<div><h4>Clinical Outcomes by Sex After Pulsed Field Ablation of Atrial Fibrillation.</h4><i>Turagam MK, Neuzil P, Schmidt B, Reichlin T, ... Kueffer T, Reddy VY</i><br /><b>Importance</b><br />Previous studies evaluating the association of patient sex with clinical outcomes using conventional thermal ablative modalities for atrial fibrillation (AF) such as radiofrequency or cryoablation are controversial due to mixed results. Pulsed field ablation (PFA) is a novel AF ablation energy modality that has demonstrated preferential myocardial tissue ablation with a unique safety profile.<br /><b>Objective</b><br />To compare sex differences in patients undergoing PFA for AF in the Multinational Survey on the Methods, Efficacy, and Safety on the Postapproval Clinical Use of Pulsed Field Ablation (MANIFEST-PF) registry.<br /><b>Design, setting, and participants</b><br />This was a retrospective cohort study of MANIFEST-PF registry data, which included consecutive patients undergoing postregulatory approval treatment with PFA to treat AF between March 2021 and May 2022 with a median follow-up of 1 year. MANIFEST-PF is a multinational, retrospectively analyzed, prospectively enrolled patient-level registry including 24 European centers. The study included all consecutive registry patients (age ≥18 years) who underwent first-ever PFA for paroxysmal or persistent AF.<br /><b>Exposure</b><br />PFA was performed on patients with AF. All patients underwent pulmonary vein isolation and additional ablation, which was performed at the discretion of the operator.<br /><b>Main outcomes and measures</b><br />The primary effectiveness outcome was freedom from clinically documented atrial arrhythmia for 30 seconds or longer after a 3-month blanking period. The primary safety outcome was the composite of acute (<7 days postprocedure) and chronic (>7 days) major adverse events (MAEs).<br /><b>Results</b><br />Of 1568 patients (mean [SD] age, 64.5 [11.5] years; 1015 male [64.7%]) with AF who underwent PFA, female patients, as compared with male patients, were older (mean [SD] age, 68 [10] years vs 62 [12] years; P < .001), had more paroxysmal AF (70.2% [388 of 553] vs 62.4% [633 of 1015]; P = .002) but had fewer comorbidities such as coronary disease (9% [38 of 553] vs 15.9% [129 of 1015]; P < .001), heart failure (10.5% [58 of 553] vs 16.6% [168 of 1015]; P = .001), and sleep apnea (4.7% [18 of 553] vs 11.7% [84 of 1015]; P < .001). Pulmonary vein isolation was performed in 99.8% of female (552 of 553) and 98.9% of male (1004 of 1015; P = .90) patients. Additional ablation was performed in 22.4% of female (124 of 553) and 23.1% of male (235 of 1015; P = .79) patients. The 1-year Kaplan-Meier estimate for freedom from atrial arrhythmia was similar in male and female patients (79.0%; 95% CI, 76.3%-81.5% vs 76.3%; 95% CI, 72.5%-79.8%; P = .28). There was also no significant difference in acute major AEs between groups (male, 1.5% [16 of 1015] vs female, 2.5% [14 of 553]; P = .19).<br /><br /><b>Conclusion:</b><br/>and relevance</b><br />Results of this cohort study suggest that after PFA for AF, there were no significant sex differences in clinical effectiveness or safety events.<br /><br /><br /><br /><small>JAMA Cardiol: 01 Nov 2023; epub ahead of print</small></div>

<div><h4>Educational Attainment and Lifetime Risk of Cardiovascular Disease.</h4><i>Magnani JW, Ning H, Wilkins JT, Lloyd-Jones DM, Allen NB</i><br /><b>Importance</b><br />Education is a social determinant of health. Quantifying its association with lifetime cardiovascular disease (CVD) risk has public health importance.<br /><b>Objective</b><br />To calculate lifetime risk estimates of incident CVD and CVD subtypes and estimate years lived with and without CVD by education.<br /><b>Design, setting, and participants</b><br />Included community-based cohort studies with adjudicated cardiovascular events used pooled individual-level data from 1985 to 2015 of 6 prospective cohort studies. The study team assessed the association between education and lifetime CVD risk with modified Kaplan-Meier and Cox models accounting for competing risk of noncardiovascular death. The study team estimated years lived with and without CVD by education with the Irwin restricted mean and the utility of adding educational attainment to CVD risk assessment. Participants (baseline 40 to 59 years old and 60 to 79 years old) were without CVD at baseline and had complete education, cardiovascular risk factors, and prospective CVD outcomes data. Data were analyzed from January 2022 to September 2022.<br /><b>Exposures</b><br />Educational attainment (less than high school, high school completion, some college, or college graduate).<br /><b>Main outcome and measures</b><br />Cardiovascular events (fatal and nonfatal coronary heart disease, heart failure, and stroke; CVD-related deaths; and total CVD encompassing any of these events).<br /><b>Results</b><br />There were 40 998 participants (23 305 female [56.2%]) with a mean (SD) age of 58.1 (9.7) years for males and 58.3 (9.9) years for females. Compared with college graduates, those with less than high school or high school completion had higher lifetime CVD risks. Among middle-aged men, the competing hazard ratios (HRs) for a CVD event were 1.58 (95% CI, 1.38-1.80), 1.30 (95% CI, 1.10-1.46), and 1.16 (95% CI, 1.00-1.34) in those with less than high school, high school, and some college, respectively, compared with those with college completion. Among women, these competing HRs were 1.70 (95% CI, 1.49-1.95), 1.19 (95% CI, 1.05-1.35), and 0.98 (95% CI, 0.83-1.15). Individuals with higher education had longer duration of life prior to incident CVD. Education provided limited contribution toward enhancing CVD risk prediction.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Lower education was associated with lifetime CVD risk across adulthood; higher education translated to healthy longevity. Educational policy initiatives may associate with long-term health benefits.<br /><br /><br /><br /><small>JAMA Cardiol: 01 Nov 2023; epub ahead of print</small></div>

