<div><h4>Merging machine learning and patient preference: a novel tool for risk prediction of percutaneous coronary interventions.</h4><i>Hamilton DE, Albright J, Seth M, Painter I, ... Sukul D, Gurm HS</i><br /><b>Background:</b><br/>and aims</b><br />Predicting personalized risk for adverse events following percutaneous coronary intervention (PCI) remains critical in weighing treatment options, employing risk mitigation strategies, and enhancing shared decision-making. This study aimed to employ machine learning models using pre-procedural variables to accurately predict common post-PCI complications.<br /><b>Methods</b><br />A group of 66 adults underwent a semiquantitative survey assessing a preferred list of outcomes and model display. The machine learning cohort included 107 793 patients undergoing PCI procedures performed at 48 hospitals in Michigan between 1 April 2018 and 31 December 2021 in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) registry separated into training and validation cohorts. External validation was conducted in the Cardiac Care Outcomes Assessment Program database of 56 583 procedures in 33 hospitals in Washington.<br /><b>Results</b><br />Overall rate of in-hospital mortality was 1.85% (n = 1999), acute kidney injury 2.51% (n = 2519), new-onset dialysis 0.44% (n = 462), stroke 0.41% (n = 447), major bleeding 0.89% (n = 942), and transfusion 2.41% (n = 2592). The model demonstrated robust discrimination and calibration for mortality {area under the receiver-operating characteristic curve [AUC]: 0.930 [95% confidence interval (CI) 0.920-0.940]}, acute kidney injury [AUC: 0.893 (95% CI 0.883-0.903)], dialysis [AUC: 0.951 (95% CI 0.939-0.964)], stroke [AUC: 0.751 (95%CI 0.714-0.787)], transfusion [AUC: 0.917 (95% CI 0.907-0.925)], and major bleeding [AUC: 0.887 (95% CI 0.870-0.905)]. Similar discrimination was noted in the external validation population. Survey subjects preferred a comprehensive list of individually reported post-procedure outcomes.<br /><b>Conclusions</b><br />Using common pre-procedural risk factors, the BMC2 machine learning models accurately predict post-PCI outcomes. Utilizing patient feedback, the BMC2 models employ a patient-centred tool to clearly display risks to patients and providers (https://shiny.bmc2.org/pci-prediction/). Enhanced risk prediction prior to PCI could help inform treatment selection and shared decision-making discussions.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 21 Feb 2024; 45:601-609</small></div>

<div><h4>Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.</h4><i>Ahn HJ, An HY, Ryu G, Lim J, ... Koh Y, Choi EK</i><br /><b>Background:</b><br/>and aims</b><br />Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF.<br /><b>Methods</b><br />Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort.<br /><b>Results</b><br />The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E\', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death).<br /><b>Conclusions</b><br />CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 07 Mar 2024; 45:778-790</small></div>

<div><h4>Aspirin-free antiplatelet strategies after percutaneous coronary interventions.</h4><i>Capranzano P, Moliterno D, Capodanno D</i><br /><AbstractText>Dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor inhibitor is the standard antithrombotic treatment after percutaneous coronary interventions (PCI). Several trials have challenged guideline-recommended DAPT after PCI by testing the relative clinical effect of an aspirin-free antiplatelet approach-consisting of P2Y12 inhibitor monotherapy after a short course (mostly 1-3 months) of DAPT-among patients undergoing PCI without a concomitant indication for oral anticoagulation (OAC). Overall, these studies have shown P2Y12 inhibitor monotherapy after short DAPT to be associated with a significant reduction in the risk of bleeding without an increase in thrombotic or ischaemic events compared with continued DAPT. Moreover, the effects of the P2Y12 inhibitor monotherapy without prior DAPT or following a very short course of DAPT after PCI are being investigated in emerging studies, of which one has recently reported unfavourable efficacy results associated with the aspirin-free approach compared with conventional DAPT. Finally, P2Y12 inhibitor alone has been compared with aspirin alone as chronic therapy after DAPT discontinuation, thus challenging the historical role of aspirin as a standard of care for secondary prevention following PCI. A thorough understanding of study designs, populations, treatments, results, and limitations of trials testing P2Y12 inhibitor monotherapy vs. DAPT or vs. aspirin is required to consider adopting this treatment in clinical practice. This review addresses the use of aspirin-free antiplatelet strategies among patients undergoing PCI without a concomitant indication for OAC, providing an overview of clinical evidence, guideline indications, practical implications, ongoing issues, and future perspectives.</AbstractText><br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 21 Feb 2024; 45:572-585</small></div>

<div><h4>Artificial intelligence-derived risk score for mortality in secondary mitral regurgitation treated by transcatheter edge-to-edge repair: the EuroSMR risk score.</h4><i>Hausleiter J, Lachmann M, Stolz L, Bedogni F, ... Rudolph V, EuroSMR Investigators </i><br /><b>Background:</b><br/>and aims</b><br />Risk stratification for mitral valve transcatheter edge-to-edge repair (M-TEER) is paramount in the decision-making process to appropriately select patients with severe secondary mitral regurgitation (SMR). This study sought to develop and validate an artificial intelligence-derived risk score (EuroSMR score) to predict 1-year outcomes (survival or survival + clinical improvement) in patients with SMR undergoing M-TEER.<br /><b>Methods</b><br />An artificial intelligence-derived risk score was developed from the EuroSMR cohort (4172 and 428 patients treated with M-TEER in the derivation and validation cohorts, respectively). The EuroSMR score was validated and compared with established risk models.<br /><b>Results</b><br />The EuroSMR risk score, which is based on 18 clinical, echocardiographic, laboratory, and medication parameters, allowed for an improved discrimination of surviving and non-surviving patients (hazard ratio 4.3, 95% confidence interval 3.7-5.0; P < .001), and outperformed established risk scores in the validation cohort. Prediction for 1-year mortality (area under the curve: 0.789, 95% confidence interval 0.737-0.842) ranged from <5% to >70%, including the identification of an extreme-risk population (2.6% of the entire cohort), which had a very high probability for not surviving beyond 1 year (hazard ratio 6.5, 95% confidence interval 3.0-14; P < .001). The top 5% of patients with the highest EuroSMR risk scores showed event rates of 72.7% for mortality and 83.2% for mortality or lack of clinical improvement at 1-year follow-up.<br /><b>Conclusions</b><br />The EuroSMR risk score may allow for improved prognostication in heart failure patients with severe SMR, who are considered for a M-TEER procedure. The score is expected to facilitate the shared decision-making process with heart team members and patients.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 14 Mar 2024; 45:922-936</small></div>

