J Am Coll Cardiol
· 2026 May · PMID 42126373
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BACKGROUND: Hypoalbuminemia is associated with several risk factors for myocardial infarction, including hypercholesterolemia, liver disease, kidney disease, and diabetes. Homozygosity of loss-of-function (LoF) variants...BACKGROUND: Hypoalbuminemia is associated with several risk factors for myocardial infarction, including hypercholesterolemia, liver disease, kidney disease, and diabetes. Homozygosity of loss-of-function (LoF) variants in the ALB gene, which encodes albumin, is a known cause of congenital hypoalbuminemia. Studies have also shown that heterozygous ALB LoF variants are associated with increases in low-density lipoprotein cholesterol (LDL-C), comparable to those seen in familial hypercholesterolemia. OBJECTIVES: This study examined the effect of ALB LoF variants and other causes of low albumin on LDL-C levels in 2 population biobanks. METHODS: This study used data from 2 large cohorts with linked electronic health record and genetic information: Geisinger's MyCode Community Health Initiative, a health care population based in Pennsylvania, USA; and the National Institutes of Health All of Us Research Program, a nationwide epidemiologic cohort. LDL-C values were adjusted for lipid-lowering medication use. Myocardial infarction diagnoses were extracted from electronic health records using International Classification of Diseases codes. A polygenic score for serum albumin was calculated for participants of European ancestry. Linear regression models were used to estimate associations, and results were meta-analyzed across cohorts using fixed-effects models. RESULTS: Among 155,530 MyCode and 405,701 All of Us adult participants, 77 individuals (1 of 7,289) carried an ALB LoF variant. Among noncarriers, a 1 g/dL decrease in serum albumin was associated with a 10.9 mg/dL (95% CI:, 10.4-11.4) decrease in LDL-C. In contrast, ALB LoF variants were associated with a 0.69 g/dL (95% CI: 0.60-0.78) reduction in serum albumin and a 38.3 mg/dL (95% CI: 28.2-48.5) increase in LDL-C. Paradoxically, whereas monogenic determinants of hypoalbuminemia were associated with increased LDL-C, polygenic determinants of lower albumin were associated with a 0.22 mg/dL (95% CI: 0.17-0.26) decrease in LDL-C per decile. CONCLUSIONS: ALB LoF variants represent a previously underrecognized monogenic cause of elevated LDL-C, with effect sizes slightly less than canonical familial hypercholesterolemia variants. The divergent effects of ALB-mediated vs polygenic or physiological reductions in albumin on LDL-C suggest distinct underlying mechanisms.
Parikh SA, DeRubertis BG, Bonaca MP
… +19 more, Krishnan P, Pin RH, Lee JK, Metzger DC, Kolluri R, Shishehbor MH, Holden AH, Iida O, Armstrong E, Kum SWC, O'Connor DJ, Bajakian DR, Garcia LA, Ying SW, Wang J, Ruster K, Martinsen BJ, Igyarto Z, Varcoe RL
J Am Coll Cardiol
· 2026 May · PMID 42126372
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BACKGROUND: Chronic limb-threatening ischemia (CLTI) caused by infrapopliteal disease is a major therapeutic challenge, with percutaneous transluminal angioplasty (PTA) associated with high rates of restenosis and reinte...BACKGROUND: Chronic limb-threatening ischemia (CLTI) caused by infrapopliteal disease is a major therapeutic challenge, with percutaneous transluminal angioplasty (PTA) associated with high rates of restenosis and reintervention. The LIFE-BTK trial previously demonstrated superior efficacy of the Esprit (Abbott Vascular) BTK drug-eluting resorbable scaffold (DRS) over PTA at 1 year, with sustained benefits at 2 years, with comparable safety at both time points. This report presents the 3-year outcomes. OBJECTIVES: We aimed to compare the 3-year safety and efficacy of DRS vs PTA in patients with CLTI and infrapopliteal artery disease. METHODS: In this randomized trial, 261 patients with CLTI were assigned 2:1 to DRS or PTA. The primary efficacy endpoint was freedom from above-ankle amputation in the target limb, target vessel occlusion, clinically driven target lesion revascularization (CD-TLR), and binary restenosis of the target lesion. The primary safety endpoint was freedom from major adverse limb events and perioperative death. RESULTS: A total of 57% of patients completed the 3-year follow-up. By Kaplan-Meier analysis, the 