Topic: Journal Club Selection

Abstract
<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>Massively Hypertrophied Right-Sided Heart with Hypoplastic Left-Sided Heart in a Neonate (A Rare Type of Hypertrophic Cardiomyopathy).</h4><i>Roberts WC, Chinta S, Guileyardo JM</i><br /><AbstractText>Described herein is a newborn boy with likely right-sided hypertrophic cardiomyopathy (HC), who survived for 18 hours after birth. At necropsy, he had a severely thickened right ventricular free wall, ventricular septum, right atrial wall and a hypoplastic left-sided heart. There was a large fossa ovale type atrial septal defect and also a patent ductus arteriosus. During peak systole, the right ventricular outflow tract was obstructed, and its contents were pushed into the thick-walled right atrium, then rapidly into the thin-walled left atrium via a large fossa ovale atrial septal defect. The contents were then pushed into the thin-walled left ventricle and finally into the small ascending aorta and into the lungs via a large patent ductus arteriosus. We were unable to find a similar published case.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>Am J Cardiol: 15 Dec 2022; epub ahead of print</small></div>
Roberts WC, Chinta S, Guileyardo JM
Am J Cardiol: 15 Dec 2022; epub ahead of print | PMID: 36528398
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<div><h4>Pathophysiology, Echocardiographic Diagnosis, and Treatment of Atrial Functional Mitral Regurgitation: JACC State-of-the-Art Review.</h4><i>Farhan S, Silbiger JJ, Halperin JL, Zhang L, ... Sharma S, Lerakis S</i><br /><AbstractText>The conventional view holds that functional mitral regurgitation (MR) is caused by restriction of leaflet motion resulting from displacement of the papillary muscle-bearing segments of the left ventricle. In the past decade, evidence has accrued suggesting functional MR can also be caused by left atrial enlargement. This underrecognized cause of secondary MR-atrial functional MR (AF-MR)-is mechanistically linked to annular enlargement, perturbations of annular contraction, and atriogenic leaflet tethering. AF-MR has been described in patients with atrial fibrillation and heart failure with preserved ejection fraction. Preliminary data suggest rhythm control may decrease MR severity in patients with atrial fibrillation. Additionally, several studies have reported reductions in MR and symptomatic improvement with restrictive annuloplasty and transcatheter edge-to-edge repair. This review discusses the pathophysiology, echocardiographic diagnosis, and treatment of AF-MR. AF-tricuspid regurgitation is also discussed.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 13 Dec 2022; 80:2314-2330</small></div>
Farhan S, Silbiger JJ, Halperin JL, Zhang L, ... Sharma S, Lerakis S
J Am Coll Cardiol: 13 Dec 2022; 80:2314-2330 | PMID: 36480974
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<div><h4>Cardiopulmonary Exercise Testing in Athletes With Hypertrophic Cardiomyopathy.</h4><i>Newman DB, Garmany R, Contreras AM, Bos JM, ... Ommen SR, Ackerman MJ</i><br /><AbstractText>Patients with hypertrophic cardiomyopathy (HCM) have historically been restricted from athletic participation because of the perceived risk of sudden cardiac death. More contemporary research has highlighted the relative safety of competitive athletics with HCM. However, lack of published data on reference values for cardiopulmonary exercise testing (CPET) complicates clinical management and counseling on sports participation in the individual athlete. We conducted a single-center, retrospective cohort study to investigate CPET in athletes with HCM and clinical characteristics associated with objective measures of aerobic capacity. We identified 58 athletes with HCM (74% male, mean age 18 ± 3 years, mean left ventricular (LV) wall thickness 20 ± 7 mm). LV outflow tract obstruction was present in 22 (38%). A total of 15 (26%) athletes were taking a β blocker (BB), but only 4 (7%) reported exertional symptoms. Overall, exercise capacity was mildly reduced, with a peak myocardial oxygen consumption (peak VO<sub>2</sub>) of 37.9 ml/min/kg (83% of predicted peak VO<sub>2</sub>). Both LV outflow tract obstruction and BB use were associated with reduced exercise capacity. Limited peak heart rate was more common in athletes taking BB (47% vs 9%, p = 0.002). At a mean 5.6 years follow-up, 5 patients underwent myectomy (9%), and 8 (14%) received an implantable cardioverter defibrillator (ICD) for primary prevention. One individual with massive LV hypertrophy experienced recurrent ICD shocks for ventricular fibrillation and underwent myectomy 7 years after initial evaluation and was no longer participating in sports. There were no deaths over the follow-up period. In conclusion, the prognostic role of CPET remains unclear in athletes with HCM. Mildly reduced exercise capacity was common; however, reduced peak VO<sub>2</sub> did not correlate with symptom status or clinical outcomes. A significant proportion went on to require myectomy and/or ICD, thus highlighting the need for close follow-up. These data provide some initial insight into the clinical evaluation of \"real world\" athletes with HCM; however, further study is warranted to help guide shared decision-making, return-to-play discussions, and the potential long-term safety of competitive athletic participation.</AbstractText><br /><br />Copyright © 2022 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 09 Dec 2022; 189:49-55</small></div>
Newman DB, Garmany R, Contreras AM, Bos JM, ... Ommen SR, Ackerman MJ
Am J Cardiol: 09 Dec 2022; 189:49-55 | PMID: 36508762
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<div><h4>Translational opportunities of single-cell biology in atherosclerosis.</h4><i>de Winther MPJ, Bäck M, Evans P, Gomez D, ... Bochaton-Piallat ML, Monaco C</i><br /><AbstractText>The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD.</AbstractText><br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 07 Dec 2022; epub ahead of print</small></div>
de Winther MPJ, Bäck M, Evans P, Gomez D, ... Bochaton-Piallat ML, Monaco C
Eur Heart J: 07 Dec 2022; epub ahead of print | PMID: 36478058
