Topic: Journal Club Selection

Abstract

Resumption of Cardiac Activity after Withdrawal of Life-Sustaining Measures.

Dhanani S, Hornby L, van Beinum A, Scales NB, ... Shemie SD, Canadian Critical Care Trials Group and the Canadian Donation and Transplantation Research Program
Background
The minimum duration of pulselessness required before organ donation after circulatory determination of death has not been well studied.
Methods
We conducted a prospective observational study of the incidence and timing of resumption of cardiac electrical and pulsatile activity in adults who died after planned withdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to be monitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiac activity prospectively. Continuous blood-pressure and electrocardiographic (ECG) waveforms were recorded and reviewed retrospectively to confirm bedside observations and to determine whether there were additional instances of resumption of cardiac activity.
Results
A total of 1999 patients were screened, and 631 were included in the study. Clinically reported resumption of cardiac activity, respiratory movement, or both that was confirmed by waveform analysis occurred in 5 patients (1%). Retrospective analysis of ECG and blood-pressure waveforms from 480 patients identified 67 instances (14%) with resumption of cardiac activity after a period of pulselessness, including the 5 reported by bedside clinicians. The longest duration after pulselessness before resumption of cardiac activity was 4 minutes 20 seconds. The last QRS complex coincided with the last arterial pulse in 19% of the patients.
Conclusions
After withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according to retrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These events occurred within 4 minutes 20 seconds after a period of pulselessness. (Funded by the Canadian Institutes for Health Research and others.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 27 Jan 2021; 384:345-352
Dhanani S, Hornby L, van Beinum A, Scales NB, ... Shemie SD, Canadian Critical Care Trials Group and the Canadian Donation and Transplantation Research Program
N Engl J Med: 27 Jan 2021; 384:345-352 | PMID: 33503343
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Impact:
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
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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
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Abstract

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation.

Andrade JG, Wells GA, Deyell MW, Bennett M, ... Verma A, EARLY-AF Investigators
Background
Guidelines recommend a trial of one or more antiarrhythmic drugs before catheter ablation is considered in patients with atrial fibrillation. However, first-line ablation may be more effective in maintaining sinus rhythm.
Methods
We randomly assigned 303 patients with symptomatic, paroxysmal, untreated atrial fibrillation to undergo catheter ablation with a cryothermy balloon or to receive antiarrhythmic drug therapy for initial rhythm control. All the patients received an implantable cardiac monitoring device to detect atrial tachyarrhythmia. The follow-up period was 12 months. The primary end point was the first documented recurrence of any atrial tachyarrhythmia (atrial fibrillation, atrial flutter, or atrial tachycardia) between 91 and 365 days after catheter ablation or the initiation of an antiarrhythmic drug. The secondary end points included freedom from symptomatic arrhythmia, the atrial fibrillation burden, and quality of life.
Results
At 1 year, a recurrence of atrial tachyarrhythmia had occurred in 66 of 154 patients (42.9%) assigned to undergo ablation and in 101 of 149 patients (67.8%) assigned to receive antiarrhythmic drugs (hazard ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66; P<0.001). Symptomatic atrial tachyarrhythmia had recurred in 11.0% of the patients who underwent ablation and in 26.2% of those who received antiarrhythmic drugs (hazard ratio, 0.39; 95% CI, 0.22 to 0.68). The median percentage of time in atrial fibrillation was 0% (interquartile range, 0 to 0.08) with ablation and 0.13% (interquartile range, 0 to 1.60) with antiarrhythmic drugs. Serious adverse events occurred in 5 patients (3.2%) who underwent ablation and in 6 patients (4.0%) who received antiarrhythmic drugs.
Conclusions
Among patients receiving initial treatment for symptomatic, paroxysmal atrial fibrillation, there was a significantly lower rate of atrial fibrillation recurrence with catheter cryoballoon ablation than with antiarrhythmic drug therapy, as assessed by continuous cardiac rhythm monitoring. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Jan 2021; 384:305-315
Andrade JG, Wells GA, Deyell MW, Bennett M, ... Verma A, EARLY-AF Investigators
N Engl J Med: 27 Jan 2021; 384:305-315 | PMID: 33197159
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Abstract

Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation.