<div><h4>Viability and Outcomes With Revascularization or Medical Therapy in Ischemic Ventricular Dysfunction: A Prespecified Secondary Analysis of the REVIVED-BCIS2 Trial.</h4><i>Perera D, Ryan M, Morgan HP, Greenwood JP, ... Chiribiri A, REVIVED-BCIS2 Investigators</i><br /><b>Importance</b><br />In the Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2) trial, percutaneous coronary intervention (PCI) did not improve outcomes for patients with ischemic left ventricular dysfunction. Whether myocardial viability testing had prognostic utility for these patients or identified a subpopulation who may benefit from PCI remained unclear.<br /><b>Objective</b><br />To determine the effect of the extent of viable and nonviable myocardium on the effectiveness of PCI, prognosis, and improvement in left ventricular function.<br /><b>Design, setting, and participants</b><br />Prospective open-label randomized clinical trial recruiting between August 28, 2013, and March 19, 2020, with a median follow-up of 3.4 years (IQR, 2.3-5.0 years). A total of 40 secondary and tertiary care centers in the United Kingdom were included. Of 700 randomly assigned patients, 610 with left ventricular ejection fraction less than or equal to 35%, extensive coronary artery disease, and evidence of viability in at least 4 myocardial segments that were dysfunctional at rest and who underwent blinded core laboratory viability characterization were included. Data analysis was conducted from March 31, 2022, to May 1, 2023.<br /><b>Intervention</b><br />Percutaneous coronary intervention in addition to optimal medical therapy.<br /><b>Main outcomes and measures</b><br />Blinded core laboratory analysis was performed of cardiac magnetic resonance imaging scans and dobutamine stress echocardiograms to quantify the extent of viable and nonviable myocardium, expressed as an absolute percentage of left ventricular mass. The primary outcome of this subgroup analysis was the composite of all-cause death or hospitalization for heart failure. Secondary outcomes were all-cause death, cardiovascular death, hospitalization for heart failure, and improved left ventricular function at 6 months.<br /><b>Results</b><br />The mean (SD) age of the participants was 69.3 (9.0) years. In the PCI group, 258 (87%) were male, and in the optimal medical therapy group, 277 (88%) were male. The primary outcome occurred in 107 of 295 participants assigned to PCI and 114 of 315 participants assigned to optimal medical therapy alone. There was no interaction between the extent of viable or nonviable myocardium and the effect of PCI on the primary or any secondary outcome. Across the study population, the extent of viable myocardium was not associated with the primary outcome (hazard ratio per 10% increase, 0.98; 95% CI, 0.93-1.04) or any secondary outcome. The extent of nonviable myocardium was associated with the primary outcome (hazard ratio, 1.07; 95% CI, 1.00-1.15), all-cause death, cardiovascular death, and improvement in left ventricular function.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />This study found that viability testing does not identify patients with ischemic cardiomyopathy who benefit from PCI. The extent of nonviable myocardium, but not the extent of viable myocardium, is associated with event-free survival and likelihood of improvement of left ventricular function.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT01920048.<br /><br /><br /><br /><small>JAMA Cardiol: 25 Oct 2023; epub ahead of print</small></div>

<div><h4>Aligning US Agency Policies for Cardiovascular Devices Through the Breakthrough Devices Program.</h4><i>Moneer O, Rathi VK, Johnston JL, Ross JS, Dhruva SS</i><br /><b>Importance</b><br />The US Food and Drug Administration (FDA) and Centers for Medicare & Medicaid Services (CMS) have different statutory authorities; FDA evaluates safety and effectiveness for market authorization of medical devices while CMS determines whether coverage is \"reasonable and necessary\" for its beneficiaries. CMS has recently enacted policies automatically providing supplemental reimbursement for new, costly devices authorized after designation in FDA\'s Breakthrough Devices Program (BDP) and in June 2023 issued notice for a new Transitional Coverage for Emerging Technologies pathway, accelerating coverage for Breakthrough devices.<br /><b>Observations</b><br />Aiming to incentivize innovation, FDA awards Breakthrough designations early in device development to expedite market authorization and can accept greater uncertainty in benefit and risk, contingent on postmarket evidence generation. Since 2020, Breakthrough designation has effectively automatically qualified devices to receive supplemental Medicare reimbursement after CMS waived a long-standing requirement that devices demonstrate \"substantial clinical improvement\" for beneficiaries. Using publicly available information, 3 examples of cardiovascular devices illustrate that the BDP may allow for FDA authorization based on less rigorous evidence, such as single-arm trials focused on surrogate end points with short-term follow-up whose participants are often not representative of Medicare beneficiaries. In 1 case, Breakthrough designation allowed a 30% decrease in enrollment of a trial used to support approval. Initial positive findings for some devices have remained unverified, and in 1 case even partially nullified, by postmarket studies. Manufacturers have also used Breakthrough designations to set the price of devices to facilitate additional pass-through payments, leading to higher short-term and long-term costs to CMS and health care systems.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />The BDP may qualify new, costly devices for higher and automatic Medicare reimbursement despite evidence not being representative of CMS beneficiaries and persistent uncertainty of benefit and risk. To ensure the best evidence is generated to inform clinical care, FDA could apply more selectivity to BDP eligibility, specify objective criteria for revoking Breakthrough designation when appropriate, and ensure timely postmarket evidence generation, whereas CMS could independently review clinical evidence, advise manufacturers about standards for coverage review, and make supplemental payments and long-term device reimbursement contingent on clinical outcome benefit and postmarket evidence generation.<br /><br /><br /><br /><small>JAMA Cardiol: 25 Oct 2023; epub ahead of print</small></div>

