Topic: Journal Club Selection

Abstract

Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial.

Oyama K, Giugliano RP, Berg DD, Ruff CT, ... Braunwald E, Morrow DA
Aims
We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding.
Methods and results
ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36-2.23 and adj-HR 1.27; 95% CI 1.07-1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02-1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36-0.65; NRI 0.42; 95% CI 0.33-0.51, respectively].
Conclusion
Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with 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: 23 Mar 2021; epub ahead of print
Oyama K, Giugliano RP, Berg DD, Ruff CT, ... Braunwald E, Morrow DA
Eur Heart J: 23 Mar 2021; epub ahead of print | PMID: 33760027
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Impact:
Abstract

Cardiac Rehabilitation for Patients With Heart Failure: JACC Expert Panel.

Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, ... Wolfel E, ACC’s Heart Failure and Transplant Section and Leadership Council
Cardiac rehabilitation is defined as a multidisciplinary program that includes exercise training, cardiac risk factor modification, psychosocial assessment, and outcomes assessment. Exercise training and other components of cardiac rehabilitation (CR) are safe and beneficial and result in significant improvements in quality of life, functional capacity, exercise performance, and heart failure (HF)-related hospitalizations in patients with HF. Despite outcome benefits, cost-effectiveness, and strong practice guideline recommendations, CR remains underused. Clinicians, health care leaders, and payers should prioritize incorporating CR as part of the standard of care for patients with HF.

Published by Elsevier Inc.

J Am Coll Cardiol: 22 Mar 2021; 77:1454-1469
Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, ... Wolfel E, ACC’s Heart Failure and Transplant Section and Leadership Council
J Am Coll Cardiol: 22 Mar 2021; 77:1454-1469 | PMID: 33736829
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Abstract

Validation of risk scores for ischaemic stroke in atrial fibrillation across the spectrum of kidney function.

de Jong Y, Fu EL, van Diepen M, Trevisan M, ... Carrero JJ, Ocak G
Aims 
The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function.
Methods and results 
Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS2, Modified CHADS2, CHA2DS2-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2], mild CKD (eGFR 30-60 mL/min/1.73 m2), and advanced CKD (eGFR <30 mL/min/1.73 m2). Predictive performance was assessed by discrimination and calibration. During 1.9 years, 3069 (8.5%) patients suffered an IS. Discrimination was dependent on eGFR: the median c-statistic in normal eGFR was 0.75 (range 0.68-0.78), but decreased to 0.68 (0.58-0.73) and 0.68 (0.55-0.74) for mild and advanced CKD, respectively. Calibration was reasonable and largely independent of eGFR. The Modified CHADS2 score showed good performance across kidney function strata, both for discrimination [c-statistic: 0.78 (95% confidence interval 0.77-0.79), 0.73 (0.71-0.74) and 0.74 (0.69-0.79), respectively] and calibration.
Conclusion 
In the most clinically relevant stages of CKD, predictive performance of the majority of risk scores was poor, increasing the risk of misclassification and thus of over- or undertreatment. The Modified CHADS2 score performed good and consistently across all kidney function strata, and should therefore be preferred for risk estimation in AF patients.

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

Eur Heart J: 25 Mar 2021; epub ahead of print
de Jong Y, Fu EL, van Diepen M, Trevisan M, ... Carrero JJ, Ocak G
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769473
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Abstract

Atherosclerotic Carotid Plaque Composition and Incident Stroke and Coronary Events.

Bos D, Arshi B, van den Bouwhuijsen QJA, Ikram MK, ... Kavousi M, van der Lugt A
Background
Increasing evidence suggests that atherosclerotic plaque composition rather than plaque size is linked to ischemic cardiovascular events, yet largescale population-based data in asymptomatic individuals remain scarce.
Objectives
This study sought to investigate carotid plaque composition in relation to incident stroke and coronary heart disease (CHD) in a population-based setting.
Methods
Between 2007 and 2012, 1,349 persons (mean age 72 years, 49.5% women) from the population-based Rotterdam Study who were free from a history of stroke or CHD, in whom carotid ultrasonography showed subclinical atherosclerosis, and who underwent high-resolution magnetic resonance imaging of the carotid arteries to assess plaque characteristics. These included the presence of specific plaque components (intraplaque hemorrhage [IPH], lipid-rich necrotic core, and calcification), and measures of plaque size (maximum plaque thickness and presence of stenosis of more than 30%). Individuals were continuously followed for the occurrence of stroke or CHD until January 1, 2015. The authors used Cox regression models to assess the association of the plaque characteristics with the incidence of stroke and CHD, with adjustments for age, sex, and cardiovascular risk factors.
Results
During a median of 5.1 years\' follow-up for stroke and 4.8 years for CHD, 51 individuals had a stroke and 83 developed CHD. Independent of maximum plaque thickness and cardiovascular risk factors, the presence of IPH was associated with incident stroke and CHD (fully adjusted hazard ratio: 2.42 [95% confidence interval: 1.30 to 4.50], and 1.95 [95% confidence interval: 1.20 to 3.14]). Presence of a lipid-rich necrotic core and calcification were not associated with stroke or CHD.
Conclusions
The presence of IPH in the carotid atherosclerotic plaque is an independent risk factor for stroke and CHD. These findings indicate the promise of IPH as a marker of plaque vulnerability in healthy persons with subclinical atherosclerosis.

