers of inflammation and hemostasis/thrombosis. This analysis provides a comprehensive, long-term, randomized assessment of biomarker changes across multiple cardiovascular pathways during tirzepatide treatment in obesity. (A Study of Tirzepatide [LY3298176] in Participants With Obesity or Overweight [SURMOUNT-1]; NCT04184622).
Ingold M, Müller C, Krolevets M
… +17 more, Yapıcı E, Rapp S, Schuster AK, Tesarz J, Heinrich I, Weinmann-Menke J, Strauch K, Lackner KJ, Konstantinides S, Ruf W, Andrade-Navarro MA, Niehrs C, Gori T, Lurz P, Wild PS, Ten Cate V, GHS Research Consortium
J Am Coll Cardiol
· 2026 Jun · PMID 42233926
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BACKGROUND: Epigenetic modifications have been linked to atherosclerotic cardiovascular disease and could constitute therapeutic targets. OBJECTIVES: In this study, we sought to identify differentially methylated CpG sit...BACKGROUND: Epigenetic modifications have been linked to atherosclerotic cardiovascular disease and could constitute therapeutic targets. OBJECTIVES: In this study, we sought to identify differentially methylated CpG sites related to atherosclerosis across vascular beds, and to investigate to what extent these epigenetic signatures reflect cardiovascular risk factors (CVRFs). METHODS: Blood DNA methylation at 767,735 CpG sites was investigated in 3,688 individuals from 2 prospective cohort studies to create a comprehensive atlas of epigenetic modifications in carotid, coronary, and peripheral atherosclerosis. Atherosclerosis was objectively assessed by medical diagnoses, ultrasonography-assessed carotid plaque presence, and ankle-brachial index. Epigenome-wide association studies (EWAS) with 5% false discovery rate correction were performed to explore the relationship between DNA methylation patterns and atherosclerosis, as well as with CVRFs. Methylation scores were trained with the use of ridge regression for each atherosclerosis phenotype in one cohort, and evaluated for discriminatory and prognostic ability in a separate cohort. The influence of CVRFs on atherosclerosis-associated methylation was investigated by: 1) quantification of overlapping CpG sites associated with CVRFs in EWAS; and 2) observing the effect of CVRF trait adjustment on estimates and P values. RESULTS: Totals of 1,687, 3,131, and 5,852 CpG sites were significantly associated with, respectively, carotid, coronary, and peripheral atherosclerosis; 2,155 sites were significantly associated in 2 or more settings. The most strongly associated CpG sites across phenotypes mapped to 4 loci-an intergenic region on chromosome 2 (near ALPP/ALPG), AHRR, PRSS23, and F2RL3-with additional strong signals in ABCG1 and DHCR24 in coronary atherosclerosis. Epigenetic scores were predictive of 3-point major adverse cerebrovascular and cardiovascular events (HRs ranging from 1.23 to 1.39; all P < 0.001). Overall, >90% of atherosclerosis-associated CpG sites intersected with CVRF-associated sites, particularly smoking (up to 90%), followed by inflammation (60%) and metabolic traits (44%). Atherosclerosis EWAS adjustment for smoking pack-years alone reduced the median absolute estimate of significant CpG sites by 19.6% to 29.0%, and joint adjustment for all CVRF markers by 25.5% to 32.8%. CONCLUSIONS: We identified novel and validated previously known associations of DNA methylation with 3 subtypes of atherosclerosis. Results suggest that in blood, the epigenetic signature of atherosclerosis largely reflects cumulative exposure, particularly smoking and cardiometabolic dysregulation, rather than strongly distinguishing vasculature-specific biological processes.