<div><h4>Prediction of Shock-Refractory Ventricular Fibrillation During Resuscitation of Out-of-Hospital Cardiac Arrest.</h4><i>Coult J, Yang BY, Kwok H, Kutz JN, ... Rea TD, Kudenchuk PJ</i><br /><b>Background</b><br />Out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation (VF) is associated with relatively poor survival. The ability to predict refractory VF (requiring ≥3 shocks) in advance of repeated shock failure could enable preemptive targeted interventions aimed at improving outcome, such as earlier administration of antiarrhythmics, reconsideration of epinephrine use or dosage, changes in shock delivery strategy, or expedited invasive treatments.<br /><b>Methods</b><br />We conducted a cohort study of VF out-of-hospital cardiac arrest to develop an ECG-based algorithm to predict patients with refractory VF. Patients with available defibrillator recordings were randomized 80%/20% into training/test groups. A random forest classifier applied to 3-s ECG segments immediately before and 1 minute after the initial shock during cardiopulmonary resuscitation was used to predict the need for ≥3 shocks based on singular value decompositions of ECG wavelet transforms. Performance was quantified by area under the receiver operating characteristic curve.<br /><b>Results</b><br />Of 1376 patients with VF out-of-hospital cardiac arrest, 311 (23%) were female, 864 (63%) experienced refractory VF, and 591 (43%) achieved functional neurological survival. Total shock count was associated with decreasing likelihood of functional neurological survival, with a relative risk (95% CI) of 0.95 (95% CI, 0.93-0.97) for each successive shock (<i>P</i><0.001). In the 275 test patients, the area under the receiver operating characteristic curve (95% CI) for predicting refractory VF was 0.85 (95% CI, 0.79-0.89), with specificity of 91%, sensitivity of 63%, and a positive likelihood ratio of 6.7.<br /><b>Conclusions</b><br />A machine learning algorithm using ECGs surrounding the initial shock predicts patients likely to experience refractory VF, and could enable rescuers to preemptively target interventions to potentially improve resuscitation outcome.<br /><br /><br /><br /><small>Circulation: 02 Jun 2023; epub ahead of print</small></div>

<div><h4>Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection.</h4><i>Zhang X, Xu H, Yu J, Cui J, ... Wu J, Xia J</i><br /><b>Background</b><br />PCSK9 (proprotein convertase subtilisin/kexin 9), which is mainly secreted by the liver, is not only a therapeutic target for hyperlipidemia and cardiovascular disease, but also has been implicated in the immune regulation of infections and tumors. However, the role of PCSK9 and the liver in heart transplant rejection (HTR) and the underlying mechanisms remain unclear.<br /><b>Methods</b><br />We assessed serum PCSK9 expression in both murine and human recipients during HTR and investigated the effect of PCSK9 ablation on HTR by using global knockout mice and a neutralizing antibody. Moreover, we performed multiorgan histological and transcriptome analyses, and multiomics and single-cell RNA-sequencing studies of the liver during HTR, as well. We further used hepatocyte-specific <i>Pcsk9</i> knockout mice to investigate whether the liver regulated HTR through PCSK9. Last, we explored the regulatory effect of the PCSK9/CD36 pathway on the phenotype and function of macrophages in vitro and in vivo.<br /><b>Results</b><br />Here, we report that murine and human recipients have high serum PCSK9 levels during HTR. PCSK9 ablation prolonged cardiac allograft survival and attenuated the infiltration of inflammatory cells in the graft and the expansion of alloreactive T cells in the spleen. Next, we demonstrated that PCSK9 was mainly produced and significantly upregulated in the recipient liver, which also showed a series of signaling changes, including changes in the TNF-α (tumor necrosis factor α) and IFN-γ (interferon γ) signaling pathways and the bile acid and fatty acid metabolism pathways. We found mechanistically that TNF-α and IFN-γ synergistically promoted PCSK9 expression in hepatocytes through the transcription factor SREBP2 (sterol regulatory element binding protein 2). Moreover, in vitro and in vivo studies indicated that PCSK9 inhibited CD36 expression and fatty acid uptake by macrophages and strengthened the proinflammatory phenotype, which facilitated their ability to promote proliferation and IFN-γ production by donor-reactive T cells. Last, we found that the protective effect of PCSK9 ablation against HTR is dependent on the CD36 pathway in the recipient.<br /><b>Conclusions</b><br />This study reveals a novel mechanism for immune regulation by the liver through the PCSK9/CD36 pathway during HTR, which influences the phenotype and function of macrophages and suggests that the modulation of this pathway may be a potential therapeutic target to prevent HTR.<br /><br /><br /><br /><small>Circulation: 26 May 2023; epub ahead of print</small></div>

<div><h4>Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry (Sarcomeric Human Cardiomyopathy).</h4><i>Alaiwi SA, Roston TM, Marstrand P, Claggett BL, ... Vissing CR, Ho CY</i><br /><b>Background</b><br />The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children.<br /><b>Methods</b><br />Data from patients with HCM in the international, multicenter SHaRe Registry (Sarcomeric Human Cardiomyopathy) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models.<br /><b>Results</b><br />We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe Registry site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41-4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16-6.52]).<br /><b>Conclusions</b><br />Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.<br /><br /><br /><br /><small>Circulation: 25 May 2023; epub ahead of print</small></div>

<div><h4>Association of HIV Infection and Incident Abdominal Aortic Aneurysm Among 143 001 Veterans.</h4><i>Filipkowski AM, Kundu S, Eden SK, Alcorn CW, ... Freiberg MS, Aday AW</i><br /><b>Background</b><br />People with HIV (PWH) have an increased risk of cardiovascular disease. Previous cross-sectional data suggest there is a higher prevalence of abdominal aortic aneurysm (AAA) in PWH than in those without HIV. Whether PWH have an increased risk of incident AAA compared with those without HIV is unknown.<br /><b>Methods</b><br />We analyzed data among participants without prevalent AAA from the Veterans Aging Cohort Study, a prospective, observational, longitudinal cohort of veterans with HIV matched 1:2 with veterans without HIV infection. We calculated AAA rates by HIV status and assessed the association between HIV infection and incident AAA using Cox proportional hazards models. We defined AAA using the International Classification of Diseases, 9th or 10th revision, or Current Procedural Terminology codes and adjusted all models for demographic characteristics, cardiovascular disease risk factors, and substance use. Secondary analyses examined the association between time-varying CD4+ T-cell count or HIV viral load and incident AAA.<br /><b>Results</b><br />Among 143 001 participants (43 766 with HIV), over a median follow-up of 8.7 years, there were 2431 incident AAA events (26.4% among PWH). Rates of incident AAA per 1000 person-years were similar among PWH (2.0 [95% CI, 1.9-2.2]) and people without HIV (2.2 [95% CI, 2.1-2.3]). There was no evidence that HIV infection increased the risk of incident AAA compared with no HIV infection (adjusted hazard ratio, 1.02 [95% CI, 0.92-1.13]). In adjusted analyses with time-varying CD4+ T-cell counts or HIV viral load, PWH with CD4+ T-cell counts <200 cells/mm<sup>3</sup> (adjusted hazard ratio, 1.29 [95% CI, 1.02-1.65]) or HIV viral load ≥500 copies/mL (adjusted hazard ratio, 1.29 [95% CI, 1.09-1.52]) had an increased risk of AAA compared with those without HIV.<br /><b>Conclusions</b><br />HIV infection is associated with an increased risk of AAA among those with low CD4+ T-cell counts or elevated HIV viral load over time.<br /><br /><br /><br /><small>Circulation: 25 May 2023; epub ahead of print</small></div>

<div><h4>Increasing Equity of Physical Activity Promotion for Optimal Cardiovascular Health in Adults: A Scientific Statement From the American Heart Association.</h4><i>Jerome GJ, Boyer WR, Bustamante EE, Kariuki J, ... Barone Gibbs B, American Heart Association Physical Activity Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease</i><br /><AbstractText>Fewer than 1 in 4 adults achieves the recommended amount of physical activity, with lower activity levels reported among some groups. Addressing low levels of physical activity among underresourced groups provides a modifiable target with the potential to improve equity in cardiovascular health. This article (1) examines physical activity levels across strata of cardiovascular disease risk factors, individual level characteristics, and environmental factors; (2) reviews strategies for increasing physical activity in groups who are underresourced or at risk for poor cardiovascular health; and (3) provides practical suggestions for physical activity promotion to increase equity of risk reduction and to improve cardiovascular health. Physical activity levels are lower among those with elevated cardiovascular disease risk factors, among certain groups (eg, older age, female, Black race, lower socioeconomic status), and in some environments (eg, rural). There are strategies for physical activity promotion that can specifically support underresourced groups such as engaging the target community in designing and implementing interventions, developing culturally appropriate study materials, identifying culturally tailored physical activity options and leaders, building social support, and developing materials for those with low literacy. Although addressing low physical activity levels will not address the underlying structural inequities that deserve attention, promoting physical activity among adults, especially those with both low physical activity levels and poor cardiovascular health, is a promising and underused strategy to reduce cardiovascular health inequalities.</AbstractText><br /><br /><br /><br /><small>Circulation: 24 May 2023; epub ahead of print</small></div>

<div><h4>Subepicardial Cardiomyopathy: A Disease Underlying J-Wave Syndromes and Idiopathic Ventricular Fibrillation.</h4><i>Miles C, Boukens BJ, Scrocco C, Wilde AAM, ... Coronel R, Behr ER</i><br /><AbstractText>Brugada syndrome (BrS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (iVF) have long been considered primary electrical disorders associated with malignant ventricular arrhythmia and sudden cardiac death. However, recent studies have revealed the presence of subtle microstructural abnormalities of the extracellular matrix in some cases of BrS, ERS, and iVF, particularly within right ventricular subepicardial myocardium. Substrate-based ablation within this region has been shown to ameliorate the electrocardiographic phenotype and to reduce arrhythmia frequency in BrS. Patients with ERS and iVF may also exhibit low-voltage and fractionated electrograms in the ventricular subepicardial myocardium, which can be treated with ablation. A significant proportion of patients with BrS and ERS, as well as some iVF survivors, harbor pathogenic variants in the voltage-gated sodium channel gene, <i>SCN5A</i>, but the majority of genetic susceptibility of these disorders is likely to be polygenic. Here, we postulate that BrS, ERS, and iVF may form part of a spectrum of subtle subepicardial cardiomyopathy. We propose that impaired sodium current, along with genetic and environmental susceptibility, precipitates a reduction in epicardial conduction reserve, facilitating current-to-load mismatch at sites of structural discontinuity, giving rise to electrocardiographic changes and the arrhythmogenic substrate.</AbstractText><br /><br /><br /><br /><small>Circulation: 23 May 2023; 147:1622-1633</small></div>

<div><h4>Effect of Torsemide vs Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.</h4><i>Greene SJ, Velazquez EJ, Anstrom KJ, Clare RM, ... Mentz RJ, TRANSFORM-HF Investigators</i><br /><AbstractText><b>Background:</b> Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As pre-specified secondary endpoints, the TRANSFORM-HF trial compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. <br /><b>Methods:</b><br/>TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2,859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomized in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on pre-specified secondary endpoints, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) (assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (PHQ-2) (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. <br /><b>Results:</b><br/>Baseline data were available for 2,787 (97.5%) patients for KCCQ-CSS and 2,624 (91.8%) patients for PHQ-2. Median baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12-months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference 0.06 [95% CI, -2.26 to 2.37]; <i>P</i>=0.96) or the proportion of patients with PHQ-2 score ≥3 (15.1% vs 13.2%: <i>P</i>=0.34). Results for KCCQ-CSS were similar at 1-month (adjusted mean difference 1.36 [95% CI, -0.64 to 3.36]; <i>P</i>=0.18) and 6-month follow-up (adjusted mean difference -0.37 [95% CI, -2.52 to 1.78]; <i>P</i>=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent prior to hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. <b>Conclusions:</b> Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, prior loop diuretic use, and baseline health status.</AbstractText><br /><br /><br /><br /><small>Circulation: 22 May 2023; epub ahead of print</small></div>

<div><h4>Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.</h4><i>Zhang TT, Lei QQ, He J, Guan X, ... Huang H, Zhou JG</i><br /><b>Background</b><br />Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive.<br /><b>Methods</b><br />Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3<sup>SMKO</sup> and Best3<sup>ECKO</sup>, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels.<br /><b>Results</b><br />Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3<sup>SMKO</sup> but not Best3<sup>ECKO</sup> mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3<sup>SMKO</sup> and ApoE<sup>-/-</sup> mice.<br /><b>Conclusions</b><br />These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.<br /><br /><br /><br /><small>Circulation: 19 May 2023; epub ahead of print</small></div>

<div><h4>Shorter Door-to-Needle Times Are Associated With Better Outcomes After Intravenous Thrombolytic Therapy and Endovascular Thrombectomy for Acute Ischemic Stroke.</h4><i>Man S, Solomon N, Mac Grory B, Alhanti B, ... Hussain MS, Fonarow GC</i><br /><b>Background</b><br />Existing data and clinical trials could not determine whether faster intravenous thrombolytic therapy (IVT) translates into better long-term functional outcomes after acute ischemic stroke among those treated with endovascular thrombectomy (EVT). Patient-level national data can provide the required large population to study the associations between earlier IVT, versus later, with longitudinal functional outcomes and mortality in patients receiving IVT+EVT combined treatment.<br /><b>Methods</b><br />This cohort study included older US patients (age ≥65 years) who received IVT within 4.5 hours or EVT within 7 hours after acute ischemic stroke using the linked 2015 to 2018 Get With The Guidelines-Stroke and Medicare database (38 913 treated with IVT only and 3946 with IVT+EVT). Primary outcome was home time, a patient-prioritized functional outcome. Secondary outcomes included all-cause mortality in 1 year. Multivariate logistic regression and Cox proportional hazards models were used to evaluate the associations between door-to-needle (DTN) times and outcomes.<br /><b>Results</b><br />Among patients treated with IVT+EVT, after adjusting for patient and hospital factors, including onset-to-EVT times, each 15-minute increase in DTN times for IVT was associated with significantly higher odds of zero home time in a year (never discharged to home) (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]), less home time among those discharged to home (adjusted odds ratio, 0.93 per 1% of 365 days [95% CI, 0.89-0.98]), and higher all-cause mortality (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.11]). These associations were also statistically significant among patients treated with IVT but at a modest degree (adjusted odds ratio, 1.04 for zero home time, 0.96 per 1% home time for those discharged to home, and adjusted hazard ratio 1.03 for mortality). In the secondary analysis where the IVT+EVT group was compared with 3704 patients treated with EVT only, shorter DTN times (≤60, 45, and 30 minutes) achieved incrementally more home time in a year, and more modified Rankin Scale 0 to 2 at discharge (22.3%, 23.4%, and 25.0%, respectively) versus EVT only (16.4%, <i>P</i><0.001 for each). The benefit dissipated with DTN>60 minutes.<br /><b>Conclusions</b><br />Among older patients with stroke treated with either IVT only or IVT+EVT, shorter DTN times are associated with better long-term functional outcomes and lower mortality. These findings support further efforts to accelerate thrombolytic administration in all eligible patients, including EVT candidates.<br /><br /><br /><br /><small>Circulation: 18 May 2023; epub ahead of print</small></div>