Wazni OM, Dandamudi G, Sood N, Hoyt R, ... Nissen SE, STOP AF First Trial Investigators
Background
In patients with symptomatic paroxysmal atrial fibrillation that has not responded to medication, catheter ablation is more effective than antiarrhythmic drug therapy for maintaining sinus rhythm. However, the safety and efficacy of cryoballoon ablation as initial first-line therapy have not been established.
Methods
We performed a multicenter trial in which patients 18 to 80 years of age who had paroxysmal atrial fibrillation for which they had not previously received rhythm-control therapy were randomly assigned (1:1) to receive treatment with antiarrhythmic drugs (class I or III agents) or pulmonary vein isolation with a cryoballoon. Arrhythmia monitoring included 12-lead electrocardiography conducted at baseline and at 1, 3, 6, and 12 months; patient-activated telephone monitoring conducted weekly and when symptoms were present during months 3 through 12; and 24-hour ambulatory monitoring conducted at 6 and 12 months. The primary efficacy end point was treatment success (defined as freedom from initial failure of the procedure or atrial arrhythmia recurrence after a 90-day blanking period to allow recovery from the procedure or drug dose adjustment, evaluated in a Kaplan-Meier analysis). The primary safety end point was assessed in the ablation group only and was a composite of several procedure-related and cryoballoon system-related serious adverse events.
Results
Of the 203 participants who underwent randomization and received treatment, 104 underwent ablation, and 99 initially received drug therapy. In the ablation group, initial success of the procedure was achieved in 97% of patients. The Kaplan-Meier estimate of the percentage of patients with treatment success at 12 months was 74.6% (95% confidence interval [CI], 65.0 to 82.0) in the ablation group and 45.0% (95% CI, 34.6 to 54.7) in the drug-therapy group (P<0.001 by log-rank test). Two primary safety end-point events occurred in the ablation group (Kaplan-Meier estimate of the percentage of patients with an event within 12 months, 1.9%; 95% CI, 0.5 to 7.5).
Conclusions
Cryoballoon ablation as initial therapy was superior to drug therapy for the prevention of atrial arrhythmia recurrence in patients with paroxysmal atrial fibrillation. Serious procedure-related adverse events were uncommon. (Supported by Medtronic; STOP AF First ClinicalTrials.gov number, NCT03118518.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Jan 2021; 384:316-324
Wazni OM, Dandamudi G, Sood N, Hoyt R, ... Nissen SE, STOP AF First Trial Investigators
N Engl J Med: 27 Jan 2021; 384:316-324 | PMID: 33197158
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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
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Abstract

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

Teerlink JR, Diaz R, Felker GM, McMurray JJV, ... Kurtz CE, GALACTIC-HF Investigators
Background
The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown.
Methods
We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes.
Results
During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups.
Conclusions
Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 Jan 2021; 384:105-116
Teerlink JR, Diaz R, Felker GM, McMurray JJV, ... Kurtz CE, GALACTIC-HF Investigators
N Engl J Med: 13 Jan 2021; 384:105-116 | PMID: 33185990
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Abstract

Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure.

Bhatt DL, Szarek M, Steg PG, Cannon CP, ... Pitt B, SOLOIST-WHF Trial Investigators
Background
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown.
Methods
We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor.
Results
A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose.
Conclusions
In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 Jan 2021; 384:117-128
Bhatt DL, Szarek M, Steg PG, Cannon CP, ... Pitt B, SOLOIST-WHF Trial Investigators
N Engl J Med: 13 Jan 2021; 384:117-128 | PMID: 33200892
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Abstract

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

Schjørring OL, Klitgaard TL, Perner A, Wetterslev J, ... Rasmussen BS, HOT-ICU Investigators
Background
Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target.
Methods
In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days.
Results
At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24).
Conclusions
Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 19 Jan 2021; epub ahead of print
Schjørring OL, Klitgaard TL, Perner A, Wetterslev J, ... Rasmussen BS, HOT-ICU Investigators
N Engl J Med: 19 Jan 2021; epub ahead of print | PMID: 33471452
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Impact:
Abstract

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization.

