<div><h4>High-Sensitivity Cardiac Troponin I Enhances Preeclampsia Prediction Beyond Maternal Factors and the sFlt-1/PlGF Ratio.</h4><i>Bacmeister L, Goßling A, Buellesbach A, Birukov A, ... Westermann D, Zeller T</i><br /><b>Background</b><br />Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence.<br /><b>Methods</b><br />This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio.<br /><b>Results</b><br />Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; <i>P</i>=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence.<br /><b>Conclusions</b><br />These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.<br /><br /><br /><br /><small>Circulation: 19 Nov 2023; epub ahead of print</small></div>

<div><h4>Long-Term Mortality in Patients With Severe Hypercholesterolemia Phenotype From a Racial and Ethnically Diverse US Cohort.</h4><i>Miles J, Scotti A, Castagna F, Kuno T, ... Virani SS, Slipczuk L</i><br /><b>Background</b><br />Tools for mortality prediction in patients with the severe hypercholesterolemia phenotype (low-density lipoprotein cholesterol ≥190 mg/dL) are limited and restricted to specific racial and ethnic cohorts. We sought to evaluate the predictors of long-term mortality in a large racially and ethnically diverse US patient cohort with low-density lipoprotein cholesterol ≥190 mg/dL.<br /><b>Methods</b><br />We conducted a retrospective analysis of all patients with a low-density lipoprotein cholesterol ≥190 mg/dL seeking care at Montefiore from 2010 through 2020. Patients <18 years of age or with previous malignancy were excluded. The primary end point was all-cause mortality. Analyses were stratified by age, sex, and race and ethnicity. Patients were stratified by primary and secondary prevention. Cox regression analyses were used to adjust for demographic, clinical, and treatment variables.<br /><b>Results</b><br />A total of 18 740 patients were included (37% non-Hispanic Black, 30% Hispanic, 12% non-Hispanic White, and 2% non-Hispanic Asian patients). The mean age was 53.9 years, and median follow-up was 5.2 years. Both high-density lipoprotein cholesterol and body mass index extremes were associated with higher mortality in univariate analyses. In adjusted models, higher low-density lipoprotein cholesterol and triglyceride levels were associated with an increased 9-year mortality risk (adjusted hazard ratio [HR], 1.08 [95% CI, 1.05-1.11] and 1.04 [95% CI, 1.02-1.06] per 20-mg/dL increase, respectively). Clinical factors associated with higher mortality included male sex (adjusted HR, 1.31 [95% CI, 1.08-1.58]), older age (adjusted HR, 1.19 per 5-year increase [95% CI, 1.15-1.23]), hypertension (adjusted HR, 2.01 [95% CI, 1.57-2.57]), chronic kidney disease (adjusted HR, 1.68 [95% CI, 1.36-2.09]), diabetes (adjusted HR, 1.79 [95% CI, 1.50-2.15]), heart failure (adjusted HR, 1.51 [95% CI, 1.16-1.95]), myocardial infarction (adjusted HR, 1.41 [95% CI, 1.05-1.90]), and body mass index <20 kg/m<sup>2</sup> (adjusted HR, 3.36 [95% CI, 2.29-4.93]). A significant survival benefit was conferred by lipid-lowering therapy (adjusted HR, 0.57 [95% CI, 0.42-0.77]). In the primary prevention group, high-density lipoprotein cholesterol <40 mg/dL was independently associated with higher mortality (adjusted HR, 1.49 [95% CI, 1.06-2.09]). Temporal trend analyses showed a reduction in statin use over time (<i>P</i><0.001). In the most recent time period (2019-2020), 56% of patients on primary prevention and 85% of those on secondary prevention were on statin therapy.<br /><b>Conclusions</b><br />In a large, diverse cohort of US patients with the severe hypercholesterolemia phenotype, we identified several patient characteristics associated with increased 9-year all-cause mortality and observed a decrease in statin use over time, in particular for primary prevention. Our results support efforts geared toward early recognition and consistent treatment for patients with severe hypercholesterolemia.<br /><br /><br /><br /><small>Circulation: 15 Nov 2023; epub ahead of print</small></div>

<div><h4>2023 American Heart Association and American Academy of Pediatrics Focused Update on Neonatal Resuscitation: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.</h4><i>Yamada NK, Szyld E, Strand ML, Finan E, ... Lee HC, American Heart Association and American Academy of Pediatrics</i><br /><AbstractText>This 2023 focused update to the neonatal resuscitation guidelines is based on 4 systematic reviews recently completed under the direction of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. Systematic reviewers and content experts from this task force performed comprehensive reviews of the scientific literature on umbilical cord management in preterm, late preterm, and term newborn infants, and the optimal devices and interfaces used for administering positive-pressure ventilation during resuscitation of newborn infants. These recommendations provide new guidance on the use of intact umbilical cord milking, device selection for administering positive-pressure ventilation, and an additional primary interface for administering positive-pressure ventilation.</AbstractText><br /><br /><br /><br /><small>Circulation: 15 Nov 2023; epub ahead of print</small></div>

<div><h4>In Vivo Base Editing of Scn5a Rescues Type 3 Long QT Syndrome in Mice.</h4><i>Qi M, Ma S, Liu J, Liu X, ... Wang Y, Lan F</i><br /><b>Background</b><br />Pathogenic variants in <i>SCN5A</i> can result in long QT syndrome type 3, a life-threatening genetic disease. Adenine base editors can convert targeted A T base pairs to G C base pairs, offering a promising tool to correct pathogenic variants.<br /><b>Methods</b><br />We generated a long QT syndrome type 3 mouse model by introducing the T1307M pathogenic variant into the <i>Scn5a</i> gene. The adenine base editor was split into 2 smaller parts and delivered into the heart by adeno-associated virus serotype 9 (AAV9-ABEmax) to correct the T1307M pathogenic variant.<br /><b>Results</b><br />Both homozygous and heterozygous T1307M mice showed significant QT prolongation. Carbachol administration induced torsades de pointes or ventricular tachycardia for homozygous T1307M mice (20%) but not for heterozygous or wild-type mice. A single intraperitoneal injection of AAV9-ABEmax at postnatal day 14 resulted in up to 99.20% <i>Scn5a</i> transcripts corrected in T1307M mice. <i>Scn5a</i> mRNA correction rate >60% eliminated QT prolongation; <i>Scn5a</i> mRNA correction rate <60% alleviated QT prolongation. Partial <i>Scn5a</i> correction resulted in cardiomyocyte heterogeneity, which did not induce severe arrhythmias. We did not detect off-target DNA or RNA editing events in ABEmax-treated mouse hearts.<br /><b>Conclusions</b><br />These findings show that in vivo AAV9-ABEmax editing can correct the variant <i>Scn5a</i> allele, effectively ameliorating arrhythmia phenotypes. Our results offer a proof of concept for the treatment of hereditary arrhythmias.<br /><br /><br /><br /><small>Circulation: 14 Nov 2023; epub ahead of print</small></div>

<div><h4>Stimulates Short-Chain Dehydrogenase/Reductase Proteins to Alleviate Heart Failure Independent of Mitochondrial Protein Deacetylation.</h4><i>Walker MA, Chen H, Yadav A, Ritterhoff J, ... Isoherranen N, Tian R</i><br /><b>Background</b><br />Strategies to increase cellular NAD<sup>+</sup> (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the benefits of NAD<sup>+</sup>-based therapies in failing hearts after the symptoms of heart failure have appeared. Most pretreatment regimens suggested mechanisms involving activation of sirtuin, especially Sirt3 (sirtuin 3), and mitochondrial protein acetylation.<br /><b>Methods</b><br />We induced cardiac dysfunction by pressure overload in SIRT3-deficient (knockout) mice and compared their response with nicotinamide riboside chloride treatment with wild-type mice. To model a therapeutic approach, we initiated the treatment in mice with established cardiac dysfunction and found nicotinamide riboside chloride improved mitochondrial function and blunted heart failure progression. Similar benefits were observed in wild-type and knockout mice. Boosting NAD<sup>+</sup> level improved the function of NAD(H) redox-sensitive SDR (short-chain dehydrogenase/reductase) family proteins. Upregulation of Mrpp2 (mitochondrial ribonuclease P protein 2), a multifunctional SDR protein and a subunit of mitochondrial ribonuclease P, improves mitochondrial DNA transcripts processing and electron transport chain function. Activation of SDRs in the retinol metabolism pathway stimulates RXRα (retinoid X receptor α)/PPARα (proliferator-activated receptor α) signaling and restores mitochondrial oxidative metabolism. Downregulation of Mrpp2 and impaired mitochondrial ribonuclease P were found in human failing hearts, suggesting a shared mechanism of defective mitochondrial biogenesis in mouse and human heart failure.<br /><b>Conclusions</b><br />These findings identify SDR proteins as important regulators of mitochondrial function and molecular targets of NAD<sup>+</sup>-based therapy. Furthermore, the benefit is observed regardless of Sirt3-mediated mitochondrial protein deacetylation, a widely held mechanism for NAD<sup>+</sup>-based therapy for heart failure. The data also show that NAD<sup>+</sup>-based therapy can be useful in pre-existing heart failure.<br /><br /><br /><br /><small>Circulation: 14 Nov 2023; epub ahead of print</small></div>

<div><h4>Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.</h4><i>Xu W, Billon C, Li H, Wilderman A, ... Burris T, Zhang L</i><br /><b>Background</b><br />Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available.<br /><b>Methods</b><br />Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity.<br /><b>Results</b><br />Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes.<br /><b>Conclusions</b><br />ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.<br /><br /><br /><br /><small>Circulation: 13 Nov 2023; epub ahead of print</small></div>

<div><h4>Effect of Mavacamten in Women Compared With Men With Obstructive Hypertrophic Cardiomyopathy: Insights From EXPLORER-HCM.</h4><i>Cresci S, Bach RG, Saberi S, Owens AT, ... Sehnert AJ, Wang A</i><br /><b>Background</b><br />Compared with men, women with hypertrophic cardiomyopathy (HCM) have a higher incidence of heart failure and worse outcomes. We investigated baseline clinical and echocardiographic characteristics and response to mavacamten among women compared with men in the EXPLORER-HCM study (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy).<br /><b>Methods</b><br />A prespecified post hoc analysis of sex from the blinded, randomized EXPLORER-HCM trial of mavacamten versus placebo in symptomatic patients with obstructive HCM was performed. Baseline characteristics were compared with <i>t</i> tests for continuous variables (expressed as mean values) and χ<sup>2</sup> tests for categorical variables. Prespecified primary, secondary, and exploratory end points and echocardiographic measurements from baseline to end of treatment (week 30) were analyzed with ANCOVA for continuous end points and a generalized linear model with binomial distribution for binary end points, with adjustment for the baseline of each outcome, New York Heart Association class, β-blocker use, and ergometer type.<br /><b>Results</b><br />At baseline, women (n=102) were older (62 years versus 56 years; <i>P</i><0.0001), had lower peak oxygen consumption (16.7 mL·kg<sup>-1</sup>·min<sup>-1</sup> versus 21.3 mL·kg<sup>-1</sup>·min<sup>-1</sup>; <i>P</i><0.0001), were more likely to be assigned New York Heart Association class III (42% versus 17%; <i>P</i><0.0001), had worse health status (Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score 64 versus 75; <i>P</i><0.0001), and had higher baseline plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels (1704 ng/L versus 990 ng/L; <i>P</i>=0.004) than men (n=149). After 30 weeks of mavacamten treatment, similar improvements were observed in women and men in the primary composite end point (percentage difference on mavacamten versus placebo, 22% versus 19%, respectively; <i>P</i>=0.759) and in the secondary end points of change in postexercise left ventricular outflow tract gradient (-42.4 mm Hg versus -33.6 mm Hg; <i>P</i>=0.348), change in peak oxygen consumption (1.2 mL·kg<sup>-1</sup>·min<sup>-1</sup> versus 1.6 mL·kg<sup>-1</sup>·min<sup>-1</sup>; <i>P</i>=0.633), and percentage achieving ≥1 New York Heart Association class improvement (41% versus 28%; <i>P</i>=0.254). However, women had greater improvement in health status (Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score 14.8 versus 6.1; <i>P</i>=0.026) and in the exploratory end point of NT-proBNP levels (-1322 ng/L versus -649 ng/L; <i>P</i>=0.0008).<br /><b>Conclusions</b><br />Although at baseline women with symptomatic obstructive HCM enrolled in EXPLORER-HCM were older and had worse heart failure and health status than men, treatment with mavacamten resulted in similar improvements in the primary and most secondary EXPLORER-HCM end points and greater improvements in health status and NT-proBNP.<br /><b>Registration</b><br />https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03470545.<br /><br /><br /><br /><small>Circulation: 13 Nov 2023; epub ahead of print</small></div>

<div><h4>Lifestyle Walking Intervention in Patients With Heart Failure With Reduced Ejection Fraction: The WATCHFUL Trial.</h4><i>Vetrovsky T, Siranec M, Frybova T, Gant I, ... Belohlavek J, WATCHFUL Investigators</i><br /><AbstractText><b>Background:</b> Physical activity is pivotal in managing heart failure with reduced ejection fraction (HFrEF), and walking integrated into daily life is an especially suitable form of such physical activity. This study aimed to determine if a 6-month lifestyle walking intervention combining self-monitoring and regular phone counseling improves functional capacity assessed by the six-minute walk test (6MWT) in stable patients with HFrEF compared to usual care. <br /><b>Methods:</b><br/>The WATCHFUL trial was a 6-month, multicenter, parallel-group, randomized, controlled trial recruiting HFrEF patients from six Czech cardiovascular centers. Eligible participants were ≥18 years old with left ventricular ejection fraction <40% and NYHA class II/III symptoms, on guidelines-recommended medication, excluding those exceeding 450m in the baseline 6MWT. Patients in the intervention group were equipped with a Garmin vívofit activity tracker and received monthly phone counseling from research nurses who encouraged them to employ behavior change techniques such as self-monitoring, goal-setting, and action planning to increase their daily step count. The control group patients continued usual care. The primary outcome was the difference between groups in the distance (in meters) walked during the 6MWT at 6 months. Secondary outcomes included daily step count and minutes of moderate-to-vigorous physical activity (MVPA) as measured by the hip-worn Actigraph wGT3X-BT accelerometer, NT-proBNP and hsCRP biomarkers, ejection fraction, anthropometric measures, depression score, self-efficacy, quality of life, and survival risk score. The primary analysis was conducted by intention-to-treat. <br /><b>Results:</b><br/>From 218 screened patients, 202 were randomized (65 years; 22.8% female; 90.6% NYHA II; left ventricular ejection fraction 32.5%; 6MWT 385m; 5071 steps/day; 10.9 minutes of MVPA per day). At six months, no between-group differences were detected for the 6MWT (7.4 m, 95% CI -8.0 to 22.7, p=0.345, N=186). The intervention group increased their average daily step count by 1420 (95% CI: 749; 2091) and daily minutes of MVPA by 8.2 (95% CI: 3.0; 13.3) over the control group. No between-group differences were detected for any other secondary outcomes. <b>Conclusions:</b> While the lifestyle intervention in patients with HFrEF improved daily steps by about 25%, it failed to demonstrate a corresponding improvement in functional capacity. Further research is needed to understand the disconnect between increased physical activity and functional outcomes.</AbstractText><br /><br /><br /><br /><small>Circulation: 12 Nov 2023; epub ahead of print</small></div>

<div><h4>Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study.</h4><i>Petek BJ, Churchill TW, Moulson N, Kliethermes SA, ... Maleszewski JJ, Harmon KG</i><br /><AbstractText><b>Background:</b> Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. <br /><b>Methods:</b><br/>This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. <br /><b>Results:</b><br/>A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63682 athlete-years (95% CI, 1:54065-1:75010). Incidence was higher in male athletes than in female athletes (1:43348 [95% CI, 1:36228-1:51867] versus 1:164504 [95% CI, 1:110552-1:244787] athlete-years, respectively) and Black athletes compared with White athletes (1:26704 [1:20417-1:34925] versus 1:74581 [1:60247-1:92326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61-0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94-1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). <b>Conclusions:</b> The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.</AbstractText><br /><br /><br /><br /><small>Circulation: 12 Nov 2023; epub ahead of print</small></div>

<div><h4>Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients with Heart Failure with Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial.</h4><i>Kosiborod MN, Verma S, Borlaug BA, Butler J, ... Abhayaratna W, Kitzman DW</i><br /><AbstractText><b>Background:</b> Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial, once-weekly semaglutide 2.4 mg improved symptoms, physical limitations and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary endpoints across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline; and on all key summary and individual KCCQ domains. <br /><b>Methods:</b><br/>STEP-HFpEF randomized 529 participants with symptomatic HF, EF ≥45% and BMI of ≥30 kg/m<sup>2</sup> to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary endpoints were change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary endpoints included change in 6-minute-walk-distance (6MWD), a hierarchical composite endpoint (death, HF events and change in KCCQ-CSS and 6MWD) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary and select exploratory endpoints (NTproBNP) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. <br /><b>Results:</b><br/>Baseline median KCCQ-CSS across tertiles was 37, 59 and 77 points, respectively. Semaglutide consistently improved primary endpoints across KCCQ tertiles 1-3 (estimated treatment differences (ETD;95% CI): for KCCQ-CSS, 10.7 (5.4,16.1), 8.1 (2.7,13.4), 4.6 (-0.6,9.9) points; for body weight, -11 (-13.2,-8.8), -9.4 (-11.5,-7.2), -11.8 (-14.0,-9.6)%, respectively; P<i>interaction</i>=0.28 and 0.29, respectively); same was observed for, confirmatory secondary and exploratory endpoints (P<i>interaction</i>>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (ETD: 6.7-9.6 points across domains; <i>P</i>≤0.001 for all). Greater proportion of semaglutide- versus placebo-treated patients experienced at least 5-, 10-, 15- and 20-point improvements in all KCCQ domains (Odds Ratios: 1.6-2.9 across domains; <i>P</i><0.05 for all). <b>Conclusions:</b> In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight and NTproBNP regardless of baseline health status. Benefits of semaglutide extended to all key KCCQ domains.</AbstractText><br /><br /><br /><br /><small>Circulation: 11 Nov 2023; epub ahead of print</small></div>

<div><h4>Direct Oral Anticoagulants for Stroke Prevention in Patients with Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials.</h4><i>McIntyre WF, Benz AP, Becher N, Healey JS, ... Kirchhof P, Lopes RD</i><br /><AbstractText><b>Background:</b> Device-detected atrial fibrillation (AF) (also known as subclinical AF or atrial high-rate episodes) is a common finding in patients with an implanted cardiac rhythm device and is associated with an increased risk of ischemic stroke. Whether oral anticoagulation is effective and safe in this patient population is unclear. <br /><b>Methods:</b><br/>We performed a systematic review of MEDLINE and Embase for randomized trials comparing oral anticoagulation to antiplatelet or no antithrombotic therapy in adults with device-detected AF recorded by a pacemaker, implantable cardioverter-defibrillator, cardiac resynchronization therapy device or implanted cardiac monitor. We used random-effects models for meta-analysis and rated the quality of evidence using the GRADE framework. The review was pre-registered (PROSPERO CRD42023463212). <br /><b>Results:</b><br/>From 785 unique citations, we identified two randomized trials with relevant clinical outcome data; NOAH-AFNET 6 (2,536 participants) evaluated edoxaban and ARTESiA (4,012 participants) evaluated apixaban. Meta-analysis demonstrated that oral anticoagulation with these agents reduced ischemic stroke (relative risk [RR] 0.68, 95% confidence interval [CI] 0.50-0.92; high-quality evidence). The results from the two trials were consistent (I<sup>2</sup> statistic for heterogeneity=0%). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction or pulmonary embolism (RR 0.85, 95% CI 0.73-1.00, I<sup>2</sup>=0%; moderate-quality evidence). There was no reduction in cardiovascular death (RR 0.95, 95% CI 0.76-1.17, I<sup>2</sup>=0%; moderate-quality evidence) or all-cause mortality (RR 1.08, 95% CI 0.96-1.21 I<sup>2</sup>=0%; moderate-quality evidence). Oral anticoagulation increased major bleeding (RR 1.62, 95% CI 1.05-2.5 I<sup>²</sup>=61%; high-quality evidence). <b>Conclusions:</b> The results of the NOAH-AFNET 6 and ARTESiA trials are consistent with each other. Meta-analysis of these two large randomized trials provides high-quality evidence that oral anticoagulation with edoxaban or apixaban reduces the risk of stroke in patients with device-detected AF and increases the risk of major bleeding.</AbstractText><br /><br /><br /><br /><small>Circulation: 11 Nov 2023; epub ahead of print</small></div>