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<div><h4>Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis.</h4><i>Shih YT, Wei SY, Chen JH, Wang WL, ... Chien S, Chiu JJ</i><br /><b>Background:</b><br/>and aims</b><br />Atherosclerosis preferentially develops in arterial branches and curvatures where vascular endothelium is exposed to disturbed flow. In this study, the effects of disturbed flow on the regulation of vascular endothelial phosphoproteins and their contribution to therapeutic application in atherogenesis were elucidated.<br /><b>Methods</b><br />Porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens were used to discover novel site-specific phosphorylation alterations induced by disturbed flow in endothelial cells (ECs).<br /><b>Results</b><br />A large-scale phosphoproteomics analysis of native endothelium from disturbed (athero-susceptible) vs. pulsatile flow (athero-resistant) regions of porcine aortas led to the identification of a novel atherosclerosis-related phosphoprotein vinculin (VCL) with disturbed flow-induced phosphorylation at serine 721 (VCLS721p). The induction of VCLS721p was mediated by G-protein-coupled receptor kinase 2 (GRK2)S29p and resulted in an inactive form of VCL with a closed conformation, leading to the VE-cadherin/catenin complex disruption to enhance endothelial permeability and atherogenesis. The generation of novel apolipoprotein E-deficient (ApoE-/-) mice overexpressing S721-non-phosphorylatable VCL mutant in ECs confirmed the critical role of VCLS721p in promoting atherosclerosis. The administration of a GRK2 inhibitor to ApoE-/- mice suppressed plaque formation by inhibiting endothelial VCLS721p. Studies on clinical specimens from patients with coronary artery disease (CAD) revealed that endothelial VCLS721p is a critical clinicopathological biomarker for atherosclerosis progression and that serum VCLS721p level is a promising biomarker for CAD diagnosis.<br /><b>Conclusions</b><br />The findings of this study indicate that endothelial VCLS721p is a valuable hemodynamic-based target for clinical assessment and treatment of vascular disorders resulting from atherosclerosis.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 16 Nov 2022; epub ahead of print</small></div>
Shih YT, Wei SY, Chen JH, Wang WL, ... Chien S, Chiu JJ
Eur Heart J: 16 Nov 2022; epub ahead of print | PMID: 36380599
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<div><h4>Progression of Atrial Fibrillation after Cryoablation or Drug Therapy.</h4><i>Andrade JG, Deyell MW, Macle L, Wells GA, ... Verma A, EARLY-AF Investigators</i><br /><b>Background</b><br />Atrial fibrillation is a chronic, progressive disorder, and persistent forms of atrial fibrillation are associated with increased risks of thromboembolism and heart failure. Catheter ablation as initial therapy may modify the pathogenic mechanism of atrial fibrillation and alter progression to persistent atrial fibrillation.<br /><b>Methods</b><br />We report the 3-year follow-up of patients with paroxysmal, untreated atrial fibrillation who were enrolled in a trial in which they had been randomly assigned to undergo initial rhythm-control therapy with cryoballoon ablation or to receive antiarrhythmic drug therapy. All the patients had implantable loop recorders placed at the time of trial entry, and evaluation was conducted by means of downloaded daily recordings and in-person visits every 6 months. Data regarding the first episode of persistent atrial fibrillation (lasting ≥7 days or lasting 48 hours to 7 days but requiring cardioversion for termination), recurrent atrial tachyarrhythmia (defined as atrial fibrillation, flutter, or tachycardia lasting ≥30 seconds), the burden of atrial fibrillation (percentage of time in atrial fibrillation), quality-of-life metrics, health care utilization, and safety were collected.<br /><b>Results</b><br />A total of 303 patients were enrolled, with 154 patients assigned to undergo initial rhythm-control therapy with cryoballoon ablation and 149 assigned to receive antiarrhythmic drug therapy. Over 36 months of follow-up, 3 patients (1.9%) in the ablation group had an episode of persistent atrial fibrillation, as compared with 11 patients (7.4%) in the antiarrhythmic drug group (hazard ratio, 0.25; 95% confidence interval [CI], 0.09 to 0.70). Recurrent atrial tachyarrhythmia occurred in 87 patients in the ablation group (56.5%) and in 115 in the antiarrhythmic drug group (77.2%) (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). The median percentage of time in atrial fibrillation was 0.00% (interquartile range, 0.00 to 0.12) in the ablation group and 0.24% (interquartile range, 0.01 to 0.94) in the antiarrhythmic drug group. At 3 years, 8 patients (5.2%) in the ablation group and 25 (16.8%) in the antiarrhythmic drug group had been hospitalized (relative risk, 0.31; 95% CI, 0.14 to 0.66). Serious adverse events occurred in 7 patients (4.5%) in the ablation group and in 15 (10.1%) in the antiarrhythmic drug group.<br /><b>Conclusions</b><br />Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 07 Nov 2022; epub ahead of print</small></div>
Andrade JG, Deyell MW, Macle L, Wells GA, ... Verma A, EARLY-AF Investigators
N Engl J Med: 07 Nov 2022; epub ahead of print | PMID: 36342178
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<div><h4>Defibrillation Strategies for Refractory Ventricular Fibrillation.</h4><i>Cheskes S, Verbeek PR, Drennan IR, McLeod SL, ... Dorian P, Scales DC</i><br /><b>Background</b><br />Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation.<br /><b>Methods</b><br />We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge.<br /><b>Results</b><br />A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% confidence interval [CI], 1.33 to 3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01 to 2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26 to 3.88] and 1.48 [95% CI, 0.81 to 2.71], respectively).<br /><b>Conclusions</b><br />Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF ClinicalTrials.gov number, NCT04080986.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Nov 2022; epub ahead of print</small></div>
Cheskes S, Verbeek PR, Drennan IR, McLeod SL, ... Dorian P, Scales DC
N Engl J Med: 06 Nov 2022; epub ahead of print | PMID: 36342151