<div><h4>Retained Metabolic Flexibility of the Failing Human Heart.</h4><i>Watson WD, Green PG, Lewis AJM, Arvidsson P, ... Herring N, Rider OJ</i><br /><b>Background</b><br />The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation by increasing oxygen efficiency of adenosine triphosphate production, with mixed results.<br /><b>Methods</b><br />To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo<sub>2</sub>), invasive arteriovenous sampling and pressure-volume loops were performed (n=9).<br /><b>Results</b><br />At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; <i>P</i>=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; <i>P</i>=0.009).Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; <i>P</i>=0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; <i>P</i><0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism.<br /><b>Conclusions</b><br />Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.<br /><br /><br /><br /><small>Circulation: 18 May 2023; epub ahead of print</small></div>

<div><h4> is a Novel Long Noncoding RNA Promoting Vascular Smooth Muscle Inflammation via Scaffolding MKL1 and USP10.</h4><i>Zhang W, Zhao J, Deng L, Ishimwe N, ... Baker AH, Long X</i><br /><b>Background</b><br />Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood.<br /><b>Methods</b><br />Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA (<i>INKILN</i>). <i>INKILN</i> expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of <i>INKILN</i> was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA-protein and protein-protein interaction assays were used to uncover a mechanistic role of <i>INKILN</i> in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study <i>INKIL</i><i>N</i> expression and function in ligation injury-induced neointimal formation.<br /><b>Results</b><br /><i>INKILN</i> expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. <i>INKILN</i> is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. <i>INKILN</i> activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. <i>INKILN</i> physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. <i>INKILN</i> depletion blocks interleukin-1β-induced nuclear localization of both p65 and MKL1. Knockdown of <i>INKILN</i> abolishes the physical interaction between p65 and MKL1 and the luciferase activity of an NF-κB reporter. Furthermore, <i>INKILN</i> knockdown enhances MKL1 ubiquitination through reduced physical interaction with the deubiquitinating enzyme USP10 (ubiquitin-specific peptidase 10). <i>INKILN</i> is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in bacterial artificial chromosome transgenic mice.<br /><b>Conclusions</b><br />These findings elucidate an important pathway of VSMC inflammation involving an <i>INKILN</i>/MKL1/USP10 regulatory axis. Human bacterial artificial chromosome transgenic mice offer a novel and physiologically relevant approach for investigating human-specific long noncoding RNAs under vascular disease conditions.<br /><br /><br /><br /><small>Circulation: 18 May 2023; epub ahead of print</small></div>

<div><h4>Safety and Effectiveness of Pulsed Field Ablation to Treat Atrial Fibrillation: One-Year Outcomes From the MANIFEST-PF Registry.</h4><i>Turagam MK, Neuzil P, Schmidt B, Reichlin T, ... Rahe G, Reddy VY</i><br /><b>Background</b><br />Pulsed field ablation is a novel nonthermal cardiac ablation modality using ultra-rapid electrical pulses to cause cell death by a mechanism of irreversible electroporation. Unlike the traditional ablation energy sources, pulsed field ablation has demonstrated significant preferentiality to myocardial tissue ablation, and thus avoids certain thermally mediated complications. However, its safety and effectiveness remain unknown in usual clinical care.<br /><b>Methods</b><br />MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-Approval Clinical Use of Pulsed Field Ablation) is a retrospective, multinational, patient-level registry wherein patients at each center were prospectively included in their respective center registries. The registry included all patients undergoing postapproval treatment with a multielectrode 5-spline pulsed field ablation catheter to treat atrial fibrillation (AF) between March 1, 2021, and May 30, 2022. The primary effectiveness outcome was freedom from clinical documented atrial arrhythmia (AF/atrial flutter/atrial tachycardia) of ≥30 seconds on the basis of electrocardiographic data after a 3-month blanking period (on or off antiarrhythmic drugs). Safety outcomes included the composite of acute (<7 days postprocedure) and latent (>7 days) major adverse events.<br /><b>Results</b><br />At 24 European centers (77 operators) pulsed field ablation was performed in 1568 patients with AF: age 64.5±11.5 years, female 35%, paroxysmal/persistent AF 65%/32%, CHA<sub>2</sub>DS<sub>2</sub>-VASc 2.2±1.6, median left ventricular ejection fraction 60%, and left atrial diameter 42 mm. Pulmonary vein isolation was achieved in 99.2% of patients. After a median (interquartile range) follow-up of 367 (289-421) days, the 1-year Kaplan-Meier estimate for freedom from atrial arrhythmia was 78.1% (95% CI, 76.0%-80.0%); clinical effectiveness was more common in patients with paroxysmal AF versus persistent AF (81.6% versus 71.5%; <i>P</i>=0.001). Acute major adverse events occurred in 1.9% of patients.<br /><b>Conclusions</b><br />In this large observational registry of the postapproval clinical use of pulsed field technology to treat AF, catheter ablation using pulsed field energy was clinically effective in 78% of patients with AF.<br /><br /><br /><br /><small>Circulation: 18 May 2023; epub ahead of print</small></div>

<div><h4>KIDS SAVE LIVES: Basic Life Support Education for Schoolchildren: A Narrative Review and Scientific Statement From the International Liaison Committee on Resuscitation.</h4><i>Schroeder DC, Semeraro F, Greif R, Bray J, ... Böttiger BW, International Liaison Committee on Resuscitation</i><br /><b>Background</b><br />Basic life support education for schoolchildren has become a key initiative to increase bystander cardiopulmonary resuscitation rates. Our objective was to review the existing literature on teaching schoolchildren basic life support to identify the best practices to provide basic life support training in schoolchildren.<br /><b>Methods</b><br />After topics and subgroups were defined, a comprehensive literature search was conducted. Systematic reviews and controlled and uncontrolled prospective and retrospective studies containing data on students <20 years of age were included.<br /><b>Results</b><br />Schoolchildren are highly motivated to learn basic life support. The CHECK-CALL-COMPRESS algorithm is recommended for all schoolchildren. Regular training in basic life support regardless of age consolidates long-term skills. Young children from 4 years of age are able to assess the first links in the chain of survival. By 10 to 12 years of age, effective chest compression depths and ventilation volumes can be achieved on training manikins. A combination of theoretical and practical training is recommended. Schoolteachers serve as effective basic life support instructors. Schoolchildren also serve as multipliers by passing on basic life support skills to others. The use of age-appropriate social media tools for teaching is a promising approach for schoolchildren of all ages.<br /><b>Conclusions</b><br />Schoolchildren basic life support training has the potential to educate whole generations to respond to cardiac arrest and to increase survival after out-of-hospital cardiac arrest. Comprehensive legislation, curricula, and scientific assessment are crucial to further develop the education of schoolchildren in basic life support.<br /><br /><br /><br /><small>Circulation: 17 May 2023; epub ahead of print</small></div>

<div><h4>Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure With Pulmonary Hypertension.</h4><i>Jani V, Aslam MI, Fenwick AJ, Ma W, ... Kass DA, Hsu S</i><br /><b>Background</b><br />Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in patients with heart failure with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. We thus sought to characterize RV myocyte contractile depression in HFrEF-PH, identify those components reflected by clinical RV indices, and uncover underlying biophysical mechanisms.<br /><b>Methods</b><br />Resting, calcium-, and load-dependent mechanics were prospectively studied in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 patients with HFrEF-PH undergoing cardiac transplantation and 9 organ donor controls.<br /><b>Results</b><br />Unsupervised machine learning using myocyte mechanical data with the highest variance yielded 2 HFrEF-PH subgroups that in turn mapped to patients with decompensated or compensated clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in decompensated clinical RV function, whereas surprisingly, many other major myocyte contractile measures including peak power and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick filament defects, myofibrillar structure was assessed by x-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in decompensated clinical RV function, but not compensated clinical RV function, as compared with controls. This corresponded to reduced myosin ATP turnover in decompensated clinical RV function myocytes, indicating less myosin in a crossbridge-ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Last, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human heart failure.<br /><b>Conclusions</b><br />Although there are many RV myocyte contractile deficits in HFrEF-PH, commonly used clinical indices only detect reduced isometric calcium-stimulated force, which is related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.<br /><br /><br /><br /><small>Circulation: 17 May 2023; epub ahead of print</small></div>

<div><h4>Sarcopenia and Cardiovascular Diseases.</h4><i>Damluji AA, Alfaraidhy M, AlHajri N, Rohant NN, ... deFilippi CR, Goyal P</i><br /><AbstractText>Sarcopenia is the loss of muscle strength, mass, and function, which is often exacerbated by chronic comorbidities including cardiovascular diseases, chronic kidney disease, and cancer. Sarcopenia is associated with faster progression of cardiovascular diseases and higher risk of mortality, falls, and reduced quality of life, particularly among older adults. Although the pathophysiologic mechanisms are complex, the broad underlying cause of sarcopenia includes an imbalance between anabolic and catabolic muscle homeostasis with or without neuronal degeneration. The intrinsic molecular mechanisms of aging, chronic illness, malnutrition, and immobility are associated with the development of sarcopenia. Screening and testing for sarcopenia may be particularly important among those with chronic disease states. Early recognition of sarcopenia is important because it can provide an opportunity for interventions to reverse or delay the progression of muscle disorder, which may ultimately impact cardiovascular outcomes. Relying on body mass index is not useful for screening because many patients will have sarcopenic obesity, a particularly important phenotype among older cardiac patients. In this review, we aimed to: (1) provide a definition of sarcopenia within the context of muscle wasting disorders; (2) summarize the associations between sarcopenia and different cardiovascular diseases; (3) highlight an approach for a diagnostic evaluation; (4) discuss management strategies for sarcopenia; and (5) outline key gaps in knowledge with implications for the future of the field.</AbstractText><br /><br /><br /><br /><small>Circulation: 16 May 2023; 147:1534-1553</small></div>

<div><h4>Racial Differences in Quality of Life in Patients With Heart Failure Treated With Sodium-Glucose Cotransporter 2 Inhibitors: A Patient-Level Meta-Analysis of the CHIEF-HF, DEFINE-HF, and PRESERVED-HF Trials.</h4><i>Gupta K, Spertus JA, Birmingham M, Gosch KL, ... Kosiborod M, Lanfear DE</i><br /><b>Background</b><br />Health status outcomes, including symptoms, function, and quality of life, are worse for Black compared with White patients with heart failure. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular mortality and improve health status in patients with heart failure, but whether the health status benefit of SGLT2is is similar across races is not established. The objective of this study was to compare the treatment effect of SGLT2is (versus placebo) on health status for Black compared with White patients with heart failure.<br /><b>Methods</b><br />We combined patient-level data from 3 randomized clinical trials of SGLT2is: DEFINE-HF (Dapagliflozin Effect on Symptoms and Biomarkers in Patients With Heart Failure; n=263), PRESERVED-HF (Dapagliflozin in Preserved Ejection Fraction Heart Failure; n=324), and CHIEF-HF (A Study on Impact of Canagliflozin on Health Status, Quality of Life, and Functional Status in Heart Failure; n=448). These 3 United States-based trials enrolled a substantial proportion of Black patients, and each used the Kansas City Cardiomyopathy Questionnaire (KCCQ) to measure health status at baseline and after 12 weeks of treatment. Among 1035 total participants, selecting self-identified Black and White patients with complete information yielded a final analytic cohort of 935 patients. The primary endpoint was KCCQ Clinical Summary score. Twelve-week change in KCCQ with SGLT2is versus placebo was compared between Black and White patients by testing the interaction between race and treatment using multivariable linear regression models adjusted for trial, baseline KCCQ (as a restricted cubic spline), race, and treatment. The data that support the findings of this study are available from the corresponding author upon reasonable request.<br /><b>Results</b><br />Among 935 participants, 236 (25%) self-identified as Black, and 469 (50.2%) were treated with an SGLT2i. Treatment with an SGLT2i, compared with placebo, resulted in KCCQ Clinical Summary score improvements at 12 weeks of +4.0 points (95% CI, 1.7-6.3; <i>P</i>=0.0007) in White patients and +4.7 points (95% CI, 0.7-8.7; <i>P</i>=0.02) in Black patients, with no significant interaction by race and treatment (<i>P</i>=0.76). Other KCCQ scales showed similar results.<br /><b>Conclusions</b><br />Treatment with an SGLT2i resulted in consistent and significant improvements in health status for both Black and White patients with heart failure.<br /><br /><br /><br /><small>Circulation: 16 May 2023; epub ahead of print</small></div>