<div><h4>Bag-Valve-Mask Ventilation and Survival from Out-of-Hospital Cardiac Arrest: A Multicenter Study.</h4><i>Idris AH, Aramendi Ecenarro E, Leroux B, Jaureguibeitia X, ... Blackwood J, Wang HE</i><br /><AbstractText><b>Background:</b> Few studies have measured ventilation during early cardiopulmonary resuscitation (CPR) before advanced airway placement. Resuscitation guidelines recommend pauses after every 30 chest compressions to deliver ventilations. The effectiveness of bag-valve-mask ventilation delivered during the pause in chest compressions is unknown. We sought to determine: (1) the incidence of lung inflation with bag-valve-mask ventilation during 30:2 CPR; and (2) the association of ventilation with outcomes after out-of-hospital cardiac arrest. <br /><b>Methods:</b><br/>We studied patients with out-of-hospital cardiac arrest from 6 sites of the Resuscitation Outcomes Consortium CCC study (Trial of Continuous Compressions versus Standard CPR in Patients with Out-of-Hospital Cardiac Arrest). We analyzed patients assigned to the 30:2 CPR arm with ≥2 minutes of thoracic bioimpedance signal recorded with a cardiac defibrillator/monitor. Detectable ventilation waveforms were defined as having a bioimpedance amplitude ≥0.5 Ω (corresponding to ≥250 mL V<sub>T</sub> ) and a duration ≥1 s. We defined a chest compression pause as a 3- to 15-s break in chest compressions. We compared the incidence of ventilation and outcomes in 2 groups: patients with ventilation waveforms in <50% of pauses (group 1) versus those with waveforms in ≥50% of pauses (group 2). <br /><b>Results:</b><br/>Among 1976 patients, the mean age was 65 years; 66% were male. From the start of chest compressions until advanced airway placement, mean±SD duration of 30:2 CPR was 9.8±4.9 minutes. During this period, we identified 26861 pauses in chest compressions; 60% of patients had ventilation waveforms in <50% of pauses (group 1, n=1177), and 40% had waveforms in ≥50% of pauses (group 2, n=799). Group 1 had a median of 12 pauses and 2 ventilations per patient versus group 2, which had 12 pauses and 12 ventilations per patient. Group 2 had higher rates of prehospital return of spontaneous circulation (40.7% versus 25.2%; <i>P</i><0.0001), survival to hospital discharge (13.5% versus 4.1%; <i>P</i><0.0001), and survival with favorable neurological outcome (10.6% versus 2.4%; <i>P</i><0.0001). These associations persisted after adjustment for confounders. <b>Conclusions:</b> In this study, lung inflation occurred infrequently with bag-valve-mask ventilation during 30:2 CPR. Lung inflation in ≥50% of pauses was associated with improved return of spontaneous circulation, survival, and survival with favorable neurological outcome.</AbstractText><br /><br /><br /><br /><small>Circulation: 11 Nov 2023; epub ahead of print</small></div>

<div><h4>Estimated Lifetime Cardiovascular, Kidney and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Non-steroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria.</h4><i>Neuen BL, Heerspink HJL, Vart P, Claggett BL, ... Solomon SD, Vaduganathan M</i><br /><AbstractText><b>Background:</b> Sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone all individually reduce cardiovascular, kidney and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known. <br /><b>Methods:</b><br/>We used data from 2 SGLT2i trials (CANVAS and CREDENCE), 2 non-steroidal MRA trials (FIDELIO-DKD and FIGARO-DKD) and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA and non-steroidal MRA in patients with type 2 diabetes and at lease moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE. <br /><b>Results:</b><br/>Compared to conventional care, combination SGLT2i, GLP-1 RA and non-steroidal MRA was associated with a hazard ratio of 0.65 (95% CI 0.55-0.76) for major adverse cardiovascular events (MACE; nonfatal myocardial infarction, nonfatal stroke or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI 3.0-5.7) with a number-needed-to-treat of 23 (95% CI 18-33). For a 50-year-old commencing combination therapy, estimated MACE event-free survival was 21.1 years compared to 17.9 years for conventional care (3.2 years gained, 95% CI 2.1-4.3). There were also projected gains in survival free from hospitalized heart failure (3.2 years, 95% CI 2.4-4.0), CKD progression (5.5 years, 95% CI 4.0-6.7), cardiovascular death (2.2 years, 95% CI 1.2-3.0) and all-cause death (2.4 years, 95% CI 1.4-3.4). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for MACE (2.4 years, 95% CI 1.1-3.5), CKD progression (4.5 years, 95% CI 2.8-5.9),) and all-cause death (1.8 years, 95% CI 0.7-2.8). <b>Conclusions:</b> In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment with SGLT2i, GLP-1 RA and non-steroidal MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.</AbstractText><br /><br /><br /><br /><small>Circulation: 11 Nov 2023; epub ahead of print</small></div>

<div><h4>Arrhythmic Risk In Biventricular Pacing Compared with Left Bundle Branch Area Pacing: Results From The International LBBAP Collaborative Study (I-CLAS).</h4><i>Herweg B, Sharma PS, Cano O, Ponnusamy SS, ... Ellenbogen KA, Vijayaraman P</i><br /><AbstractText><b>Background:</b> Left bundle branch area pacing (LBBAP) may be associated with greater improvement in left ventricular ejection fraction and reduction in death or heart failure hospitalization when compared with biventricular pacing (BVP) in patients requiring cardiac resynchronization therapy (CRT). We sought to compare the occurrence of sustained ventricular tachycardia or ventricular fibrillation (VT/VF) and new onset atrial fibrillation (AF) in patients undergoing BVP and LBBAP. <br /><b>Methods:</b><br/>This International Collaborative LBBAP Study (I-CLAS) included patients with LVEF≤35% who underwent BVP or LBBAP for CRT between Jan 2018 to June 2022 at 15 centers. We performed propensity score matched (PS) analysis of LBBAP and BVP in a 1:1 ratio. We assessed the incidence of VT/VF and new-onset AF among patients with no prior history of AF. Time to sustained VT/VF and time to new-onset AF was analyzed using Cox proportional hazards survival model. <br /><b>Results:</b><br/>Among 1778 patients undergoing CRT (981-BVP, 797-LBBAP), PS matched 1414 patients (PS-BVP:707, PS-LBBAP:707). The occurrence of VT/VF was significantly lower with LBBAP compared with BVP (4.2% vs 9.3%;HR 0.46;95%CI 0.29-0.74;p<0.001). The incidence of VT storm (>3 episodes in 24 hours) was also significantly lower with LBBAP compared with BVP (0.8% vs 2.5%;p=0.013). Among 299 patients with CRT-pacemakers (BVP-111, LBBAP-188), VT/VF occurred in 8 patients in the BVP group vs. none in the LBBAP group (7.2% vs 0%;p<0.001). In 1194 patients with no prior history of VT/VF or antiarrhythmic therapy (BVP-591, LBBAP-603), the occurrence of VT/VF was significantly lower with LBBAP compared with BVP (3.2% vs 7.3%;HR 0.46;95%CI 0.26-0.81;p=0.007). Among patients with no prior history of AF (n=890), the occurrence of new-onset AF >30 seconds was significantly lower with LBBAP compared with BVP (2.8% vs 6.6%;HR 0.34;95%CI 0.16-0.73;p=0.008). The incidence of AF lasting >24 hours was also significantly lower with LBBAP compared with BVP (0.7% vs 2.9%;p=0.015). <b>Conclusions:</b> LBBAP was associated with lower incidence of sustained VT/VF and new-onset AF compared with BVP. This difference remained significant after adjustment for differences in baseline characteristics between patients with BVP and LBBAP. Physiologic resynchronization by LBBAP may be associated with lower risk of arrhythmias compared with BVP.</AbstractText><br /><br /><br /><br /><small>Circulation: 10 Nov 2023; epub ahead of print</small></div>

<div><h4>Optimal Screening for Predicting and Preventing the Risk of Heart Failure Among Adults With Diabetes Without Atherosclerotic Cardiovascular Disease: a Pooled Cohort Analysis.</h4><i>Patel KV, Segar MW, Klonoff DC, Khan MS, ... Vaduganathan M, Pandey A</i><br /><AbstractText><b>Background:</b> The optimal approach to identify individuals with diabetes who are at high-risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD). <br /><b>Methods:</b><br/>Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high-risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM≥12); N-terminal pro-B-type natriuretic peptide (NT-proBNP;≥125 pg/mL); high-sensitivity cardiac troponin (hs-cTnT ≥14 ng/L, hs-cTnI≥31 ng/L); echocardiography-based diabetic cardiomyopathy (echo-DbCM; LA enlargement, LV hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to additionally identify residual risk among those deemed low-risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat (NNT<sup>5</sup>) and number needed to screen (NNS<sup>5</sup>) to prevent 1 HF event with an SGLT2i among high-risk participants, and cost of screening were estimated. <br /><b>Results:</b><br/>The initial study cohort included 6,293 participants (48.2% women), of which 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The NNT<sup>5</sup> to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95%CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had low NNT<sup>5</sup> (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low-risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). 2-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable NNT<sup>5</sup> as the 1-step screening approaches (30-32). The NNS<sup>5</sup> to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1,061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2,894; NT-proBNP/echo-DbCM: $16,358). <b>Conclusions:</b> Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF.</AbstractText><br /><br /><br /><br /><small>Circulation: 10 Nov 2023; epub ahead of print</small></div>

<div><h4>Cardiac Remodeling After Hypertensive Pregnancy Following Physician-Optimized Blood Pressure Self-Management: The POP-HT Randomized Clinical Trial Imaging Sub-study.</h4><i>Kitt J, Krasner S, Barr L, Frost A, ... McManus RJ, Leeson P</i><br /><AbstractText><b>Background:</b> Hypertensive pregnancy disorders are associated with adverse cardiac remodeling, which can fail to reverse postpartum in some women. The Physician Optimized Postpartum Hypertension Treatment trial demonstrated improved blood pressure control, while the cardiovascular system recovers postpartum, associates with persistently reduced blood pressure. We now report the impact on cardiac remodeling. <br /><b>Methods:</b><br/>In this prospective, randomized, open-label, blinded endpoint trial, in a single UK hospital, 220 women were randomly assigned 1:1 to self-monitoring with research physician-optimized antihypertensive titration, or usual postnatal care from primary care physician and midwife. Participants were aged 18 years or over, with pre-eclampsia or gestational hypertension, requiring antihypertensives on hospital discharge postnatally. Pre-specified secondary cardiac imaging outcomes were recorded by echocardiography around delivery, and again at blood pressure primary outcome assessment, around nine months postpartum, when cardiovascular magnetic resonance was also performed. <br /><b>Results:</b><br/>187 women (101 intervention; 86 usual care) underwent echocardiography at baseline and follow up, at a mean 258+/-14.6 days postpartum, of which 174 (93 intervention; 81 usual care) also had cardiovascular magnetic resonance at follow up. Relative wall thickness by echocardiography was 0.06 (95% CI0.07 to 0.05, P=<0.001) lower in the intervention group between baseline and follow up, and cardiovascular magnetic resonance at follow up demonstrated a lower left ventricular mass (-6.37g/m<sup>2</sup> (95% CI -7.99 to -4.74, P<0.001), end diastolic volume (-3.87ml/m<sup>2</sup>, 95% CI -6.77 to -0.98, P=0.009) and end systolic volume (-3.25ml/m<sup>2</sup>, 95% CI 4.87 to -1.63, P <0.001) and higher left and right ventricular ejection fraction by 2.6% (95% CI 1.3 to 3.9, P<0.001) and 2.8% (95% CI 1.4 to 4.1, P<0.001) respectively. Echocardiography assessed left ventricular diastolic function demonstrated a mean difference in average E/E\' of 0.52 (95% CI -0.97 to -0.07, P=0.024), and a reduction in left atrial volumes of -4.33ml/m<sup>2</sup> (95% CI -5.52 to -3.21, P=<0.001) between baseline and follow up, when adjusted for baseline differences in measures. <b>Conclusions:</b> Short-term postnatal optimization of blood pressure control following hypertensive pregnancy, through self-monitoring and physician-guided antihypertensive titration, associates with long term changes in cardiovascular structure and function, in a pattern associated with more favorable cardiovascular outcomes.</AbstractText><br /><br /><br /><br /><small>Circulation: 10 Nov 2023; epub ahead of print</small></div>

<div><h4>Development and Validation of the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) Equations.</h4><i>Khan SS, Matsushita K, Sang Y, Ballew SH, ... Coresh J, Chronic Kidney Disease Prognosis Consortium and the American Heart Association Cardiovascular-Kidney-Metabolic Science Advisory Group</i><br /><AbstractText><b>Background:</b> Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the AHA Predicting Risk of CVD EVENTs (PREVENT) equations among US adults aged 30-79 years without known CVD. <br /><b>Methods:</b><br/>The derivation sample included individual-level participant data from 25 datasets (N=3,281,919) between 1992-2017. The primary outcome was CVD (atherosclerotic CVD [ASCVD] and heart failure [HF]). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, anti-hypertensive or statin use, diabetes) and estimated glomerular filtration rate [eGFR]. Models were sex-specific, race-free, developed on the age-scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each dataset and meta-analyzed. Discrimination was assessed using Harrell\'s C-statistic. Calibration was calculated as the slope of the observed vs. predicted risk by decile. Additional equations to predict each CVD subtype (ASCVD, HF) and include optional predictors (urine albumin-to-creatinine ratio [UACR], hemoglobin A1c [HbA1c]), and social deprivation index [SDI]) were also developed. External validation was performed in 3,330,085 participants from 21 additional datasets. <br /><b>Results:</b><br/>Among 6,612,004 adults included, mean (SD) age was 53 (12) years and 56% were female. Over a mean (SD) follow-up of 4.8 (3.1) years, there were 211,515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval [IQI]: 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (IQI 0.81 -1.16) and 0.94 (0.81-1.13) among females and males, respectively. Similar estimates for discrimination and calibration were observed for ASCVD- and HF-specific models. The improvement in discrimination was small but statistically significant when UACR, HbA1c, and SDI were added together to the base model to total CVD (ΔC-statistic [IQI] 0.004 [0.004, 0.005] and 0.005 [0.004, 0.007] among females and males, respectively). Calibration improved significantly when UACR was added to the base model among those with marked albuminuria (>300mg/g) (1.05 [0.84-1.20] vs. 1.39 [1.14-1.65], p=0.01). <b>Conclusions:</b> PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults using routinely available clinical variables.</AbstractText><br /><br /><br /><br /><small>Circulation: 09 Nov 2023; epub ahead of print</small></div>

<div><h4>Novel Prediction Equations for Absolute Risk Assessment of Total Cardiovascular Disease Incorporating Cardiovascular-Kidney-Metabolic Health: A Scientific Statement From the American Heart Association.</h4><i>Khan SS, Coresh J, Pencina MJ, Ndumele CE, ... Lloyd-Jones DM, American Heart Association</i><br /><AbstractText>Cardiovascular-kidney-metabolic (CKM) syndrome is a novel construct recently defined by the American Heart Association in response to the high prevalence of metabolic and kidney disease. Epidemiological data demonstrate higher absolute risk of both atherosclerotic cardiovascular disease (CVD) and heart failure as an individual progresses from CKM stage 0 to stage 3, but optimal strategies for risk assessment need to be refined. Absolute risk assessment with the goal to match type and intensity of interventions with predicted risk and expected treatment benefit remains the cornerstone of primary prevention. Given the growing number of therapies in our armamentarium that simultaneously address all 3 CKM axes, novel risk prediction equations are needed that incorporate predictors and outcomes relevant to the CKM context. This should also include social determinants of health, which are key upstream drivers of CVD, to more equitably estimate and address risk. This scientific statement summarizes the background, rationale, and clinical implications for the newly developed sex-specific, race-free risk equations: PREVENT (AHA Predicting Risk of CVD Events). The PREVENT equations enable 10- and 30-year risk estimates for total CVD (composite of atherosclerotic CVD and heart failure), include estimated glomerular filtration rate as a predictor, and adjust for competing risk of non-CVD death among adults 30 to 79 years of age. Additional models accommodate enhanced predictive utility with the addition of CKM factors when clinically indicated for measurement (urine albumin-to-creatinine ratio and hemoglobin A1c) or social determinants of health (social deprivation index) when available. Approaches to implement risk-based prevention using PREVENT across various settings are discussed.</AbstractText><br /><br /><br /><br /><small>Circulation: 09 Nov 2023; epub ahead of print</small></div>

<div><h4>2023 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces.</h4><i>Berg KM, Bray JE, Ng KC, Liley HG, ... Nolan JP, Collaborators</i><br /><AbstractText>The International Liaison Committee on Resuscitation engages in a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation and first aid science. Draft Consensus on Science With Treatment Recommendations are posted online throughout the year, and this annual summary provides more concise versions of the final Consensus on Science With Treatment Recommendations from all task forces for the year. Topics addressed by systematic reviews this year include resuscitation of cardiac arrest from drowning, extracorporeal cardiopulmonary resuscitation for adults and children, calcium during cardiac arrest, double sequential defibrillation, neuroprognostication after cardiac arrest for adults and children, maintaining normal temperature after preterm birth, heart rate monitoring methods for diagnostics in neonates, detection of exhaled carbon dioxide in neonates, family presence during resuscitation of adults, and a stepwise approach to resuscitation skills training. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, using Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces list priority knowledge gaps for further research. Additional topics are addressed with scoping reviews and evidence updates.</AbstractText><br /><br /><br /><br /><small>Circulation: 08 Nov 2023; epub ahead of print</small></div>

<div><h4>Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.</h4><i>Gao L, Zhao Y, Wu H, Lin X, ... Wu Y, Huang H</i><br /><b>Background</b><br />Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear.<br /><b>Methods</b><br />Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Patients with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models.<br /><b>Results</b><br />Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C<sup>+</sup> monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C<sup>+</sup> monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in patients with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14<sup>++</sup>CD16<sup>-</sup> monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional <i>Vcam1</i> silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI.<br /><b>Conclusions</b><br />Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.<br /><br /><br /><br /><small>Circulation: 07 Nov 2023; epub ahead of print</small></div>

<div><h4>Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease.</h4><i>Rogers MA, Bartoli-Leonard F, Zheng KH, Small AM, ... Singh SA, Aikawa E</i><br /><b>Background</b><br />High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein-targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake.<br /><b>Methods</b><br />Here, unbiased ligand-receptor capture mass spectrometry was used to identify MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor/cofactor involved in Lp(a) uptake.<br /><b>Results</b><br />Reducing <i>MFSD5</i> expression by a computationally identified small molecule or small interfering RNA suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. <i>MFSD5</i> variants were associated with aortic stenosis (<i>P</i>=0.027 after multiple hypothesis testing) with evidence suggestive of an interaction with plasma Lp(a) levels.<br /><b>Conclusions</b><br /><i>MFSD5</i> knockdown suppressing human valvular cell Lp(a) uptake and calcification, along with meta-analysis of <i>MFSD5</i> variants associating with aortic stenosis, supports further preclinical assessment of <i>MFSD5</i> in cardiovascular diseases, the leading cause of death worldwide.<br /><br /><br /><br /><small>Circulation: 07 Nov 2023; epub ahead of print</small></div>

