Journal: Circulation

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<div><h4>Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus.</h4><i>Dimopoulos K, Constantine A, Clift P, Condliffe R, ... Broberg CS, for Down Syndrome International (DSi)</i><br /><AbstractText>Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular condition in this group, present in up to 50% of people with Down syndrome and contributing to poor outcomes. Additional factors contributing to cardiovascular outcomes include pulmonary hypertension; coexistent pulmonary, endocrine, and metabolic diseases; and risk factors for atherosclerotic disease. Moreover, disparities in the cardiovascular care of people with Down syndrome compared with the general population, which vary across different geographies and health care systems, further contribute to cardiovascular mortality; this issue is often overlooked by the wider medical community. This review focuses on the diagnosis, prevalence, and management of cardiovascular disease encountered in people with Down syndrome and summarizes available evidence in 10 key areas relating to Down syndrome and cardiac disease, from prenatal diagnosis to disparities in care in areas of differing resource availability. All specialists and nonspecialist clinicians providing care for people with Down syndrome should be aware of best clinical practice in all aspects of care of this distinct population.</AbstractText><br /><br /><br /><br /><small>Circulation: 31 Jan 2023; 147:425-441</small></div>
Dimopoulos K, Constantine A, Clift P, Condliffe R, ... Broberg CS, for Down Syndrome International (DSi)
Circulation: 31 Jan 2023; 147:425-441 | PMID: 36716257
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<div><h4>Myocardial Involvement After Hospitalization for COVID-19 Complicated by Troponin Elevation: A Prospective, Multicenter, Observational Study.</h4><i>Artico J, Shiwani H, Moon JC, Gorecka M, ... OxAMI (Oxford Acute Myocardial Infarction Study) Investigators; COVID-HEART Investigators†, Greenwood JP</i><br /><b>Background</b><br />Acute myocardial injury in hospitalized patients with coronavirus disease 2019 (COVID-19) has a poor prognosis. Its associations and pathogenesis are unclear. Our aim was to assess the presence, nature, and extent of myocardial damage in hospitalized patients with troponin elevation.<br /><b>Methods</b><br />Across 25 hospitals in the United Kingdom, 342 patients with COVID-19 and an elevated troponin level (COVID+/troponin+) were enrolled between June 2020 and March 2021 and had a magnetic resonance imaging scan within 28 days of discharge. Two prospective control groups were recruited, comprising 64 patients with COVID-19 and normal troponin levels (COVID+/troponin-) and 113 patients without COVID-19 or elevated troponin level matched by age and cardiovascular comorbidities (COVID-/comorbidity+). Regression modeling was performed to identify predictors of major adverse cardiovascular events at 12 months.<br /><b>Results</b><br />Of the 519 included patients, 356 (69%) were men, with a median (interquartile range) age of 61.0 years (53.8, 68.8). The frequency of any heart abnormality, defined as left or right ventricular impairment, scar, or pericardial disease, was 2-fold greater in cases (61% [207/342]) compared with controls (36% [COVID+/troponin-] versus 31% [COVID-/comorbidity+]; <i>P</i><0.001 for both). More cases than controls had ventricular impairment (17.2% versus 3.1% and 7.1%) or scar (42% versus 7% and 23%; <i>P</i><0.001 for both). The myocardial injury pattern was different, with cases more likely than controls to have infarction (13% versus 2% and 7%; <i>P</i><0.01) or microinfarction (9% versus 0% and 1%; <i>P</i><0.001), but there was no difference in nonischemic scar (13% versus 5% and 14%; <i>P</i>=0.10). Using the Lake Louise magnetic resonance imaging criteria, the prevalence of probable recent myocarditis was 6.7% (23/342) in cases compared with 1.7% (2/113) in controls without COVID-19 (<i>P</i>=0.045). During follow-up, 4 patients died and 34 experienced a subsequent major adverse cardiovascular event (10.2%), which was similar to controls (6.1%; <i>P</i>=0.70). Myocardial scar, but not previous COVID-19 infection or troponin, was an independent predictor of major adverse cardiovascular events (odds ratio, 2.25 [95% CI, 1.12-4.57]; <i>P</i>=0.02).<br /><b>Conclusions</b><br />Compared with contemporary controls, patients with COVID-19 and elevated cardiac troponin level have more ventricular impairment and myocardial scar in early convalescence. However, the proportion with myocarditis was low and scar pathogenesis was diverse, including a newly described pattern of microinfarction.<br /><b>Registration</b><br />URL: https://www.isrctn.com; Unique identifier: 58667920.<br /><br /><br /><br /><small>Circulation: 27 Jan 2023:364-374; epub ahead of print</small></div>
Artico J, Shiwani H, Moon JC, Gorecka M, ... OxAMI (Oxford Acute Myocardial Infarction Study) Investigators; COVID-HEART Investigators†, Greenwood JP
Circulation: 27 Jan 2023:364-374; epub ahead of print | PMID: 36705028
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<div><h4>In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity.</h4><i>Cao Y, Zhang X, Akerberg BN, Yuan H, ... Kelly DP, Pu WT</i><br /><b>Background</b><br />Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined.<br /><b>Methods</b><br />We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus-mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-highly integrative chromatin immunoprecipitation on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP-mediated inactivation of ERRα and ERRγ in cardiomyocytes.<br /><b>Results</b><br />We identified 152 832 and 54 824 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus-mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27-anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs.<br /><b>Conclusions</b><br />We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi-transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.<br /><br /><br /><br /><small>Circulation: 27 Jan 2023; epub ahead of print</small></div>
Cao Y, Zhang X, Akerberg BN, Yuan H, ... Kelly DP, Pu WT
Circulation: 27 Jan 2023; epub ahead of print | PMID: 36705030
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<div><h4>Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials.</h4><i>Friedman DJ, Al-Khatib SM, Dalgaard F, Fudim M, ... Inoue LYT, Sanders GD</i><br /><b>Background</b><br />Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups.<br /><b>Methods</b><br />The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death.<br /><b>Results</b><br />Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; <i>P</i><sub>interaction</sub> <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death.<br /><b>Conclusions</b><br />CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single \"non-LBBB\" category when selecting patients for CRT should be reconsidered.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.<br /><br /><br /><br /><small>Circulation: 26 Jan 2023; epub ahead of print</small></div>
Friedman DJ, Al-Khatib SM, Dalgaard F, Fudim M, ... Inoue LYT, Sanders GD
Circulation: 26 Jan 2023; epub ahead of print | PMID: 36700426
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<div><h4>Interleukin-33 Mediates Cardiomyopathy After Acute Kidney Injury by Signaling to Cardiomyocytes.</h4><i>Florens N, Kasam RK, Rudman-Melnick V, Lin SC, Prasad V, Molkentin JD</i><br /><b>Background</b><br />Acute kidney injury (AKI) is a short-term life-threatening condition that, if survived, can lead to renal insufficiency and development of chronic kidney disease. The pathogenesis of AKI and chronic kidney disease involves direct effects on the heart and the development of hypertrophy and cardiomyopathy.<br /><b>Methods</b><br />We used mouse models of ischemia/reperfusion AKI and unilateral ureteral obstruction to investigate the role of IL-33 (interleukin-33) and its receptor-encoding gene <i>Il1rl1</i> (also called ST2L [suppression of tumorigenicity 2]) in cardiac remodeling after AKI. Mice with cell type-specific genetic disruption of the IL-33/ST2L axis were used, and IL-33 monoclonal antibody, adeno-associated virus encoding IL-33 or ST2L, and recombinant IL-33, as well.<br /><b>Results</b><br />Mice deficient in <i>Il33</i> were refractory to cardiomyopathy associated with 2 models of kidney injury. Treatment of mice with monoclonal IL-33 antibody also protected the heart after AKI. Moreover, overexpression of IL-33 or injection of recombinant IL-33 induced cardiac hypertrophy or cardiomyopathy, or both, but not in mice lacking <i>Il1rl1</i>. AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte-specific deletion of <i>Il1rl1</i> but not in endothelial cell- or fibroblast-specific deletion of <i>Il1rl1</i>. Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy.<br /><b>Conclusions</b><br />These results indicate that IL-33 released from the kidney during AKI underlies cardiorenal syndrome by directly signaling to cardiac myocytes, suggesting that antagonism of IL-33/ST2 axis would be cardioprotective in patients with kidney disease.<br /><br /><br /><br /><small>Circulation: 25 Jan 2023; epub ahead of print</small></div>
Florens N, Kasam RK, Rudman-Melnick V, Lin SC, Prasad V, Molkentin JD
Circulation: 25 Jan 2023; epub ahead of print | PMID: 36695175
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<div><h4>Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association.</h4><i>Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, ... Martin SS, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee</i><br /><b>Background</b><br />The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).<br /><b>Methods</b><br />The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year\'s worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year\'s edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains.<br /><b>Results</b><br />Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.<br /><b>Conclusions</b><br />The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.<br /><br /><br /><br /><small>Circulation: 25 Jan 2023; epub ahead of print</small></div>
Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, ... Martin SS, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
Circulation: 25 Jan 2023; epub ahead of print | PMID: 36695182
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<div><h4>Surgical Management and Mechanical Circulatory Support in High-Risk Pulmonary Embolisms: Historical Context, Current Status, and Future Directions: A Scientific Statement From the American Heart Association.</h4><i>Goldberg JB, Giri J, Kobayashi T, Ruel M, ... American Heart Association Council on Cardiovascular Surgery and Anesthesia; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease</i><br /><AbstractText>Acute pulmonary embolism is the third leading cause of cardiovascular death, with most pulmonary embolism-related mortality associated with acute right ventricular failure. Although there has recently been increased clinical attention to acute pulmonary embolism with the adoption of multidisciplinary pulmonary embolism response teams, mortality of patients with pulmonary embolism who present with hemodynamic compromise remains high when current guideline-directed therapy is followed. Because historical data and practice patterns affect current consensus treatment recommendations, surgical embolectomy has largely been relegated to patients who have contraindications to other treatments or when other treatment modalities fail. Despite a selection bias toward patients with greater illness, a growing body of literature describes the safety and efficacy of the surgical management of acute pulmonary embolism, especially in the hemodynamically compromised population. The purpose of this document is to describe modern techniques, strategies, and outcomes of surgical embolectomy and venoarterial extracorporeal membrane oxygenation and to suggest strategies to better understand the role of surgery in the management of pulmonary embolisms.</AbstractText><br /><br /><br /><br /><small>Circulation: 23 Jan 2023; epub ahead of print</small></div>
Goldberg JB, Giri J, Kobayashi T, Ruel M, ... American Heart Association Council on Cardiovascular Surgery and Anesthesia; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease
Circulation: 23 Jan 2023; epub ahead of print | PMID: 36688837
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<div><h4>A New Era in Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies, and Priorities.</h4><i>Beatty AL, Beckie TM, Dodson J, Goldstein CM, ... Wu WC, Franklin BA</i><br /><AbstractText>Cardiac rehabilitation (CR) is a guideline-recommended, multidisciplinary program of exercise training, risk factor management, and psychosocial counseling for people with cardiovascular disease (CVD) that is beneficial but underused and with substantial disparities in referral, access, and participation. The emergence of new virtual and remote delivery models has the potential to improve access to and participation in CR and ultimately improve outcomes for people with CVD. Although data suggest that new delivery models for CR have safety and efficacy similar to traditional in-person CR, questions remain regarding which participants are most likely to benefit from these models, how and where such programs should be delivered, and their effect on outcomes in diverse populations. In this review, we describe important gaps in evidence, identify relevant research questions, and propose strategies for addressing them. We highlight 4 research priorities: (1) including diverse populations in all CR research; (2) leveraging implementation methodologies to enhance equitable delivery of CR; (3) clarifying which populations are most likely to benefit from virtual and remote CR; and (4) comparing traditional in-person CR with virtual and remote CR in diverse populations using multicenter studies of important clinical, psychosocial, and cost-effectiveness outcomes that are relevant to patients, caregivers, providers, health systems, and payors. By framing these important questions, we hope to advance toward a goal of delivering high-quality CR to as many people as possible to improve outcomes in those with CVD.</AbstractText><br /><br /><br /><br /><small>Circulation: 17 Jan 2023; 147:254-266</small></div>
