Topic: Journal Club Selection

Abstract

Novel plasma biomarkers predicting biventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

Akdis D, Chen L, Saguner AM, Zhang N, ... Song J, Duru F
Background
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular involvement in ARVC may lead to heart failure. This study aimed to investigate the role of plasma biomarkers soluble (s)ST2, Galectin-3 (Gal-3) and GDF-15 in predicting biventricular involvement and adverse outcomes in ARVC.
Methods and results
ARVC patients from 2 independent cohorts, were studied. The Bejing (Chinese) cohort (n = 108) was the discovery cohort, whereas the Zurich (Swiss) cohort (n = 47) served as validation. All patients had a definite ARVC diagnosis at time of blood withdrawal. Biomarkers were independently correlated with NT-proBNP and left ventricular (LV)-function. ARVC patients with LV involvement had higher levels of sST2 and GDF-15 as compared to controls and patients with isolated right ventricle (RV) involvement. sST2 and GDF-15 were significantly correlated with late gadolinium enhancement in CMR and with adverse heart failure outcomes. Gal-3 was elevated in ARVC patients with and without LV involvement. The combined use of the three biomarkers (sST2, GDF-15 and NT-proBNP) showed the best performance in predicting LV involvement in both cohorts. Plasma drawn from the coronary arteries and coronary sinus indicated a transmyocardial elevation of sST2, but no transmyocardial gradient of GDF-15. After heart transplantation, both sST2 and GDF-15 returned to near-normal levels.
Conclusion
Our study showed that sST2 and GDF-15 may predict biventricular involvement in ARVC. The combined use of sST2, GDF-15 and NT-proBNP showed the best prediction of biventricular involvement in ARVC.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Am Heart J: 30 Jan 2022; 244:66-76
Akdis D, Chen L, Saguner AM, Zhang N, ... Song J, Duru F
Am Heart J: 30 Jan 2022; 244:66-76 | PMID: 34756894
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Impact:
Abstract

Management of Atrial Fibrillation in Patients 75 Years and Older: JACC State-of-the-Art Review.

Volgman AS, Nair G, Lyubarova R, Merchant FM, ... Kirkpatrick JN, Benjamin EJ
The prevalence of atrial fibrillation (AF) is increasing as the population ages. AF treatment-related complications also increase markedly in older adults (defined as ≥75 years of age for this review). The older AF population has a high risk of stroke, bleeding, and death. Syncope and fall-related injuries are the most common reasons for nonprescription of oral anticoagulation (OAC), and are more common in older adults when OACs are used with antiarrhythmic drugs. Digoxin may be useful for rate control, but associations with increased mortality limit its use. Beyond rate and rhythm control considerations, stroke prophylaxis is critical to AF management, and the benefits of direct OACs, compared with warfarin, extend to older adults. Invasive procedures such as AF catheter ablation, pacemaker implantation/atrioventricular junction ablation, and left atrial appendage occlusion may be useful in appropriately selected cases. However, older adults have generally been under-represented in clinical trials.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Jan 2022; 79:166-179
Volgman AS, Nair G, Lyubarova R, Merchant FM, ... Kirkpatrick JN, Benjamin EJ
J Am Coll Cardiol: 17 Jan 2022; 79:166-179 | PMID: 35027110
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Impact:
Abstract

Risk-Adjusted, 30-Day Home Time After Transcatheter Aortic Valve Replacement as a Hospital-Level Performance Metric.