<div><h4>Non-ischemic or Dual Cardiomyopathy in Patients with Coronary Artery Disease.</h4><i>Bawaskar P, Thomas N, Ismail KF, Guo Y, ... Kanda A, Shenoy C</i><br /><AbstractText><b>Background:</b> Randomized trials in obstructive coronary artery disease (CAD) have largely shown no prognostic benefit from coronary revascularization. While there are several potential reasons for the lack of benefit, an underexplored possible reason is the presence of coincidental non-ischemic cardiomyopathy (NICM). We investigated the prevalence and prognostic significance of NICM in patients with CAD (CAD-NICM). <br /><b>Methods:</b><br/>We conducted a registry study of consecutive patients with obstructive CAD on coronary angiography who underwent contrast-enhanced cardiovascular magnetic resonance imaging (CMR) for the assessment of ventricular function and scar at 4 hospitals from 2004 to 2020. We identified the presence and cause of cardiomyopathy using CMR and coronary angiography data, blinded to clinical outcomes. The primary outcome was a composite of all-cause death or heart failure (HF) hospitalization, and secondary outcomes were all-cause death, HF hospitalization, and cardiovascular death. <br /><b>Results:</b><br/>Among 3,023 patients (median age 66 years, 76% men), 18.2% had no cardiomyopathy (CAD+noCM), 64.8% had ischemic cardiomyopathy (CAD+ICM), 9.3% had CAD+NICM, and 7.7% had dual cardiomyopathy (CAD+dualCM) defined as both ICM and NICM. Thus, 16.9% had CAD+NICM or dualCM. During a median follow-up of 4.8 years (interquartile range, 2.9, 7.6), 1,116 patients experienced the primary outcome. In Cox multivariable analysis, CAD+NICM or dualCM was independently associated with a higher risk of the primary outcome compared with CAD+ICM [adjusted hazard ratio (HR) 1.23; 95% confidence interval (CI) 1.06-1.43; P = 0.007] after adjustment for potential confounders. The risks of the secondary outcomes of all-cause death and HF hospitalization were also higher with CAD+NICM or dualCM (HR 1.21; 95% CI 1.02-1.43; P = 0.032 and HR 1.37; 95% CI 1.11-1.69; P = 0.003 respectively), while the risk of cardiovascular death did not differ from that of CAD+ICM (HR 1.15; 95% CI 0.89-1.48; P = 0.28). <b>Conclusions:</b> In patients with CAD referred for clinical CMR, NICM or dualCM was identified in 1 of every 6 patients and was associated with worse long-term outcomes compared with ICM. In patients with obstructive CAD, coincidental NICM or dualCM may contribute to the lack of prognostic benefit from coronary revascularization.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2023; epub ahead of print</small></div>

<div><h4>Meta-analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.</h4><i>Topriceanu CC, Pereira AC, Moon JC, Captur G, Ho CY</i><br /><AbstractText><b>Background:</b> Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease, as penetrance (proportion of G+ who develop disease) is variable, age-dependent, and not reliably predicted. <br /><b>Methods:</b><br/>A systematic search of the literature was performed. We employed random effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere genes in two different contexts: clinically-based studies on patients and families with HCM versus population/community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. <br /><b>Results:</b><br/>455 full text manuscripts were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in non-proband relatives carrying P/LP variants identified during cascade screening was 57% (95% confidence interval [CI] [52,63]) and the mean age of HCM diagnosis was 38 years (95% CI [36, 40]). Penetrance varied from ~32% for myosin light chain (<i>MYL3</i>) to ~55% for myosin binding protein C (<i>MYBPC3</i>), ~60% troponin T (<i>TNNT2</i>) and troponin I (<i>TNNI3</i>), and ~65% for myosin heavy chain (<i>MYH7</i>). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population, but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower; approximatively 11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ~8 years of follow up, starting from a mean age of ~16 years. However, short-term gene-specific phenotypic conversion varied between ~12% for <i>MYBPC3</i> to ~23% for <i>MYH7</i>. <b>Conclusions:</b> The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve understanding of true lifetime penetrance in families and in the community, and to identify drivers of the transition from subclinical to overt HCM.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2023; epub ahead of print</small></div>

<div><h4>Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13970 Contemporary High-Risk Patients With Statin Intolerance.</h4><i>Ridker PM, Lei L, Louie MJ, Haddad T, ... Libby P, Nissen SE</i><br /><AbstractText><b>Background:</b> Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. <br /><b>Methods:</b><br/>The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. <br /><b>Results:</b><br/>Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. <b>Conclusions:</b> Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2023; epub ahead of print</small></div>

<div><h4>Associations Between End-Tidal Carbon Dioxide During Pediatric Cardiopulmonary Resuscitation, CPR Quality, and Survival.</h4><i>Morgan RW, Reeder RW, Bender D, Cooper KK, ... Berg RA, Sutton RM</i><br /><AbstractText><b>Background:</b> Supported by laboratory and clinical investigations of adult cardiopulmonary arrest, resuscitation guidelines recommend monitoring end-tidal carbon dioxide (ETCO2) as an indicator of CPR quality but note that \"specific values to guide therapy have not been established in children.\" <br /><b>Methods:</b><br/>This prospective observational cohort study was an NHLBI-funded ancillary study of children in the <i>ICU-RESUS</i>citation trial (NCT02837497). Hospitalized children (≤18 years of age and ≥37 weeks post-gestational age) who received chest compressions of any duration for cardiopulmonary arrest, had an endotracheal or tracheostomy tube at the start of CPR, and had evaluable intra-arrest ETCO2 data were included. The primary exposure was event-level average ETCO2 during the first 10 minutes of CPR (dichotomized as ≥20 mmHg vs. <20 mmHg based on adult literature). The primary outcome was survival to hospital discharge. Secondary outcomes were sustained return of spontaneous circulation (ROSC), survival to discharge with favorable neurologic outcome, and new morbidity among survivors. Poisson regression measured associations between ETCO2 and outcomes as well as the association between ETCO2 and other CPR characteristics: 1) invasively measured systolic and diastolic blood pressures and 2) CPR quality and chest compression mechanics metrics (i.e., time to CPR start; chest compression rate, depth, and fraction; ventilation rate). <br /><b>Results:</b><br/>Among 234 included patients, 133 (57%) had an event-level average ETCO2 ≥20 mmHg. After controlling for <i>a priori</i> covariates, average ETCO2 ≥20 mmHg was associated with higher incidence of survival to hospital discharge (86/133 (65%) versus 48/101 (48%); aRR 1.33, CI95 1.04 - 1.69, p=0.023) and ROSC (95/133 (71%) versus 59/101 (58%); aRR 1.22, CI95 1.00 - 1.49, p=0.046) compared with lower values. ETCO2 ≥20 mmHg was not associated with survival with favorable neurologic outcome or new morbidity among survivors. Average ETCO2 ≥20 mmHg was associated with higher systolic and diastolic blood pressures during CPR, lower CPR ventilation rates, and briefer pre-CPR arrest durations compared with lower values. Chest compression rate, depth, and fraction did not differ between ETCO2 groups. <b>Conclusions:</b> In this multicenter study of children with in-hospital cardiopulmonary arrest, ETCO2 ≥20 mmHg was associated with better outcomes and higher intra-arrest blood pressures, but not with chest compression quality metrics.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2023; epub ahead of print</small></div>

<div><h4>Single-Cell Meta-Analysis of Neutrophil Activation in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Reveals Potential Shared Immunological Drivers.</h4><i>Beltran JVB, Lin FP, Chang CL, Ko TM</i><br /><b>Background</b><br />Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) share similar clinical manifestations, including cardiovascular complications, suggesting similar underlying immunopathogenic processes. Aberrant neutrophil activation may play a crucial role in the shared pathologies of KD and MIS-C; however, the associated pathogenic mechanisms and molecular drivers remain unknown.<br /><b>Methods</b><br />We performed a single-cell meta-analysis of neutrophil activation with 103 pediatric single-cell transcriptomic peripheral blood mononuclear cell data across 9 cohorts, including healthy controls, KD, MIS-C, compared with dengue virus infection, juvenile idiopathic arthritis, and pediatric celiac disease. We used a series of computational analyses to investigate the shared neutrophil transcriptional programs of KD and MIS-C that are linked to systemic damage and cardiac pathologies, and suggested Food and Drug Administration-approved drugs to consider as KD and MIS-C treatment.<br /><b>Results</b><br />We meta-analyzed 521 950 high-quality cells. We found that blood signatures associated with risks of cardiovascular events are enriched in neutrophils of KD and MIS-C. We revealed the expansion of CD177<sup>+</sup> neutrophils harboring hyperactivated effector functions in both KD and MIS-C, but not in healthy controls or in other viral-, inflammatory-, or immune-related pediatric diseases. KD and MIS-C CD177<sup>+</sup> neutrophils had highly similar transcriptomes, marked by conserved signatures and pathways related to molecular damage. We found the induction of a shared neutrophil expression program, potentially regulated by SPI1 (Spi-1 proto-oncogene), which confers enhanced effector functions, especially neutrophil degranulation. CD177 and shared neutrophil expression program expressions were associated with acute stages and attenuated during KD intravenous immunoglobulin treatment and MIS-C recovery. Network analysis identified hub genes that correlated with the high activation of CD177<sup>+</sup> neutrophils. Disease-gene association analysis revealed that the CD177<sup>+</sup> neutrophil shared neutrophil expression program was associated with the development of coronary and myocardial disorders. Last, we identified and validated TSPO (translocator protein) and S100A12 (S100 calcium-binding protein A12) as main molecular targets, for which the Food and Drug Administration-approved drugs methotrexate, zaleplon, metronidazole, lorazepam, clonazepam, temazepam, and zolpidem, among others, are primary candidates for drug repurposing.<br /><b>Conclusions</b><br />Our findings indicate that CD177<sup>+</sup> neutrophils may exert systemic pathological damage contributing to the shared morbidities in KD and MIS-C. We uncovered potential regulatory drivers of CD177<sup>+</sup> neutrophil hyperactivation and pathogenicity that may be targeted as a single therapeutic strategy for either KD or MIS-C.<br /><br /><br /><br /><small>Circulation: 31 Oct 2023; epub ahead of print</small></div>

<div><h4>Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.</h4><i>Gao F, Liang T, Wei Lu Y, Pu L, ... Wang DZ, Chen J</i><br /><b>Background</b><br />The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation.<br /><b>Methods</b><br />We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed.<br /><b>Results</b><br />We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5<sup>+/-</sup> mice; furthermore, ATF4 (activating transcription factor 4) regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5<sup>+/-</sup>/Atf4<sup>+/-</sup>), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes.<br /><b>Conclusions</b><br />These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.<br /><br /><br /><br /><small>Circulation: 31 Oct 2023; epub ahead of print</small></div>

<div><h4>ChaMP-CMD: A Phenotype-Blinded, Randomized Controlled, Cross-Over Trial.</h4><i>Sinha A, Rahman H, Douiri A, Demir OM, ... Webb AJ, Perera D</i><br /><b>Background</b><br />Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy.<br /><b>Methods</b><br />Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379).<br /><b>Results</b><br />Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; <i>P</i><0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; <i>P</i>=0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; <i>P</i>=0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; <i>P</i>=0.549).<br /><b>Conclusions</b><br />Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.<br /><br /><br /><br /><small>Circulation: 31 Oct 2023; epub ahead of print</small></div>

<div><h4>Projected Change in the Burden of Excess Cardiovascular Deaths Associated With Extreme Heat by Midcentury (2036-2065) in the Contiguous United States.</h4><i>Khatana SAM, Eberly LA, Nathan AS, Groeneveld PW</i><br /><AbstractText><b>Background:</b> Climate change is causing an increase in extreme heat. Individuals with cardiovascular disease are at high risk of heat-related adverse health effects. How the burden of extreme heat-associated cardiovascular deaths in the United States will change with the projected rise in extreme heat is unknown. <br /><b>Methods:</b><br/>We obtained data on cardiovascular deaths among adults and the number of extreme heat days (maximum heat index ≥90 °F [32.2 °C]) in each county in the contiguous United States from 2008 to 2019. Based on representative concentration pathway trajectories that model greenhouse gas emissions and shared socioeconomic pathways (SSP) that model future socioeconomic scenarios and demographic projections, we obtained county-level projected numbers of extreme heat days and populations under 2 scenarios for the midcentury period 2036 to 2065: SSP2-4.5 (representing demographic projections from a \"middle-of-the-road\" socioeconomic scenario and an intermediate increase in emissions) and SSP5-8.5 (demographic projections in an economy based on \"fossil-fueled development\" and a large increase in emissions). The association of cardiovascular mortality with extreme heat was estimated with a Poisson fixed-effects model. Using estimates from this model, the projected number of excess cardiovascular deaths associated with extreme heat was calculated. <br /><b>Results:</b><br/>Extreme heat was associated with 1651 (95% CI, 921-2381) excess cardiovascular deaths per year from 2008 to 2019. By midcentury, extreme heat is projected to be associated with 4320 (95% CI, 2369-6272) excess deaths annually, which is an increase of 162% (95% CI, 142-182) under SSP2-4.5, and 5491 (95% CI, 3011-7972) annual excess deaths, which is an increase of 233% (95% CI, 206-259) under SSP5-8.5. Elderly adults are projected to have a 3.5 (95% CI, 3.2- 3.8) times greater increase in deaths in the SSP2-4.5 scenario compared with nonelderly adults. Non-Hispanic Black adults are projected to have a 4.6 (95% CI, 2.8-6.4) times greater increase compared with non-Hispanic White adults. The projected change in deaths was not statistically significantly different for other race and ethnicity groups or between men and women. <b>Conclusions:</b> By midcentury, extreme heat is projected to be associated with a significantly greater burden of excess cardiovascular deaths in the contiguous United States.</AbstractText><br /><br /><br /><br /><small>Circulation: 30 Oct 2023; epub ahead of print</small></div>

<div><h4>Next Generation, Modifiable Cardiometabolic Biomarkers: Mitochondrial Adaptation and Metabolic Resilience: A Scientific Statement From the American Heart Association.</h4><i>Mietus-Snyder M, Perak AM, Cheng S, Hayman LL, ... Hypertension and Obesity in the Young Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Lifestyle and Cardiometabolic Health; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular and Stroke Nursing</i><br /><AbstractText>Cardiometabolic risk is increasing in prevalence across the life span with disproportionate ramifications for youth at socioeconomic disadvantage. Established risk factors and associated disease progression are harder to reverse as they become entrenched over time; if current trends are unchecked, the consequences for individual and societal wellness will become untenable. Interrelated root causes of ectopic adiposity and insulin resistance are understood but identified late in the trajectory of systemic metabolic dysregulation when traditional cardiometabolic risk factors cross current diagnostic thresholds of disease. Thus, children at cardiometabolic risk are often exposed to suboptimal metabolism over years before they present with clinical symptoms, at which point life-long reliance on pharmacotherapy may only mitigate but not reverse the risk. Leading-edge indicators are needed to detect the earliest departure from healthy metabolism, so that targeted, primordial, and primary prevention of cardiometabolic risk is possible. Better understanding of biomarkers that reflect the earliest transitions to dysmetabolism, beginning in utero, ideally biomarkers that are also mechanistic/causal and modifiable, is critically needed. This scientific statement explores emerging biomarkers of cardiometabolic risk across rapidly evolving and interrelated \"omic\" fields of research (the epigenome, microbiome, metabolome, lipidome, and inflammasome). Connections in each domain to mitochondrial function are identified that may mediate the favorable responses of each of the omic biomarkers featured to a heart-healthy lifestyle, notably to nutritional interventions. Fuller implementation of evidence-based nutrition must address environmental and socioeconomic disparities that can either facilitate or impede response to therapy.</AbstractText><br /><br /><br /><br /><small>Circulation: 30 Oct 2023; epub ahead of print</small></div>

<div><h4>Versican Promotes Cardiomyocyte Proliferation and Cardiac Repair.</h4><i>Feng J, Li Y, Li Y, Yin Q, ... Hu S, Nie Y</i><br /><b>Background</b><br />The adult mammalian heart is incapable of regeneration, whereas a transient regenerative capacity is maintained in the neonatal heart, primarily through the proliferation of preexisting cardiomyocytes. Neonatal heart regeneration after myocardial injury is accompanied by an expansion of cardiac fibroblasts and compositional changes in the extracellular matrix. Whether and how these changes influence cardiomyocyte proliferation and heart regeneration remains to be investigated.<br /><b>Methods</b><br />We used apical resection and myocardial infarction surgical models in neonatal and adult mice to investigate extracellular matrix components involved in heart regeneration after injury. Single-cell RNA sequencing and liquid chromatography-mass spectrometry analyses were used for versican identification. Cardiac fibroblast-specific <i>Vcan</i> deletion was achieved using the mouse strains <i>Col1a2-2A-CreER</i> and <i>Vcan</i><sup><i>fl/fl</i></sup>. Molecular signaling pathways related to the effects of versican were assessed through Western blot, immunostaining, and quantitative reverse transcription polymerase chain reaction. Cardiac fibrosis and heart function were evaluated by Masson trichrome staining and echocardiography, respectively.<br /><b>Results</b><br />Versican, a cardiac fibroblast-derived extracellular matrix component, was upregulated after neonatal myocardial injury and promoted cardiomyocyte proliferation. Conditional knockout of <i>Vcan</i> in cardiac fibroblasts decreased cardiomyocyte proliferation and impaired neonatal heart regeneration. In adult mice, intramyocardial injection of versican after myocardial infarction enhanced cardiomyocyte proliferation, reduced fibrosis, and improved cardiac function. Furthermore, versican augmented the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. Mechanistically, versican activated integrin β1 and downstream signaling molecules, including ERK1/2 and Akt, thereby promoting cardiomyocyte proliferation and cardiac repair.<br /><b>Conclusions</b><br />Our study identifies versican as a cardiac fibroblast-derived pro-proliferative proteoglycan and clarifies the role of versican in promoting adult cardiac repair. These findings highlight its potential as a therapeutic factor for ischemic heart diseases.<br /><br /><br /><br /><small>Circulation: 27 Oct 2023; epub ahead of print</small></div>

<div><h4>MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.</h4><i>Shridhar P, Glennon MS, Pal S, Waldron CJ, ... Gingras S, Becker JR</i><br /><b>Background</b><br />Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy.<br /><b>Methods</b><br />We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes <i>Mybpc3</i>(cardiac myosin binding protein 3) or <i>Myh6</i> (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms.<br /><b>Results</b><br />We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models.<br /><b>Conclusions</b><br />Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.<br /><br /><br /><br /><small>Circulation: 27 Oct 2023; epub ahead of print</small></div>

<div><h4>Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.</h4><i>Bergeman AT, Lieve KVV, Kallas D, Bos JM, ... Wilde AAM, van der Werf C</i><br /><b>Background</b><br />In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia.<br /><b>Methods</b><br />From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients.<br /><b>Results</b><br />A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; <i>P</i>=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; <i>P</i>=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; <i>P</i><0.001).<br /><b>Conclusions</b><br />For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.<br /><br /><br /><br /><small>Circulation: 27 Oct 2023; epub ahead of print</small></div>

