Topic: Journal Club Selection

Abstract
<div><h4>Infective Endocarditis After Transcatheter Aortic Valve Replacement: JACC State-of-the-Art Review.</h4><i>Del Val D, Panagides V, Mestres CA, Miró JM, Rodés-Cabau J</i><br /><AbstractText>Infective endocarditis (IE) is a rare but serious complication following transcatheter aortic valve replacement (TAVR). Despite substantial improvements in the TAVR procedure (less invasive) and its expansion to younger and healthier patients, the incidence of IE after TAVR remains stable, with incidence rates similar to those reported after surgical aortic valve replacement. Although IE after TAVR is recognized as a subtype of prosthetic valve endocarditis, this condition represents a particularly challenging scenario given its unique clinical and microbiological profile, the high incidence of IE-related complications, the uncertain role of cardiac surgery, and the dismal prognosis in most patients with TAVR-IE. The number of TAVR procedures is expected to grow exponentially in the coming years, increasing the number of patients at risk of developing this life-threatening complication. Therefore, a detailed understanding of this disease and its complications will be essential to improve clinical outcomes.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 31 Jan 2023; 81:394-412</small></div>
Del Val D, Panagides V, Mestres CA, Miró JM, Rodés-Cabau J
J Am Coll Cardiol: 31 Jan 2023; 81:394-412 | PMID: 36697140
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<div><h4>Worsening Heart Failure: Nomenclature, Epidemiology, and Future Directions: JACC Review Topic of the Week.</h4><i>Greene SJ, Bauersachs J, Brugts JJ, Ezekowitz JA, ... Zieroth S, Butler J</i><br /><AbstractText>Heart failure (HF) is a progressive disease characterized by variable durations of symptomatic stability often punctuated by episodes of worsening despite continued therapy. These periods of clinical worsening are increasingly recognized as a distinct phase in the history of HF, termed worsening HF (WHF). The definition of WHF continues to evolve from a historical focus solely on hospitalization to now include nonhospitalization events (eg, need for intravenous diuretic therapy in the emergency or outpatient setting). Most HF clinical trials to date have had HF hospitalization and death as primary endpoints, and only recently, some studies have included other WHF events regardless of location of care. This article reviews the evolution of the WHF definition, highlights the importance of considering the onset of WHF as an event that marks a new phase of HF, summarizes the latest clinical trials investigating novel therapies, and outlines unmet needs regarding identification and treatment of WHF.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 31 Jan 2023; 81:413-424</small></div>
Greene SJ, Bauersachs J, Brugts JJ, Ezekowitz JA, ... Zieroth S, Butler J
J Am Coll Cardiol: 31 Jan 2023; 81:413-424 | PMID: 36697141
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<div><h4>Performance of 8- vs 16 ECG-gated reconstructions in assessing myocardial function using Rubidium-82 myocardial perfusion imaging: Findings in a young, healthy population.</h4><i>Lassen ML, Wissenberg M, Byrne C, Kjaer A, Hasbak P</i><br /><b>Background</b><br />Current imaging guidelines recommend using at least 16 ECG gates when performing MUGA and cardiac SPECT to assess left ventricular ejection fraction (LVEF). However, for Rubidium-82 (<sup>82</sup>Rb) PET, 8 ECG-gated reconstructions have been a mainstay. This study investigated the implications of quantitative assessments when employing 16 gate, instead of 8 gate, reconstructions for <sup>82</sup>Rb myocardial perfusion imaging (MPI).<br /><b>Methods</b><br />The study comprised 25 healthy volunteers (median age 23 years) who underwent repeat MPI sessions employing <sup>82</sup>Rb PET/CT. We report LVEF, its reserve (stress LVEF - rest LVEF), and their repeatability measures (RMS method) obtained for 8- and 16 ECG-gated reconstructions.<br /><b>Results</b><br />Similar LVEF and LVEF reserve estimates were found for the 8- and 16-gated reconstructions ([%] LVEF (8/16 gates): rest = 61 ± 6/64 ± 6, stress = 68 ± 7/71 ± 6, LVEF reserve (8/16 gates): 8 ± 3/6 ± 4, and all P ≥ 0.13). Similar test-retest repeatability measures were observed for rest and stress LVEF and their reserves [LVEF (8/16 gates); Rest = 4.5/4.6 (P = 0.81), Stress = 3.5/3.2 (P = 0.33), LVEF reserve = 46.7/49.3 (P = 0.13)].<br /><b>Conclusion</b><br />In healthy subjects, 8 and 16 ECG gates can be used interchangeably if only volumetric assessments are desired. However, if filling and emptying rates are of interest, a minimum of 16 ECG gates should be employed.<br /><br />© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.<br /><br /><small>J Nucl Cardiol: 28 Jan 2023; epub ahead of print</small></div>
