Topic: Journal Club Selection

Abstract

Once-Weekly Semaglutide in Adults with Overweight or Obesity.

Wilding JPH, Batterham RL, Calanna S, Davies M, ... Kushner RF, STEP 1 Study Group
Background
Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.
Methods
In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.
Results
The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).
Conclusions
In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 09 Feb 2021; epub ahead of print
Wilding JPH, Batterham RL, Calanna S, Davies M, ... Kushner RF, STEP 1 Study Group
N Engl J Med: 09 Feb 2021; epub ahead of print | PMID: 33567185
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Glycemic Index, Glycemic Load, and Cardiovascular Disease and Mortality.

Jenkins DJA, Dehghan M, Mente A, Bangdiwala SI, ... Yusuf S, PURE Study Investigators
Background
Most data regarding the association between the glycemic index and cardiovascular disease come from high-income Western populations, with little information from non-Western countries with low or middle incomes. To fill this gap, data are needed from a large, geographically diverse population.
Methods
This analysis includes 137,851 participants between the ages of 35 and 70 years living on five continents, with a median follow-up of 9.5 years. We used country-specific food-frequency questionnaires to determine dietary intake and estimated the glycemic index and glycemic load on the basis of the consumption of seven categories of carbohydrate foods. We calculated hazard ratios using multivariable Cox frailty models. The primary outcome was a composite of a major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, stroke, and heart failure) or death from any cause.
Results
In the study population, 8780 deaths and 8252 major cardiovascular events occurred during the follow-up period. After performing extensive adjustments comparing the lowest and highest glycemic-index quintiles, we found that a diet with a high glycemic index was associated with an increased risk of a major cardiovascular event or death, both among participants with preexisting cardiovascular disease (hazard ratio, 1.51; 95% confidence interval [CI], 1.25 to 1.82) and among those without such disease (hazard ratio, 1.21; 95% CI, 1.11 to 1.34). Among the components of the primary outcome, a high glycemic index was also associated with an increased risk of death from cardiovascular causes. The results with respect to glycemic load were similar to the findings regarding the glycemic index among the participants with cardiovascular disease at baseline, but the association was not significant among those without preexisting cardiovascular disease.
Conclusions
In this study, a diet with a high glycemic index was associated with an increased risk of cardiovascular disease and death. (Funded by the Population Health Research Institute and others.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 23 Feb 2021; epub ahead of print
Jenkins DJA, Dehghan M, Mente A, Bangdiwala SI, ... Yusuf S, PURE Study Investigators
N Engl J Med: 23 Feb 2021; epub ahead of print | PMID: 33626252
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prognostic Implications of Declining Hemoglobin Content in Patients Hospitalized With Acute Coronary Syndromes.

Leonardi S, Gragnano F, Carrara G, Gargiulo G, ... Windecker S, Valgimigli M
Background
Contemporary definitions of bleeding endpoints are restricted mostly to clinically overt events. Whether hemoglobin drop per se, with or without overt bleeding, adversely affects the prognosis of patients with acute coronary syndrome (ACS) remains unclear.
Objectives
The aim of this study was to examine in the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial the incidence, predictors, and prognostic implications of in-hospital hemoglobin drop in patients with ACS managed invasively stratified by the presence of in-hospital bleeding.
Methods
Patients were categorized by the presence and amount of in-hospital hemoglobin drop on the basis of baseline and nadir hemoglobin values and further stratified by the occurrence of adjudicated in-hospital bleeding. Hemoglobin drop was defined as minimal (<3 g/dl), minor (≥3 and <5 g/dl), or major (≥5 g/dl). Using multivariate Cox regression, we modeled the association between hemoglobin drop and mortality in patients with and without overt bleeding.
Results
Among 7,781 patients alive 24 h after randomization with available hemoglobin data, 6,504 patients (83.6%) had hemoglobin drop, of whom 5,756 (88.5%) did not have overt bleeding and 748 (11.5%) had overt bleeding. Among patients without overt bleeding, minor (hazard ratio [HR]: 2.37; 95% confidence interval [CI]: 1.32 to 4.24; p = 0.004) and major (HR: 2.58; 95% CI: 0.98 to 6.78; p = 0.054) hemoglobin drop were independently associated with higher 1-year mortality. Among patients with overt bleeding, the association of minor and major hemoglobin drop with 1-year mortality was directionally similar but had wider CIs (minor: HR: 3.53 [95% CI: 1.06 to 11.79]; major: HR: 13.32 [95% CI: 3.01 to 58.98]).
Conclusions
Among patients with ACS managed invasively, in-hospital hemoglobin drop ≥3 g/dl, even in the absence of overt bleeding, is common and is independently associated with increased risk for 1-year mortality. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox; NCT01433627).