<div><h4>Deep Learning of Electrocardiograms in Sinus Rhythm From US Veterans to Predict Atrial Fibrillation.</h4><i>Yuan N, Duffy G, Dhruva SS, Oesterle A, ... Keyhani S, Ouyang D</i><br /><b>Importance</b><br />Early detection of atrial fibrillation (AF) may help prevent adverse cardiovascular events such as stroke. Deep learning applied to electrocardiograms (ECGs) has been successfully used for early identification of several cardiovascular diseases.<br /><b>Objective</b><br />To determine whether deep learning models applied to outpatient ECGs in sinus rhythm can predict AF in a large and diverse patient population.<br /><b>Design, setting, and participants</b><br />This prognostic study was performed on ECGs acquired from January 1, 1987, to December 31, 2022, at 6 US Veterans Affairs (VA) hospital networks and 1 large non-VA academic medical center. Participants included all outpatients with 12-lead ECGs in sinus rhythm.<br /><b>Main outcomes and measures</b><br />A convolutional neural network using 12-lead ECGs from 2 US VA hospital networks was trained to predict the presence of AF within 31 days of sinus rhythm ECGs. The model was tested on ECGs held out from training at the 2 VA networks as well as 4 additional VA networks and 1 large non-VA academic medical center.<br /><b>Results</b><br />A total of 907 858 ECGs from patients across 6 VA sites were included in the analysis. These patients had a mean (SD) age of 62.4 (13.5) years, 6.4% were female, and 93.6% were male, with a mean (SD) CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age, sex category) score of 1.9 (1.6). A total of 0.2% were American Indian or Alaska Native, 2.7% were Asian, 10.7% were Black, 4.6% were Latinx, 0.7% were Native Hawaiian or Other Pacific Islander, 62.4% were White, 0.4% were of other race or ethnicity (which is not broken down into subcategories in the VA data set), and 18.4% were of unknown race or ethnicity. At the non-VA academic medical center (72 483 ECGs), the mean (SD) age was 59.5 (15.4) years and 52.5% were female, with a mean (SD) CHA2DS2-VASc score of 1.6 (1.4). A total of 0.1% were American Indian or Alaska Native, 7.9% were Asian, 9.4% were Black, 2.9% were Latinx, 0.03% were Native Hawaiian or Other Pacific Islander, 74.8% were White, 0.1% were of other race or ethnicity, and 4.7% were of unknown race or ethnicity. A deep learning model predicted the presence of AF within 31 days of a sinus rhythm ECG on held-out test ECGs at VA sites with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI, 0.85-0.86), accuracy of 0.78 (95% CI, 0.77-0.78), and F1 score of 0.30 (95% CI, 0.30-0.31). At the non-VA site, AUROC was 0.93 (95% CI, 0.93-0.94); accuracy, 0.87 (95% CI, 0.86-0.88); and F1 score, 0.46 (95% CI, 0.44-0.48). The model was well calibrated, with a Brier score of 0.02 across all sites. Among individuals deemed high risk by deep learning, the number needed to screen to detect a positive case of AF was 2.47 individuals for a testing sensitivity of 25% and 11.48 for 75%. Model performance was similar in patients who were Black, female, or younger than 65 years or who had CHA2DS2-VASc scores of 2 or greater.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Deep learning of outpatient sinus rhythm ECGs predicted AF within 31 days in populations with diverse demographics and comorbidities. Similar models could be used in future AF screening efforts to reduce adverse complications associated with this disease.<br /><br /><br /><br /><small>JAMA Cardiol: 18 Oct 2023; epub ahead of print</small></div>

<div><h4>Lead Extraction and Mortality Among Patients With Cardiac Implanted Electronic Device Infection.</h4><i>Pokorney SD, Zepel L, Greiner MA, Fowler VG, ... Hardy C, Piccini JP</i><br /><b>Importance</b><br />Complete hardware removal is a class I recommendation for cardiovascular implantable electronic device (CIED) infection, but practice patterns and outcomes remain unknown.<br /><b>Objective</b><br />To quantify the number of Medicare patients with CIED infections who underwent implantation from 2006 to 2019 and lead extraction from 2007 to 2019 to analyze the outcomes in these patients in a nationwide clinical practice cohort.<br /><b>Design, setting, and participants</b><br />This cohort study included fee-for-service Medicare Part D beneficiaries from January 1, 2006, to December 31, 2019, who had a de novo CIED implantation and a CIED infection more than 1 year after implantation. Data were analyzed from January 1, 2005, to December 31, 2019.<br /><b>Exposure</b><br />A CIED infection, defined as (1) endocarditis or infection of a device implant and (2) documented antibiotic therapy.<br /><b>Main outcomes and measures</b><br />The primary outcomes of interest were device infection, device extraction, and all-cause mortality. Time-varying multivariable Cox proportional hazards regression models were used to evaluate the association between extraction and survival.<br /><b>Results</b><br />Among 1 065 549 patients (median age, 78.0 years [IQR, 72.0-84.0 years]; 50.9% male), mean (SD) follow-up was 4.6 (2.9) years after implantation. There were 11 304 patients (1.1%) with CIED infection (median age, 75.0 years [IQR, 67.0-82.0 years]); 60.1% were male, and 7724 (68.3%) had diabetes. A total of 2102 patients with CIED infection (18.6%) underwent extraction within 30 days of diagnosis. Infection occurred a mean (SD) of 3.7 (2.4) years after implantation, and 1-year survival was 68.3%. There was evidence of highly selective treatment, as most patients did not have extraction within 30 days of diagnosed infection (9202 [81.4%]), while 1511 (13.4%) had extraction within 6 days of diagnosis and 591 (5.2%) had extraction between days 7 and 30. Any extraction was associated with lower mortality compared with no extraction (adjusted hazard ratio [AHR], 0.82; 95% CI, 0.74-0.90; P < .001). Extraction within 6 days was associated with even lower risk of mortality (AHR, 0.69; 95% CI, 0.61-0.78; P < .001).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this study, a minority of patients with CIED infection underwent extraction. Extraction was associated with a lower risk of death compared with no extraction. The findings suggest a need to improve adherence to guideline-directed care among patients with CIED infection.<br /><br /><br /><br /><small>JAMA Cardiol: 18 Oct 2023; epub ahead of print</small></div>

<div><h4>Cardio-Oncology Rehabilitation for Cancer Survivors With High Cardiovascular Risk: A Randomized Clinical Trial.</h4><i>Viamonte SG, Joaquim AV, Alves AJ, Vilela E, ... Santos M, Ribeiro F</i><br /><b>Importance</b><br />Cardiovascular disease is a leading cause of morbidity in cancer survivors, which makes strategies aimed at mitigating cardiovascular risk a subject of major contemporary importance.<br /><b>Objective</b><br />To assess whether a center-based cardiac rehabilitation (CBCR) framework compared with usual care encompassing community-based exercise training (CBET) is superior for cardiorespiratory fitness improvement and cardiovascular risk factor control among cancer survivors with high cardiovascular risk.<br /><b>Design, setting, and participants</b><br />This prospective, single-center, randomized clinical trial (CORE trial) included adult cancer survivors who had exposure to cardiotoxic cancer treatment and/or previous cardiovascular disease. Enrollment took place from March 1, 2021, to March 31, 2022. End points were assessed at baseline and after the 8-week intervention.<br /><b>Interventions</b><br />Participants were randomly assigned in a 1:1 ratio to 8 weeks of CBCR or CBET. The combined aerobic and resistance exercise sessions were performed twice a week.<br /><b>Main outcomes and measures</b><br />The powered primary efficacy measure was change in peak oxygen consumption (V̇o2) at 2 months. Secondary outcomes included handgrip maximal strength, functional performance, blood pressure (BP), body composition, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), lipid profile, plasma biomarker levels, physical activity (PA) levels, psychological distress, quality of life (QOL), and health literacy.<br /><b>Results</b><br />A total of 75 participants completed the study (mean [SD] age, 53.6 [12.3] years; 58 [77.3%] female), with 38 in the CBCR group and 37 in the CBET group. Participants in CBCR achieved a greater mean (SD) increase in peak V̇o2 than those in CBET (2.1 [2.8] mL/kg/min vs 0.8 [2.5] mL/kg/min), with a between-group mean difference of 1.3 mL/kg/min (95% CI, 0.1-2.6 mL/kg/min; P = .03). Compared with the CBET group, the CBCR group also attained a greater mean (SD) reduction in systolic BP (-12.3 [11.8] mm Hg vs -1.9 [12.9] mm Hg; P < .001), diastolic BP (-5.0 [5.7] mm Hg vs -0.5 [7.0] mm Hg; P = .003), and BMI (-1.2 [0.9] vs 0.2 [0.7]; P < .001) and greater mean (SD) improvements in PA levels (1035.2 [735.7] metabolic equivalents [METs]/min/wk vs 34.1 [424.4] METs/min/wk; P < .001), QOL (14.0 [10.0] points vs 0.4 [12.9] points; P < .001), and health literacy scores (2.7 [1.6] points vs 0.1 [1.4] points; P < .001). Exercise adherence was significantly higher in the CBCR group than in the CBET group (mean [SD] sessions completed, 90.3% [11.8%] vs 68.4% [22.1%]; P < .001).<br /><br /><b>Conclusion:</b><br/>and relevance</b><br />The CORE trial showed that a cardio-oncology rehabilitation model among cancer survivors with high cardiovascular risk was associated with greater improvements in peak V̇o2 compared with usual care encompassing an exercise intervention in a community setting. The CBCR also showed superior results in exercise adherence, cardiovascular risk factor control, QOL, and health literacy.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT05132998.<br /><br /><br /><br /><small>JAMA Cardiol: 11 Oct 2023; epub ahead of print</small></div>