Lassen ML, Wissenberg M, Byrne C, Kjaer A, Hasbak P
J Nucl Cardiol: 28 Jan 2023; epub ahead of print | PMID: 36708439
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<div><h4>Long-term outcomes of perioperative myocardial infarction/injury after non-cardiac surgery.</h4><i>Puelacher C, Gualandro DM, Glarner N, Lurati Buse G, ... Mueller C, BASEL-PMI Investigators </i><br /><b>Aims</b><br />Perioperative myocardial infarction/injury (PMI) following non-cardiac surgery is a frequent cardiac complication. Better understanding of the underlying aetiologies and outcomes is urgently needed.<br /><b>Methods and results</b><br />Aetiologies of PMIs detected within an active surveillance and response programme were centrally adjudicated by two independent physicians based on all information obtained during clinically indicated PMI work-up including cardiac imaging among consecutive high-risk patients undergoing major non-cardiac surgery in a prospective multicentre study. PMI aetiologies were hierarchically classified into \'extra-cardiac\' if caused by a primarily extra-cardiac disease such as severe sepsis or pulmonary embolism; and \'cardiac\', further subtyped into type 1 myocardial infarction (T1MI), tachyarrhythmia, acute heart failure (AHF), or likely type 2 myocardial infarction (lT2MI). Major adverse cardiac events (MACEs) including acute myocardial infarction, AHF (both only from day 3 to avoid inclusion bias), life-threatening arrhythmia, and cardiovascular death as well as all-cause death were assessed during 1-year follow-up. Among 7754 patients (age 45-98 years, 45% women), PMI occurred in 1016 (13.1%). At least one MACE occurred in 684/7754 patients (8.8%) and 818/7754 patients died (10.5%) within 1 year. Outcomes differed starkly according to aetiology: in patients with extra-cardiac PMI, T1MI, tachyarrhythmia, AHF, and lT2MI 51%, 41%, 57%, 64%, and 25% had MACE, and 38%, 27%, 40%, 49%, and 17% patients died within 1 year, respectively, compared to 7% and 9% in patients without PMI. These associations persisted in multivariable analysis.<br /><b>Conclusion</b><br />At 1 year, most PMI aetiologies have unacceptably high rates of MACE and all-cause death, highlighting the urgent need for more intensive treatments.<br /><b>Study registration</b><br />https://clinicaltrials.gov/ct2/show/NCT02573532.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 27 Jan 2023; epub ahead of print</small></div>
Puelacher C, Gualandro DM, Glarner N, Lurati Buse G, ... Mueller C, BASEL-PMI Investigators
Eur Heart J: 27 Jan 2023; epub ahead of print | PMID: 36705050
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<div><h4>Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity.</h4><i>Landstrom AP, Yang Q, Sun B, Perelli RM, ... Kim JJ, Wehrens XHT</i><br /><b>Background</b><br />Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca<sup>2+</sup>) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca<sup>2+</sup> clock is critical to understanding nodal arrhythmias. We previously demonstrated a role for Jph2 (junctophilin 2) in regulating Ca<sup>2+</sup>-signaling through inhibition of RyR2 (ryanodine receptor 2) Ca<sup>2+</sup> leak in cardiac myocytes; however, its role in pacemaker function and nodal arrhythmias remains unknown. We sought to determine whether nodal Jph2 expression silencing causes increased sinoatrial and atrioventricular nodal cell automaticity due to aberrant RyR2 Ca<sup>2+</sup> leak.<br /><b>Methods</b><br />A tamoxifen-inducible, nodal tissue-specific, knockdown mouse of Jph2 was achieved using a Cre-recombinase-triggered short RNA hairpin directed against Jph2 (Hcn4:shJph2). In vivo cardiac rhythm was monitored by surface ECG, implantable cardiac telemetry, and intracardiac electrophysiology studies. Intracellular Ca<sup>2+</sup> imaging was performed using confocal-based line scans of isolated nodal cells loaded with fluorescent Ca<sup>2+</sup> reporter Cal-520. Whole cell patch clamp was conducted on isolated nodal cells to determine action potential kinetics and sodium-calcium exchanger function.