Beatty AL, Beckie TM, Dodson J, Goldstein CM, ... Wu WC, Franklin BA
Circulation: 17 Jan 2023; 147:254-266 | PMID: 36649394
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<div><h4>Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry.</h4><i>Mortensen MB, Dzaye O, Erik Bøtker H, Møller Jensen J, ... Blaha MJ, Linde Nørgaard B</i><br /><b>Background</b><br />Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC.<br /><b>Methods</b><br />The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the <i>National Heart, Lung, and Blood Institute</i>-funded Multi-Ethnic Study of Atherosclerosis.<br /><b>Results</b><br />During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04-1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06-1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87-1.18]). Similarly, a very high LDL-C level (<i>></i>193 mg/dL) versus LDL-C <116 mg/dL was associated with ASCVD in patients with CAC>0 (aHR, 2.42 [95% CI, 1.59-3.67]) but not in those without CAC (aHR, 0.92 [0.48-1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis.<br /><b>Conclusions</b><br />LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis.<br /><br /><br /><br /><small>Circulation: 09 Jan 2023; epub ahead of print</small></div>
Mortensen MB, Dzaye O, Erik Bøtker H, Møller Jensen J, ... Blaha MJ, Linde Nørgaard B
Circulation: 09 Jan 2023; epub ahead of print | PMID: 36621817
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<div><h4>Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study.</h4><i>Aengevaeren VL, Mosterd A, Bakker EA, Braber TL, ... Velthuis BK, Eijsvogels TMH</i><br /><b>Background</b><br />Physical activity and exercise training are associated with a lower risk for coronary events. However, cross-sectional studies in middle-aged and older male athletes revealed increased coronary artery calcification (CAC) and atherosclerotic plaques, which were related to the amount and intensity of lifelong exercise. We examined the longitudinal relationship between exercise training characteristics and coronary atherosclerosis.<br /><b>Methods</b><br />Middle-aged and older men from the MARC-1 (Measuring Athlete\'s Risk of Cardiovascular Events 1) study were invited for follow-up in MARC-2 (Measuring Athlete\'s Risk of Cardiovascular Events 2) study. The prevalence and severity of CAC and plaques were determined by coronary computed tomography angiography. The volume (metabolic equivalent of task [MET] hours/week) and intensity (moderate [3 to 6 MET hours/week]; vigorous [6 to 9 MET hours/week]; and very vigorous [≥9 MET hours/week]) of exercise training were quantified during follow-up. Linear and logistic regression analyses were performed to determine the association between exercise volume/intensity and markers of coronary atherosclerosis.<br /><b>Results</b><br />We included 289 (age, 54 [50 to 60] years [median (Q1 to Q3)]) of the original 318 MARC-1 participants with a follow-up of 6.3±0.5 years (mean±SD). Participants exercised for 41 (25 to 57) MET hours/week during follow-up, of which 0% (0 to 19%) was at moderate intensity, 44% (0 to 84%) was at vigorous intensity, and 34% (0 to 80%) was at very vigorous intensity. Prevalence of CAC and the median CAC score increased from 52% to 71% and 1 (0 to 32) to 31 (0 to 132), respectively. Exercise volume during follow-up was not associated with changes in CAC or plaque. Vigorous intensity exercise (per 10% increase) was associated with a lesser increase in CAC score (β, -0.05 [-0.09 to -0.01]; <i>P</i>=0.02), whereas very vigorous intensity exercise was associated with a greater increase in CAC score (β, 0.05 [0.01 to 0.09] per 10%; <i>P</i>=0.01). Very vigorous exercise was also associated with increased odds of dichotomized plaque progression (adjusted odds ratio [aOR], 1.09 [1.01 to 1.18] per 10% vs 2.04 [0.93 to 4.15] for highest vs lowest very vigorous intensity tertiles, respectively), and specifically with increased calcified plaques (aOR, 1.07 [1.00 to 1.15] per 10% vs 2.09 [1.09 to 4.00] for highest vs lowest tertile, respectively).<br /><b>Conclusions</b><br />Exercise intensity but not volume was associated with progression of coronary atherosclerosis during 6-year follow-up. It is intriguing that very vigorous intensity exercise was associated with greater CAC and calcified plaque progression, whereas vigorous intensity exercise was associated with less CAC progression.<br /><br /><br /><br /><small>Circulation: 04 Jan 2023; epub ahead of print</small></div>
Aengevaeren VL, Mosterd A, Bakker EA, Braber TL, ... Velthuis BK, Eijsvogels TMH
Circulation: 04 Jan 2023; epub ahead of print | PMID: 36597865
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<div><h4>Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis.</h4><i>Yonker LM, Swank Z, Bartsch YC, Burns MD, ... Fasano A, Walt DR</i><br /><b>Background</b><br />Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-targeted mRNA vaccines have been reported globally, but the underlying immunoprofiles of these individuals have not been described in detail.<br /><b>Methods</b><br />From January 2021 through February 2022, we prospectively collected blood from 16 patients who were hospitalized at Massachusetts General for Children or Boston Children\'s Hospital for myocarditis, presenting with chest pain with elevated cardiac troponin T after SARS-CoV-2 vaccination. We performed extensive antibody profiling, including tests for SARS-CoV-2-specific humoral responses and assessment for autoantibodies or antibodies against the human-relevant virome, SARS-CoV-2-specific T-cell analysis, and cytokine and SARS-CoV-2 antigen profiling. Results were compared with those from 45 healthy, asymptomatic, age-matched vaccinated control subjects.<br /><b>Results</b><br />Extensive antibody profiling and T-cell responses in the individuals who developed postvaccine myocarditis were essentially indistinguishable from those of vaccinated control subjects, despite a modest increase in cytokine production. A notable finding was that markedly elevated levels of full-length spike protein (33.9±22.4 pg/mL), unbound by antibodies, were detected in the plasma of individuals with postvaccine myocarditis, whereas no free spike was detected in asymptomatic vaccinated control subjects (unpaired <i>t</i> test; <i>P</i><0.0001).<br /><b>Conclusions</b><br />Immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals who developed myocarditis and individuals who did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post-mRNA vaccine myocarditis, advancing insight into its potential underlying cause.<br /><br /><br /><br /><small>Circulation: 04 Jan 2023; epub ahead of print</small></div>
Yonker LM, Swank Z, Bartsch YC, Burns MD, ... Fasano A, Walt DR
Circulation: 04 Jan 2023; epub ahead of print | PMID: 36597886
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<div><h4>Cardiovascular Disease Among Persons Living With HIV: New Insights Into Pathogenesis and Clinical Manifestations in a Global Context.</h4><i>Ntsekhe M, Baker JV</i><br /><AbstractText>Widespread use of contemporary antiretroviral therapy globally has transformed HIV disease into a chronic illness associated with excess risk for disorders of the heart and circulatory system. Current clinical care and research has focused on improving HIV-related cardiovascular disease outcomes, survival, and quality of life. In high-income countries, emphasis on prevention of atherosclerotic coronary artery disease over the past decade, including aggressive management of traditional risk factors and earlier initiation of antiretroviral therapy, has reduced risk for myocardial infarction among persons living with human immunodeficiency virus-1 infection. Still, across the globe, persons living with human immunodeficiency virus-1 infection on effective antiretroviral therapy treatment remain at increased risk for ischemic outcomes such as myocardial infarction and stroke relative to the persons without HIV. Unique features of HIV-related cardiovascular disease, in part, include the pathogenesis of coronary disease characterized by remodeling ectasia and unusual plaque morphology, the relative high proportion of type 2 myocardial infarction events, abnormalities of the aorta such as aneurysms and diffuse aortic inflammation, and HIV cerebrovasculopathy as a contributor to stroke risk. Literature over the past decade has also reflected a shift in the profile and prevalence of HIV-associated heart failure, with a reduced but persistent risk of heart failure with reduced ejection fraction and a growing risk of heart failure with preserved ejection fraction. Cardiac magnetic resonance imaging and autopsy data have emphasized the central importance of intramyocardial fibrosis for the pathogenesis of both heart failure with preserved ejection fraction and the increase in risk of sudden cardiac death. Still, more research is needed to better characterize the underlying mechanisms and clinical phenotype of HIV-associated myocardial disease in the current era. Across the different cardiovascular disease manifestations, a common pathogenic feature is that HIV-associated inflammation working through different mechanisms may amplify underlying pathology because of traditional risk and other host factors. The prevalence and phenotype of individual cardiovascular disease manifestations is ultimately influenced by the degree of injury from HIV disease combined with the profile of underlying cardiometabolic factors, both of which may differ substantially by region globally.</AbstractText><br /><br /><br /><br /><small>Circulation: 03 Jan 2023; 147:83-100</small></div>
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<div><h4>Targeting Epsins to Inhibit Fibroblast Growth Factor Signaling While Potentiating Transforming Growth Factor-β Signaling Constrains Endothelial-to-Mesenchymal Transition in Atherosclerosis.</h4><i>Dong Y, Wang B, Du M, Zhu B, ... Linton MF, Chen H</i><br /><b>Background</b><br />Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, the underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) in atherosclerosis and assessed the efficacy of a therapeutic peptide in a preclinical model of this disease.<br /><b>Methods</b><br />Using single-cell RNA sequencing combined with molecular, cellular, and biochemical analyses, we investigated the role of epsins in stimulating EndoMT using knockout in <i>Apoe</i><sup><i>-/-</i></sup> and lineage tracing/proprotein convertase subtilisin/kexin type 9 serine protease mutant viral-induced atherosclerotic mouse models. The therapeutic efficacy of a synthetic peptide targeting atherosclerotic plaques was then assessed in <i>Apoe</i><sup><i>-/-</i></sup> mice.<br /><b>Results</b><br />Single-cell RNA sequencing and lineage tracing revealed that epsins 1 and 2 promote EndoMT and that the loss of endothelial epsins inhibits EndoMT marker expression and transforming growth factor-β signaling in vitro and in atherosclerotic mice, which is associated with smaller lesions in the <i>Apoe</i><sup><i>-/-</i></sup> mouse model. Mechanistically, the loss of endothelial cell epsins results in increased fibroblast growth factor receptor-1 expression, which inhibits transforming growth factor-β signaling and EndoMT. Epsins directly bind ubiquitinated fibroblast growth factor receptor-1 through their ubiquitin-interacting motif, which results in endocytosis and degradation of this receptor complex. Consequently, administration of a synthetic ubiquitin-interacting motif-containing peptide atheroma ubiquitin-interacting motif peptide inhibitor significantly attenuates EndoMT and progression of atherosclerosis.<br /><b>Conclusions</b><br />We conclude that epsins potentiate EndoMT during atherogenesis by increasing transforming growth factor-β signaling through fibroblast growth factor receptor-1 internalization and degradation. Inhibition of EndoMT by reducing epsin-fibroblast growth factor receptor-1 interaction with a therapeutic peptide may represent a novel treatment strategy for atherosclerosis.<br /><br /><br /><br /><small>Circulation: 02 Jan 2023; epub ahead of print</small></div>
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<div><h4>The MIDA-Q Mortality Risk Score: A Quantitative Prognostic Tool for the Mitral Valve Prolapse Spectrum.</h4><i>Essayagh B, Benfari G, Antoine C, Grigioni F, ... Michelena HI, Enriquez-Sarano M</i><br /><b>Background</b><br />Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials.<br /><b>Methods</b><br />The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point.<br /><b>Results</b><br />MVP was associated with DMR absent/mild (ERO <20 mm<sup>2</sup>) in 50%, moderate (ERO 20-40 mm<sup>2</sup>) in 25%, and severe or higher (ERO ≥40 mm<sup>2</sup>) in 25%, with mean ERO 24±24 mm<sup>2</sup>, regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%-90%; range, 0-9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; <i>P</i> < 0.0001) but with wide overlap (10%-90%; range, 4-11 versus 0-7) and mediocre correlation (<i>R</i><sup>2</sup> 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29-1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11-1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02-1.14]) or ≥1% (hazard ratio, 1.11 [1.08-1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10-1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10-1.16], all per 1-point increment with <i>P</i><0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all <i>P</i><0.0001).<br /><b>Conclusion</b><br />This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.<br /><br /><br /><br /><small>Circulation: 27 Dec 2022; epub ahead of print</small></div>
Essayagh B, Benfari G, Antoine C, Grigioni F, ... Michelena HI, Enriquez-Sarano M
Circulation: 27 Dec 2022; epub ahead of print | PMID: 36573420