<div><h4>Concordance of a High Lipoprotein(a) Concentration Among Relatives.</h4><i>Reeskamp LF, Tromp TR, Patel AP, Ibrahim S, ... Natarajan P, Khera AV</i><br /><b>Importance</b><br />Lipoprotein(a) (Lp[a]) concentrations are a highly heritable and potential causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent consensus statements by the European Atherosclerosis Society and American Heart Association recommend screening of relatives of individuals with high Lp(a) concentrations, but the expected yield of this approach has not been quantified in large populations.<br /><b>Objective</b><br />To measure the prevalence of high Lp(a) concentrations among first- and second-degree relatives of individuals with high Lp(a) concentrations compared with unrelated participants.<br /><b>Design, setting, and participants</b><br />In this cross-sectional analysis, pairs of first-degree (n = 19 899) and second-degree (n = 9715) relatives with measured Lp(a) levels from the UK Biobank study and random pairs of unrelated individuals (n = 184 764) were compared. Data for this study were collected from March 2006 to August 2010 and analyzed from December 2021 to August 2023.<br /><b>Exposure</b><br />Serum Lp(a) levels, with a high Lp(a) level defined as at least 125 nmol/L.<br /><b>Main outcome and measure</b><br />Concordance of clinically relevant high Lp(a) levels in first- and second-degree relatives of index participants with high Lp(a) levels.<br /><b>Results</b><br />A total of 52 418 participants were included in the analysis (mean [SD] age, 57.3 [8.0] years; 29 825 [56.9%] women). Levels of Lp(a) were correlated among pairs of first-degree (Spearman ρ = 0.45; P < .001) and second-degree (Spearman ρ = 0.22; P < .001) relatives. A total of 1607 of 3420 (47.0% [95% CI, 45.3%-48.7%]) first-degree and 514 of 1614 (31.8% [95% CI, 29.6%-34.2%]) second-degree relatives of index participants with high Lp(a) levels also had elevated concentrations compared with 4974 of 30 258 (16.4% [95% CI, 16.0%-16.9%]) pairs of unrelated individuals. The concordance in high Lp(a) levels was generally consistent among subgroups (eg, those with prior ASCVD, postmenopausal women, and statin users). The odds ratios for relatives to have high Lp(a) levels if their index relative had a high Lp(a) level compared with those whose index relatives did not have high Lp(a) levels were 7.4 (95% CI, 6.8-8.1) for first-degree relatives and 3.0 (95% CI, 2.7-3.4) for second-degree relatives.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />The findings of this cross-sectional study suggest that the yield of cascade screening of first-degree relatives of individuals with high Lp(a) levels is over 40%. These findings support recent recommendations to use this approach to identify additional individuals at ASCVD risk based on Lp(a) concentrations.<br /><br /><br /><br /><small>JAMA Cardiol: 11 Oct 2023; epub ahead of print</small></div>

<div><h4>Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial.</h4><i>Sleem A, Effron MB, Stebbins A, Wruck LM, ... Jones WS, Hernandez AF</i><br /><b>Importance</b><br />Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations.<br /><b>Objective</b><br />To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes.<br /><b>Design, setting, and participants</b><br />This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023.<br /><b>Intervention</b><br />ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months.<br /><b>Main outcomes and measures</b><br />The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population.<br /><b>Results</b><br />Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02697916.<br /><br /><br /><br /><small>JAMA Cardiol: 04 Oct 2023; epub ahead of print</small></div>

<div><h4>The Role of Posterior Wall Isolation in Catheter Ablation for Persistent Atrial Fibrillation and Systolic Heart Failure: A Secondary Analysis of a Randomized Clinical Trial.</h4><i>William J, Chieng D, Sugumar H, Ling LH, ... Kalman JM, Kistler PM</i><br /><b>Importance</b><br />Catheter ablation for patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) is associated with improved left ventricular ejection fraction (LVEF) and survival compared with medical therapy. Nonrandomized studies have reported improved success with posterior wall isolation (PWI).<br /><b>Objective</b><br />To determine the impact of pulmonary vein isolation (PVI) with PWI vs PVI alone on outcomes in patients with HFrEF.<br /><b>Design, setting, and participants</b><br />This was an ad hoc secondary analysis of the CAPLA trial, a multicenter, prospective, randomized control trial that involved 11 centers in 3 countries (Australia, Canada, and UK). CAPLA featured 338 patients with persistent AF randomized to either PVI plusPWI or PVI alone. This substudy included patients in the original CAPLA study who had symptomatic HFrEF (LVEF <50% and New York Heart Association class ≥II).<br /><b>Interventions</b><br />Pulmonary vein isolation with PWI vs PVI alone.<br /><b>Main outcomes and measures</b><br />The primary end point was freedom from any documented atrial arrhythmia greater than 30 seconds, after a single ablation procedure, without the use of antiarrhythmic drug (AAD) therapy at 12 months.<br /><b>Results</b><br />A total of 98 patients with persistent AF and symptomatic HFrEF were identified (mean [SD] age, 62.1 [9.8] years; 79.5% men; and mean [SD] LVEF at baseline, 34.6% [7.9%]). After 12 months, 58.7% of patients with PVI plus PWI were free from recurrent atrial arrhythmia without the use of AAD therapy vs 61.5% with PVI alone (hazard ratio, 1.02; 95% CI, 0.54-1.91; P = .96). There were no significant differences in freedom from atrial arrhythmia with or without AAD therapy after multiple procedures (PVI plus PWI vs PVI alone, 60.9% vs 65.4%; P = .73) or AF burden (median, 0% in both groups; P = .78). Mean LVEF improved substantially in PVI plus PWI (∆ LVEF, 19.3% [13.0%; P < .01) and PVI alone (18.2% [14.1%; P < .01), with no difference between groups (P = .71). Normalization of LV function occurred in 65.2% of patients in the PVI plus PWI group and 50.0% of patients with PVI alone (P = .13).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />The results of this study indicate that addition of PWI to PVI did not improve freedom from arrhythmia recurrence or recovery of LVEF in patients with persistent AF and symptomatic HFrEF. Catheter ablation was associated with significant improvements in systolic function, irrespective of ablation strategy used. These results caution against the routine inclusion of PWI in patients with HFrEF undergoing first-time catheter ablation for persistent AF.<br /><b>Trial registration</b><br />http://anzctr.org.au Identifier: ACTRN12616001436460.<br /><br /><br /><br /><small>JAMA Cardiol: 27 Sep 2023; epub ahead of print</small></div>