Mentias A, Keshvani N, Desai MY, Kumbhani DJ, ... Girotra S, Pandey A
Background
Patient-centric measures of hospital performance for transcatheter aortic valve replacement (TAVR) are needed.
Objectives
This study evaluated 30-day, risk-adjusted home time as a hospital performance metric for patients who underwent TAVR.
Methods
This study identified 160,792 Medicare beneficiaries who underwent elective TAVR from 2015 to 2019. Home time was calculated for each patient as the number of days alive and spent outside the hospital, skilled nursing facility (SNF), and long-term acute care facility for 30 days after the TAVR procedure date. Correlations between risk-adjusted, 30-day home time and other metrics (30-day, risk-adjusted readmission rate [RSRR], 30-day, risk-adjusted mortality rate [RSMR], and annual TAVR volume) were estimated using Pearson\'s correlation. Meaningful upward or downward reclassification (≥2 quartile ranks) in hospital performance based on quartiles of risk-adjusted, 30-day home time compared with quartiles of other measures were assessed.
Results
Median risk-adjusted, 30-day home time was 27.4 days (interquartile range [IQR]: 26.3-28.5 days). The largest proportion of days lost from 30-day home time was hospital stay after TAVR and SNF stay. An inverse correlation was observed between hospital-level, risk-adjusted, 30-day home time and 30-day RSRR (r = -0.465; P < 0.001) and 30-day RSMR (r = -0.3996; P < 0.001). The use of the 30-day, risk-adjusted home time was associated with reclassification in hospital performance rank hospitals compared with other metrics (9.1% up-classified, 11.2% down-classified vs RSRR; 9.1% up-classified, 10.3% down-classified vs RSMR; and 20.1% up-classified, 19.3% down-classified vs annual TAVR volume).
Conclusions
Risk-adjusted, 30-day home time represents a novel patient-centered performance metric for TAVR hospitals that may provide a complimentary assessment to currently used metrics.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Jan 2022; 79:132-144
Mentias A, Keshvani N, Desai MY, Kumbhani DJ, ... Girotra S, Pandey A
J Am Coll Cardiol: 17 Jan 2022; 79:132-144 | PMID: 35027108
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Impact:
Abstract

Genes that Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts.

Aguado BA, Walker CJ, Grim JC, Schroeder ME, ... Leinwand LA, Anseth KS
Background: Aortic valve stenosis (AVS) is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain under explored.
Methods:
Hydrogel scaffolds were designed to recapitulate key aspects of the valve tissue microenvironment and serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to pro-fibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA-sequencing was used to define pathways involved in driving sex-dependent activation. Interventions using small molecule inhibitors and small interfering RNA (siRNA) transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors.
Results:
In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker, alpha-smooth muscle actin (α-SMA), compared to male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-SMA stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase (RhoA/ROCK) signaling as a potential driver of this sex-dependent myofibroblast activation. Further, we found that genes that escape X-chromosome inactivation, such as BMX and STS (encoding for Bmx non-receptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation via RhoA/ROCK signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation via RhoA/ROCK signaling. Conclusions: Together, in vivo and in vitro results confirm sex-dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent AVS progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of AVS and help guide sex-based precision therapies.




Circulation: 09 Jan 2022; epub ahead of print
Aguado BA, Walker CJ, Grim JC, Schroeder ME, ... Leinwand LA, Anseth KS
Circulation: 09 Jan 2022; epub ahead of print | PMID: 35000411
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Impact:
Abstract

ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis.

Cheng P, Wirka RC, Clarke LS, Zhao Q, ... Kundaje A, Quertermous T
Background: Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in the atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci.
Methods:
We employed CRISPR-Cas 9 genome and epigenome editing to identify the causal gene and cell(s) for a complex CAD GWAS signal at 2q22.3. Subsequently, single-cell epigenetic and transcriptomic profiling in murine models and human coronary artery smooth muscle cells were employed to understand the cellular and molecular mechanism by which this CAD risk gene exerts its function.
Results:
CRISPR-Cas 9 genome and epigenome editing showed that the complex CAD genetic signals within a genomic region at 2q22.3 lie within smooth muscle long-distance enhancers for ZEB2, a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. ZEB2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, thus altering the epigenetic trajectory of SMC transitions. SMC specific loss of ZEB2 resulted in an inability of transitioning SMCs to turn off contractile programing and take on a fibroblast-like phenotype, but accelerated the formation of chondromyocytes, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. Conclusions: These studies identify ZEB2 as a new CAD GWAS gene that affects features of plaque vulnerability through direct effects on the epigenome, providing a new thereapeutic approach to target vascular disease.




Circulation: 05 Jan 2022; epub ahead of print
Cheng P, Wirka RC, Clarke LS, Zhao Q, ... Kundaje A, Quertermous T
Circulation: 05 Jan 2022; epub ahead of print | PMID: 34990206
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Impact:
Abstract

Coronary Atherosclerotic Plaque Regression: JACC State-of-the-Art Review.