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<div><h4>Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age.</h4><i>Dellborg M, Giang KW, Eriksson P, Liden H, ... Rosengren A, Mandalenakis Z</i><br /><b>Background</b><br />The survival of children with congenital heart disease has increased substantially over the past decades, with 97% currently reaching adulthood. The total effect of advanced treatment on future mortality and morbidity in adult survivors with congenital heart disease (CHD) is less well described.<br /><b>Methods</b><br />We used data from the Swedish National Inpatient, Outpatient, and Cause of Death Register to identify patients with CHD who were born between 1950 and 1999 and were alive at 18 years of age. Ten controls identified from the Total Population Register were matched for year of birth and sex and with each patient with CHD. Follow-up was from 1968 and 18 years of age until death or at the end of the study (2017). Survival percentage with 95% CI for all-cause mortality were performed with Kaplan-Meier survival function. Cox proportional hazard regression models with hazard ratios (HRs) and 95% CI were used to estimate the risk of all-cause mortality.<br /><b>Results</b><br />We included 37 278 patients with adult CHD (ACHD) and 412 799 controls. Mean follow-up was 19.2 years (±13.6). Altogether, 1937 patients with ACHD (5.2%) and 6690 controls (1.6%) died, a death rate of 2.73 per 1000 person-years and 0.84 per 1000 person years, respectively. Mortality was 3.2 times higher (95% CI, 3.0-3.4; <i>P</i><0.001) among patients with ACHD compared with matched controls. Up to the maximum of 50 years of follow-up, >75% of patients with ACHD were still alive. Mortality was highest among patients with conotruncal defects (HR, 10.13 [95% CI, 8.78-11.69]), but also significantly higher for the more benign lesions, with the lowest risk in patients with atrial septal defects (HR, 1.36 [95% CI, 1.19-1.55]). At least 75% of patients with ACHD alive at 18 years of age lived past middle age and became sexagenerians.<br /><b>Conclusions</b><br />In this large, nationwide, register-based cohort study of patients with ACHD surviving to 18 years of age, the risk of mortality up to 68 years of age was >3 times higher compared with matched controls without ACHD. Despite this, at least 75% of patients with CHD alive at 18 years of age lived past middle age and became sexagenerians. A notable risk decline in the mortality for patients with ACHD was noted for those born after 1975.<br /><br /><br /><br /><small>Circulation: 26 Dec 2022; epub ahead of print</small></div>
Dellborg M, Giang KW, Eriksson P, Liden H, ... Rosengren A, Mandalenakis Z
Circulation: 26 Dec 2022; epub ahead of print | PMID: 36571845
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<div><h4>Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia.</h4><i>Ma Z, Mao C, Chen X, Yang S, ... Fu Y, Kong W</i><br /><b>Background</b><br />The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents.<br /><b>Methods</b><br />We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas <i>ApoE</i><sup><i>-/</i>-</sup> and <i>LDLR</i><sup><i>-/</i>-</sup> (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia.<br /><b>Results</b><br />A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic <i>ApoE</i><sup><i>-/</i>-</sup> and <i>LDLR</i><sup><i>-/</i>-</sup> mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7-mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization.<br /><b>Conclusions</b><br />ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.<br /><br /><br /><br /><small>Circulation: 23 Dec 2022; epub ahead of print</small></div>
Ma Z, Mao C, Chen X, Yang S, ... Fu Y, Kong W
Circulation: 23 Dec 2022; epub ahead of print | PMID: 36562301
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<div><h4>Prospective Association of Daily Steps With Cardiovascular Disease: A Harmonized Meta-Analysis.</h4><i>Paluch AE, Bajpai S, Ballin M, Bassett DR, ... Fulton JE, Steps for Health Collaborative</i><br /><b>Background</b><br />Taking fewer than the widely promoted \"10 000 steps per day\" has recently been associated with lower risk of all-cause mortality. The relationship of steps and cardiovascular disease (CVD) risk remains poorly described. A meta-analysis examining the dose-response relationship between steps per day and CVD can help inform clinical and public health guidelines.<br /><b>Methods</b><br />Eight prospective studies (20 152 adults [ie, ≥18 years of age]) were included with device-measured steps and participants followed for CVD events. Studies quantified steps per day and CVD events were defined as fatal and nonfatal coronary heart disease, stroke, and heart failure. Cox proportional hazards regression analyses were completed using study-specific quartiles and hazard ratios (HR) and 95% CI were meta-analyzed with inverse-variance-weighted random effects models.<br /><b>Results</b><br />The mean age of participants was 63.2±12.4 years and 52% were women. The mean follow-up was 6.2 years (123 209 person-years), with a total of 1523 CVD events (12.4 per 1000 participant-years) reported. There was a significant difference in the association of steps per day and CVD between older (ie, ≥60 years of age) and younger adults (ie, <60 years of age). For older adults, the HR for quartile 2 was 0.80 (95% CI, 0.69 to 0.93), 0.62 for quartile 3 (95% CI, 0.52 to 0.74), and 0.51 for quartile 4 (95% CI, 0.41 to 0.63) compared with the lowest quartile. For younger adults, the HR for quartile 2 was 0.79 (95% CI, 0.46 to 1.35), 0.90 for quartile 3 (95% CI, 0.64 to 1.25), and 0.95 for quartile 4 (95% CI, 0.61 to 1.48) compared with the lowest quartile. Restricted cubic splines demonstrated a nonlinear association whereby more steps were associated with decreased risk of CVD among older adults.<br /><b>Conclusions</b><br />For older adults, taking more daily steps was associated with a progressively decreased risk of CVD. Monitoring and promoting steps per day is a simple metric for clinician-patient communication and population health to reduce the risk of CVD.<br /><br /><br /><br /><small>Circulation: 20 Dec 2022; epub ahead of print</small></div>
Paluch AE, Bajpai S, Ballin M, Bassett DR, ... Fulton JE, Steps for Health Collaborative
Circulation: 20 Dec 2022; epub ahead of print | PMID: 36537288
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<div><h4>Effect of Intensive Blood Pressure Control on Troponin and Natriuretic Peptide Levels: Findings From SPRINT.</h4><i>Berry JD, Chen H, Nambi V, Ambrosius WT, ... Ballantyne CM, de Lemos JA</i><br /><b>Background</b><br />Given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure and strong associations observed between hypertension and its sequelae on hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, we hypothesized that intensive systolic blood pressure (SBP) lowering would decrease levels of hs-cTnT and NT-proBNP.<br /><b>Methods</b><br />hs-cTnT and NT-proBNP were measured at baseline and 1 year from stored specimens in SPRINT (Systolic Blood Pressure Intervention Trial). Changes in biomarkers were evaluated continuously on the log scale and according to categories (≥50% increase, ≥50% decrease, or <50% change). The effect of intensive SBP lowering on continuous and categorical changes in biomarker levels were assessed using linear and multinomial logistic regression models, respectively. The association between changes in biomarkers on heart failure and death was assessed using multivariable-adjusted Cox proportional hazards models.<br /><b>Results</b><br />Randomization to intensive SBP lowering (versus standard SBP management) resulted in a 3% increase in hs-cTnT levels over 1-year follow-up (geometric mean ratio, 1.03 [95% CI, 1.01-1.04]) and a higher proportion of participants with ≥50% increase (odds ratio, 1.47 [95% CI, 1.13, 1.90]). In contrast, randomization to intensive SBP lowering led to a 10% decrease in NT-proBNP (geometric mean ratio, 0.90 [95% CI, 0.87-0.93]) and a lower probability of ≥50% increase in NT-proBNP (odds ratio, 0.57 [95% CI, 0.46-0.72]). The association of randomized treatment assignment on change in hs-cTnT was completely attenuated after accounting for changes in estimated glomerular filtration rate over follow-up, whereas the association of treatment with NT-proBNP was completely attenuated after adjusting for change in SBP. Increases in hs-cTnT and NT-proBNP from baseline to 1 year were associated with higher risk for heart failure and death, with no significant interactions by treatment assignment.<br /><b>Conclusions</b><br />Intensive SBP lowering increased hs-cTnT, mediated by the effect of SBP lowering on reduced kidney filtration. In contrast, intensive SBP lowering decreased NT-proBNP, a finding that was explained by the drop in SBP. These findings highlight the importance of noncardiac factors influencing variation in cardiac biomarkers and raise questions about the potential role of hs-cTnT as a surrogate marker for heart failure or death in SBP-lowering studies.<br /><br /><br /><br /><small>Circulation: 19 Dec 2022; epub ahead of print</small></div>
Berry JD, Chen H, Nambi V, Ambrosius WT, ... Ballantyne CM, de Lemos JA
Circulation: 19 Dec 2022; epub ahead of print | PMID: 36533535
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<div><h4>Challenging the Hemodynamic Hypothesis in Heart Failure With Preserved Ejection Fraction: Is Exercise Capacity Limited by Elevated Pulmonary Capillary Wedge Pressure?</h4><i>Sarma S, MacNamara JP, Balmain BN, Hearo CM, ... Babb TG, Levine BD</i><br /><b>Background</b><br />Exercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF.<br /><b>Methods</b><br />Thirty patients with HFpEF (70±6 years of age; 63% female) underwent 2 bouts of upright, seated cycle exercise dosed with sublingual nitroglycerin or placebo control every 15 minutes in a single-blind, randomized, crossover design. PCWP (right heart catheterization), oxygen uptake (breath × breath gas exchange), and cardiac output (direct Fick) were assessed at rest, 20W, and peak exercise during both placebo and nitroglycerin conditions.<br /><b>Results</b><br />PCWP increased from 8±4 to 35±9 mm Hg from rest to peak exercise with placebo. With nitroglycerin, there was a graded decrease in PCWP compared with placebo at rest (-1±2 mm Hg), 20W (-5±5 mm Hg), and peak exercise (-7±6 mm Hg; drug*exercise stage <i>P</i>=0.004). Nitroglycerin did not affect oxygen uptake at rest, 20W, or peak (placebo, 1.34±0.48 versus nitroglycerin, 1.32±0.46 L/min; drug*exercise <i>P</i>=0.984). Compared with placebo, nitroglycerin lowered stroke volume at rest (-8±13 mL) and 20W (-7±11 mL), but not peak exercise (0±10 mL).<br /><b>Conclusions</b><br />Sublingual nitroglycerin lowered PCWP during submaximal and maximal exercise. Despite reduction in PCWP, peak oxygen uptake was not changed. These results suggest that acute reductions in PCWP are insufficient to improve exercise capacity, and further argue that high PCWP during exercise is not by itself a limiting factor for exercise performance in patients with HFpEF.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04068844.<br /><br /><br /><br /><small>Circulation: 16 Dec 2022; epub ahead of print</small></div>
Sarma S, MacNamara JP, Balmain BN, Hearo CM, ... Babb TG, Levine BD
Circulation: 16 Dec 2022; epub ahead of print | PMID: 36524474
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<div><h4>Coronary Artery Lesion Lipid Content and Plaque Burden in Diabetic and Nondiabetic Patients: PROSPECT II.</h4><i>Gyldenkerne C, Maeng M, Kjøller-Hansen L, Maehara A, ... Stone GW, Erlinge D</i><br /><b>Background</b><br />Patients with diabetes have increased rates of major adverse cardiac events (MACEs). We hypothesized that this is explained by diabetes-associated differences in coronary plaque morphology and lipid content.<br /><b>Methods</b><br />In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), 898 patients with acute myocardial infarction with or without ST-segment elevation underwent 3-vessel quantitative coronary angiography and coregistered near-infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Subsequent MACEs were adjudicated to either treated culprit lesions or untreated nonculprit lesions. This substudy stratified patients by diabetes status and assessed baseline culprit and nonculprit prevalence of high-risk plaque characteristics defined as maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Separate covariate-adjusted multivariable models were performed to identify whether diabetes was associated with nonculprit lesion-related MACEs and high-risk plaque characteristics.<br /><b>Results</b><br />Diabetes was present in 109 of 898 patients (12.1%). During a median 3.7-year follow-up, MACEs occurred more frequently in patients with versus without diabetes (20.1% versus 13.5% [odds ratio (OR), 1.94 (95% CI, 1.14-3.30)]), primarily attributable to increased risk of myocardial infarction related to culprit lesion restenosis (4.3% versus 1.1% [OR, 3.78 (95% CI, 1.12-12.77)]) and nonculprit lesion-related spontaneous myocardial infarction (9.3% versus 3.8% [OR, 2.74 (95% CI, 1.25-6.04)]). However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes concerning culprit (maximum plaque burden ≥70%: 90% versus 93%, <i>P</i>=0.34; maximum lipid core burden index ≥324.7: 66% versus 70%, <i>P</i>=0.49) and nonculprit lesions (maximum plaque burden ≥70%: 23% versus 22%, <i>P</i>=0.37; maximum lipid core burden index ≥324.7: 26% versus 24%, <i>P</i>=0.47). In multivariable models, diabetes was associated with MACEs in nonculprit lesions (adjusted OR, 2.47 [95% CI, 1.21-5.04]) but not with prevalence of high-risk plaque characteristics (adjusted OR, 1.21 [95% CI, 0.86-1.69]).<br /><b>Conclusions</b><br />Among patients with recent myocardial infarction, both treated and untreated lesions contributed to the diabetes-associated ≈2-fold increased MACE rate during the 3.7-year follow-up. Diabetes-related plaque characteristics that might underlie this increased risk were not identified by multimodality imaging.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT02171065.<br /><br /><br /><br /><small>Circulation: 16 Dec 2022; epub ahead of print</small></div>
Gyldenkerne C, Maeng M, Kjøller-Hansen L, Maehara A, ... Stone GW, Erlinge D
Circulation: 16 Dec 2022; epub ahead of print | PMID: 36524476
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<div><h4>Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.</h4><i>Shelbaya K, Claggett B, Dorbala P, Skali H, ... Mosley TH, Shah AM</i><br /><b>Background</b><br />Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life.<br /><b>Methods</b><br />Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011-2013) and 7 (2018-2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition.<br /><b>Results</b><br />Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1-7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%.<br /><b>Conclusions</b><br />Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.<br /><br /><br /><br /><small>Circulation: 16 Dec 2022; epub ahead of print</small></div>