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<div><h4>Pathogenesis of Cardiomyopathy Caused by Variants in , an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere.</h4><i>Agarwal R, Wakimoto H, Paulo JA, Zhang Q, ... Seidman JG, Seidman CE</i><br /><b>Background</b><br /><i>ALPK3</i> encodes α-kinase 3, a muscle-specific protein of unknown function. <i>ALPK3</i> loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood.<br /><b>Methods</b><br />We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues.<br /><b>Results</b><br />Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. <i>ALPK3</i> loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function.<br /><b>Conclusions</b><br />ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that <i>ALPK3</i> cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.<br /><br /><br /><br /><small>Circulation: 02 Nov 2022; epub ahead of print</small></div>
Agarwal R, Wakimoto H, Paulo JA, Zhang Q, ... Seidman JG, Seidman CE
Circulation: 02 Nov 2022; epub ahead of print | PMID: 36321451
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<div><h4>Early Active Mobilization during Mechanical Ventilation in the ICU.</h4><i>TEAM Study Investigators and the ANZICS Clinical Trials Group, Hodgson CL, Bailey M, Bellomo R, ... Webb S, Young PJ</i><br /><b>Background</b><br />Intensive care unit (ICU)-acquired weakness often develops in patients who are undergoing invasive mechanical ventilation. Early active mobilization may mitigate ICU-acquired weakness, increase survival, and reduce disability.<br /><b>Methods</b><br />We randomly assigned 750 adult patients in the ICU who were undergoing invasive mechanical ventilation to receive increased early mobilization (sedation minimization and daily physiotherapy) or usual care (the level of mobilization that was normally provided in each ICU). The primary outcome was the number of days that the patients were alive and out of the hospital at 180 days after randomization.<br /><b>Results</b><br />The median number of days that patients were alive and out of the hospital was 143 (interquartile range, 21 to 161) in the early-mobilization group and 145 days (interquartile range, 51 to 164) in the usual-care group (absolute difference, -2.0 days; 95% confidence interval [CI], -10 to 6; P = 0.62). The mean (±SD) daily duration of active mobilization was 20.8±14.6 minutes and 8.8±9.0 minutes in the two groups, respectively (difference, 12.0 minutes per day; 95% CI, 10.4 to 13.6). A total of 77% of the patients in both groups were able to stand by a median interval of 3 days and 5 days, respectively (difference, -2 days; 95% CI, -3.4 to -0.6). By day 180, death had occurred in 22.5% of the patients in the early-mobilization group and in 19.5% of those in the usual-care group (odds ratio, 1.15; 95% CI, 0.81 to 1.65). Among survivors, quality of life, activities of daily living, disability, cognitive function, and psychological function were similar in the two groups. Serious adverse events were reported in 7 patients in the early-mobilization group and in 1 patient in the usual-care group. Adverse events that were potentially due to mobilization (arrhythmias, altered blood pressure, and desaturation) were reported in 34 of 371 patients (9.2%) in the early-mobilization group and in 15 of 370 patients (4.1%) in the usual-care group (P = 0.005).<br /><b>Conclusions</b><br />Among adults undergoing mechanical ventilation in the ICU, an increase in early active mobilization did not result in a significantly greater number of days that patients were alive and out of the hospital than did the usual level of mobilization in the ICU. The intervention was associated with increased adverse events. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; TEAM ClinicalTrials.gov number, NCT03133377.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 26 Oct 2022; epub ahead of print</small></div>
TEAM Study Investigators and the ANZICS Clinical Trials Group, Hodgson CL, Bailey M, Bellomo R, ... Webb S, Young PJ
N Engl J Med: 26 Oct 2022; epub ahead of print | PMID: 36286256
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<div><h4>Cerebral Embolic Protection during Transcatheter Aortic-Valve Replacement.</h4><i>Kapadia SR, Makkar R, Leon M, Abdel-Wahab M, ... Linke A, PROTECTED TAVR Investigators</i><br /><b>Background</b><br />Transcatheter aortic-valve replacement (TAVR) for the treatment of aortic stenosis can lead to embolization of debris. Capture of debris by devices that provide cerebral embolic protection (CEP) may reduce the risk of stroke.<br /><b>Methods</b><br />We randomly assigned patients with aortic stenosis in a 1:1 ratio to undergo transfemoral TAVR with CEP (CEP group) or without CEP (control group). The primary end point was stroke within 72 hours after TAVR or before discharge (whichever came first) in the intention-to-treat population. Disabling stroke, death, transient ischemic attack, delirium, major or minor vascular complications at the CEP access site, and acute kidney injury were also assessed. A neurology professional examined all the patients at baseline and after TAVR.<br /><b>Results</b><br />A total of 3000 patients across North America, Europe, and Australia underwent randomization; 1501 were assigned to the CEP group and 1499 to the control group. A CEP device was successfully deployed in 1406 of the 1489 patients (94.4%) in whom an attempt was made. The incidence of stroke within 72 hours after TAVR or before discharge did not differ significantly between the CEP group and the control group (2.3% vs. 2.9%; difference, -0.6 percentage points; 95% confidence interval, -1.7 to 0.5; P = 0.30). Disabling stroke occurred in 0.5% of the patients in the CEP group and in 1.3% of those in the control group. There were no substantial differences between the CEP group and the control group in the percentage of patients who died (0.5% vs. 0.3%); had a stroke, a transient ischemic attack, or delirium (3.1% vs. 3.7%); or had acute kidney injury (0.5% vs. 0.5%). One patient (0.1%) had a vascular complication at the CEP access site.<br /><b>Conclusions</b><br />Among patients with aortic stenosis undergoing transfemoral TAVR, the use of CEP did not have a significant effect on the incidence of periprocedural stroke, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of CEP during TAVR. (Funded by Boston Scientific; PROTECTED TAVR ClinicalTrials.gov number, NCT04149535.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 17 Sep 2022; epub ahead of print</small></div>