<div><h4>C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project.</h4><i>Arnold N, Blaum C, Goßling A, Brunner FJ, ... Koenig W, Waldeyer C</i><br /><b>Background:</b><br/>and aims</b><br />Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population.<br /><b>Methods</b><br />Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L).<br /><b>Results</b><br />Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024).<br /><b>Conclusions</b><br />While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 27 Mar 2024; 45:1043-1054</small></div>

<div><h4>The American Heart Association Emergency Cardiovascular Care 2030 Impact Goals and Call to Action to Improve Cardiac Arrest Outcomes: A Scientific Statement From the American Heart Association.</h4><i>Merchant RM, Becker LB, Brooks SC, Chan PS, ... Sasson C, American Heart Association</i><br /><AbstractText>Every 10 years, the American Heart Association (AHA) Emergency Cardiovascular Care Committee establishes goals to improve survival from cardiac arrest. These goals align with broader AHA Impact Goals and support the AHA\'s advocacy efforts and strategic investments in research, education, clinical care, and quality improvement programs. This scientific statement focuses on 2030 AHA emergency cardiovascular care priorities, with a specific focus on bystander cardiopulmonary resuscitation, early defibrillation, and neurologically intact survival. This scientific statement also includes aspirational goals, such as establishing cardiac arrest as a reportable disease and mandating reporting of standardized outcomes from different sources; advancing recognition of and knowledge about cardiac arrest; improving dispatch system response, availability, and access to resuscitation training in multiple settings and at multiple time points; improving availability, access, and affordability of defibrillators; providing a focus on early defibrillation, in-hospital programs, and establishing champions for debriefing and review of cardiac arrest events; and expanding measures to track outcomes beyond survival. The ability to track and report data from these broader aspirational targets will potentially require expansion of existing data sets, development of new data sets, and enhanced integration of technology to collect process and outcome data, as well as partnerships of the AHA with national, state, and local organizations. The COVID-19 (coronavirus disease 2019) pandemic, disparities in COVID-19 outcomes for historically excluded racial and ethnic groups, and the longstanding disparities in cardiac arrest treatment and outcomes for Black and Hispanic or Latino populations also contributed to an explicit focus and target on equity for the AHA Emergency Cardiovascular Care 2030 Impact Goals.</AbstractText><br /><br /><br /><br /><small>Circulation: 20 Mar 2024; 149:e914-e933</small></div>

<div><h4>Effect of Gamification, Financial Incentives, or Both to Increase Physical Activity Among Patients at High Risk of Cardiovascular Events: The BE ACTIVE Randomized Controlled Trial.</h4><i>Fanaroff AC, Patel MS, Chokshi N, Coratti S, ... Small DS, Volpp KGM</i><br /><b>Background</b><br />Physical activity is associated with a lower risk of major adverse cardiovascular events, but few individuals achieve guideline recommended levels of physical activity. Strategies informed by behavioral economics increase physical activity, but their longer-term effectiveness is uncertain. We sought to determine the effect of behaviorally-designed gamification, loss-framed financial incentives, or the combination on physical activity compared with attention control over 12-month intervention and 6-month post-intervention follow-up periods.<br /><b>Methods</b><br />Between May 2019 and January 2024, participants with clinical ASCVD or 10-year risk of myocardial infarction, stroke, or cardiovascular death ≥ 7.5% by the pooled cohort equation were enrolled in a pragmatic randomized clinical trial. Participants received a wearable device to track daily steps, established a baseline, selected a step goal increase, and were randomly assigned to control (n = 151), behaviorally-designed gamification (n = 304), loss-framed financial incentives (n = 302), or gamification + financial incentives (n = 305). The trial\'s primary outcome was change in mean daily steps from baseline through the 12-month intervention period.<br /><b>Results</b><br />A total of 1062 patients (mean [SD] age 67 [8], 61% female, 31% non-white) were enrolled. Compared with controls, participants had significantly greater increases in mean daily steps from baseline during the 12-month intervention in the gamification arm (adjusted difference, 538.0; 95% CI, 186.2-889.9; <i>P</i> = 0.0027), financial incentives arm (adjusted difference, 491.8; 95% CI, 139.6-844.1; <i>P</i> = 0.0062), and gamification + financial incentives arm (adjusted difference, 868.0; 95% CI, 516.3-1219.7; <i>P</i> < 0.0001). During 6-month follow-up, physical activity remained significantly greater in the gamification + financial incentives arm than in the control arm (adjusted difference, 576.2; 95% CI, 198.5-954; <i>P</i> = 0.0028) but was not significantly greater in the gamification (adjusted difference, 459.8; 95% CI, 82.0-837.6; <i>P</i> = 0.0171) or financial incentives (adjusted difference, 327.9; 95% CI, -50.2 to 706; <i>P</i> = 0.09) arms, after adjusting for multiple comparisons.<br /><b>Conclusions</b><br />Behaviorally-designed gamification, loss-framed financial incentives, and the combination of both increased physical activity compared with control over a 12-month intervention period, with the largest effect in gamification + financial incentives. These interventions could be a useful component of strategies to reduce cardiovascular risk in high-risk patients.<br /><br /><br /><br /><small>Circulation: 07 Apr 2024; epub ahead of print</small></div>

<div><h4>2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.</h4><i>Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, ... Palaniappan LP, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee</i><br /><b>Background</b><br />The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).<br /><b>Methods</b><br />The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2024 AHA Statistical Update is the product of a full year\'s worth of effort in 2023 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. The AHA strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year\'s edition includes additional global data, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains.<br /><b>Results</b><br />Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.<br /><b>Conclusions</b><br />The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.<br /><br /><br /><br /><small>Circulation: 20 Feb 2024; 149:e347-e913</small></div>