Shelbaya K, Claggett B, Dorbala P, Skali H, ... Mosley TH, Shah AM
Circulation: 16 Dec 2022; epub ahead of print | PMID: 36524478
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<div><h4>Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.</h4><i>Bersell KR, Yang T, Mosley JD, Glazer AM, ... Knollmann BC, Roden DM</i><br /><b>Background</b><br />Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene <i>SCN5A</i> (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor <i>TBX5</i> (T-box transcription factor 5) and no <i>SCN5A</i> variant.<br /><b>Methods</b><br />We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals).<br /><b>Results</b><br />TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced \"late\" cardiac sodium current (I<sub>Na</sub>), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct <i>SCN5A</i> down-regulation caused decreased peak I<sub>Na</sub>, and that reduced PDGF receptor (<i>PDGFRA</i> [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late I<sub>Na</sub>. Tbx5 regulation of the PDGF axis and disruption of PDGF signaling, which causes arrhythmia risk, were both conserved in murine model systems. The PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (<i>P</i><0.001).<br /><b>Conclusions</b><br />These results not only establish decreased <i>SCN5A</i> transcription by the <i>TBX5</i> variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.<br /><br /><br /><br /><small>Circulation: 16 Dec 2022; epub ahead of print</small></div>
Bersell KR, Yang T, Mosley JD, Glazer AM, ... Knollmann BC, Roden DM
Circulation: 16 Dec 2022; epub ahead of print | PMID: 36524479
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<div><h4>Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.</h4><i>Born E, Lipskaia L, Breau M, Houssaini A, ... Adnot S, Abid S</i><br /><b>Background</b><br />Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models.<br /><b>Methods</b><br />We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16<sup>LUC/+</sup>) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16<sup>LUC/LUC</sup> mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT<sup>+</sup>), and rats given monocrotaline.<br /><b>Results</b><br />Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16<sup>LUC/+</sup> mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16<sup>LUC/LUC</sup> mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT<sup>+</sup> mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs.<br /><b>Conclusion</b><br />Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.<br /><br /><br /><br /><small>Circulation: 14 Dec 2022; epub ahead of print</small></div>
Born E, Lipskaia L, Breau M, Houssaini A, ... Adnot S, Abid S
Circulation: 14 Dec 2022; epub ahead of print | PMID: 36515093
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<div><h4>The Effect of Lymphangiogenesis in Transplant Arteriosclerosis.</h4><i>Chen K, Mou R, Zhu P, Xu X, ... Xiao Q, Xu Q</i><br /><b>Background</b><br />Transplant arteriosclerosis is a major complication in long-term survivors of heart transplantation. Increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis, but how lymphangiogenesis affects this process is unknown.<br /><b>Methods</b><br />Vascular allografts were transplanted among various combinations of mice, including wild-type, <i>Lyve1</i>-CreER<sup>T2</sup>;R26-tdTomato, CAG-Cre-tdTomato, severe combined immune deficiency, <i>Ccr2</i><sup>KO</sup>, <i>Foxn1</i><sup>KO</sup>, and <i>lghm</i>/<i>lghd</i><sup>KO</sup> mice. Whole-mount staining and 3-dimensional reconstruction identified lymphatic vessels within the grafted arteries. Lineage tracing strategies delineated the cellular origin of lymphatic endothelial cells. Adeno-associated viral vectors and a selective inhibitor were used to regulate lymphangiogenesis.<br /><b>Results</b><br />Lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 (chemokine [C-C motif] ligand 21) were associated with these immune structures. Fibroblasts in the vascular allografts released VEGF-C (vascular endothelial growth factor C), which stimulated lymphangiogenesis into the grafts. Inhibition of VEGF-C signaling inhibited lymphangiogenesis, neointima formation, and adventitial fibrosis of vascular allografts. These studies identified VEGF-C released from fibroblasts as a signal stimulating lymphangiogenesis extending from the host into the vascular allografts.<br /><b>Conclusions</b><br />Formation of lymphatic vessels plays a key role in the immune response to vascular transplantation. The inhibition of lymphangiogenesis may be a novel approach to prevent transplant arteriosclerosis.<br /><br /><br /><br /><small>Circulation: 14 Dec 2022; epub ahead of print</small></div>
Chen K, Mou R, Zhu P, Xu X, ... Xiao Q, Xu Q
Circulation: 14 Dec 2022; epub ahead of print | PMID: 36515099
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<div><h4>GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes.</h4><i>Marx N, Husain M, Lehrke M, Verma S, Sattar N</i><br /><AbstractText>Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community.</AbstractText><br /><br /><br /><br /><small>Circulation: 13 Dec 2022; 146:1882-1894</small></div>
Marx N, Husain M, Lehrke M, Verma S, Sattar N
Circulation: 13 Dec 2022; 146:1882-1894 | PMID: 36508493
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<div><h4>Direct Reprogramming Improves Cardiac Function and Reverses Fibrosis in Chronic Myocardial Infarction.</h4><i>Tani H, Sadahiro T, Yamada Y, Isomi M, ... Fukuda K, Ieda M</i><br /><b>Background</b><br />Because adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts (CFs) synthesize extracellular matrix after myocardial infarction (MI) to form fibrosis, leading to cardiac dysfunction and heart failure. Therapies that can regenerate the myocardium and reverse fibrosis in chronic MI are lacking. The overexpression of cardiac transcription factors, including <i>Mef2c/Gata4/Tbx5/Hand2</i> (MGTH), can directly reprogram CFs into induced cardiomyocytes (iCMs) and improve cardiac function under acute MI. However, the ability of in vivo cardiac reprogramming to repair chronic MI with established scars is undetermined.<br /><b>Methods</b><br />We generated a novel Tcf21<sup>iCre</sup>/reporter/MGTH2A transgenic mouse system in which tamoxifen treatment could induce both MGTH and reporter expression in the resident CFs for cardiac reprogramming and fibroblast lineage tracing. We first tested the efficacy of this transgenic system in vitro and in vivo for acute MI. Next, we analyzed in vivo cardiac reprogramming and fusion events under chronic MI using Tcf21<sup>iCre</sup>/Tomato/MGTH2A and Tcf21<sup>iCre</sup>/mTmG/MGTH2A mice, respectively. Microarray and single-cell RNA sequencing were performed to determine the mechanism of cardiac repair by in vivo reprogramming.<br /><b>Results</b><br />We confirmed the efficacy of transgenic in vitro and in vivo cardiac reprogramming for acute MI. In chronic MI, in vivo cardiac reprogramming converted ≈2% of resident CFs into iCMs, in which a majority of iCMs were generated by means of bona fide cardiac reprogramming rather than by fusion with cardiomyocytes. Cardiac reprogramming significantly improved myocardial contraction and reduced fibrosis in chronic MI. Microarray analyses revealed that the overexpression of MGTH activated cardiac program and concomitantly suppressed fibroblast and inflammatory signatures in chronic MI. Single-cell RNA sequencing demonstrated that resident CFs consisted of 7 subclusters, in which the profibrotic CF population increased under chronic MI. Cardiac reprogramming suppressed fibroblastic gene expression in chronic MI by means of conversion of profibrotic CFs to a quiescent antifibrotic state. MGTH overexpression induced antifibrotic effects partly by suppression of Meox1, a central regulator of fibroblast activation.<br /><b>Conclusions</b><br />These results demonstrate that cardiac reprogramming could repair chronic MI by means of myocardial regeneration and reduction of fibrosis. These findings present opportunities for the development of new therapies for chronic MI and heart failure.<br /><br /><br /><br /><small>Circulation: 12 Dec 2022; epub ahead of print</small></div>
Tani H, Sadahiro T, Yamada Y, Isomi M, ... Fukuda K, Ieda M
Circulation: 12 Dec 2022; epub ahead of print | PMID: 36503256
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<div><h4>Associations Between Extreme Temperatures and Cardiovascular Cause-Specific Mortality: Results From 27 Countries.</h4><i>Alahmad B, Khraishah H, Royé D, Vicedo-Cabrera AM, ... Gasparrini A, Koutrakis P</i><br /><b>Background</b><br />Cardiovascular disease is the leading cause of death worldwide. Existing studies on the association between temperatures and cardiovascular deaths have been limited in geographic zones and have generally considered associations with total cardiovascular deaths rather than cause-specific cardiovascular deaths.<br /><b>Methods</b><br />We used unified data collection protocols within the Multi-Country Multi-City Collaborative Network to assemble a database of daily counts of specific cardiovascular causes of death from 567 cities in 27 countries across 5 continents in overlapping periods ranging from 1979 to 2019. City-specific daily ambient temperatures were obtained from weather stations and climate reanalysis models. To investigate cardiovascular mortality associations with extreme hot and cold temperatures, we fit case-crossover models in each city and then used a mixed-effects meta-analytic framework to pool individual city estimates. Extreme temperature percentiles were compared with the minimum mortality temperature in each location. Excess deaths were calculated for a range of extreme temperature days.<br /><b>Results</b><br />The analyses included deaths from any cardiovascular cause (32 154 935), ischemic heart disease (11 745 880), stroke (9 351 312), heart failure (3 673 723), and arrhythmia (670 859). At extreme temperature percentiles, heat (99th percentile) and cold (1st percentile) were associated with higher risk of dying from any cardiovascular cause, ischemic heart disease, stroke, and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality. Across a range of extreme temperatures, hot days (above 97.5th percentile) and cold days (below 2.5th percentile) accounted for 2.2 (95% empirical CI [eCI], 2.1-2.3) and 9.1 (95% eCI, 8.9-9.2) excess deaths for every 1000 cardiovascular deaths, respectively. Heart failure was associated with the highest excess deaths proportion from extreme hot and cold days with 2.6 (95% eCI, 2.4-2.8) and 12.8 (95% eCI, 12.2-13.1) for every 1000 heart failure deaths, respectively.<br /><b>Conclusions</b><br />Across a large, multinational sample, exposure to extreme hot and cold temperatures was associated with a greater risk of mortality from multiple common cardiovascular conditions. The intersections between extreme temperatures and cardiovascular health need to be thoroughly characterized in the present day-and especially under a changing climate.<br /><br /><br /><br /><small>Circulation: 12 Dec 2022; epub ahead of print</small></div>
Alahmad B, Khraishah H, Royé D, Vicedo-Cabrera AM, ... Gasparrini A, Koutrakis P
Circulation: 12 Dec 2022; epub ahead of print | PMID: 36503273
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<div><h4>Management of Acute Coronary Syndrome in the Older Adult Population: A Scientific Statement From the American Heart Association.</h4><i>Damluji AA, Forman DE, Wang TY, Chikwe J, ... Alexander KP, American Heart Association Cardiovascular Disease in Older Populations Committee of the Council on Clinical Cardiology; Council on Lifestyle and Cardiometabolic Health; and Council on Cardiovascular Radiology and Intervention</i><br /><AbstractText>Diagnostic and therapeutic advances during the past decades have substantially improved health outcomes for patients with acute coronary syndrome. Both age-related physiological changes and accumulated cardiovascular risk factors increase the susceptibility to acute coronary syndrome over a lifetime. Compared with younger patients, outcomes for acute coronary syndrome in the large and growing demographic of older adults are relatively worse. Increased atherosclerotic plaque burden and complexity of anatomic disease, compounded by age-related cardiovascular and noncardiovascular comorbid conditions, contribute to the worse prognosis observed in older individuals. Geriatric syndromes, including frailty, multimorbidity, impaired cognitive and physical function, polypharmacy, and other complexities of care, can undermine the therapeutic efficacy of guidelines-based treatments and the resiliency of older adults to survive and recover, as well. In this American Heart Association scientific statement, we (1) review age-related physiological changes that predispose to acute coronary syndrome and management complexity; (2) describe the influence of commonly encountered geriatric syndromes on cardiovascular disease outcomes; and (3) recommend age-appropriate and guideline-concordant revascularization and acute coronary syndrome management strategies, including transitions of care, the use of cardiac rehabilitation, palliative care services, and holistic approaches. The primacy of individualized risk assessment and patient-centered care decision-making is highlighted throughout.</AbstractText><br /><br /><br /><br /><small>Circulation: 12 Dec 2022; epub ahead of print</small></div>
Damluji AA, Forman DE, Wang TY, Chikwe J, ... Alexander KP, American Heart Association Cardiovascular Disease in Older Populations Committee of the Council on Clinical Cardiology; Council on Lifestyle and Cardiometabolic Health; and Council on Cardiovascular Radiology and Intervention
Circulation: 12 Dec 2022; epub ahead of print | PMID: 36503287