Oyama K, Furtado RHM, Fagundes A, Zelniker TA, ... Sabatine MS, Bergmark BA
Objectives
This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization.
Background
PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall.
Methods
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG).
Results
In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years).
Conclusions
Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

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

J Am Coll Cardiol: 25 Jan 2021; 77:259-267
Oyama K, Furtado RHM, Fagundes A, Zelniker TA, ... Sabatine MS, Bergmark BA
J Am Coll Cardiol: 25 Jan 2021; 77:259-267 | PMID: 33197560
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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
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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
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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
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Impact:
Abstract

Prognostic Value of Non-Ischemic Ring-Like Left Ventricular Scar in Patients with Apparently Idiopathic Non-Sustained Ventricular Arrhythmias.

Muser D, Nucifora G, Pieroni M, Castro SA, ... Marchlinski FE, Santangeli P
Background: Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VA). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ring-like pattern of fibrosis.
Methods:
686 patients with apparently idiopathic non-sustained VA underwent contrast enhanced CMR. A ring-like pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The endpoint of the study was time to the composite outcome of all cause death, resuscitated cardiac arrest due to ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) and appropriate implantable cardioverter defibrillator therapy.
Results:
A total of 28 (4%) patients had a ring-like pattern of scar (Group A), 78 (11%) a non ring-like pattern (Group B), and 580 (85%) had normal CMR with no LGE (Group C). Group A patients were younger compared to Group B and Group C (median age 40 vs. 52 vs. 45 years, p<0.01), more frequently males (96% vs. 82% vs. 55%, p<0.01) with a higher prevalence of family history of sudden cardiac death/cardiomyopathy (39% vs. 14% vs. 6%; p<0.01), and more frequent history of unexplained syncope (18% vs. 9% vs. 3%, p<0.01). All patients in Group A showed VA with a right bundle branch block morphology vs. 69% in Group B and 21% in Group C (p<0.01). Multifocal VA were observed in 46% of Group A patients compared to 26% of Group B and 4% of Group C (p<0.01). After a median follow-up of 61 (34-84) months, the composite outcome occurred in 14 patients (50%) in Group A vs. 15 (19%) in Group B and 2 (0.3%) in Group C (p<0.01). After multivariable adjustment, the presence of LGE with ring-like pattern remained independently associated with increased risk of the composite endpoint (HR 68.98, 95% CI 14.67-324.39, p<0.01). Conclusions: In patients with apparently idiopathic non-sustained VA, nonischemic LV scar with a ring-like pattern is associated with malignant arrhythmic events.




Circulation: 05 Jan 2021; epub ahead of print
Muser D, Nucifora G, Pieroni M, Castro SA, ... Marchlinski FE, Santangeli P
Circulation: 05 Jan 2021; epub ahead of print | PMID: 33401956
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Abstract

Association of maternal dietary intakes and CBS gene polymorphisms with congenital heart disease in offspring.