3-year primary efficacy endpoint was higher with DRS than PTA (59.5% vs 44.8%; P = 0.0025), binary restenosis occurred less frequently with DRS (38.0% vs 49.0%), and CD-TLR was numerically lower with DRS (10.2% vs 18.4%). Limb salvage remained high and comparable (93.8% vs 95.7%), as did the primary safety endpoint (90.8% vs 94.2%). In multivariable Cox regression at 3 years, treatment with DRS was associated with a lower hazard of CD-TLR compared with PTA (HR: 0.46 [95% CI: 0.22-0.97]), with previous minor amputation, greater preintervention stenosis, higher residual stenosis after predilatation, and use of postprocedure dual antiplatelet therapy being independent predictors of CD-TLR. Subgroup analyses showed that outcomes generally favored DRS for patency and reintervention across most patient and lesion characteristics. CONCLUSIONS: At 3 years, DRS demonstrated sustained advantages over PTA in preserving vessel patency, with lower restenosis and fewer reinterventions while maintaining a comparable safety profile. These findings support the use of DRS in selected patients with CLTI and infrapopliteal disease. (Pivotal Investigation of Safety and Efficacy of Drug-Eluting Resorbable Scaffold Treatment-Below the Knee [LIFE-BTK]; NCT04227899).
Schaffer JM, Shih E, Squiers JJ
… +5 more, Banwait JK, Hale S, Gasparini A, Mack MJ, DiMaio JM
J Am Coll Cardiol
· 2026 Jun · PMID 42126371
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BACKGROUND: Randomized trials evaluating multiarterial grafting (MAG) vs single arterial grafting (SAG) during coronary artery bypass grafting (CABG) have not demonstrated a long-term survival benefit, whereas convention...BACKGROUND: Randomized trials evaluating multiarterial grafting (MAG) vs single arterial grafting (SAG) during coronary artery bypass grafting (CABG) have not demonstrated a long-term survival benefit, whereas conventional retrospective studies have consistently reported improved survival with MAG. Whether this discordance reflects true treatment effect heterogeneity or bias from unmeasured confounding in observational analysis remains unclear. OBJECTIVES: Our objective was to evaluate whether the apparent survival advantage associated with MAG in conventional observational analyses persists after accounting for unmeasured confounding using a quasi-experimental instrumental variable (IV) approach and to assess the implications of these findings for long-term survival in an older Medicare population. METHODS: We retrospectively analyzed Medicare beneficiaries who underwent CABG from 2001 to 2019. Surgeon MAG rate during the 12 months preceding each operation was leveraged as an IV. Flexible parametric survival models with time-dependent effects were developed with MAG vs SAG as the exposure variable. The non-IV model adjusted for patient demographics, pre-existing comorbidities, hospital and surgeon characteristics, and procedural details. The IV model incorporated these same covariates plus the IV (surgeon MAG rate) using a 2-stage residual inclusion approach. Regression standardization was used to derive standardized survival probabilities and their differences. RESULTS: Among 1,291,314 beneficiaries, 1,145,760 (88.7%) underwent SAG and 145,554 (12.3%) underwent MAG. In the non-IV model, MAG recipients had improved risk-adjusted median survival as compared with SAG recipients: 10.74 years (95% CI: 10.70-10.79 years) vs 10.33 years (95% CI: 10.31-10.35 years), a difference of 0.41 years. Across 4,164 surgeons, the MAG rate during the 12 months preceding the index CABG was 7.7% ± 9.5% in SAG recipients and 32.9% ± 25.8% in MAG recipients. In the IV model, MAG recipients had similar risk-adjusted median survival compared with SAG recipients: 10.38 years (95% CI: 10.29-10.48 years) vs 10.38 years (95% CI: 10.35-10.40 years), a difference of 0.01 years. CONCLUSIONS: MAG was associated with a modest improvement in long-term survival in a conventional risk-adjusted analysis. However, this association was not robust to a quasi-experimental analysis in which surgeon MAG rate was incorporated as an IV to address unmeasured confounding. The contrast between these models suggests that traditional observational studies may overestimate the survival benefit of MAG because of unmeasured or difficult-to-measure patient characteristics that influence a surgeon's decision to offer MAG.