<div><h4>Prevalence and Overlap of Cardiac, Renal, and Metabolic Conditions in US Adults, 1999-2020.</h4><i>Ostrominski JW, Arnold SV, Butler J, Fonarow GC, ... Kosiborod MN, Vaduganathan M</i><br /><b>Importance</b><br />Individually, cardiac, renal, and metabolic (CRM) conditions are common and leading causes of death, disability, and health care-associated costs. However, the frequency with which CRM conditions coexist has not been comprehensively characterized to date.<br /><b>Objective</b><br />To examine the prevalence and overlap of CRM conditions among US adults currently and over time.<br /><b>Design, setting, and participants</b><br />To establish prevalence of CRM conditions, nationally representative, serial cross-sectional data included in the January 2015 through March 2020 National Health and Nutrition Examination Survey (NHANES) were evaluated in this cohort study. To assess temporal trends in CRM overlap, NHANES data between 1999-2002 and 2015-2020 were compared. Data on 11 607 nonpregnant US adults (≥20 years) were included. Data analysis occurred between November 10, 2020, and November 23, 2022.<br /><b>Main outcomes and measures</b><br />Proportion of participants with CRM conditions, overall and stratified by age, defined as cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes (T2D), or all 3.<br /><b>Results</b><br />From 2015 through March 2020, of 11 607 US adults included in the analysis (mean [SE] age, 48.5 [0.4] years; 51.0% women), 26.3% had at least 1 CRM condition, 8.0% had at least 2 CRM conditions, and 1.5% had 3 CRM conditions. Overall, CKD plus T2D was the most common CRM dyad (3.2%), followed by CVD plus T2D (1.7%) and CVD plus CKD (1.6%). Participants with higher CRM comorbidity burden were more likely to be older and male. Among participants aged 65 years or older, 33.6% had 1 CRM condition, 17.1% had 2 CRM conditions, and 5.0% had 3 CRM conditions. Within this subset, CKD plus T2D (7.3%) was most common, followed by CVD plus CKD (6.0%) and CVD plus T2D (3.8%). The CRM comorbidity burden was disproportionately high among participants reporting non-Hispanic Black race or ethnicity, unemployment, low socioeconomic status, and no high school degree. Among participants with 3 CRM conditions, nearly one-third (30.5%) did not report statin use, and only 4.8% and 3.0% used glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, respectively. Between 1999 and 2020, the proportion of US adults with multiple CRM conditions increased significantly (from 5.3% to 8.0%; P < .001 for trend), as did the proportion having all 3 CRM conditions (0.7% to 1.5%; P < .001 for trend).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />This cohort study found that CRM multimorbidity is increasingly common and undertreated among US adults, highlighting the importance of collaborative and comprehensive management strategies.<br /><br /><br /><br /><small>JAMA Cardiol: 27 Sep 2023; epub ahead of print</small></div>

<div><h4>Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management.</h4><i>Bhatt AS, Vaduganathan M, Claggett BL, Fonarow GC, ... Solomon SD, Gaziano TA</i><br /><b>Importance</b><br />The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown.<br /><b>Objective</b><br />To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF.<br /><b>Design, setting, and participants</b><br />This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023.<br /><b>Main outcomes and measures</b><br />A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs.<br /><b>Results</b><br />Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.<br /><br /><br /><br /><small>JAMA Cardiol: 27 Sep 2023; epub ahead of print</small></div>

<div><h4>Repurposing the β3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial.</h4><i>Balligand JL, Brito D, Brosteanu O, Casadei B, ... Wachter R, Pouleur AC</i><br /><b>Importance</b><br />Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The β3-adrenergic receptors (β3ARs) may represent a new target, as their activation attenuates LV remodeling.<br /><b>Objective</b><br />To determine whether activation of β3ARs by repurposing a β3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF.<br /><b>Design, setting, and participants</b><br />The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022.<br /><b>Intervention</b><br />Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months.<br /><b>Main outcomes and measures</b><br />The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e\'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication.<br /><b>Results</b><br />Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e\' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial.<br /><b>Conclusions</b><br />In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT02599480.<br /><br /><br /><br /><small>JAMA Cardiol: 20 Sep 2023; epub ahead of print</small></div>

<div><h4>Deep Learning for Cardiovascular Imaging: A Review.</h4><i>Wehbe RM, Katsaggleos AK, Hammond KJ, Hong H, ... McCarthy PM, Thomas JD</i><br /><b>Importance</b><br />Artificial intelligence (AI), driven by advances in deep learning (DL), has the potential to reshape the field of cardiovascular imaging (CVI). While DL for CVI is still in its infancy, research is accelerating to aid in the acquisition, processing, and/or interpretation of CVI across various modalities, with several commercial products already in clinical use. It is imperative that cardiovascular imagers are familiar with DL systems, including a basic understanding of how they work, their relative strengths compared with other automated systems, and possible pitfalls in their implementation. The goal of this article is to review the methodology and application of DL to CVI in a simple, digestible fashion toward demystifying this emerging technology.<br /><b>Observations</b><br />At its core, DL is simply the application of a series of tunable mathematical operations that translate input data into a desired output. Based on artificial neural networks that are inspired by the human nervous system, there are several types of DL architectures suited to different tasks; convolutional neural networks are particularly adept at extracting valuable information from CVI data. We survey some of the notable applications of DL to tasks across the spectrum of CVI modalities. We also discuss challenges in the development and implementation of DL systems, including avoiding overfitting, preventing systematic bias, improving explainability, and fostering a human-machine partnership. Finally, we conclude with a vision of the future of DL for CVI.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Deep learning has the potential to meaningfully affect the field of CVI. Rather than a threat, DL could be seen as a partner to cardiovascular imagers in reducing technical burden and improving efficiency and quality of care. High-quality prospective evidence is still needed to demonstrate how the benefits of DL CVI systems may outweigh the risks.<br /><br /><br /><br /><small>JAMA Cardiol: 20 Sep 2023; epub ahead of print</small></div>