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<div><h4>Placental Inflammation Leads to Abnormal Embryonic Heart Development.</h4><i>Ward EJ, Bert S, Fanti S, Malone KM, ... Marelli-Berg FM, Nadkarni S</i><br /><b>Background</b><br />Placental heart development and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain unresolved.<br /><b>Methods</b><br />In this study, we use an in vivo neutrophil-driven placental inflammation model through antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy: embryonic days 4.5 and 7.5. Pregnant mice were culled at embryonic day 14.5 to assess placental and embryonic heart development. A combination of flow cytometry, histology, and bulk RNA sequencing was used to assess placental immune cell composition and tissue architecture. We also used flow cytometry and single-cell sequencing to assess embryonic cardiac immune cells at embryonic day 14.5 and histology and gene analyses to investigate embryonic heart structure and development. In some cases, offspring were culled at postnatal days 5 and 28 to assess any postnatal cardiac changes in immune cells, structure, and cardiac function, as measured by echocardiography.<br /><b>Results</b><br />In the present study, we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable of migration to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Last, we show that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.<br /><b>Conclusions</b><br />Taken together, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development, which has major implications on cardiac function into adult life.<br /><br /><br /><br /><small>Circulation: 09 Dec 2022; epub ahead of print</small></div>
Ward EJ, Bert S, Fanti S, Malone KM, ... Marelli-Berg FM, Nadkarni S
Circulation: 09 Dec 2022; epub ahead of print | PMID: 36484244
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<div><h4>Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction.</h4><i>Masurkar N, Bouvet M, Logeart D, Jouve C, ... Valente M, Hulot JS</i><br /><b>Background</b><br />Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells.<br /><b>Methods</b><br />We performed a bioinformatic secretome analysis of cardiac stromal PW1<sup>+</sup> cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations.<br /><b>Results</b><br />Cardiac stromal PW1<sup>+</sup> cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1<sup>+</sup> cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-β (transforming growth factor-β) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; <i>P</i>=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments.<br /><b>Conclusions</b><br />Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT01113268.<br /><br /><br /><br /><small>Circulation: 09 Dec 2022; epub ahead of print</small></div>
Masurkar N, Bouvet M, Logeart D, Jouve C, ... Valente M, Hulot JS
Circulation: 09 Dec 2022; epub ahead of print | PMID: 36484260
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<div><h4>Complementary and Alternative Medicines in the Management of Heart Failure: A Scientific Statement From the American Heart Association.</h4><i>Chow SL, Bozkurt B, Baker WL, Bleske BE, ... Yancy CW, American Heart Association Clinical Pharmacology Committee and Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing</i><br /><AbstractText>Complementary and alternative medicines (CAM) are commonly used across the world by diverse populations and ethnicities but remain largely unregulated. Although many CAM agents are purported to be efficacious and safe by the public, clinical evidence supporting the use of CAM in heart failure remains limited and controversial. Furthermore, health care professionals rarely inquire or document use of CAM as part of the medical record, and patients infrequently disclose their use without further prompting. The goal of this scientific statement is to summarize published efficacy and safety data for CAM and adjunctive interventional wellness approaches in heart failure. Furthermore, other important considerations such as adverse effects and drug interactions that could influence the safety of patients with heart failure are reviewed and discussed.</AbstractText><br /><br /><br /><br /><small>Circulation: 08 Dec 2022; epub ahead of print</small></div>
Chow SL, Bozkurt B, Baker WL, Bleske BE, ... Yancy CW, American Heart Association Clinical Pharmacology Committee and Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing
Circulation: 08 Dec 2022; epub ahead of print | PMID: 36475715
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<div><h4>Distinct Transcriptomic and Proteomic Profile Specifies Patients Who Have Heart Failure With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support.</h4><i>Drakos SG, Badolia R, Makaju A, Kyriakopoulos CP, ... Selzman CH, Franklin S</i><br /><b>Background</b><br />Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed \"responders\"). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown.<br /><b>Methods</b><br />To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders.<br /><b>Results</b><br />These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions.<br /><b>Conclusions</b><br />This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets.<br /><br /><br /><br /><small>Circulation: 30 Nov 2022; epub ahead of print</small></div>
Drakos SG, Badolia R, Makaju A, Kyriakopoulos CP, ... Selzman CH, Franklin S
Circulation: 30 Nov 2022; epub ahead of print | PMID: 36448446
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<div><h4>Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries.</h4><i>Gao P, Cao M, Jiang X, Wang X, ... Li L, Zou Y</i><br /><b>Background</b><br />Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway.<br /><b>Methods</b><br />Type 2 diabetes models were established using <i>db/db</i> leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein-coupled receptor-targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies.<br /><b>Results</b><br />Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase-mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes <i>Rip1</i>, <i>Rip3</i>, and <i>Mlkl</i>. Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of <i>Bach2</i> diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries.<br /><b>Conclusions</b><br />CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.<br /><br /><br /><br /><small>Circulation: 30 Nov 2022; epub ahead of print</small></div>
Gao P, Cao M, Jiang X, Wang X, ... Li L, Zou Y
Circulation: 30 Nov 2022; epub ahead of print | PMID: 36448459
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<div><h4>Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.</h4><i>Figtree GA, Adamson PD, Antoniades C, Blumenthal RS, ... Wong DT, Nicholls SJ</i><br /><AbstractText>Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.</AbstractText><br /><br /><br /><br /><small>Circulation: 29 Nov 2022; 146:1712-1727</small></div>
Figtree GA, Adamson PD, Antoniades C, Blumenthal RS, ... Wong DT, Nicholls SJ
Circulation: 29 Nov 2022; 146:1712-1727 | PMID: 36441819
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<div><h4>Lipoprotein(a) in Youth and Prediction of Major Cardiovascular Outcomes in Adulthood.</h4><i>Raitakari O, Kartiosuo N, Pahkala K, Hutri-Kähönen N, ... Juonala M, Viikari J</i><br /><b>Background</b><br />Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. We examined its potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease (ASCVD).<br /><b>Methods</b><br />Lp(a) levels measured in youth 9 to 24 years of age were linked to adult ASCVD and carotid intima-media thickness in the YFS (Cardiovascular Risk in Young Finns Study), in which 95 of the original 3596 participants (2.7%) recruited as children have been diagnosed with ASCVD at a median of 47 years of age. Results observed in YFS were replicated with the use of data for White participants from the BHS (Bogalusa Heart Study). In BHS, 587 White individuals had data on youth Lp(a) (measured at 8-17 years of age) and information on adult events, including 15 cases and 572 noncases. Analyses were performed with the use of Cox proportional hazard regression.<br /><b>Results</b><br />In YFS, those who had been exposed to high Lp(a) level in youth [defined as Lp(a) ≥30 mg/dL] had ≈2 times greater risk of developing adult ASCVD compared with nonexposed individuals (hazard ratio, 2.0 [95% CI, 1.4-2.6]). Youth risk factors, including Lp(a), low-density lipoprotein cholesterol, body mass index, and smoking, were all independently associated with higher risk. In BHS, in an age- and sex-adjusted model, White individuals who had been exposed to high Lp(a) had 2.5 times greater risk (95% CI, 0.9-6.8) of developing adult ASCVD compared with nonexposed individuals. When also adjusted for low-density lipoprotein cholesterol and body mass index, the risk associated with high Lp(a) remained unchanged (hazard ratio, 2.4 [95% CI, 0.8-7.3]). In a multivariable model for pooled data, individuals exposed to high Lp(a) had 2.0 times greater risk (95% CI, 1.0-3.7) of developing adult ASCVD compared with nonexposed individuals. No association was detected between youth Lp(a) and adult carotid artery thickness in either cohort or pooled data.<br /><b>Conclusions</b><br />Elevated Lp(a) level identified in youth is a risk factor for adult atherosclerotic cardiovascular outcomes but not for increased carotid intima-media thickness.<br /><br /><br /><br /><small>Circulation: 28 Nov 2022; epub ahead of print</small></div>
Raitakari O, Kartiosuo N, Pahkala K, Hutri-Kähönen N, ... Juonala M, Viikari J
Circulation: 28 Nov 2022; epub ahead of print | PMID: 36440577
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<div><h4>NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload.</h4><i>Higashikuni Y, Liu W, Numata G, Tanaka K, ... Komuro I, Sata M</i><br /><b>Background</b><br />Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that NLRP3 (neural signals activate the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart.<br /><b>Methods</b><br />C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2\'(3\')-<i>O</i>-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1β and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed.<br /><b>Results</b><br />Genetic disruption of NLRP3 resulted in significant loss of IL-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1β production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1β-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy during pressure overload.<br /><b>Conclusions</b><br />Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.<br /><br /><br /><br /><small>Circulation: 28 Nov 2022; epub ahead of print</small></div>
Higashikuni Y, Liu W, Numata G, Tanaka K, ... Komuro I, Sata M
Circulation: 28 Nov 2022; epub ahead of print | PMID: 36440584
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<div><h4>Metabolic Changes Associated With Cardiomyocyte Dedifferentiation Enable Adult Mammalian Cardiac Regeneration.</h4><i>Cheng YY, Gregorich Z, Prajnamitra RP, Lundy DJ, ... Kamp TJ, Hsieh PCH</i><br /><b>Background</b><br />Cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, certain animals readily regenerate lost myocardium through a process involving dedifferentiation, which unlocks their proliferative capacities.<br /><b>Methods</b><br />We bred mice with inducible, CM-specific expression of the Yamanaka factors, enabling adult CM reprogramming and dedifferentiation in vivo.<br /><b>Results</b><br />Two days after induction, adult CMs presented a dedifferentiated phenotype and increased proliferation in vivo. Microarray analysis revealed that upregulation of ketogenesis was central to this process. Adenovirus-driven HMGCS2 overexpression induced ketogenesis in adult CMs and recapitulated CM dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue, and HMGCS2 knockout mice showed impaired cardiac function and response to injury. Finally, we showed that exogenous HMGCS2 rescues cardiac function after ischemic injury.<br /><b>Conclusions</b><br />Our data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to CM injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.<br /><br /><br /><br /><small>Circulation: 24 Nov 2022; epub ahead of print</small></div>
Cheng YY, Gregorich Z, Prajnamitra RP, Lundy DJ, ... Kamp TJ, Hsieh PCH
Circulation: 24 Nov 2022; epub ahead of print | PMID: 36420731
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<div><h4>Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity.</h4><i>Fanti S, Stephenson E, Rocha-Vieira E, Protonotarios A, ... Mohiddin SA, Marelli-Berg FM</i><br /><b>Background</b><br />Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)-expressing (c-Met<sup>+</sup>) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans.<br /><b>Methods</b><br />In-depth phenotyping of peripheral blood T cells, including c-Met<sup>+</sup> T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation.<br /><b>Results</b><br />We show that c-Met<sup>+</sup> T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met<sup>+</sup> T cells are distinct from those of c-Met-negative (c-Met<sup>-</sup>) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met<sup>+</sup> T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met<sup>+</sup> T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met<sup>+</sup> T cells.<br /><b>Conclusions</b><br />Our study demonstrates that the detection of circulating c-Met<sup>+</sup> T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury.<br /><br /><br /><br /><small>Circulation: 23 Nov 2022; epub ahead of print</small></div>
Fanti S, Stephenson E, Rocha-Vieira E, Protonotarios A, ... Mohiddin SA, Marelli-Berg FM
Circulation: 23 Nov 2022; epub ahead of print | PMID: 36417924
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<div><h4>Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling.</h4><i>Canfrán-Duque A, Rotllan N, Zhang X, Andrés-Blasco I, ... Fernández-Hernando C, Suárez Y</i><br /><b>Background</b><br />Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear.<br /><b>Methods</b><br />The levels of 25-HC were analyzed by liquid chromatography-mass spectrometry, and the expression of <i>CH25H</i> in different macrophage populations of human or mouse atherosclerotic plaques, respectively. The effect of CH25H on atherosclerosis progression was analyzed by bone marrow adoptive transfer of cells from wild-type or <i>Ch25h</i><sup><i>-/-</i></sup> mice to lethally irradiated <i>Ldlr</i><sup><i>-/-</i></sup> mice, followed by a Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis and effects on macrophage function and signaling were analyzed in vitro from lipid-loaded macrophage isolated from <i>Ldlr</i><sup><i>-/-</i></sup> or <i>Ch25h-/-;Ldlr-/- mice</i>. The contribution of secreted 25-HC to fibrous cap formation was analyzed using a smooth muscle cell lineage-tracing mouse model, <i>Myh11</i><sup><i>ERT2CRE</i></sup><i>mT/mG;Ldlr</i><sup><i>-/-</i></sup>, adoptively transferred with wild-type or <i>Ch25h</i><sup><i>-/-</i></sup> mice bone marrow followed by 12 weeks of Western diet feeding.<br /><b>Results</b><br />We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB-mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC-mediated modulation of liver X receptor or SREBP (sterol regulatory element-binding protein) transcriptional activity.<br /><b>Conclusions</b><br />Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.<br /><br /><br /><br /><small>Circulation: 23 Nov 2022; epub ahead of print</small></div>