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Mar 2021; 77:375-388
Leonardi S, Gragnano F, Carrara G, Gargiulo G, ... Windecker S, Valgimigli M
J Am Coll Cardiol: 01 Mar 2021; 77:375-388 | PMID: 33509394
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Pre-Diabetes Increases Stroke Risk in Patients With Nonvalvular Atrial Fibrillation.

Kezerle L, Tsadok MA, Akriv A, Senderey AB, ... Leventer-Roberts M, Haim M
Background
Diabetes mellitus (DM) increases the risk of embolism in nonvalvular atrial fibrillation (NVAF). The association between pre-diabetes and risk of ischemic stroke has not been studied separately in this population.
Objectives
The purpose of this study was to evaluate whether pre-diabetes is associated with increased risk of stroke and death in patients with NVAF.
Methods
We conducted a historical cohort study using the Clalit Health Services electronic medical records. The study population included all members aged ≥25 years, with a first diagnosis of NVAF between January 1, 2010, and December 31, 2016. We compared 3 groups of individuals: those with pre-diabetes, those with diabetes, and normoglycemic patients.
Results
A total of 44,451 cases were identified. The median age was 75 years, and 52.5% were women. During a mean follow-up of 38 months, the incidence rates of stroke (per 100 person-years) were: 1.14 in normoglycemic individuals, 1.40 in those with pre-diabetes, and 2.15 in those with diabetes. In both univariate and multivariate analyses, pre-diabetes was associated with an increased risk of stroke compared with normoglycemic persons (adjusted hazard ratio [adjHR]: 1.19; 95% confidence interval [CI]: 1.01 to 1.4) even after adjustment for CHA2DS2-Vasc risk factors and use of anticoagulants, while diabetes conferred an even higher risk (vs. normoglycemia (adjHR: 1.56; 95% CI: 1.37 to 1.79). The risk for mortality was higher for individuals with diabetes (adjHR: 1.47; 95% CI: 1.41 to 1.54) but not for those with pre-diabetes (adjHR: 0.98; 95% CI: 0.92 to 1.03).
Conclusions
In this cohort of patients with incident NVAF, pre-diabetes was associated with an increased risk of stroke even after accounting for other recognized risk factors.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 22 Feb 2021; 77:875-884
Kezerle L, Tsadok MA, Akriv A, Senderey AB, ... Leventer-Roberts M, Haim M
J Am Coll Cardiol: 22 Feb 2021; 77:875-884 | PMID: 33602470
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction.

Frisk M, Le C, Shen X, Røe ÅT, ... Altara R, Louch WE
Background
Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.
Objectives
This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.
Methods
T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions.
Results
HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.
Conclusions
Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.

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

J Am Coll Cardiol: 01 Mar 2021; 77:405-419
Frisk M, Le C, Shen X, Røe ÅT, ... Altara R, Louch WE
J Am Coll Cardiol: 01 Mar 2021; 77:405-419 | PMID: 33509397
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart \'OMics\' in AGEing (HOMAGE) randomized clinical trial.

Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Aims 
To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.
Methods and results 
Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.
Conclusions 
Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 10 Feb 2021; 42:684-696
Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Eur Heart J: 10 Feb 2021; 42:684-696 | PMID: 33215209
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

Abraham WT, Lindenfeld J, Ponikowski P, Agostoni P, ... Salsali A, Anker SD
Aims
The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF).
Methods and results
HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported.
Conclusion
The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 10 Feb 2021; 42:700-710
Abraham WT, Lindenfeld J, Ponikowski P, Agostoni P, ... Salsali A, Anker SD
Eur Heart J: 10 Feb 2021; 42:700-710 | PMID: 33351892
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Paradoxical impact of socioeconomic factors on outcome of atrial fibrillation in Europe: trends in incidence and mortality from atrial fibrillation.