Dawson LP, Lum M, Nerleker N, Nicholls SJ, Layland J
Over the last 3 decades there have been substantial improvements in treatments aimed at reducing cardiovascular (CV) events. As these treatments have been developed, there have been parallel improvements in coronary imaging modalities that can assess plaque volumes and composition, using both invasive and noninvasive techniques. Plaque progression can be seen to precede CV events, and therefore, many studies have longitudinally assessed changes in plaque characteristics in response to various treatments, aiming to demonstrate plaque regression and improvements in high-risk features, with the rationale being that this will reduce CV events. In the past, decisions surrounding treatments for atherosclerosis have been informed by population-based risk scores for initiation in primary prevention and low-density lipoprotein cholesterol levels for titration in secondary prevention. If outcome data linking plaque regression to reduced CV events emerge, it may become possible to directly image plaque treatment response to guide management decisions.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Jan 2022; 79:66-82
Dawson LP, Lum M, Nerleker N, Nicholls SJ, Layland J
J Am Coll Cardiol: 03 Jan 2022; 79:66-82 | PMID: 34991791
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Impact:
Abstract

Safety of transoesophageal echocardiography during structural heart disease interventions under procedural sedation: a single-centre study.

Afzal S, Zeus T, Hofsähs T, Kuballa M, ... Kelm M, Hellhammer K
Aims
The aim of this study was to determine the incidence of transoesophageal echocardiography (TOE)-related adverse events (AEs) during structural heart disease (SHD) interventions and to identify potential risk factors.
Methods and results
We retrospectively analysed 898 consecutive patients undergoing TOE-guided SHD interventions under procedural sedation. TOE-related AEs were classified as bleeding complications, mechanical lesions, conversion to general anaesthesia with intubation, and the occurrence of pneumonia. A follow-up was conducted up to 3 months after the intervention. TOE-related AEs were observed in 5.3% of the patients (n = 48). The highest rate of AEs was observed in the percutaneous mitral valve repair (PMVR) group with 8.2% (n = 32), whereas 4.8% (n = 11) of the patients in the left atrial appendage group and 1.8% (n = 5) in the patent foramen ovale/atrial septal defect group developed a TOE-related AE (P = 0.001). The most frequent AE was pneumonia with an incidence of 2.6% (n = 26) in the total cohort. Bleeding events occurred in 1.8% (n = 16) of the patients, mostly in the PMVR group with 2.1% (n = 8). In the multivariate regression analysis, we found a lower haemoglobin {odds ratio (OR) [95% confidence interval (CI)]: 8.82 (0.68-0.98) P = 0.025} and an obstructive sleep apnoea syndrome (OSAS) [OR (95% CI): 2.51 (1.08-5.84) P = 0.033] to be associated with AE. Furthermore, AEs were related to procedural time [OR (95% CI): 1.01 (1.0-1.01) P = 0.056] and oral anticoagulation [OR (95% CI): 1.97 (0.9-4.3) P = 0.076] with borderline significance in the multivariate regression analysis. No persistent damages were observed.
Conclusion
TOE-related AEs during SHD interventions are clinically relevant. It was highest in patients undergoing PMVR. A lower baseline haemoglobin level and an OSAS were found to be associated with the occurrence of a TOE-related AE.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Imaging: 02 Jan 2022; epub ahead of print
Afzal S, Zeus T, Hofsähs T, Kuballa M, ... Kelm M, Hellhammer K
Eur Heart J Cardiovasc Imaging: 02 Jan 2022; epub ahead of print | PMID: 34977935
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Impact:
Abstract

The year in cardiovascular medicine 2021: heart failure and cardiomyopathies.

Bauersachs J, de Boer RA, Lindenfeld J, Bozkurt B
In the year 2021, the universal definition and classification of heart failure (HF) was published that defines HF as a clinical syndrome with symptoms and/or signs caused by a cardiac abnormality and corroborated by elevated natriuretic peptide levels or objective evidence of cardiogenic congestion. This definition and the classification of HF with reduced ejection fraction (HFrEF), mildly reduced, and HF with preserved ejection fraction (HFpEF) is consistent with the 2021 ESC Guidelines on HF. Among several other new recommendations, these guidelines give a Class I indication for the use of the sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin in HFrEF patients. As the first evidence-based treatment for HFpEF, in the EMPEROR-Preserved trial, empagliflozin reduced the composite endpoint of cardiovascular death and HF hospitalizations. Several reports in 2021 have provided novel and detailed analyses of device and medical therapy in HF, especially regarding sacubitril/valsartan, SGLT2 inhibitors, mineralocorticoid receptor antagonists, ferric carboxymaltose, soluble guanylate cyclase activators, and cardiac myosin activators. In patients hospitalized with COVID-19, acute HF and myocardial injury is quite frequent, whereas myocarditis and long-term damage to the heart are rather uncommon.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]