Kapadia SR, Makkar R, Leon M, Abdel-Wahab M, ... Linke A, PROTECTED TAVR Investigators
N Engl J Med: 17 Sep 2022; epub ahead of print | PMID: 36121045
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<div><h4>Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.</h4><i>Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, ... Yusuf S, INVICTUS Investigators</i><br /><b>Background</b><br />Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited.<br /><b>Methods</b><br />We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA<sub>2</sub>DS<sub>2</sub>VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm<sup>2</sup>, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis.<br /><b>Results</b><br />Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted.<br /><b>Conclusions</b><br />Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 28 Aug 2022; epub ahead of print</small></div>
Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, ... Yusuf S, INVICTUS Investigators
N Engl J Med: 28 Aug 2022; epub ahead of print | PMID: 36036525
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<div><h4>Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.</h4><i>Mullens W, Dauw J, Martens P, Verbrugge FH, ... Dupont M, ADVOR Study Group</i><br /><b>Background</b><br />Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear.<br /><b>Methods</b><br />In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed.<br /><b>Results</b><br />A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups.<br /><b>Conclusions</b><br />The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 27 Aug 2022; epub ahead of print</small></div>
Mullens W, Dauw J, Martens P, Verbrugge FH, ... Dupont M, ADVOR Study Group
N Engl J Med: 27 Aug 2022; epub ahead of print | PMID: 36027559
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<div><h4>Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.</h4><i>Solomon SD, McMurray JJV, Claggett B, de Boer RA, ... Langkilde AM, DELIVER Trial Committees and Investigators</i><br /><b>Background</b><br />Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.<br /><b>Methods</b><br />We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis.<br /><b>Results</b><br />Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups.<br /><b>Conclusions</b><br />Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 27 Aug 2022; epub ahead of print</small></div>
Solomon SD, McMurray JJV, Claggett B, de Boer RA, ... Langkilde AM, DELIVER Trial Committees and Investigators
N Engl J Med: 27 Aug 2022; epub ahead of print | PMID: 36027570
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<div><h4>Benefit of Early Revascularization Based on Inducible Ischemia and Left Ventricular Ejection Fraction.</h4><i>Rozanski A, Miller RJH, Gransar H, Han D, ... Thomson L, Berman DS</i><br /><b>Background</b><br />The utility of performing early myocardial revascularization among patients presenting with inducible myocardial ischemia and low left ventricular ejection fraction (LVEF) is currently unknown.<br /><b>Objectives</b><br />In this study, we sought to assess the relationship between stress-induced myocardial ischemia, revascularization, and all-cause mortality (ACM) among patients with normal vs low LVEF.<br /><b>Methods</b><br />We evaluated 43,443 patients undergoing stress-rest single-photon emission computed tomography myocardial perfusion imaging from 1998 to 2017. Median follow-up was 11.4 years. Myocardial ischemia was assessed for its interaction between early revascularization and mortality. A propensity score was used to adjust for nonrandomization to revascularization, followed by multivariable Cox modeling adjusted for the propensity score and clinical variables to predict ACM.<br /><b>Results</b><br />The frequency of myocardial ischemia varied markedly according to LVEF and angina, ranging from 6.7% among patients with LVEF ≥55% and no typical angina to 64.0% among patients with LVEF <45% and typical angina (P < 0.001). Among 39,883 patients with LVEF ≥45%, early revascularization was associated with increased mortality risk among patients without ischemia and lower mortality risk among patients with severe (≥15%) ischemia (HR: 0.70; 95% CI: 0.52-0.95). Among 3,560 patients with LVEF <45%, revascularization was not associated with mortality benefit among patients with no or mild ischemia, and was associated with decreased mortality among patients with moderate (10%-14%) (HR: 0.67; 95% CI: 0.49-0.91) and severe (≥15%) (HR: 0.55; 95% CI: 0.38-0.80) ischemia.<br /><b>Conclusions</b><br />Within this cohort, early myocardial revascularization was associated with a significant reduction in mortality among both patients with normal LVEF and severe inducible myocardial ischemia and patients with low LVEF and moderate or severe inducible myocardial ischemia.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>J Am Coll Cardiol: 19 Jul 2022; 80:202-215</small></div>
Rozanski A, Miller RJH, Gransar H, Han D, ... Thomson L, Berman DS
J Am Coll Cardiol: 19 Jul 2022; 80:202-215 | PMID: 35835493
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<div><h4>Clinical Spectrum of Children with Acute Hepatitis of Unknown Cause.</h4><i>Kelgeri C, Couper M, Gupte GL, Brant A, ... Sharif K, Hartley J</i><br /><b>Background</b><br />Since January 2022, there has been an increase in reports of cases of acute hepatitis of unknown cause in children. Although cases have been reported across multiple continents, most have been reported in the United Kingdom. Investigations are ongoing to identify the causative agent or agents.<br /><b>Methods</b><br />We conducted a retrospective study involving children referred to a single pediatric liver-transplantation center in the United Kingdom between January 1 and April 11, 2022. These children were 10 years of age or younger and had hepatitis that met the case definition of the U.K. Health Security Agency for confirmed acute hepatitis that was not hepatitis A through E and did not have a metabolic, inherited or genetic, congenital, or mechanical cause, in the context of a serum aminotransferase level greater than 500 IU per liter. We reviewed medical records and documented demographic characteristics, clinical features, and results of liver biochemical, serologic, and molecular tests for hepatotropic and other viruses, as well as radiologic and clinical outcomes. The outcomes were classified as an improving condition, liver transplantation, or death.