<div><h4>Role of the CCL5 and Its Receptor, CCR5, in the Genesis of Aldosterone-Induced Hypertension, Vascular Dysfunction, and End-Organ Damage.</h4><i>Costa RM, Cerqueira DM, Bruder-Nascimento A, Alves JV, ... Ho J, Bruder-Nascimento T</i><br /><b>Background</b><br />Aldosterone has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of CCL5 (C-C motif chemokine ligand 5) and its receptor CCR5 (C-C motif chemokine receptor 5) are well known in infectious diseases, their contributions to aldosterone-induced vascular injury and hypertension remain unknown.<br /><b>Methods</b><br />We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5<sup>+/+</sup>) and CCR5 knockout (CCR5<sup>-/-</sup>) mice treated with aldosterone (600 µg/kg per day for 14 days) while receiving 1% saline to drink. Vascular function was analyzed in aorta and mesenteric arteries, blood pressure was measured by telemetry and renal injury and inflammation were analyzed via histology and flow cytometry. Endothelial cells were used to study the molecular signaling whereby CCL5 induces endothelial dysfunction.<br /><b>Results</b><br />Aldosterone treatment resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression in CCR5<sup>+/+</sup> mice accompanied by endothelial dysfunction, hypertension, and renal inflammation and damage. CCR5<sup>-/-</sup> mice were protected from these aldosterone-induced effects. Mechanistically, we demonstrated that CCL5 increased NOX1 (NADPH oxidase 1) expression, reactive oxygen species formation, NFκB (nuclear factor kappa B) activation, and inflammation and reduced NO production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aorta incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking NOX1, NFκB, or CCR5.<br /><b>Conclusions</b><br />Our data demonstrate that CCL5/CCR5, through activation of NFκB and NOX1, is critically involved in aldosterone-induced vascular and renal damage and hypertension placing CCL5 and CCR5 as potential therapeutic targets for conditions characterized by aldosterone excess.<br /><br /><br /><br /><small>Hypertension: 01 Apr 2024; 81:776-786</small></div>

<div><h4>Atlas of Cell Repertoire Within Neointimal Lesions Is Metabolically Altered in Hypertensive Rats.</h4><i>Sun X, Wu J, Zhang X, Xie C, ... Cheng J, Xu Q</i><br /><b>Background</b><br />High blood pressure has been suggested to accelerate vascular injury-induced neointimal formation and progression. However, little is known about the intricate relationships between vascular injury and hypertension in the context of arterial remodeling.<br /><b>Methods</b><br />Single-cell RNA-sequencing analysis was used to depict the cell atlas of carotid arteries of Wistar Kyoto rats and spontaneously hypertensive rats with or without balloon injury.<br /><b>Results</b><br />We found that hypertension significantly aggravated balloon injury-induced arterial stenosis. A total of 36 202 cells from carotid arteries with or without balloon injury were included in single-cell RNA-sequencing analysis. Cell composition analysis showed that vascular injury and hypertension independently induced distinct aortic cell phenotypic alterations including immune cells, endothelial cells (ECs), and smooth muscle cells. Specifically, our data showed that injury and hypertension-induced specific EC phenotypic alterations, and revealed a transition from functional ECs to hypermetabolic, and eventually dysfunctional ECs in hypertensive rats upon balloon injury. Importantly, our data also showed that vascular injury and hypertension-induced different smooth muscle cell phenotypic alterations, characterized by deferential expression of synthetic signatures. Interestingly, pathway analysis showed that dysregulated metabolic pathways were a common feature in monocytes/macrophages, ECs, and smooth muscle cells in response to injury and hypertension. Functionally, we demonstrate that inhibition of mitochondrial respiration significantly ameliorated injury-induced neointimal formation in spontaneously hypertensive rats.<br /><b>Conclusions</b><br />This study provides the cell landscape changes of the main aortic cell phenotypic alterations in response to injury and hypertension. Our findings suggest that targeting cellular mitochondrial respiration could be a novel therapeutic for patients with hypertension undergoing vascular angioplasty.<br /><br /><br /><br /><small>Hypertension: 01 Apr 2024; 81:787-800</small></div>

<div><h4>Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors.</h4><i>Wijnker PJM, Dinani R, van der Laan NC, Algül S, ... Kuster DWD, van der Velden J</i><br /><b>Aims</b><br />Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation.<br /><b>Methods and results</b><br />Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring an HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7-R403Q) or cardiac troponin T (TNNT2-R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance the relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin\'s effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed, electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current.<br /><b>Conclusion</b><br />SGLT2i (canagliflozin > dapagliflozin > empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM.<br /><br />© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 14 Mar 2024; 120:301-317</small></div>

<div><h4>Renalase mediates macrophage-to-fibroblast crosstalk to attenuate pressure overload-induced pathological myocardial fibrosis.</h4><i>Fu R, You N, Li R, Zhao X, ... Li X, Jiang W</i><br /><AbstractText>A potential antifibrotic mechanism in pathological myocardial remodeling is the recruitment of beneficial functional subpopulations of macrophages or the transformation of their phenotype. Macrophages are required to activate molecular cascades that regulate fibroblast behavior. Identifying mediators that activate the antifibrotic macrophage phenotype is tantamount to identifying the button that retards pathological remodeling of the myocardium; however, relevant studies are inadequate. Circulating renalase (RNLS) is mainly of renal origin, and cardiac myocytes also secrete it autonomously. Our previous studies revealed that RNLS delivers cell signaling to exert multiple cardiovascular protective effects, including the improvement of myocardial ischemia, and heart failure. Here, we further investigated the potential mechanism by which macrophage phenotypic transformation is targeted by RNLS to mediate stress load-induced myocardial fibrosis. Mice subjected to transverse aortic constriction (TAC) were used as a model of myocardial fibrosis. The co-incubation of macrophages and cardiac fibroblasts was used to study intercellular signaling. The results showed that RNLS co-localized with macrophages and reduced protein expression after cardiac pressure overload. TAC mice exhibited improved cardiac function and alleviated left ventricular fibrosis when exogenous RNLS was administered. Flow sorting showed that RNLS is essential for macrophage polarization towards a restorative phenotype (M2-like), thereby inhibiting myofibroblast activation, as proven by both mouse RAW264.7 and bone marrow-derived macrophage models. Mechanistically, we found that activated protein kinase B is a major pathway by which RNLS promotes M2 polarization in macrophages. RNLS may serve as a prognostic biomarker and a potential clinical candidate for the treatment of myocardial fibrosis.</AbstractText><br /><br />Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>J Hypertens: 01 Apr 2024; 42:629-643</small></div>