Al-Khayatt BM, Salciccioli JD, Marshall DC, Krahn AD, Shalhoub J, Sikkel MB
Aims
The aim of this study was to understand the changing trends in atrial fibrillation (AF) incidence and mortality across Europe from 1990 to 2017, and how socioeconomic factors and sex differences play a role.
Methods and results
We performed a temporal analysis of data from the 2017 Global Burden of Disease Database for 20 countries across Europe using Joinpoint regression analysis. Age-adjusted incidence, mortality, and mortality-to-incidence ratios (MIRs) to approximate case fatality rate are presented. Incidence and mortality trends were heterogenous throughout Europe, with Austria, Denmark, and Sweden experiencing peaks in incidence in the middle of the study period. Mortality rates were higher in wealthier countries with the highest being Sweden for both men and women (8.83 and 8.88 per 100 000, respectively) in 2017. MIRs were higher in women in all countries studied, with the disparity increasing the most over time in Germany (43.6% higher in women vs. men in 1990 to 74.5% higher in women in 2017).
Conclusion
AF incidence and mortality across Europe did not show a general trend, but unique patterns for some nations were observed. Higher mortality rates were observed in wealthier countries, potentially secondary to a survivor effect where patients survive long enough to suffer from AF and its complications. Outcomes for women with AF were worse than men, represented by higher MIRs. This suggests that there is widespread healthcare inequality between the sexes across Europe, or that there are biological differences between them in terms of their risk of adverse outcomes from AF.

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 Feb 2021; 42:847-857
Al-Khayatt BM, Salciccioli JD, Marshall DC, Krahn AD, Shalhoub J, Sikkel MB
Eur Heart J: 20 Feb 2021; 42:847-857 | PMID: 33495788
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs.

Al-Mashhadi RH, Al-Mashhadi AL, Nasr ZP, Mortensen MB, ... Vázquez J, Bentzon JF
Background
The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries.
Objectives
This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms.
Methods
Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)D374Y Yucatan minipigs for >1 year. Caudal pressures remained normal.
Results
Under hypercholesterolemic conditions in PCSK9D374Y transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries.
Conclusions
Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Feb 2021; 77:575-589
Al-Mashhadi RH, Al-Mashhadi AL, Nasr ZP, Mortensen MB, ... Vázquez J, Bentzon JF
J Am Coll Cardiol: 08 Feb 2021; 77:575-589 | PMID: 33538256
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Endothelial Cell Indoleamine 2, 3-Dioxygenase 1 Alters Cardiac Function After Myocardial Infarction Through Kynurenine.

Melhem NJ, Chajadine M, Gomez I, Howangyin KY, ... Silvestre JS, Taleb S
Background
Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI), is one of the leading causes of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes 1 rate-limiting step of L-tryptophan metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI.
Methods
Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction.
Results
We show that kynurenine generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not affect cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo kynurenine supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Kynurenine precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism.
Conclusions
These data suggest that IDO could constitute a new therapeutic target during acute MI.



Circulation: 08 Feb 2021; 143:566-580
Melhem NJ, Chajadine M, Gomez I, Howangyin KY, ... Silvestre JS, Taleb S
Circulation: 08 Feb 2021; 143:566-580 | PMID: 33272024
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

MiR-21-Dependent Macrophage-to-Fibroblast Signaling Determines the Cardiac Response to Pressure Overload.