<div><h4>Transcatheter or Surgical Aortic Valve Replacement in Patients with Severe Aortic Stenosis and Small Aortic Annulus: A Randomized Clinical Trial.</h4><i>Rodés-Cabau J, Ribeiro H, Mohammadi S, Serra V, ... Pibarot P, VIVA Trial Investigators</i><br /><AbstractText><b>Background:</b> The optimal treatment in patients with severe aortic stenosis (AS) and small aortic annulus (SAA) remains to be determined. The objectives of this study were to compare the hemodynamic and clinical outcomes between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in patients with a SAA. <br /><b>Methods:</b><br/>Prospective multicenter international randomized trial performed in 15 university hospitals. Participants were 151 patients with severe AS and SAA (mean diameter <23 mm) were randomized (1:1) to TAVR (n=77) vs SAVR (n=74), The primary outcome was impaired valve hemodynamics (i.e. severe prosthesis patient mismatch [PPM ] or moderate-severe aortic regurgitation [AR]) at 60 days as evaluated by Doppler-echocardiography and analyzed in a central echocardiography core laboratory. Clinical events were secondary outcomes. <br /><b>Results:</b><br/>The mean age of the participants was 75±5 years, with 140 (93%) women, a median STS of 2.50 (1.67-3.28)%, and a median annulus diameter of 21.1 (IQR: 20.4-22.0) mm. There were no differences between groups in the rate of severe PPM or moderate-severe AR (severe PPM (TAVR: 4 [5.6 %], SAVR: 7 [10.3%], p=0.30), and moderate-severe AR (none in both groups). There were no differences between groups regarding mortality (TAVR: 1 [1.3%], SAVR: 1 [1.4%], p=1.00) and stroke (TAVR:0, SAVR: 2 [2.7%], p=0.24) at 30 days. After a median follow-up of 2 (1-4) years, there were no differences between groups regarding mortality (TAVR: 7 [9.1%], SAVR: 6 [8.1%], p=0.89), stroke (TAVR: 3 [3.9%], SAVR: 3 [4.1%], p=0.95), and cardiac hospitalization (TAVR: 15 [19.5%], SAVR: 15 [ 20.3%], p=0.80). <b>Conclusions:</b> In patients with severe AS and SAA (women in the vast majority), there was no evidence of superiority of contemporary TAVR vs. SAVR regarding valve hemodynamic results. After a median follow-up of 2 years, there were no differences in clinical outcomes between groups. These findings suggest that the 2 therapies represent a valid alternative for treating patients with SA and SAA, and treatment selection should likely be individualized according to baseline characteristics, additional anatomical risk factors, and patient preference. However, the results of this study should be interpreted with caution due to the limited sample size leading to an underpowered study, and need to be confirmed in future larger studies.</AbstractText><br /><br /><br /><br /><small>Circulation: 26 Oct 2023; epub ahead of print</small></div>

<div><h4>Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure at 6 Months Following Medication Escalation: The RADIANCE Clinical Trial Program.</h4><i>Azizi M, Sharp ASP, Fisher NDL, Weber MA, ... Kirtane AJ, RADIANCE Investigators</i><br /><AbstractText><b>Background:</b> The RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, and RADIANCE II randomized, sham-controlled trials independently met their primary endpoint of a greater reduction in daytime ambulatory systolic blood pressure (SBP) at 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN vs. sham at 6 months, following the blinded addition of antihypertensive treatments (AHT), we pooled individual patient data across these three similarly designed trials. <br /><b>Methods:</b><br/>Patients with mild-to-moderate hypertension on no AHT or with hypertension resistant to standardized combination triple AHT were randomized to uRDN (n=293 in total) vs. sham (n=213 in total); they were to remain off added AHT throughout 2 months of follow-up unless specified BP criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mmHg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mmHg under blinding to initial treatment assignment. Six-month outcomes included (1) baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP, (2) change in AHT, and (3) safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. <br /><b>Results:</b><br/>Patients (70% men) were aged 54.1±9.3 years with baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mmHg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients vs. sham patients (P=0.001). While unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mmHg (95%CI: -5.7,-0.2; p=0.033) in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mmHg (-6.8, -4.0; P<0.001) and -5.2 mmHg (-7.1,-3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. <b>Conclusions:</b> This individual patient-data analysis of 506 patients included in RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN vs. sham at 6 months, with fewer added AHT.</AbstractText><br /><br /><br /><br /><small>Circulation: 26 Oct 2023; epub ahead of print</small></div>

<div><h4>Stopping Aspirin Within 1 Month After Stenting for Ticagrelor Monotherapy in Acute Coronary Syndrome: The T-PASS Randomized Noninferiority Trial.</h4><i>Hong SJ, Lee SJ, Suh Y, Yun KH, ... Hong MK, T-PASS investigators</i><br /><AbstractText><b>Background:</b> Stopping aspirin within 1 month after implantation of a drug-eluting stent (DES) for ticagrelor monotherapy has not been exclusively evaluated for patients with acute coronary syndrome (ACS). The aim of this study was to investigate whether ticagrelor monotherapy after <1 month of dual antiplatelet therapy (DAPT) is noninferior to 12 months of ticagrelor-based DAPT for adverse cardiovascular and bleeding events in patients with ACS. <br /><b>Methods:</b><br/>In this randomized, open-label, non-inferiority trial, 2850 patients with ACS who underwent DES implantation at 24 centres in South Korea were randomly assigned (1:1) to receive either ticagrelor monotherapy (90 mg twice daily) after <1 month of DAPT (n=1426) or 12 months of ticagrelor-based DAPT (n=1424) between Apr 24, 2019, and May 31, 2022. The primary endpoint was the net clinical benefit as a composite of all-cause death, myocardial infarction, definite or probable stent thrombosis, stroke, and major bleeding at 1 year after the index procedure in the intention-to-treat population. Key secondary endpoints were the individual components of the primary endpoint. <br /><b>Results:</b><br/>Among 2850 patients who were randomized (mean age, 61 years; 40% ST-elevation myocardial infarction), 2823 (99.0%) completed the trial. Aspirin was discontinued at a median of 16 days (interquartile range, 12 to 25 days) in the group receiving ticagrelor monotherapy after <1 month of DAPT. The primary endpoint occurred in 40 patients (2.8%) in the group receiving ticagrelor monotherapy after <1-month DAPT, and in 73 patients (5.2%) in the ticagrelor-based 12-month DAPT group (hazard ratio [HR], 0.54 [95% CI, 0.37-0.80]; <i>P</i><0.001 for noninferiority; <i>P</i>=0.002 for superiority). This finding was consistent in the per-protocol population as a sensitivity analysis. The occurrence of major bleeding was significantly lower in the ticagrelor monotherapy after <1-month DAPT group compared with the 12-month DAPT group (1.2% versus 3.4%; HR, 0.35 [95% CI, 0.20-0.61]; <i>P</i><0.001). <b>Conclusions:</b> This study provides evidence that stopping aspirin within 1 month for ticagrelor monotherapy is both noninferior and superior to 12-month DAPT as for the 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily due to a significant reduction in major bleeding, among ACS patients receiving DES implantation. Low event rates which may suggest enrolment of relatively non-high-risk patients should be considered in interpreting the trial.</AbstractText><br /><br /><br /><br /><small>Circulation: 25 Oct 2023; epub ahead of print</small></div>

<div><h4>Portfolio Diet Score and Risk of Cardiovascular Disease: Findings From 3 Prospective Cohort Studies.</h4><i>Glenn AJ, Guasch-Ferré M, Malik VS, Kendall CWC, ... Hu FB, Sievenpiper JL</i><br /><b>Background</b><br />The plant-based Portfolio dietary pattern includes recognized cholesterol-lowering foods (ie, plant protein, nuts, viscous fiber, phytosterols, and plant monounsaturated fats) shown to improve several cardiovascular disease (CVD) risk factors in randomized controlled trials. However, there is limited evidence on the role of long-term adherence to the diet and CVD risk. The primary objective was to examine the relationship between the Portfolio Diet Score (PDS) and the risk of total CVD, coronary heart disease (CHD), and stroke.<br /><b>Methods</b><br />We prospectively followed 73924 women in the Nurses\' Health Study (1984-2016), 92346 women in the Nurses\' Health Study II (1991-2017), and 43970 men in the Health Professionals Follow-up Study (1986-2016) without CVD or cancer at baseline. Diet was assessed using validated food frequency questionnaires at baseline and every 4 years using a PDS that positively ranks plant protein (legumes), nuts and seeds, viscous fiber sources, phytosterols (mg/day), and plant monounsaturated fat sources, and negatively ranks foods high in saturated fat and cholesterol.<br /><b>Results</b><br />During up to 30 years of follow-up, 16917 incident CVD cases, including 10666 CHD cases and 6473 strokes, were documented. After multivariable adjustment for lifestyle factors and a modified Alternate Healthy Eating Index (excluding overlapping components), comparing the highest with the lowest quintile, participants with a higher PDS had a lower risk of total CVD (pooled hazard ratio [HR], 0.86 [95% CI, 0.81-0.92]; <i>P</i><sub>trend</sub> <0.001), CHD (pooled HR, 0.86 [95% CI, 0.80-0.93]; <i>P</i><sub>trend</sub>=0.0001), and stroke (pooled HR, 0.86 [95% CI, 0.78-0.95]; <i>P</i><sub>trend</sub>=0.0003). In addition, a 25-percentile higher PDS was associated with a lower risk of total CVD (pooled HR, 0.92 [95% CI, 0.89-0.95]), CHD (pooled HR, 0.92 [95% CI, 0.88-0.95]), and stroke (pooled HR, 0.92 [95% CI, 0.87-0.96]). Results remained consistent across sensitivity and most subgroup analyses, and there was no evidence of departure from linearity for CVD, CHD, or stroke. In a subset of participants, a higher PDS was associated with a more favorable blood lipid and inflammatory profile.<br /><b>Conclusions</b><br />The PDS was associated with a lower risk of CVD, including CHD and stroke, and a more favorable blood lipid and inflammatory profile, in 3 large prospective cohorts.<br /><br /><br /><br /><small>Circulation: 25 Oct 2023; epub ahead of print</small></div>

<div><h4>Concomitant Left Atrial Appendage Occlusion and Transcatheter Aortic Valve Replacement Among Patients with Atrial Fibrillation.</h4><i>Kapadia SR, Krishnaswamy A, Whisenant B, Potluri S, ... Wang Q, Leon MB</i><br /><b>Background</b><br />Atrial fibrillation (AF) is common in patients undergoing transcatheter aortic valve replacement (TAVR) and is associated with increased risk of bleeding and stroke. While left atrial appendage occlusion (LAAO) is approved as an alternative to anticoagulants for stroke prevention in patients with AF, placement of these devices neither in patients with severe AS, nor at the same time as TAVR, has been extensively studied.<br /><b>Methods</b><br />WATCH-TAVR was a multicenter, randomized trial evaluating the safety and effectiveness of concomitant TAVR and LAAO with WATCHMAN in AF patients. Patients were randomized 1:1 to TAVR+LAAO or TAVR+medical therapy. WATCHMAN patients received anticoagulation for 45 days followed by dual antiplatelet therapy until 6 months. Anticoagulation was per treating physician preference for patients randomized to TAVR+medical therapy. The primary non-inferiority endpoint was all-cause mortality, stroke, and major bleeding at 2-years between the two strategies.<br /><b>Results</b><br />The study enrolled 349 patients, 177 TAVR+LAAO and 172 TAVR+medical therapy, between December-2017 and November-2020 at 34 US centers. The mean age was 81 years, CHA<sub>2</sub>DS<sub>2</sub>-VASc score was 4.9 and HAS-BLED score was 3.0. At baseline, 85.4% of patients were taking anticoagulation and 71.3% patients were on antiplatelet therapy. The cohorts were well-balanced for baseline characteristics. The incremental LAAO procedure time was 38 minutes; the median contrast volume was 119 mL for combined procedures versus 70 mL with TAVR alone. At 24 months follow-up, 82.5% compared to 50.8% of patients were on any antiplatelet therapy, and 13.9% compared to 66.7% of patients were on any anticoagulation therapy in TAVR+LAAO compared to TAVR+medical therapy group respectively. For the composite primary endpoint, TAVR+.LAAO was non-inferior to TAVR+ medical therapy (22.7 vs 27.3 events/100 patient years for TAVR+LAAO and TAVR+medical therapy respectively; Hazard Ratio 0.86, 95% CI 0.60 -1.22, P<sub>noninferiority</sub><0.001).<br /><b>Conclusions</b><br />Concomitant WATCHMAN LAAO and TAVR is noninferior to TAVR with medical therapy in severe aortic stenosis patients with AF. The increased complexity and risks of the combined procedure should be considered when concomitant LAAO is viewed as an alternative to medical therapy for patients with AF undergoing TAVR.<br /><br /><br /><br /><small>Circulation: 24 Oct 2023; epub ahead of print</small></div>

<div><h4>Safety and Efficacy of Ticagrelor Monotherapy in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: an Individual Patient Data Meta-analysis of TWILIGHT and TICO Randomized Trials.</h4><i>Baber U, Jang Y, Oliva A, Cao D, ... Hong MK, Mehran R</i><br /><AbstractText><b>Background:</b> Dual antiplatelet therapy (DAPT) with a potent P2Y<sub>12</sub> Inhibitor coupled with aspirin for 1 year is the recommended treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Alternatively, monotherapy with a P2Y<sub>12</sub> inhibitor after a short period of DAPT has emerged as a bleeding reduction strategy. <br /><b>Methods:</b><br/>We pooled individual patient data from randomized trials that included ACS patients undergoing PCI treated with an initial 3-month course of DAPT followed by ticagrelor monotherapy versus continued ticagrelor plus aspirin. Patients sustaining a major ischemic or bleeding event in the first 3 months after PCI were excluded from analysis. The primary outcome was Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding occurring between 3 and 12 months after index PCI. The key secondary endpoint was the composite of death, myocardial infarction (MI), or stroke. Hazard ratios (HR) and 95% confidence intervals (CI) were generated using Cox regression with a one-stage approach in the intention to treat population. <br /><b>Results:</b><br/>The pooled cohort (N = 7,529) was characterized by a mean age of 62.8 years, 23.2% of patients were female and 55% presented with biomarker positive ACS. Between 3 and 12 months, ticagrelor monotherapy significantly reduced BARC 3 or 5 bleeding as compared with ticagrelor plus aspirin (0.8% vs. 2.1%; HR 0.37, 95% CI 0.24-0.56; p < 0.001). Rates of all-cause death, MI, or stroke were not significantly different between groups (2.4% vs. 2.7%; HR 0.91, 95% CI 0.68-1.21; P = 0.515). Findings were unchanged among patients presenting with biomarker positive ACS. <b>Conclusions:</b> Among ACS patients undergoing PCI who have completed a 3-month course of DAPT, discontinuation of aspirin followed by ticagrelor monotherapy significantly reduced major bleeding without incremental ischemic risk, as compared with ticagrelor plus aspirin.</AbstractText><br /><br /><br /><br /><small>Circulation: 23 Oct 2023; epub ahead of print</small></div>

<div><h4>Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.</h4><i>Wiegman A, Greber-Platzer S, Ali S, Doortje Reijman M, ... Hirshberg B, Pordy R</i><br /><b>Background</b><br />Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDLR (LDL receptor) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study.<br /><b>Methods</b><br />The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks.<br /><b>Results</b><br />Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related.<br /><b>Conclusions</b><br />Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04233918.<br /><br /><br /><br /><small>Circulation: 20 Oct 2023; epub ahead of print</small></div>

<div><h4>Performance of Thrombectomy-Capable, Comprehensive, and Primary Stroke Centers in Reperfusion Therapies for Acute Ischemic Stroke: Report From the Get With The Guidelines-Stroke Registry.</h4><i>Raychev R, Sun JL, Schwamm L, Smith EE, ... Grory BM, Saver JL</i><br /><b>Background</b><br />The thrombectomy-capable stroke center (TSC) is a recently introduced intermediate tier of accreditation for hospitals at which patients with acute ischemic stroke receive care. The comparative quality and clinical outcomes of reperfusion therapies at TSCs, primary stroke centers (PSCs), and comprehensive stroke centers (CSCs) have not been well delineated.<br /><b>Methods</b><br />We conducted a retrospective, observational, cohort study from 2018 to 2020 that included patients with acute ischemic stroke who received endovascular thrombectomy (EVT) and intravenous thrombolysis reperfusion therapies at CSCs, TSCs, or PSCs. Participants were recruited from Get With The Guidelines-Stroke registry. Study end points included timeliness of intravenous thrombolysis and EVT, successful reperfusion, discharge destination, discharge mortality, and functional independence at discharge.<br /><b>Results</b><br />Among 84 903 patients, 48 682 received EVT, of whom 73% were treated at CSCs, 22% at PSCs, and 4% at TSCs. The median annual EVT volume was 76 for CSCs, 55 for TSCs, and 32 for PSCs. Patient differences by center status included higher National Institutes of Health Stroke Scale score, longer onset-to-arrival time, and higher transfer-in rates for CSCs, TSCs, and PSCs, respectively. In adjusted analyses, the likelihood of achieving the goal door-to-needle time was higher in CSCs compared with PSCs (odds ratio [OR], 1.39 [95% CI, 1.17-1.66]) and in TSCs compared with PSCs (OR, 1.45 [95% CI, 1.08-1.96]). Likewise, the odds of achieving the goal door-to-puncture time were higher in CSCs compared with PSCs (OR, 1.58 [95% CI, 1.13-2.21]). CSCs and TSCs also demonstrated better clinical efficacy outcomes compared with PSCs. The odds of discharge to home or rehabilitation were higher in CSCs compared with PSCs (OR, 1.18 [95% CI, 1.06-1.31]), whereas the odds of in-hospital mortality or discharge to hospice were lower in both CSCs compared with PSCs (OR, 0.87 [95% CI, 0.81-0.94]) and TSCs compared with PSCs (OR, 0.86 [95% CI, 0.75-0.98]). There were no significant differences in any of the quality-of-care metrics and clinical outcomes between TSCs and CSCs.<br /><b>Conclusions</b><br />In this study representing national US practice, CSCs and TSCs exceeded PSCs in key quality-of-care reperfusion metrics and outcomes, whereas TSCs and CSCs demonstrated a similar performance. With more than one-fifth of all EVT procedures during the study period conducted at PSCs, it may be desirable to explore national initiatives aimed at facilitating the elevation of eligible PSCs to a higher certification status.<br /><br /><br /><br /><small>Circulation: 19 Oct 2023; epub ahead of print</small></div>

<div><h4>Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects.</h4><i>van Duijvenboden S, Ramírez J, Orini M, Aung N, ... Munroe PB, Lambiase PD</i><br /><b>Background</b><br />The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality.<br /><b>Methods</b><br />A neural network was developed to count PVCs from ECGs recorded during exercise (6 minutes) and recovery (1 minute) in 48 315 asymptomatic participants from UK Biobank. Associations were estimated using multivariable Cox proportional hazard models. Explorative studies were conducted in subgroups with cardiovascular magnetic resonance imaging data (n=6290) and NT-proBNP (N-terminal Pro-B-type natriuretic peptide) levels (n=4607) to examine whether PVC burden was associated with subclinical cardiomyopathy.<br /><b>Results</b><br />Mean age was 56.8±8.2 years; 51.1% of the participants were female; and median follow-up was 12.6 years. Low PVC counts during exercise and recovery were both associated with MI/HF/LTVA risk, independently of clinical factors: adjusted hazard ratio (HR), 1.2 (1-5 exercise PVCs, <i>P</i><0.001) and HR, 1.3 (1-5 recovery PVCs, <i>P</i><0.001). Risks were higher with increasing PVC count: HR, 1.8 (>20 exercise PVCs, <i>P</i><0.001) and HR, 1.6 (>5 recovery PVCs, <i>P</i><0.001). A similar trend was observed for all-cause mortality, although associations were only significant for high PVC burdens: HRs, 1.6 (>20 exercise PVCs, <i>P</i><0.001) and 1.5 (>5 recovery PVCs, <i>P</i><0.001). Complex PVC rhythms were associated with higher risk compared with PVC count alone. PVCs were also associated with incident HF, LTVA, and cardiovascular mortality, but not MI. In the explorative studies, high PVC burden was associated with larger left ventricular volumes, lower ejection fraction, and higher levels of NT-proBNP compared with participants without PVCs.<br /><b>Conclusion</b><br />In this cohort of middle-aged and older adults, PVC count during submaximal exercise and recovery were both associated with MI/HF/LTVA, all-cause mortality, HF, LTVAs, and cardiovascular mortality, independent of clinical and exercise test factors, indicating an incremental increase in risk as PVC count rises. Complex PVC rhythms were associated with higher risk compared with PVC count alone. Underlying mechanisms may include the presence of subclinical cardiomyopathy.<br /><br /><br /><br /><small>Circulation: 19 Oct 2023; epub ahead of print</small></div>