<div><h4>Incidences, risk factors, and clinical correlates of severe QT prolongation after the use of quetiapine or haloperidol.</h4><i>Wang CL, Wu VC, Lee CH, Wu CL, ... Huang YT, Chang SH</i><br /><b>Background</b><br />Case reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes.<br /><b>Objective</b><br />The purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users.<br /><b>Methods</b><br />This study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression.<br /><b>Results</b><br />Mean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95-4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44-3.66).<br /><b>Conclusion</b><br />More than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP.<br /><br />Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.<br /><br /><small>Heart Rhythm: 01 Mar 2024; 21:321-328</small></div>

<div><h4>Coronary Flow Reserve and Myocardial Resistance Reserve Changes After Transcatheter Aortic Valve Implantation in Aortic Stenosis.</h4><i>Gutiérrez-Barrios A, Cañadas-Pruaño D, Alfaro LM, Gheorghe L, ... Vázquez-García R, Toro-Cebada R</i><br /><AbstractText>Aortic valve stenosis (AS) induces an alteration in hemodynamic conditions that are responsible for coronary microvasculature impairment. Relief of AS by transcatheter aortic valve implantation (TAVI) is expected to improve the coronary artery hemodynamic. We aimed to assess the midterm effects of TAVI in coronary flow reserve (CFR) and myocardial resistance reserve (MRR) by a continuous intracoronary thermodilution technique. At-rest and hyperemic coronary flow was measured by a continuous thermodilution technique in 23 patients with AS and compared with that in 17 matched controls, and repeated 6 ± 3 months after TAVI in 11 of the patients with AS. In patients with AS, absolute coronary flow at rest was significantly greater, and absolute resistance at rest was significantly less, than in controls (p <0.01 for both), causing less CFR and MRR (1.73 ± 0.4 vs 2.85 ± 1.1, p <0.01 and 1.95 ± 0.4 vs 3.22 ± 1.4, p <0.01, respectively). TAVI implantation yielded a significant 35% increase in CFR (p >0.01) and a 39% increase in MRR (p <0.01) driven by absolute coronary flow at rest reduction (p = 0.03). In patients with AS, CFR and MRR determined by continuous thermodilution are significantly impaired. At 6-month follow-up, TAVI improves these indexes and partially relieves the pathophysiologic alterations, leading to a partial restoration of CFR and MRR.</AbstractText><br /><br />Copyright © 2024 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 01 Mar 2024; 214:109-114</small></div>

<div><h4>Comparison of interleukin-6 and high-sensitivity C-reactive protein for cardiovascular risk assessment: Findings from the MESA study.</h4><i>Ferreira JP, Vasques-Nóvoa F, Neves JS, Zannad F, Leite-Moreira A</i><br /><b>Background:</b><br/>and aims</b><br />Inflammation is a risk factor for major adverse cardiovascular events (MACE). Elevated levels of both high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL6) have been associated with MACE. However, few studies have compared IL6 to hsCRP for cardiovascular risk assessment. Using the MESA (Multi-Ethnic Study of Atherosclerosis) study cohort, we aim to compare IL6 to hsCRP.<br /><b>Methods</b><br />We divided IL6 and hsCRP by their median values and created 4 groups i.e., low-low, high-low, low-high and high-high. The median follow-up was 14 years.<br /><b>Results</b><br />6614 (97 %) participants had complete baseline IL6 and hsCRP data. The correlation between hsCRP and IL6 was modest (Rho = 0.53). IL6 ≥1.2 pg/mL (median) was present in 3309 participants, and hsCRP ≥1.9 mg/L (median) was present in 3339 participants. Compared to participants with low IL6 and low hsCRP, those with high IL6 and high hsCRP were older (64 vs. 60 years), more frequently women (63 % vs. 45 %), and with more cardiovascular co-morbidities. hsCRP outcome associations lost statistical significance when adjusting for IL6: MACE HR (95 %CI) 1.06 (0.93-1.20), p =0.39, whereas IL6 associations remained significant after adjusting for hsCRP: HR (95 %CI) 1.44 (1.25-1.64), p <0.001. The C-index of Framingham score for did not improve with hsCRP but improved with IL6. Compared to participants with low IL6 and low hsCRP, those with high IL6, regardless of hsCRP, experienced an increased risk of MACE, heart failure and mortality.<br /><b>Conclusions</b><br />In a diverse and asymptomatic population, IL6 showed a stronger association with atherosclerotic, heart failure and fatal outcomes than hsCRP.<br /><br />Copyright © 2024 Elsevier B.V. All rights reserved.<br /><br /><small>Atherosclerosis: 01 Mar 2024; 390:117461</small></div>