Ramanujam D, Schön AP, Beck C, Vaccarello P, ... Schulz C, Engelhardt S
Background: Cardiac macrophages (cMP) are increasingly recognized as important regulators of myocardial homeostasis and disease, yet the role of noncoding RNA in these cells is largely unknown. Small RNA sequencing of the entire miRNomes of the major cardiac cell fractions revealed microRNA-21 (miR-21) as the single highest expressed microRNA in cMPs, both in health and disease (25% and 43% of all microRNA reads respectively). MiR-21 has been previously reported as a key microRNA driving tissue fibrosis. Here, we aimed to determine the function of macrophage miR-21 on myocardial homeostasis and disease-associated remodeling.
Methods:
Macrophage-specific ablation of miR-21 in mice driven by Cx3cr1-Cre was used to determine the function of miR-21 in this cell type. As a disease model, mice were subjected to pressure overload for 6 and 28 days. Cardiac function was assessed in vivo by echocardiography, followed by histological analyses and single cell sequencing. Co-cultures of macrophages and cardiac fibroblasts were employed to study macrophage-to-fibroblast signaling.
Results:
Mice with macrophage-specific genetic deletion of miR-21 were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload of the left ventricle. Single cell sequencing of pressure-overloaded hearts from these mice revealed that miR-21 in macrophages is essential for their polarization towards a M1-like phenotype. Systematic quantification of intercellular communication mediated by ligand-receptor interactions across all cell types revealed that miR-21 primarily determined macrophage-fibroblast communication, promoting the transition from quiescent fibroblasts to myofibroblasts. Polarization of isolated macrophages in vitro towards a pro-inflammatory (M1) phenotype activated myofibroblast transdifferentiation of cardiac fibroblasts in a paracrine manner and was dependent on the rapid induction of miR-21 in cMPs. Conclusions: Our data indicate a critical role of cMPs in pressure overload-induced cardiac fibrosis and dysfunction and reveal macrophage miR-21 as a key molecule for the pro-fibrotic role of cMPs.




Circulation: 07 Feb 2021; epub ahead of print
Ramanujam D, Schön AP, Beck C, Vaccarello P, ... Schulz C, Engelhardt S
Circulation: 07 Feb 2021; epub ahead of print | PMID: 33550817
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Mortality 10 Years After Percutaneous or Surgical Revascularization in Patients With Total Coronary Artery Occlusions.

Kawashima H, Takahashi K, Ono M, Hara H, ... Onuma Y, SYNTAX Extended Survival Investigators
Background
The long-term clinical benefit after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with total occlusions (TOs) and complex coronary artery disease has not yet been clarified.
Objectives
The objective of this analysis was to assess 10-year all-cause mortality in patients with TOs undergoing PCI or CABG.
Methods
This is a subanalysis of patients with at least 1 TO in the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study, which investigated 10-year all-cause mortality in the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trial, beyond its original 5-year follow-up. Patients with TOs were further stratified according to the status of TO recanalization or revascularization.
Results
Of 1,800 randomized patients to the PCI or CABG arm, 460 patients had at least 1 lesion of TO. In patients with TOs, the status of TO recanalization or revascularization was not associated with 10-year all-cause mortality, irrespective of the assigned treatment (PCI arm: 29.9% vs. 29.4%; adjusted hazard ratio [HR]: 0.992; 95% confidence interval [CI]: 0.474 to 2.075; p = 0.982; and CABG arm: 28.0% vs. 21.4%; adjusted HR: 0.656; 95% CI: 0.281 to 1.533; p = 0.330). When TOs existed in left main and/or left anterior descending artery, the status of TO recanalization or revascularization did not have an impact on the mortality (34.5% vs. 26.9%; adjusted HR: 0.896; 95% CI: 0.314 to 2.555; p = 0.837).
Conclusions
At 10-year follow-up, the status of TO recanalization or revascularization did not affect mortality, irrespective of the assigned treatment and location of TOs. The present study might support contemporary practice among high-volume chronic TO-PCI centers where recanalization is primarily offered to patients for the management of angina refractory to medical therapy when myocardial viability is confirmed. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]; NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972).

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 08 Feb 2021; 77:529-540
Kawashima H, Takahashi K, Ono M, Hara H, ... Onuma Y, SYNTAX Extended Survival Investigators
J Am Coll Cardiol: 08 Feb 2021; 77:529-540 | PMID: 33538250
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation.

Steffel J, Ruff CT, Yin O, Braunwald E, ... Antman EM, Giugliano RP
Background
In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation.
Objectives
The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients).
Methods
This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER.
Results
The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings.
Conclusions
In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391).