<br /><b>Results</b><br />Hcn4:shJph2 mice demonstrated a 40% reduction in nodal Jph2 expression, resting sinus tachycardia, and impaired heart rate response to pharmacologic stress. In vivo intracardiac electrophysiology studies and ex vivo optical mapping demonstrated accelerated junctional rhythm originating from the atrioventricular node. Hcn4:shJph2 nodal cells demonstrated increased and irregular Ca<sup>2+</sup> transient generation with increased Ca<sup>2+</sup> spark frequency and Ca<sup>2+</sup> leak from the sarcoplasmic reticulum. This was associated with increased nodal cell AP firing rate, faster diastolic repolarization rate, and reduced sodium-calcium exchanger activity during repolarized states compared to control. Phenome-wide association studies of the <i>JPH2</i> locus identified an association with sinoatrial nodal disease and atrioventricular nodal block.<br /><b>Conclusions</b><br />Nodal-specific Jph2 knockdown causes increased nodal automaticity through increased Ca<sup>2+</sup> leak from intracellular stores. Dysregulated intracellular Ca<sup>2+</sup> underlies nodal arrhythmogenesis in this mouse model.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 27 Jan 2023:e010858; epub ahead of print</small></div>
Landstrom AP, Yang Q, Sun B, Perelli RM, ... Kim JJ, Wehrens XHT
Circ Arrhythm Electrophysiol: 27 Jan 2023:e010858; epub ahead of print | PMID: 36706317
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<div><h4>Meta-Analysis on the Safety and Efficacy of Transradial Approach in Chronic Total Occlusion Percutaneous Coronary Intervention.</h4><i>Nguyen DV, Nguyen QN, Pham HM, Le TX, Nguyen HTT</i><br /><AbstractText>The aim of this study was to compare the efficacy and safety of transradial approach (TRA) in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) with the efficacy and safety of transfemoral approach (TFA). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies (OS) reporting the outcomes of TRA versus TFA in CTO PCI. The primary end point was procedural success. Secondary end points included access-site complications, in-hospital adverse events, procedural efficacy outcomes, and 30-day all-cause mortality. A total of 28,754 CTO PCI cases from 19 studies were included (2 RCTs and 17 OS). The pooled mean J-CTO score is 2.3. The main analysis showed a trend toward a higher success rate for TRA (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.00 to 1.38), but this was not the case in the secondary analysis, which included only RCTs and OS with moderate risk of bias (OR 0.99, 95% CI 0.81 to 1.22). TRA was associated with significant reductions in access-site complications (OR 0.33, 95% CI 0.24 to 0.45) and major bleeding (OR 0.34, 95% CI 0.20 to 0.59), and a similar risk of other in-hospital adverse events and 30-day mortality (p >0.05) to that of TFA. Moreover, there was less fluoroscopy time (minutes) and contrast volume use (ml) in the transradial CTO PCI (mean difference: -6.19 [-10.98 to -1.40] and -22.14[-34.56 to -9.72], respectively). In conclusion, the transradial PCI in appropriate CTO lesions was associated with a lower incidence of access-site complications/major bleeding than was TFA and a similar other periprocedural complications rate, without compromising procedural success.</AbstractText><br /><br />Copyright © 2023 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 27 Jan 2023; epub ahead of print</small></div>
Nguyen DV, Nguyen QN, Pham HM, Le TX, Nguyen HTT
Am J Cardiol: 27 Jan 2023; epub ahead of print | PMID: 36710142
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<div><h4>Substance Use Disorders Are Prevalent in Adults With Congenital Heart Disease and Are Associated With Increased Healthcare Use.</h4><i>Shalen EF, McGrath LB, Bhamidipati CM, Garcia IC, ... Broberg CS, Khan AM</i><br /><AbstractText>Adults with congenital heart disease (CHD) represent a heterogeneous group with significant long-term health risks. Previous studies have demonstrated a high prevalence of psychiatric disorders among adults with CHD; however, little is known about the frequency of co-morbid substance use disorders (SUDs) in patients with CHD. The Oregon All Payer All Claims (APAC) database for the years 2014 to 2017 was queried for adults aged 18 to 65 years with International Classification of Diseases, Ninth or Tenth Revision codes consistent with CHD. Alcohol and substance use