Variation in cardiovascular care completion is well documented. However, less is known about differences originating from earlier, intermediate stages such as ordering or scheduling of testing or referrals, despite their role as key prerequisites for care access. To examine the care cascades for coronary artery disease (CAD) after emergency department (ED) visits and to identify the specific stages at which variation emerges for CAD testing and cardiology referrals. This was a retrospective cohort study using data and metadata from electronic health records from a large multicenter health system. Participants were adult patients with established primary care and no history of ischemic heart disease or cardiology care who presented to an ED from January 1, 2020, to June 30, 2022, and underwent a troponin test, a proxy for clinically suspected myocardial ischemia. Variation in cardiovascular follow-up care (CAD testing and cardiology referrals) was identified and analyzed. Analyses were restricted to patients with above-median electrocardiogram (ECG)-derived ischemia risk scores to enrich for higher likelihood of benefit from cardiovascular follow-up. Receipt of an order for CAD testing (stress tests, coronary computed tomography angiography) or cardiology referral, scheduling of the service, and completion within 6 months. Outcomes were compared by insurance type, race and ethnicity, language, and sex using multivariable logistic regression adjusted for demographic characteristics, clinical factors, and ECG-derived cardiovascular risk. Among 16 475 patients with an ED visit (median [IQR] age, 67.4 [54.9-77.9] years; 36% female and 64% male individuals) and elevated cardiovascular risk, marked variation in follow-up care emerged. Compared to commercially insured patients, those with Medicare dual or disabled coverage had lower adjusted odds of completing CAD testing (adjusted odds ratio [aOR], 0.45; 95% CI, 0.36-0.56) and cardiology referrals (aOR, 0.47; 95% CI, 0.39-0.57); similar patterns were seen for Medicaid coverage. Patients whose primary language was not English were less likely to complete either service (CAD testing aOR, 0.77; 95% CI, 0.61-0.98; referral aOR, 0.75, 95% CI, 0.61-0.92), and female patients had lower adjusted odds of completing CAD testing (aOR, 0.86; 95% CI, 0.77- 0.96). Adjusted differences by race and ethnicity were modest. Variation was primarily associated with ordering differences and with additional scheduling barriers for select groups. Once scheduled, completion rates exceeded 75%, without differences between groups. This retrospective cohort study found that among patients who visited the ED with elevated ischemic risk, attrition in follow-up care was concentrated early in care cascades and most pronounced among those with noncommercial health insurance. This stepwise analytic framework offers a novel, reproducible approach for health systems to identify where and for whom care gaps arise, which can enable targeted interventions to improve equity and efficiency.
Patient-facing large language model (LLM) outputs for inflammatory bowel disease (IBD) must be decision-relevant, readable, and verifiable. In a cross-sectional benchmark using a guideline-derived question set, five publicly available LLMs provided answers to 20 single-intent patient IBD questions, mapped to prespecified decision-critical domains across the care pathway (100 model-question responses). Queries were conducted from January 17-24, 2026, via official web interfaces under default settings (privacy mode; new chat per prompt). Two blinded raters evaluated informational quality and completeness (using DISCERN, EQIP, and the Global Quality Scale), transparency proxies (based on JAMA benchmark criteria), and readability through the Automated Readability Index, Flesch Reading Ease, Gunning Fog Index, Flesch-Kincaid Grade Level, Coleman-Liau Index, and SMOG. Overall differences were assessed using within-question paired Friedman tests with Holm adjustment, and effect size was quantified with Kendall's W. Interrater agreement was high [DISCERN ICC(A,1) = 0.842; EQIP ICC(A,1) = 0.760; GQS weighted κ = 0.812; JAMA weighted κ = 0.936]. Median DISCERN scores ranged from 43.5 to 57.5, and EQIP scores ranged from 67.5 to 77.5, while transparency remained limited (JAMA median 0-1/4). Readability consistently failed to meet patient targets, with grade-level indices exceeding sixth grade and Flesch Reading Ease medians ranging from 15 to 36 (compared to a target of ≥80 for "easy" readability). All 10 outcomes varied significantly across models (Holm-adjusted P < 0.001; W = 0.238-0.702). Under default settings, publicly available LLMs exhibit variable informational quality for IBD but consistently poor transparency and readability. Patient-facing deployment should mandate provenance, currency, and disclosure fields, as well as outputs targeted to appropriate grade levels.