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

J Am Coll Cardiol: 22 Mar 2021; 77:1426-1435
Bos D, Arshi B, van den Bouwhuijsen QJA, Ikram MK, ... Kavousi M, van der Lugt A
J Am Coll Cardiol: 22 Mar 2021; 77:1426-1435 | PMID: 33736825
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Abstract

COVID-19 in Adults With Congenital Heart Disease.

Broberg CS, Kovacs AH, Sadeghi S, Rosenbaum MS, ... Cotts TB, Aboulhosn JA
Background
Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications.
Objectives
This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes.
Methods
Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined.
Results
From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not.
Conclusions
COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

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

J Am Coll Cardiol: 05 Apr 2021; 77:1644-1655
Broberg CS, Kovacs AH, Sadeghi S, Rosenbaum MS, ... Cotts TB, Aboulhosn JA
J Am Coll Cardiol: 05 Apr 2021; 77:1644-1655 | PMID: 33795039
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Abstract

Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced.

Ferreira JP, Zannad F, Pocock SJ, Anker SD, ... Schueler E, Packer M
Background
Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction.
Objectives
This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods
Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization.
Results
The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group.
Conclusions
In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

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

J Am Coll Cardiol: 22 Mar 2021; 77:1397-1407
Ferreira JP, Zannad F, Pocock SJ, Anker SD, ... Schueler E, Packer M
J Am Coll Cardiol: 22 Mar 2021; 77:1397-1407 | PMID: 33736821
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Abstract

Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials.

Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Aims
Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE).
Methods and results
We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060).
Conclusion
Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.

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: 25 Mar 2021; epub ahead of print
Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769515
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Impact:
Abstract

Association of Phosphodiesterase-5 Inhibitors Versus Alprostadil With Survival in Men With Coronary Artery Disease.

Andersson DP, Landucci L, Lagerros YT, Grotta A, ... Lehtihet M, Holzmann MJ
Background
Phosphodiesterase 5 inhibitor (PDE5i) treatment is associated with reduced mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI).
Objectives
This study sought to investigate the association between treatment with PDE5i or alprostadil and outcomes in men with stable coronary artery disease.
Methods
All Swedish men with a prior MI or revascularization who received PDE5i or alprostadil during 2006 through 2013 at >6 months after the event were included, using the Swedish Patient Register and the Swedish Prescribed Drug Register. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals for all-cause mortality, MI, heart failure, cardiovascular mortality, noncardiovascular mortality, cardiac revascularization, peripheral arterial disease, and stroke in men treated with PDE5i versus alprostadil.
Results
This study included 16,548 men treated with PDE5i and 1,994 treated with alprostadil. The mean follow-up was 5.8 years, with 2,261 deaths (14%) in the PDE5i group and 521 (26%) in the alprostadil group. PDE5i compared with alprostadil treatment was associated with lower mortality (hazard ratio: 0.88; 95% confidence interval: 0.79 to 0.98) and with similar associations for MI, heart failure, cardiovascular mortality, and revascularization. When quintiles (q) of filled PDE5i prescriptions were compared using q1 as reference, patients in q3, q4, and q5 had lower all-cause mortality. Among alprostadil users, those in q5 had a lower all-cause mortality compared to q1.
Conclusions
In men with stable coronary artery disease, treatment with PDE5i is associated with lower risks of death, MI, heart failure, and revascularization compared with alprostadil treatment. Although the decrease in all-cause mortality was PDE5i dose dependent, the data do not permit the inference of causality or any clinical benefits of PDE5i because of the observational study design.