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

J Am Coll Cardiol: 08 Mar 2021; 77:1197-1207
Steffel J, Ruff CT, Yin O, Braunwald E, ... Antman EM, Giugliano RP
J Am Coll Cardiol: 08 Mar 2021; 77:1197-1207 | PMID: 33663737
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Single Nuclei Sequencing Reveals Novel Insights into the Regulation of Cellular Signatures in Children with Dilated Cardiomyopathy.

Nicin L, Abplanalp WT, Schänzer A, Sprengel A, ... Rupp S, Dimmeler S
Background: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology and molecular fingerprints into account. We present snRNA-seq from pediatric DCM patients as the next step in identifying cellular signatures.
Methods:
We performed single nuclei RNA sequencing with heart tissues from six children with DCM with an age of 0.5, 0.75, 5, 6, 12 and 13 years. Unsupervised clustering of 18,211 nuclei led to the identification of 14 distinct clusters with 6 major cell types.
Results:
The number of nuclei in fibroblast clusters increased with age in DCM patients, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of DCM patients over 6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms and signatures of fibroblast activation. Additionally, a population of cardiomyocytes with a high pro-regenerative profile was identified in infant DCM patients, but was absent in > 6-year-old children. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes and alterations in ß-adrenergic signaling genes. Conclusions: Novel insights into the cellular transcriptomes of hearts from pediatric DCM patients provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched pro-regenerative signatures in infants.




Circulation: 22 Feb 2021; epub ahead of print
Nicin L, Abplanalp WT, Schänzer A, Sprengel A, ... Rupp S, Dimmeler S
Circulation: 22 Feb 2021; epub ahead of print | PMID: 33618539
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Venous flow variation predicts preoperative pulmonary venous obstruction in children with total anomalous pulmonary venous connection.

White BR, Faerber JA, Katcoff H, Glatz AC, Mascio CE, Cohen MS
Objective
Identifying preoperative pulmonary venous obstruction in total anomalous pulmonary venous connection (TAPVC) is important to guide treatment-planning and risk prognostication. No standardized echocardiographic definition of obstruction exists in the literature. Definitions based on absolute velocities are affected by technical limitations and variations in pulmonary venous return. We developed a metric to quantify pulmonary venous blood flow variation: pulmonary venous variability index (PVVI). We aimed to demonstrate its accuracy in defining obstruction.
Methods
All patients cared for with TAPVC at our institution were identified. Echocardiograms were reviewed, and maximum (Vmax), mean (Vmean), and minimum velocities (Vmin) along the pulmonary venous pathway were measured. PVVI was defined as (Vmax-Vmin)/Vmean. These metrics were compared to pressures measured by cardiac catheterization. Echocardiographic measures were then compared between the patients with and without clinical preoperative obstruction (defined as a need for preoperative intubation, catheter-based intervention, or surgery within one day of diagnosis), as well as pulmonary edema by chest X-ray and markers of lactic acidosis. 137 patients were included with 22 having catheterization pressure recordings.
Results
Maximum and mean velocity were not different between patients with catheter gradients ≥4 mmHg and <4 mmHg, while PVVI was significantly lower and minimum velocity higher in those with gradients ≥4 mmHg. The composite outcome of preoperative obstruction occurred in 51 patients (37%). Absolute velocities were not different between patients with and without clinical obstruction, while PVVI was significantly lower in patients with obstruction. All metrics except maximum velocity were associated with pulmonary edema; none were associated with blood gas metrics.
Conclusions
We developed a novel quantitative metric of pulmonary venous flow, which was superior to traditional echocardiographic metrics. Decreased PVVI was highly associated with elevated gradients measured by catheterization and clinical preoperative obstruction. These results should aid risk assessment and diagnosis preoperatively in patients with TAPVC.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 14 Feb 2021; epub ahead of print
White BR, Faerber JA, Katcoff H, Glatz AC, Mascio CE, Cohen MS
J Am Soc Echocardiogr: 14 Feb 2021; epub ahead of print | PMID: 33600926
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Percutaneous mitral valve repair in adults with congenital heart disease: Report of the first case-series.