This JAMA Clinical Guidelines Synopsis summarizes the 2024 recommendations from the American Heart Association and American College of Cardiology on perioperative cardiovascular medication management for noncardiac surgery.
Prepregnancy care and counseling optimize maternal health before conception to improve outcomes for mothers and infants. In the US, 66.4% of reproductive-aged women have at least 1 modifiable risk factor for adverse pregnancy outcomes. For all individuals desiring pregnancy, recommended interventions include folic acid supplementation; cessation of tobacco, alcohol, cannabis, and opioids; immunizations against hepatitis B virus, varicella, and rubella; and screening for syphilis and HIV. Folic acid use before pregnancy is associated with reduced fetal neural tube defects (relative risk [RR], 0.67; 95% CI, 0.52-0.87). Maternal tobacco smoking is associated with increased risks of stillbirth (summary RR [sRR], 1.46; 95% CI, 1.38-1.54), neonatal death (sRR, 1.22; 95% CI, 1.14-1.30), and perinatal death (sRR, 1.33; 95% CI, 1.25-1.41). Screening for and treatment of syphilis and HIV prior to and during pregnancy decrease rates of fetal and neonatal infection. Prepregnancy immunizations against hepatitis B virus, varicella, and rubella decrease neonatal infection and mortality. Individuals using tobacco, alcohol, cannabis, and opioids should receive counseling and treatment prior to pregnancy (eg, buprenorphine or methadone for opioid use disorder). For individuals with chronic disease, routine health examinations and contraceptive care in the year before conception can optimize pregnancy timing and are associated with decreased risk of severe maternal morbidity. Compared with planned pregnancies, unintended pregnancies are associated with increased risk of postpartum depression (15.7% vs 9.6%; adjusted odds ratio [aOR], 1.51; 95% CI, 1.40-1.70), preterm birth (9.4% vs 7.7%; aOR, 1.21; 95% CI, 1.12-1.31), and low infant birth weight (7.3% vs 5.2%; aOR, 1.09; 95% CI, 1.02-1.21). Weight loss prior to conception is recommended for individuals with a body mass index of 25 or greater because overweight and obesity are associated with increased risk of gestational diabetes, gestational hypertension, and cesarean delivery. Among patients with pregestational diabetes (type 1 or 2), hemoglobin A1c of less than 6.5% is associated with a decreased risk of fetal anomaly compared with hemoglobin A1c of 6.5% or greater. Cardiovascular complications such as hypertension and heart failure occur in 15% of pregnancies and are more common among those with preexisting cardiovascular disease. These patients should receive counseling on maternal and neonatal risk, monitoring, and medication management by specialists in cardiology and maternal fetal medicine. Prepregnancy counseling and care reduce maternal morbidity and neonatal morbidity and mortality. Primary care-based discussion of reproductive goals, immunizations, screening for infections and substance use, and risk-reducing interventions such as folate supplementation can optimize outcomes in individuals contemplating pregnancy.
This JAMA Clinical Guidelines Synopsis summarizes the 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndrome.