Eur Heart J: 02 Jan 2022; epub ahead of print
Bauersachs J, de Boer RA, Lindenfeld J, Bozkurt B
Eur Heart J: 02 Jan 2022; epub ahead of print | PMID: 34974611
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Abstract

Implantable cardiac defibrillator events in patients with arrhythmogenic right ventricular cardiomyopathy.

Woźniak O, Borowiec K, Konka M, Cicha-Mikołajczyk A, ... Poślednik K, Biernacka EK
Objective
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a risk of sudden cardiac death. Optimal risk stratification is still under debate. The main purpose of this long-term, single-centre observation was to analyse predictors of appropriate and inappropriate implantable cardioverter-defibrillator (ICD) interventions in the population of patients with ARVC with a high risk of life-threatening arrhythmias.
Methods
The study comprised 65 adult patients (median age 40 years, 48 men) with a definite diagnosis of ARVC who received ICD over a time span of 20 years in primary (40%) or secondary (60%) prevention of sudden cardiac death. The study endpoints were first appropriate and inappropriate ICD interventions (shock or antitachycardia pacing) after device implantation.
Results
During a median follow-up of 7.75 years after ICD implantation, nine patients died and six individuals underwent heart transplantation. Appropriate ICD interventions occurred in 43 patients (66.2%) and inappropriate ICD interventions in 18 patients (27.7%). Multivariable analysis using cause-specific hazard model identified three predictors of appropriate ICD interventions: right ventricle dysfunction (cause-specific HR 2.85, 95% CI 1.56 to 5.21, p<0.001), age <40 years at ICD implantation (cause-specific HR 2.37, 95% CI 1.13 to 4.94, p=0.022) and a history of sustained ventricular tachycardia (cause-specific HR 2.55, 95% CI 1.16 to 5.63, p=0.020). Predictors of inappropriate ICD therapy were not found. Complications related to ICD implantation occurred in 12 patients.
Conclusions
Right ventricle dysfunction, age <40 years and a history of sustained ventricular tachycardia were predictors of appropriate ICD interventions in patients with ARVC. The results may be used to improve risk stratification before ICD implantation.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Dec 2021; 108:22-28
Woźniak O, Borowiec K, Konka M, Cicha-Mikołajczyk A, ... Poślednik K, Biernacka EK
Heart: 30 Dec 2021; 108:22-28 | PMID: 33674353
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Abstract

Risk of left atrial appendage thrombus and stroke in patients with atrial fibrillation and mitral regurgitation.