<div><h4>Polycomb Group Protein CBX7 Represses Cardiomyocyte Proliferation Through Modulation of the TARDBP/RBM38 Axis.</h4><i>Cho KW, Andrade M, Bae S, Kim S, ... Park C, Yoon YS</i><br /><b>Background</b><br />Shortly after birth, cardiomyocytes exit the cell cycle and cease proliferation. At present, the regulatory mechanisms for this loss of proliferative capacity are poorly understood. CBX7 (chromobox 7), a polycomb group (PcG) protein, regulates the cell cycle, but its role in cardiomyocyte proliferation is unknown.<br /><b>Methods</b><br />We profiled CBX7 expression in the mouse hearts through quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. We overexpressed CBX7 in neonatal mouse cardiomyocytes through adenoviral transduction. We knocked down CBX7 by using constitutive and inducible conditional knockout mice (<i>Tnnt2-Cre;Cbx7</i><sup><i>fl/+</i></sup> and <i>Myh6-MCM;Cbx7</i><sup><i>fl/fl</i></sup>, respectively). We measured cardiomyocyte proliferation by immunostaining of proliferation markers such as Ki67, phospho-histone 3, and cyclin B1. To examine the role of CBX7 in cardiac regeneration, we used neonatal cardiac apical resection and adult myocardial infarction models. We examined the mechanism of CBX7-mediated repression of cardiomyocyte proliferation through coimmunoprecipitation, mass spectrometry, and other molecular techniques.<br /><b>Result</b><br />We explored <i>Cbx7</i> expression in the heart and found that mRNA expression abruptly increased after birth and was sustained throughout adulthood. Overexpression of CBX7 through adenoviral transduction reduced proliferation of neonatal cardiomyocytes and promoted their multinucleation. On the other hand, genetic inactivation of <i>Cbx7</i> increased proliferation of cardiomyocytes and impeded cardiac maturation during postnatal heart growth. Genetic ablation of <i>Cbx7</i> promoted regeneration of neonatal and adult injured hearts. Mechanistically, CBX7 interacted with TARDBP (TAR DNA-binding protein 43) and positively regulated its downstream target, RBM38 (RNA Binding Motif Protein 38), in a TARDBP-dependent manner. Overexpression of RBM38 inhibited the proliferation of CBX7-depleted neonatal cardiomyocytes.<br /><b>Conclusions</b><br />Our results demonstrate that CBX7 directs the cell cycle exit of cardiomyocytes during the postnatal period by regulating its downstream targets TARDBP and RBM38. This is the first study to demonstrate the role of CBX7 in regulation of cardiomyocyte proliferation, and CBX7 could be an important target for cardiac regeneration.<br /><br /><br /><br /><small>Circulation: 09 May 2023; epub ahead of print</small></div>

<div><h4>Economic Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients with Severe Aortic Stenosis and Low Surgical Risk: Results from the PARTNER 3 Trial.</h4><i>Galper BZ, Chinnakondepalli KM, Wang K, Magnuson EA, ... Cohen DJ, PARTNER Investigators</i><br /><b>Background</b><br />In patients with severe symptomatic aortic stenosis at low surgical risk, transfemoral transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve has been shown to reduce the composite of death, stroke, or rehospitalization at 2-year follow-up compared with surgical aortic valve replacement (SAVR). Whether TAVR is cost-effective compared with SAVR for low-risk patients remains uncertain.<br /><b>Methods</b><br />Between 2016 and 2017, 1000 low-risk patients with aortic stenosis were randomly assigned to TAVR with the SAPIEN 3 valve or SAVR in the PARTNER 3 trial (Placement of Aortic Transcatheter Valves). Of these patients, 929 underwent valve replacement, were enrolled in the United States, and were included in the economic substudy. Procedural costs were estimated using measured resource use. Other costs were determined by linkage with Medicare claims or by regression models when linkage was not feasible. Health utilities were estimated using the EuroQOL 5-item questionnaire. With the use of a Markov model informed by in-trial data, lifetime cost-effectiveness from the perspective of the US health care system was estimated in terms of cost per quality-adjusted life-year gained.<br /><b>Results</b><br />Although procedural costs were nearly $19 000 higher with TAVR, total index hospitalization costs were only $591 more with TAVR compared with SAVR. Follow-up costs were lower with TAVR such that TAVR led to 2-year cost savings of $2030/patient compared with SAVR (95% CI, -$6222 to $1816) and a gain of 0.05 quality-adjusted life-years (95% CI, -0.003 to 0.102). In our base-case analysis, TAVR was projected to be an economically dominant strategy with a 95% probability that the incremental cost-effectiveness ratio for TAVR would be <$50 000/quality-adjusted life-year gained (consistent with high economic value from a US health care perspective). These findings were sensitive to differences in long-term survival, however, such that a modest long-term survival advantage with SAVR would render SAVR cost-effective (although not cost saving) compared with TAVR.<br /><b>Conclusions</b><br />For patients with severe aortic stenosis and low surgical risk similar to those enrolled in the PARTNER 3 trial, transfemoral TAVR with the SAPIEN 3 valve is cost saving compared with SAVR at 2 years and is projected to be economically attractive in the long run as long as there are no substantial differences in late death between the 2 strategies. Long-term follow-up will be critical to ultimately determine the preferred treatment strategy for low-risk patients from both a clinical and economic perspective.<br /><br /><br /><br /><small>Circulation: 08 May 2023; epub ahead of print</small></div>

<div><h4>Epidemiology of Diabetes and Atherosclerotic Cardiovascular Disease Among Asian American Adults: Implications, Management, and Future Directions: A Scientific Statement From the American Heart Association.</h4><i>Kwan TW, Wong SS, Hong Y, Kanaya AM, ... American Heart Association Council on Epidemiology and Prevention; Council on Lifestyle and Cardiometabolic Health; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and Council on Genomic and Precision Medicine</i><br /><AbstractText>Asian American individuals make up the fastest growing racial and ethnic group in the United States. Despite the substantial variability that exists in type 2 diabetes and atherosclerotic cardiovascular disease risk among the different subgroups of Asian Americans, the current literature, when available, often fails to examine these subgroups individually. The purpose of this scientific statement is to summarize the latest disaggregated data, when possible, on Asian American demographics, prevalence, biological mechanisms, genetics, health behaviors, acculturation and lifestyle interventions, pharmacological therapy, complementary alternative interventions, and their impact on type 2 diabetes and atherosclerotic cardiovascular disease. On the basis of available evidence to date, we noted that the prevalences of type 2 diabetes and stroke mortality are higher in all Asian American subgroups compared with non-Hispanic White adults. Data also showed that atherosclerotic cardiovascular disease risk is highest among South Asian and Filipino adults but lowest among Chinese, Japanese, and Korean adults. This scientific statement discusses the biological pathway of type 2 diabetes and the possible role of genetics in type 2 diabetes and atherosclerotic cardiovascular disease among Asian American adults. Challenges to provide evidence-based recommendations included the limited data on Asian American adults in risk prediction models, national surveillance surveys, and clinical trials, leading to significant research disparities in this population. The large disparity within this population is a call for action to the public health and clinical health care community, for whom opportunities for the inclusion of the Asian American subgroups should be a priority. Future studies of atherosclerotic cardiovascular disease risk in Asian American adults need to be adequately powered, to incorporate multiple Asian ancestries, and to include multigenerational cohorts. With advances in epidemiology and data analysis and the availability of larger, representative cohorts, furthering refining the Pooled Cohort Equations, in addition to enhancers, would allow better risk estimation in segments of the population. Last, this scientific statement provides individual- and community-level intervention suggestions for health care professionals who interact with the Asian American population.</AbstractText><br /><br /><br /><br /><small>Circulation: 08 May 2023; epub ahead of print</small></div>

<div><h4>Rivaroxaban for Prevention of Thrombotic Events, Hospitalization, and Death in Outpatients With COVID-19: A Randomized Clinical Trial.</h4><i>Piazza G, Spyropoulos AC, Hsia J, Goldin M, ... Bonaca MP, PREVENT-HD Investigators</i><br /><b>Background</b><br />COVID-19 (coronavirus disease 2019) is associated with heightened risks of venous and arterial thrombosis and hospitalization due to respiratory failure. To assess whether prophylactic anticoagulation can safely reduce the frequency of venous and arterial thrombosis, hospitalization, and death in nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor, we conducted the PREVENT-HD double-blind, placebo-controlled randomized trial (A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic COVID-19] Infection).<br /><b>Methods</b><br />PREVENT-HD was conducted between August 2020 and April 2022 at 14 US integrated health care delivery networks. A virtual trial design used remote informed consent and clinical monitoring and facilitated data collection through electronic health record integration with a cloud-based research platform. Nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor were enrolled and randomly assigned to either 10 mg of oral rivaroxaban or placebo daily for 35 days. The primary efficacy outcome was time to first occurrence of a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic arterial embolism, hospitalization, or death through day 35. The principal safety end point was International Society on Thrombosis and Hemostasis critical-site or fatal bleeding. The last study visit was on day 49.<br /><b>Results</b><br />The study was terminated prematurely because of enrollment challenges and a lower-than-expected blinded pooled event rate. A total of 1284 patients underwent randomization with complete accrual of primary events through May 2022. No patients were lost to follow-up. The primary efficacy outcome occurred in 22 of 641 in the rivaroxaban group and 19 of 643 in the placebo group (3.4% versus 3.0%; hazard ratio, 1.16 [95% CI, 0.63-2.15]; <i>P</i>=0.63). No patient in either group experienced critical-site or fatal bleeding. One patient receiving rivaroxaban had a major bleed.<br /><b>Conclusions</b><br />The study was terminated prematurely after enrollment of 32% of planned accrual because of recruitment challenges and lower-than-expected event rate. Rivaroxaban prescribed for 35 days in nonhospitalized patients with symptomatic COVID-19 at risk for thrombosis did not appear to reduce a composite end point of venous and arterial thrombotic events, hospitalization, and death.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04508023.<br /><br /><br /><br /><small>Circulation: 08 May 2023; epub ahead of print</small></div>

<div><h4>Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study.</h4><i>Sattar N, McMurray J, Boren J, Rawshani A, ... Bhatt D, Rawshani A</i><br /><b>Background</b><br />The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects.<br /><b>Methods</b><br />This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643  800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model.<br /><b>Results</b><br />Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF.<br /><b>Conclusions</b><br />Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.<br /><br /><br /><br /><small>Circulation: 08 May 2023; epub ahead of print</small></div>

<div><h4>CIB2 Is a Novel Endogenous Repressor of Atrial Remodeling.</h4><i>Wang Y, Wang J, Shi L, Chen X, ... Song L, Zhao S</i><br /><b>Background</b><br />Atrial fibrillation (AF) is a highly prevalent condition that can cause or exacerbate heart failure, is an important risk factor for stroke, and is associated with pronounced morbidity and mortality. Genes uniquely expressed in the atria are known to be essential for maintaining atrial structure and function. Atrial tissue remodeling contributes to arrhythmia recurrence and maintenance. However, the mechanism underlying atrial remodeling remains poorly understood. This study was designed to investigate whether other uncharacterized atrial specific genes play important roles in atrial physiology and arrhythmogenesis.<br /><b>Methods</b><br />RNA-sequencing analysis was used to identify atrial myocyte specific and angiotensin II-responsive genes. Genetically modified, cardiomyocyte-specific mouse models (knockout and overexpression) were generated. In vivo and in vitro electrophysiological, histology, and biochemical analyses were performed to determine the consequences of CIB2 (calcium and integrin binding family member 2 protein) gain and loss of function in the atrium.<br /><b>Results</b><br />Using RNA-sequencing analysis, we identified CIB2 as an atrial-enriched protein that is significantly downregulated in the left atria of patients with AF and mouse models of AF from angiotensin II infusion or pressure overload. Using cardiomyocyte-specific C<i>ib2</i> knockout (<i>Cib2</i><sup><i>-/</i>-</sup>) and atrial myocyte-specific <i>Cib2</i>-overexpressing mouse models, we found that loss of C<i>ib2</i> enhances AF occurrence, prolongs AF duration, and correlates with a significant increase in atrial fibrosis under stress. Conversely, <i>C</i><i>ib2</i> overexpression mitigates AF occurrence and atrial fibrosis triggered by angiotensin II stress. Mechanistically, we revealed that CIB2 competes with and inhibits CIB1-mediated calcineurin activation, thereby negating stress-induced structural remodeling and AF.<br /><b>Conclusions</b><br />Our data suggest that CIB2 represents a novel endogenous and atrial-enriched regulator that protects against atrial remodeling and AF under stress conditions. Therefore, CIB2 may represent a new potential target for treating AF.<br /><br /><br /><br /><small>Circulation: 02 May 2023; epub ahead of print</small></div>

<div><h4>Restoration of Cardiac Myosin Light Chain Kinase Ameliorates Systolic Dysfunction by Reducing Superrelaxed Myosin.</h4><i>Hitsumoto T, Tsukamoto O, Matsuoka K, Li J, ... Haruta JI, Takashima S</i><br /><b>Background</b><br />Cardiac-specific myosin light chain kinase (cMLCK), encoded by <i>MYLK3</i>, regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure.<br /><b>Methods</b><br />We generated the knock-in mice (<i>Mylk3</i><sup>+/fs</sup> and <i>Mylk</i>3<sup>fs/fs</sup>) with a familial dilated cardiomyopathy-associated <i>MYLK3</i> frameshift mutation (<i>MYLK3</i><sup>+/fs</sup>) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154).<br /><b>Results</b><br />Both mice (<i>Mylk3</i><sup>+/fs</sup> and <i>Mylk</i>3<sup>fs/fs</sup>) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_<i>MYLK3</i> vector. <i>MYLK3</i><sup>+/fs</sup> induced pluripotent stem cell-derived cardiomyocytes reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_<i>MYLK3</i> vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the <i>V</i><sub>max</sub> for ventricular myosin regulatory light chain phosphorylation without affecting the <i>K</i><sub>m</sub>. LEUO-1154 treatment of human <i>MYLK3</i><sup>+/fs</sup> induced pluripotent stem cell-derived cardiomyocytes restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower <i>MYLK3</i>/<i>PPP1R12B</i> messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes.<br /><b>Conclusions</b><br />cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.<br /><br /><br /><br /><small>Circulation: 02 May 2023; epub ahead of print</small></div>

<div><h4>Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.</h4><i>Johns DG, Campeau LC, Banka P, Bautmans A, ... Walji A, Wood HB</i><br /><b>Background</b><br />Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design.<br /><b>Methods</b><br />Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (low density lipoprotein cholesterol).<br /><b>Results</b><br />MK-0616 displayed high affinity (<i>K</i><sub>i</sub> = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616.<br /><b>Conclusions</b><br />This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.<br /><br /><br /><br /><small>Circulation: 01 May 2023; epub ahead of print</small></div>