Apolipoprotein B (apoB) is a superior marker of residual atherosclerotic cardiovascular disease risk in patients treated with lipid-lowering therapy (LLT) compared with low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). The cost-effectiveness of LDL-C, non-HDL-C, and apoB goals has not been established. To determine the relative cost-effectiveness of intensifying LLT for primary prevention based on LDL-C, non-HDL-C, and apoB goals. This economic evaluation used a computer simulation model to evaluate the cost-effectiveness of intensifying LLT with high-intensity statins or ezetimibe according to LDL-C, non-HDL-C, or apoB goals. A cohort of 250 000 statin-eligible and atherosclerotic cardiovascular disease-free US adults was constructed from 2005 to 2016 National Health and Nutrition Examination Survey participants (N = 4149). Individuals commenced the simulation after lipid screening and received statin therapy based on 2018 American Heart Association/American College of Cardiology guidelines. Model inputs were derived from national survey data, pooled longitudinal cohort studies, and published literature. Uncertainty was explored with traditional and probabilistic sensitivity analysis. Lipid-lowering therapy was intensified if individuals did not achieve treated LDL-C level less than 100 mg/dL, non-HDL-C level less than 118 mg/dL, or apoB level less than 78.7 mg/dL. Lifetime quality-adjusted life-years (QALYs) and costs (in 2025 US dollars), discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. Strategies were considered cost-effective if they cost less than $120 000 per QALY gained. Compared with an LDL-C goal, 965 QALYs (95% uncertainty interval [UI], -3551 to 5341 QALYs) would be gained with a non-HDL-C goal, alongside a $2.1 million (95% UI, -$94.2 million to $92.0 million) reduction in costs. Compared with a non-HDL-C goal, 1324 QALYs (95% UI, -2602 to 5669 QALYs) would be gained with an apoB goal, alongside a $40.2 million (95% UI, -$43.6 million to $134 million) increase in costs, yielding an incremental cost-effectiveness ratio of $30 300 per QALY gained. At a willingness-to-pay threshold of $120 000 per QALY gained, an apoB goal was optimal in 65% of probabilistic analyses and a non-HDL-C goal was optimal in 25%. The cost of apoB testing was marginal; higher costs reflected longer life expectancy and prolonged preventive treatment. The results of this computer simulation study suggest that apoB can be used as a cost-effective marker to guide primary prevention LLT and improve population health.
Transcatheter tricuspid valve replacement (TTVR) demonstrated superior outcomes over medical therapy in patients with severe tricuspid regurgitation (TR) in the Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy Using a Novel Device II (TRISCEND II) randomized clinical trial, and received regulatory approval in the US in 2024. Contemporary real-world data on its effectiveness and safety remain limited. To evaluate 30-day clinical, echocardiographic, and health status outcomes of TTVR in real-world use. Retrospective cohort study of all consecutive patients who underwent TTVR in the US from February 2024 through March 2025 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Patients had symptomatic, severe TR despite optimal medical therapy and TTVR was deemed appropriate by a heart team. Statistical analysis was conducted from September 2025 to February 2026. Device-enabled TTVR. Thirty-day event rates (all-cause death, stroke, bleeding, new cardiac implantable electronic device [CIED] implantation, heart failure hospitalizations), TR reduction, and changes in health status (New York Heart Association [NYHA] functional class and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) are reported. Subgroup analyses examined the impact of baseline CIED status on outcomes. Among 1034 attempted procedures at 82 centers (mean [SD] age, 77.1 [10.6] years; 69.1% female; 73.2% NYHA functional class III/IV), a valve was successfully implanted in 1017 patients (98.4%). Mild or less TR was achieved in 98.4% of patients post procedure and in 97.7% at 30 days. At 30 days, all-cause mortality was 3.1%; stroke, 0.2%; bleeding, 7.9%; new CIED, 15.9% in CIED-naive patients; and heart failure hospitalization, 3.1%. There were significant improvements in NYHA functional class (class I/II, 82.7%; P < .001) and mean KCCQ-OS score (22.4 points; P < .001) from baseline to 30 days. There were no significant differences in 30-day mortality (P = .47), heart failure hospitalization (P > .99), and functional outcomes (P = .55) when patients were stratified by baseline CIED status. Early US real-world experience with TTVR confirms safety and effectiveness in patients with severe TR. Thirty-day outcomes are consistent with the TRISCEND II pivotal trial, demonstrating acceptable safety, near-complete TR elimination, and significant health status improvements in an older, comorbid population. Rates of new CIED implantation and bleeding were lower than randomized clinical trial experience.
This Medical News article is an interview with Katie Berlacher, MD, MS, an associate professor of medicine at the University of Pittsburgh Medical Center and chair of this year’s American College of Cardiology Scientific Sessions.