<div><h4>Longer-Term Efficacy and Safety of Evinacumab in Patients With Refractory Hypercholesterolemia.</h4><i>Rosenson RS, Burgess LJ, Ebenbichler CF, Baum SJ, ... Gaudet D, Pordy R</i><br /><b>Importance</b><br />Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD).<br /><b>Objective</b><br />To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia.<br /><b>Design, setting, and participants</b><br />This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period. Patients from 85 sites across 20 countries were recruited for the study; patients with primary hypercholesterolemia (defined as heterozygous familial hypercholesterolemia or established clinical ASCVD without familial hypercholesterolemia) who entered the 48-week OLTP were included. In addition, the patients\' hypercholesterolemia was refractory to maximally tolerated LLTs.<br /><b>Interventions</b><br />All patients entering the OLTP received evinacumab, 15 mg/kg, intravenously Q4W.<br /><b>Main outcomes and measures</b><br />Efficacy outcomes included change in LDL-C level and other lipid/lipoprotein parameters from baseline to week 72 (end of the OLTP). Safety outcomes included assessment of treatment-emergent adverse events (TEAEs).<br /><b>Results</b><br />A total of 96 patients (mean [SD] age, 54.4 [11.3] years; 52 female [54.2%]) entered the OLTP, of whom 88 (91.7%) completed the OLTP. Mean (SD) baseline LDL-C level was 145.9 (55.2) mg/dL. At week 72, evinacumab, 15 mg/kg, reduced mean (SD) LDL-C level from baseline by 45.5% (28.7%) in the overall cohort. Evinacumab, 15 mg/kg, reduced mean (SD) apolipoprotein B (38.0% [22.1%]), non-high density lipoprotein cholesterol (48.4% [23.2%]), total cholesterol (42.6% [17.5%]), and median (IQR) fasting triglyceride (57.2% [65.4%-44.4%]) levels at week 72 from baseline in the overall cohort. TEAEs occurred in 78 of 96 patients (81.3%). Serious TEAEs occurred in 9 of 96 patients (9.4%); all were considered unrelated to study treatment.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In patients with refractory hypercholesterolemia, evinacumab provided sustained reductions in LDL-C level and was generally well tolerated.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03175367.<br /><br /><br /><br /><small>JAMA Cardiol: 13 Sep 2023; epub ahead of print</small></div>

<div><h4>Long-Term Quality of Life After Out-of-Hospital Cardiac Arrest.</h4><i>Yonis H, Sørensen KK, Bøggild H, Ringgren KB, ... Torp-Pedersen C, Kragholm K</i><br /><b>Importance</b><br />Allocating resources to increase survival after cardiac arrest requires survivors to have a good quality of life, but long-term data are lacking.<br /><b>Objective</b><br />To determine the quality of life of survivors of out-of-hospital cardiac arrest from 2001 to 2019.<br /><b>Design, setting, and participants</b><br />This survey study used the EuroQol Health Questionnaire, 12-Item Short Form Health Survey (SF-12), and Hospital Anxiety and Depression Scale (HADS) to assess the health-related quality of life of all adult survivors of out-of-hospital cardiac arrest included in the Danish Cardiac Arrest Registry between June 1, 2001, and August 31, 2019, who were alive in October 2020 (follow-up periods, 0-1, >1-2, >2-4, >4-6, >6-8, >8-10, >10-15, and >15-20 years since arrest). The survey was conducted from October 1, 2020, through May 31, 2021.<br /><b>Exposure</b><br />All patients who experienced an out-of-hospital cardiac arrest.<br /><b>Main outcome and measures</b><br />Self-reported health was measured using the EuroQol Health Questionnaire index (EQ index) score and EQ visual analog scale. Physical and mental health were measured using the SF-12, and anxiety and depression were measured using the HADS. Descriptive statistics were used for the analysis.<br /><b>Results</b><br />Of 4545 survivors, 2552 (56.1%) completed the survey, with a median follow-up since their event of 5.5 years (IQR, 2.9-8.9 years). Age was comparable between responders and nonresponders (median [IQR], 67 [58-74] years vs 68 [56-78] years), and 2075 responders (81.3%) were men and 477 (18.7%) women (vs 1473 male [73.9%] and 520 female [26.1%] nonresponders). For the shortest follow-up (0-1 year) and longest follow-up (>15-20 years) groups, the median EQ index score was 0.9 (IQR, 0.7-1.0) and 0.9 (0.8-1.0), respectively. For all responders, the mean (SD) SF-12 physical health score was 43.3 (12.3) and SF-12 mental health score, 52.9 (8.3). All 3 scores were comparable to a general Danish reference population. Based on HADS scores, a low risk for anxiety was reported by 73.0% (54 of 74) of 0- to 1-year survivors vs 89.3% (100 of 112) of greater than 15- to 20-year survivors; for symptoms of depression, these proportions were 79.7% (n = 59) and 87.5% (n = 98), respectively. Health-related quality of life was similar in survivor groups across all follow-up periods.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among this survey study\'s responders, who comprised more than 50% of survivors of out-of-hospital cardiac arrest in Denmark, long-term health-related quality of life up to 20 years after their event was consistently high and comparable to that of the general population. These findings support resource allocation and efforts targeted to increasing survival after out-of-hospital cardiac arrest.<br /><br /><br /><br /><small>JAMA Cardiol: 13 Sep 2023; epub ahead of print</small></div>