<div><h4>Sex Differences in Cardiac Troponin Trajectories Over the Life Course.</h4><i>de Bakker M, Anand A, Shipley M, Fujisawa T, ... Mills NL, Kimenai DM</i><br /><b>Background</b><br />Cardiac troponin concentrations are lower in women than men. We examined whether age- and risk factor-related changes in cardiac troponin over the life course differ by sex and if the trajectory of cardiac troponin was informative in respect of cardiovascular outcomes in women and men in the general population.<br /><b>Methods</b><br />In the Whitehall II cohort, high-sensitivity cardiac troponin I concentrations were measured on 3 occasions over a 15-year period. Using linear mixed-effects models, the sex-specific trajectories of cardiac troponin were evaluated, and the relationship with conventional cardiovascular risk factors determined. Using multistate joint models, the association between sex-specific trajectories of cardiac troponin and a composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death was evaluated.<br /><b>Results</b><br />In 2142 women and 5151 men (mean, 58±7 and 57±7 years of age, respectively), there were 177 (8.3%) and 520 (10.1%) outcome events, respectively, during a median follow-up of 20.9 (25th to 75th percentile, 15.8-21.3) years. Cardiac troponin concentrations were persistently lower in women than in men (median baseline concentration: 2.4 [25th to 75th percentile, 1.7-3.6] ng/L versus 3.7 [25th to 75th percentile, 2.6-5.8] ng/L, respectively, <i>P</i><0.001), with women exhibiting a relatively larger increase with advancing age as compared with men (<i>P</i><sub><i>interaction</i></sub><0.001). Apart from age, a significant and divergent interaction with sex was found for the association between cardiac troponin and body mass index (BMI) (<i>P</i><sub><i>interaction</i></sub>=0.008) and diabetes (<i>P</i><sub><i>interaction</i></sub>=0.003). During follow-up, cardiac troponin concentrations were associated to the outcome in both women and men (adjusted hazard ratio per 2-fold difference [95% CI, 1.34 (1.17-1.52) and 1.30 (1.21-1.40), respectively], <i>P</i><sub><i>interaction</i></sub><i>=</i>0.752). The slope of cardiac troponin was significantly associated with the outcome in women, but not in men (adjusted hazard ratio [95% CI, 2.70 (1.01-7.33) and 1.31 (0.62-2.75), respectively], <i>P</i><sub><i>interaction</i></sub><i>=</i>0.250).<br /><b>Conclusions</b><br />Trajectories of cardiac troponin differ between women and men in the general population, with differing associations to conventional risk factors and cardiovascular outcomes. Our findings highlight the importance of a sex-specific approach when serial cardiac troponin testing is applied for cardiovascular risk prediction.<br /><br /><br /><br /><small>Circulation: 28 Apr 2023; epub ahead of print</small></div>

<div><h4>Popular Dietary Patterns: Alignment With American Heart Association 2021 Dietary Guidance: A Scientific Statement From the American Heart Association.</h4><i>Gardner CD, Vadiveloo MK, Petersen KS, Anderson CAM, ... Joseph JJ, American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Council on Peripheral Vascular Disease</i><br /><AbstractText>The evolution of dietary guidelines from isolated nutrients to broader dietary pattern recommendations results from growing knowledge of the synergy between nutrients and their food sources as they influence health. Macronutrient and micronutrient needs can be met by consuming various dietary patterns, but guidance is often required to facilitate population-wide adherence to wise food choices to achieve a healthy dietary pattern. This is particularly true in this era with the proliferation of nutrition misinformation and misplaced emphasis. In 2021, the American Heart Association issued a scientific statement outlining key principles of a heart-healthy dietary pattern that could be operationalized in various ways. The objective of this scientific statement is to assess alignment of commonly practiced US dietary patterns with the recently published American Heart Association criteria, to determine clinical and cultural factors that affect long-term adherence, and to propose approaches for adoption of healthy dietary patterns. This scientific statement is intended to serve as a tool for clinicians and consumers to evaluate whether these popular dietary pattern(s) promote cardiometabolic health and suggests factors to consider when adopting any pattern to improve alignment with the 2021 American Heart Association Dietary Guidance. Numerous patterns strongly aligned with 2021 American Heart Association Dietary Guidance (ie, Mediterranean, DASH [Dietary Approaches to Stop Hypertension], pescetarian, vegetarian) can be adapted to reflect personal and cultural preferences and budgetary constraints. Thus, optimal cardiovascular health would be best supported by developing a food environment that supports adherence to these patterns wherever food is prepared or consumed.</AbstractText><br /><br /><br /><br /><small>Circulation: 27 Apr 2023; epub ahead of print</small></div>

<div><h4>Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension.</h4><i>Guignabert C, Savale L, Boucly A, Thuillet R, ... Sitbon O, Humbert M</i><br /><b>Background</b><br />Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers.<br /><b>Methods</b><br />Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues.<br /><b>Results</b><br />Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; <i>P</i>=0.037 and 1.263 [95% CI, 1.049-1.520]; <i>P</i>=0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; <i>P</i>=0.001 and 1.365 [95% CI, 1.185-1.573]; <i>P</i><0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; <i>P</i>=0.009) and 0.17 (95% CI, 0.06-0.45; <i>P</i><0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; <i>P</i>=0.019) and 0.27 (95% CI, 0.09-0.78, <i>P</i>=0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin.<br /><b>Conclusions</b><br />These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.<br /><br /><br /><br /><small>Circulation: 25 Apr 2023; epub ahead of print</small></div>

<div><h4>Myocardial Injury Thresholds for 4 High-Sensitivity Troponin Assays in a Population-Based Sample of US Children and Adolescents.</h4><i>McEvoy JW, Wang D, Brady T, Tang O, ... Christenson RH, Selvin E</i><br /><b>Background</b><br />Myocardial injury is an important pediatric diagnosis. Establishing normative data from a representative pediatric sample is vital to provide accurate upper reference limits (URLs) for defining myocardial injury using high-sensitivity cardiac troponin.<br /><b>Methods</b><br />Among participants 1 to 18 years of age in the 1999-2004 National Health and Nutrition Examination Survey, we measured high-sensitivity troponin T using one assay (Roche) and high-sensitivity troponin I using 3 assays (Abbott, Siemens, and Ortho). In a strictly defined healthy subgroup, we estimated 97.5th and 99th percentile URLs for each assay using the recommended nonparametric method.<br /><b>Results</b><br />Of 5695 pediatric participants, 4029 met criteria for the healthy subgroup (50% males; mean age 12.6 years). Our 99th percentile URL estimates for all 4 high-sensitivity troponin assays among children and adolescents were lower than the manufacturer-reported URLs (derived from adults). The 99th percentile URLs (95% CI) were 15 ng/L (95% CI, 12-17) for high-sensitivity troponin T, 16 ng/L (95% CI, 12-19) for high-sensitivity troponin I with the Abbott assay, 38 ng/L (95% CI, 25-46) for high-sensitivity troponin I with the Siemens assay, and 7 ng/L (95% CI, 5, 12) for high-sensitivity troponin I with the Ortho assay. The 95% CIs for age-, sex-, and race-specific 99th percentile URLs overlapped. However, the 97.5th percentile URL for each assay was measured with superior statistical precision (ie, tighter 95% CIs) and demonstrated differences by sex. For male compared with female children, 97.5th percentile URLs were 11 ng/L (95% CI, 10-12) versus 6 ng/L (95% CI, 6-7) for high-sensitivity troponin T, 9 ng/L (95% CI, 7-10) versus 5 ng/L (95% CI, 4-6) for high-sensitivity troponin I with the Abbott assay, 21 ng/L (95% CI, 18-25) versus 11 ng/L (95% CI, 9-13) for high-sensitivity troponin I with the Siemens assay, and 4 ng/L (95% CI, 3-5) versus 2 ng/L (95% CI, 1-3) for high-sensitivity troponin I with the Ortho assay. In contrast to the 99th percentiles, the point estimates of 97.5th percentile pediatric URLs for cardiac troponin were also much more stable to differences in the analytic approaches taken to estimate URLs.<br /><b>Conclusions</b><br />Because myocardial infarction is rare in adolescents, the use of statistically more precise and reliable sex-specific 97.5th percentile URLs might be considered to define pediatric myocardial injury.<br /><br /><br /><br /><small>Circulation: 20 Apr 2023; epub ahead of print</small></div>

<div><h4>Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial.</h4><i>Hundertmark MJ, Adler A, Antoniades C, Coleman R, ... Mahmod M, Neubauer S</i><br /><b>Background</b><br />Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness.<br /><b>Methods</b><br />EMPA-VISION is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr:ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated.<br /><b>Results</b><br />Empagliflozin treatment did not change cardiac energetics (ie, PCr:ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; <i>P</i>=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; <i>P</i>=0.47]. Likewise, there were no changes in PCr:ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; <i>P</i>=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; <i>P</i>=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed.<br /><b>Conclusions</b><br />In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03332212.<br /><br /><br /><br /><small>Circulation: 18 Apr 2023; epub ahead of print</small></div>

<div><h4>Unloading the Left Ventricle in Venoarterial ECMO: In Whom, When, and How?</h4><i>Ezad SM, Ryan M, Donker DW, Pappalardo F, ... Kapur NK, Perera D</i><br /><AbstractText>Venoarterial extracorporeal membrane oxygenation provides cardiorespiratory support to patients in cardiogenic shock. This comes at the cost of increased left ventricle (LV) afterload that can be partly ascribed to retrograde aortic flow, causing LV distension, and leads to complications including cardiac thrombi, arrhythmias, and pulmonary edema. LV unloading can be achieved by using an additional circulatory support device to mitigate the adverse effects of mechanical overload that may increase the likelihood of myocardial recovery. Observational data suggest that these strategies may improve outcomes, but in whom, when, and how LV unloading should be employed is unclear; all techniques require balancing presumed benefits against known risks of device-related complications. This review summarizes the current evidence related to LV unloading with venoarterial extracorporeal membrane oxygenation.</AbstractText><br /><br /><br /><br /><small>Circulation: 18 Apr 2023; 147:1237-1250</small></div>

<div><h4> Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension.</h4><i>Walters R, Vasilaki E, Aman J, Chen CN, ... Zhao L, Rhodes CJ</i><br /><b>Background</b><br />Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) <i>SOX17</i> containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in <i>SOX17</i> cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of <i>SOX17</i>, which in turn reduces <i>SOX17</i> expression and contributes to disturbed endothelial cell function and PAH development.<br /><b>Methods</b><br />CRISPR manipulation and siRNA were used to modulate <i>SOX17</i> expression. Electromobility shift assays were used to confirm in silico<i>-</i>predicted TF differential binding to the <i>SOX17</i> variants. Functional assays in hPAECs were used to establish the biological consequences of <i>SOX17</i> loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed <i>SOX17</i> signaling. Mice with deletion of the <i>SOX17</i> signal 1 enhancer region (<i>SOX17</i>-4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia.<br /><b>Results</b><br />CRISPR inhibition of <i>SOX17</i>-signal 2 and deletion of <i>SOX17</i>signal 1 specifically decreased <i>SOX17</i> expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both <i>SOX17</i> signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on <i>SOX17</i> silencing, including extracellular matrix regulation. <i>SOX17</i> silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416/hypoxia-induced pulmonary hypertension.<br /><b>Conclusions</b><br />Common PAH risk variants upstream of the <i>SOX17</i> promoter reduce endothelial <i>SOX17</i> expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature.<br /><br /><br /><br /><small>Circulation: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy.</h4><i>Tang Y, Feng M, Su Y, Ma T, ... Wei K, Xu D</i><br /><b>Background</b><br />A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear.<br /><b>Methods</b><br />We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed <i>Jmjd4</i> in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy.<br /><b>Results</b><br />We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of <i>Jmjd4</i> led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with <i>Jmjd4</i> deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by <i>Jmjd4</i> deficiency, and heart failure induced by pressure overload, as well.<br /><b>Conclusion</b><br />Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.<br /><br /><br /><br /><small>Circulation: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Effects of Systematic Atrial Fibrillation Screening According to N-Terminal Pro-B-Type Natriuretic Peptide: a Secondary Analysis of the Randomized LOOP Study.</h4><i>Xing LY, Diederichsen SZ, Højberg S, Krieger DW, ... Haugan KJ, Svendsen JH</i><br /><b>Background</b><br />Research suggests N-terminal pro-B-type natriuretic peptide (NT-proBNP) to be a strong predictor of incident atrial fibrillation (AF) and stroke. However, its utility in AF screening remains unknown. This study aimed to investigate NT-proBNP as a potential marker for screening efficacy with respect to AF yield and stroke prevention.<br /><b>Methods</b><br />In the LOOP Study, 6004 AF-naïve individuals aged 70-90 years with additional stroke risk factors were randomized 1:3 to either continuous screening with implantable loop recorder (ILR) and anticoagulation initiation upon detection of AF episodes ≥6 minutes, or usual care (Control). This post-hoc analysis included the study participants with available NT-proBNP measurement at baseline.<br /><b>Results</b><br />A total of 5819 participants were included (mean age 74.7 years (standard deviation, 4.1), 47.5%females). The median NT-proBNP level was 15 pmol/L [interquartile range: 9-28], corresponding to 125 pg/mL [interquartile range: 76-233]. NT-proBNP above median was associated with an increased risk of AF diagnosis both in the ILR group (hazard ratio (HR) 1.84 [95% confidence interval (CI): 1.51-2.25]) and the Control group (HR 2.79 [95% CI: 2.30-3.40]). Participants with NT-proBNP above median were also at higher risk of clinical events compared with those having lower levels (HR 1.21 [95% CI: 0.96-1.54] for stroke or systemic embolism (SE), 1.60 [95% CI: 1.32-1.95] for stroke/SE/cardiovascular death, and 1.91 [95% CI: 1.61-2.26] for all-cause death). Compared with usual care, ILR screening was associated with significant reductions in stroke/SE and stroke/SE/cardiovascular death among participants with NT-proBNP above median (HR 0.60 [95% CI: 0.40-0.90] and 0.70 [95% CI: 0.53-0.94], respectively), but not among those with lower levels (p<sub>interaction</sub>=0.029 for stroke/SE and 0.045 for stroke/SE/cardiovascular death). No risk reduction in all-cause death was observed in either NT-proBNP subgroup for ILR versus Control (p<sub>interaction</sub>=0.68). Analyzing NT-proBNP as a continuous variable yielded similar findings.<br /><b>Conclusions</b><br />In an elderly population with additional stroke risk factors, ILR screening for AF was associated with a significant reduction in stroke risk among individuals with higher NT-proBNP levels, but not among those with lower levels. These findings should be considered hypothesis-generating and warrant further study before clinical implementation.<br /><br /><br /><br /><small>Circulation: 15 Apr 2023; epub ahead of print</small></div>

<div><h4>Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis.</h4><i>Filippatos G, Ponikowski P, Farmakis D, Anker SD, ... AFFIRM-AHF (randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure) investigators</i><br /><b>Background</b><br />Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects.<br /><b>Methods</b><br />AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others.<br /><b>Results</b><br />Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (<i>P</i><sub>interaction</sub>=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia.<br /><b>Conclusions</b><br />The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT02937454.<br /><br /><br /><br /><small>Circulation: 13 Apr 2023; epub ahead of print</small></div>