In individuals with heterozygous familial hypercholesterolemia (HeFH), it is uncertain whether and to what extent the reduction in low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy is dependent on the residual functional activity of the LDLR gene carrying the pathogenic variant. To evaluate the reduction in LDL-C achieved with PCSK9 inhibition according to FH genotype in a large cohort of patients with HeFH. This nonrandomized clinical trial reports on a predefined, pooled subanalysis of participants with HeFH requiring additional lipid-lowering therapy in the open-label worldwide phase 3 study of the PSCK9 inhibitor lerodalcibep. This study included participants randomized to 5 phase 3 studies with the plasma PSCK9 inhibitor lerodalcibep and who participated in the open-label extension study from December 2020 to May 2025. Data were analyzed from March 2025 to February 2026. All participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks. The co-primary efficacy end points were LDL-C reduction at weeks 48 and 72. Secondary and exploratory end points included LDL-C response according to FH genotype and the achievement of currently recommended LDL-C goals. Among 703 included participants (mean [range] age, 53.8 [18-80] years; 372 male [52.9%]), 86 (12.2%) were Black, South Asian, or multiracial and 617 (87.8%) were White; 217 participants (72.3%) had atherosclerotic cardiovascular disease (ASCVD) or were at very high risk for ASCVD and 195 participants (27.7%) were at high risk for ASCVD. Despite most participants receiving treatment with statins or ezetimibe, the mean (SD) baseline LDL-C was 144.9 (61.9) mg/dL. Mean (SD) reductions in LDL-C associated with lerodalcibep were 50.3% (28.9%) and 50.3% (28.7%) (mean [SD] absolute change, -72.6 [50.5] mg/dL and -71.8 [48.0] mg/dL) at weeks 48 and 72, respectively. Of 740 participants (92.5%) who underwent genetic testing, monogenic FH-causing variants were found in 455 participants (61.5%), including 432 participants (95.7%) with the LDLR pathogenic variant. LDL-C reduction with lerodalcibep was independent of LDLR variant functional activity. More than 70% of participants achieved both a reduction in LDL-C of at least 50% and their ASCVD risk-based LDL-C goal. These findings suggest that lerodalcibep was associated with significantly and consistently reduced LDL-C in patients with HeFH, with response found to be independent of LDLR function of the pathogenic variant. These findings support that LDL-C reductions in patients with HeFH with PCSK9 inhibition are predominantly mediated by upregulation of the unaffected wild-type LDLR. ClinicalTrials.gov Identifier: NCT04798430.
Familial hypercholesterolemia is a common genetic disorder associated with premature cardiovascular disease. Genetic cascade screening is recommended but remains underused due to privacy laws that prevent clinicians from directly contacting at-risk relatives. To examine whether implementing a web-based communication platform in a patient-mediated genetic cascade screening program for familial hypercholesterolemia increases uptake compared with usual care. This open-label, multicenter, implementation randomized clinical trial (CATCH) was conducted between November 1, 2020, and October 31, 2023, at 7 cardiovascular prevention or lipid clinics across Switzerland, representing French-, German-, and Italian-speaking regions. Adults aged 16 years or older with genetically confirmed familial hypercholesterolemia and at least 1 eligible first-degree relative living in Switzerland participated. A total of 87 index patients with 359 eligible first-degree relatives were randomized by family cluster (1:1) to the intervention or usual care arm. A secure web-based platform allowing participants to send preprepared electronic messages (email or text) to their relatives, linking them directly to participating centers for genetic testing. The primary outcome was cascade screening uptake, defined as the proportion of eligible first-degree relatives undergoing genetic testing within 6 months. The secondary outcome was new cases identified. Among 221 adults screened across multiple families, 87 (39.4%) had genetically confirmed familia hypercholesterolemia (median [IQR] age, 49.2 [16.4-83.7] years; 46 [52.9%] female; median [IQR] highest low-density lipoprotein cholesterol, 289.58 [139.00-498.07] mg/dL); 43 were randomized to the usual care arm, and 44 were randomized to the intervention arm. Among the 359 eligible relatives (median family size, 4), 99 (27.6%) underwent genetic testing. Uptake was higher in the intervention arm (30.4%; 95% CI, 22.0%-40.4%) than in usual care arm (16.7%; 95% CI, 10.1%-26.3%), yielding an odds ratio of 2.18 (95% CI, 1.06-4.51; P = .03). New case identification was also greater (17.0% vs 8.1%; odds ratio, 2.32; 95% CI, 1.07-5.05; P = .03). Newly identified patients were often untreated or had modifiable risk factors. In this randomized clinical trial of patient-mediated genetic cascade screening supported by a web-based platform, participation in genetic testing and detection of familial hypercholesterolemia was increased compared with usual care. These results suggest that the use of digital communication tools enhanced the reach and effectiveness of genetic screening programs within privacy-regulated health systems. ClinicalTrials.gov Identifier: NCT04419090.