Melduni R, Nkomo VT, Wysokinski W, Gersh BJ, ... Oh JK, Lee HC
Objective
To investigate the association of mitral regurgitation (MR) on thromboembolic risk of patients with non-valvular atrial fibrillation (NVAF) undergoing transoesophageal echocardiography (TEE)-guided cardioversion.
Methods
Data for consecutive patients who underwent TEE-guided cardioversion for NVAF between 2000 and 2012 were analysed. MR severity was assessed by Doppler echocardiography and classified as ≤mild, moderate or severe. Left atrial appendage emptying velocities were averaged for five consecutive cycles. Multivariable regression models were used to identify independent predictors of left atrial appendage thrombus (LAAT) and stroke.
Results
2950 patients (age, 69.3±12.2 years, 67% men) were analysed. 2173 (73.7%) had ≤mild MR; 631 (21.4%), moderate MR; and 146 (4.9%), severe MR. Patients with moderate (age, 72.4±10.7 years) and severe (age, 72.8±12.1 years) MR were older than those with ≤mild MR (age, 68.2±12.5 years). The prevalence of LAAT was 1.5% (n=43). CHA2DS2-VASc scores (≤mild MR, 3.0±1.6; moderate MR, 3.5±1.5; severe MR, 3.9±1.5; p<0.001) and heart failure frequency (≤mild MR, 38.4%; moderate MR, 48.0%; severe MR, 69.2%; p<0.001) were increasingly higher with greater MR severity. Multivariable logistic regression analysis showed no association of moderate MR (OR 0.77, 95% CI 0.38 to 1.56) or severe MR (OR 0.55, 95% CI 0.21 to 1.49) with LAAT. During a mean follow-up of 7.3±5.1 years (median 7.5, IQR, 2.7-10.9), 216 patients had an ischaemic stroke. Adjusted Cox regression analysis showed no significant association of moderate MR (HR 1.22, 95% CI 0.88 to 1.68) or severe MR (HR 0.73, 95% CI 0.31 to 1.46) with stroke.
Conclusions
Among patients with NVAF, the presence or severity of MR was not associated with a decreased risk of LAAT or stroke.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Dec 2021; 108:29-36
Melduni R, Nkomo VT, Wysokinski W, Gersh BJ, ... Oh JK, Lee HC
Heart: 30 Dec 2021; 108:29-36 | PMID: 33766985
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Impact:
Abstract

Determinants of outcomes following surgery for type A acute aortic dissection: the UK National Adult Cardiac Surgical Audit.

Benedetto U, Dimagli A, Kaura A, Sinha S, ... Tsang G, Akowuah E
Aims 
Operability of type A acute aortic dissections (TAAAD) is currently based on non-standardized decision-making process, and it lacks a disease-specific risk evaluation model that can predict mortality. We investigated patient, intraoperative data, surgeon, and centre-related variables for patients who underwent TAAAD in the UK.
Methods and results
We identified 4203 patients undergoing TAAAD surgery in the UK (2009-18), who were enrolled into the UK National Adult Cardiac Surgical Audit dataset. The primary outcome was operative mortality. A multivariable logistic regression analysis was performed with fast backward elimination of variables and the bootstrap-based optimism-correction was adopted to assess model performance. Variation related to hospital or surgeon effects were quantified by a generalized mixed linear model and risk-adjusted funnel plots by displaying the individual standardized mortality ratio against expected deaths. Final variables retained in the model were: age [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.02-1.03; P < 0.001]; malperfusion (OR 1.79, 95% CI 1.51-2.12; P < 0.001); left ventricular ejection fraction (moderate: OR 1.40, 95% CI 1.14-1.71; P = 0.001; poor: OR 2.83, 95% CI 1.90-4.21; P < 0.001); previous cardiac surgery (OR 2.29, 95% CI 1.71-3.07; P < 0.001); preoperative mechanical ventilation (OR 2.76, 95% CI 2.00-3.80; P < 0.001); preoperative resuscitation (OR 3.36, 95% CI 1.14-9.87; P = 0.028); and concomitant coronary artery bypass grafting (OR 2.29, 95% CI 1.86-2.83; P < 0.001). We found a significant inverse relationship between surgeons but not centre annual volume with outcomes.
Conclusions 
Patient characteristics, intraoperative factors, cardiac centre, and high-volume surgeons are strong determinants of outcomes following TAAAD surgery. These findings may help refining clinical decision-making, supporting patient counselling and be used by policy makers for quality assurance and service provision improvement.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 27 Dec 2021; 43:44-52
Benedetto U, Dimagli A, Kaura A, Sinha S, ... Tsang G, Akowuah E
Eur Heart J: 27 Dec 2021; 43:44-52 | PMID: 34468733
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Impact:
Abstract

Pharmacological Inhibition of CETP (Cholesteryl Ester Transfer Protein) Increases HDL (High-Density Lipoprotein) That Contains ApoC3 and Other HDL Subspecies Associated With Higher Risk of Coronary Heart Disease.

Furtado JD, Ruotolo G, Nicholls SJ, Dullea R, Carvajal-Gonzalez S, Sacks FM
Objective
Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and
Results:
We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (130 mg evacetrapib; n=126) and ILLUMINATE (60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug.
Conclusions
CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.