<div><h4>Complete Coronary Revascularization and Outcomes in Patients Who Underwent Coronary Artery Bypass Grafting: Insights from The REGROUP Trial.</h4><i>Belyayev L, Stock EM, Hattler B, Bakaeen FG, ... Biswas K, Zenati MA</i><br /><AbstractText>There is growing evidence in support of coronary complete revascularization (CR). Nonetheless, there is no universally accepted definition of CR in patients who undergo coronary bypass grafting surgery (CABG). We sought to investigate the outcomes of CR, defined as surgical revascularization of any territory supplied by a suitable coronary artery with ≥50% stenosis. We performed a preplanned subanalysis in the Randomized Trial of Endoscopic or Open Saphenous Vein Graft Harvesting (REGROUP) clinical trial cohort. Of 1,147 patients who underwent CABG, 810 (70.6%) received CR. The primary outcome was a composite of major adverse cardiac events (MACEs), including death from any cause, nonfatal myocardial infarction, or repeat revascularization over a median 4.7 years of follow-up. MACE occurred in 175 patients (21.6%) in the CR group and 86 patients (25.5%) in the incomplete revascularization (IR) group (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.67 to 1.13, p = 0.29). A total of 97 patients (12.0%) in the CR group and 48 patients (14.2%) in the IR group died (HR 0.93, 95% CI 0.65 to 1.32, p = 0.67); nonfatal myocardial infarction occurred in 49 patients (6.0%) in the CR group and 30 patients (8.9%) in the IR group (HR 0.76, 95% CI 0.48 to 1.2, p = 0.24), and repeat revascularization occurred in 62 patients (7.7%) in the CR group and 39 patients (11.6%) in the IR group (HR 0.64; 95% CI 0.42 to 0.95, p = 0.027). In conclusion, in patients with a great burden of co-morbidities who underwent CABG in the REGROUP trial over a median follow-up period of a median 4.7 years, CR was associated with similar MACE rates but a reduced risk of repeat revascularization. Longer-term follow-up is warranted.</AbstractText><br /><br />Published by Elsevier Inc.<br /><br /><small>Am J Cardiol: 15 Apr 2024; 217:127-135</small></div>

<div><h4>Association of GAL-8 promoter methylation levels with coronary plaque inflammation.</h4><i>Xia B, Lu Y, Liang J, Li F, ... Guo B, Shen Z</i><br /><b>Background:</b><br/>and aims</b><br />Coronary heart disease (CHD) is a condition that carries a high risk of mortality and is associated with aging. CHD is characterized by the chronic inflammatory response of the coronary intima. Recent studies have shown that the methylation level of blood mononuclear cell DNA is closely associated with adverse events in CHD, but the roles and mechanisms of DNA methylation in CHD remain elusive.<br /><b>Methods and results</b><br />In this study, the DNA methylation status within the epigenome of human coronary tissue in the sudden coronary death (SCD) group and control (CON) group of coronary heart disease was analyzed using the Illumina® Infinium Methylation EPIC BeadChip (850 K chip), resulting in the identification of a total of 2553 differentially methylated genes (DMGs). The differentially methylated genes were then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and significant differential DNA methylation was found. Among the differentially hypomethylated genes were GAL-8, LTF, and RFPL3, while the highly methylated genes were TMEM9B, ANK3, and C6orF48. These genes were mainly enriched in 10 significantly enriched pathways, such as cell adhesion junctions, among which the differentially methylated gene GAL-8 was involved in inflammatory pathway signaling. For functional analysis of GAL-8, we first examined the differences in GAL-8 promoter methylation levels among different subgroups of human coronary tissue in the CON, CHD, and SCD groups using pyrophosphate sequencing. The results revealed reduced GAL-8 promoter methylation levels in the SCD group, while the difference between the CHD and CON groups was not statistically significant (P > 0.05). The reduced GAL-8 promoter methylation level was associated with upregulated GAL-8 expression, which led to increased expression of the inflammatory markers TNF-α, IL-1β, MCP-1, MIP-2, MMP-2, and MMP-9. This enhanced inflammatory response contributed to the accumulation of foam cells, thickening of the intima of human coronary arteries, and increased luminal stenosis, which promoted the occurrence of sudden coronary death. Next, we found that GAL-8 promoter methylation levels in PBMC were consistent with human coronary tissue. The unstable angina group (UAP) had significantly lower GAL-8 promoter methylation levels than stable angina (SAP) and healthy controls (CON) (P < 0.05), and there was a significant correlation between reduced GAL-8 promoter methylation levels and risk factors for coronary heart disease. These findings highlight the association between decreased GAL-8 promoter methylation and the presence of coronary heart disease risk factors. ROC curve analysis suggests that methylation of the GAL 8 promoter region is an independent risk factor for CHD. In conclusion, our study confirmed differential expression of GAL-8, LTF, MUC4D, TMEM9B, MYOM2, and ANK3 genes due to DNA methylation in the SCD group. We also established the consistency of GAL-8 promoter methylation alterations between human coronary tissue and patient peripheral blood monocytes. The decreased methylation level of the GAL-8 promoter may be related to the increased expression of GAL-8 and the coronary risk factors.<br /><b>Conclusions</b><br />Accordingly, we hypothesized that reduced levels of GAL-8 promoter methylation may be an independent risk factor for adverse events in coronary heart disease.<br /><br />Copyright © 2024 Elsevier B.V. All rights reserved.<br /><br /><small>Int J Cardiol: 15 Apr 2024; 401:131782</small></div>

<div><h4>Comparative efficacy of vericiguat to sacubitril/valsartan for patients with heart failure reduced ejection fraction: Systematic review and network meta-analysis.</h4><i>Kang DW, Kang SH, Lee K, Nam K, ... Yoon JC, Park SK</i><br /><b>Background</b><br />Despite the established efficacy of vericiguat compared to placebo, uncertainties remain regarding its comparative efficacy to sacubitril/valsartan for patients with heart failure reduced ejection fraction (HFrEF). This study aimed to assess the relative efficacy of vericiguat and sacubitril/valsartan through a systematic review, network meta-analysis, and non-inferiority tests.<br /><b>Methods</b><br />A systematic review was conducted to identify the randomized phase 3 clinical trials involving vericiguat and sacubitril/valsartan. The hazard ratios (HRs) with 95% confidence intervals (CI) for cardiovascular death (CVD) and hospitalization due to HF (hHF) were extracted from these trials and synthesized via network meta-analysis. Non-inferiority testing of vericiguat was performed using a fixed-margin method with a predefined non-inferiority margin (1.24). Sensitivity analyses explored the impact of the time from hHF to screening.<br /><b>Results</b><br />Among the 1366 studies, two trials (VICTORIA and PARADIGM-HF) met the inclusion criteria. Network meta-analysis demonstrated that the HR for CVD or hHF with vericiguat did not significantly differ from that for sacubitril/valsartan (HR: 0.88, 95% CI:0.62-1.23). The upper limit of the 95% CI was less than the predefined margin of 1.24, confirming vericiguat\'s non-inferiority to sacubitril/valsartan. Sensitivity analyses affirmed the robustness of the base-case results.<br /><b>Conclusion</b><br />Vericiguat exhibited a comparable risk of CVD or hHF when contrasted with sacubitril/valsartan. Importantly, in patients with HFrEF, vericiguat\'s efficacy was not statistically inferior to that of sacubitril/valsartan. These findings reinforce the potential of vericiguat as a viable treatment option for this patient population.<br /><br />Copyright © 2024. Published by Elsevier B.V.<br /><br /><small>Int J Cardiol: 01 Apr 2024; 400:131786</small></div>