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

J Am Coll Cardiol: 29 Mar 2021; 77:1535-1550
Andersson DP, Landucci L, Lagerros YT, Grotta A, ... Lehtihet M, Holzmann MJ
J Am Coll Cardiol: 29 Mar 2021; 77:1535-1550 | PMID: 33766260
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Abstract

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Background
Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention.
Objectives
This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload.
Methods
This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment.
Results
Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients.
Conclusions
Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

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

J Am Coll Cardiol: 22 Mar 2021; 77:1381-1392
Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
J Am Coll Cardiol: 22 Mar 2021; 77:1381-1392 | PMID: 33736819
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Impact:
Abstract

Time-Restricted Salutary Effects of Blood Flow Restoration on Venous Thrombosis and Vein Wall Injury in Mouse and Human Subjects.

Li W, Kessinger CW, Orii M, Lee H, ... Henke PK, Jaffer FA
Background
Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution.
Methods
First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes.
Results
Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, P<0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days.
Conclusions
Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT.



Circulation: 22 Mar 2021; 143:1224-1238
Li W, Kessinger CW, Orii M, Lee H, ... Henke PK, Jaffer FA
Circulation: 22 Mar 2021; 143:1224-1238 | PMID: 33445952
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Abstract

Prognostic Value of Nonischemic Ringlike Left Ventricular Scar in Patients With Apparently Idiopathic Nonsustained Ventricular Arrhythmias.

Muser D, Nucifora G, Muser D, Nucifora G, ... Marchlinski FE, Santangeli P
Background
Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ringlike pattern of fibrosis.
Methods
A total of 686 patients with apparently idiopathic nonsustained VA underwent contrast-enhanced cardiac magnetic resonance. A ringlike pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The end point of the study was time to the composite outcome of all-cause death, resuscitated cardiac arrest because of ventricular fibrillation or hemodynamically unstable ventricular tachycardia and appropriate implantable cardioverter defibrillator therapy.
Results
A total of 28 patients (4%) had a ringlike pattern of scar (group A), 78 (11%) had a non-ringlike pattern (group B), and 580 (85%) had normal cardiac magnetic resonance with no LGE (group C). Group A patients were younger compared with groups B and C (median age, 40 vs 52 vs 45 years; P<0.01), more frequently men (96% vs 82% vs 55%; P<0.01), with a higher prevalence of family history of sudden cardiac death or 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 versus 69% in group B and 21% in group C (P<0.01). Multifocal VAs were observed in 46% of group A patients compared with 26% of group B and 4% of group C (P<0.01). After a median follow-up of 61 months (range, 34-84 months), the composite outcome occurred in 14 patients (50.0%) in group A versus 15 (19.0%) in group B and 2 (0.3%) in group C (P<0.01). After multivariable adjustment, the presence of LGE with ringlike pattern remained independently associated with increased risk of the composite end point (hazard ratio, 68.98 [95% CI, 14.67-324.39], P<0.01).
Conclusions
In patients with apparently idiopathic nonsustained VA, nonischemic LV scar with a ringlike pattern is associated with malignant arrhythmic events.



Circulation: 05 Apr 2021; 143:1359-1373
Muser D, Nucifora G, Muser D, Nucifora G, ... Marchlinski FE, Santangeli P
Circulation: 05 Apr 2021; 143:1359-1373 | PMID: 33401956
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Impact:
Abstract

BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State.