<br /><b>Results</b><br />A total of 44 children had hepatitis that met the confirmed case definition, and most were previously healthy. The median age was 4 years (range, 1 to 7). Common presenting features were jaundice (in 93% of the children), vomiting (in 54%), and diarrhea (in 32%). Among the 30 patients who underwent molecular testing for human adenovirus, 27 (90%) were positive. Fulminant liver failure developed in 6 patients (14%), all of whom received a liver transplant. None of the patients died. All the children, including the 6 who received liver transplants, were discharged home.<br /><b>Conclusions</b><br />In this series involving 44 young children with acute hepatitis of uncertain cause, human adenovirus was isolated in most of the children, but its role in the pathogenesis of this illness has not been established.<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 13 Jul 2022; epub ahead of print</small></div>
Kelgeri C, Couper M, Gupte GL, Brant A, ... Sharif K, Hartley J
N Engl J Med: 13 Jul 2022; epub ahead of print | PMID: 35830627
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<div><h4>Cardiac magnetic resonance identifies raised left ventricular filling pressure: prognostic implications.</h4><i>Garg P, Gosling R, Swoboda P, Jones R, ... Alabed S, Swift AJ</i><br /><b>Aims</b><br />Non-invasive imaging is routinely used to estimate left ventricular (LV) filling pressure (LVFP) in heart failure (HF). Cardiovascular magnetic resonance (CMR) is emerging as an important imaging tool for sub-phenotyping HF. However, currently, LVFP cannot be estimated from CMR. This study sought to investigate (i) if CMR can estimate LVFP in patients with suspected HF and (ii) if CMR-modelled LVFP has prognostic power.<br /><b>Methods and results</b><br />Suspected HF patients underwent right heart catheterization (RHC), CMR and transthoracic echocardiography (TTE) (validation cohort only) within 24 h of each other. Right heart catheterization measured pulmonary capillary wedge pressure (PCWP) was used as a reference for LVFP. At follow-up, death was considered as the primary endpoint. We enrolled 835 patients (mean age: 65 ± 13 years, 40% male). In the derivation cohort (n = 708, 85%), two CMR metrics were associated with RHC PCWP:LV mass and left atrial volume. When applied to the validation cohort (n = 127, 15%), the correlation coefficient between RHC PCWP and CMR-modelled PCWP was 0.55 (95% confidence interval: 0.41-0.66, P < 0.0001). Cardiovascular magnetic resonance-modelled PCWP was superior to TTE in classifying patients as normal or raised filling pressures (76 vs. 25%). Cardiovascular magnetic resonance-modelled PCWP was associated with an increased risk of death (hazard ratio: 1.77, P < 0.001). At Kaplan-Meier analysis, CMR-modelled PCWP was comparable to RHC PCWP (≥15 mmHg) to predict survival at 7-year follow-up (35 vs. 37%, χ2 = 0.41, P  = 0.52).<br /><b>Conclusion</b><br />A physiological CMR model can estimate LVFP in patients with suspected HF. In addition, CMR-modelled LVFP has a prognostic role.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 04 May 2022; epub ahead of print</small></div>
Garg P, Gosling R, Swoboda P, Jones R, ... Alabed S, Swift AJ
Eur Heart J: 04 May 2022; epub ahead of print | PMID: 35512290
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<div><h4>Progressive Reduction in Right Ventricular Contractile Function Due to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy.</h4><i>Camors EM, Roth AH, Alef JR, Sullivan RD, ... Purevjav E, Towbin JA</i><br /><b>Background</b><br />Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 (PKP2) has been reported to be the most common disease-causing gene when mutation-positive. In the early \"concealed\" phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs due to mistargeted ion channels and altered Ca<sup>2+</sup> handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown.<br /><b>Methods</b><br />We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of <i>Pkp2</i>, which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies.<br /><b>Results</b><br />Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than three months of age. By contrast, left ventricular (LV) function remained normal. Electrocardiograms of six-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg.kg<sup>-1</sup>) plus caffeine (120 mg.kg<sup>-1</sup>) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histologic staining showed no significant fibrosis or adipocyte infiltration in the RVs and LVs of six- and twelve-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca<sup>2+</sup> indicator Fura-2 showed comparable Ca<sup>2+</sup> transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, while actin immunoprecipitation followed by a 2, 4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het LV myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Finally, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in RVs of end-stage ACM patients.<br /><b>Conclusions</b><br />During the early \"concealed\" phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.<br /><br /><br /><br /><small>Circulation: 19 Apr 2022; epub ahead of print</small></div>
Camors EM, Roth AH, Alef JR, Sullivan RD, ... Purevjav E, Towbin JA
Circulation: 19 Apr 2022; epub ahead of print | PMID: 35437032