<div><h4>Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial.</h4><i>Raal F, Durst R, Bi R, Talloczy Z, ... Kastelein JJP, ORION-5 Study Investigators</i><br /><b>Background</b><br />Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. Phase 2 of ORION (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia.<br /><b>Methods</b><br />ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150.<br /><b>Results</b><br />The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%; <i>P</i>=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (<i>P</i><0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study.<br /><b>Conclusions</b><br />Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03851705.<br /><br /><br /><br /><small>Circulation: 18 Oct 2023; epub ahead of print</small></div>

<div><h4>Early Left Ventricular Unloading or Conventional Approach After Venoarterial Extracorporeal Membrane Oxygenation: The EARLY-UNLOAD Randomized Clinical Trial.</h4><i>Chul Kim M, Lim Y, Hun Lee S, Shin Y, ... Jeong IS, Ahn Y</i><br /><b>Background</b><br />Although venoarterial extracorporeal membrane oxygenation (VA-ECMO) is beneficial for the treatment of profound cardiogenic shock, peripheral VA-ECMO cannulation can increase left ventricular afterload, thus compromising myocardial recovery. We investigated whether early routine left ventricular unloading can reduce 30-day mortality compared with the conventional approach in patients with cardiogenic shock undergoing VA-ECMO.<br /><b>Methods</b><br />This randomized clinical trial involved 116 patients with cardiogenic shock undergoing VA-ECMO from March 2021 to September 2022 at Chonnam National University Hospital, Gwangju, South Korea. The patients were randomly assigned to undergo either early routine left ventricular unloading with transseptal left atrial cannulation within 12 hours after randomization (n=58) or the conventional approach, which permitted rescue transseptal left atrial cannulation in case of an increased left ventricular afterload (n=58). The primary outcome was all-cause mortality within 30 days.<br /><b>Results</b><br />All 116 randomized patients (mean age, 67.6±13.5 years; 34 [29.3%] women) completed the trial. At 30 days, all-cause death had occurred in 27 (46.6%) patients in the early group and 26 (44.8%) patients in the conventional group (hazard ratio, 1.02 [95% CI, 0.59-1.74]; <i>P</i>=0.942). Crossover to rescue transseptal left atrial cannulation occurred in 29 patients (50%) in the conventional group according to a clear indication. Time to rescue transseptal cannulation in the conventional group was a median of 21.8 (interquartile range, 12.4-52.2) hours after randomization. There were no significant differences in other secondary outcomes between the 2 groups except for a shorter time to disappearance of pulmonary congestion in the early group (median, 3 [interquartile range, 2-6] versus 5 [interquartile range, 3-7] days; <i>P</i>=0.027).<br /><b>Conclusions</b><br />Among patients with cardiogenic shock undergoing VA-ECMO, early routine left ventricular unloading with transseptal left atrial cannulation did not reduce 30-day mortality compared with the conventional strategy, which permitted rescue transseptal left atrial cannulation. These findings should be cautiously interpreted until the results of multicenter trials using other unloading modalities become available.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04775472.<br /><br /><br /><br /><small>Circulation: 18 Oct 2023; epub ahead of print</small></div>

<div><h4>Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug-Gene Networks: From Biology to Precision Therapeutics.</h4><i>Decano JL, Maiorino E, Matamalas JT, Chelvanambi S, ... Aikawa E, Aikawa M</i><br /><b>Background</b><br />Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions.<br /><b>Methods</b><br />Primary human macrophages activated by IFNγ (M[IFNγ]) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis.<br /><b>Results</b><br />Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M[IFNγ]<sup><i>i</i></sup>) and phagocytic (M[IFNγ]<sup><i>p</i></sup>). M(IFNγ)<sup><i>i</i></sup> had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ)<sup><i>p</i></sup>. M(IFNγ)<sup><i>p</i></sup> were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ)<sup><i>i</i></sup>. Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ)<sup><i>i</i></sup> subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ)<sup><i>i</i></sup> subpopulation while expanding the M(IFNγ)<sup><i>p</i></sup> subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification.<br /><b>Conclusions</b><br />We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.<br /><br /><br /><br /><small>Circulation: 18 Oct 2023; epub ahead of print</small></div>

<div><h4>Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-β-Blocking R-Enantiomer Carvedilol.</h4><i>Seo K, Yamamoto Y, Kirillova A, Kawana M, ... Parikh VN, Ashley EA</i><br /><b>Background</b><br />Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown.<br /><b>Methods</b><br />We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (<i>Myh6</i><sup>R403Q</sup><sup>/+</sup> [myosin heavy chain 6]) and iPSC cardiomyocytes derived from patients with HCM (<i>MYH7</i><sup>R403Q/+</sup>) [myosin heavy chain 7]).<br /><b>Results</b><br />We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β<sub>1</sub>-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α<sub>1</sub>-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α<sub>1</sub>-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In <i>Myh6</i><sup>R403Q/+</sup> mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in <i>MYH7</i><sup>R403Q/+</sup> induced pluripotent stem cell cardiomyocytes.<br /><b>Conclusions</b><br />R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α<sub>1</sub>-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.<br /><br /><br /><br /><small>Circulation: 18 Oct 2023; epub ahead of print</small></div>

<div><h4>Rivaroxaban Plus Aspirin Versus Aspirin Alone After Endovascular Revascularization for Symptomatic PAD: Insights From VOYAGER PAD.</h4><i>Rymer J, Anand SS, Sebastian Debus E, Haskell LP, ... Bonaca MP, Patel MR</i><br /><b>Background</b><br />Rivaroxaban plus aspirin compared with aspirin alone reduced major cardiac and ischemic limb events after lower extremity revascularization (LER) in the VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) trial. The effect has not been described in patients undergoing endovascular LER.<br /><b>Methods</b><br />The VOYAGER PAD trial randomized 6564 patients with symptomatic peripheral artery disease to a double-blinded to treatment with 2.5 mg of rivaroxaban BID or matching placebo and 100 mg of aspirin daily. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular pathogenesis, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was Thrombolysis in Myocardial Infarction major bleeding. A prespecified subgroup of patients who underwent endovascular revascularization was included.<br /><b>Results</b><br />Endovascular LER occurred in 4379 (66.7%) patients and surgical LER in 2185 (33.3%). Over a 3-year follow-up, rivaroxaban reduced the risk of the primary outcome by 15% (hazard ratio [HR], 0.85 [95% CI, 0.76-0.96]) with an absolute risk reduction of 0.92% at 6 months and 1.04% at 3 years and a consistent benefit in those receiving endovascular (HR, 0.89 [95% CI, 0.76-1.03]) or surgical LER (HR, 0.81 [95% CI, 0.67-0.98]; <i>P</i> interaction=0.43). For endovascular-treated patients, rivaroxaban reduced the risk of acute limb ischemia or major amputation of a vascular pathogenesis by 30% (HR, 0.70 [95% CI, 0.54-0.90]; <i>P</i>=0.005) with an absolute risk reduction of 1.0% at 6 months and 2.0% at 3 years compared with aspirin alone. Among endovascular-treated patients, the median duration of concomitant dual antiplatelet therapy with clopidogrel treatment was 31 days (interquartile range, 30-58). There was a consistent benefit for rivaroxaban regardless of background clopidogrel. Thrombolysis in Myocardial Infarction major bleeding was significantly higher for the rivaroxaban and aspirin group for the endovascular cohort (HR, 1.66 [95% CI, 1.06-2.59]) with an absolute risk increase of 0.9% at 3 years with no increase in intracranial or fatal bleeding observed (HR, 0.86 [95% CI, 0.40-1.87]; <i>P</i>=0.71). Mortality with rivaroxaban was higher in the endovascular-treated patients (HR, 1.24 [95% CI, 1.02-1.52]), although this finding was isolated to specific regions.<br /><b>Conclusions</b><br />Rivaroxaban added to aspirin or dual antiplatelet therapy after LER for peripheral artery disease reduces ischemic risk and increases major bleeding without an increased risk of intracranial or fatal bleeding. These benefits are consistent in those treated with endovascular and surgical approaches with significant benefits for major adverse limb events. These data support the use of rivaroxaban in addition to aspirin or dual antiplatelet therapy after endovascular intervention for symptomatic peripheral artery disease.<br /><br /><br /><br /><small>Circulation: 18 Oct 2023; epub ahead of print</small></div>

<div><h4>Asymptomatic Patients With Brugada ECG Pattern: Long-Term Prognosis From a Large Prospective Study.</h4><i>Gaita F, Cerrato N, Giustetto C, Martino A, ... Scaglione M, Calò L</i><br /><b>Background</b><br />Brugada syndrome poses significant challenges in terms of risk stratification and management, particularly for asymptomatic patients who comprise the majority of individuals exhibiting Brugada pattern ECG (BrECG). The aim of this study was to evaluate the long-term prognosis of a large cohort of asymptomatic patients with BrECG.<br /><b>Methods</b><br />Asymptomatic patients with BrECG (1149) were consecutively collected from 2 Italian centers and followed-up at least annually for 2 to 22 years. For the 539 asymptomatic patients (men, 433 [80%]; mean age, 46±13 years) with spontaneous type 1 documented on baseline ECG (87%) or 12-lead 24-hour Holter monitoring (13%), an electrophysiologic study (EPS) was proposed; for the 610 patients with drug-induced-only type 1 (men, 420 [69%]; mean age, 44±14 years), multiple ECGs and 12-lead Holter were advised in order to detect the occurrence of a spontaneous type-1 BrECG pattern. Arrhythmic events were defined as sudden death or documented ventricular fibrillation or tachycardia.<br /><b>Results</b><br />Median follow-up was 6 (4-9) years. Seventeen (1.5%) arrhythmic events occurred in the overall asymptomatic population (corresponding to an event-rate of 0.2% per year), including 16 of 539 (0.4% per year) in patients with spontaneous type-1 BrECG and 1 of 610 in those with drug-induced type-1 BrECG (0.03% per year; <i>P</i><0.001). EPS was performed in 339 (63%) patients with spontaneous type-1 BrECG. Patients with spontaneous type-1 BrECG and positive EPS had significantly higher event rates than patients with negative EPS (7 of 103 [0.7% per year] versus 4 of 236 [0.2% per year]; <i>P</i>=0.025). Among 200 patients who declined EPS, 5 events (0.4% per year) occurred. There was 1 device-related death.<br /><b>Conclusions</b><br />The entire population of asymptomatic patients with BrECG exhibits a relatively low event rate per year, which is important in view of the long life expectancy of these young patients. The presence of spontaneous type-1 BrECG associated with positive EPS identifies a subgroup at higher risk. Asymptomatic patients with drug-induced-only BrECG have a minimal arrhythmic risk, but ongoing follow-up with 12-lead Holter monitoring is recommended to detect the appearance of spontaneous type-1 BrECG pattern.<br /><br /><br /><br /><small>Circulation: 13 Oct 2023; epub ahead of print</small></div>

<div><h4>Comparative Discrimination of Life\'s Simple 7 and Life\'s Essential 8 to Stratify Cardiovascular Risk: Is the Added Complexity Worth It?</h4><i>Howard G, Cushman M, Blair J, Wilson NR, ... Judd SE, Howard VJ</i><br /><b>Background</b><br />Life\'s Simple 7 (LS7) is an easily calculated and interpreted metric of cardiovascular health based on 7 domains: smoking, diet, physical activity, body mass index, blood pressure, cholesterol, and fasting glucose. The Life\'s Essential 8 (LE8) metric was subsequently introduced, adding sleep metrics and revisions of the previous 7 domains. Although calculating LE8 requires additional information, we hypothesized that it would be a more reliable index of cardiovascular health.<br /><b>Methods</b><br />Both the LS7 and LE8 metrics yield scores with higher values indicating lower risk. These were calculated among 11 609 Black and White participants free of baseline cardiovascular disease (CVD) in the Reasons for Geographic and Racial Differences in Stroke study, enrolled in 2003 to 2007, and followed for a median of 13 years. Differences in 10-year risk of incident CVD (coronary heart disease or stroke) were calculated as a function LS7, and LE8 scores were calculated using Kaplan-Meier and proportional hazards analyses. Differences in incident CVD discrimination were quantified by difference in the c-statistic.<br /><b>Results</b><br />For both LS7 and LE8, the 10-year risk was approximately 5% for participants around the 99th percentile of scores, and a 4× higher 20% risk for participants around the first percentile. Comparing LS7 to LE8, 10-year risk was nearly identical for individuals at the same relative position in score distribution. For example, the \"cluster\" of 2013 participants with an LS7 score of 7 was at the 35.8th percentile in distribution of LS7 scores, and had an estimated 10-year CVD risk of 8.4% (95% CI, 7.2%-9.8%). In a similar location in the LE8 distribution, the 1457 participants with an LE8 score of 60±2.5 at the 39.4th percentile of LE8 scores, with a 10-year risk of CVD of 8.5% (95% CI, 7.1%-10.1%), similar to the cluster defined by LS7. The age-race-sex adjusted c-statistic of the LS7 model was 0.691 (95% CI, 0.667-0.705), and 0.695 for LE8 (95% CI, 0.681-0.709) (<i>P</i> for difference, 0.12).<br /><b>Conclusions</b><br />Both LS7 and LE8 were associated with incident CVD, with discrimination of the 2 indices practically indistinguishable. As a simpler metric, LS7 may be favored for use by the general population and clinicians.<br /><br /><br /><br /><small>Circulation: 13 Oct 2023; epub ahead of print</small></div>

<div><h4>Dapagliflozin and Apparent Treatment-Resistant Hypertension in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The DELIVER Trial.</h4><i>Ostrominski JW, Vaduganathan M, Selvaraj S, Claggett BL, ... McMurray JJV, Solomon SD</i><br /><b>Background</b><br />Apparent treatment-resistant hypertension (aTRH) is prevalent and associated with adverse outcomes in heart failure with mildly reduced or preserved ejection fraction. Less is known about the potential role of sodium-glucose co-transporter 2 inhibition in this high-risk population. In this post hoc analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), we evaluated clinical profiles and treatment effects of dapagliflozin among participants with aTRH.<br /><b>Methods</b><br />DELIVER participants were categorized on the basis of baseline blood pressure (BP), with aTRH defined as BP ≥140/90 mm Hg (≥130/80 mm Hg if diabetes) despite treatment with 3 antihypertensive drugs including a diuretic. Nonresistant hypertension was defined as BP above threshold but not meeting aTRH criteria. Controlled BP was defined as BP under threshold. Incidence of the primary outcome (cardiovascular death or worsening heart failure event), key secondary outcomes, and safety events was assessed by baseline BP category.<br /><b>Results</b><br />Among 6263 DELIVER participants, 3766 (60.1%) had controlled BP, 1779 (28.4%) had nonresistant hypertension, and 718 (11.5%) had aTRH at baseline. Participants with aTRH had more cardiometabolic comorbidities and tended to have higher left ventricular ejection fraction and worse kidney function. Rates of the primary outcome were 8.7 per 100 patient-years in those with controlled BP, 8.5 per 100 patient-years in the nonresistant hypertension group, and 9.5 per 100 patient-years in the aTRH group. Relative treatment benefits of dapagliflozin versus placebo on the primary outcome were consistent across BP categories (<i>P</i><sub>interaction</sub>=0.114). Participants with aTRH exhibited the greatest absolute reduction in the rate of primary events with dapagliflozin (4.1 per 100 patient-years) compared with nonresistant hypertension (2.7 per 100 patient-years) and controlled BP (0.8 per 100 patient-years). Irrespective of assigned treatment, participants with aTRH experienced a higher rate of reported vascular events, including myocardial infarction and stroke, over study follow-up. Dapagliflozin modestly reduced systolic BP (by ≈1 to 3 mm Hg) without increasing risk of hypotension, hypovolemia, or other serious adverse events, irrespective of BP category, but did not improve the proportion of participants with aTRH attaining goal BP over time.<br /><b>Conclusions</b><br />aTRH was identified in >1 in 10 patients with heart failure and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin consistently improved clinical outcomes and was well-tolerated, including among those with aTRH.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03619213.<br /><br /><br /><br /><small>Circulation: 13 Oct 2023; epub ahead of print</small></div>

<div><h4>Effects of Synchronizing Foot Strike and Cardiac Phase on Exercise Hemodynamics in Patients With Cardiac Resynchronization Therapy: A Within-Subjects Pilot Study to Fine-Tune Cardio-Locomotor Coupling for Heart Failure.</h4><i>Wakeham DJ, Ivey E, Saland S, Lewis J, ... Hieda M, Levine BD</i><br /><b>Background</b><br />Despite advances in medical and cardiac resynchronization therapy (CRT), individuals with chronic congestive heart failure (CHF) have persistent symptoms, including exercise intolerance. Optimizing cardio-locomotor coupling may increase stroke volume and skeletal muscle perfusion as previously shown in healthy runners. Therefore, we tested the hypothesis that exercise stroke volume and cardiac output would be higher during fixed-paced walking when steps were synchronized with the diastolic compared with systolic portion of the cardiac cycle in patients with CHF and CRT.<br /><b>Methods</b><br />Ten participants (58±17 years of age; 40% female) with CHF and previously implanted CRT pacemakers completed 5-minute bouts of walking on a treadmill (range, 1.5-3 mph). Participants were randomly assigned to walking to an auditory tone to synchronize their foot strike to either the systolic (0% or 100±15% of the R-R interval) or diastolic phase (45±15% of the R-R interval) of their cardiac cycle and underwent assessments of oxygen uptake (V̇o<sub>2</sub>; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples <i>t</i> tests.<br /><b>Results</b><br />V̇o<sub>2</sub> was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min; <i>P</i>=0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL; <i>P</i>=0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min; <i>P</i>=0.004) were higher during diastolic walking; heart rate (paced) was not different between conditions. Mean arterial pressure was significantly lower during diastolic walking (85±12 versus 98±20 mm Hg; <i>P</i>=0.007).<br /><b>Conclusions</b><br />In patients with CHF who have received CRT, diastolic stepping increases stroke volume and oxygen delivery and decreases afterload. We speculate that, if added to pacemakers, this cardio-locomotor coupling technology may maximize CRT efficiency and increase exercise participation and quality of life in patients with CHF.<br /><br /><br /><br /><small>Circulation: 13 Oct 2023; epub ahead of print</small></div>

<div><h4>A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association.</h4><i>Ndumele CE, Neeland IJ, Tuttle KR, Chow SL, ... Rangaswami J, American Heart Association</i><br /><AbstractText>A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.</AbstractText><br /><br /><br /><br /><small>Circulation: 09 Oct 2023; epub ahead of print</small></div>