<div><h4>Clinical characteristics and outcome of end stage hypertrophic cardiomyopathy: Role of age and heart failure phenotypes.</h4><i>Musumeci B, Tini G, Biagini E, Merlo M, ... Boni L, Autore C</i><br /><b>Background</b><br />A minority of patients with hypertrophic cardiomyopathy (HCM) presents advanced heart failure (HF) during their clinical course, in the context of left ventricular (LV) remodeling with reduced LV ejection fraction (LVEF), or of severe diastolic dysfunction without impaired LVEF. Aim of this study was to describe a multicentric end stage (ES) HCM population and analyze clinical course and outcome among its different phenotypes.<br /><b>Methods</b><br />Data of all HCM patients from 7 Italian referral centres were retrospectively evaluated. ES was diagnosed in presence of: LVEF <50% (ES-rEF) or NYHA functional class ≥II with severe diastolic dysfunction (ES-pEF). Outcomes were: HCM-related and all-cause mortality; combined arrhythmic events; advanced HF treatments.<br /><b>Results</b><br />Study population included 331 ES patients; 87% presented ES-rEF and 13% ES-pEF. At ES recognition, patients with ES-pEF were more commonly females, had more frequently NYHA III/IV, atrial fibrillation and greater maximal LV wall thickness. Over a median follow-up of 5.6 years, 83 (25%) patients died, 46 (15%) experienced arrhythmic events and (26%) 85 received advanced HF treatments. Incidence of HCM-related and all-cause mortality, and of combined arrhythmic events did not differ in ES-pEF and ES-rEF patients, but ES-pEF patients were less likely to receive advanced HF treatments. Older age at ES recognition was an independent predictor of increased HCM-related mortality (p = 0.01) and reduced access to advanced HF treatments (p < 0.0001).<br /><b>Conclusions</b><br />Two different HCM-ES phenotypes can be recognized, with ES-pEF showing distinctive features at ES recognition and receiving less frequently advanced HF treatments. Older age at ES recognition has a major impact on outcomes.<br /><br />Copyright © 2024 Elsevier B.V. All rights reserved.<br /><br /><small>Int J Cardiol: 01 Apr 2024; 400:131784</small></div>

<div><h4>Tolerability and effectiveness of beta-blockers in patients with cardiac amyloidosis: A systematic review and meta-analysis.</h4><i>Kang Y, Qu N, Zhang Z, Zhang Q, Chen X, Fu M</i><br /><b>Objective</b><br />This systematic review aimed to assess the tolerability of patients with cardiac amyloidosis (CA) to beta-blockers (BBs) and evaluate its association with adverse outcomes.<br /><b>Methods</b><br />We performed a comprehensive search from January 1, 2000 to October 20, 2023. Studies examining BB use and tolerance or the relationship between BB use and outcomes in patients with CA were included. Pooled adjusted hazard ratios (aHRs) for all-cause mortality were calculated using random- and fixed-effects models.<br /><b>Results</b><br />Eight observational studies involving 4002 patients with CA (87.5% with transthyretin CA [ATTR-CA] and 12.5% with immunoglobulin light chain CA [AL-CA]) were assessed. BBs were used by 52.5% of the patients. However, 26.3% of the patients discontinued BBs because of hypotension, bradycardia, or fatigue. Regarding the association between BB use and all-cause death, four studies were identified that included 2874 patients with ATTR-CA and 16 patients with AL-CA. The meta-analysis revealed no apparent relationship between BB use and all-cause mortality (pooled aHR = 0.78, 95% confidence interval (CI) = 0.40-1.51). Two studies on patients with ATTR-CA found no impact of BB use on all-cause mortality in the subgroup with left ventricular ejection fraction (LVEF) > 40%, but conflicting results exist for those with LVEF ≤40% (pooled aHR = 0.78, 95% CI = 0.40-1.54).<br /><b>Conclusion</b><br />The limited number of observational studies that predominantly enrolled patients with ATTR-CA showed that BBs were used in almost half of the patients with CA, with varying tolerability. However, no significant association was observed between BB use and all-cause mortality.<br /><br />Copyright © 2024. Published by Elsevier B.V.<br /><br /><small>Int J Cardiol: 01 May 2024; 402:131813</small></div>

<div><h4>Geographic disparity of pathophysiological coronary artery disease characteristics: Insights from ASET trials.</h4><i>Kotoku N, Ninomiya K, Masuda S, Tsai TY, ... Serruys PW, ASET Japan and ASET Brazil Investigators</i><br /><b>Background</b><br />The geographical disparity in the pathophysiological pattern of coronary artery disease (CAD) among patients undergoing percutaneous coronary intervention (PCI) is unknown.<br /><b>Objectives</b><br />To elucidate the geographical variance in the pathophysiological characteristics of CAD.<br /><b>Methods</b><br />Physiological indices derived from angiography-based fractional flow reserve pullbacks from patients with chronic coronary syndrome enrolled in the ASET Japan (n = 206) and ASET Brazil (n = 201) studies, which shared the same eligibility criteria, were analysed. The pathophysiological patterns of CAD were characterised using Murray law-based quantitative flow ratio (μQFR)-derived indices acquired from pre-PCI angiograms. The diffuseness of CAD was defined by the μQFR pullback pressure gradient index.<br /><b>Results</b><br />Significant functional stenoses pre-PCI (μQFR ≤0.80) were more frequent in ASET Japan compared to ASET Brazil (89.9% vs. 67.5%, p < 0.001), as were rates of a post-PCI μQFR <0.91 (22.1% vs. 12.9%, p = 0.013). In the multivariable analysis, pre-procedural μQFR and diffuse disease were independent factors for predicting a post-PCI μQFR <0.91, which contributed to the different rates of post-PCI μQFR ≥0.91 between the studies. Among vessels with a post-PCI μQFR <0.91, a consistent diffuse pattern of CAD pre- and post-PCI occurred in 78.3% and 76.7% of patients in ASET Japan and Brazil, respectively; only 6.3% (Japan) and 10.0% (Brazil) of vessels had a major residual gradient. Independent risk factors for diffuse disease were diabetes mellitus in ASET Japan, and age and male gender in Brazil.<br /><b>Conclusions</b><br />There was geographic disparity in pre-procedural angiography-based pathophysiological characteristics. The combined pre-procedural physiological assessment of vessel μQFR and diffuseness of CAD may potentially identify patients who will benefit most from PCI.<br /><br />Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.<br /><br /><small>Int J Cardiol: 01 Apr 2024; 400:131805</small></div>