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<div><h4>Prevalence and Prognostic Implications of Left Ventricular Systolic Dysfunction in Adults With Congenital Heart Disease.</h4><i>Egbe AC, Miranda WR, Pellikka PA, DeSimone CV, Connolly HM</i><br /><b>Background</b><br />Although the prevalence and prognostic implications of left ventricular systolic dysfunction (LVSD), and the effect of cardiac therapies on LVSD are well described in patients with acquired heart disease, such data are sparse in adults with congenital heart disease (CHD).<br /><b>Objectives</b><br />The purpose of this study was to determine the prevalence, risk factors, and prognostic implications of LVSD, and the effect of cardiac therapies (guideline-directed medical therapy [GDMT] and cardiac resynchronization therapy [CRT]) on LVSD in adults with CHD.<br /><b>Methods</b><br />This was a retrospective study of adults with CHD with systemic LV (2003-2019). LVSD was defined as left ventricular ejection fraction (LVEF) <52%/<54% (men/women). Cardiovascular event was defined as heart failure hospitalization, heart transplant, and cardiovascular death.<br /><b>Results</b><br />Of 4,358 patients, 554 (12%) had LVSD, and the prevalence of LVSD was higher in right-sided lesions compared with left-sided lesions (15% vs 10%; P < 0.001). Cardiovascular events occurred in 312 (7%) patients. LVEF was independently associated with cardiovascular events (HR: 0.95; 95% CI: 0.93-0.97; P = 0.009). Of 544 patients with LVSD, 311 received GDMT and 48 patients received CRT. LVEF increased by 6% (95% CI: 2%-10%) and 11% (95% CI: 8%-14%), and N-terminal pro-hormone brain natriuretic peptide decreased by 151 pg/mL (95% CI: 62-289 pg/mL) and 201 pg/mL (95% CI: 119-321 pg/mL) in patients who received GDMT and CRT, respectively.<br /><b>Conclusions</b><br />LVSD was present in 12% of adults with CHD, was more common in patients with right-sided lesions, and was associated with cardiovascular events. GDMT and CRT were associated with improvement in LVEF. These results provide a foundation for clinical trials to rigorously test the benefits of these therapies in CHD patients.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 12 Apr 2022; 79:1356-1365</small></div>
Egbe AC, Miranda WR, Pellikka PA, DeSimone CV, Connolly HM
J Am Coll Cardiol: 12 Apr 2022; 79:1356-1365 | PMID: 35393016
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<div><h4>Monogenic and Polygenic Contributions to QTc Prolongation in the Population.</h4><i>Nauffal V, Morrill VN, Jurgens SJ, Choi SH, ... Ellinor PT, Lubitz SA</i><br /><AbstractText><b>Background:</b> Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. <br /><b>Methods:</b><br/>We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. <br /><b>Results:</b><br/>Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/<sub>decile of PRS</sub> = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10<sup>-196</sup>). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). <b>Conclusions:</b> QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.</AbstractText><br /><br /><br /><br /><small>Circulation: 07 Apr 2022; epub ahead of print</small></div>
Nauffal V, Morrill VN, Jurgens SJ, Choi SH, ... Ellinor PT, Lubitz SA
Circulation: 07 Apr 2022; epub ahead of print | PMID: 35389749
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<div><h4>Mechanical Left Ventricular Unloading in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation.</h4><i>Grandin EW, Nunez JI, Willar B, Kennedy K, ... Shaefi S, Garan AR</i><br /><b>Background</b><br />Venoarterial extracorporeal membrane oxygenation (VA-ECMO) increases left ventricular (LV) afterload, potentially provoking LV distention and impairing recovery. LV mechanical unloading (MU) with intra-aortic balloon pump (IABP) or percutaneous ventricular assist device (pVAD) can prevent LV distension, potentially at the risk of more complications, and net clinical benefit remains uncertain.<br /><b>Objectives</b><br />This study aims to determine the association between MU and outcomes for patients undergoing VA-ECMO.<br /><b>Methods</b><br />The authors queried the Extracorporeal Life Support Organization registry for adults receiving peripheral VA-ECMO from 2010 to 2019 and stratified them by MU with IABP or pVAD. The primary outcome was in-hospital mortality; secondary outcomes included on-support mortality and complications during VA-ECMO.<br /><b>Results</b><br />Among 12,734 VA-ECMO patients, 3,399 (26.7%) received MU: 2,782 (82.9%) IABP and 580 (17.1%) pVAD. MU patients were older (age 56.3 vs 52.7 years) and, before extracorporeal membrane oxygenation, more often required >2 vasopressors (41.7% vs 27.2%) and had respiratory (21.1% vs 15.9%), renal (24.6% vs 15.8%), and liver failure (4.4% vs 3.1%) (all P < 0.001). MU patients had lower in-hospital mortality (56.6% vs 59.3%, P = 0.006), which persisted in multivariable modeling (adjusted OR [aOR]: 0.84; 95% CI: 0.77-0.92; P < 0.001). MU was associated with more cannula site bleeding (aOR: 1.25; 95% CI: 1.11-1.40; P < 0.001) and hemolysis (aOR: 1.27; 95% CI: 1.03-1.57; P = 0.02). Compared to pVAD, MU patients with IABP had similar mortality (aOR: 0.80; 95% CI: 0.64-1.01; P = 0.06) and less medical bleeding (aOR: 0.45; 95% CI: 0.31-0.64; P < 0.001), cannula site bleeding (aOR: 0.72; 95% CI: 0.54-0.96; P = 0.03), and renal injury (aOR: 0.78; 95% CI: 0.62-0.98; P = 0.03).<br /><b>Conclusions</b><br />Among adults receiving VA-ECMO, MU was associated with lower in-hospital mortality despite increased complications including hemolysis and cannulation site bleeding. Compared to pVAD, MU with IABP was associated with similar mortality and lower complication rates.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 05 Apr 2022; 79:1239-1250</small></div>
Grandin EW, Nunez JI, Willar B, Kennedy K, ... Shaefi S, Garan AR
J Am Coll Cardiol: 05 Apr 2022; 79:1239-1250 | PMID: 35361346
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<div><h4>Left Ventricular Thrombus Following Acute Myocardial Infarction: JACC State-of-the-Art Review.</h4><i>Camaj A, Fuster V, Giustino G, Bienstock SW, ... Dweck MR, Goldman ME</i><br /><AbstractText>The incidence of left ventricular (LV) thrombus following acute myocardial infarction has markedly declined in recent decades caused by advancements in reperfusion and antithrombotic therapies. Despite this, embolic events remain the most feared complication of LV thrombus necessitating systemic anticoagulation. Mechanistically, LV thrombus development depends on Virchow\'s triad (ie, endothelial injury from myocardial infarction, blood stasis from LV dysfunction, and hypercoagulability triggered by inflammation, with each of these elements representing potential therapeutic targets). Diagnostic modalities include transthoracic echocardiography with or without ultrasound-enhancing agents and cardiac magnetic resonance. Most LV thrombi develop within the first 2 weeks post-acute myocardial infarction, and the role of surveillance imaging appears limited. Vitamin K antagonists remain the mainstay of therapy because the efficacy of direct oral anticoagulants is less well established. Only meager data support the routine use of prophylactic anticoagulation, even in high-risk patients.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>J Am Coll Cardiol: 14 Mar 2022; 79:1010-1022</small></div>