<div><h4>Direct Oral Anticoagulants Versus Warfarin Across the Spectrum of Kidney Function: Patient-Level Network Meta-Analyses From COMBINE AF.</h4><i>Harrington J, Carnicelli AP, Hua K, Wallentin L, ... Hong H, Granger CB</i><br /><b>Background</b><br />There is uncertainty surrounding the use of direct oral anticoagulants (DOACs) in patients with kidney dysfunction.<br /><b>Methods</b><br />Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY [Randomized Evaluation of Long-term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), we performed an individual patient-level network meta-analysis to evaluate the safety and efficacy of DOACs versus warfarin across continuous creatinine clearance (CrCl). A multivariable Cox model including treatment-by-CrCl interaction with random effects was fitted to estimate hazard ratios for paired treatment strategies (standard-dose DOAC, lower-dose DOAC, and warfarin). Outcomes included stroke and systemic embolism (S/SE), major bleeding, intracranial hemorrhage (ICH), and death.<br /><b>Results</b><br />Among 71 683 patients (mean age, 70.6±9.4 years; 37.3% female; median follow-up, 23.1 months), the mean CrCl was 75.5±30.5 mL/min. The incidence of S/SE, major bleeding, ICH, and death increased significantly with worsening kidney function. Across continuous CrCl values down to 25 mL/min, the hazard of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin (<i>P</i><sub>interaction</sub>=0.61). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of ICH at CrCl values <122 mL/min, with a trend for increased safety with DOAC as CrCl decreased (6.2% decrease in hazard ratio per 10-mL/min decrease in CrCl; <i>P</i><sub>interaction</sub>=0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl <87 mL/min, with a significant treatment-by-CrCl effect (4.8% decrease in hazard ratio per 10-mL/min decrease in CrCl; <i>P</i><sub>interaction</sub>=0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with CrCl <77 mL/min, with a trend toward increasing benefit with lower CrCl (2.1% decrease in hazard ratio per 10-mL/min decrease in CrCl; <i>P</i><sub>interaction</sub>=0.08). Use of lower-dose rather than standard-dose DOACs was not associated with a significant difference in incident bleeding or ICH in patients with reduced kidney function but was associated with a higher incidence4 of death and S/SE.<br /><b>Conclusions</b><br />Standard-dose DOACs are safer and more effective than warfarin down to a CrCl of at least 25 mL/min. Lower-dose DOACs do not significantly lower the incidence of bleeding or ICH compared with standard-dose DOACs but are associated with a higher incidence of S/SE and death. These findings support the use of standard-dose DOACs over warfarin in patients with kidney dysfunction.<br /><br /><br /><br /><small>Circulation: 12 Apr 2023; epub ahead of print</small></div>

<div><h4>Cardiovascular Health and Life Expectancy Among Adults in the United States.</h4><i>Ma H, Wang X, Xue Q, Li X, ... Franco OH, Qi L</i><br /><b>Background</b><br />Cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. The American Heart Association recently released an updated algorithm for evaluating cardiovascular health (CVH)-Life\'s Essential 8 (LE8) score. We aimed to quantify the associations of CVH levels, estimated by the LE8 score, with life expectancy in a nationally representative sample of US adults.<br /><b>Methods</b><br />We included 23 003 nonpregnant, noninstitutionalized participants aged 20 to 79 years who participated in the National Health and Nutrition Examination Survey from 2005 to 2018 and whose mortality was identified through linkage to the National Death Index through December 31, 2019. The overall CVH was evaluated by the LE8 score (range, 0-100), as well as the score for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure. Life table method was used to estimate life expectancy by levels of the CVH.<br /><b>Results</b><br />During a median of 7.8 years of follow-up, 1359 total deaths occurred. The estimated life expectancy at age 50 years was 27.3 years (95% CI, 26.1-28.4), 32.9 years (95% CI, 32.3-33.4), and 36.2 years (95% CI, 34.2-38.2) in participants with low (LE8 score <50), moderate (50≤ LE8 score <80), and high (LE8 score ≥80) CVH, respectively. Equivalently, participants with high CVH had an average 8.9 (95% CI, 6.2-11.5) more years of life expectancy at age 50 years compared with those with low CVH. On average, 42.6% of the gained life expectancy at age 50 years from adhering to high CVH was attributable to reduced cardiovascular disease death. Similarly significant associations of CVH with life expectancy were observed in men and women, respectively. Similarly significant associations of CVH with life expectancy were observed in White participants and Black participants but not in Mexican participants.<br /><b>Conclusions</b><br />Adhering to a high CVH, defined as the LE8 score, is related to a considerably increased life expectancy in US adults, but more research needs to be done in other races and ethnicities (eg, Hispanic and Asian).<br /><br /><br /><br /><small>Circulation: 11 Apr 2023; 147:1137-1146</small></div>

<div><h4>Achieving Equity in Hospital Performance Assessments Using Composite Race-Specific Measures of Risk-Standardized Readmission and Mortality Rates for Heart Failure.</h4><i>Mentias A, Peterson ED, Keshvani N, Kumbhani DJ, ... Cram P, Pandey A</i><br /><b>Background</b><br />The contemporary measures of hospital performance for heart failure hospitalization and 30-day risk-standardized readmission rate (RSRR) and risk-standardized mortality rate (RSMR) are estimated using the same risk adjustment model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial and ethnic group, and may not adequately represent the hospital performance for patients of Black and other races.<br /><b>Methods</b><br />Fee-for-service Medicare beneficiaries from January 2014 to December 2019 hospitalized with heart failure were identified. Hospital-level 30-day RSRR and RSMR were estimated using the traditional race-agnostic models and the race-specific approach. The composite race-specific performance metric was calculated as the average of the RSRR/RMSR measures derived separately for each race and ethnicity group. Correlation and concordance in hospital performance for all patients and patients of Black and other races were assessed using the composite race-specific and race-agnostic metrics.<br /><b>Results</b><br />The study included 1 903 232 patients (75.7% White [n=1 439 958]; 14.5% Black [n=276 684]; and 9.8% other races [n=186 590]) with heart failure from 1860 hospitals. There was a modest correlation between hospital-level 30-day performance metrics for patients of White versus Black race (Pearson correlation coefficient: RSRR=0.42; RSMR=0.26). Compared with the race-agnostic RSRR and RSMR, composite race-specific metrics for all patients demonstrated stronger correlation with RSRR (correlation coefficient: 0.60 versus 0.74) and RSMR (correlation coefficient: 0.44 versus 0.51) for Black patients. Concordance in hospital performance for all patients and patients of Black race was also higher with race-specific (versus race-agnostic) metrics (RSRR=64% versus 53% concordantly high-performing; 61% versus 51% concordantly low-performing). Race-specific RSRR and RSMR metrics (versus race-agnostic) led to reclassification in performance ranking of 35.8% and 39.2% of hospitals, respectively, with better 30-day and 1-year outcomes for patients of all race groups at hospitals reclassified as high-performing.<br /><b>Conclusions</b><br />Among patients hospitalized with heart failure, race-specific 30-day RSMR and RSRR are more equitable in representing hospital performance for patients of Black and other races.<br /><br /><br /><br /><small>Circulation: 11 Apr 2023; 147:1121-1133</small></div>

<div><h4>Endothelin-1, Outcomes in Patients With Heart Failure and Reduced Ejection Fraction, and Effects of Dapagliflozin: Findings From DAPA-HF.</h4><i>Ern Yeoh S, Docherty KF, Campbell RT, Jhund PS, ... Morrow DA, McMurray JJV</i><br /><b>Background</b><br />ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure).<br /><b>Methods</b><br />We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level.<br /><b>Results</b><br />Overall, 3048 participants had baseline ET-1 measurements of: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28-4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53-2.50] for T3 and 1.36 [95% CI, 1.06-1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, -3.19 [95% CI, -3.66 to -2.72] mL/min/1.73 m<sup>2</sup>/y, T2, -2.08 [95% CI, -2.52 to -1.63] and T1 -2.35 [95% CI, -2.79 to -1.91]; <i>P</i>=0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25-0.01; <i>P</i>=0.029).<br /><b>Conclusions</b><br />Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03036124.<br /><br /><br /><br /><small>Circulation: 11 Apr 2023; epub ahead of print</small></div>

<div><h4>Cardiovascular Disease Risk Factors in Women: The Impact of Race and Ethnicity: A Scientific Statement From the American Heart Association.</h4><i>Mehta LS, Velarde GP, Lewey J, Sharma G, ... Mieres JH, American Heart Association Cardiovascular Disease and Stroke in Women and Underrepresented Populations Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Stroke Council</i><br /><AbstractText>Cardiovascular disease is the leading cause of death in women, yet differences exist among certain racial and ethnic groups. Aside from traditional risk factors, behavioral and environmental factors and social determinants of health affect cardiovascular health and risk in women. Language barriers, discrimination, acculturation, and health care access disproportionately affect women of underrepresented races and ethnicities. These factors result in a higher prevalence of cardiovascular disease and significant challenges in the diagnosis and treatment of cardiovascular conditions. Culturally sensitive, peer-led community and health care professional education is a necessary step in the prevention of cardiovascular disease. Equitable access to evidence-based cardiovascular preventive health care should be available for all women regardless of race and ethnicity; however, these guidelines are not equally incorporated into clinical practice. This scientific statement reviews the current evidence on racial and ethnic differences in cardiovascular risk factors and current cardiovascular preventive therapies for women in the United States.</AbstractText><br /><br /><br /><br /><small>Circulation: 10 Apr 2023; epub ahead of print</small></div>

<div><h4>Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.</h4><i>Gollmann-Tepeköylü C, Graber M, Hirsch J, Mair S, ... Tancevski I, Holfeld J</i><br /><b>Background</b><br />Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling.<br /><b>Methods</b><br />Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (<i>Bgn</i>), <i>Tlr3</i>, and IFN-α/β receptor alpha chain (<i>Ifnar1</i>)-deficient mice and a specific zebrafish model were used to study the implication of the byglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans.<br /><b>Results</b><br />Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that <i>Bgn</i><sup><i>-/-</i></sup>, <i>Tlr3</i><sup><i>-/-</i></sup>, and <i>Ifnar1</i><sup><i>-/-</i></sup> mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans.<br /><b>Conclusions</b><br />This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.<br /><br /><br /><br /><small>Circulation: 04 Apr 2023; epub ahead of print</small></div>

<div><h4>Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms.</h4><i>Benson TW, Conrad KA, Li XS, Wang Z, ... Hazen SL, Owens AP</i><br /><b>Background</b><br />Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.<br /><b>Methods</b><br />TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (<i>Ldlr<sup>-/-</sup></i>) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (<i>Fmo3<sup>-/-</sup></i>). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA.<br /><b>Results</b><br />Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, <i>Fmo3<sup>-/-</sup></i> mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK.<br /><b>Conclusions</b><br />These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.<br /><br /><br /><br /><small>Circulation: 04 Apr 2023; 147:1079-1096</small></div>

<div><h4>Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study.</h4><i>Pérez de Isla L, Díaz-Díaz JL, Romero MJ, Muñiz-Grijalvo O, ... Mata P, SAFEHEART study group</i><br /><b>Background</b><br />The effect of alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, on coronary plaque burden in patients with familial hypercholesterolemia has not been addressed. Our aim was to assess changes in coronary plaque burden and its characteristics after treatment with alirocumab by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of a noninvasive analysis of coronary computed tomographic angiography in asymptomatic subjects with familial hypercholesterolemia receiving optimized and stable treatment with maximum tolerated statin dose with or without ezetimibe.<br /><b>Methods</b><br />This study is a phase IV, open-label, multicenter, single-arm clinical trial to assess changes in coronary plaque burden and its characteristics after 78 weeks of treatment with alirocumab in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent an initial coronary computed tomographic angiography at baseline and another at 78 weeks. Every patient received 150 mg of alirocumab subcutaneiously every 14 days in addition to high-intensity statin therapy. The main outcome was the change on coronary plaque burden and its characteristics by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of analysis of coronary computed tomographic angiography.<br /><b>Results</b><br />The study was completed by 104 patients. The median age was 53.3 (46.2-59.4) years. Of these patients, 54 were women (51.9%). Median low-density lipoprotein cholesterol was 138.9 (117.5-175.3) mg/dL at entry and 45.0 (36.0-65.0) mg/dL at follow-up (<i>P</i><0.001). Coronary plaque burden changed from 34.6% (32.5%-36.8%) at entry to 30.4% (27.4%-33.4%) at follow-up (<i>P</i><0.001). A significant change in the characteristics of the coronary atherosclerosis was also found: an increase in the proportion of calcified (+0.3%; <i>P</i><0.001) and mainly fibrous (+6.2%; <i>P</i><0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (-3.9%; <i>P</i><0.001) and necrotic plaque (-0.6%; <i>P</i><0.001).<br /><b>Conclusions</b><br />Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks in these groups of patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) could link and explain ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) results.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT05465278.<br /><br /><br /><br /><small>Circulation: 03 Apr 2023; epub ahead of print</small></div>

<div><h4>Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis.</h4><i>Cai W, Liu L, Shi X, Liu Y, ... Zhu Y, Zhang X</i><br /><b>Background</b><br />Myocardial ischemia-reperfusion (I/R) injury causes cardiac dysfunction to myocardial cell loss and fibrosis. Prevention of cell death is important to protect cardiac function after I/R injury. The process of reperfusion can lead to multiple types of cardiomyocyte death, including necrosis, apoptosis, autophagy, and ferroptosis. However, the time point at which the various modes of cell death occur after reperfusion injury and the mechanisms underlying ferroptosis regulation in cardiomyocytes are still unclear.<br /><b>Methods</b><br />Using a left anterior descending coronary artery ligation mouse model, we sought to investigate the time point at which the various modes of cell death occur after reperfusion injury. To discover the key molecules involved in cardiomyocyte ferroptosis, we performed a metabolomics study. Loss/gain-of-function approaches were used to understand the role of 15-lipoxygenase (Alox15) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) in myocardial I/R injury.<br /><b>Results</b><br />We found that apoptosis and necrosis occurred in the early phase of I/R injury, and that ferroptosis was the predominant form of cell death during the prolonged reperfusion. Metabolomic profiling of eicosanoids revealed that Alox15 metabolites accumulated in ferroptotic cardiomyocytes. We demonstrated that Alox15 expression was specifically increased in the injured area of the left ventricle below the suture and colocalized with cardiomyocytes. Furthermore, myocardial-specific knockout of Alox15 in mice alleviated I/R injury and restored cardiac function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an intermediate metabolite derived from arachidonic acid by Alox15, was identified as a trigger for cardiomyocyte ferroptosis. We explored the mechanism underlying its effects and found that 15-HpETE promoted the binding of Pgc1α to the ubiquitin ligase ring finger protein 34, leading to its ubiquitin-dependent degradation. Consequently, attenuated mitochondrial biogenesis and abnormal mitochondrial morphology were observed. ML351, a specific inhibitor of Alox15, increased the protein level of Pgc1α, inhibited cardiomyocyte ferroptosis, protected the injured myocardium, and caused cardiac function recovery.<br /><b>Conclusions</b><br />Together, our results established that Alox15/15-HpETE-mediated cardiomyocyte ferroptosis plays an important role in prolonged I/R injury.<br /><br /><br /><br /><small>Circulation: 29 Mar 2023; epub ahead of print</small></div>