Arterioscler Thromb Vasc Biol: 22 Dec 2021:ATVBAHA121317181; epub ahead of print
Furtado JD, Ruotolo G, Nicholls SJ, Dullea R, Carvajal-Gonzalez S, Sacks FM
Arterioscler Thromb Vasc Biol: 22 Dec 2021:ATVBAHA121317181; epub ahead of print | PMID: 34937388
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Impact:
Abstract

Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results from the CABANA Trial.

Bahnson TD, Giczewska A, Mark DB, Russo AM, ... Lee KL, Packer D
Background: Observational data suggest catheter ablation may be safe and effective to treat younger and older patients with atrial fibrillation (AF). No large randomized trial has examined this issue. This report describes outcomes according to age at entry in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial (CABANA).
Methods:
Patients with AF age ≥65, or <65 with ≥1 risk factor for stroke, were randomly assigned to catheter ablation versus drug therapy. The primary outcome was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Secondary outcomes included all-cause mortality, the composite of mortality or cardiovascular hospitalization, and recurrence of AF. Treatment effect estimates were adjusted for baseline covariables using proportional hazards regression models.
Results:
Of 2204 patients randomized in CABANA, 766 (34.8%) were age <65, 1130 (51.3%) were 65-74, and 308 (14.0%) were ≥75. Catheter ablation was associated with a 43% reduction in the primary outcome for age <65 patients (adjusted hazard ratio [aHR] 0.57, 95% confidence interval [CI] 0.30-1.09), a 21% reduction for age 65-74 (aHR 0.79; 95% CI 0.54-1.16), and an indeterminate effect for age ≥75 (aHR 1.39; 95% CI 0.75-2.58). Four year event rates for ablation versus drug therapy across age groups, respectively, were 3.2% versus 7.8%, 7.8% versus 9.6%, and 14.8% versus 9.0%. For every 10-year increase in age, the primary outcome aHR increased (i.e., less favorable to ablation) an average of 27% (interaction p value= 0.215). A similar pattern was seen with all-cause mortality: for every 10-year increase in age, the aHR increased an average of 46% (interaction p value= 0.111). AF recurrence rates were lower with ablation compared to drug therapy across age subgroups (aHR 0.47, 0.58, and 0.49, respectively). Treatment-related complications were infrequent for both arms (<3%) regardless of age. Conclusions: We found age-based variations in clinical outcomes for catheter ablation compared with drug therapy, with the largest relative and absolute benefits of catheter ablation in younger patients. No prognostic benefits for ablation were seen in the oldest patients. No differences were found by age in treatment-related complications or in the relative effectiveness of catheter ablation in preventing recurrent atrial arrhythmias.




Circulation: 21 Dec 2021; epub ahead of print
Bahnson TD, Giczewska A, Mark DB, Russo AM, ... Lee KL, Packer D
Circulation: 21 Dec 2021; epub ahead of print | PMID: 34933570
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Impact:
Abstract

Orifice areas of balloon-expandable transcatheter heart valves: a three-dimensional transesophageal echocardiography study.

Watson RA, Vishnevsky A, Dikdan S, Marcantuono R, ... Ruggiero N, Mehrotra P
Introduction
Accurate expected effective orifice area (EOA) values for balloon-expandable (BE) transcatheter heart valves (THV) are crucial for preventing patient prosthesis mismatch (PPM) and assessment of THV function. Currently published reference EOAs, however, are based on transthoracic echocardiography (TTE) which may be subject to left ventricular outflow tract diameter underestimation and/or suboptimal THV Doppler interrogation. The objective of this study was to establish reference EOA values for BE THVs based on Doppler and three-dimensional (3D) transesophageal echocardiography (TEE).
Methods
We retrospectively reviewed 212 intra-procedural TEEs performed during BE THV implantation with optimal post-implant Doppler and 3D imaging. We compared continuity equation-derived EOAs to geometric orifice areas by 3D-planimetry (GOA3D). Performance indices (i.e., EOA normalized to valve size) and PPM rates were determined. TTE-based EOAs performed within 30 days were also calculated in a subset of 170 patients.
Results
The average EOA for all BE THV valves (77% Sapien 3) was 2.3 cm2 ± 0.5, while the average EOA was 1.6 ± 0.2 cm2 for 20 mm, 2.0 ± 0.2 cm2 for 23 mm, 2.5 ± 0.3 cm2 for 26 mm and 3.0 ± 0.3 cm2 for 29 mm THV size (p<0.001). Bland-Altman analysis demonstrated very good agreement between EOA and GOA3D (bias -0.04 ± 0.15 cm2). There was a strong correlation between annular area and TEE-based EOA (R=0.84) and GOA3D (R=0.87). The mean performance index was 47 ± 5% and was similar for all THV sizes (p=0.21). EOAs based on TTE were smaller compared to TEE, while the correlation with annular area (R=0.67) and agreement with GOA3D (bias -0.26 ± 0.43 cm2) was not as strong. The overall PPM rate was 2% in the TEE cohort and 12% in the TTE cohort.
Conclusions
Effective orifice areas for BE THVs based on intra-procedural Doppler and 3D-TEE suggest that previously published TTE-based reference values for EOA are underestimated while PPM rates may be overestimated. Our findings have important clinical implications for pre-implant decision making and for the evaluation of THV hemodynamics and function during follow-up.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 21 Dec 2021; epub ahead of print
Watson RA, Vishnevsky A, Dikdan S, Marcantuono R, ... Ruggiero N, Mehrotra P
J Am Soc Echocardiogr: 21 Dec 2021; epub ahead of print | PMID: 34954049
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Abstract