Clinical risk factors, lifestyle factors, and social determinants of health have established sex-specific associations with new-onset cardiovascular disease (CVD). However, little is known about the role of patient-reported health measures in individuals without CVD. To determine whether self-rated health is independently associated with the development of CVD and whether this association differs by sex. This retrospective cohort study included community-dwelling adults enrolled in the Ontario Health Study from March 1, 2009, to December 31, 2017, with no prior CVD or active cancer. Outcome ascertainment was via linkage to administrative databases for follow-up outcomes to March 31, 2024, and data were analyzed from January 5, 2025, to January 16, 2026. Excellent, very good to good, and fair to poor self-rated health. The primary outcome was CVD events (hospitalization for myocardial infarction, stroke, heart failure, and cardiovascular death). Cause-specific hazard models with an interaction between self-rated health and sex were adjusted for age, traditional risk factors, lifestyle factors, social determinants of health, and family history of CVD. The cohort consisted of 170 197 participants (104 789 [61.6%] women; median age, 48 [IQR, 36-58] years) followed up for a median of 12.1 (IQR, 12.0-12.3) years. Fair to poor health was reported in 11 661 women (11.1%) and 6381 (9.8%) men; very good to good health, in 75 819 (72.4%) women and 47 865 (73.2%) men; and excellent health, in 17 309 (16.5%) women and 11 162 (17.1%) men. After adjustment, poorer self-rated health was associated with a higher rate of CVD in both sexes. Compared with excellent self-rated health, the fully adjusted hazard ratios (HRs) for fair to poor self-rated health were 2.08 (95% CI, 1.80-2.40) in women and 1.45 (95% CI, 1.29-1.64) in men; the HRs for very good to good self-rated health compared with excellent health were 1.26 (95% CI, 1.11-1.43) in women and 1.04 (95% CI, 0.94-1.14) in men (P < .001 for interaction). In this cohort study of individuals without CVD, as many as 1 in 10 rated their health as fair to poor. Fair to poor self-rated health was an independent risk factor associated with new CVD, and its relative hazard was greater in women than in men. These findings support the use of a simple self-assessment of health to aid in risk stratification in the primary prevention of CVD.
Hypertrophic cardiomyopathy (HCM) is associated with an elevated risk of sudden cardiac death, often preceded by an out-of-hospital cardiac arrest (OHCA). However, population-based estimates of OHCA risk in patients with HCM are limited. To estimate the risk of OHCA in patients with HCM and identify characteristics associated with OHCA. This cohort study used multiple Danish registers during an observation period ranging from June 1, 2001, to December 31, 2022, and included a nested case-control study. All Danish residents aged 18 to 85 years during the study period constituted the source population. Patients with HCM were identified using codes from the International Statistical Classification of Diseases, Tenth Revision. The cohort included patients with a first-time HCM diagnosis and exposure-matched controls. In the nested case-control study, patients with HCM who experienced OHCA were risk-set matched with controls with HCM and no OHCA at the index time. Analyses were performed between September 1 and November 30, 2025. First-time diagnosis of HCM. Time to OHCA from exposure or the matching date was the primary outcome. Risk estimates were determined using the Aalen-Johansen estimator. Association between covariates and OHCA was determined by conditional logistic regression. The cohort included a total of 29 240 individuals: 5901 patients with HCM (median age, 65 [IQR, 54-75] years; 3277 male [55.5%]) and 23 339 matched controls (median age, 65 [IQR, 55-75] years; 12 982 male [55.6%]). In the group aged 61 to 85 years, the 10-year risk of OHCA was 4.3% (95% CI, 3.4%-5.1%) in patients and 3.3% (95% CI, 3.0%-3.7%) in controls. In the group aged 18 to 60 years, the 10-year risk was 2.8% (95% CI, 1.9%-3.7%) in patients and 1.5% (95% CI, 1.2%-1.8%) in controls. The nested case-control study included 250 cases with HCM and OHCA (167 male [66.8%]; median age, 68 [IQR, 59-76] years) and 1000 controls with HCM and no OHCA (668 male [66.8%]; median age, 68 [IQR, 59-76] years). Heart failure, both recent and longer term, was associated with an increased rate of OHCA (hazard ratio, 3.63 [95% CI, 1.55-8.50] and 2.82 [95% CI, 1.88-4.22], respectively). The findings of this cohort study suggest that HCM was associated with an increased risk of OHCA in people aged 18 to 85 years. The rate of OHCA was associated with heart failure, underscoring the need for improved risk stratification to optimize primary prevention.