<div><h4>Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy.</h4><i>Chun YW, Miyamoto M, Williams CH, Neitzel LR, ... Ru Su Y, Hong CC</i><br /><b>Background</b><br />During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure.<br /><b>Methods</b><br />We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and <i>Drosophila</i> models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further.<br /><b>Results</b><br />Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified <i>RTTN</i>, the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient\'s condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and <i>Drosophila</i> confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes.<br /><b>Conclusions</b><br />This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for <i>RTTN</i> in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.<br /><br /><br /><br /><small>Circulation: 27 Mar 2023; epub ahead of print</small></div>

<div><h4>Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study.</h4><i>Sipilä PN, Lindbohm JV, David Batty G, Heikkilä N, ... Hayward AC, Kivimäki M</i><br /><b>Background</b><br />The excess risk of cardiovascular disease associated with a wide array of infectious diseases is unknown. We quantified the short- and long-term risk of major cardiovascular events in people with severe infection and estimated the population-attributable fraction.<br /><b>Methods</b><br />We analyzed data from 331 683 UK Biobank participants without cardiovascular disease at baseline (2006-2010) and replicated our main findings in an independent population from 3 prospective cohort studies comprising 271 533 community-dwelling participants from Finland (baseline 1986-2005). Cardiovascular risk factors were measured at baseline. We diagnosed infectious diseases (the exposure) and incident major cardiovascular events after infections, defined as myocardial infarction, cardiac death, or fatal or nonfatal stroke (the outcome) from linkage of participants to hospital and mortality registers. We computed adjusted hazard ratios (HRs) and 95% CIs for infectious diseases as short- and long-term risk factors for incident major cardiovascular events. We also calculated population-attributable fractions for long-term risk.<br /><b>Results</b><br />In the UK Biobank (mean follow-up, 11.6 years), 54 434 participants were hospitalized for an infection, and 11 649 had an incident major cardiovascular event at follow-up. Relative to participants with no record of infectious disease, those who were hospitalized experienced increased risk of major cardiovascular events, largely irrespective of the subtype of infection. This association was strongest during the first month after infection (HR, 7.87 [95% CI, 6.36-9.73]), but remained elevated during the entire follow-up (HR, 1.47 [95% CI, 1.40-1.54]). The findings were similar in the replication cohort (HR, 7.64 [95% CI, 5.82-10.03] during the first month; HR, 1.41 [95% CI, 1.34-1.48] during mean follow-up of 19.2 years). After controlling for traditional cardiovascular risk factors, the population-attributable fraction for severe infections and major cardiovascular events was 4.4% in the UK Biobank and 6.1% in the replication cohort.<br /><b>Conclusions</b><br />Infections severe enough to require hospital treatment were associated with increased risks for major cardiovascular disease events immediately after hospitalization. A small excess risk was also observed in the long-term, but residual confounding cannot be excluded.<br /><br /><br /><br /><small>Circulation: 27 Mar 2023; epub ahead of print</small></div>

<div><h4>Long-Term Outcomes of Brugada Substrate Ablation: A Report from BRAVO (Brugada Ablation of VF Substrate Ongoing Multicenter Registry).</h4><i>Nademanee K, Chung FP, Sacher F, Nogami A, ... Vardhanabhuti S, Haissaguerre M</i><br /><b>Background</b><br />Treatment options for high-risk Brugada syndrome (BrS) with recurrent ventricular fibrillation (VF) are limited. Catheter ablation is increasingly performed but a large study with long-term outcome data is lacking. We report the results of the multicenter, international BRAVO (Brugada Ablation of VF Substrate Ongoing Registry) for treatment of high-risk symptomatic BrS.<br /><b>Methods</b><br />We enrolled 159 patients (median age 42 years; 156 male) with BrS and spontaneous VF in BRAVO; 43 (27%) of them had BrS and early repolarization pattern. All but 5 had an implantable cardioverter-defibrillator for cardiac arrest (n=125) or syncope (n=34). A total of 140 (88%) had experienced numerous implantable cardioverter-defibrillator shocks for spontaneous VF before ablation. All patients underwent a percutaneous epicardial substrate ablation with electroanatomical mapping except for 8 who underwent open-thoracotomy ablation.<br /><b>Results</b><br />In all patients, VF/BrS substrates were recorded in the epicardial surface of the right ventricular outflow tract; 45 (29%) patients also had an arrhythmic substrate in the inferior right ventricular epicardium and 3 in the posterior left ventricular epicardium. After a single ablation procedure, 128 of 159 (81%) patients remained free of VF recurrence; this number increased to 153 (96%) after a repeated procedure (mean 1.2±0.5 procedures; median=1), with a mean follow-up period of 48±29 months from the last ablation. VF burden and frequency of shocks decreased significantly from 1.1±2.1 per month before ablation to 0.003±0.14 per month after the last ablation (<i>P</i><0.0001). The Kaplan-Meier VF-free survival beyond 5 years after the last ablation was 95%. The only variable associated with a VF-free outcome in multivariable analysis was normalization of the type 1 Brugada ECG, both with and without sodium-channel blockade, after the ablation (hazard ratio, 0.078 [95% CI, 0.008 to 0.753]; <i>P</i>=0.0274). There were no arrhythmic or cardiac deaths. Complications included hemopericardium in 4 (2.5%) patients.<br /><b>Conclusions</b><br />Ablation treatment is safe and highly effective in preventing VF recurrence in high-risk BrS. Prospective studies are needed to determine whether it can be an alternative treatment to implantable cardioverter-defibrillator implantation for selected patients with BrS.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04420078.<br /><br /><br /><br /><small>Circulation: 24 Mar 2023; epub ahead of print</small></div>

<div><h4>Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration.</h4><i>Luo S, Kong C, Zhao S, Tang X, ... Xie L, Ji Y</i><br /><b>Background</b><br />Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism.<br /><b>Methods</b><br />Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H<sub>2</sub>S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H<sub>2</sub>S system and the findings were confirmed in transgenic mice.<br /><b>Results</b><br />Higher plasma H<sub>2</sub>S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of <i>CTH</i>, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H<sub>2</sub>S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD.<br /><b>Conclusions</b><br />Decreased plasma H<sub>2</sub>S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses <i>CTH</i>, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.<br /><br /><br /><br /><small>Circulation: 23 Mar 2023; epub ahead of print</small></div>

<div><h4>Supervised Exercise Training for Chronic Heart Failure With Preserved Ejection Fraction: A Scientific Statement From the American Heart Association and American College of Cardiology.</h4><i>Sachdev V, Sharma K, Keteyian SJ, Alcain CF, ... American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and American College of Cardiology</i><br /><AbstractText>Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life. This success may be attributed, at least in part, to the pleiotropic effects of exercise, which may favorably affect the full range of abnormalities-peripheral vascular, skeletal muscle, and cardiovascular-that contribute to exercise intolerance in HFpEF. Accordingly, this scientific statement critically examines the currently available literature on the effects of exercise-based therapies for chronic stable HFpEF, potential mechanisms for improvement of exercise capacity and symptoms, and how these data compare with exercise therapy for other cardiovascular conditions. Specifically, data reviewed herein demonstrate a comparable or larger magnitude of improvement in exercise capacity from supervised exercise training in patients with chronic HFpEF compared with those with heart failure with reduced ejection fraction, although Medicare reimbursement is available only for the latter group. Finally, critical gaps in implementation of exercise-based therapies for patients with HFpEF, including exercise setting, training modalities, combinations with other strategies such as diet and medications, long-term adherence, incorporation of innovative and more accessible delivery methods, and management of recently hospitalized patients are highlighted to provide guidance for future research.</AbstractText><br /><br /><br /><br /><small>Circulation: 21 Mar 2023; epub ahead of print</small></div>

<div><h4>Effectiveness of the Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial.</h4><i>Kinnamon DD, Jordan E, Haas GJ, Hofmeyer M, ... Hershberger RE, DCM (Dilated Cardiomyopathy) Precision Medicine Study of the DCM Consortium</i><br /><b>Background</b><br />Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive.<br /><b>Methods</b><br />The DCM Precision Medicine Study developed <i>Family Heart Talk</i>, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the <i>Family Heart Talk</i> booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive and not enrolled on the same day as the proband.<br /><b>Results</b><br />Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive <i>Family Heart Talk</i> (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the <i>Family Heart Talk</i> arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the <i>Family Heart Talk</i> arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the <i>Family Heart Talk</i> arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (<i>P</i>=0.90).<br /><b>Conclusions</b><br /><i>Family Heart Talk,</i> a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of patients with DCM.<br /><b>Registration</b><br />URL: https://clinicaltrials.gov; Unique identifier: NCT03037632.<br /><br /><br /><br /><small>Circulation: 20 Mar 2023; epub ahead of print</small></div>

<div><h4>Evaluation and Management of Pulmonary Hypertension in Noncardiac Surgery: A Scientific Statement From the American Heart Association.</h4><i>Rajagopal S, Ruetzler K, Ghadimi K, Horn EM, ... Perioperative and Resuscitation, and the Council on Cardiovascular and Stroke Nursing</i><br /><AbstractText>Pulmonary hypertension, defined as an elevation in blood pressure in the pulmonary arteries, is associated with an increased risk of death. The prevalence of pulmonary hypertension is increasing, with an aging population, a rising prevalence of heart and lung disease, and improved pulmonary hypertension survival with targeted therapies. Patients with pulmonary hypertension frequently require noncardiac surgery, although pulmonary hypertension is associated with excess perioperative morbidity and death. This scientific statement provides guidance on the evaluation and management of pulmonary hypertension in patients undergoing noncardiac surgery. We advocate for a multistep process focused on (1) classification of pulmonary hypertension group to define the underlying pathology; (2) preoperative risk assessment that will guide surgical decision-making; (3) pulmonary hypertension optimization before surgery to reduce perioperative risk; (4) intraoperative management of pulmonary hypertension to avoid right ventricular dysfunction and to maintain cardiac output; and (5) postoperative management of pulmonary hypertension to ensure recovery from surgery. Last, this scientific statement highlights the paucity of evidence to support perioperative pulmonary hypertension management and identifies areas of uncertainty and opportunities for future investigation.</AbstractText><br /><br /><br /><br /><small>Circulation: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation.</h4><i>Gordon LB, Norris W, Hamren S, Goodson R, ... Kieran MW, Kleinman ME</i><br /><b>Background</b><br />Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin\'s quantity, response to progerin-targeted therapy, and relationship to patient survival.<br /><b>Methods</b><br />Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children\'s Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization.<br /><b>Results</b><br />The assay\'s dynamic detection range was 59 to 30 000 pg/mL (<i>R</i><sup>2</sup>=0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2-71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1-17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children (<i>P</i><0.0001). Progerin levels did not differ by sex (<i>P</i>=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all <i>P</i><0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (<i>P</i><0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration.<br /><b>Conclusions</b><br />A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov. Unique identifiers: NCT00879034 and NCT00916747.<br /><br /><br /><br /><small>Circulation: 15 Mar 2023; epub ahead of print</small></div>

<div><h4>Pharmacology and Clinical Development of Factor XI Inhibitors.</h4><i>Greco A, Laudani C, Spagnolo M, Agnello F, ... Scalia L, Capodanno D</i><br /><AbstractText>Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.</AbstractText><br /><br /><br /><br /><small>Circulation: 14 Mar 2023; 147:897-913</small></div>

<div><h4>Atrial Fibrillation Occurring During Acute Hospitalization: A Scientific Statement From the American Heart Association.</h4><i>Chyou JY, Barkoudah E, Dukes JW, Goldstein LB, ... Critical Care, Perioperative and Resuscitation; Council on Cardiovascular and Stroke Nursing; and Stroke Council</i><br /><AbstractText>Acute atrial fibrillation is defined as atrial fibrillation detected in the setting of acute care or acute illness; atrial fibrillation may be detected or managed for the first time during acute hospitalization for another condition. Atrial fibrillation after cardiothoracic surgery is a distinct type of acute atrial fibrillation. Acute atrial fibrillation is associated with high risk of long-term atrial fibrillation recurrence, warranting clinical attention during acute hospitalization and over long-term follow-up. A framework of substrates and triggers can be useful for evaluating and managing acute atrial fibrillation. Acute management requires a multipronged approach with interdisciplinary care collaboration, tailoring treatments to the patient\'s underlying substrate and acute condition. Key components of acute management include identification and treatment of triggers, selection and implementation of rate/rhythm control, and management of anticoagulation. Acute rate or rhythm control strategy should be individualized with consideration of the patient\'s capacity to tolerate rapid rates or atrioventricular dyssynchrony, and the patient\'s ability to tolerate the risk of the therapeutic strategy. Given the high risks of atrial fibrillation recurrence in patients with acute atrial fibrillation, clinical follow-up and heart rhythm monitoring are warranted. Long-term management is guided by patient substrate, with implications for intensity of heart rhythm monitoring, anticoagulation, and considerations for rhythm management strategies. Overall management of acute atrial fibrillation addresses substrates and triggers. The 3As of acute management are acute triggers, atrial fibrillation rate/rhythm management, and anticoagulation. The 2As and 2Ms of long-term management include monitoring of heart rhythm and modification of lifestyle and risk factors, in addition to considerations for atrial fibrillation rate/rhythm management and anticoagulation. Several gaps in knowledge related to acute atrial fibrillation exist and warrant future research.</AbstractText><br /><br /><br /><br /><small>Circulation: 13 Mar 2023; epub ahead of print</small></div>