were identified by International Classification of Diseases codes for use or dependence and classified in mutually exclusive categories of none, alcohol only, and other drugs (with or without alcohol). Descriptive statistics were used to characterize prevalence and chi-square tests were used to test for associations between variables. A total of 12,366 adults with CHD were identified. The prevalence of substance use was 15.7%. The prevalence of isolated alcohol use was 3.9%. A total of 19% of patients used tobacco. Insurance type, presence of a concurrent mental health diagnosis, and age were associated with substance use, whereas CHD complexity was not. Cardiovascular co-morbidities were more common in patients with reported substance use. Inpatient and emergency care use were higher in those with SUD. In conclusion, this study of substance and alcohol use among adults with CHD demonstrates high rates of co-morbid SUD, particularly among patients with mental health disorders and Medicaid insurance, associated with increased healthcare utilization. We identify a population in need of targeted interventions to improve long-term health.</AbstractText><br /><br />Copyright © 2023 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 27 Jan 2023; 192:24-30</small></div>
Shalen EF, McGrath LB, Bhamidipati CM, Garcia IC, ... Broberg CS, Khan AM
Am J Cardiol: 27 Jan 2023; 192:24-30 | PMID: 36709526
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<div><h4>In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity.</h4><i>Cao Y, Zhang X, Akerberg BN, Yuan H, ... Kelly DP, Pu WT</i><br /><b>Background</b><br />Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined.<br /><b>Methods</b><br />We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus-mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-highly integrative chromatin immunoprecipitation on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP-mediated inactivation of ERRα and ERRγ in cardiomyocytes.<br /><b>Results</b><br />We identified 152 832 and 54 824 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus-mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27-anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs.<br /><b>Conclusions</b><br />We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi-transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.<br /><br /><br /><br /><small>Circulation: 27 Jan 2023; epub ahead of print</small></div>
Cao Y, Zhang X, Akerberg BN, Yuan H, ... Kelly DP, Pu WT
Circulation: 27 Jan 2023; epub ahead of print | PMID: 36705030
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<div><h4>Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials.</h4><i>Friedman DJ, Al-Khatib SM, Dalgaard F, Fudim M, ... Inoue LYT, Sanders GD</i><br /><b>Background</b><br />Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups.<br /><b>Methods</b><br />The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death.<br /><b>Results</b><br />Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; <i>P</i><sub>interaction</sub> <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death.<br /><b>Conclusions</b><br />CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single \"non-LBBB\" category when selecting patients for CRT should be reconsidered.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.<br /><br /><br /><br /><small>Circulation: 26 Jan 2023; epub ahead of print</small></div>
Friedman DJ, Al-Khatib SM, Dalgaard F, Fudim M, ... Inoue LYT, Sanders GD
Circulation: 26 Jan 2023; epub ahead of print | PMID: 36700426
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<div><h4>Potential mechanisms linking high-volume exercise with coronary artery calcification.</h4><i>Zambrano A, Tintut Y, Demer LL, Hsu JJ</i><br /><AbstractText>Recent studies have found an association between high volumes of physical activity and increased levels of coronary artery calcification (CAC) among older male endurance athletes, yet the underlying mechanisms have remained largely elusive. Potential mechanisms include greater exposure to inflammatory cytokines, reactive oxygen species and oxidised low-density lipoproteins, as acute strenuous physical activity has been found to enhance their systemic release. Other possibilities include post-exercise elevations in circulating parathyroid hormone, which can modify the amount and morphology of calcific plaque, and long-term exposure to non-laminar blood flow within the coronary arteries during vigorous physical activity, particularly in individuals with pre-existing atherosclerosis. Further, although the association has only been identified in men, the role of testosterone in this process remains unclear. This brief review discusses the association between high-volume endurance exercise and CAC in older men, elaborates on the potential mechanisms underlying the increased calcification, and provides clinical implications and recommendations for those at risk.</AbstractText><br /><br />© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>Heart: 26 Jan 2023; epub ahead of print</small></div>