<div><h4>Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association.</h4><i>Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, ... Elkind MSV, American Heart Association</i><br /><AbstractText>Cardiovascular-kidney-metabolic health reflects the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system and has profound impacts on morbidity and mortality. There are multisystem consequences of poor cardiovascular-kidney-metabolic health, with the most significant clinical impact being the high associated incidence of cardiovascular disease events and cardiovascular mortality. There is a high prevalence of poor cardiovascular-kidney-metabolic health in the population, with a disproportionate burden seen among those with adverse social determinants of health. However, there is also a growing number of therapeutic options that favorably affect metabolic risk factors, kidney function, or both that also have cardioprotective effects. To improve cardiovascular-kidney-metabolic health and related outcomes in the population, there is a critical need for (1) more clarity on the definition of cardiovascular-kidney-metabolic syndrome; (2) an approach to cardiovascular-kidney-metabolic staging that promotes prevention across the life course; (3) prediction algorithms that include the exposures and outcomes most relevant to cardiovascular-kidney-metabolic health; and (4) strategies for the prevention and management of cardiovascular disease in relation to cardiovascular-kidney-metabolic health that reflect harmonization across major subspecialty guidelines and emerging scientific evidence. It is also critical to incorporate considerations of social determinants of health into care models for cardiovascular-kidney-metabolic syndrome and to reduce care fragmentation by facilitating approaches for patient-centered interdisciplinary care. This presidential advisory provides guidance on the definition, staging, prediction paradigms, and holistic approaches to care for patients with cardiovascular-kidney-metabolic syndrome and details a multicomponent vision for effectively and equitably enhancing cardiovascular-kidney-metabolic health in the population.</AbstractText><br /><br /><br /><br /><small>Circulation: 09 Oct 2023; epub ahead of print</small></div>

<div><h4>Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial.</h4><i>Sidik NP, Stanley B, Sykes R, Morrow AJ, ... McConnachie A, Berry C</i><br /><b>Background</b><br />We investigated the usefulness of invasive coronary function testing to diagnose the cause of angina in patients with no obstructive coronary arteries.<br /><b>Methods</b><br />Outpatients referred for coronary computed tomography angiography in 3 hospitals in the United Kingdom were prospectively screened. After coronary computed tomography angiography, patients with unobstructed coronary arteries, and who consented, underwent invasive endotyping. The diagnostic assessments included coronary angiography, fractional flow reserve (patient excluded if ≤0.80), and, for those without obstructive coronary artery disease, coronary flow reserve (abnormal <2.0), index of microvascular resistance (abnormal ≥25), and intracoronary infusion of acetylcholine (0.182, 1.82, and 18.2 μg/mL; 2 mL/min for 2 minutes) to assess for microvascular and coronary spasm. Participants were randomly assigned to disclosure of the results of the coronary function tests to the invasive cardiologist (intervention group) or nondisclosure (control group, blinded). In the control group, a diagnosis of vasomotor angina was based on medical history, noninvasive tests, and coronary angiography. The primary outcome was the between-group difference in the reclassification rate of the initial diagnosis on the basis of coronary computed tomography angiography versus the final diagnosis after invasive endotyping. The Seattle Angina Questionnaire summary score and Treatment Satisfaction Questionnaire for Medication were secondary outcomes.<br /><b>Results</b><br />Of 322 eligible patients, 250 (77.6%) underwent invasive endotyping; 19 (7.6%) had obstructive coronary disease, 127 (55.0%) had microvascular angina, 27 (11.7%) had vasospastic angina, 17 (7.4%) had both, and 60 (26.0%) had no abnormality. A total of 231 patients (mean age, 55.7 years; 64.5% women) were randomly assigned and followed up (median duration, 19.9 [12.6-26.9] months). The clinician diagnosed vasomotor angina in 51 (44.3%) patients in the intervention group and in 55 (47.4%) patients in the control group. After randomization, patients in the intervention group were 4-fold (odds ratio, 4.05 [95% CI, 2.32-7.24]; <i>P</i><0.001) more likely to be diagnosed with a coronary vasomotor disorder; the frequency of this diagnosis increased to 76.5%. The frequency of normal coronary function (ie, no vasomotor disorder) was not different between the groups before randomization (51.3% versus 50.9%) but was reduced in the intervention group after randomization (23.5% versus 50.9%, <i>P</i><0.001). At 6 and 12 months, the Seattle Angina Questionnaire summary score in the intervention versus control groups was 59.2±24.2 (2.3±16.2 change from baseline) versus 60.4±23.9 (4.6±16.4 change) and 63.7±23.5 (4.7±14.7 change) versus 66.0±19.3 (7.9±17.1 change), respectively, and not different between groups (global <i>P</i>=0.36). Compared with the control group, global treatment satisfaction was higher in the intervention group at 12 months (69.9±22.8 versus 61.7±26.9, <i>P</i>=0.013).<br /><b>Conclusions</b><br />For patients with angina and no obstructive coronary arteries, a diagnosis informed by invasive functional assessment had no effect on long-term angina burden, whereas treatment satisfaction improved.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03477890.<br /><br /><br /><br /><small>Circulation: 05 Oct 2023; epub ahead of print</small></div>

<div><h4>Longitudinal Follow-Up of Children With HLHS and Association Between Norwood Shunt Type and Long-Term Outcomes: The SVRIII Study.</h4><i>Goldberg CS, Trachtenberg F, William Gaynor J, Mahle WT, ... Newburger JW, Pediatric Heart Network Investigators</i><br /><b>Objective</b><br />In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age.<br /><b>Methods</b><br />Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival.<br /><b>Results</b><br />Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; <i>P</i>=0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; <i>P</i>=0.11), percentage predicted peak Vo<sub>2</sub> for age and sex (74±18% [n=91] versus 72±18% [n=84]; <i>P</i>=0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; <i>P</i>=0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; <i>P</i>=0.04) and of catheter interventions (14 versus 10 per 100 patient-years; <i>P</i>=0.01), but had similar rates of other complications.<br /><b>Conclusions</b><br />By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo<sub>2</sub>, complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT00115934.<br /><br /><br /><br /><small>Circulation: 05 Oct 2023; epub ahead of print</small></div>

<div><h4>Nondental Invasive Procedures and Risk of Infective Endocarditis: Time for a Revisit: A Science Advisory From the American Heart Association.</h4><i>Baddour LM, Janszky I, Thornhill MH, Esquer Garrigos Z, ... Dayer MJ, American Heart Association Council on Lifelong Congenital Heart Disease and Heart Health in the Young (Young Hearts) and Council on Cardiovascular and Stroke Nursing</i><br /><AbstractText>There have been no published prospective randomized clinical trials that have: (1) established an association between invasive dental and nondental invasive procedures and risk of infective endocarditis; or (2) defined the efficacy and safety of antibiotic prophylaxis administered in the setting of invasive procedures in the prevention of infective endocarditis in high-risk patients. Moreover, previous observational studies that examined the association of nondental invasive procedures with the risk of infective endocarditis have been limited by inadequate sample size. They have typically focused on a few potential at-risk surgical and nonsurgical invasive procedures. However, recent investigations from Sweden and England that used nationwide databases and demonstrated an association between nondental invasive procedures, and the subsequent development of infective endocarditis (in particular, in high-risk patients with infective endocarditis) prompted the development of the current science advisory.</AbstractText><br /><br /><br /><br /><small>Circulation: 05 Oct 2023; epub ahead of print</small></div>

<div><h4>Blood Pressure and Oxygen Targets on Kidney Injury After Cardiac Arrest.</h4><i>Rasmussen SB, Jeppesen KK, Kjaergaard J, Hassager C, ... Stengaard Meyer MA, Møller JE</i><br /><b>Background</b><br />Acute kidney injury (AKI) represents a common and serious complication to out-of-hospital cardiac arrest. The importance of post-resuscitation care targets for blood pressure and oxygenation for the development of AKI is unknown.<br /><b>Methods</b><br />This is a substudy of a randomized 2-by-2 factorial trial, in which 789 comatose adult patients who had out-of-hospital cardiac arrest with presumed cardiac cause and sustained return of spontaneous circulation were randomly assigned to a target mean arterial blood pressure of either 63 or 77 mm Hg. Patients were simultaneously randomly assigned to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao<sub>2</sub>) of 9 to 10 kPa or a liberal oxygenation target of a Pao<sub>2</sub> of 13 to 14 kPa. The primary outcome for this study was AKI according to KDIGO (Kidney Disease: Improving Global Outcomes) classification in patients surviving at least 48 hours (N=759). Adjusted logistic regression was performed for patients allocated to high blood pressure and liberal oxygen target as reference.<br /><b>Results</b><br />The main population characteristics at admission were: age, 64 (54-73) years; 80% male; 90% shockable rhythm; and time to return of spontaneous circulation, 18 (12-26) minutes. Patients allocated to a low blood pressure and liberal oxygen target had an increased risk of developing AKI compared with patients with high blood pressure and liberal oxygen target (84/193 [44%] versus 56/187 [30%]; adjusted odds ratio, 1.87 [95% CI, 1.21-2.89]). Multinomial logistic regression revealed that the increased risk of AKI was only related to mild-stage AKI (KDIGO stage 1). There was no difference in risk of AKI in the other groups. Plasma creatinine remained high during hospitalization in the low blood pressure and liberal oxygen target group but did not differ between groups at 6- and 12-month follow-up.<br /><b>Conclusions</b><br />In comatose patients who had been resuscitated after out-of-hospital cardiac arrest, patients allocated to a combination of a low mean arterial blood pressure and a liberal oxygen target had a significantly increased risk of mild-stage AKI. No difference was found in terms of more severe AKI stages or other kidney-related adverse outcomes, and creatinine had normalized at 1 year after discharge.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03141099.<br /><br /><br /><br /><small>Circulation: 04 Oct 2023; epub ahead of print</small></div>

<div><h4>Standardized Definitions for Cardiogenic Shock Research and Mechanical Circulatory Support Devices: Scientific Expert Panel From the Shock Academic Research Consortium (SHARC).</h4><i>Waksman R, Pahuja M, van Diepen S, Proudfoot AG, ... Krucoff M, Abraham WT</i><br /><AbstractText>The Shock Academic Research Consortium is a multi-stakeholder group, including representatives from the US Food and Drug Administration and other government agencies, industry, and payers, convened to develop pragmatic consensus definitions useful for the evaluation of clinical trials enrolling patients with cardiogenic shock, including trials evaluating mechanical circulatory support devices. Several in-person and virtual meetings were convened between 2020 and 2022 to discuss the need for developing the standardized definitions required for evaluation of mechanical circulatory support devices in clinical trials for cardiogenic shock patients. The expert panel identified key concepts and topics by performing literature reviews, including previous clinical trials, while recognizing current challenges and the need to advance evidence-based practice and statistical analysis to support future clinical trials. For each category, a lead (primary) author was assigned to perform a literature search and draft a proposed definition, which was presented to the subgroup. These definitions were further modified after feedback from the expert panel meetings until a consensus was reached. This manuscript summarizes the expert panel recommendations focused on outcome definitions, including efficacy and safety.</AbstractText><br /><br /><br /><br /><small>Circulation: 03 Oct 2023; 148:1113-1126</small></div>

<div><h4>Association Between Mental Health Burden, Clinical Presentation, and Outcomes in Individuals With Symptomatic Peripheral Artery Disease: A Scientific Statement From the American Heart Association.</h4><i>Smolderen KG, Samaan Z, Decker C, Collins T, ... Mena-Hurtado C, American Heart Association Council on Peripheral Vascular Disease; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Lifestyle and Cardiometabolic Health; and Council on Quality of Care and Outcomes Research</i><br /><AbstractText>Along with the rising burden of peripheral artery disease (PAD), mental health concerns are increasingly being recognized as a comorbidity to address in the chronic disease management of symptomatic PAD. Apart from a high prevalence of comorbid mental health conditions, the role of pain and changing health behaviors and the broader impacts of illness and adaptation to living with PAD require specialized behavioral health expertise. This scientific statement builds a case that this expertise should be integrated within the multidisciplinary PAD team. Furthermore, areas such as cognitive dysfunction and palliative care are highlighted as needing psychological interventions. Although much of the evidence of the efficacy of psychological and psychotropic interventions has been extrapolated from other cardiovascular populations, evidence for the role of psychological interventions for behavior change, for example, uptake of exercise regimens, is increasingly being accrued within PAD. Areas for behavioral health needs and interactions with PAD treatment are discussed, including the use of opioids, depression management, anxiety and stress reduction interventions, the use of benzodiazepines and antidepressants, smoking cessation, rehabilitation trajectories after amputation, and the role of cognitive decline for PAD treatment and outcomes. A case summary highlights the stigma around mental health and vascular disease and the fragmentation of care. This scientific statement provides remarks for building a road map for integrated behavioral PAD care and potential solutions to overcome these barriers. Instrumental to reaching these changes are interprofessional advocacy efforts and initiatives that help break down the stigma around mental health and promote evidence-based collaborative, nonhierarchical, and multidisciplinary PAD care.</AbstractText><br /><br /><br /><br /><small>Circulation: 02 Oct 2023; epub ahead of print</small></div>

<div><h4>BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Clonal Hematopoiesis.</h4><i>Yalcinkaya M, Liu W, Thomas LA, Olszewska M, ... Tabas I, Tall AR</i><br /><b>Background</b><br />Clonal hematopoiesis (CH) has emerged as an independent risk factor for atherosclerotic cardiovascular disease, with activation of macrophage inflammasomes as a potential underlying mechanism. The NLRP3 (NLR family pyrin domain containing 3) inflammasome has a key role in promoting atherosclerosis in mouse models of <i>Tet2</i> CH, whereas inhibition of the inflammasome product interleukin-1β appeared to particularly benefit patients with <i>TET2</i> CH in CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events]). <i>TET2</i> is an epigenetic modifier that decreases promoter methylation. However, the mechanisms underlying macrophage NLRP3 inflammasome activation in TET2 (Tet methylcytosine dioxygenase 2) deficiency and potential links with epigenetic modifications are poorly understood.<br /><b>Methods</b><br />We used cholesterol-loaded TET2-deficient murine and embryonic stem cell-derived isogenic human macrophages to evaluate mechanisms of NLRP3 inflammasome activation in vitro and hypercholesterolemic <i>Ldlr</i><sup>-<i>/</i>-</sup> mice modeling <i>TET2</i> CH to assess the role of NLRP3 inflammasome activation in atherosclerosis.<br /><b>Results</b><br /><i>Tet2</i> deficiency in murine macrophages acted synergistically with cholesterol loading in cell culture and with hypercholesterolemia in vivo to increase JNK1 (c-Jun N-terminal kinase 1) phosphorylation and NLRP3 inflammasome activation. The mechanism of JNK (c-Jun N-terminal kinase) activation in TET2 deficiency was increased promoter methylation and decreased expression of the JNK-inactivating dual-specificity phosphatase <i>Dusp10</i>. Active Tet1-deadCas9-targeted editing of <i>Dusp10</i> promoter methylation abolished cholesterol-induced inflammasome activation in <i>Tet2</i>-deficient macrophages. Increased JNK1 signaling led to NLRP3 deubiquitylation and activation by the deubiquitinase BRCC3 (<i>BRCA1/BRCA2</i>-containing complex subunit 3). Accelerated atherosclerosis and neutrophil extracellular trap formation (NETosis) in <i>Tet2</i> CH mice were reversed by holomycin, a BRCC3 deubiquitinase inhibitor, and also by hematopoietic deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex. Human <i>TET2</i><sup>-<i>/</i>-</sup> macrophages displayed increased JNK1 and NLRP3 inflammasome activation, especially after cholesterol loading, with reversal by holomycin treatment, indicating human relevance.<br /><b>Conclusions</b><br />Hypercholesterolemia and TET2 deficiency converge on a common pathway of NLRP3 inflammasome activation mediated by JNK1 activation and BRCC3-mediated NLRP3 deubiquitylation, with potential therapeutic implications for the prevention of cardiovascular disease in <i>TET2</i> CH.<br /><br /><br /><br /><small>Circulation: 02 Oct 2023; epub ahead of print</small></div>

<div><h4>An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract.</h4><i>Yamaguchi N, Chang EW, Lin Z, Shekhar A, ... Moskowitz IP, Park DS</i><br /><b>Background</b><br />Conotruncal defects due to developmental abnormalities of the outflow tract (OFT) are an important cause of cyanotic congenital heart disease. Dysregulation of transcriptional programs tuned by NKX2-5, GATA6, and TBX1 have been implicated in abnormal OFT morphogenesis. However, there remains no consensus on how these transcriptional programs function in a unified gene regulatory network within the OFT.<br /><b>Methods</b><br />We generated mice harboring a 226-nucleotide deletion of a highly conserved cardiac enhancer containing 2 GATA-binding sites located ≈9.4 kb upstream of the transcriptional start site of <i>Nkx2-5</i> (<i>Nkx2-5</i><sup><i>∆enh</i></sup>) using CRISPR-Cas9 gene editing and assessed phenotypes. Cardiac defects in <i>Nkx2-5</i><sup><i>∆enh/∆enh</i></sup> mice were structurally characterized using histology and scanning electron micrography, and physiologically assessed using electrocardiography, echocardiography, and optical mapping. Transcriptome analyses were performed using RNA sequencing and single-cell RNA sequencing data sets. Endogenous GATA6 interaction with and activity on the <i>NKX2-5</i> enhancer was studied using chromatin immunoprecipitation sequencing and transposase-accessible chromatin sequencing in human induced pluripotent stem cell-derived cardiomyocytes.<br /><b>Results</b><br /><i>Nkx2-5</i><sup><i>∆enh/∆enh</i></sup> mice recapitulated cyanotic conotruncal defects seen in patients with <i>NKX2-5, GATA6,</i> and <i>TBX1</i> mutations. <i>Nkx2-5</i><sup><i>∆enh/∆enh</i></sup> mice also exhibited defects in right Purkinje fiber network formation, resulting in right bundle-branch block. Enhancer deletion reduced embryonic <i>Nkx2-5</i> expression selectively in the right ventricle and OFT of mutant hearts, indicating that enhancer activity is localized to the anterior second heart field. Transcriptional profiling of the mutant OFT revealed downregulation of important genes involved in OFT rotation and septation, such as <i>Tbx1, Pitx2,</i> and <i>Sema3c</i>. Endogenous GATA6 interacted with the highly conserved enhancer in human induced pluripotent stem cell-derived cardiomyocytes and in wild-type mouse hearts. We found critical dose dependency of cardiac enhancer accessibility on GATA6 gene dosage in human induced pluripotent stem cell-derived cardiomyocytes.<br /><b>Conclusions</b><br />Our results using human and mouse models reveal an essential gene regulatory network of the OFT that requires an anterior second heart field enhancer to link GATA6 with NKX2-5-dependent rotation and septation gene programs.<br /><br /><br /><br /><small>Circulation: 29 Sep 2023; epub ahead of print</small></div>