<div><h4>Mechanical Thrombectomy Global Access For Stroke (MT-GLASS): A Mission Thrombectomy (MT-2020 Plus) Study.</h4><i>Asif KS, Otite FO, Desai SM, Herial N, ... Ortega-Gutierrez S, Yavagal DR</i><br /><b>Background</b><br />Despite the well-established potent benefit of mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke, access to MT has not been studied globally. We conducted a worldwide survey of countries on 6 continents to define MT access (MTA), the disparities in MTA, and its determinants on a global scale.<br /><b>Methods</b><br />Our survey was conducted in 75 countries through the Mission Thrombectomy 2020+ global network between November 22, 2020, and February 28, 2021. The primary end points were the current annual MTA, MT operator availability, and MT center availability. MTA was defined as the estimated proportion of patients with LVO receiving MT in a given region annually. The availability metrics were defined as ([current MT operators×50/current annual number of estimated thrombectomy-eligible LVOs]×100 = MT operator availability) and ([current MT centers×150/current annual number of estimated thrombectomy-eligible LVOs]×100= MT center availability). The metrics used optimal MT volume per operator as 50 and an optimal MT volume per center as 150. Multivariable-adjusted generalized linear models were used to evaluate factors associated with MTA.<br /><b>Results</b><br />We received 887 responses from 67 countries. The median global MTA was 2.79% (interquartile range, 0.70-11.74). MTA was <1.0% for 18 (27%) countries and 0 for 7 (10%) countries. There was a 460-fold disparity between the highest and lowest nonzero MTA regions and low-income countries had 88% lower MTA compared with high-income countries. The global MT operator availability was 16.5% of optimal and the MT center availability was 20.8% of optimal. On multivariable regression, country income level (low or lower-middle versus high: odds ratio, 0.08 [95% CI, 0.04-0.12]), MT operator availability (odds ratio, 3.35 [95% CI, 2.07-5.42]), MT center availability (odds ratio, 2.86 [95% CI, 1.84-4.48]), and presence of prehospital acute stroke bypass protocol (odds ratio, 4.00 [95% CI, 1.70-9.42]) were significantly associated with increased odds of MTA.<br /><b>Conclusions</b><br />Access to MT on a global level is extremely low, with enormous disparities between countries by income level. The significant determinants of MT access are the country\'s per capita gross national income, prehospital LVO triage policy, and MT operator and center availability.<br /><br /><br /><br /><small>Circulation: 08 Mar 2023; epub ahead of print</small></div>

<div><h4>Nitrative Modification of Caveolin-3: A Novel Mechanism of Cardiac Insulin Resistance and a Potential Therapeutic Target Against Ischemic Heart Failure in Prediabetic Animals.</h4><i>Meng Z, Zhang Z, Zhao J, Liu C, ... Ma X, Wang Y</i><br /><b>Background</b><br />Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, including adiponectin and preconditioning. The \"universal\" resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad prosurvival signaling cascades. Cav (Caveolin) is a scaffolding protein coordinating transmembrane signaling transduction. However, the role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown.<br /><b>Methods</b><br />Wild-type and gene-manipulated mice were fed a normal diet or high-fat diet for 2 to 12 weeks and subjected to myocardial ischemia and reperfusion. Insulin cardioprotection was determined.<br /><b>Results</b><br />Compared with the normal diet group, the cardioprotective effect of insulin was significantly blunted as early as 4 weeks of high-fat diet feeding (prediabetes), a time point where expression levels of insulin-signaling molecules remained unchanged. However, Cav3/insulin receptor-β complex formation was significantly reduced. Among multiple posttranslational modifications altering protein/protein interaction, Cav3 (not insulin receptor-β) tyrosine nitration is prominent in the prediabetic heart. Treatment of cardiomyocytes with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride reduced the signalsome complex and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr<sup>73</sup> as the Cav3 nitration site. Phenylalanine substitution of Tyr<sup>73</sup> (Cav3<sup>Y73F</sup>) abolished 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride-induced Cav3 nitration, restored Cav3/insulin receptor-β complex, and rescued insulin transmembrane signaling. It is most important that adeno-associated virus 9-mediated cardiomyocyte-specific Cav3<sup>Y73F</sup> reexpression blocked high-fat diet-induced Cav3 nitration, preserved Cav3 signalsome integrity, restored transmembrane signaling, and rescued insulin-protective action against ischemic heart failure. Last, diabetic nitrative modification of Cav3 at Tyr<sup>73</sup> also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling.<br /><b>Conclusion</b><br />Nitration of Cav3 at Tyr<sup>73</sup> and resultant signal complex dissociation results in cardiac insulin/adiponectin resistance in the prediabetic heart, contributing to ischemic heart failure progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic heart failure.<br /><br /><br /><br /><small>Circulation: 08 Mar 2023; epub ahead of print</small></div>

<div><h4>Pregnancy Complications and Long-Term Mortality in a Diverse Cohort.</h4><i>Hinkle SN, Schisterman EF, Liu D, Pollack AZ, ... Mendola P, Zhang C</i><br /><b>Background</b><br />Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant women. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant women.<br /><b>Methods</b><br />The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant women at 12 US clinical centers (1959-1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants\' vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year.<br /><b>Results</b><br />Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45-54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03-1.1]); premature rupture of membranes (aHR, 1.23 [1.05-1.44]); induced labor (aHR, 1.31 [1.03-1.66]); prelabor cesarean delivery (aHR, 2.09 [1.75-2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97-1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99-1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20-1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00-1.30]) compared with normoglycemic. <i>P</i> values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10-2.46]) compared with White (aHR, 1.29 [0.97-1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90-2.90]) compared with Black (aHR, 1.40 [1.00-1.96]) participants.<br /><b>Conclusions</b><br />In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.<br /><br /><br /><br /><small>Circulation: 08 Mar 2023; epub ahead of print</small></div>

<div><h4>Pulsed Field Ablation for the Treatment of Atrial Fibrillation: PULSED AF Pivotal Trial.</h4><i>Verma A, Haines DE, Boersma LV, Sood N, ... DeLurgio DB, PULSED AF Investigators</i><br /><AbstractText><b>BACKGROUND:</b> Pulsed field ablation uses electrical pulses to cause nonthermal irreversible electroporation and induce cardiac cell death. Pulsed field ablation may have effectiveness comparable to traditional catheter ablation while preventing thermally mediated complications. <br /><b>Methods:</b><br/>The PULSED AF pivotal study (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF) was a prospective, global, multicenter, nonrandomized, paired single-arm study in which patients with paroxysmal (n=150) or persistent (n=150) symptomatic atrial fibrillation (AF) refractory to class I or III antiarrhythmic drugs were treated with pulsed field ablation. All patients were monitored for 1 year using weekly and symptomatic transtelephonic monitoring; 3-, 6-, and 12-month ECGs; and 6- and 12-month 24-hour Holter monitoring. The primary effectiveness end point was freedom from a composite of acute procedural failure, arrhythmia recurrence, or antiarrhythmic escalation through 12 months, excluding a 3-month blanking period to allow recovery from the procedure. The primary safety end point was freedom from a composite of serious procedure- and device-related adverse events. Kaplan-Meier methods were used to evaluate the primary end points. <br /><b>Results:</b><br/>Pulsed field ablation was shown to be effective at 1 year in 66.2% (95% CI, 57.9 to 73.2) of patients with paroxysmal AF and 55.1% (95% CI, 46.7 to 62.7) of patients with persistent AF. The primary safety end point occurred in 1 patient (0.7%; 95% CI, 0.1 to 4.6) in both the paroxysmal and persistent AF cohorts. <br /><b>Conclusions:</b><br/>PULSED AF demonstrated a low rate of primary safety adverse events (0.7%) and provided effectiveness consistent with established ablation technologies using a novel irreversible electroporation energy to treat patients with AF.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Mar 2023; epub ahead of print</small></div>

<div><h4>Patient Characteristics, Outcomes, and Effects of Dapagliflozin According to the Duration of Heart Failure: A Prespecified Analysis of the DELIVER Trial.</h4><i>Kondo T, Jering KS, Borleffs CJW, de Boer RA, ... Solomon SD, McMurray JJV</i><br /><b>Background</b><br />How patient characteristics and outcomes vary according to the duration of heart failure (HF) is unknown in individuals with mildly reduced or preserved ejection fraction. We compared these, and the efficacy and safety of dapagliflozin, according to the time from diagnosis of HF in a prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure).<br /><b>Methods</b><br />HF duration was categorized as ≤6 months, >6 to 12 months, >1 to 2 years, >2 to 5 years, or >5 years. Outcomes were adjusted for prognostic variables and analyzed using Cox regression. The primary outcome was the composite of worsening HF or cardiovascular death. The effect of treatment was examined by HF duration category.<br /><b>Results</b><br />The number of patients in each category was as follows: 1160 (≤6 months), 842 (>6 to 12 months), 995 (>1 to 2 years), 1569 (>2 to 5 years), and 1692 (>5 years). Patients with longer-duration HF were older and had more comorbidities with worse symptoms. The rate of the primary outcome (per 100 person-years) increased with HF duration: ≤6 months, 7.3 (95% CI, 6.3 to 8.4); >6 to 12 months, 7.1 (6.0 to 8.5); >1 to 2 years, 8.4 (7.2 to 9.7); >2 to 5 years, 8.9 (7.9 to 9.9); and >5 years, 10.6 (9.5 to 11.7). Similar trends were seen for other outcomes. The benefit of dapagliflozin was consistent across HF duration category: the hazard ratio for the primary outcome in the ≤6-month group was 0.67 (95% CI, 0.50 to 0.91); >6 to 12 months, 0.78 (0.55 to 1.12); >1 to 2 years, 0.81 (0.60 to 1.09); >2 to 5 years, 0.97 (0.77 to 1.22); and >5 years, 0.78 (0.64 to 0.96; <i>P</i><sub>interaction</sub>=0.41). The absolute benefit was greatest in longest-duration HF; the number needed to treat for HF >5 years was 24 versus 32 for ≤6 months.<br /><b>Conclusions</b><br />Patients with longer-duration HF were older, had more comorbidities and symptoms, and had higher rates of worsening HF and death. The benefits of dapagliflozin were consistent across HF duration. Even patients with long-standing HF and generally mild symptoms are not stable, and it is not too late for such patients to benefit from a sodium-glucose cotransporter 2 inhibitor.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03619213.<br /><br /><br /><br /><small>Circulation: 06 Mar 2023; epub ahead of print</small></div>

<div><h4>Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice With Chronic Heart Failure.</h4><i>Skogestad J, Albert I, Hougen K, Lothe GB, ... Carlson CR, Aronsen JM</i><br /><b>Background</b><br />Increasing SERCA2 (sarco[endo]-plasmic reticulum Ca<sup>2+</sup> ATPase 2) activity is suggested to be beneficial in chronic heart failure, but no selective SERCA2-activating drugs are available. PDE3A (phosphodiesterase 3A) is proposed to be present in the SERCA2 interactome and limit SERCA2 activity. Disruption of PDE3A from SERCA2 might thus be a strategy to develop SERCA2 activators.<br /><b>Methods</b><br />Confocal microscopy, 2-color direct stochastic optical reconstruction microscopy, proximity ligation assays, immunoprecipitations, peptide arrays, and surface plasmon resonance were used to investigate colocalization between SERCA2 and PDE3A in cardiomyocytes, map the SERCA2/PDE3A interaction sites, and optimize disruptor peptides that release PDE3A from SERCA2. Functional experiments assessing the effect of PDE3A-binding to SERCA2 were performed in cardiomyocytes and HEK293 vesicles. The effect of SERCA2/PDE3A disruption by an optimized disruptor peptide (Opt) F on cardiac mortality and function was evaluated during 20 weeks in 2 consecutive randomized, blinded, and controlled preclinical trials in a total of 148 mice injected with recombinant adeno-associated virus 9 (rAAV9)-OptF, rAAV9-control (Ctrl), or PBS, before undergoing aortic banding (AB) or sham surgery and subsequent phenotyping with serial echocardiography, cardiac magnetic resonance imaging, histology, and functional and molecular assays.<br /><b>Results</b><br />PDE3A colocalized with SERCA2 in human nonfailing, human failing, and rodent myocardium. Amino acids 277-402 of PDE3A bound directly to amino acids 169-216 within the actuator domain of SERCA2. Disruption of PDE3A from SERCA2 increased SERCA2 activity in normal and failing cardiomyocytes. SERCA2/PDE3A disruptor peptides increased SERCA2 activity also in the presence of protein kinase A inhibitors and in phospholamban-deficient mice, and had no effect in mice with cardiomyocyte-specific inactivation of SERCA2. Cotransfection of PDE3A reduced SERCA2 activity in HEK293 vesicles. Treatment with rAAV9-OptF reduced cardiac mortality compared with rAAV9-Ctrl (hazard ratio, 0.26 [95% CI, 0.11 to 0.63]) and PBS (hazard ratio, 0.28 [95% CI, 0.09 to 0.90]) 20 weeks after AB. Mice injected with rAAV9-OptF had improved contractility and no difference in cardiac remodeling compared with rAAV9-Ctrl after aortic banding.<br /><b>Conclusions</b><br />Our results suggest that PDE3A regulates SERCA2 activity through direct binding, independently of the catalytic activity of PDE3A. Targeting the SERCA2/PDE3A interaction prevented cardiac mortality after aortic banding, most likely by improving cardiac contractility.<br /><br /><br /><br /><small>Circulation: 06 Mar 2023; epub ahead of print</small></div>

<div><h4>Self-management Support Using Advertising Principles for Older Low Income Adults at High Cardiovascular Risk: a Randomized Controlled Trial.</h4><i>Campbell DJT, Tonelli M, Hemmelgarn BR, Faris P, ... Manns BJ, Interdisciplinary Chronic Disease Collaboration</i><br /><AbstractText><b>Background:</b> Self-management education and support (SMES) interventions have modest effects on intermediate outcomes for those at risk of cardiovascular disease, but few studies have measured or demonstrated an impact on clinical endpoints. Advertising for commercial products is known to influence behavior, but advertising principles are not typically incorporated into SMES design. <br /><b>Methods:</b><br/>This randomized trial studied the impact of a novel tailored SMES program designed by an advertising firm among a population of low-income older adults at high cardiovascular risk in Alberta, Canada. The intervention included health promotion messaging from a fictitious \"peer\" and facilitated relay of clinical information to patients\' primary care provider and pharmacist. The primary outcome was the composite of death, myocardial infarction, stroke, coronary revascularization, and hospitalizations for cardiovascular-related ambulatory care-sensitive conditions. Rates of the primary outcome and its components were compared using negative binomial regression. Secondary outcomes included quality of life (EQ-5D index score), medication adherence, and overall healthcare costs. <br /><b>Results:</b><br/>We randomized 4,761 individuals, with a mean age of 74.4 years, of whom 46.8% were female. There was no evidence of statistical interaction (p=0.99) or of a synergistic effect between the two interventions in the factorial trial with respect to the primary outcome, which allowed us to evaluate the effect of each intervention separately. Over a median follow-up time of 36 months, the rate of the primary outcome was lower in the group that received SMES compared with the control group (incidence rate ratio (IRR): 0.78, 95% confidence interval (CI): 0.61-1.00, p=0.047). No significant between-group changes in quality of life over time were observed (mean difference 0.0001, 95%CI -0.018 to 0.018, p=0.99). The proportion of participants who were adherent to medications was not different between the two groups (p = 0.199 for statins, and p=0.754 for ACEi/ARBs). Overall adjusted health care costs did not differ between those receiving SMES and the control group ($2,015, 95%CI -1,953 to 5,985, p=0.320). <b>Conclusions:</b> In low-income older adults, a tailored SMES program using advertising principles reduced the rate of clinical outcomes compared with usual care, though the mechanisms of improvement are unclear and further studies are required.</AbstractText><br /><br /><br /><br /><small>Circulation: 05 Mar 2023; epub ahead of print</small></div>