Psoriasis is a chronic immune-mediated disease associated with cardiovascular, metabolic, musculoskeletal, psychiatric, hepatic, kidney, and pulmonary comorbidities. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved by the US Food and Drug Administration for type 2 diabetes, obesity, cardiovascular risk reduction, chronic kidney disease, obstructive sleep apnea, and metabolic dysfunction-associated steatohepatitis-conditions common in psoriasis. Emerging evidence suggests GLP-1 RAs and dual glucose-dependent insulinotropic polypeptide/GLP-1 agonists may improve psoriatic skin disease, partly through immune modulation. If confirmed in larger randomized clinical trials, GLP-1-based therapies may offer an opportunity to address both cutaneous disease and cardiometabolic comorbidities. This primer from the US National Psoriasis Foundation Medical Board sought to provide an evidence-informed narrative synthesis and practical considerations to introduce dermatologists to GLP-1 RAs for psoriasis treatment. GLP-1 RAs have been associated with reductions in Psoriasis Area and Severity Index (PASI) scores, particularly in patients with obesity or type 2 diabetes. Studies report relative PASI reductions ranging from approximately 40% to 80% with parallel quality-of-life gains, although most of these studies are small (7-48 patients), short term (≤6 months), and lack a control group. Semaglutide and liraglutide have been associated with reductions in C-reactive protein, interleukin-6, lipids, and visceral adiposity. In small, translational cohorts, PASI improvement has been correlated with reductions in superficial adiposity and dermal γδ T-cell density. GLP-1 RAs combine safely with methotrexate, cyclosporine, and biologics. Adverse effects are mainly transient gastrointestinal symptoms; pancreatitis and gallbladder events are rare. Early data show both metabolic and immunomodulatory benefits. This review found that GLP-1-based therapies target shared metabolic and inflammatory pathways in psoriasis. Current evidence supports consideration of adjunctive use in selected patients with metabolic comorbidities, although definitive conclusions await larger randomized clinical trials.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmogenic syndrome in which exercise stress testing is the primary method for provoking adrenergically mediated ventricular arrhythmias. Traditional exercise testing protocols, such as the Bruce protocol, may lack sensitivity, leading to missed diagnoses and undertreatment, whereas early pilot data suggest that a sudden high-intensity Burst protocol may better unmask arrhythmias. To evaluate the diagnostic yield and therapeutic impact of the Burst exercise stress testing protocol compared with the traditional Bruce protocol in CPVT. This retrospective cohort study included pediatric and adult patients evaluated for CPVT at 2 tertiary referral centers in Vancouver, British Columbia, Canada. Data were collected from May 2017 through May 2024, and data analysis was performed from May 2024 through April 2025. Of 38 screened patients, 28 were included who had undergone consecutive Bruce and Burst exercise tests, with available tracings and a diagnostic phenotype on at least 1 test. Arrhythmia severity was scored using the Ventricular Arrhythmia Score. Type of exercise stress testing protocol (Bruce vs Burst). The main outcome was the Ventricular Arrhythmia Score (ranging from 0 = no premature ventricular contractions to 4 = nonsustained ventricular tachycardia). Other outcomes included changes in pharmacologic therapy and adverse events. The cohort included 13 female patients (46%) and 18 probands (64%), including 23 (82%) with a causative RYR2 variant. Median (IQR) age at testing was 19.9 (14.8-33.9) years for Bruce testing and 21.0 (16.1-35.5) years at Burst testing. Bruce and Burst exercise tests were performed a median (IQR) of 1.3 (0.6-2.0) years apart, with all Burst tests performed on equivalent or intensified therapy. The Burst protocol provoked more severe arrhythmias in 20 of 28 patients (71%) with a higher median (IQR) Ventricular Arrhythmia Score (3 [2-4] vs 1 [1-2]; P < .001). These findings prompted β-blocker or flecainide initiation or dose escalation in 13 patients (65%). No adverse safety events occurred. In this cohort study, the Burst exercise stress testing protocol detected a greater burden and severity of ventricular arrhythmias than the Bruce protocol in patients with CPVT, frequently prompting treatment escalation without observed safety concerns. These data suggest that incorporating Burst protocol exercise stress testing into the routine care of patients with CPVT is low risk and often informative.