<div><h4>Computed Tomography Cardiac Angiography Before Invasive Coronary Angiography in Patients With Previous Bypass Surgery: The BYPASS-CTCA Trial.</h4><i>Jones DA, Beirne AM, Kelham M, Rathod KS, ... Mathur A, BYPASS-CTCA Trial Committees and Investigators</i><br /><b>Background</b><br />Patients with previous coronary artery bypass grafting often require invasive coronary angiography (ICA). However, for these patients, the procedure is technically more challenging and has a higher risk of complications. Observational studies suggest that computed tomography cardiac angiography (CTCA) may facilitate ICA in this group, but this has not been tested in a randomized controlled trial.<br /><b>Methods</b><br />This study was a single-center, open-label randomized controlled trial assessing the benefit of adjunctive CTCA in patients with previous coronary artery bypass grafting referred for ICA. Patients were randomized 1:1 to undergo CTCA before ICA or ICA alone. The co-primary end points were procedural duration of the ICA (defined as the interval between local anesthesia administration for obtaining vascular access and removal of the last catheter), patient satisfaction after ICA using a validated questionnaire, and the incidence of contrast-induced nephropathy. Linear regression was used for procedural duration and patient satisfaction score; contrast-induced nephropathy was analyzed using logistic regression. We applied the Bonferroni correction, with <i>P</i><0.017 considered significant and 98.33% CIs presented. Secondary end points included incidence of procedural complications and 1-year major adverse cardiac events.<br /><b>Results</b><br />Over 3 years, 688 patients were randomized with a median follow-up of 1.0 years. The mean age was 69.8±10.4 years, 108 (15.7%) were women, 402 (58.4%) were White, and there was a high burden of comorbidity (85.3% hypertension and 53.8% diabetes). The median time from coronary artery bypass grafting to angiography was 12.0 years, and there were a median of 3 (interquartile range, 2 to 3) grafts per participant. Procedure duration of the ICA was significantly shorter in the CTCA+ICA group (CTCA+ICA, 18.6±9.5 minutes versus ICA alone, 39.5±16.9 minutes [98.33% CI, -23.5 to -18.4]; <i>P</i><0.001), alongside improved mean ICA satisfaction scores (1=very good to 5=very poor; -1.1 difference [98.33% CI, -1.2 to -0.9]; <i>P</i><0.001), and reduced incidence of contrast-induced nephropathy (3.4% versus 27.9%; odds ratio, 0.09 [98.33% CI, 0.04-0.2]; <i>P</i><0.001). Procedural complications (2.3% versus 10.8%; odds ratio, 0.2 [95% CI, 0.1-0.4]; <i>P</i><0.001) and 1-year major adverse cardiac events (16.0% versus 29.4%; hazard ratio, 0.4 [95% CI, 0.3-0.6]; <i>P</i><0.001) were also lower in the CTCA+ICA group.<br /><b>Conclusions</b><br />For patients with previous coronary artery bypass grafting, CTCA before ICA leads to reductions in procedure time and contrast-induced nephropathy, with improved patient satisfaction. CTCA before ICA should be considered in this group of patients.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03736018.<br /><br /><br /><br /><small>Circulation: 29 Sep 2023; epub ahead of print</small></div>

<div><h4>Food Is Medicine: A Presidential Advisory From the American Heart Association.</h4><i>Volpp KG, Berkowitz SA, Sharma SV, Anderson CAM, ... Zachariah JPV, American Heart Association</i><br /><AbstractText>Unhealthy diets are a major impediment to achieving a healthier population in the United States. Although there is a relatively clear sense of what constitutes a healthy diet, most of the US population does not eat healthy food at rates consistent with the recommended clinical guidelines. An abundance of barriers, including food and nutrition insecurity, how food is marketed and advertised, access to and affordability of healthy foods, and behavioral challenges such as a focus on immediate versus delayed gratification, stand in the way of healthier dietary patterns for many Americans. Food Is Medicine may be defined as the provision of healthy food resources to prevent, manage, or treat specific clinical conditions in coordination with the health care sector. Although the field has promise, relatively few studies have been conducted with designs that provide strong evidence of associations between Food Is Medicine interventions and health outcomes or health costs. Much work needs to be done to create a stronger body of evidence that convincingly demonstrates the effectiveness and cost-effectiveness of different types of Food Is Medicine interventions. An estimated 90% of the $4.3 trillion annual cost of health care in the United States is spent on medical care for chronic disease. For many of these diseases, diet is a major risk factor, so even modest improvements in diet could have a significant impact. This presidential advisory offers an overview of the state of the field of Food Is Medicine and a road map for a new research initiative that strategically approaches the outstanding questions in the field while prioritizing a human-centered design approach to achieve high rates of patient engagement and sustained behavior change. This will ideally happen in the context of broader efforts to use a health equity-centered approach to enhance the ways in which our food system and related policies support improvements in health.</AbstractText><br /><br /><br /><br /><small>Circulation: 28 Sep 2023; epub ahead of print</small></div>

<div><h4>Biodegradable-Polymer or Durable-Polymer Stents in Patients at High Bleeding Risk: A Randomized, Open-Label Clinical Trial.</h4><i>Valgimigli M, Wlodarczak A, Tölg R, Merkely B, ... Cayla G, Bioflow-DAPT Investigators</i><br /><b>Background</b><br />Limited information is available on the comparative efficacy and safety of different stent platforms in patients at high bleeding risk undergoing an abbreviated dual antiplatelet therapy duration after percutaneous coronary intervention (PCI). The aim of this study was to compare the safety and effectiveness of the biodegradable-polymer sirolimus-eluting stent with the durable-polymer zotarolimus-eluting stent in patients at high bleeding risk receiving 1 month of dual antiplatelet therapy after PCI.<br /><b>Methods</b><br />The Bioflow-DAPT Study is an international, randomized, open-label trial conducted at 52 interventional cardiology hospitals in 18 countries from February 24, 2020, through September 20, 2021. Patients with a clinical indication to PCI because of acute or chronic coronary syndrome who fulfilled 1 or more criteria for high bleeding risk were eligible for enrollment. Patients were randomized to receive either biodegradable-polymer sirolimus-eluting stents or durable-polymer, slow-release zotarolimus-eluting stents after successful lesion preparation, followed by 1 month of dual antiplatelet therapy and thereafter single antiplatelet therapy. The primary outcome was the composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year, and was powered for noninferiority, with an absolute margin of 4.1% at 1-sided 5% alpha.<br /><b>Results</b><br />A total of 1948 patients at high bleeding risk were randomly assigned (1:1) to receive biodegradable-polymer sirolimus-eluting stents (969 patients) or durable-polymer zotarolimus-eluting stents (979 patients). At 1 year, the primary outcome was observed in 33 of 969 patients (3.6%) in the biodegradable-polymer sirolimus-eluting stent group and in 32 of 979 patients (3.4%) in the durable-polymer zotarolimus-eluting stent group (risk difference, 0.2 percentage points; upper boundary of the 1-sided 95% CI, 1.8; upper boundary of the 1-sided 97.5% CI, 2.1; <i>P</i><0.0001 for noninferiority for both tests).<br /><b>Conclusions</b><br />Among patients at high risk for bleeding who received 1 month of dual antiplatelet therapy after PCI, the use of biodegradable-polymer sirolimus-eluting stents was noninferior to the use of durable-polymer zotarolimus-eluting stents with regard to the composite of death from cardiac causes, myocardial infarction, or stent thrombosis.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04137510.<br /><br /><br /><br /><small>Circulation: 26 Sep 2023; 148:989-999</small></div>

<div><h4>Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure.</h4><i>Packer M, Butler J, Zeller C, Pocock SJ, ... Zannad F, Anker SD</i><br /><b>Background</b><br />It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy.<br /><b>Methods</b><br />In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment.<br /><b>Results</b><br />From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), <i>P</i>=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, <i>P</i>=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (<i>P</i><0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all <i>P</i><0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients.<br /><b>Conclusions</b><br />These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifiers: NCT03057977 and NCT03057951.<br /><br /><br /><br /><small>Circulation: 26 Sep 2023; 148:1011-1022</small></div>

<div><h4>Expanding the Paradigm for Cardiovascular Palliative Care.</h4><i>Godfrey S, Kirkpatrick JN, Kramer DB, Sulistio MS</i><br /><AbstractText>Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite medical advances, patients with CVD experience high morbidity and mortality rates, affecting their quality of life and death. Among CVD conditions, palliative care has been studied mostly in patients with heart failure, where palliative care interventions have been associated with improvements in patient-centered outcomes, including quality of life, end-of-life care, and health care use. Although palliative care is now incorporated into the American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines for heart failure, the role of palliative care for non-heart failure CVD remains uncertain. Across all causes of CVD, palliative care can play an important role in all domains of CVD care from initial diagnosis to terminal care. In addition to general cardiovascular palliative care practices applicable to all areas, disease-specific palliative care needs may warrant individualized palliative care models. In this review, we discuss the role of cardiovascular palliative care for ischemic heart disease, valvular disease, arrhythmias, peripheral artery disease, and adult congenital heart disease. Although there are multiple barriers to cardiovascular palliative care, we recommend a framework for studying and developing cardiovascular palliative care models to improve patient-centered goal-concordant care for this underserved patient population.</AbstractText><br /><br /><br /><br /><small>Circulation: 26 Sep 2023; 148:1039-1052</small></div>

<div><h4>Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.</h4><i>Henriksen PA, Hall P, MacPherson IR, Joshi SS, ... Oikonomidou O, Lang NN</i><br /><b>Background</b><br />Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy.<br /><b>Methods</b><br />In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%.<br /><b>Results</b><br />Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; <i>P</i>=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; <i>P</i>=0.92, not equivalent).<br /><b>Conclusions</b><br />Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline.<br /><b>Registration</b><br />URL: https://doi.org/10.1186/ISRCTN24439460; Unique identifier, ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2017-000896-99; Unique identifier: EudraCT 2017-000896-99.<br /><br /><br /><br /><small>Circulation: 25 Sep 2023; epub ahead of print</small></div>

<div><h4>Bivalirudin Versus Heparin During PCI in NSTEMI: Individual Patient Data Meta-Analysis of Large Randomized Trials.</h4><i>Bikdeli B, Erlinge D, Valgimigli M, Kastrati A, ... Zhou Z, Stone GW</i><br /><b>Background</b><br />The benefit:risk profile of bivalirudin versus heparin anticoagulation in patients with non-ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) is uncertain. Study-level meta-analyses lack granularity to provide conclusive answers. We sought to compare the outcomes of bivalirudin and heparin in patients with non-ST-segment-elevation myocardial infarction undergoing PCI.<br /><b>Methods</b><br />We performed an individual patient data meta-analysis of patients with non-ST-segment-elevation myocardial infarction in all 5 trials that randomized ≥1000 patients with any myocardial infarction undergoing PCI to bivalirudin versus heparin (MATRIX, VALIDATE-SWEDEHEART, ISAR-REACT 4, ACUITY [Acute Catheterization and Urgent Intervention Triage Strategy], and BRIGHT). The primary effectiveness and safety end points were 30-day all-cause mortality and serious bleeding.<br /><b>Results</b><br />A total of 12 155 patients were randomized: 6040 to bivalirudin (52.3% with a post-PCI bivalirudin infusion), and 6115 to heparin (53.2% with planned glycoprotein IIb/IIIa inhibitor use). Thirty-day mortality was not significantly different between bivalirudin and heparin (1.2% versus 1.1%; adjusted odds ratio, 1.24 [95% CI, 0.86-1.79]; <i>P</i>=0.25). Cardiac mortality, reinfarction, and stent thrombosis rates were also not significantly different. Bivalirudin reduced serious bleeding (both access site-related and non-access site-related) compared with heparin (3.3% versus 5.5%; adjusted odds ratio, 0.59; 95% CI, 0.48-0.72; <i>P</i><0.0001). Outcomes were consistent regardless of use of a post-PCI bivalirudin infusion or routine lycoprotein IIb/IIIa inhibitor use with heparin and during 1-year follow-up.<br /><b>Conclusions</b><br />In patients with non-ST-segment-elevation myocardial infarction undergoing PCI, procedural anticoagulation with bivalirudin and heparin did not result in significantly different rates of mortality or ischemic events, including stent thrombosis and reinfarction. Bivalirudin reduced serious bleeding compared with heparin arising both from the access site and nonaccess sites.<br /><br /><br /><br /><small>Circulation: 25 Sep 2023; epub ahead of print</small></div>

<div><h4>Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis.</h4><i>Ma P, Liu J, Qin J, Lai L, ... Moslehi J, Lavine KJ</i><br /><b>Background</b><br />Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages.<br /><b>Methods</b><br />We used an established murine ICI myocarditis model (<i>Ctla4</i><sup><i>+/-</i></sup><i>Pdcd1</i><sup><i>-/-</i></sup> mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies.<br /><b>Results</b><br />We observed marked increases in CCR2 (C-C chemokine receptor type 2)<sup>+</sup> monocyte-derived macrophages and CD8<sup>+</sup> T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2<sup>+</sup> subpopulation highly expressing <i>Cxcl9</i> (chemokine [C-X-C motif] ligand 9), <i>Cxcl10</i> (chemokine [C-X-C motif] ligand 10), <i>Gbp2b</i> (interferon-induced guanylate-binding protein 2b), and <i>Fcgr4</i> (Fc receptor, IgG, low affinity IV) that originated from CCR2<sup>+</sup> monocytes. It is important that a similar macrophage population expressing <i>CXCL9</i>, <i>CXCL10</i>, and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and <i>Cxcl9</i><sup><i>+</i></sup><i>Cxcl10</i><sup><i>+</i></sup> macrophages by IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8<sup>+</sup> T-cells, macrophages, and blockade of IFN-γ signaling blunted the expansion of <i>Cxcl9</i><sup><i>+</i></sup><i>Cxcl10</i><sup><i>+</i></sup> macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis.<br /><b>Conclusions</b><br />These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition.<br /><br /><br /><br /><small>Circulation: 25 Sep 2023; epub ahead of print</small></div>

<div><h4>Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis.</h4><i>Jex N, Greenwood JP, Cubbon RM, Rider OJ, ... Dweck MR, Levelt E</i><br /><b>Background</b><br />Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR.<br /><b>Methods</b><br />Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (71 years of age [69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing.<br /><b>Results</b><br />Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (median [interquartile range]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; <i>P</i><0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; <i>P</i><0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; <i>P</i>=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; <i>P</i>=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; <i>P</i>=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; <i>P</i>=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; <i>P</i>=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; <i>P</i>=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; <i>P</i>=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; <i>P</i>=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D.<br /><b>Conclusions</b><br />Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.<br /><br /><br /><br /><small>Circulation: 25 Sep 2023; epub ahead of print</small></div>

<div><h4>Cardiovascular Imaging in Contemporary Cardio-Oncology: A Scientific Statement From the American Heart Association.</h4><i>Addison D, Neilan TG, Barac A, Scherrer-Crosbie M, ... Zaha VG, American Heart Association Council on Cardiovascular Radiology and Intervention; Cardio-Oncology Committee of the Council on Clinical Cardiology and Council on Genomic and Precision Medicine; and Council on Cardiovascular and Stroke Nursing</i><br /><AbstractText>Advances in cancer therapeutics have led to dramatic improvements in survival, now inclusive of nearly 20 million patients and rising. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Advances in cardiovascular imaging have solidified the critical role for robust methods for detecting, monitoring, and prognosticating cardiac risk among patients with cancer. However, decentralized evaluations have led to a lack of consensus on the optimal uses of imaging in contemporary cancer treatment (eg, immunotherapy, targeted, or biological therapy) settings. Similarly, available isolated preclinical and clinical studies have provided incomplete insights into the effectiveness of multiple modalities for cardiovascular imaging in cancer care. The aims of this scientific statement are to define the current state of evidence for cardiovascular imaging in the cancer treatment and survivorship settings and to propose novel methodological approaches to inform the optimal application of cardiovascular imaging in future clinical trials and registries. We also propose an evidence-based integrated approach to the use of cardiovascular imaging in routine clinical settings. This scientific statement summarizes and clarifies available evidence while providing guidance on the optimal uses of multimodality cardiovascular imaging in the era of emerging anticancer therapies.</AbstractText><br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES).</h4><i>Choi DY, Hayes D, Maidman SD, Dhaduk N, ... Donnino R, Smilowitz NR</i><br /><b>Background</b><br />Preoperative cardiovascular risk stratification before noncardiac surgery is a common clinical challenge. Coronary artery calcium scores from ECG-gated chest computed tomography (CT) imaging are associated with perioperative events. At the time of preoperative evaluation, many patients will not have had ECG-gated CT imaging, but will have had nongated chest CT studies performed for a variety of noncardiac indications. We evaluated relationships between coronary calcium severity estimated from previous nongated chest CT imaging and perioperative major clinical events (MCE) after noncardiac surgery.<br /><b>Methods</b><br />We retrospectively identified consecutive adults age ≥45 years who underwent in-hospital, major nongated surgery from 2016 to 2020 at a large academic health system composed of 4 acute care centers. All patients had nongated (contrast or noncontrast) chest CT imaging performed within 1 year before surgery. Coronary calcium in each vessel was retrospectively graded from absent to severe using a 0 to 3 scale (absent, mild, moderate, severe) by physicians blinded to clinical data. The estimated coronary calcium burden (ECCB) was computed as the sum of scores for each coronary artery (0 to 9 scale). A Revised Cardiac Risk Index was calculated for each patient. Perioperative MCE was defined as all-cause death or myocardial infarction within 30 days of surgery.<br /><b>Results</b><br />A total of 2554 patients (median age, 68 years; 49.7% women; median Revised Cardiac Risk Index, 1) were included. The median time interval from nongated chest CT imaging to nongated surgery was 15 days (interquartile range, 3-106 days). The median ECCB was 1 (interquartile range, 0-3). Perioperative MCE occurred in 136 (5.2%) patients. Higher ECCB values were associated with stepwise increases in perioperative MCE (0: 2.9%, 1-2: 3.7%, 3-5: 8.0%; 6-9: 12.6%, <i>P</i><0.001). Addition of ECCB to a model with the Revised Cardiac Risk Index improved the C-statistic for MCE (from 0.675 to 0.712, <i>P</i>=0.018), with a net reclassification improvement of 0.428 (95% CI, 0.254-0.601, <i>P</i><0.0001). An ECCB ≥3 was associated with 2-fold higher adjusted odds of MCE versus an ECCB <3 (adjusted odds ratio, 2.11 [95% CI, 1.42-3.12]).<br /><b>Conclusions</b><br />Prevalence and severity of coronary calcium obtained from existing nongated chest CT imaging improve preoperative clinical risk stratification before nongated surgery.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Oral Anticoagulation Use and Left Atrial Appendage Occlusion in LAAOS III.</h4><i>Connolly SJ, Healey JS, Belley-Cote EP, Balasubramanian K, ... Yusuf S, Whitlock RP</i><br /><b>Background</b><br />LAAOS III (Left Atrial Appendage Occlusion Study III) showed that left atrial appendage (LAA) occlusion reduces the risk of ischemic stroke or systemic embolism in patients with atrial fibrillation undergoing cardiac surgery. This article examines the effect of LAA occlusion on stroke reduction according to variation in the use of oral anticoagulants (OACs).<br /><b>Methods</b><br />Information regarding OAC use was collected at every follow-up visit. Adjusted proportional hazards modeling, including using landmarks of hospital discharge, 1 and 2 years after randomization, evaluated the effect of LAA occlusion on the risk of ischemic stroke or systemic embolism, according to OAC use. Adjusted proportional hazard modeling, with OAC use as a time-dependent covariate, was also performed to assess the effect of LAA occlusion, according to OAC use throughout the study.<br /><b>Results</b><br />At hospital discharge, 3027 patients (63.5%) were receiving a vitamin K antagonist, and 879 (18.5%) were receiving a non-vitamin K antagonist oral anticoagulant (direct OAC), with no difference in OAC use between treatment arms. There were 2887 (60.5%) patients who received OACs at all follow-up visits, 1401 (29.4%) who received OAC at some visits, and 472 (9.9%) who never received OACs. The effect of LAA occlusion on the risk of ischemic stroke or systemic embolism was consistent after discharge across all 3 groups: hazard ratios of 0.70 (95% CI, 0.51-0.96), 0.63 (95% CI, 0.43-0.94), and 0.76 (95% CI, 0.32-1.79), respectively. An adjusted proportional hazards model with OAC use as a time-dependent covariate showed that the reduction in stroke or systemic embolism with LAA occlusion was similar whether patients were receiving OACs or not.<br /><b>Conclusions</b><br />The benefit of LAA occlusion was consistent whether patients were receiving OACs or not. LAA occlusion provides thromboembolism reduction in patients independent of OAC use.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.</h4><i>Cheng YC, Hsieh ML, Lin CJ, Chang CMC, ... Kamp TJ, Hsieh PCH</i><br /><b>Background</b><br />Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs.<br /><b>Methods</b><br />We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in NOD-SCID mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated.<br /><b>Results</b><br />We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion.<br /><b>Conclusions</b><br />These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.</h4><i>Aggarwal R, Ruff CT, Virdone S, Perreault S, ... Shen C, Yeh RW</i><br /><b>Background</b><br />Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs).<br /><b>Methods</b><br />Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l\'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score.<br /><b>Results</b><br />Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit <i>P</i>=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; <i>P</i><0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; <i>P</i> for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; <i>P</i> for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; <i>P</i> for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; <i>P</i> for difference <0.001).<br /><b>Conclusions</b><br />In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.<br /><br /><br /><br /><small>Circulation: 19 Sep 2023; 148:936-946</small></div>