Wang L, Rice M, Swist S, Kubin T, ... Schneider A, Braun T
Background
Vascular smooth muscle cells (VSMCs) show a remarkable phenotypic plasticity, allowing acquisition of contractile or synthetic states, but critical information is missing about the physiologic signals, promoting formation, and maintenance of contractile VSMCs in vivo. BMP9 and BMP10 (bone morphogenetic protein) are known to regulate endothelial quiescence after secretion from the liver and right atrium, whereas a direct role in the regulation of VSMCs was not investigated. We studied the role of BMP9 and BMP10 for controlling formation of contractile VSMCs.
Methods
We generated several cell type-specific loss- and gain-of-function transgenic mouse models to investigate the physiologic role of BMP9, BMP10, ALK1 (activin receptor-like kinase 1), and SMAD7 in vivo. Morphometric assessments, expression analysis, blood pressure measurements, and single molecule fluorescence in situ hybridization were performed together with analysis of isolated pulmonary VSMCs to unravel phenotypic and transcriptomic changes in response to absence or presence of BMP9 and BMP10.
Results
Concomitant genetic inactivation of Bmp9 in the germ line and Bmp10 in the right atrium led to dramatic changes in vascular tone and diminution of the VSMC layer with attenuated contractility and decreased systemic as well as right ventricular systolic pressure. On the contrary, overexpression of Bmp10 in endothelial cells of adult mice dramatically enhanced formation of contractile VSMCs and increased systemic blood pressure as well as right ventricular systolic pressure. Likewise, BMP9/10 treatment induced an ALK1-dependent phenotypic switch from synthetic to contractile in pulmonary VSMCs. Smooth muscle cell-specific overexpression of Smad7 completely suppressed differentiation and proliferation of VSMCs and reiterated defects observed in adult Bmp9/10 double mutants. Deletion of Alk1 in VSMCs recapitulated the Bmp9/10 phenotype in pulmonary but not in aortic and coronary arteries. Bulk expression analysis and single molecule RNA-fluorescence in situ hybridization uncovered vessel bed-specific, heterogeneous expression of BMP type 1 receptors, explaining phenotypic differences in different Alk1 mutant vessel beds.
Conclusions
Our study demonstrates that BMP9 and BMP10 act directly on VSMCs for induction and maintenance of their contractile state. The effects of BMP9/10 in VSMCs are mediated by different combinations of BMP type 1 receptors in a vessel bed-specific manner, offering new opportunities to manipulate blood pressure in the pulmonary circulation.



Circulation: 05 Apr 2021; 143:1394-1410
Wang L, Rice M, Swist S, Kubin T, ... Schneider A, Braun T
Circulation: 05 Apr 2021; 143:1394-1410 | PMID: 33334130
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Impact:
Abstract

Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T-Cell Activation in the Heart and Promote Cardiac Dysfunction.

Ngwenyama N, Kirabo A, Aronovitz M, Velázquez F, ... Harrison DG, Alcaide P
Background
Despite the well-established association between T-cell-mediated inflammation and nonischemic heart failure, the specific mechanisms triggering T-cell activation during the progression of heart failure and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T-cell receptor (TCR) activation and promote heart failure.
Methods
We used transverse aortic constriction in mice to trigger myocardial oxidative stress and T-cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77GFP reporter mice, which transiently express GFP on TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII-/- mice and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species and IsoLGs in eliciting T-cell immune responses in vivo by treating mice with the antioxidant TEMPOL and the IsoLG scavenger 2-hydroxybenzylamine during transverse aortic constriction, and ex vivo in mechanistic studies of CD4+ T-cell proliferation in response to IsoLG-modified cardiac proteins.
Results
We discovered that TCR antigen recognition increases in the left ventricle as cardiac dysfunction progresses and identified a limited repertoire of activated CD4+ T-cell clonotypes in the left ventricle. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction because MhcII-/- mice reconstituted with CD4+ T cells and OTII mice immunized with their cognate antigen were protected from transverse aortic constriction-induced cardiac dysfunction despite the presence of left ventricle-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-hydroxybenzylamine reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in reactive oxygen species-dependent dendritic cell accumulation of IsoLG protein adducts, which induced robust CD4+ T-cell proliferation.
Conclusions
Our study demonstrates an important role of reactive oxygen species-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T-cell activation within the heart.



Circulation: 22 Mar 2021; 143:1242-1255
Ngwenyama N, Kirabo A, Aronovitz M, Velázquez F, ... Harrison DG, Alcaide P
Circulation: 22 Mar 2021; 143:1242-1255 | PMID: 33463362
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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)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 24 Mar 2021; epub ahead of print
Melduni R, Nkomo VT, Wysokinski W, Gersh BJ, ... Oh JK, Lee HC
Heart: 24 Mar 2021; epub ahead of print | PMID: 33766985
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Abstract

Prognostic implications of left atrial dilation in aortic regurgitation due to bicuspid aortic valve.

Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Objective
To investigate the prognostic value of left atrial volume index (LAVI) in patients with moderate to severe aortic regurgitation (AR) and bicuspid aortic valve (BAV).
Methods
554 individuals (45 (IQR 33-57) years, 80% male) with BAV and moderate or severe AR were selected from an international, multicentre registry. The association between LAVI and the combined endpoint of all-cause mortality or aortic valve surgery was investigated with Cox proportional hazard regression analyses.
Results
Dilated LAVI was observed in 181 (32.7%) patients. The mean indexed aortic annulus, sinus of Valsalva, sinotubular junction and ascending aorta diameters were 13.0±2.0 mm/m2, 19.4±3.7 mm/m2, 16.5±3.8 mm/m2 and 20.4±4.5 mm/m2, respectively. After a median follow-up of 23 (4-82) months, 272 patients underwent aortic valve surgery (89%) or died (11%). When compared with patients with normal LAVI (<35 mL/m2), those with a dilated LAVI (≥35 mL/m2) had significantly higher rates of aortic valve surgery or mortality (43% and 60% vs 23% and 36%, at 1 and 5 years of follow-up, respectively, p<0.001). Dilated LAVI was independently associated with reduced event-free survival (HR=1.450, 95% CI 1.085 to 1.938, p=0.012) after adjustment for LV ejection fraction, aortic root diameter, LV end-diastolic diameter and LV end-systolic diameter.
Conclusions
In this large, multicentre registry of patients with BAV and moderate to severe AR, left atrial dilation was independently associated with reduced event-free survival. The role of this parameter for the risk stratification of individuals with significant AR merits further investigation.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 07 Apr 2021; epub ahead of print
Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Heart: 07 Apr 2021; epub ahead of print | PMID: 33833069
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Abstract

Cardiovascular magnetic resonance imaging: emerging techniques and applications.

Chowdhary A, Garg P, Das A, Nazir MS, Plein S
This review gives examples of emerging cardiovascular magnetic resonance (CMR) techniques and applications that have the potential to transition from research to clinical application in the near future. Four-dimensional flow CMR (4D-flow CMR) allows time-resolved three-directional, three-dimensional (3D) velocity-encoded phase-contrast imaging for 3D visualisation and quantification of valvular or intracavity flow. Acquisition times of under 10 min are achievable for a whole heart multidirectional data set and commercial software packages are now available for data analysis, making 4D-flow CMR feasible for inclusion in clinical imaging protocols. Diffusion tensor imaging (DTI) is based on the measurement of molecular water diffusion and uses contrasting behaviour in the presence and absence of boundaries to infer tissue structure. Cardiac DTI is capable of non-invasively phenotyping the 3D micro-architecture within a few minutes, facilitating transition of the method to clinical protocols. Hybrid positron emission tomography-magnetic resonance (PET-MR) provides quantitative PET measures of biological and pathological processes of the heart combined with anatomical, morphological and functional CMR imaging. Cardiac PET-MR offers opportunities in ischaemic, inflammatory and infiltrative heart disease.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:697-704
Chowdhary A, Garg P, Das A, Nazir MS, Plein S
Heart: 29 Apr 2021; 107:697-704 | PMID: 33402364
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Abstract

Dynamic Systolic Changes in Tricuspid Regurgitation Vena Contracta Size and Proximal Isovelocity Surface Area in Hypoplastic Left Heart Syndrome: A Three-Dimensional Color Doppler Echocardiography Study.

Li L, Colen TM, Jani V, Barnes BT, ... Danford DA, Kutty S
Purpose
The purpose of our study was to investigate the dynamic changes in the vena contracta (VC) and proximal isovelocity surface area (PISA) through systole in patients with hypoplastic left heart syndrome (HLHS) and tricuspid regurgitation (TR), and to identify the stage of systole (early, mid, or late) where VC and PISA radius are optimal.
Methods
We prospectively studied 28 patients with HLHS using continuous 2D and 3D echocardiography (2DE, 3DE) (X7-2, iE33, Philips). 2D vena contracta width (VCW), 3D vena contracta area (VCA), and PISA radii (2D and 3D) were measured frame-by-frame throughout systole. The maximal 2D VCW, 3D VCA, and PISA radii in the first, middle, and last third of systole were compared, and correlations explored with 3D tricuspid annular areas, right atrial (RA) volumes and right ventricular (RV) volumes.
Results
In all, 35 datasets that met inclusion criteria were analyzed. On frame-by-frame analysis, maximal 2D VCW and 3D VCA were found in the 1st third of systole in 17% and 20% of studies, in the 2nd third in 34% and 31%, and final third in 49% and 49%. Similarly, the maximal 2D and 3D PISA radii were found in the 1st third of systole in 26% and 17% of studies, in the 2nd third in 28% and 34%, and in the final third in 46% and 49%.
Conclusions
In HLHS, detailed temporal analysis of TR associated VC and PISA by 2DE and 3DE reveals no reliable pattern predicting when in systole these parameters peak. Frame by frame measurement is necessary for identification of maximal VC and PISA radius on 2DE and 3DE color Doppler because the severity of TR could be underestimated due to temporal variability in VC and PISA.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 18 Mar 2021; epub ahead of print
Li L, Colen TM, Jani V, Barnes BT, ... Danford DA, Kutty S
J Am Soc Echocardiogr: 18 Mar 2021; epub ahead of print | PMID: 33753189
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Abstract

Three-Dimensional Echocardiographic Left Atrial Appendage Volumetric Analysis.