Canfrán-Duque A, Rotllan N, Zhang X, Andrés-Blasco I, ... Fernández-Hernando C, Suárez Y
Circulation: 23 Nov 2022; epub ahead of print | PMID: 36416142
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<div><h4>Increasing Societal Benefit From Cardiovascular Drugs.</h4><i>Tonelli M, Straus S</i><br /><AbstractText>During the past few years, several innovative treatments for noncommunicable chronic disease have become available, including SGLT2i (sodium-glucose cotransporter-2 inhibitors), GLP-1a (glucagon-like-peptide 1 agonists), ARNI (angiotensin receptor-neprilysin inhibitors), and finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist. Each of these medications improves clinically relevant outcomes when added to existing therapies, and the indications for their use are rapidly expanding. Because existing drug regimens are already complex and costly, ensuring that society derives the maximal benefit from these new agents represents a major challenge. This Primer discusses how society can meet this challenge, which we address in terms of 5 principles: maximizing benefit, minimizing harm, optimizing uptake, increasing value for money, and ensuring equitable access. The Primer is most relevant for stakeholders in high-income countries, but the principles are broadly applicable to stakeholders in other settings, including low- and middle-income countries. We have focused the discussion on SGLT-2i, but the 5 principles herein could be used with reference to ARNI, finerenone, or any other health product.</AbstractText><br /><br /><br /><br /><small>Circulation: 22 Nov 2022; 146:1627-1635</small></div>
Tonelli M, Straus S
Circulation: 22 Nov 2022; 146:1627-1635 | PMID: 36409780
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<div><h4>Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension.</h4><i>Zhou W, Liu K, Zeng L, He J, ... Zhang F, Chen Y</i><br /><b>Background</b><br />Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear.<br /><b>Methods</b><br />VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (<i>Vefgr2</i><sup><i>Y949F</i></sup>) and mice with conditional endothelial deletion of <i>Vegfr2</i> after chronic hypoxia exposure.<br /><b>Results</b><br />We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by <i>Vefgr2</i><sup><i>Y949F</i></sup> point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of <i>Vegfr2</i> promotes the development of PH.<br /><b>Conclusions</b><br />Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.<br /><br /><br /><br /><small>Circulation: 17 Nov 2022; epub ahead of print</small></div>
Zhou W, Liu K, Zeng L, He J, ... Zhang F, Chen Y
Circulation: 17 Nov 2022; epub ahead of print | PMID: 36384284
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<div><h4>Cardiac Troponin I-interacting Kinase Impacts Cardiomyocyte S-phase Activity But Not Cardiomyocyte Proliferation.</h4><i>Reuter SP, Soonpaa MH, Field D, Simpson E, ... Wollert KC, Field LJ</i><br /><b>Background</b><br />Identifying genetic variants which impact the level of cell cycle reentry and establishing the degree of cell cycle progression in those variants could help guide development of therapeutic interventions aimed at effecting cardiac regeneration. We observed that C57Bl6/NCR (B6N) mice have a marked increase in cardiomyocyte S-phase activity following permanent coronary artery ligation as compared to infarcted DBA/2J (D2J) mice.<br /><b>Methods</b><br />Cardiomyocyte cell cycle activity post-infarction was monitored in D2J, (D2J x B6N)-F1 and [(D2J x B6N)-F1 x D2J] backcross mice via bromodeoxyuridine or 5-ethynyl-2\' -deoxyuridine incorporation, using a nuclear-localized transgenic reporter to identify cardiomyocyte nuclei. Genome-wide quantitative trait locus (QTL) analysis, fine scale genetic mapping, whole exome sequencing and RNA-seq analyses of the backcross mice were performed to identify the gene responsible for the elevated cardiomyocyte S-phase phenotype.<br /><b>Results</b><br />(D2J x B6N)-F1 mice exhibited a 14-fold increase in cardiomyocyte S-phase activity in ventricular regions remote from infarct scar as compared to D2J mice (0.798 ± 0.09% vs. 0.056 ± 0.004%; p < 0.001). QTL analysis of [(D2J x B6N)-F1 x D2J] backcross mice revealed that the gene responsible for differential S-phase activity was located on the distal arm of Chromosome 3 (LOD score = 6.38; p < 0.001). Additional genetic and molecular analyses identified 3 potential candidates. Of these, troponin I-interacting kinase (<i>Tnni3k</i>) is expressed in B6N hearts but not in D2J hearts. Transgenic expression of Tnni3k in a D2J genetic background results in elevated cardiomyocyte S-phase activity post-injury. Cardiomyocyte S-phase activity in both TNNI3K-expressing and TNNI3K-nonexpressing mice results in the formation of polyploid nuclei.<br /><b>Conclusions</b><br />These data indicate that TNNI3K expression increases the level of cardiomyocyte S-phase activity following injury.<br /><br /><br /><br /><small>Circulation: 16 Nov 2022; epub ahead of print</small></div>
Reuter SP, Soonpaa MH, Field D, Simpson E, ... Wollert KC, Field LJ
Circulation: 16 Nov 2022; epub ahead of print | PMID: 36382596
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<div><h4>An Overview of Telehealth in the Management of Cardiovascular Disease: A Scientific Statement From the American Heart Association.</h4><i>Takahashi EA, Schwamm LH, Adeoye OM, Alabi O, ... Council on the Kidney in Cardiovascular Disease, and Stroke Council</i><br /><AbstractText>Telehealth enables the remote delivery of health care through telecommunication technologies and has substantially affected the evolving medical landscape. The COVID-19 pandemic accelerated the utilization of telehealth as health care professionals were forced to limit face-to-face in-person visits. It has been shown that information delivery, diagnosis, disease monitoring, and follow-up care can be conducted remotely, resulting in considerable changes specific to cardiovascular disease management. Despite increasing telehealth utilization, several factors such as technological infrastructure, reimbursement, and limited patient digital literacy can hinder the adoption of remote care. This scientific statement reviews definitions pertinent to telehealth discussions, summarizes the effect of telehealth utilization on cardiovascular and peripheral vascular disease care, and identifies obstacles to the adoption of telehealth that need to be addressed to improve health care accessibility and equity.</AbstractText><br /><br /><br /><br /><small>Circulation: 14 Nov 2022; epub ahead of print</small></div>
Takahashi EA, Schwamm LH, Adeoye OM, Alabi O, ... Council on the Kidney in Cardiovascular Disease, and Stroke Council
Circulation: 14 Nov 2022; epub ahead of print | PMID: 36373541
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<div><h4>Consumer-Led Screening for Atrial Fibrillation: Frontier Review of the AF-SCREEN International Collaboration.</h4><i>Brandes A, Stavrakis S, Freedman B, Antoniou S, ... Steinhubl S, Turakhia MP</i><br /><AbstractText>The technological evolution and widespread availability of wearables and handheld ECG devices capable of screening for atrial fibrillation (AF), and their promotion directly to consumers, has focused attention of health care professionals and patient organizations on consumer-led AF screening. In this Frontiers review, members of the AF-SCREEN International Collaboration provide a critical appraisal of this rapidly evolving field to increase awareness of the complexities and uncertainties surrounding consumer-led AF screening. Although there are numerous commercially available devices directly marketed to consumers for AF monitoring and identification of unrecognized AF, health care professional-led randomized controlled studies using multiple ECG recordings or continuous ECG monitoring to detect AF have failed to demonstrate a significant reduction in stroke. Although it remains uncertain if consumer-led AF screening reduces stroke, it could increase early diagnosis of AF and facilitate an integrated approach, including appropriate anticoagulation, rate or rhythm management, and risk factor modification to reduce complications. Companies marketing AF screening devices should report the accuracy and performance of their products in high- and low-risk populations and avoid claims about clinical outcomes unless improvement is demonstrated in randomized clinical trials. Generally, the diagnostic yield of AF screening increases with the number, duration, and temporal dispersion of screening sessions, but the prognostic importance may be less than for AF detected by single-time point screening, which is largely permanent, persistent, or high-burden paroxysmal AF. Consumer-initiated ECG recordings suggesting possible AF always require confirmation by a health care professional experienced in ECG reading, whereas suspicion of AF on the basis of photoplethysmography must be confirmed with an ECG. Consumer-led AF screening is unlikely to be cost-effective for stroke prevention in the predominantly young, early adopters of this technology. Studies in older people at higher stroke risk are required to demonstrate both effectiveness and cost-effectiveness. The direct interaction between companies and consumers creates new regulatory gaps in relation to data privacy and the registration of consumer apps and devices. Although several barriers for optimal use of consumer-led screening exist, results of large, ongoing trials, powered to detect clinical outcomes, are required before health care professionals should support widespread adoption of consumer-led AF screening.</AbstractText><br /><br /><br /><br /><small>Circulation: 08 Nov 2022; 146:1461-1474</small></div>
Brandes A, Stavrakis S, Freedman B, Antoniou S, ... Steinhubl S, Turakhia MP
Circulation: 08 Nov 2022; 146:1461-1474 | PMID: 36343103
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<div><h4>Sex Differences in Characteristics, Outcomes and Treatment Response with Dapagliflozin across the Range of Ejection Fraction in Patients with Heart Failure: Insights from DAPA-HF and DELIVER.</h4><i>Wang X, Vaduganathan M, Claggett BL, Hegde SM, ... Solomon SD, Lam CSP</i><br /><b>Background</b><br />Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of SGLT2 inhibitors remains unclear. Our analyses aim to assess the impact of sex on the efficacy and safety of dapagliflozin.<br /><b>Methods</b><br />In a pre-specified patient-level pooled analysis of DAPA-HF and DELIVER, clinical outcomes were compared by sex (including the composite of cardiovascular [CV] death or worsening HF events; CV death; all-cause death, total events (first and recurrent HF hospitalization and CV death), and Kansas City Cardiomyopathy Questionnaire [KCCQ] scores) across the spectrum of left ventricular ejection fraction (EF).<br /><b>Results</b><br />Of a total of 11,007 randomized patients, 3856 (35%) were women. Women with HF were older, had higher body mass index, but were less likely to have a history of diabetes and myocardial infarction/stroke; and more likely to have hypertension and atrial fibrillation, compared to men. At baseline, women had higher EF but worse KCCQ scores than men. After adjusting for baseline differences, women were less likely than men to experience CV death (adjusted hazard ratio [aHR] 0.69, 95% CI 0.60-0.79), all-cause death (aHR 0.69, 95% 0.62-0.78), HF hospitalizations (aHR 0.82, 95% CI 0.72-0.94), and total events (adjusted rate ratio 0.77, 95% CI 0.71-0.84). Dapagliflozin reduced the primary endpoint in both men and women similarly (p-interaction=0.77) with no sex-related differences in secondary outcomes (all p-interactions > 0.35) or safety events. The benefit of dapagliflozin was observed across the entire EF spectrum and was not modified by sex (p-interaction > 0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation due to adverse events.<br /><b>Conclusions</b><br />In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.<br /><br /><br /><br /><small>Circulation: 07 Nov 2022; epub ahead of print</small></div>
Wang X, Vaduganathan M, Claggett BL, Hegde SM, ... Solomon SD, Lam CSP
Circulation: 07 Nov 2022; epub ahead of print | PMID: 36342789
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<div><h4>Incidental Coronary Artery Calcium: Opportunistic Screening of Prior Non-gated Chest CTs to Improve Statin Rates (NOTIFY-1 Project).</h4><i>Sandhu AT, Rodriguez F, Ngo S, Patel BN, ... Sousa D, Maron DJ</i><br /><b>Background</b><br />Coronary artery calcium (CAC) can be identified on non-gated chest CTs, but this finding is not consistently incorporated into care. A deep learning algorithm enables opportunistic CAC screening of non-gated chest CTs. Our objective was to evaluate the impact of notifying clinicians and patients of incidental CAC on statin initiation.<br /><b>Methods</b><br />NOTIFY-1 was a randomized quality improvement project in the Stanford healthcare system. Patients without known atherosclerotic cardiovascular disease (ASCVD) or prior statin prescription were screened for CAC on a prior non-gated chest CT from 2014-2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental CAC were randomized to notification of the primary care clinician and patient versus usual care. Notification included a patient-specific image of CAC and guideline recommendations regarding statin use. The primary outcome was statin prescription within 6 months.<br /><b>Results</b><br />Among 2,113 patients who met initial clinical inclusion criteria, CAC was identified by the algorithm in 424 patients. After additional exclusions following chart review, a radiologist confirmed CAC among 173 of 194 patients (89.2%) who were randomized to notification or usual care. At 6 months, the statin prescription rate was 51.2% (44/86) in the notification arm versus 6.9% (6/87) with usual care (p<0.001). There was also more coronary artery disease testing in the notification arm (15.1% [13/86] vs. 2.3% [2/87], p=0.008).<br /><b>Conclusions</b><br />Opportunistic CAC screening of prior non-gated chest CTs followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is needed to determine whether this approach can reduce ASCVD events.<br /><br /><br /><br /><small>Circulation: 07 Nov 2022; epub ahead of print</small></div>
