Topic: Journal Club Selection

Abstract
<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>Diagnosis of cardiac sarcoidosis in patients presenting with cardiac arrest or life-threatening arrhythmias.</h4><i>Hatipoglu S, Gardezi SKM, Azzu A, Baksi J, ... Pennell DJ, Mohiaddin R</i><br /><b>Objective</b><br />Cardiac sarcoidosis (CS) may present with cardiac arrest or life-threatening arrhythmias. There are limited data on this subgroup of patients with CS. Advanced imaging including cardiovascular magnetic resonance (CMR) and cardiac 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) are used for diagnosis. This study aimed to describe advanced imaging patterns suggestive of CS among patients presenting with cardiac arrest or life-threatening arrhythmias.<br /><b>Methods</b><br />An imaging database of a CS referral centre (Royal Brompton Hospital, London) was screened for patients presenting with cardiac arrest or life-threatening arrhythmias and having imaging features of suspected CS. Patients diagnosed with definite or probable/possible CS were included.<br /><b>Results</b><br />Study population included 60 patients (median age 49 years) with male predominance (76.7%). The left ventricle was usually non-dilated with mildly reduced ejection fraction (53.4±14.8%). CMR studies showed extensive late gadolinium enhancement (LGE) with 5 (4-8) myocardial segments per patient affected; the right ventricular (RV) side of the septum (28/45) and basal anteroseptum (28/45) were most frequently involved. Myocardial inflammation by FDG-PET was detected in 45 out of 58 patients vs 11 out of 33 patients with oedema imaging available on CMR. When PET was treated as reference to detect myocardial inflammation, CMR oedema imaging was 33.3% sensitive and 77% specific.<br /><b>Conclusions</b><br />In patients with CS presenting with cardiac arrest or life-threatening arrhythmias, LGE was located in areas where the cardiac conduction system travels (basal anteroseptal wall and RV side of the septum). While CMR was the imaging technique that raised possibility of cardiac scarring, oedema imaging had low sensitivity to detect myocardial inflammation compared with FDG-PET.<br /><br />© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>Heart: 10 Jan 2023; epub ahead of print</small></div>
Hatipoglu S, Gardezi SKM, Azzu A, Baksi J, ... Pennell DJ, Mohiaddin R
Heart: 10 Jan 2023; epub ahead of print | PMID: 36627181
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<div><h4>Biventricular Noncompaction Cardiomyopathy in a Patient Presenting With a New Cerebrovascular Event.</h4><i>Madnawat H, Atallah I, Ahmad A, Harjai K</i><br /><AbstractText>Noncompaction (NC) cardiomyopathy (NCCM) is a rare, genetically heterogeneous cardiomyopathy (CM) caused by failure to compact the intertrabecular recesses of the myocardium. This condition usually affects the apical segment of the left ventricle, yet there are noted basal segment, biventricular, and right ventricular predominant cases. NCCM is largely diagnosed in the pediatric population; however, there is increasing recognition in older patients with heart failure and stroke and patients with arrhythmias. Treatment focuses on symptomatic management of heart failure, anticoagulation, and implantable cardiac defibrillators.</AbstractText><br /><br />Copyright © 2022 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 06 Jan 2023; 190:110-112</small></div>
Madnawat H, Atallah I, Ahmad A, Harjai K
Am J Cardiol: 06 Jan 2023; 190:110-112 | PMID: 36621285
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<div><h4>Prognosis of patients with hypertrophic cardiomyopathy and low-normal left ventricular ejection fraction.</h4><i>Choi YJ, Kim HK, Hwang IC, Park CS, ... Cho GY, Kim YJ</i><br /><b>Objective</b><br />To investigate whether low-normal left ventricular ejection fraction (LVEF) is associated with adverse outcomes in hypertrophic cardiomyopathy (HCM) and evaluate the incremental value of predictive power of LVEF in the conventional HCM sudden cardiac death (SCD)-risk model.<br /><b>Methods</b><br />This retrospective study included 1858 patients with HCM from two tertiary hospitals between 2008 and 2019. We classified LVEF into three categories: preserved (<b>≥</b>60%), low normal (50%-60%) and reduced (<50%); there were 1399, 415, and 44 patients with preserved, low-normal, and reduced LVEF, respectively. The primary outcome was a composite of SCD, ventricular tachycardia/fibrillation and appropriate implantable cardioverter-defibrillator shocks. Secondary outcomes were hospitalisation for heart failure (HHF), cardiovascular death and all-cause death.<br /><b>Results</b><br />During the median follow-up of 4.09 years, the primary outcomes occurred in 1.9%. HHF, cardiovascular death, and all-cause death occurred in 3.3%, 1.9%, and 5.3%, respectively. Reduced LVEF was an independent predictor of SCD/equivalent events (adjusted HR (aHR) 5.214, 95% CI 1.574 to 17.274, p=0.007), adding predictive value to the HCM risk-SCD model (net reclassification improvement 0.625). Compared with patients with HCM with preserved LVEF, those with low-normal and reduced LVEF had a higher risk of HHF (LVEF 50%-60%, aHR 2.457, 95% CI 1.423 to 4.241, p=0.001; LVEF <50%, aHR 7.937, 95% CI 3.315 to 19.002, p<0.001) and cardiovascular death (LVEF 50%-60%, aHR 2.641, 95% CI 1.314 to 5.309, p=0.006; LVEF <50%, aHR 5.405, 95% CI 1.530 to 19.092, p=0.009), whereas there was no significant association with all-cause death.<br /><b>Conclusions</b><br />Low-normal LVEF was an independent predictor of HHF and cardiovascular death in patients with HCM.<br /><br />© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>Heart: 29 Dec 2022; epub ahead of print</small></div>