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Clonal hematopoiesis of indeterminate potential (CHIP) is linked to an increased incidence of cardiovascular and malignant diseases. To determine whether CHIP is associated with cardiotoxic effects in patients with breast cancer receiving trastuzumab. Analyses of human cohorts with complementary animal experimentation were performed using a nationwide population-based cohort (UK Biobank), 1 tertiary referral center (Seoul National University Hospital [SNUH]), and a controlled laboratory setting. UK Biobank participants were enrolled between 2006 and 2010, and SNUH patients were enrolled from January 2004 to March 2024. Data were analyzed from March 2021 to February 2026. Incident heart failure (HF) in the UK Biobank cohort and trastuzumab-related cardiotoxic effects in the SNUH cohort were the main outcome measures. Trastuzumab-related cardiotoxic effects were defined using established clinical criteria (European Society of Cardiology [ESC], Canadian Trastuzumab Working Group, and Cardiac Review and Evaluation Committee [CREC]). Fine-Gray competing risk models were used to account for death and myocardial infarction; multivariable models were adjusted for age and cardiovascular risk factors in both cohorts, with additional adjustment for anthracycline use in the SNUH cohort. Changes in left ventricular ejection fraction (LVEF) were assessed in Tet2-deficient bone marrow chimeric mice following trastuzumab exposure. Overall, 15 729 patients with breast cancer from the UK Biobank cohort (mean [SD] age, 58.8 [7.3] years; 107 [0.68%] male) and 454 female patients with breast cancer who received trastuzumab from the SNUH cohort (mean [SD] age, 52.0 [9.6] years) were included. The corresponding 2-year cumulative incidence values for trastuzumab-related cardiotoxic effects were 15.7% vs 5.0% by ESC criteria (Gray test P = .001), 19.9% vs 10.8% by Canadian criteria (P = .01), and 20.9% vs 11.3% by CREC criteria (P = .02). Using the ESC definition, CHIP positivity (variant allele frequency ≥1.0%) was associated with cardiotoxic effects in multivariable competing risk analysis (adjusted subdistribution hazard ratio, 1.91; 95% CI, 1.32-2.76). Tet2-deficient mice demonstrated a significant LVEF reduction following trastuzumab treatment (effect size, -4.2%; 95% CI, -7.91 to -0.49; P = .03); other experimental groups showed no significant change. In this cohort study, the presence of CHIP was associated with increased susceptibility to trastuzumab-related cardiotoxic effects.