Sandhu AT, Rodriguez F, Ngo S, Patel BN, ... Sousa D, Maron DJ
Circulation: 07 Nov 2022; epub ahead of print | PMID: 36342823
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<div><h4>Exercise for the Prevention of Anthracycline-induced Functional Disability and Cardiac Dysfunction: The BReast Cancer Randomized EXercise InTervention (BREXIT) Study.</h4><i>Foulkes SJ, Howden EJ, Haykowsky MJ, Antill Y, ... Fraser SF, La Gerche A</i><br /><AbstractText><b>Background:</b> Breast cancer (BC) survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 early-stage BC patients scheduled for AC to determine if 12-months of exercise training (ExT) could attenuate functional disability (primary endpoint), improve cardiorespiratory fitness (VO<sub>2</sub>peak) and prevent cardiac dysfunction. <br /><b>Methods:</b><br/>Women aged 40-75 years with stage I-III BC scheduled for AC were randomized to 3-4 days/wk of aerobic and resistance ExT for 12-months (n = 52) or usual care ([ UC ], n = 52). Functional measures were performed at baseline, 4-weeks following AC (4-months) and at 12-months comprising: 1) cardiopulmonary exercise testing to quantify VO<sub>2</sub>peak and functional disability (VO<sub>2</sub>peak ≤18.0mL/kg/min), 2) cardiac reserve (response from rest to peak exercise) quantified using exercise cardiac magnetic resonance measures to determine changes in left- and right-ventricular ejection fraction [ LVEF, RVEF ], cardiac output [ CO ], and stroke volume [ SV ]), 3) standard-of-care echocardiography-derived resting LVEF and global longitudinal strain [ GLS ], and 4) biochemistry (troponin and B-type natriuretic peptide [ BNP ]). <br /><b>Results:</b><br/>Among 104 participants randomized, greater study attrition was observed among UC participants (P=0.031) with 93 women assessed at 4-months (ExT: n=49, UC: n=44) and 87 at 12-months (ExT: n=49, UC: n=38). ExT attenuated functional disability at 4-months (OR: 0.32 [95% CI 0.11, 0.94], P=0.03), but not at 12-months (OR: 0.27, [95% CI 0.06, 1.12], P=0.07). In a per-protocol analysis, functional disability was entirely prevented at 12-months among participants adherent to ExT (ExT: 0% vs. UC: 20%, P=0.005). As compared with UC at 12-months, ExT was associated with a net +3.5 mL/kg/min improvement in VO<sub>2</sub>peak that coincided with greater CO, SV, LVEF and RVEF reserve (P<0.001 for all). There was no effect of ExT on resting measures of LV function. Post-chemotherapy troponin increased less in ExT than UC (8-fold vs. 16-fold increase, P=0.002). There were no changes in BNP in either group. <b>Conclusions:</b> In women with early-stage BC undergoing AC, 12-months of ExT did not attenuate functional disability but provided large and clinically meaningful benefits on VO2peak and cardiac reserve. <b>Clinical Trial Registration:</b> URL: https://www.anzctr.org.au/ Unique Identifier: ACTRN12617001408370.</AbstractText><br /><br /><br /><br /><small>Circulation: 07 Nov 2022; epub ahead of print</small></div>
Foulkes SJ, Howden EJ, Haykowsky MJ, Antill Y, ... Fraser SF, La Gerche A
Circulation: 07 Nov 2022; epub ahead of print | PMID: 36342348
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<div><h4>Aspirin vs. Clopidogrel for Chronic Maintenance Monotherapy after Percutaneous Coronary Intervention: the HOST-EXAM Extended Study.</h4><i>Kang J, Park KW, Lee H, Hwang D, ... Koo BK, Kim HS</i><br /><AbstractText><b>Background:</b> Long term outcomes of antiplatelet monotherapy in patients who receive percutaneous coronary intervention (PCI) are unknown. The HOST-EXAM Extended study reports the post-trial follow-up results of the original HOST-EXAM trial. <br /><b>Methods:</b><br/>From March 2014 through May 2018, 5438 patients who maintained dual antiplatelet therapy without clinical events for 12±6 months after PCI with drug-eluting stents (DES) were randomly assigned in a 1:1 ratio to receive clopidogrel 75mg once daily or aspirin 100mg once daily. The primary endpoint (a composite of all-cause death, nonfatal myocardial infarction (MI), stroke, readmission due to acute coronary syndrome (ACS), and BARC type ≥3 bleeding), secondary thrombotic endpoint (cardiac death, non-fatal MI, ischemic stroke, readmission due to ACS, and definite or probable stent thrombosis), bleeding endpoint (BARC type ≥2 bleeding) were analyzed during the extended follow-up period. Analysis was performed on the per-protocol population (2431 patients in the clopidogrel group and 2286 patients in the aspirin group). <br /><b>Results:</b><br/>During median follow-up of 5.8 years (interquartile range, 4.8 and 6.2 years), the primary endpoint occurred in 12.8% and 16.9% in the clopidogrel and aspirin groups, respectively (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.63 to 0.86, p<0.001). The clopidogrel group had a lower risk for the secondary thrombotic endpoint (7.9% vs. 11.9%; HR 0.66, 95% CI 0.55 to 0.79, p<0.001) and secondary bleeding endpoint (4.5% vs. 6.1%; HR 0.74, 95% CI 0.57 to 0.94, p=0.016). There was no significant difference in the incidence of all-cause death between the two groups (6.2% vs. 6.0%; HR 1.04, 95% CI 0.82 to 1.31, p=0.742). Landmark analysis at 2 years showed that the beneficial effect of clopidogrel was consistent throughout the follow-up period. <b>Conclusions:</b> During an extended follow-up of over 5 years after randomization, clopidogrel monotherapy as compared with aspirin monotherapy was associated with lower rates of the composite net clinical outcome in patients without clinical events for 12±6 months after PCI with DES.</AbstractText><br /><br /><br /><br /><small>Circulation: 07 Nov 2022; epub ahead of print</small></div>
Kang J, Park KW, Lee H, Hwang D, ... Koo BK, Kim HS
Circulation: 07 Nov 2022; epub ahead of print | PMID: 36342475
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<div><h4>Indobufen or Aspirin on Top of Clopidogrel after Coronary Drug-eluting Stent Implantation (OPTION): a Randomized, Open-label, Endpoint-blinded, Non-inferiority Trial.</h4><i>Wu H, Xu L, Zhao X, Zhang H, ... Qian J, Ge J</i><br /><AbstractText><b>Background:</b> Dual antiplatelet therapy (DAPT) with aspirin as a background therapy has become the standard care following percutaneous coronary intervention (PCI). However, some adverse non-cardiac effects limited the use of aspirin in clinical practice. Thus, evaluation of pharmacological alternatives to aspirin is attractive. Previous data indicated that indobufen could lessen the unwanted side effects of aspirin while retain the antithrombotic efficacy, but its combination with a P2Y12 inhibitor is still lack of randomized clinical trial (RCT) evidence. <br /><b>Methods:</b><br/>In this randomized, open-label, non-inferiority trial, patients with negative cardiac troponin undergoing coronary drug-eluting stent (DES) implantation were randomly assigned in a 1:1 ratio to receive either indobufen-based DAPT (indobufen 100mg twice a day plus clopidogrel 75mg/d for 12 months) or conventional DAPT (aspirin 100mg/d plus clopidogrel 75mg/d for 12 months). The primary endpoint was a 1-year composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), ischemic stroke, definite or probable stent thrombosis (ST), or Bleeding Academic Research Consortium (BARC) criteria type 2, 3 or 5 bleeding. The endpoints were adjudicated by an independent Clinical Event Committee. <br /><b>Results:</b><br/>Between January 11, 2018 and October 12, 2020, 4551 patients were randomized in 103 cardiovascular centers: 2258 patients to the indobufen-based DAPT group and 2293 to the conventional DAPT group. The primary endpoint occurred in 101 (4.47%) patients in the indobufen-based DAPT group and 140 (6.11%) patients in the conventional DAPT group (absolute difference -1.63%, pnon-inferiority <0.001; hazard ratio (HR) 0.73, 95% CI 0.56 to 0.94, p=0.015). CV death, nonfatal MI, ischemic stroke and ST were observed in 0.13%, 0.40%, 0.80%, and 0.22% of patients in the indobufen-based DAPT group, and 0.17%, 0.44%, 0.83%, and 0.17% of patients in the conventional DAPT group (all p>0.05). The occurrence of BARC criteria type 2, 3 or 5 bleeding events was lower in the indobufen-based DAPT group compared to the conventional DAPT group (2.97% vs 4.71%, HR 0.63, 95%CI 0.46 to 0.85, p=0.002), with main decrease in type 2 bleeding (1.68% vs 3.49%, HR 0.48, 95%CI 0.33 to 0.70, p<0.001). <b>Conclusions:</b> In Chinese patients with negative cardiac troponin undergoing DES implantation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of 1-year net clinical outcomes, which was mainly driven by a reduction in bleeding events without an increase in ischemic events.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Wu H, Xu L, Zhao X, Zhang H, ... Qian J, Ge J
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335890
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<div><h4>Apixaban for Patients with Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial.</h4><i>Pokorney SD, Chertow GM, Al-Khalidi HR, Gallup D, ... Winkelmayer WC, Granger CB</i><br /><b>Background</b><br />There is no randomized data evaluating the safety or efficacy of apixaban for stroke prevention in patients with end-stage kidney disease (ESKD) on hemodialysis and with atrial fibrillation (AF).<br /><b>Methods</b><br />The RENAL-AF trial was a prospective, randomized, open-label, blinded-outcome evaluation (PROBE) of apixaban versus warfarin in patients receiving hemodialysis with AF and CHA<sub>2</sub>DS<sub>2</sub>-VASc score ≥2. Patients were randomized 1:1 to apixaban 5mg twice daily (2.5mg twice daily with age ≥80 years and/or weight ≤60kg) or dose-adjusted warfarin. The primary outcome was time to major or clinically relevant non-major bleeding. Secondary outcomes included stroke, mortality, and apixaban pharmacokinetics. Pharmacokinetic sampling was day 1, day 3, and month 1.<br /><b>Results</b><br />From January 2017 through January 2019, 154 patients were randomized to apixaban (n=82) or warfarin (n=72). The trial stopped prematurely due to enrollment challenges. Time in therapeutic range (INR 2.0-3.0) for warfarin-treated patients was 44% (interquartile range; 23-59%). The 1-year rates for major or clinically relevant non-major bleeding were 32% and 26% in apixaban and warfarin groups, respectively (HR 1.20, 95% CI 0.63-2.30), while 1-year rates for stroke or systemic embolism were 3.0% and 3.3% in apixaban and warfarin groups, respectively. Death was the most common major event in the apixaban (21 patients [26%]) and warfarin (13 patients [18%]) arms. The pharmacokinetic substudy enrolled the target 50 patients. Median steady state 12-hour area under the curve (AUC0-12) was 2,475 ng-h/mL (10<sup>th</sup>-90<sup>th</sup> percentiles 1,342-3,285) for 5mg apixaban twice daily and 1,269 ng-h/mL (10<sup>th</sup>-90<sup>th</sup> percentiles 615-1,946) for 2.5mg apixaban twice daily. There was substantial overlap between minimum apixaban blood concentration, 12-hour AUC0-12, and maximum apixaban blood concentration for patients with and without a major or clinically relevant non-major bleeding events.<br /><b>Conclusions</b><br />There was inadequate power to draw any conclusion regarding rates of major or clinically relevant non-major bleeding comparing apixaban and warfarin in patients with AF and ESKD on hemodialysis. Clinically relevant bleeding events were approximately 10-fold more frequent than stroke or systemic embolism among this population on anticoagulation, highlighting the need for future randomized studies evaluating the risks versus benefits of anticoagulation among patients with AF and ESKD on hemodialysis.<br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Pokorney SD, Chertow GM, Al-Khalidi HR, Gallup D, ... Winkelmayer WC, Granger CB
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335914
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<div><h4>A Randomized Controlled Trial Comparing Apixaban to the Vitamin K-antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 study.</h4><i>Reinecke H, Engelbertz C, Bauersachs R, Breithardt G, ... Kirchhof P, Goerlich D</i><br /><AbstractText><b>Background:</b> Non-vitamin K oral anticoagulants (NOACs) have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of NOACs in patients on hemodialysis is not well known. <br /><b>Methods:</b><br/>From June 2017 until May 2022, the investigator-initiated, prospective, randomized, open, blinded outcome assessment \'A Safety Study Assessing Oral Anticoagulation with ApiXAban versus Vitamin K-Antagonists in Patients with Atrial Fibrillation and End-Stage Kidney Disease on Chronic HemoDIAlysis Treatment\' (AXADIA) trial randomized patients with AF on chronic hemodialysis to either apixaban 2.5 mg bid or the vitamin K antagonist (VKA) phenprocoumon (INR 2.0-3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically-relevant non-major bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis and/or pulmonary embolism. Our hypothesis was that apixaban is non-inferior to VKA. <br /><b>Results:</b><br/>Thirty-nine sites randomized 97 patients (30% women, mean age 75 years, mean CHA2DS2-VASc score 4.5, baseline characteristics balanced between groups), 48 to apixaban and 49 to VKA. The median follow-up time was 429 (range 37-1,370) vs. 506 (range 101-1,379) days, respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 (45.8%) patients on apixaban and in 25 (51.0%) patients on VKA (HR 0.93, 95% CI 0.53-1.65, p(noninferiority)=0.157). Composite primary efficacy outcome events occurred in 10 (20.8%) patients on apixaban and in 15 (30.6%) patients on VKA (p=0.51, log rank). There were no significant differences regarding individual outcomes (all-cause mortality 18.8% vs. 24.5%; major bleedings 10.4% vs. 12.2%; myocardial infarctions 4.2% vs. 6.1%, respectively). <b>Conclusions:</b> In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis. <b>Clinical Trial Registration:</b> EudraCT No. 2015-005503-84, NCT02933697.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Reinecke H, Engelbertz C, Bauersachs R, Breithardt G, ... Kirchhof P, Goerlich D
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335915