<div><h4>Fractional Flow Reserve-Negative High-Risk Plaques and Clinical Outcomes After Myocardial Infarction.</h4><i>Mol JQ, Volleberg RHJA, Belkacemi A, Hermanides RS, ... van Geuns RM, van Royen N</i><br /><b>Importance</b><br />Even after fractional flow reserve (FFR)-guided complete revascularization, patients with myocardial infarction (MI) have high rates of recurrent major adverse cardiovascular events (MACE). These recurrences may be caused by FFR-negative high-risk nonculprit lesions.<br /><b>Objective</b><br />To assess the association between optical coherence tomography (OCT)-identified high-risk plaques of FFR-negative nonculprit lesions and occurrence of MACE in patients with MI.<br /><b>Design, setting, and participants</b><br />PECTUS-obs (Identification of Risk Factors for Acute Coronary Events by OCT After STEMI [ST-segment elevation MI] and NSTEMI [non-STEMI] in Patients With Residual Non-flow Limiting Lesions) is an international, multicenter, prospective, observational cohort study. In patients presenting with MI, OCT was performed on all FFR-negative (FFR > 0.80) nonculprit lesions. A high-risk plaque was defined containing at least 2 of the following prespecified criteria: (1) a lipid arc at least 90°, (2) a fibrous cap thickness less than 65 μm, and (3) either plaque rupture or thrombus presence. Patients were enrolled from December 14, 2018, to September 15, 2020. Data were analyzed from December 2, 2022, to June 28, 2023.<br /><b>Main outcome and measure</b><br />The primary end point of MACE, a composite of all-cause mortality, nonfatal MI, or unplanned revascularization, at 2-year follow-up was compared in patients with and without a high-risk plaque.<br /><b>Results</b><br />A total of 438 patients were enrolled, and OCT findings were analyzable in 420. Among included patients, mean (SD) age was 63 (10) years, 340 (81.0) were men, and STEMI and non-STEMI were equally represented (217 [51.7%] and 203 [48.3%]). A mean (SD) of 1.17 (0.42) nonculprit lesions per patient was imaged. Analysis of OCT images revealed at least 1 high-risk plaque in 143 patients (34.0%). The primary end point occurred in 22 patients (15.4%) with a high-risk plaque and 23 of 277 patients (8.3%) without a high-risk plaque (hazard ratio, 1.93 [95% CI, 1.08-3.47]; P = .02), primarily driven by more unplanned revascularizations in patients with a high-risk plaque (14 of 143 [9.8%] vs 12 of 277 [4.3%]; P = .02).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />Among patients with MI and FFR-negative nonculprit lesions, the presence of a high-risk plaque is associated with a worse clinical outcome, which is mainly driven by a higher number of unplanned revascularizations. In a population with a high recurrent event rate despite physiology-guided complete revascularization, these results call for research on additional pharmacological or focal treatment strategies in patients harboring high-risk plaques.<br /><br /><br /><br /><small>JAMA Cardiol: 13 Sep 2023; epub ahead of print</small></div>

<div><h4>Insulin Resistance and N-Terminal Pro-B-Type Natriuretic Peptide Among Healthy Adults.</h4><i>Echouffo-Tcheugui JB, Zhang S, McEvoy JW, Juraschek SP, ... Christenson RH, Selvin E</i><br /><b>Importance</b><br />It is unclear to what extent insulin resistance is associated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the general population after accounting for body composition.<br /><b>Objective</b><br />To characterize the association of insulin resistance with NT-proBNP independently of measures of body composition in US adults.<br /><b>Design, setting, and participants</b><br />In a cross-sectional design, data on participants aged 20 years or older were obtained from the 1999-2004 National Health and Nutrition Examination Survey with measures of NT-pro-BNP, body mass index (BMI), and dual energy x-ray absorptiometry (DEXA)-derived measures of body composition (fat and lean masses). Linear and logistic regression was used to characterize the associations of measures of body mass and composition (BMI, waist circumference, fat mass, and lean mass) with NT-proBNP, adjusting for cardiovascular risk factors. Linear regression was used to characterize the associations of homeostasis model assessment of insulin resistance [HOMA-IR] and NT-proBNP after adjusting for cardiovascular risk factors and body composition measures. The quantitative insulin sensitivity check index [QUICKI], triglyceride-glucose index [TyG index], insulin to glucose ratio [IGR], fasting insulin, and homeostasis model assessment of β-cell function (HOMA-β) were also examined. Data for this study were analyzed from August 10, 2022, to June 30, 2023.<br /><b>Main outcomes and measures</b><br />Adjusted changes in NT-proBNP by insulin resistance levels.<br /><b>Results</b><br />A total of 4038 adults without diabetes or cardiovascular disease were included (mean [SD] age, 44 years; 51.2% female; and 74.3% White). In sex-specific analyses, insulin resistance measures were inversely associated with NT-pro-BNP. After adjustment including cardiovascular risk factors, BMI, waist circumference, and DEXA-derived fat mass and lean mass, the percent change in NT-proBNP associated with an SD increase in HOMA-IR was -16.84% (95% CI, -21.23% to -12.21%) in women and -19.04% (95% CI, -24.14 to -13.59) in men. Similar associations were observed for other indices of insulin resistance, including QUICKI (women: 17.27; 95% CI, 10.92-23.99 vs men: 22.17; 95% CI, 15.27 to 29.48), TyG index women: -11.47; 95% CI, -16.12 to -6.57 vs men: -15.81; 95% CI, -20.40 to -10.95), IGR women: -15.15; 95% CI, -19.35 to -10.74 vs men: -16.61; 95% CI, -21.63 to -11.26), and fasting insulin (women: -16.32; 95% CI, -20.63 to -11.78 vs men: -18.22; 95% CI, -23.30 to -12.79), as well as HOMA-β (women: -10.71; 95% CI, -14.71 to -6.52 vs men: -11.72; 95% CI, -16.35 to -6.85).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In a national sample of US adults, insulin resistance was inversely associated with NT-proBNP, even after rigorously accounting for multiple measures of fat mass and lean mass. These results suggest that the mechanisms linking NT-proBNP to insulin resistance are partially independent of excess adiposity and may be associated with hyperinsulinemia.<br /><br /><br /><br /><small>JAMA Cardiol: 06 Sep 2023; epub ahead of print</small></div>

<div><h4>Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial.</h4><i>Vissing CR, Axelsson Raja A, Day SM, Russell MW, ... Ho CY, Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Investigators</i><br /><b>Importance</b><br />Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression.<br /><b>Objective</b><br />To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM.<br /><b>Design, setting, and participants</b><br />The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E\' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022.<br /><b>Interventions</b><br />Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years).<br /><b>Main outcomes and measures</b><br />The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E\' velocity and S\' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels).<br /><b>Results</b><br />This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT01912534.<br /><br /><br /><br /><small>JAMA Cardiol: 06 Sep 2023; epub ahead of print</small></div>