<div><h4>Tricuspid Regurgitation and Clinical Outcomes in Heart Failure With Reduced Ejection Fraction.</h4><i>Adamo M, Metra M, Claggett BL, Miao ZM, ... Teerlink JR, GALACTIC-HF Investigators and Patients</i><br /><b>Background</b><br />Tricuspid regurgitation (TR) is common and is associated with poor outcomes in patients with heart failure (HF). However, data with adjudicated events from fully characterized patients with heart failure with reduced ejection fraction (HFrEF) are lacking.<br /><b>Objectives</b><br />This study sought to explore the association between mild or moderate/severe TR and clinical outcomes of patients with HFrEF.<br /><b>Methods</b><br />GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a double-blind, placebo-controlled randomized trial comparing omecamtiv mecarbil vs placebo in patients with symptomatic HFrEF.<br /><b>Results</b><br />Among the 8,232 patients analyzed in the GALACTIC-HF trial, 8,180 (99%) had data regarding baseline TR (none: n = 6,476 [79%], mild: n = 919 [11%], and moderate/severe: n = 785 [10%]). The primary composite outcome of a first HF event or cardiovascular death occurred in 2,368 (36.6%) patients with no TR, 353 (38.4%) patients with mild TR, and 389 (49.6%) patients with moderate/severe TR. Moderate/severe TR was independently associated with a higher relative risk of the primary composite outcome compared with either no TR (adjusted HR: 1.12 [95% CI: 1.01-1.26]; P = 0.046) or no/mild TR (adjusted HR: 1.14 [95% CI: 1.02-1.27]; P = 0.025) driven predominantly by HF events. The association between moderate/severe TR and clinical outcomes was more pronounced in outpatients with worse renal function, higher left ventricular ejection fraction, and lower N-terminal pro-B-type natriuretic peptide and bilirubin levels. The beneficial treatment effect of omecamtiv mecarbil vs placebo on clinical outcomes was not modified by TR.<br /><b>Conclusions</b><br />In symptomatic patients with HFrEF, baseline moderate/severe TR was independently associated with cardiovascular death or HF events driven predominantly by HF events. The beneficial treatment effect of omecamtiv mecarbil on the primary outcome was not modified by TR.<br /><br />Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Mar 2024; 12:552-563</small></div>

<div><h4>Increasing Utilization of Extended Criteria Donor Hearts for Transplantation: The OCS Heart EXPAND Trial.</h4><i>Schroder JN, Patel CB, DeVore AD, Casalinova S, ... Milano CA, Smith JW</i><br /><b>Background</b><br />Extended criteria donor (ECD) hearts available with donation after brain death (DBD) are underutilized for transplantation due to limitations of cold storage.<br /><b>Objectives</b><br />This study evaluated use of an extracorporeal perfusion system on donor heart utilization and post-transplant outcomes in ECD DBD hearts.<br /><b>Methods</b><br />In this prospective, single-arm, multicenter study, adult heart transplant recipients received ECD hearts using an extracorporeal perfusion system if hearts met study criteria. The primary outcome was a composite of 30-day survival and absence of severe primary graft dysfunction (PGD). Secondary outcomes were donor heart utilization rate, 30-day survival, and incidence of severe PGD. The safety outcome was the mean number of heart graft-related serious adverse events within 30 days. Additional outcomes included survival through 2 years benchmarked to concurrent nonrandomized control subjects.<br /><b>Results</b><br />A total of 173 ECD DBD hearts were perfused; 150 (87%) were successfully transplanted; 23 (13%) did not meet study transplantation criteria. At 30 days, 92% of patients had survived and had no severe PGD. The 30-day survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of heart graft-related serious adverse events within 30 days was 0.17 (95% CI: 0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months, respectively, and was comparable with concurrent nonrandomized control subjects.<br /><b>Conclusions</b><br />Use of an extracorporeal perfusion system resulted in successfully transplanting 87% of donor hearts with excellent patient survival to 2 years post-transplant and low rates of severe PGD. The ability to safely use ECD DBD hearts could substantially increase the number of heart transplants and expand access to patients in need. (International EXPAND Heart Pivotal Trial [EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol; NCT03835754).<br /><br />Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Mar 2024; 12:438-447</small></div>