<div><h4>2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.</h4><i>Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, ... Drennan IR, American Heart Association</i><br /><AbstractText>In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, β-adrenergic receptor antagonists (also known as β-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.</AbstractText><br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>Mental Health Conditions Among Children and Adolescents With Congenital Heart Disease: A Danish Population-Based Cohort Study.</h4><i>Miles KG, Farkas DK, Laugesen K, Sørensen HT, Kasparian NA, Madsen N</i><br /><b>Background</b><br />Despite the known mental health burden among children with congenital heart disease (CHD), the literature is constrained by a lack of comparison cohorts and population-based follow-up data. We examined the incidence of mental health conditions among children with CHD, relative to 3 comparison cohorts.<br /><b>Methods</b><br />This population-based cohort study identified all children with CHD (<18 years of age; n=16 473) in Denmark from 1996 to 2017, through linkage of individual-level data across national registries. This allowed for complete follow-up of the population. Comparison cohorts included children from the general population (n=162 204), siblings of children with CHD (n=20 079), and children with non-CHD major congenital anomalies (n=47 799). Mental health conditions were identified using inpatient and outpatient hospital discharge codes, prescription data, and data on use of community-based psychology, psychiatry, and psychotherapy services. We computed cumulative incidence by 18 years of age, incidence rates, and adjusted hazard ratios (aHRs) using Cox regression. aHRs accounted for sex, year of CHD diagnosis, parental mental health, and socioeconomic status. All estimates were stratified by age, sex, and CHD complexity.<br /><b>Results</b><br />The cumulative incidence of mental health conditions by 18 years of age in the CHD cohort was 35.1% (95% CI, 34.0%-36.1%), corresponding to aHRs of 1.64 (95% CI, 1.58-1.71), 1.41 (95% CI, 1.30-1.52), and 1.02 (95% CI, 0.98-1.07) compared with the general population, sibling, and major congenital anomaly cohorts, respectively. Mental health incidence rates showed prominent peaks in early childhood and adolescence. Males and children with severe or single-ventricle CHD demonstrated higher incidence rates of mental health conditions relative to females and children with mild or moderate CHD, respectively. Compared with the general population and sibling cohorts, incidence rates and aHRs in the CHD cohort were highest for severe stress reactions, attention deficit/hyperactivity disorder, intellectual disability, and autism spectrum disorder. Compared with children in the major congenital anomaly cohort, the aHRs were close to 1.<br /><b>Conclusions</b><br />More than one-third of children with CHD were diagnosed or treated for a mental health condition by 18 years of age. Mental health conditions began early in life and were most prominent among males and children with severe or single-ventricle heart disease.<br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>DNA Damage and Nuclear Morphological Changes in Cardiac Hypertrophy Are Mediated by SNRK Through Actin Depolymerization.</h4><i>Stanczyk P, Tatekoshi Y, Shapiro JS, Nayudu K, ... Chang HC, Ardehali H</i><br /><b>Background</b><br />Proper nuclear organization is critical for cardiomyocyte function, because global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy; however, the mechanism for this process is not well delineated. AMPK (AMP-activated protein kinase) family of proteins regulates metabolism and DNA damage response (DDR). Here, we examine whether a member of this family, SNRK (SNF1-related kinase), which plays a role in cardiac metabolism, is also involved in hypertrophic remodeling through changes in DDR and structural properties of the nucleus.<br /><b>Methods</b><br />We subjected cardiac-specific <i>Snrk</i><sup>-/-</sup> mice to transaortic banding to assess the effect on cardiac function and DDR. In parallel, we modulated SNRK in vitro and assessed its effects on DDR and nuclear parameters. We also used phosphoproteomics to identify novel proteins that are phosphorylated by SNRK. Last, coimmunoprecipitation was used to verify Destrin (DSTN) as the binding partner of SNRK that modulates its effects on the nucleus and DDR.<br /><b>Results</b><br />Cardiac-specific <i>Snrk</i><sup>-/-</sup> mice display worse cardiac function and cardiac hypertrophy in response to transaortic banding, and an increase in DDR marker pH2AX (phospho-histone 2AX) in their hearts. In addition, in vitro <i>Snrk</i> knockdown results in increased DNA damage and chromatin compaction, along with alterations in nuclear flatness and 3-dimensional volume. Phosphoproteomic studies identified a novel SNRK target, DSTN, a member of F-actin depolymerizing factor proteins that directly bind to and depolymerize F-actin. SNRK binds to DSTN, and DSTN downregulation reverses excess DNA damage and changes in nuclear parameters, in addition to cellular hypertrophy, with SNRK knockdown. We also demonstrate that SNRK knockdown promotes excessive actin depolymerization, measured by the increased ratio of G-actin to F-actin. Last, jasplakinolide, a pharmacological stabilizer of F-actin, rescues the increased DNA damage and aberrant nuclear morphology in SNRK-downregulated cells.<br /><b>Conclusions</b><br />These results indicate that SNRK is a key player in cardiac hypertrophy and DNA damage through its interaction with DSTN. This interaction fine-tunes actin polymerization to reduce DDR and maintain proper cardiomyocyte nuclear shape and morphology.<br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>Elimination of CaMKIIδ Autophosphorylation by CRISPR-Cas9 Base Editing Improves Survival and Cardiac Function in Heart Failure in Mice.</h4><i>Lebek S, Caravia XM, Chemello F, Tan W, ... Bassel-Duby R, Olson EN</i><br /><b>Background</b><br />Cardiovascular diseases are the main cause of worldwide morbidity and mortality, highlighting the need for new therapeutic strategies. Autophosphorylation and subsequent overactivation of the cardiac stress-responsive enzyme CaMKIIδ (Ca<sup>2+</sup>/calmodulin-dependent protein kinase IIδ) serves as a central driver of multiple cardiac disorders.<br /><b>Methods</b><br />To develop a comprehensive therapy for heart failure, we used CRISPR-Cas9 adenine base editing to ablate the autophosphorylation site of CaMKIIδ. We generated mice harboring a phospho-resistant CaMKIIδ mutation in the germline and subjected these mice to severe transverse aortic constriction, a model for heart failure. Cardiac function, transcriptional changes, apoptosis, and fibrosis were assessed by echocardiography, RNA sequencing, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and standard histology, respectively. Specificity toward <i>CaMKIIδ</i> gene editing was assessed using deep amplicon sequencing. Cellular Ca<sup>2+</sup> homeostasis was analyzed using epifluorescence microscopy in Fura-2-loaded cardiomyocytes.<br /><b>Results</b><br />Within 2 weeks after severe transverse aortic constriction surgery, 65% of all wild-type mice died, and the surviving mice showed a dramatically impaired cardiac function. In contrast to wild-type mice, CaMKIIδ phospho-resistant gene-edited mice showed a mortality rate of only 11% and exhibited a substantially improved cardiac function after severe transverse aortic constriction. Moreover, CaMKIIδ phospho-resistant mice were protected from heart failure-related aberrant changes in cardiac gene expression, myocardial apoptosis, and subsequent fibrosis, which were observed in wild-type mice after severe transverse aortic constriction. On the basis of identical mouse and human genome sequences encoding the autophosphorylation site of <i>CaMKIIδ</i>, we deployed the same editing strategy to modify this pathogenic site in human induced pluripotent stem cells. It is notable that we detected a >2000-fold increased specificity for editing of <i>CaMKIIδ</i> compared with other <i>CaMKII</i> isoforms, which is an important safety feature. Although wild-type cardiomyocytes showed impaired Ca<sup>2+</sup> transients and an increased frequency of arrhythmias after chronic β-adrenergic stress, <i>CaMKIIδ</i>-edited cardiomyocytes were protected from these adverse responses.<br /><b>Conclusions</b><br />Ablation of CaMKIIδ autophosphorylation by adenine base editing may offer a potential broad-based therapeutic concept for human cardiac disease.<br /><br /><br /><br /><small>Circulation: 15 Sep 2023; epub ahead of print</small></div>

<div><h4>ANGPTL3 Deficiency and Risk of Hepatic Steatosis.</h4><i>D\'Erasmo L, Di Martino M, Neufeld T, Fraum TJ, ... Arca M, Stitziel NO</i><br /><b>Background</b><br />ANGPTL3 (angiopoietin-like 3 protein) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3.<br /><b>Methods</b><br />The authors recruited participants with ANGPTL3 deficiency related to <i>ANGPTL3</i> loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study.<br /><b>Results</b><br />We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to <i>ANGPTL3</i> LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; <i>P</i><0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; <i>P</i><0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 7.9%; partial deficiency, 6.4%; WT, 6.9%; <i>P</i>>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (<i>P</i>=1.7×10<sup>-17</sup>) and triglycerides (<i>P</i>=3.2×10<sup>-18</sup>) but not with hepatic fat (<i>P</i>=0.22).<br /><b>Conclusions</b><br />ANGPTL3 deficiency related to LoF mutations in <i>ANGPTL3</i>, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.<br /><br /><br /><br /><small>Circulation: 15 Sep 2023; epub ahead of print</small></div>

<div><h4>Implementation of Prevention Science to Eliminate Health Care Inequities in Achieving Cardiovascular Health: A Scientific Statement From the American Heart Association.</h4><i>Agarwala A, Patel J, Stephens J, Roberson S, ... Jackson EA, American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention and Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council</i><br /><AbstractText>Prevention of cardiovascular and related diseases is foundational to attaining ideal cardiovascular health to improve the overall health and well-being of individuals and communities. Social determinants of health and health care inequities adversely affect ideal cardiovascular health and prevention of disease. Achieving optimal cardiovascular health in an effective and equitable manner requires a coordinated multidisciplinary and multilayered approach. In this scientific statement, we examine barriers to ideal cardiovascular health and its related conditions in the context of leveraging existing resources to reduce health care inequities and to optimize the delivery of preventive cardiovascular care. We systematically discuss (1) interventions across health care environments involving direct patient care, (2) leveraging health care technology, (3) optimizing multispecialty/multiprofession collaborations and interventions, (4) engaging local communities, and (5) improving the community environment through health-related government policies, all with a focus on making ideal cardiovascular health equitable for all individuals.</AbstractText><br /><br /><br /><br /><small>Circulation: 12 Sep 2023; epub ahead of print</small></div>

<div><h4>Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction.</h4><i>Cochran J, Yura Y, Thel MC, Doviak H, ... Dyck JRB, Walsh K</i><br /><b>Background</b><br />Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model.<br /><b>Methods</b><br />Using a panel of 20 candidate CH driver genes and a variant allele frequency cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%).<br /><b>Results</b><br />Compared with controls, there was an enrichment of <i>TET2</i>-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; <i>P</i>=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e\' (14.9 versus 11.7, respectively; <i>P</i>=0.0096) and E/A (1.69 versus 0.89, respectively; <i>P</i>=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of 59 individuals with HFpEF. In accordance, patients with HFpEF with CH and age ≥70 years exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; <i>P</i>=0.042) compared with patients with HFpEF without CH and age ≥70 years. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with <i>Tet2</i>-wild-type or <i>Tet2</i>-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (N<sub>ω</sub>-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of <i>Tet2</i>-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e\' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the <i>Tet2</i>-wild-type condition.<br /><b>Conclusions</b><br />CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of <i>Tet2</i>-mediated CH displays greater features of HFpEF.<br /><br /><br /><br /><small>Circulation: 08 Sep 2023; epub ahead of print</small></div>

<div><h4>Changes in Cardiovascular Spending, Care Utilization, and Clinical Outcomes Associated With Participation in Bundled Payments for Care Improvement Advanced.</h4><i>Shashikumar SA, Zheng J, Orav EJ, Epstein AM, Joynt Maddox KE</i><br /><b>Background</b><br />Bundled Payments for Care Improvement Advanced (BPCI-A) is a Medicare initiative that aims to incentivize reductions in spending for episodes of care that start with a hospitalization and end 90 days after discharge. Cardiovascular disease, an important driver of Medicare spending, is one of the areas of focus BPCI-A. It is unknown whether BPCI-A is associated with spending reductions or quality improvements for the 3 cardiovascular medical events or 5 cardiovascular procedures in the model.<br /><b>Methods</b><br />In this retrospective cohort study, we conducted difference-in-differences analyses using Medicare claims for patients discharged between January 1, 2017, and September 30, 2019, to assess differences between BPCI-A hospitals and matched nonparticipating control hospitals. Our primary outcomes were the differential changes in spending, before versus after implementation of BPCI-A, for cardiac medical and procedural conditions at BPCI-A hospitals compared with controls. Secondary outcomes included changes in patient complexity, care use, healthy days at home, readmissions, and mortality.<br /><b>Results</b><br />Baseline spending for cardiac medical episodes at BPCI-A hospitals was $25 606. The differential change in spending for cardiac medical episodes at BPCI-A versus control hospitals was $16 (95% CI, -$228 to $261; <i>P</i>=0.90). Baseline spending for cardiac procedural episodes at BPCI-A hospitals was $37 961. The differential change in spending for cardiac procedural episodes was $171 (95% CI, -$429 to $772; <i>P</i>=0.58). There were minimal differential changes in physicians\' care patterns such as the complexity of treated patients or in their care use. At BPCI-A versus control hospitals, there were no significant differential changes in rates of 90-day readmissions (differential change, 0.27% [95% CI, -0.25% to 0.80%] for medical episodes; differential change, 0.31% [95% CI, -0.98% to 1.60%] for procedural episodes) or mortality (differential change, -0.14% [95% CI, -0.50% to 0.23%] for medical episodes; differential change, -0.36% [95% CI, -1.25% to 0.54%] for procedural episodes).<br /><b>Conclusions</b><br />Participation in BPCI-A was not associated with spending reductions, changes in care use, or quality improvements for the cardiovascular medical events or procedures offered in the model.<br /><br /><br /><br /><small>Circulation: 08 Sep 2023; epub ahead of print</small></div>

<div><h4>Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease.</h4><i>Xu Y, Chang AR, Inker LA, McAdams-DeMarco M, Grams ME, Shin JI</i><br /><b>Background</b><br />Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown.<br /><b>Methods</b><br />With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose.<br /><b>Results</b><br />Among 4313 apixaban new users, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. Patients treated with 5 mg apixaban were younger (mean age, 72 versus 80 years), with greater weight (95 versus 80 kg) and higher serum creatinine (2.7 versus 2.5 mg/dL). Mean estimated glomerular filtration rate was not different between the groups (24 versus 24 mL·min<sup>-1</sup>·1.73 m<sup>-2</sup>). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]).<br /><b>Conclusions</b><br />Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration.<br /><br /><br /><br /><small>Circulation: 08 Sep 2023; epub ahead of print</small></div>

<div><h4>Cost-Effectiveness of Vericiguat in Patients With Heart Failure With Reduced Ejection Fraction: The VICTORIA Randomized Clinical Trial.</h4><i>Chew DS, Li Y, Bigelow R, Cowper PA, ... Mark DB, VICTORIA Study Group</i><br /><b>Background</b><br />The VICTORIA trial (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) demonstrated that, in patients with high-risk heart failure, vericiguat reduced the primary composite outcome of cardiovascular death or heart failure hospitalization relative to placebo. The hazard ratio for all-cause mortality was 0.95 (95% CI, 0.84-1.07). In a prespecified analysis, treatment effects varied substantially as a function of baseline NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, with survival benefit for vericiguat in the lower NT-proBNP quartiles (hazard ratio, 0.82 [95% CI, 0.69-0.97]) and no benefit in the highest NT-proBNP quartile (hazard ratio, 1.14 [95% CI, 0.95-1.38]). An economic analysis was a major secondary objective of the VICTORIA research program.<br /><b>Methods</b><br />Medical resource use data were collected for all VICTORIA patients (N=5050). Costs were estimated by applying externally derived US cost weights to resource use counts. Life expectancy was projected from patient-level empirical trial survival results with the use of age-based survival modeling methods. Quality-of-life adjustments were based on prospectively collected EQ-5D-based utilities. The primary outcome was the incremental cost-effectiveness ratio, comparing vericiguat with placebo, assessed from the US health care sector perspective over a lifetime horizon. Cost-effectiveness was estimated using the total VICTORIA cohort, both with and without interaction between treatment and baseline NT-proBNP.<br /><b>Results</b><br />Life expectancy modeling results varied according to whether the observed heterogeneity of treatment effect by baseline NT-proBNP values was incorporated into the modeling. Including the interaction term, the vericiguat arm had an estimated quality-adjusted life expectancy of 4.56 quality-adjusted life-years (QALYs) compared with 4.13 QALYs for placebo (incremental discounted QALY, 0.43). Without the treatment heterogeneity/interaction term, vericiguat had 4.50 QALYs compared with 4.33 QALYs for placebo (incremental discounted QALY, 0.17). Incremental discounted costs (vericiguat minus placebo) were $28 546 with the treatment interaction and $20 948 without it. Corresponding incremental cost-effectiveness ratios were $66 509 per QALY allowing for treatment heterogeneity and $124 512 without heterogeneity.<br /><b>Conclusions</b><br />Vericiguat use in the VICTORIA trial met criteria for intermediate value, but the incremental cost-effectiveness ratio estimates were sensitive to whether the analysis accounted for observed NT-proBNP treatment effect heterogeneity. The cost-effectiveness of vericiguat was driven by the projected incremental life expectancy among patients in the lowest 3 quartiles of NT-proBNP.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT02861534.<br /><br /><br /><br /><small>Circulation: 06 Sep 2023; epub ahead of print</small></div>

<div><h4>Principles for Health Information Collection, Sharing, and Use: A Policy Statement From the American Heart Association.</h4><i>Spector-Bagdady K, Armoundas AA, Arnaout R, Hall JL, ... Chung MK, American Heart Association Advocacy Coordinating Committee</i><br /><AbstractText>The evolution of the electronic health record, combined with advances in data curation and analytic technologies, increasingly enables data sharing and harmonization. Advances in the analysis of health-related and health-proxy information have already accelerated research discoveries and improved patient care. This American Heart Association policy statement discusses how broad data sharing can be an enabling driver of progress by providing data to develop, test, and benchmark innovative methods, scalable insights, and potential new paradigms for data storage and workflow. Along with these advances come concerns about the sensitive nature of some health data, equity considerations about the involvement of historically excluded communities, and the complex intersection of laws attempting to govern behavior. Data-sharing principles are therefore necessary across a wide swath of entities, including parties who collect health information, funders, researchers, patients, legislatures, commercial companies, and regulatory departments and agencies. This policy statement outlines some of the key equity and legal background relevant to health data sharing and responsible management. It then articulates principles that will guide the American Heart Association\'s engagement in public policy related to data collection, sharing, and use to continue to inform its work across the research enterprise, as well as specific examples of how these principles might be applied in the policy landscape. The goal of these principles is to improve policy to support the use or reuse of health information in ways that are respectful of patients and research participants, equitable in impact in terms of both risks and potential benefits, and beneficial across broad and demographically diverse communities in the United States.</AbstractText><br /><br /><br /><br /><small>Circulation: 30 Aug 2023; epub ahead of print</small></div>

<div><h4>Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study.</h4><i>Hofmeyer M, Haas GJ, Jordan E, Cao J, ... Hershberger RE, DCM Precision Medicine Study of the DCM Consortium</i><br /><b>Background</b><br />Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied.<br /><b>Methods</b><br />We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link.<br /><b>Results</b><br />Patients\' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD.<br /><b>Conclusions</b><br />Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03037632.<br /><br /><br /><br /><small>Circulation: 29 Aug 2023; epub ahead of print</small></div>