Camaj A, Fuster V, Giustino G, Bienstock SW, ... Dweck MR, Goldman ME
J Am Coll Cardiol: 14 Mar 2022; 79:1010-1022 | PMID: 35272796
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<div><h4>Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation.</h4><i>Shi J, Tong R, Zhou M, Gao Y, ... Lu X, Pu J</i><br /><b>Aims</b><br />Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported.<br /><b>Methods and results</b><br />Here, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway.<br /><b>Conclusion</b><br />We provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.<br /><b>Key question</b><br />Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Whether circadian nuclear receptor Rev-erba is present in platelets and regulates platelet function remains unknown.<br /><b>Key finding</b><br />We provide the first evidence that Rev-erba is functionally expressed in platelets and acts as a positive regulator of platelet activation/thrombus formation through the oligophrenin-1-mediated RhoA/ERM signalling pathway.<br /><b>Take home message</b><br />Our observations highlight the importance of circadian clock machinery in platelet physiology and support the notion that Rev-erba may serve as a novel therapeutic target for managing thrombosis-based cardiovascular diseases.<br /><br />© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.<br /><br /><small>Eur Heart J: 09 Mar 2022; epub ahead of print</small></div>
Shi J, Tong R, Zhou M, Gao Y, ... Lu X, Pu J
Eur Heart J: 09 Mar 2022; epub ahead of print | PMID: 35267019
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<div><h4>CT or Invasive Coronary Angiography in Stable Chest Pain.</h4><i>Maurovich-Horvat P, Bosserdt M, Kofoed KF, Rieckmann N, ... Martus P, Dewey M</i><br /><b>Background</b><br />In the diagnosis of obstructive coronary artery disease (CAD), computed tomography (CT) is an accurate, noninvasive alternative to invasive coronary angiography (ICA). However, the comparative effectiveness of CT and ICA in the management of CAD to reduce the frequency of major adverse cardiovascular events is uncertain.<br /><b>Methods</b><br />We conducted a pragmatic, randomized trial comparing CT with ICA as initial diagnostic imaging strategies for guiding the treatment of patients with stable chest pain who had an intermediate pretest probability of obstructive CAD and were referred for ICA at one of 26 European centers. The primary outcome was major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) over 3.5 years. Key secondary outcomes were procedure-related complications and angina pectoris.<br /><b>Results</b><br />Among 3561 patients (56.2% of whom were women), follow-up was complete for 3523 (98.9%). Major adverse cardiovascular events occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 (3.0%) in the ICA group (hazard ratio, 0.70; 95% confidence interval [CI], 0.46 to 1.07; P = 0.10). Major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 (1.9%) in the ICA group (hazard ratio, 0.26; 95% CI, 0.13 to 0.55). Angina during the final 4 weeks of follow-up was reported in 8.8% of the patients in the CT group and in 7.5% of those in the ICA group (odds ratio, 1.17; 95% CI, 0.92 to 1.48).<br /><b>Conclusions</b><br />Among patients referred for ICA because of stable chest pain and intermediate pretest probability of CAD, the risk of major adverse cardiovascular events was similar in the CT group and the ICA group. The frequency of major procedure-related complications was lower with an initial CT strategy. (Funded by the European Union Seventh Framework Program and others; DISCHARGE ClinicalTrials.gov number, NCT02400229.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Mar 2022; epub ahead of print</small></div>
Maurovich-Horvat P, Bosserdt M, Kofoed KF, Rieckmann N, ... Martus P, Dewey M
N Engl J Med: 03 Mar 2022; epub ahead of print | PMID: 35240010
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<div><h4>Mortality from Congenital Zika Syndrome - Nationwide Cohort Study in Brazil.</h4><i>Paixao ES, Cardim LL, Costa MCN, Brickley EB, ... Barreto ML, Teixeira MG</i><br /><b>Background</b><br />Prenatal exposure to Zika virus has potential teratogenic effects, with a wide spectrum of clinical presentation referred to as congenital Zika syndrome. Data on survival among children with congenital Zika syndrome are limited.<br /><b>Methods</b><br />In this population-based cohort study, we used linked, routinely collected data in Brazil, from January 2015 through December 2018, to estimate mortality among live-born children with congenital Zika syndrome as compared with those without the syndrome. Kaplan-Meier curves and survival models were assessed with adjustment for confounding and with stratification according to gestational age, birth weight, and status of being small for gestational age.<br /><b>Results</b><br />A total of 11,481,215 live-born children were followed to 36 months of age. The mortality rate was 52.6 deaths (95% confidence interval [CI], 47.6 to 58.0) per 1000 person-years among live-born children with congenital Zika syndrome, as compared with 5.6 deaths (95% CI, 5.6 to 5.7) per 1000 person-years among those without the syndrome. The mortality rate ratio among live-born children with congenital Zika syndrome, as compared with those without the syndrome, was 11.3 (95% CI, 10.2 to 12.4). Among infants born before 32 weeks of gestation or with a birth weight of less than 1500 g, the risks of death were similar regardless of congenital Zika syndrome status. Among infants born at term, those with congenital Zika syndrome were 14.3 times (95% CI, 12.4 to 16.4) as likely to die as those without the syndrome (mortality rate, 38.4 vs. 2.7 deaths per 1000 person-years). Among infants with a birth weight of 2500 g or greater, those with congenital Zika syndrome were 12.9 times (95% CI, 10.9 to 15.3) as likely to die as those without the syndrome (mortality rate, 32.6 vs. 2.5 deaths per 1000 person-years). The burden of congenital anomalies, diseases of the nervous system, and infectious diseases as recorded causes of deaths was higher among live-born children with congenital Zika syndrome than among those without the syndrome.<br /><b>Conclusions</b><br />The risk of death was higher among live-born children with congenital Zika syndrome than among those without the syndrome and persisted throughout the first 3 years of life. (Funded by the Ministry of Health of Brazil and others.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 23 Feb 2022; 386:757-767</small></div>