The Cardiology Society of India-Kerala Acute Heart Failure Registry: poor adherence to guideline-directed medical therapy.

Joseph S, Panniyammakal J, Abdullakutty J, S S, ... Natesan S, Sivadasanpillai H
Aims
Data on the burden of acute heart failure (AHF) admissions, practice patterns, and outcomes are rare from India and other low- and middle-income countries. We aimed to describe the baseline characteristics, guideline-directed medical therapy (GDMT) prescribing patterns and 90-day mortality rates in patients admitted with AHF in Kerala, India.
Methods and results
The Cardiology Society of India-Kerala Acute Heart Failure Registry (CSI-KHFR) is an observational registry from 50 hospitals in Kerala, India, with prospective follow-up. Consecutive patients with AHF, who consented to participate, were enrolled. The 2016 European Society of Cardiology criteria were used for the diagnosis of AHF. Kaplan-Meier survival analysis and Cox-proportional hazard models were used for data analysis. The variables in the MAGGIC risk score were used in the multivariable model. A total of 7507 patients with AHF (37% female) participated in the CSI-KHFR. The mean age was 64.3 (12.9) years. More than two-third had reduced ejection fraction (EF) (67.5%). Nearly one-fourth (28%) of patients with heart failure (HF) with reduced EF received GDMT. Overall, in-hospital and 90-day mortality rates were 7% and 11.6%, respectively. Prescriptions of different components of GDMT were independently associated with 90-day mortality.
Conclusion
The CSI-KHFR recorded an in-hospital and 90-day mortality of 7% and 11.6%, respectively. Only one of four patients received GDMT. AHF mortality was independently associated with GDMT initiation. Quality improvement initiatives that focus on increasing GDMT prescription may improve the survival of HF patients in India.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 20 Dec 2021; epub ahead of print
Joseph S, Panniyammakal J, Abdullakutty J, S S, ... Natesan S, Sivadasanpillai H
Eur Heart J: 20 Dec 2021; epub ahead of print | PMID: 34931232
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Abstract

Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.

Glazer AM, Davogustto GE, Shaffer CM, Vanoye CG, ... Roden DM, eMERGE Network
Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results (RoR) is unclear. In addition, the majority of discovered variants are currently classified as Variants of Uncertain Significance (VUS), limiting clinical actionability.
Methods:
The eMERGE-III study is a multi-center prospective cohort which included 21,846 participants without prior indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with Electronic Health Record (EHR)-derived phenotypes and follow-up clinical examination. Selected VUS (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells.
Results:
As previously reported, 3.0% of participants had pathogenic or likely pathogenic (P/LP) variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared to non-carriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their EHRs. Fifty four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 12/19 of these diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and in vitro functional studies.




Circulation: 20 Dec 2021; epub ahead of print
Glazer AM, Davogustto GE, Shaffer CM, Vanoye CG, ... Roden DM, eMERGE Network
Circulation: 20 Dec 2021; epub ahead of print | PMID: 34930020
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This program is still in alpha version.