Schenker N, Borof K, Goette A
… +25 more, Schmidt-Lauber C, Breithardt G, Camm AJ, Crijns H, Eckardt L, Elvan A, Fabritz L, van Gelder I, Gulizia M, Haegeli L, Heidbuchel H, Kautzner J, Lemoine M, Ng GA, Schnabel RB, Suling A, Szumowski L, Themistoclakis S, Vardas P, Wegscheider K, Willems S, Zapf A, Metzner A, Rillig A, Kirchhof P
J Am Coll Cardiol
· 2026 May · PMID 42126365
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BACKGROUND: Atrial fibrillation (AF) increases cardiovascular risk in patients with chronic kidney disease (CKD). The safety and efficacy of early rhythm control (ERC) in patients with CKD is not fully established. OBJEC...BACKGROUND: Atrial fibrillation (AF) increases cardiovascular risk in patients with chronic kidney disease (CKD). The safety and efficacy of early rhythm control (ERC) in patients with CKD is not fully established. OBJECTIVES: This predefined secondary analysis of the EAST-AFNET 4 trial assessed the effectiveness and safety of ERC in patients with CKD defined by estimated glomerular filtration rate (GFR). METHODS: EAST-AFNET 4 randomized patients with recently diagnosed AF and comorbidities to ERC or usual care (UC). Key outcomes were analyzed by Kidney Disease Improving Global Outcomes defined CKD groups. The primary efficacy outcome combined cardiovascular death, stroke, hospitalization for worsening heart failure, or acute coronary syndrome. The safety outcome combined death, stroke, and serious rhythm control-related adverse events. Recurrent AF was a secondary outcome. RESULTS: Baseline creatinine was available in 2,742 of 2,789 (98.3%) patients. In this study, 23% had CKD (GFR: <60 mL/min/1.73 m). Patients with CKD were older (CKD: 74 ± 7.4 years; no CKD: 69 ± 8.3 years; P < 0.001), had higher CHADS-VASc scores (CKD: 4 ± 1.4; no CKD: 3.2 ± 1.2; P < 0.001), and more primary outcome events over 5.1 years of follow-up (HR: 0.98 per mL GFR decrease [95% CI: 0.97-0.99 per mL GFR decrease]). ERC reduced the primary outcome with and without CKD (no CKD:ERC: 3.4%/100 patient-years; UC: 4.1%/100 patient-years; HR: 0.84; P < 0.001; CKD:ERC: 5.8%/100 patient-years; UC: 8.5%/100 patient-years; HR: 0.67; P < 0.001; P = 0.133). CKD increased safety outcomes without interaction with ERC (P = 0.927). Patients with CKD experienced more AF recurrences with UC (P = 0.036). CONCLUSION: ERC effectively and safely reduces cardiovascular events in patients with recently diagnosed AF and stroke risk factors with and without CKD. (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST); NCT01288352).