Alshawabkeh L, Mahmud E, Reeves R
Background
Systemic atrioventricular valve regurgitation (AVVR) is frequently encountered in adults with congenital heart disease (CHD). Surgical intervention is the mainstay of therapy, but in a specific high-risk subset, percutaneous valve repair might offer a lower-risk alternative.
Methods
Three patients with complex CHD and severe symptomatic AVVR underwent percutaneous mitral valve repair at a single center. All were deemed to be high-risk for surgery by a multidisciplinary CHD team and provided informed consent for the compassionate use of the MitraClip (Abbott, Santa Clara, CA). Three-dimensional heart models were generated for the procedure, which was performed by an adult CHD cardiologist (who provided imaging support) and an interventional cardiologist with expertise in CHD and percutaneous mitral valve repair.
Results
The first case was a 39 year-old-woman with [S,L,D] dextrocardia, double outlet right ventricle, mild tricuspid hypoplasia, and a secundum atrial septal defect, who was palliated at age 35 with a right bidirectional Glenn and later developed severe, symptomatic mitral regurgitation, and underwent placement of one MitraClip XTR device. Two patients with L-loop transposition of the great arteries each successfully underwent placement of two MitraClip XTR devices; one patient had a single-leaflet detachment of one of the clips with no change in regurgitation or clip position on follow-up. All patients had significant reduction of AVVR and improvement in NYHA functional class.
Conclusions
Percutaneous atrioventricular valve repair in adults with CHD is feasible with the MitraClip but requires significant preprocedural planning and a multidisciplinary team that combines CHD and interventional therapeutic expertise.

© 2020 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 14 Feb 2021; 97:542-548
Alshawabkeh L, Mahmud E, Reeves R
Catheter Cardiovasc Interv: 14 Feb 2021; 97:542-548 | PMID: 32898313
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiac Resynchronization Therapy response assessment with electromechanical activation mapping within 24 hours of device implantation - a pilot study.

Melki L, Wang DY, Grubb CS, Weber R, ... Garan H, Konofagou EE
Background
Cardiac Resynchronization Therapy (CRT) response assessment relies on the QRS complex narrowing criterion. Yet, a third of patients do not improve despite narrowed QRS post-implantation. Electromechanical Wave Imaging (EWI) is a quantitative echocardiography-based technique capable of non-invasively mapping cardiac electromechanical activation in 3D. This exploratory study investigates the EWI technique, sensitive to ventricular dyssynchrony, for informing CRT response on the day of implantation.
Methods
Forty-four (N=44) heart failure patients with left bundle branch block or right-ventricular paced rhythm and decreased left ventricular ejection fraction (LVEF = 25.3 ± 9.6%), underwent EWI without and with CRT within 24 hours of device implantation. Of those, sixteen were also scanned while in LV pacing. Improvement in LVEF at 3-, 6-, or 9-month follow-up defined: (i) super-responders(LVEF≥20%); (ii) responders(10%≤LVEF<20%); and (iii) non-responders(LVEF≤5%). 3D-rendered electromechanical maps were obtained under RV, LV and biventricular (BiV) CRT pacing conditions. Mean RV free wall and LV lateral wall activation times (LWAT) were computed. The percentage of resynchronized myocardium (%RMLV) was measured by quantifying the percentage of LV activated within 120 ms of QRS onset. Correlations between %RMLV and the type of CRT response were assessed.
Results
LWAT was significantly different (p≤0.05) between all three pacing conditions in the sixteen patients: LWAT with CRT in BiV pacing (73.1±17.6ms) was lower compared to LV pacing (89.5±21.5ms) and RV pacing (120.3±17.8ms), respectively. Retrospective analysis showed that the %RMLVmetric with CRT was a reliable response predictor within 24 hours of implantation for significantly (p≤0.05) identifying super-responders (n=7, 97.7±1.9%) from non-responders (n=17, 89.9±9.9%).
Conclusion
Electromechanical activation mapping constitutes a valuable 3D visualization tool within 24 hours of implantation and could potentially aid in the timely assessment of CRT response rates, including during implantation for adjustment of lead placement and pacing outcomes.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 02 Mar 2021; epub ahead of print
Melki L, Wang DY, Grubb CS, Weber R, ... Garan H, Konofagou EE
J Am Soc Echocardiogr: 02 Mar 2021; epub ahead of print | PMID: 33675941
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.