Paixao ES, Cardim LL, Costa MCN, Brickley EB, ... Barreto ML, Teixeira MG
N Engl J Med: 23 Feb 2022; 386:757-767 | PMID: 35196428
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<div><h4>Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest.</h4><i>Ruijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, ... Hofmeijer J, TELSTAR Investigators</i><br /><b>Background</b><br />Whether the treatment of rhythmic and periodic electroencephalographic (EEG) patterns in comatose survivors of cardiac arrest improves outcomes is uncertain.<br /><b>Methods</b><br />We conducted an open-label trial of suppressing rhythmic and periodic EEG patterns detected on continuous EEG monitoring in comatose survivors of cardiac arrest. Patients were randomly assigned in a 1:1 ratio to a stepwise strategy of antiseizure medications to suppress this activity for at least 48 consecutive hours plus standard care (antiseizure-treatment group) or to standard care alone (control group); standard care included targeted temperature management in both groups. The primary outcome was neurologic outcome according to the score on the Cerebral Performance Category (CPC) scale at 3 months, dichotomized as a good outcome (CPC score indicating no, mild, or moderate disability) or a poor outcome (CPC score indicating severe disability, coma, or death). Secondary outcomes were mortality, length of stay in the intensive care unit (ICU), and duration of mechanical ventilation.<br /><b>Results</b><br />We enrolled 172 patients, with 88 assigned to the antiseizure-treatment group and 84 to the control group. Rhythmic or periodic EEG activity was detected a median of 35 hours after cardiac arrest; 98 of 157 patients (62%) with available data had myoclonus. Complete suppression of rhythmic and periodic EEG activity for 48 consecutive hours occurred in 49 of 88 patients (56%) in the antiseizure-treatment group and in 2 of 83 patients (2%) in the control group. At 3 months, 79 of 88 patients (90%) in the antiseizure-treatment group and 77 of 84 patients (92%) in the control group had a poor outcome (difference, 2 percentage points; 95% confidence interval, -7 to 11; P = 0.68). Mortality at 3 months was 80% in the antiseizure-treatment group and 82% in the control group. The mean length of stay in the ICU and mean duration of mechanical ventilation were slightly longer in the antiseizure-treatment group than in the control group.<br /><b>Conclusions</b><br />In comatose survivors of cardiac arrest, the incidence of a poor neurologic outcome at 3 months did not differ significantly between a strategy of suppressing rhythmic and periodic EEG activity with the use of antiseizure medication for at least 48 hours plus standard care and standard care alone. (Funded by the Dutch Epilepsy Foundation; TELSTAR ClinicalTrials.gov number, NCT02056236.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 23 Feb 2022; 386:724-734</small></div>
Ruijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, ... Hofmeijer J, TELSTAR Investigators
N Engl J Med: 23 Feb 2022; 386:724-734 | PMID: 35196426
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<div><h4>Fetal Brain Volume Predicts Neurodevelopment in Congenital Heart Disease.</h4><i>Sadhwani A, Wypij D, Rofeberg V, Gholipour A, ... Ortinau CM, Rollins CK</i><br /><AbstractText><b>Background:</b> Neurodevelopmental impairment is common in children with congenital heart disease (CHD), yet postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedents for neurodevelopmental disabilities might begin <i>in utero</i>, we analyzed whether fetal brain volume predicted subsequent neurodevelopmental outcome in children with CHD. <br /><b>Methods:</b><br/>Fetuses with isolated CHD and sociodemographically comparable healthy control fetuses underwent fetal brain MRI and 2-year neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development (Bayley-III) and the Adaptive Behavior Assessment System (ABAS-3). Hierarchical regression evaluated potential predictors of Bayley-III and ABAS-3 outcomes in the CHD group, including fetal total brain volume adjusted for gestational age and sex, sociodemographic characteristics, birth parameters, and medical history. <br /><b>Results:</b><br/>The CHD group (n=52) had lower Bayley-III cognitive, language, and motor scores than the control group (n=26), but fetal brain volumes were similar. Within the CHD group, larger fetal total brain volume correlated with higher Bayley-III cognitive, language, and motor scores, and ABAS-3 adaptive functioning scores (r=0.32-0.47; all P<0.05), but not in the control group. Fetal brain volume predicted 10 21% of the variance in neurodevelopmental outcome measures in univariate analyses. Multivariable models that also included social class and postnatal factors explained 18-45% of the variance in outcome, depending on developmental domain. Moreover, in final multivariable models, fetal brain volume was the most consistent predictor of neurodevelopmental outcome across domains. <b>Conclusions:</b> Small fetal brain volume is a strong independent predictor of 2-year neurodevelopmental outcomes and may be an important imaging biomarker of future neurodevelopmental risk in CHD. Future studies are needed to support this hypothesis. Our findings support inclusion of fetal brain volume in risk stratification models and as a possible outcome in fetal neuroprotective intervention studies.</AbstractText><br /><br /><br /><br /><small>Circulation: 09 Feb 2022; epub ahead of print</small></div>
Sadhwani A, Wypij D, Rofeberg V, Gholipour A, ... Ortinau CM, Rollins CK
Circulation: 09 Feb 2022; epub ahead of print | PMID: 35143287
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