Choi YJ, Kim HK, Hwang IC, Park CS, ... Cho GY, Kim YJ
Heart: 29 Dec 2022; epub ahead of print | PMID: 36581445
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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>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>Prevention of cardiorenal damage: importance of albuminuria.</h4><i>Ruilope LM, Ortiz A, Lucia A, Miranda B, ... Ruiz-Hurtado G, Pitt B</i><br /><AbstractText>Chronic kidney disease (CKD) is projected to become a leading global cause of death by 2040, and its early detection is critical for effective and timely management. The current definition of CKD identifies only advanced stages, when kidney injury has already destroyed >50% of functioning kidney mass as reflected by an estimated glomerular filtration rate <60 mL/min/1.73 m2 or a urinary albumin/creatinine ratio >six-fold higher than physiological levels (i.e. > 30 mg/g). An elevated urinary albumin-excretion rate is a known early predictor of future cardiovascular events. There is thus a \'blind spot\' in the detection of CKD, when kidney injury is present but is undetectable by current diagnostic criteria, and no intervention is made before renal and cardiovascular damage occurs. The present review discusses the CKD \'blind spot\' concept and how it may facilitate a holistic approach to CKD and cardiovascular disease prevention and implement the call for albuminuria screening implicit in current guidelines. Cardiorenal risk associated with albuminuria in the high-normal range, novel genetic and biochemical markers of elevated cardiorenal risk, and the role of heart and kidney protective drugs evaluated in recent clinical trials are also discussed. As albuminuria is a major risk factor for cardiovascular and renal disease, starting from levels not yet considered in the definition of CKD, the implementation of opportunistic or systematic albuminuria screening and therapy, possibly complemented with novel early biomarkers, has the potential to improve cardiorenal outcomes and mitigate the dismal 2040 projections for CKD and related cardiovascular burden.</AbstractText><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: 07 Dec 2022; epub ahead of print</small></div>
Ruilope LM, Ortiz A, Lucia A, Miranda B, ... Ruiz-Hurtado G, Pitt B
Eur Heart J: 07 Dec 2022; epub ahead of print | PMID: 36477861
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<div><h4>Trial of Deferiprone in Parkinson\'s Disease.</h4><i>Devos D, Labreuche J, Rascol O, Corvol JC, ... Moreau C, FAIRPARK-II Study Group</i><br /><b>Background</b><br />Iron content is increased in the substantia nigra of persons with Parkinson\'s disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson\'s disease, but its effects on disease progression are unclear.<br /><b>Methods</b><br />We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson\'s disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson\'s Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.<br /><b>Results</b><br />A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.<br /><b>Conclusions</b><br />In participants with early Parkinson\'s disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Dec 2022; 387:2045-2055</small></div>
Devos D, Labreuche J, Rascol O, Corvol JC, ... Moreau C, FAIRPARK-II Study Group
N Engl J Med: 01 Dec 2022; 387:2045-2055 | PMID: 36449420
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<div><h4>The association of disparities in neighborhood median household income and mortality in patients admitted to the hospital with atrial fibrillation.</h4><i>Dhore-Patil A, Crawford M, Nedunchezhian S, El Hajjar AH, ... Sidhu G, Marrouche N</i><br /><b>Background</b><br />Lower neighborhood median household income (nMHI) is associated with increased adverse outcomes in patients with atrial fibrillation (AF). However, its effect on mortality is yet unknown.<br /><b>Methods</b><br />Data from the regional United States (U.S.) electronic medical records database, Research Action for Health Network (REACHnet), was extracted for adult patients with AF at Tulane Medical Center over 10 years. Annual nMHI & neighborhood high school graduation (HSG) data was collected from the US Census bureau. Only African Americans (AA) and Caucasians (CC) who had socioeconomic data were included. Low nMHI and low HSG were defined as ≤$25,000 & <90% respectively. High nMHI and HSG were defined as >$50,000 & ≥90% respectively. Primary endpoints were all cause and cardiovascular (CV) mortality. Cox-proportional hazard ratios were used to evaluate the endpoints.