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Abstract

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19.

Weinreich DM, Sivapalasingam S, Norton T, Ali S, ... Yancopoulos GD, Trial Investigators
Background
In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern.
Methods
In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated.
Results
Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups.
Conclusions
REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 28 Sep 2021; epub ahead of print
Weinreich DM, Sivapalasingam S, Norton T, Ali S, ... Yancopoulos GD, Trial Investigators
N Engl J Med: 28 Sep 2021; epub ahead of print | PMID: 34587383
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Abstract

Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.

Witberg G, Barda N, Hoss S, Richter I, ... Balicer RD, Kornowski R
Background
Reports have suggested an association between the development of myocarditis and the receipt of messenger RNA (mRNA) vaccines against coronavirus disease 2019 (Covid-19), but the frequency and severity of myocarditis after vaccination have not been extensively explored.
Methods
We searched the database of Clalit Health Services, the largest health care organization (HCO) in Israel, for diagnoses of myocarditis in patients who had received at least one dose of the BNT162b2 mRNA vaccine (Pfizer-BioNTech). The diagnosis of myocarditis was adjudicated by cardiologists using the case definition used by the Centers for Disease Control and Prevention. We abstracted the presentation, clinical course, and outcome from the patient\'s electronic health record. We performed a Kaplan-Meier analysis of the incidence of myocarditis up to 42 days after the first vaccine dose.
Results
Among more than 2.5 million vaccinated HCO members who were 16 years of age or older, 54 cases met the criteria for myocarditis. The estimated incidence per 100,000 persons who had received at least one dose of vaccine was 2.13 cases (95% confidence interval [CI], 1.56 to 2.70). The highest incidence of myocarditis (10.69 cases per 100,000 persons; 95% CI, 6.93 to 14.46) was reported in male patients between the ages of 16 and 29 years. A total of 76% of cases of myocarditis were described as mild and 22% as intermediate; 1 case was associated with cardiogenic shock. After a median follow-up of 83 days after the onset of myocarditis, 1 patient had been readmitted to the hospital, and 1 had died of an unknown cause after discharge. Of 14 patients who had left ventricular dysfunction on echocardiography during admission, 10 still had such dysfunction at the time of hospital discharge. Of these patients, 5 underwent subsequent testing that revealed normal heart function.
Conclusions
Among patients in a large Israeli health care system who had received at least one dose of the BNT162b2 mRNA vaccine, the estimated incidence of myocarditis was 2.13 cases per 100,000 persons; the highest incidence was among male patients between the ages of 16 and 29 years. Most cases of myocarditis were mild or moderate in severity. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 05 Oct 2021; epub ahead of print
Witberg G, Barda N, Hoss S, Richter I, ... Balicer RD, Kornowski R
N Engl J Med: 05 Oct 2021; epub ahead of print | PMID: 34614329
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Abstract

Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.

Mevorach D, Anis E, Cedar N, Bromberg M, ... Keinan-Boker L, Alroy-Preis S
Background
Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance.
Methods
We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons.
Results
Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637.
Conclusions
The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 05 Oct 2021; epub ahead of print
Mevorach D, Anis E, Cedar N, Bromberg M, ... Keinan-Boker L, Alroy-Preis S
N Engl J Med: 05 Oct 2021; epub ahead of print | PMID: 34614328
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Abstract

Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism.

Haghikia A, Zimmermann F, Schumann P, Jasina A, ... Haghikia A, Landmesser U
Aims
Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism.
Methods and results
Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels.
Conclusion
Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

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: 30 Sep 2021; epub ahead of print
Haghikia A, Zimmermann F, Schumann P, Jasina A, ... Haghikia A, Landmesser U
Eur Heart J: 30 Sep 2021; epub ahead of print | PMID: 34597388
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Abstract

Troponin-Guided Coronary Computed Tomographic Angiography After Exclusion of Myocardial Infarction.