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<div><h4>Survival After Invasive or Conservative Management of Stable Coronary Disease.</h4><i>Hochman JS, Anthopolos R, Reynolds HR, Bangalore S, ... Maron DJ, ISCHEMIA-EXTEND Research Group</i><br /><AbstractText><b>Background:</b> The ISCHEMIA trial compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes over a median of 3.2 years. Extended follow-up for mortality is ongoing. <br /><b>Methods:</b><br/>ISCHEMIA participants were randomized to an initial invasive strategy (INV) added to guideline-directed medical therapy or a conservative strategy (CON). Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and non-cardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models and Bayesian methods. Undetermined deaths were classified as cardiovascular as pre-specified in the trial protocol. <br /><b>Results:</b><br/>Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23 % women, 16% Hispanic, 4% Black, 42% diabetes, and median EF 0.60. A total of 557 deaths accrued over a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 non-cardiovascular deaths and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate 12.7% in INV, 13.4% in CON; adjusted hazard ratio (HR)=1.00, 95% CI: 0.85-1.18). There was a lower 7-year rate cardiovascular mortality (6.4% vs. 8.6%, adjusted HR=0.78, 95% CI: 0.63-0.96) with an initial invasive strategy but a higher 7-year rate of non-cardiovascular mortality (5.6% vs. 4.4%, adjusted HR=1.44, 95% CI: 1.08-1.91) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. <b>Conclusions:</b> There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of non-cardiovascular mortality with an initial invasive strategy over a median follow-up of 5.7 years. <b>Clinical Trial Registration:</b> ClinicalTrials.gov Identifier: NCT04894877; https://clinicaltrials.gov/ct2/show/NCT04894877.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Hochman JS, Anthopolos R, Reynolds HR, Bangalore S, ... Maron DJ, ISCHEMIA-EXTEND Research Group
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335918
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<div><h4>The Prevalence and Association of Exercise Test Abnormalities with Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.</h4><i>Conway J, Min S, Villa C, Weintraub RG, ... Howard T, Mital S</i><br /><b>Background</b><br />Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, an abnormal exercise stress test is predictive of heart failure outcomes. Our goal was to determine if an abnormal exercise response is associated with adverse outcomes in pediatric HCM patients.<br /><b>Methods</b><br />In an international cohort study with 20 centers, phenotype-positive children with primary HCM <18 years at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response, and new or worsened ST-T wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of an abnormal exercise test with transplant and SCD event-free survival.<br /><b>Results</b><br />Of 724 eligible patients, 630 underwent at least one exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8yrs (IQR 4.7yrs); 78% were male, 39% were receiving beta-blockers. 175 (28%) had an abnormal test. Patients with an abnormal test had more severe septal hypertrophy, higher left atrial diameter z-scores, higher resting LV outflow tract gradient, and higher frequency of myectomy compared to those with a normal test (p<0.05). Compared to those with a normal test, an abnormal test was independently associated with a lower 5-year transplant-free survival (97% vs. 88% respectively, p=0.005). Those with exercise-induced ischemia were most likely to experience all-cause death or transplant [Hazard ratio (HR) 4.86, CI 1.69-13.99], followed by those with an abnormal blood pressure response (HR 3.19, CI 1.32-7.71). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (HR 3.32, CI 1.27-8.70). Exercise-induced ectopy was not associated with survival.<br /><b>Conclusions</b><br />Exercise abnormalities are common in childhood HCM. An abnormal exercise test was independently associated with lower transplant-free survival especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.<br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Conway J, Min S, Villa C, Weintraub RG, ... Howard T, Mital S
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335467
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<div><h4>Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial.</h4><i>Ostadal P, Rokyta R, Karasek J, Kruger A, ... Belohlavek J, ECMO-CS Investigators</i><br /><AbstractText><b>Background:</b> Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used for circulatory support in cardiogenic shock patients, although the evidence supporting its use in this context remains insufficient. The aim of the Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS) trial was to compare immediate implementation of VA-ECMO vs. an initially conservative therapy (allowing downstream use of VA-ECMO) in patients with rapidly deteriorating or severe cardiogenic shock. <br /><b>Methods:</b><br/>This multicenter, randomized, investigator-initiated, academic clinical trial included patients with either rapidly deteriorating or severe cardiogenic shock. Patients were randomly assigned to immediate VA-ECMO or no immediate VA-ECMO. Other diagnostic and therapeutic procedures were performed as per current standard(s) of care. In the early conservative group, VA-ECMO could be used downstream in case of worsening hemodynamic status. The primary endpoint was the composite of death from any cause, resuscitated circulatory arrest, and implementation of another mechanical circulatory support device at 30 days. <br /><b>Results:</b><br/>A total of 122 patients were randomized; after excluding 5 patients due to the absence of informed consent, 117 subjects were included in the analysis, of whom 58 randomized to immediate VA-ECMO and 59 to no immediate VA-ECMO. The composite primary endpoint occurred in 37 (63.8%) and 42 (71.2%) of patients in the immediate VA-ECMO and the no early VA-ECMO groups, respectively (hazard ratio, 0.72; 95% confidence intervals [CI], 0.46 to 1.12; P=0.21). VA-ECMO was used in 23 (39%) of no early VA-ECMO patients. The 30-day incidence of resuscitated cardiac arrest (10.3. % vs. 13.6%; risk difference [RD], -3.2; 95% CI, -15.0 to 8.5), all-cause mortality (50.0% versus 47.5%; RD, 2.5; 95% CI, -15.6 to 20.7), serious adverse events (60.3% vs. 61.0%; RD, -0.7; 95% CI, -18.4 to 17.0), sepsis, pneumonia, stroke, leg ischemia, and bleeding was not statistically different between the immediate VA-ECMO and the no immediate VA-ECMO groups. <b>Conclusions:</b> Immediate implementation of VA-ECMO in patients with rapidly deteriorating or severe cardiogenic shock did not improve clinical outcomes compared with an early conservative strategy that permitted downstream use of VA-ECMO in case of worsening hemodynamic status. <b>Clinical Trial Registration:</b> URL: https://www.clinicaltrials.gov; Unique identifier NCT02301819.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Ostadal P, Rokyta R, Karasek J, Kruger A, ... Belohlavek J, ECMO-CS Investigators
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335478
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<div><h4>Decongestion with Acetazolamide in Acute Decompensated Heart Failure across the Spectrum of Left Ventricular Ejection Fraction: a Pre-specified Analysis from the ADVOR trial.</h4><i>Martens P, Dauw J, Verbrugge FH, Nijst P, ... Dupont M, Mullens W</i><br /><b>Background</b><br />Acetazolamide inhibits proximal tubular sodium reabsorption and improved decongestion in the Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial. It remains unclear whether the decongestive effects of acetazolamide differ across the spectrum of left ventricular ejection fraction (LVEF).<br /><b>Methods</b><br />This is a pre-specified analysis of the randomized, double blind, placebo-controlled ADVOR trial that enrolled 519 patients with acute heart failure, clinical signs of volume overload (edema, pleural effusion or ascites), NTproBNP >1,000 ng/L or BNP >250 ng/ml, to receive intravenous acetazolamide (500 mg once daily) or placebo on top of standardized intravenous loop diuretics (twice oral home maintenance dose). Randomization was stratified according to LVEF (≤40% or >40%). The primary endpoint was successful decongestion, defined as the absence of signs of volume overload within three days from randomization without the need for mandatory escalation of decongestive therapy because of poor urine output.<br /><b>Results</b><br />Median LVEF was 45% (25-75<sup>th</sup> percentile: 30-55%) and 43% had a LVEF ≤40%. Patients with lower LVEF were younger, more likely to be male, with a higher prevalence of ischemic heart disease, a higher NTproBNP, less atrial fibrillation, and lower estimated glomerular filtration rate. No interaction on the overall beneficial treatment effect of acetazolamide on the primary endpoint of Successful decongestion (OR=1.77, 95% CI=[1.18-2.63], p=0.005, all p-values for interaction >0.401) was found when LVEF was assessed per randomization stratum (≤/ >40%), or as HFrEF, HFmrEF and HFpEF, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (all p-values for interaction >0.160).<br /><b>Conclusions</b><br />Acetazolamide when added to treatment with loop diuretics in patients with AHF improves the incidence of successful decongestion, improves diuretic response and shortens length of stay, without treatment effect modification by baseline LVEF.<br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Martens P, Dauw J, Verbrugge FH, Nijst P, ... Dupont M, Mullens W
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335479
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<div><h4>Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.</h4><i>Connelly KA, Mazer CD, Puar P, Teoh H, ... Yan AT, Verma S</i><br /><AbstractText><b>Background:</b> Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. While it has been theorized that SGLT2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine if SGLT2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. <br /><b>Methods:</b><br/>Between April 2021 and January 2022, 169 individuals, 40-80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomized to empagliflozin (10 mg/day; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area (BSA) as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to baseline BSA and LV ejection fraction. <br /><b>Results:</b><br/>Among the 169 participants (141 men [83%], mean age 59.3 ± 10.5 years), baseline LVMi was 63.2 ± 17.9 g/m<sup>2</sup> and 63.8 ± 14.0 g/m<sup>2</sup> for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group vs. placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1,1.5 g/m<sup>2</sup>) (P=0.74). Median baseline (IQR) NT-proBNP was 51 pg/mL (20, 105 pg/mL) and 55 pg/mL (21, 132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin vs. placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mmHg (-5.2, 2.6 mmHg) (P=0.52), 0.69 mmHg (-1.9, 3.3 mmHg) (P=0.60) and -6.1 pg/mL (-37.0, 24.8 pg/mL) (P=0.70) for systolic blood pressure, diastolic blood pressure and NT-proBNP, respectively. No clinically meaningful between group differences in LV volumes (diastolic and systolic indexed to baseline BSA) or ejection fraction were observed. No difference in adverse events was noted between the groups. <b>Conclusions:</b> Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, SGLT2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. <b>Clinical Trial Registration:</b> https://clinicaltrials.gov/ct2/show/NCT04461041clinicaltrials.gov Identifier: NCT04461041.</AbstractText><br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Connelly KA, Mazer CD, Puar P, Teoh H, ... Yan AT, Verma S
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335517
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<div><h4>Dose-Blinded Myosin Inhibition in Patients with Obstructive HCM Referred for Septal Reduction Therapy: Outcomes Through 32-Weeks.</h4><i>Desai MY, Owens AT, Geske JB, Wolski K, ... Sehnert AJ, Nissen SE</i><br /><b>Background</b><br />Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial examined the effect of mavacamten on the need for SRT through Week 32 in oHCM.<br /><b>Methods</b><br />A double-blind randomized placebo-controlled multicenter trial at 19 US sites included oHCM patients on maximal tolerated medical therapy referred for SRT, with left ventricular outflow tract (LVOT) gradient ≥50 mmHg at rest or provocation (enrollment 7/202010/2021). The group initially randomized to mavacamten continued the drug for 32 weeks and the placebo group crossed over to dose-blinded mavacamten from Week 16 to 32. Dose titrations were based on investigator-blinded echocardiographic assessment of LVOT gradient and LV ejection fraction. The principal endpoint was proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups.<br /><b>Results</b><br />From the 112 randomized oHCM patients, 108 (mean age 60.3 years, 50% men and 94% in New York Heart Association [NYHA] class III/IV) qualified for Week 32 evaluation (56 in original mavacamten and 52 in placebo crossover group). After 32 weeks, 6/56 (10.7%) patients in original mavacamten and 7/52 (13.5%) in placebo crossover group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting LVOT gradient (-33.0 mmHg 95% confidence interval [CI] -41.1 to -24.9) and Valsalva LVOT gradient (-43.0 mmHg, 95% CI -52.1 to -33.9) was observed in the original mavacamten group. A similar reduction in resting (-33.7 mmHg, 95% CI -42.2 to -25.2) and Valsalva gradients (-52.9 mmHg, 95% CI -63.2 to -42.6) was quantified in the crossover group after 16 weeks of mavacamten. After 32 weeks, ≥1 NYHA class improvement was observed in 48/53 (90.6%) of original mavacamten and 35/50 (70%) after 16 weeks in the crossover group.<br /><b>Conclusions</b><br />In severely symptomatic oHCM patients, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients crossed over from placebo after 16 weeks.<br /><b>Trial registration</b><br />URL: Clinicaltrials.gov Unique Identifier: NCT04349072.<br /><br /><br /><br /><small>Circulation: 06 Nov 2022; epub ahead of print</small></div>
Desai MY, Owens AT, Geske JB, Wolski K, ... Sehnert AJ, Nissen SE
Circulation: 06 Nov 2022; epub ahead of print | PMID: 36335531
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This program is still in alpha version.