<br /><b>Results</b><br />We included 4616 patients diagnosed with AF. During a median follow up of 4.6 years, 434 patients died of which 32.7% patients had CV mortality. There was a stepwise decrease in incidence of both all-cause and CV mortality as nMHI increased. Patients with low nMHI had the greatest risk of all-cause mortality (HR 1.9, C.I. 1.2-3.2, P 0.004). The association between low nMHI and all-cause mortality persisted after adjusting for age, sex, race, HSG and stroke risk factors using CHA<sub>2</sub>DS<sub>2</sub>VASC, delta CHA<sub>2</sub>DS<sub>2</sub>VASC scores and oral anticoagulant use. CV mortality followed a similar trend as all-cause mortality, however, this association was not significant after adjusting for the above variables. Apart from low nMHI, CHA<sub>2</sub>DS<sub>2</sub>VASC delta CHA<sub>2</sub>DS<sub>2</sub>VASC were statistically significant independent predictors of both all-cause and CV mortality.<br /><b>Conclusion</b><br />Low nMHI is an independent risk factor for all cause and CV mortality in AF. Higher burden of co-morbidities is the driving force behind this disparity. Future studies should evaluate the role of educational and therapeutic intervention in these populations to reduce mortality.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>Prog Cardiovasc Dis: 30 Nov 2022; epub ahead of print</small></div>
Dhore-Patil A, Crawford M, Nedunchezhian S, El Hajjar AH, ... Sidhu G, Marrouche N
Prog Cardiovasc Dis: 30 Nov 2022; epub ahead of print | PMID: 36462553
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<div><h4>Lecanemab in Early Alzheimer\'s Disease.</h4><i>van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, ... Kramer LD, Iwatsubo T</i><br /><b>Background</b><br />The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer\'s disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer\'s disease.<br /><b>Methods</b><br />We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer\'s disease (mild cognitive impairment or mild dementia due to Alzheimer\'s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer\'s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer\'s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer\'s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).<br /><b>Results</b><br />A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.<br /><b>Conclusions</b><br />Lecanemab reduced markers of amyloid in early Alzheimer\'s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer\'s disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 29 Nov 2022; epub ahead of print</small></div>
van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, ... Kramer LD, Iwatsubo T
N Engl J Med: 29 Nov 2022; epub ahead of print | PMID: 36449413
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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>Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin\'s Lymphoma.</h4><i>Castellino SM, Pei Q, Parsons SK, Hodgson D, ... Keller FG, Kelly KM</i><br /><b>Background</b><br />In adults with advanced-stage Hodgkin\'s lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin\'s lymphoma is unclear.<br /><b>Methods</b><br />We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin\'s lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed.<br /><b>Results</b><br />Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.<br /><b>Conclusions</b><br />The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Nov 2022; 387:1649-1660</small></div>
Castellino SM, Pei Q, Parsons SK, Hodgson D, ... Keller FG, Kelly KM
N Engl J Med: 03 Nov 2022; 387:1649-1660 | PMID: 36322844
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<div><h4>Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease.</h4><i>Bhandari S, Mehta S, Khwaja A, Cleland JGF, ... Cockwell P, STOP ACEi Trial Investigators</i><br /><b>Background</b><br />Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline.<br /><b>Methods</b><br />In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m<sup>2</sup> of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.<br /><b>Results</b><br />At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m<sup>2</sup> in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m<sup>2</sup> in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P = 0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22).<br /><b>Conclusions</b><br />Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISTRCTN number, 62869767.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Nov 2022; epub ahead of print</small></div>
Bhandari S, Mehta S, Khwaja A, Cleland JGF, ... Cockwell P, STOP ACEi Trial Investigators
N Engl J Med: 03 Nov 2022; epub ahead of print | PMID: 36326117
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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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This program is still in alpha version.