<div><h4>Childhood Parental Incarceration and Adult-Onset Hypertension and Cardiovascular Risk.</h4><i>Tung EL, Wroblewski KE, Makelarski JA, Glasser NJ, Lindau ST</i><br /><b>Importance</b><br />Parental incarceration is an adverse childhood experience that disproportionately affects racially minoritized individuals and has been associated with long-term health risks. Although cardiovascular disease remains the primary cause of mortality differences between Black and White individuals in the US, the association between parental incarceration and cardiovascular risk remains poorly understood.<br /><b>Objective</b><br />To examine the association between parental incarceration during childhood and incident cardiovascular risk in adulthood.<br /><b>Design, setting, and participants</b><br />This population-based cohort study included data from waves IV (2008-2009) and V (2016-2018) of the US National Longitudinal Study of Adolescent to Adult Health. Participants represented US adults transitioning from young adulthood to adulthood. Data were analyzed from October 28, 2021, to May 1, 2023.<br /><b>Main outcomes and measures</b><br />Parental incarceration was defined as a parent or parent-like figure going to jail or prison when participants were aged younger than 18 years. Outcome measures included self-reported diagnoses of obesity, hyperlipidemia, hypertension, diabetes, or heart disease as well as serum elevations in non-high-density lipoprotein cholesterol (≥160 mg/dL) and high-sensitivity C-reactive protein (hsCRP >3 mg/L), a marker of inflammation used to estimate risk of future coronary events. Using sampling weights, incident development of each outcome was modeled as a function of parental incarceration, adjusting for participant- and neighborhood-level characteristics.<br /><b>Results</b><br />This study included 9629 participants representing 16 077 108 US adults. Approximately half of participants were women (5498 [weighted 50.3%]) and the majority (5895 [weighted 71.4%]) were White. The mean participant age was 37.8 years (95% CI, 37.5 to 38.0 years) in wave V compared with 28.9 years (95% CI, 28.6 to 29.1 years) in wave IV. In wave V, those with childhood exposure to parental incarceration had lower educational attainment (91 [weighted 8.2%] vs 245 [weighted 4.2%] completing less than high school), had higher rates of public insurance (257 [weighted 20.6%] vs 806 [weighted 11.0%]), and were disproportionately Black (374 [weighted 22.5%] vs 1488 [weighted 13.6%]). Parental incarceration was associated with 33% higher adjusted odds (95% CI, 1.05 to 1.68) of developing hypertension and 60% higher adjusted odds (95% CI, 1.03 to 2.48) of developing elevated hsCRP. Associations between childhood parental incarceration and other diagnoses (ie, obesity, hyperlipidemia, diabetes, or heart disease) and serum lipid levels were not observed.<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this cohort study of US adults transitioning from young adulthood to adulthood, an increased incidence of hypertension and high-risk hsCRP, but not other cardiovascular risk factors, was observed among those exposed to parental incarceration during childhood. These findings suggest possible transgenerational health consequences of mass incarceration.<br /><br /><br /><br /><small>JAMA Cardiol: 30 Aug 2023; epub ahead of print</small></div>

<div><h4>Modification of the GRACE Risk Score for Risk Prediction in Patients With Acute Coronary Syndromes.</h4><i>Georgiopoulos G, Kraler S, Mueller-Hennessen M, Delialis D, ... Stellos K, Stamatelopoulos K</i><br /><b>Importance</b><br />The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury.<br /><b>Objective</b><br />To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury.<br /><b>Design, setting, and participants</b><br />This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023.<br /><b>Exposures</b><br />In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE).<br /><b>Main outcomes and measures</b><br />The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event.<br /><b>Results</b><br />Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.<br /><br /><br /><br /><small>JAMA Cardiol: 30 Aug 2023; epub ahead of print</small></div>

<div><h4>Atherosclerotic Coronary Plaque Regression and Risk of Adverse Cardiovascular Events: A Systematic Review and Updated Meta-Regression Analysis.</h4><i>Iatan I, Guan M, Humphries KH, Yeoh E, Mancini GBJ</i><br /><b>Importance</b><br />The association between changes in atherosclerotic plaque induced by lipid-lowering therapies (LLTs) and reduction in major adverse cardiovascular events (MACEs) remains controversial.<br /><b>Objective</b><br />To evaluate the association between coronary plaque regression assessed by intravascular ultrasound (IVUS) and MACEs.<br /><b>Data sources</b><br />A comprehensive, systematic search of publications in PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was performed.<br /><b>Study selection</b><br />Clinical prospective studies of LLTs reporting change in percent atheroma volume (PAV) assessed by IVUS and describing MACE components were selected.<br /><b>Data extraction and synthesis</b><br />Reporting was performed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The association between mean change in PAV and MACEs was analyzed by meta-regression using mixed-effects, 2-level binomial logistic regression models, unadjusted and adjusted for clinical covariates, including mean age, baseline PAV, baseline low-density lipoprotein cholesterol level, and study duration.<br /><b>Main outcome and measures</b><br />Mean PAV change and MACE in intervention and comparator arms were assessed in an updated systematic review and meta-regression analysis of IVUS trials of LLTs that also reported MACEs.<br /><b>Results</b><br />This meta-analysis included 23 studies published between July 2001 and July 2022, including 7407 patients and trial durations ranging from 11 to 104 weeks. Mean (SD) patient age ranged from 55.8 (9.8) to 70.2 (7.6) years, and the number of male patients from 245 of 507 (48.3%) to 24 of 26 (92.3%). Change in PAV across 46 study arms ranged from -5.6% to 3.1%. The number of MACEs ranged from 0 to 72 per study arm (17 groups [37%] reported no events, 9 [20%] reported 1-2 events, and 20 [43%] reported ≥3 events). In unadjusted analysis, a 1% decrease in mean PAV was associated with 17% reduced odds of MACEs (unadjusted OR, 0.83; 95% CI, 0.71-0.98; P = .03), and with a 14% reduction in MACEs in adjusted analysis (adjusted OR, 0.86; 95% CI, 0.75-1.00; P = .050). Further adjustment for cardiovascular risk factors showed a 19% reduced risk (adjusted OR, 0.81; 95% CI, 0.68-0.96; P = .01) per 1% decrease in PAV. A 1% reduction of PAV change between intervention and comparator arms within studies was also associated with a significant 25% reduction in MACEs (OR, 0.75; 95% CI, 0.56-1.00; P = .046).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this meta-analysis, regression of atherosclerotic plaque by 1% was associated with a 25% reduction in the odds of MACEs. These findings suggest that change in PAV could be a surrogate marker for MACEs, but given the heterogeneity in the outcomes, additional data are needed.<br /><br /><br /><br /><small>JAMA Cardiol: 30 Aug 2023; epub ahead of print</small></div>