Zambrano A, Tintut Y, Demer LL, Hsu JJ
Heart: 26 Jan 2023; epub ahead of print | PMID: 36702539
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<div><h4>Inhibition of Intimal Thickening By PRH (Proline-Rich Homeodomain) in Mice.</h4><i>Reolizo LM, Williams H, Wadey K, Frankow A, ... Johnson J, George SJ</i><br /><b>Background</b><br />Late vein graft failure is caused by intimal thickening resulting from endothelial cell (EC) damage and inflammation which promotes vascular smooth muscle cell (VSMC) dedifferentiation, migration, and proliferation. Nonphosphorylatable PRH (proline-rich homeodomain) S163C:S177C offers enhanced stability and sustained antimitotic effect. Therefore, we investigated whether adenovirus-delivered PRH S163C:S177C protein attenuates intimal thickening via VSMC phenotype modification without detrimental effects on ECs.<br /><b>Methods</b><br />PRH S163C:S177C was expressed in vitro (human saphenous vein-VSMCs and human saphenous vein-ECs) and in vivo (ligated mouse carotid arteries) by adenoviruses. Proliferation, migration, and apoptosis were quantified and phenotype was assessed using Western blotting for contractile filament proteins and collagen gel contraction. EC inflammation was quantified using VCAM (vascular cell adhesion protein)-1, ICAM (intercellular adhesion molecule)-1, interleukin-6, and monocyte chemotactic factor-1 measurement and monocyte adhesion. Next Generation Sequencing was utilized to identify novel downstream mediators of PRH action and these and intimal thickening were investigated in vivo.<br /><b>Results</b><br />PRH S163C:S177C inhibited proliferation, migration, and apoptosis and promoted contractile phenotype (enhanced contractile filament proteins and collagen gel contraction) compared with virus control in human saphenous vein-VSMCs. PRH S163C:S177C expression in human saphenous vein-ECs significantly reduced apoptosis, without affecting cell proliferation and migration, while reducing TNF (tumor necrosis factor)-α-induced VCAM-1 and ICAM-1 and monocyte adhesion and suppressing interleukin-6 and monocyte chemotactic factor-1 protein levels. PRH S163C:S177C expression in ligated murine carotid arteries significantly impaired carotid artery ligation-induced neointimal proliferation and thickening without reducing endothelial coverage. Next Generation Sequencing revealed STAT-1 (signal transducer and activator of transcription 1) and HDAC-9 (histone deacetylase 9) as mediators of PRH action and was supported by in vitro and in vivo analyses.<br /><b>Conclusions</b><br />We observed PRH S163C:S177C attenuated VSMC proliferation, and migration and enhanced VSMC differentiation at least in part via STAT-1 and HDAC-9 signaling while promoting endothelial repair and anti-inflammatory properties. These findings highlight the potential for PRH S163C:S177C to preserve endothelial function whilst suppressing intimal thickening, and reducing late vein graft failure.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print</small></div>
Reolizo LM, Williams H, Wadey K, Frankow A, ... Johnson J, George SJ
Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print | PMID: 36700427
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<div><h4>Endothelial Damage Arising From High Salt Hypertension Is Elucidated by Vascular Bed Systematic Profiling.</h4><i>Vinaiphat A, Pazhanchamy K, JebaMercy G, Ngan SC, ... McCarthy NE, Sze SK</i><br /><b>Background</b><br />Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach.<br /><b>Methods</b><br />We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation.<br /><b>Results</b><br />Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart.<br /><b>Conclusions</b><br />These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print</small></div>
Vinaiphat A, Pazhanchamy K, JebaMercy G, Ngan SC, ... McCarthy NE, Sze SK
Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print | PMID: 36700429
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<div><h4>Improving representativeness in trials: a call to action from the Global Cardiovascular Clinical Trialists Forum.</h4><i>Filbey L, Zhu JW, D\'Angelo F, Thabane L, ... Zannad F, Van Spall HGC</i><br /><AbstractText>Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities.</AbstractText><br /><br />© The Author(s) 2023. 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: 25 Jan 2023; epub ahead of print</small></div>
Filbey L, Zhu JW, D'Angelo F, Thabane L, ... Zannad F, Van Spall HGC
Eur Heart J: 25 Jan 2023; epub ahead of print | PMID: 36702610
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<div><h4>Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association.</h4><i>Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, ... Martin SS, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee</i><br /><b>Background</b><br />The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).<br /><b>Methods</b><br />The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year\'s worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year\'s edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains.<br /><b>Results</b><br />Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.<br /><b>Conclusions</b><br />The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.<br /><br /><br /><br /><small>Circulation: 25 Jan 2023; epub ahead of print</small></div>
Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, ... Martin SS, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
Circulation: 25 Jan 2023; epub ahead of print | PMID: 36695182
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<div><h4>Right ventricular free wall strain and effect of defibrillator implantation in patients with non-ischemic systolic heart failure.</h4><i>Elming MB, Jensen DH, Winsløw UC, Risum N, ... Køber L, Thune JJ</i><br /><b>Aims</b><br />Patients with non-ischemic systolic heart failure have an increased risk of malignant ventricular arrhythmias and sudden cardiovascular death. Since the risk is less pronounced than for patients with ischemic cause of heart failure more discriminating tools are needed to identify patients most likely to benefit from implantable cardioverter-defibrillator (ICD) implantation. Right ventricular (RV) dysfunction is associated with a worse prognosis, but whether RV free wall strain (RV-FWS) measured with echocardiography can identify the patients most likely to benefit from ICD implantation is not known.<br /><b>Methods</b><br />In this extended follow-up analysis of the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial, RV-FWS was measured with echocardiography in 445 patients prior to randomization. RV dysfunction was defined as RV-FWS > -20%. The primary endpoint was all-cause mortality.<br /><b>Results</b><br />Median RV-FWS was -18% (quartiles: -23% to -14%), and RV dysfunction was measured in 255 (57%) patients. During a median follow-up of 5.7 years, 170 (38%) patients died. There was a statistically significant interaction between RV dysfunction and the effect of ICD implantation (p=0.003), also after adjusting for known cardiovascular risk factors (p=0.01). ICD implantation significantly reduced all-cause mortality in patients with RV dysfunction, HR 0.54 (95% CI 0.36-0.80), p = 0.002, but not in patients with normal RV function, HR 1.34 (95% CI 0.84-2.12), p = 0.22.<br /><b>Conclusions</b><br />In patients with non-ischemic systolic heart failure, RV dysfunction on echocardiography was associated with greater effect of ICD implantation and could be used to select patients with benefit from ICD treatment.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Card Fail: 25 Jan 2023; epub ahead of print</small></div>
Elming MB, Jensen DH, Winsløw UC, Risum N, ... Køber L, Thune JJ
J Card Fail: 25 Jan 2023; epub ahead of print | PMID: 36708755