<div><h4>The Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: a Prespecified Analysis of the NUDGE-FLU Trial.</h4><i>Modin D, Johansen ND, Vaduganathan M, Bhatt AS, ... Krause TG, Biering-Sørensen T</i><br /><AbstractText><b>Background:</b> Influenza vaccines have been demonstrated to effectively reduce the incidence of influenza infection and potentially associated risks of cardiovascular events in patients with cardiovascular disease (CVD). Despite strong guideline and public health endorsements, global influenza vaccination rates in patients with CVD are highly variable. This prespecified analysis of NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing InFLUenza Vaccine Uptake) examined the effect of digital behavioral nudges on influenza vaccine uptake based on the presence of cardiovascular disease. <br /><b>Methods:</b><br/>NUDGE-FLU was a randomized, pragmatic, nationwide, register-based trial including Danish citizens aged 65 years or older during the 2022-2023 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 electronic letters with designs based on behavioral concepts. Danish nationwide registers were used to collect baseline and outcome data. The primary endpoint was receipt of an influenza vaccine on or before January 1, 2023. The effects of the intervention letters were examined according to the presence of cardiovascular disease and across cardiovascular subgroups including heart failure, ischemic heart disease, and atrial fibrillation. <br /><b>Results:</b><br/>Of 964,870 NUDGE-FLU participants from 691,820 households, 264,392 (27.4%) had CVD. During follow-up, 83.1% of participants with CVD vs 79.2% of participants without CVD received influenza vaccination (p<0.001). Compared with usual care, a letter emphasizing the potential cardiovascular benefits of influenza vaccination increased vaccination rates; this effect was consistent in participants with CVD (absolute difference +0.60 percentage points, 99.55% CI -0.48 to 1.68) and without CVD (+0.98 percentage points, 99.55% CI 0.27 to 1.70; P for interaction=0.41). A repeated letter strategy with a reminder follow-up letter 14 days later was also effective in increasing influenza vaccination, irrespective of CVD (CVD: absolute difference +0.80 percentage points, 99.55% CI -0.27 to 1.86; no CVD: +0.67 percentage points, 99.55% CI -0.06 to 1.40; P for interaction=0.77). Effectiveness of both nudging strategies was consistent across all major CVD subgroups. None of the other seven nudging strategies were effective, regardless of CVD status. <b>Conclusions:</b> Electronic letter interventions emphasizing the potential cardiovascular benefits of influenza vaccination and using a reminder letter strategy were similarly beneficial in increasing influenza vaccination rates among older adults with and without CVD and across cardiovascular subgroups. Electronic nudges may improve influenza vaccine uptake in individuals with CVD.</AbstractText><br /><br /><br /><br /><small>Circulation: 05 Mar 2023; epub ahead of print</small></div>

<div><h4>Eliminating Medication Copayments for Low-income Older Adults at High Cardiovascular Risk: A Randomized Controlled Trial.</h4><i>Campbell DJT, Mitchell C, Hemmelgarn BR, Tonelli M, ... Manns BJ, Interdisciplinary Chronic Disease Collaboration</i><br /><AbstractText><b>Background:</b> One in eight people with heart disease has poor medication adherence that, in part, is related to copayment costs. This study tested whether eliminating copayments for high-value medications among low-income older adults at high cardiovascular risk would improve clinical outcomes. <br /><b>Methods:</b><br/>This randomized 2x2 factorial trial studied 2 distinct interventions in Alberta, Canada: eliminating copayments for high value preventive medications and a self-management education and support program (reported separately). The findings for the first intervention, which waived the usual 30% copayment on 15 medication classes commonly used to reduce cardiovascular events, compared to usual copayment, is reported herein. The primary outcome was the composite of death, myocardial infarction, stroke, coronary revascularization, and cardiovascular-related hospitalizations over a three-year followup. Rates of the primary outcome and its components were compared using negative binomial regression. Secondary outcomes included quality of life(EQ-5D index score), medication adherence, and overall healthcare costs. <br /><b>Results:</b><br/>4,761 individuals were randomized and followed for a median of 36 months. There was no evidence of statistical interaction(p=0.99) or of a synergistic effect between the two interventions in the factorial trial with respect to the primary outcome, which allowed us to evaluate the effect of each intervention separately. The rate of the primary outcome was not reduced by copayment elimination, (521 vs 533 events, incidence rate ratio(IRR) 0.84, 95%CI 0.66 to 1.07, p=0.162). The IRR for non-fatal MI, non-fatal stroke, and cardiovascular death (0.97; 95% CI 0.67 to 1.39), death (0.94 (95%CI 0.80 to 1.11) and for cardiovascular-related hospitalizations (0.78 (95%CI 0.57 to 1.06) did not differ between groups. No significant between-group changes in quality of life over time were observed(mean difference 0.012, 95%CI -0.006 to 0.030, p=0.19). The proportion of participants who were adherent to statins was 0.72 vs 0.69 for the copayment elimination vs usual copayment groups, respectively(mean difference 0.03, 95% CI 0.006-0.06, p=0.016). Overall adjusted health care costs did not differ ($3,575, 95%CI -605 to 7,168, p=0.098). <b>Conclusions:</b> In low-income adults at high cardiovascular risk, eliminating copayments (average $35 a month) did not improve clinical outcomes or reduce healthcare costs, despite a modest improvement in adherence to medications.</AbstractText><br /><br /><br /><br /><small>Circulation: 05 Mar 2023; epub ahead of print</small></div>

<div><h4>Comparison Of 3-6 Month Versus 12 Month Dual Antiplatelet Therapy After Coronary Intervention Using the Contemporary Drug-eluting Stents With Ultrathin Struts: The HOST-IDEA Randomized Clinical Trial.</h4><i>Han JK, Hwang D, Yang S, Park SH, ... Kim JW, Kim HS</i><br /><AbstractText><b>Background:</b> Limited data are available on short-term dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) using third-generation drug-eluting stents (DES) with ultrathin struts and advanced polymer technology. We investigated whether 3-6 month DAPT was non-inferior to 12 month one after implantation of DES with ultrathin struts and advanced polymer technology. <br /><b>Methods:</b><br/>We performed an open-label, randomized trial at 37 centers in South Korea. We enrolled patients undergoing PCI using the Orsiro biodegradable-polymer sirolimus-eluting stents (SES) or the Coroflex ISAR polymer-free SES. Patients with ST-segment elevation myocardial infarction were excluded. Patients were randomized to receive either 3-6 month or 12 month DAPT after PCI. The choice of antiplatelet medications was at the physician\'s discretion. The primary outcome was a net adverse clinical event (NACE), a composite of cardiac death, target vessel myocardial infarction (TVMI), clinically driven target lesion revascularization (CD-TLR), stent thrombosis, or major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 at 12 months. The major secondary outcomes were target lesion failure (TLF), a composite of cardiac death, TVMI, CD-TLR, and major bleeding. <br /><b>Results:</b><br/>A total of 2,013 patients (mean age 65.7±10.5, 1,487 male [73.9%], 1,110 [55.1%] presented with acute coronary syndrome) were randomized to 3-6 month DAPT (n=1,002) or 12 month DAPT (n=1,011). The primary outcome occurred in 37 (3.7%) patients in the 3-6 month DAPT group and 41 (4.1%) in the 12 month DAPT group. The non-inferiority of the 3-6 month DAPT group to the 12 month DAPT group was met (absolute risk difference, -0.4% [1-sided 95% confidence interval (CI), -∞% to 1.1%; P<0.001 for non-inferiority]). There were no significant differences in TLF (hazard ratio [HR] 0.98, 95% CI 0.56-1.71, P=0.94) or major bleeding (HR 0.82, 95% CI 0.41-1.61, P=0.56) between the two groups. Across various subgroups, the treatment effect of 3-6 month DAPT was consistent for NACE. <b>Conclusions:</b> Among patients undergoing PCI using third-generation DES, 3-6 month DAPT was non-inferior to 12 month DAPT for NACE. Further research is needed to generalize this finding to other populations and to determine the ideal regimen for 3-6 month DAPT.</AbstractText><br /><br /><br /><br /><small>Circulation: 05 Mar 2023; epub ahead of print</small></div>

<div><h4>On-Site Computed Tomography-Derived Fractional Flow Reserve to Guide the Management of Patients with Stable Coronary Artery Disease: the TARGET Randomized Trial.</h4><i>Yang J, Shan D, Wang X, Sun X, ... Chen Y, TARGET Investigators</i><br /><AbstractText><b>Background:</b> Computed tomography-derived fractional flow reserve (CT-FFR) using on-site machine learning enables identification of both the presence of coronary artery disease and vessel-specific ischemia. However, it is unclear whether on-site CT-FFR improves clinical or economic outcomes when compared with the standard of care in patients with stable coronary artery disease. <br /><b>Methods:</b><br/>In total 1,216 patients with stable coronary artery disease and an intermediate stenosis of 30% to 90% on coronary computed tomographic angiography (CCTA) were randomized to an on-site CT-FFR care pathway using machine learning or to standard care in 6 Chinese medical centers. The primary endpoint was the proportion of patients undergoing invasive coronary angiography without obstructive coronary artery disease or with obstructive disease who did not undergo intervention within 90 days. Secondary endpoints included major adverse cardiovascular events (MACE), quality of life, symptoms of angina, and medical expenditure at 1 year. <br /><b>Results:</b><br/>Baseline characteristics were similar in both groups with 72.4% (881/1,216) having either typical or atypical anginal symptoms. A total of 421 of 608 patients (69.2%) in the CT-FFR care group and 483 of 608 patients (79.4%) in the standard care group underwent invasive coronary angiography. Compared to standard care, the proportion of patients undergoing invasive coronary angiography without obstructive coronary artery disease or with obstructive disease not undergoing intervention was significantly reduced in the CT-FFR care group (28.3% [119/421] vs. 46.2% [223/483] P<0.001). Overall more patients underwent revascularization in the CT-FFR care group than in the standard care group (49.7% [302/608] vs. 42.8% [260/608], P=0.02), but of MACE at 1 year did not differ (hazard ratio, 0.88; 95%CI, 0.59 to 1.30). Quality of life and symptoms improved similarly during follow-up in both groups and there was a trend towards lower costs in the CT-FFR care group (difference, -¥4233; 95%CI, -¥8165 to ¥973, P=0.07). <b>Conclusions:</b> On-site CT-FFR using machine learning reduced the proportion of patients with stable coronary artery disease undergoing invasive coronary angiography without obstructive disease or requiring intervention within 90 days, but increased revascularization overall without improving symptoms or quality of life, or reducing major adverse cardiovascular events.</AbstractText><br /><br /><br /><br /><small>Circulation: 04 Mar 2023; epub ahead of print</small></div>

<div><h4>Comparison of Unibody and Non-Unibody Endografts for Abdominal Aortic Aneurysm Repair in Medicare Beneficiaries: The SAFE-AAA Study.</h4><i>Secemsky EA, Song Y, Sun T, Johnson CG, ... Xu J, Yeh RW</i><br /><b>Background</b><br />Concerns have been raised about the long-term performance of aortic stent grafts for the treatment of abdominal aortic aneurysms, in particular, unibody stent grafts (eg, Endologix AFX AAA stent grafts). Only limited data sets are available to evaluate the long-term risks related to these devices. The SAFE-AAA Study was designed with the Food and Drug Administration to provide a longitudinal assessment of the safety of unibody aortic stent grafts among Medicare beneficiaries.<br /><b>Methods</b><br />The SAFE-AAA Study was a prespecified, retrospective cohort study evaluating whether unibody aortic stent grafts are noninferior to non-unibody stent grafts with respect to the composite primary outcome of aortic reintervention, rupture, and mortality. Procedures were evaluated from August 1, 2011, through December 31, 2017. The primary end point was evaluated through December 31, 2019. Inverse probability weighting was used to account for imbalances in observed characteristics. Sensitivity analyses were used to evaluate the effect of unmeasured confounding, including the falsification end points of heart failure, stroke, and pneumonia. A prespecified subgroup includes patients treated from February 22, 2016, through December 31, 2017, corresponding to the market release of the most contemporary unibody endograft (Endologix AFX2 AAA stent graft).<br /><b>Results</b><br />Of 87 163 patients who underwent aortic stent grafting at 2146 US hospitals, 11 903 (13.7%) received a unibody device. The average age was 77.0±6.7 years, 21.1% were female, 93.5% were White, 90.8% had hypertension, and 35.8% used tobacco. The primary end point occurred in 73.4% of unibody device-treated patients versus 65.0% of non-unibody device-treated patients (hazard ratio, 1.19 [95% CI, 1.15-1.22]; noninferior <i>P</i> value of 1.00; median follow-up, 3.4 years). Falsification end points were negligibly different between groups. In a contemporary subgroup of procedures, the cumulative incidence of the primary end point was 37.5% of unibody device-treated patients and 32.7% of non-unibody device-treated patients (hazard ratio, 1.06 [95% CI, 0.98-1.14]).<br /><b>Conclusions</b><br />In the SAFE-AAA Study, unibody endografts failed to meet noninferiority compared with non-unibody endografts with respect to aortic reintervention, rupture, and mortality. These data support the urgency of instituting a prospective longitudinal surveillance program for monitoring safety events related to aortic stent grafts.<br /><br /><br /><br /><small>Circulation: 03 Mar 2023; epub ahead of print</small></div>