Meltzer SN, Phatak PM, Fazlalizadeh H, Chang I, ... Kumar P, Medvedofsky D
Background
Left atrial appendage (LAA) echocardiographic assessment is difficult because of its complex shape and relatively small size. Three-dimensional echocardiographic (3DE) imaging can overcome the limitations of two-dimensional (2D) imaging. Pulsed wave (PW) Doppler is the only currently standard LAA functional parameter. The aim of this study was to test a new approach for 3DE volumetric analysis to obtain LAA ejection fraction (EF), its size and shape.
Methods
Transesophageal 2D and 3D LAA images were prospectively obtained in 159 consecutive patients. LAA volumes were measured from 3DE images using available software. PW Doppler was considered the reference value for LAA function, and used for comparison with LAA EF. Comparison to cardiac computed tomography (CT) was performed in a subgroup of 32 patients. Comparisons included linear regression and Bland-Altman analyses. Repeated measurements were performed to assess measurement variability.
Results
Nine patients were excluded because of suboptimal image quality (94%feasibility). 3D LAA calculated EF was in good agreement with LAA PW measurements. 3D morphologic evaluation showed that 43% of the patients had \"chicken wing\", 33% \"cactus\", 19% \"windsock\" and 5% Cauliflower shape. At the time of data acquisition, patients with atrial fibrillation had non-significantly larger LAA end-systolic and diastolic volumes (ESV, EDV), leading to a lower calculated EF. 3DE LAA ESVs were in good agreement with cardiac CT (r = 0.75), with small biases: -2.5±3.9ml. Reproducibility was better for larger LAA volumes.
Conclusions
A novel 3DE approach can determine geometry, size, and function of the LAA. A new parameter, LAA EF, provides functional quantitation.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 24 Mar 2021; epub ahead of print
Meltzer SN, Phatak PM, Fazlalizadeh H, Chang I, ... Kumar P, Medvedofsky D
J Am Soc Echocardiogr: 24 Mar 2021; epub ahead of print | PMID: 33775733
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Abstract

Current gaps in HFpEF trials: Time to reconsider patients\' selection and to target phenotypes.

Palazzuoli A, Caravita S, Paolillo S, Ghio S, ... Senni M, Italian Society of Cardiology Heart Failure Study Group
Heart Failure with preserved Ejection Fraction (HFpEF) is an increasingly prevalent clinical condition associated with cardiovascular aging, characterized by different pathophysiological mechanisms and poor outcomes. In this manuscript, we analysed the main differences in terms of updated diagnostic criteria and patients\' selection in the most recent HFpEF trials. Recent algorithm purposed for HFpEF diagnosis, does not reflect common criteria adopted in clinical trials. Patients included in the larger studies experienced different characteristics in terms of clinical presentation and echocardiographic features. Current concerns complicate results interpretation and could hypothesize different stages of disease progression, rather than different cardiac phenotypes. Both the lack of diagnostic standardization and the population heterogeneity, might explain why trials investigating the effects of different therapeutic interventions failed to show improved outcomes for patients with HFpEF. Accordingly, we propose to exceed current view mainly based on the morphological adaptations evaluating patients\' characterisation, their cardiovascular risk, associated diseases, and structural features consistent with disease progression. Detailed clinical, imaging and biological characterisation of this population, along with the identification of mechanisms linked with disease progression and prognosis, would allow for tailored treatments and provide important mechanistic insights into the complex HFpEF pathophysiology.

Copyright © 2021. Published by Elsevier Inc.

Prog Cardiovasc Dis: 07 Apr 2021; epub ahead of print
Palazzuoli A, Caravita S, Paolillo S, Ghio S, ... Senni M, Italian Society of Cardiology Heart Failure Study Group
Prog Cardiovasc Dis: 07 Apr 2021; epub ahead of print | PMID: 33839166
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This program is still in alpha version.