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<div><h4>Hemodynamic Profiling and Prognosis in Cardiac Amyloidosis.</h4><i>Martens P, Bhattacharya S, Longinow J, Ives L, ... Hanna M, Tang WHW</i><br /><b>Background</b><br />Little information is available on the prognostic relevance of cardiac hemodynamic cutoffs in cardiac amyloidosis (CA) and its subtypes.<br /><b>Methods</b><br />Consecutive patients diagnose with light chain-CA or transthyretin CA undergoing right heart catheterization were analyzed. Prognostic relevance of classic hemodynamic cutoffs of cardiac index (CI <2.2 L/min per m<sup>2</sup>), pulmonary capillary wedge pressure (>18 mm Hg), right atrial pressure (>8 mm Hg), and mean pulmonary artery pressure (≥25 mm Hg or pulmonary hypertension) with the combined end point of cardiac transplant/left ventricular assist device and death and heart failure admissions separately was assessed.<br /><b>Results</b><br />A total of 469 CA patients underwent right heart catheterization (light chain CA=42% and transthyretin CA=52%) of whom 69%, 64%, and 79% had elevated right atrial pressure, pulmonary capillary wedge pressure, and pulmonary hypertension, respectively. The classic hemodynamic cutoffs for right atrial pressure (hazard ratio, 1.26 [0.98-1.62]) and mean pulmonary artery pressure (hazard ratio, 1.28 [0.96-1.71]) did not identify patients at higher risk for adverse outcome; however, cutoffs of 14 mm Hg for right atrial pressure (hazard ratio, 1.59 [1.26-2.00]) and 35 mm Hg for mean pulmonary artery pressure (hazard ratio, 1.30 [1.01-1.66]) performed better to detect worse outcome (<i>P</i><0.05 for both). Reduced CI occurred in 55% of patients and was the strongest variable associated with the risk for cardiac transplant/left ventricular assist device and death, heart failure admissions, and reduced functional capacity. Reduced CI independently predicted risk on top of the Mayo-score in light chain CA and National Amyloid Center score in transthyretin CA (<i>P</i><0.05 for both). Patients with light chain CA had higher pulmonary capillary wedge pressure and lower stroke volume index but maintained CI through a higher heart rate.<br /><b>Conclusions</b><br />Hemodynamic variables are grossly abnormal in CA, but elevated filling pressures are prognostic at significantly higher threshold values than classic cutoff values. CI is the hemodynamic variable most strongly associated with outcome and functionality in CA.<br /><br /><br /><br /><small>Circ Heart Fail: 25 Jan 2023:e010078; epub ahead of print</small></div>
Martens P, Bhattacharya S, Longinow J, Ives L, ... Hanna M, Tang WHW
Circ Heart Fail: 25 Jan 2023:e010078; epub ahead of print | PMID: 36695180
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<div><h4>Interleukin-33 Mediates Cardiomyopathy After Acute Kidney Injury by Signaling to Cardiomyocytes.</h4><i>Florens N, Kasam RK, Rudman-Melnick V, Lin SC, Prasad V, Molkentin JD</i><br /><b>Background</b><br />Acute kidney injury (AKI) is a short-term life-threatening condition that, if survived, can lead to renal insufficiency and development of chronic kidney disease. The pathogenesis of AKI and chronic kidney disease involves direct effects on the heart and the development of hypertrophy and cardiomyopathy.<br /><b>Methods</b><br />We used mouse models of ischemia/reperfusion AKI and unilateral ureteral obstruction to investigate the role of IL-33 (interleukin-33) and its receptor-encoding gene <i>Il1rl1</i> (also called ST2L [suppression of tumorigenicity 2]) in cardiac remodeling after AKI. Mice with cell type-specific genetic disruption of the IL-33/ST2L axis were used, and IL-33 monoclonal antibody, adeno-associated virus encoding IL-33 or ST2L, and recombinant IL-33, as well.<br /><b>Results</b><br />Mice deficient in <i>Il33</i> were refractory to cardiomyopathy associated with 2 models of kidney injury. Treatment of mice with monoclonal IL-33 antibody also protected the heart after AKI. Moreover, overexpression of IL-33 or injection of recombinant IL-33 induced cardiac hypertrophy or cardiomyopathy, or both, but not in mice lacking <i>Il1rl1</i>. AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte-specific deletion of <i>Il1rl1</i> but not in endothelial cell- or fibroblast-specific deletion of <i>Il1rl1</i>. Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy.<br /><b>Conclusions</b><br />These results indicate that IL-33 released from the kidney during AKI underlies cardiorenal syndrome by directly signaling to cardiac myocytes, suggesting that antagonism of IL-33/ST2 axis would be cardioprotective in patients with kidney disease.<br /><br /><br /><br /><small>Circulation: 25 Jan 2023; epub ahead of print</small></div>
Florens N, Kasam RK, Rudman-Melnick V, Lin SC, Prasad V, Molkentin JD
Circulation: 25 Jan 2023; epub ahead of print | PMID: 36695175
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