Mahajan R, Pace DF, Friedman SF
… +12 more, Kany S, D'Souza V, Roshandelpoor A, Kimball TN, Prapiadou S, Tan BYQ, Waks JW, Ho JE, Ellinor PT, Maddah M, Anderson CD, Khurshid S
J Am Coll Cardiol
· 2026 May · PMID 42126358
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BACKGROUND: Scalable risk stratification for ischemic stroke remains an unmet need. OBJECTIVES: In this study, the authors sought to assess whether deep learning of 12-lead electrocardiograms (ECGs) can estimate longitud...BACKGROUND: Scalable risk stratification for ischemic stroke remains an unmet need. OBJECTIVES: In this study, the authors sought to assess whether deep learning of 12-lead electrocardiograms (ECGs) can estimate longitudinal ischemic stroke risk and quantify the extent to which risk signals reflect plausible mechanisms (eg, atrial cardiopathy). METHODS: We trained a convolutional neural network to estimate the 10-year risk of incident ischemic stroke with the use of 12-lead ECG among patients receiving longitudinal care at Massachusetts General Hospital (MGH). Neural network-derived stroke probabilities, age, and sex were integrated into a Cox proportional hazards model ("ECG2Stroke"). Within an MGH test set ("MGH Test"), as well as independent samples from Brigham and Women's Hospital (BWH) and Beth Israel Deaconess Medical Center (BIDMC), we assessed model discrimination (area under the curve [AUC]) and calibration (integrated calibration index [ICI]). ECG2Stroke was compared with the revised Framingham Stroke Risk Profile (FSRP). Saliency mapping, associations with clinical factors and structured ECG features, and performance across stroke subtypes were assessed. RESULTS: ECG2Stroke was developed in 101,496 individuals from MGH (age 57 ± 16 years, 48% women), and evaluated in MGH Test (n = 4,771; age 57 ± 16 years, 49% women), BWH (n = 68,884; age 57 ± 16 years, 55% women), and BIDMC (n = 29,882; age 56 ± 17 years, 54% women). At 10 years, there were 346 stroke events in MGH Test, 3,209 in BWH, and 1,236 in BIDMC. ECG2Stroke demonstrated moderate discrimination of incident stroke (10-year AUCs: MGH Test, 0.795; BWH, 0.774; BIDMC, 0.772) and low calibration error (ICIs: MGH Test, 0.030; BWH, 0.005; BIDMC, 0.026). In patients with available data, 10-year AUC for ECG2Stroke was similar to FSRP (MGH/BWH Test: ECG2Stroke, 0.791; FSRP, 0.779; BIDMC: ECG2Stroke, 0.745; FSRP, 0.728). Stratification persisted across subgroups, including patients with and without atrial fibrillation. Saliency maps highlighted the ECG P-wave, and risk estimates correlated with structured P-wave indices. ECG2Stroke was strongly associated with cardioembolic stroke (cause-specific HR: 2.17 per 1-SD of logit-transformed probability; 95% CI: 1.64-2.87) but not noncardioembolic stroke. CONCLUSIONS: ECG-based artificial intelligence (AI) can predict 10-year ischemic stroke with performance similar to a validated clinical score, possibly by encoding markers of abnormal atrial substrate linked to cardioembolism. AI-enabled ECG analysis may enable efficient prioritization for stroke prevention.
Abdalla M, Juraschek SP, Biaggioni I
… +30 more, Bowling CB, Balijepalli RC, Brady TM, Bress AP, Brook RD, Cohen JB, Commodore-Mensah Y, Dart RA, Desvigne-Nickens P, Drawz P, Ferdinand KC, Flynn JT, Foti K, Green BB, Hoppe KK, Kirley K, Lipsitz L, Oh YS, Melgarejo JD, Mukkamala R, Muntner P, Ravenell J, Shimbo D, South AM, Townsend RR, Varagic J, Wall HK, Wang P, Einhorn P, Wolz M
J Am Coll Cardiol
· 2026 May · PMID 42126153
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Full text
Hypertension is a modifiable risk factor for cardiovascular disease (CVD) and its prevalence is high in the United States and worldwide. Adequate characterization of blood pressure (BP) is essential for the diagnosis and...Hypertension is a modifiable risk factor for cardiovascular disease (CVD) and its prevalence is high in the United States and worldwide. Adequate characterization of blood pressure (BP) is essential for the diagnosis and management of hypertension. However, BP assessment can be challenging because of the unique influences across the lifespan, disease conditions, and physical environmental context. Moreover, complex uncertainties in BP assessment may contribute to underdiagnosis, undertreatment, and preventable morbidity and mortality. Recent advances in BP measurement devices have enabled comprehensive characterization of BP that could dramatically change how hypertension is managed to optimize CVD risk reduction, avoid complications of low BP, and improve hypertension control rates. To address the rapidly evolving landscape in BP assessment, the National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health convened a 2-day workshop of clinicians and researchers in December 2024. The present report summarizes the topics presented and discussed during the meeting, which focused on the latest evidence on BP assessment as well as obstacles and knowledge gaps to be addressed to advance BP assessment in clinical practice and research.