<div><h4>Impact of Bempedoic Acid on Total Cardiovascular Events: A Prespecified Analysis of the CLEAR Outcomes Randomized Clinical Trial.</h4><i>Nicholls SJ, Nelson AJ, Lincoff AM, Brennan D, ... Bloedon L, Nissen SE</i><br /><b>Importance</b><br />The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remain unknown.<br /><b>Objective</b><br />To determine the impact of bempedoic acid on the total incidence of MACE.<br /><b>Design, setting, and participants</b><br />Included in this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial were patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and inability to take guideline-recommended statins. Study data were analyzed from December 2016 to November 2022.<br /><b>Interventions</b><br />Patients were randomly assigned to treatment with bempedoic acid or placebo daily.<br /><b>Main outcomes and measures</b><br />The primary end point was the time to first event for a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4). The key secondary end point was time to first event for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE-3). This prespecified analysis compared the total number of cardiovascular events in the treatment groups.<br /><b>Results</b><br />A total of 13 970 patients (mean [SD] age, 65 [9] years; 7230 male [51.8%]) were included in the study. A total of 9764 participants (69.9%) had prior atherosclerotic cardiovascular disease and a baseline LDL-C level of 139 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C level and a 22% reduction in high-sensitivity C-reactive protein (hsCRP) level at 6 months. Median (IQR) follow-up was 3.4 (3.1-3.9) years. A total of 1746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of cardiovascular events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% CI, 0.72-0.89; P <.001), MACE-3 (HR, 0.83; 95% CI, 0.73-0.93; P = .002), myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001), although no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients.<br /><br /><b>Conclusion:</b><br/>and relevance</b><br />Lowering LDL-C level with bempedoic acid reduced the total number of cardiovascular events in patients with high cardiovascular risk, statin therapy intolerance, and elevated LDL-C levels.<br /><br /><br /><br /><small>JAMA Cardiol: 01 Mar 2024; 9:245-253</small></div>

<div><h4>Recruiting a Diverse Cardiology Physician Workforce.</h4><i>Snow SC, Alhanti B, Douglas PS</i><br /><b>Importance</b><br />Understanding trends in the representation of women and individuals from underrepresented racial and ethnic populations in cardiovascular disease and cardiovascular subspecialty fellowships is essential to improving the diversity of the cardiology workforce.<br /><b>Objective</b><br />To examine changes in the representation of women and underrepresented individuals in cardiovascular disease and cardiovascular subspecialty fellowships over time.<br /><b>Design, setting, and participants</b><br />This cross-sectional study of trainee sex and race and ethnicity in various training programs from 2008 to 2022 used data from the Accreditation Council for Graduate Medical Education\'s publicly available online source. Participants included all residents, internal medicine residents, general surgery residents, and fellows in cardiovascular disease and cardiovascular subspecialty fellowships.<br /><b>Main outcomes and measures</b><br />Percentages of women and Black and Hispanic trainees in these programs were calculated for each year. Mann-Kendall tests were used to determine if changes over the years represented a significant trend.<br /><b>Results</b><br />Among the 3320 cardiovascular disease trainees in 2022, 848 (25.5%) were women, and 459 (13.8%) were Black or Hispanic, less than the representation among internal medicine trainees at 43.8% and 15.6%, respectively. However, the percentage of women trainees in cardiovascular disease significantly increased from 17.6% in 2008 (P = .001 for time trend) and also increased for interventional cardiology fellowships (from 6.3% in 2008 to 20.1% in 2022; P = .002). Over the same period, the proportion of women in general surgery increased from 27.4% to 45.2% (P < .001). The percentage of Black and Hispanic trainees in internal medicine significantly increased from 8.6% in 2012 (P < .001) while increases in general surgery were not statistically significant (9.7% to 16.1%; P = .35). There were also important increases in the percentages of Black and Hispanic trainees in cardiovascular disease (from 8.3% in 2012; P = .09) and interventional cardiology (3.8% to 13.4%; P = .12).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />In this study, the representation of women in cardiovascular fellowships, including interventional cardiology, increased over recent years. While representation of Black and Hispanic individuals is low in all residencies, including cardiovascular fellowships, recent positive trends are important to recognize and provide hope to drive future efforts.<br /><br /><br /><br /><small>JAMA Cardiol: 01 Mar 2024; 9:290-294</small></div>

<div><h4>Dapagliflozin and Mode of Death in Heart Failure With Improved Ejection Fraction: A Post Hoc Analysis of the DELIVER Trial.</h4><i>Vardeny O, Desai AS, Jhund PS, Fang JC, ... McMurray JJV, Solomon SD</i><br /><b>Importance</b><br />Heart failure with improved ejection fraction (HFimpEF), defined as prior left ventricular ejection fraction (LVEF) 40% or lower that has increased to greater than 40%, is understudied.<br /><b>Objective</b><br />To examine mode of death and the association of dapagliflozin with reductions in cause-specific death in patients with HFimpEF.<br /><b>Design, setting, and participants</b><br />This was a post hoc analysis from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) randomized clinical trial, conducted from August 2018 to December 2020. The trial randomly assigned patients with HF with LVEF greater than 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The presence of HFimpEF was captured through study case report forms. The primary outcome was a composite of worsening HF events (hospitalization or urgent HF visits) or cardiovascular death. Clinical outcomes were adjudicated by a blinded clinical end points committee. Data were analyzed from May 2022 to August 2023.<br /><b>Intervention</b><br />Dapagliflozin vs placebo.<br /><b>Main outcomes and measures</b><br />The mode of death in relation to HFimpEF status was examined, as well as the association of randomized treatment with cause-specific death in Cox regression models.<br /><b>Results</b><br />Of 1151 patients with HFimpEF in DELIVER, 190 (16.5%) died, compared with 833 patients (16.3%) of 5112 with LVEF consistently greater than 40%. The overall distribution of mode of death was similar in those with HFimpEF compared with those with LVEF consistently greater than 40% (noncardiovascular death: 103 of 190 [54%] vs 428 of 833 [51%]; cardiovascular death: 87 of 190 [46%] vs 405 of 833 [49%], respectively). Most deaths in individuals with HFimpEF were noncardiovascular (103 of 180 [54%]). For cardiovascular deaths, sudden deaths were most common (36 of 190 events [19%]), followed by HF-related (29 of 190 events [15%]). Among patients with HFimpEF, treatment with dapagliflozin was associated with lower rates of cardiovascular death relative to placebo, a difference primarily due to lower rates of sudden death (hazard ratio, 0.38; 95% CI, 0.18-0.79; P for interaction = .01).<br /><br /><b>Conclusions:</b><br/>and relevance</b><br />The findings in this study support current guideline recommendations for use of sodium-glucose transport protein 2 inhibitor therapy, and further suggest that the addition of a sodium-glucose transport protein 2 inhibitor therapy to other guideline-directed medical therapies may help reduce cardiovascular mortality in patients with HFimpEF.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier: NCT03619213.<br /><br /><br /><br /><small>JAMA Cardiol: 01 Mar 2024; 9:283-289</small></div>