Li Y, Diao J, Li J, Luo L, ... Zhu P, Qin J
Background
Although it is generally acknowledged that genetic and environmental factors are associated with risk of congenital heart disease (CHD), the causes are not fully understood. This study aimed at assessing the association of maternal dietary intakes, genetic variants of cystathionine beta synthase (CBS) gene and their interactions with risk of CHDs in offspring.
Method
A hospital-based case-control study of 464 mothers with CHD infants and 504 control mothers of health infant was performed. The exposures of interest were maternal dietary intakes in early pregnancy, single nucleotide polymorphisms (SNPs) of CBS gene.
Results
More frequent intake of pickled vegetables (adjusted odds ratio[aOR] = 1.81; 95% confidence interval[CI]: 1.38-2.37), smoked foods (aOR = 2.00; 95%CI: 1.53-2.60), barbecued foods (aOR = 1.63; 95%CI: 1.19-2.25) and fried foods (aOR = 1.57; 95%CI: 1.22-2.03) were associated with higher risk of CHD, while salted eggs (aOR = 0.20; 95%CI: 0.12-0.33), fish and shrimp (aOR = 0.34; 95%CI: 0.27-0.44), fresh fruits (aOR = 0.49; 95%CI: 0.37-0.66), and milk products (aOR = 0.54; 95%CI: 0.45-0.65) were associated with lower risk of CHD. The SNPs of CBS gene at rs2851391 (T/T vs C/C: aOR = 1.91, 95%CI: 1.15-3.15) and rs234714 (T/T vs C/C: aOR = 2.22, 95%CI: 1.32-3.73) significantly increased the risk of CHD. Additionally, significant interaction effects between maternal dietary intakes and CBS genetic variants on CHD risks were observed.
Conclusions
Maternal dietary factors, CBS genetic variants and their interactions were significantly associated with risk of CHD in offspring. However, it is still unclear how these factors jointly work in the development of CHD, and more studies with larger samples and prospective design are required.

Copyright © 2020 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Dec 2020; 322:121-128
Li Y, Diao J, Li J, Luo L, ... Zhu P, Qin J
Int J Cardiol: 31 Dec 2020; 322:121-128 | PMID: 32800907
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Impact:
Abstract

Pediatric Heart Network Echocardiographic Z Scores: Comparison with Other Published Models.

Lopez L, Frommelt PC, Colan SD, Trachtenberg FL, ... LuAnn Minich L, Pediatric Heart Network Investigators
Background
Different methods have resulted in variable Z scores for echocardiographic measurements. Using the measurements from 3,215 healthy North American children in the Pediatric Heart Network (PHN) echocardiographic Z score database, the authors compared the PHN model with previously published Z score models.
Methods
Z scores were derived for cardiovascular measurements using four models (PHN, Boston, Italy, and Detroit). Model comparisons were performed by evaluating (1) overlaid graphs of measurement versus body surface area with curves at Z = -2, 0, and +2; (2) scatterplots of PHN versus other Z scores with correlation coefficients; (3) Bland-Altman plots of PHN versus other Z scores; and (4) comparison of median Z scores for each model.
Results
For most measurements, PHN Z score curves were similar to Boston and Italian curves but diverged from Detroit curves at high body surface areas. Correlation coefficients were high when comparing the PHN model with the others, highest with Boston (mean, 0.99) and lowest with Detroit (mean, 0.90). Scatterplots suggested systematic differences despite high correlations. Bland-Altman plots also revealed poor agreement at both extremes of size and a systematic bias for most when comparing PHN against Italian and Detroit Z scores. There were statistically significant differences when comparing median Z scores between the PHN and other models.
Conclusions
Z scores from the multicenter PHN model correlated well with previous single-center models, especially the Boston model, which also had a large sample size and similar methodology. The Detroit Z scores diverged from the PHN Z scores at high body surface area, possibly because there were more subjects in this category in the PHN database. Despite excellent correlation, significant differences in Z scores between the PHN model and others were seen for many measurements. This is important when comparing publications using different models and for clinical care, particularly when Z score thresholds are used to guide diagnosis and management.

Copyright © 2020 American Society of Echocardiography. All rights reserved.

J Am Soc Echocardiogr: 30 Jan 2021; 34:185-192
Lopez L, Frommelt PC, Colan SD, Trachtenberg FL, ... LuAnn Minich L, Pediatric Heart Network Investigators
J Am Soc Echocardiogr: 30 Jan 2021; 34:185-192 | PMID: 33189460
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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
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Impact:

This program is still in alpha version.