Timely diagnosis of transthyretin cardiac amyloidosis (ATTR-CM) is critical for early treatment to reduce morbidity and mortality, yet the timeliness of contemporary ATTR-CM diagnosis remains poorly understood. To describe the time from incident heart failure (HF) diagnosis to ATTR-CM diagnosis and identify predictors of delayed diagnosis among Medicare beneficiaries. This was a cohort study using US Medicare fee-for-service data from January 2016 to December 2022. Medicare fee-for-service beneficiaries with HF and ATTR-CM were included. Data were analyzed from November 2024 to July 2025. HF diagnosis with ATTR-CM diagnosis following HF diagnosis or within 1 year prior. The primary outcome was time to ATTR-CM diagnosis, measured as the number of days between each patient's first HF diagnosis and first ATTR-CM diagnosis. Multivariable logistic regression assessed demographic, clinical, and socioeconomic factors associated with delayed ATTR-CM diagnosis (defined as >6 months from HF diagnosis to ATTR-CM diagnosis). A total of 7770 patients with HF and ATTR-CM were identified in the Medicare dataset. The median (IQR) age at the time of ATTR-CM diagnosis was 81 (76-86) years; 5995 enrollees (77%) were men. The median (IQR) time from HF diagnosis to ATTR-CM diagnosis was 494 (63-1340) days. For the 6175 patients with a loop diuretic prescription before ATTR-CM diagnosis, the median (IQR) time between initial loop prescription and ATTR-CM diagnosis was 840 (252-1768) days. After adjustment, older age (odds ratio [OR], 0.68; 95% CI, 0.63-0.74), history of atrial fibrillation (OR, 0.39; 95% CI, 0.33-0.49), and carpal tunnel syndrome (OR, 0.85; 95% CI, 0.74-0.97) were associated with lower odds of delayed diagnosis. Female sex (OR, 1.28; 95% CI, 1.13-1.45), a history of aortic stenosis (OR 1.39; 95% CI, 1.20-1.62), chronic obstructive pulmonary disease (OR, 1.18; 95% CI, 1.03-1.34), coronary artery disease (OR, 1.26; 95% CI, 1.13-1.40), diabetes (OR, 1.21; 95% CI, 1.07-1.37), and hypertension (OR, 1.28; 95% CI, 1.13-1.45) were associated with higher odds of delayed diagnosis. There were substantial delays between incident HF and diagnosis of ATTR-CM found in this study. Female sex and having a history of aortic stenosis, coronary artery disease, diabetes, hypertension, or chronic obstructive pulmonary disease, which are each associated with cardiomyopathy and breathlessness, were associated with delayed diagnosis. These findings highlight the need for a heightened index of suspicion for ATTR-CM in patients with other possible etiologies of cardiomyopathy or HF symptoms.
Several integrative indices at the neighborhood level have been developed in the US, but direct comparisons across these indices for the prevalence of cardiovascular-kidney-metabolic (CKM) conditions are limited. Moreover, it is not known whether certain indices better capture place-based variability in CKM conditions or provide additional information when compared with a single measure of income. To determine how much variability is explained by neighborhood indices in the prevalence of CKM conditions at the census tract level and the incremental value of each index when added to median household income. This cross-sectional study of US national surveillance data (Behavioral Risk Factor Surveillance System and American Community Survey) included all census tracts with complete data for exposures, covariates, and outcomes from 2010 to 2022. Analyses were completed between October 2024 and July 2025. Seven neighborhood indices available at the census tract level (Area Deprivation Index, Child Opportunity Index, Environmental Justice Index, Neighborhood Deprivation Index, Social Deprivation Index, Social Vulnerability Index, Structural Racism Effect Index) and median household income at the census tract level from the American Community Survey. The primary outcome was prevalence of CKM conditions (coronary heart disease [CHD], stroke, and chronic kidney disease [CKD]) at the census tract level. Differences in the exposures and outcomes were visualized by mapping index scores, median household income, and prevalences of CKM conditions for all census tracts. To assess index agreement, pairwise correlations were computed with Spearman rank correlation coefficients, and to assess the incremental variability explained by each index when added to median household income, change in r2 was calculated. Of the 65 476 US census tracts included, median (IQR) prevalence was 5.9% (4.7%-7.4%) for CHD, 3.3% (2.6%-4.1%) for stroke, and 2.9% (2.5%-3.4%) for CKD. The indices and income were modestly to highly correlated (range, 0.46-0.94), with some discordance in how each measure classified census tracts by quartiles of index scores. All indices and income were significantly associated with CKM condition prevalence at the census tract level in multivariable linear regression models, adjusted for median population size and age. The r2 values of the indices with CHD, stroke, and CKD ranged from 0.379 (SE = 0.033) for the correlation between the Environmental Justice Index and stroke to 0.688 (SE = 0.002) for the correlation between the Structural Racism Effect Index and stroke. Additionally, the improvement in variability for CHD, stroke, and CKD (change in r2) explained by the addition of each index to income ranged from 0.014 (SE = 0.001) for the correlation between the Environmental Justice Index and CHD to 0.195 (SE = 0.002) for the correlation between Structural Racism Effect Index and stroke. In this cross-sectional study, there were similar associations across neighborhood indices and income with the prevalence of CKM conditions. These findings inform how different place-based measures can be applied in public health research and policy.