Lee KK, Bularga A, O\'Brien R, Ferry AV, ... Gray AJ, Mills NL
Background
Patients with suspected acute coronary syndrome in whom myocardial infarction has been excluded are at risk of future adverse cardiac events.
Objectives
This study evaluated the usefulness of high-sensitivity cardiac troponin I (hs-cTnI) to select patients for further investigation after myocardial infarction has been excluded.
Methods
This is a prospective cohort study of patients presenting to the emergency department with suspected acute coronary syndrome and hs-cTnI concentrations below the sex-specific 99th percentile. Patients were recruited in a 2:1 fashion, stratified by peak hs-cTnI concentration above and below the risk stratification threshold of 5 ng/L. All patients underwent coronary computed tomography angiography (CCTA) after hospital discharge.
Results
Overall, 250 patients were recruited (61.4 ± 12.2 years 31% women) in whom 62.4% (156 of 250 patients) had coronary artery disease (CAD). Patients with intermediate hs-cTnI concentrations (between 5 ng/L and the sex-specific 99th percentile) were more likely to have CAD than those with hs-cTnI concentrations <5 ng/L (71.9% [120 of 167 patients] vs 43.4% [36 of 83 patients]; odds ratio: 3.33; 95% CI: 1.92-5.78). Conversely, there was no association between anginal symptoms and CAD (63.2% [67 of 106 patients] vs 61.8% [89 of 144 patients]; odds ratio: 0.92; 95% CI: 0.48-1.76). Most patients with CAD did not have a previous diagnosis (53.2%; 83 of 156 patients) and were not on antiplatelet and statin therapies (63.5%; 99 of 156 patients) before they underwent CCTA.
Conclusions
In patients who had myocardial infarction excluded, CAD was 3× more likely in those with intermediate hs-cTnI concentrations compared with low hs-cTnI concentrations. In such patients, CCTA could help to identify those with occult CAD and to target preventative treatments, thereby improving clinical outcomes.

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

J Am Coll Cardiol: 04 Oct 2021; 78:1407-1417
Lee KK, Bularga A, O'Brien R, Ferry AV, ... Gray AJ, Mills NL
J Am Coll Cardiol: 04 Oct 2021; 78:1407-1417 | PMID: 34593122
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Abstract

Day-to-day measurement of physical activity and risk of atrial fibrillation.

Bonnesen MP, Frodi DM, Haugan KJ, Kronborg C, ... Svendsen JH, Diederichsen SZ
Aims 
The aim of this study was to investigate the association between within-individual changes in physical activity and onset of atrial fibrillation (AF).
Methods and results 
A total of 1410 participants from the general population (46.2% women, mean age 74.7 ± 4.1 years) with risk factors but with no prior AF diagnosis underwent continuous monitoring for AF episodes along with daily accelerometric assessment of physical activity using an implantable loop recorder during ≈3.5 years. The combined duration of monitoring was ≈1.6 million days, where 10 851 AF episodes lasting ≥60 min were detected in 361 participants (25.6%) with a median of 5 episodes (2, 25) each. The median daily physical activity was 112 (66, 168) min/day. A dynamic parameter describing within-individual changes in daily physical activity, i.e. average daily activity in the last week compared to the previous 100 days, was computed and used to model the onset of AF. A 1-h decrease in average daily physical activity was associated with AF onset the next day [odds ratio 1.24 (1.18-1.31)]. This effect was modified by overall level of activity (P < 0.001 for interaction), and the signal was strongest in the tertile of participants with lowest activity overall [low: 1.62 (1.41-1.86), mid: 1.27 (1.16-1.39), and high: 1.10 (1.01-1.19)].
Conclusions 
Within-individual changes in physical activity are associated with the onset of AF episodes as detected by continuous monitoring in a high-risk population. For each person, a 1-h decrease in daily physical activity during the last week increased the odds of AF onset the next day by ≈25%, while the strongest association was seen in the group with the lowest activity overall.
Clinical trial registration
ClinicalTrials.gov, identifier: NCT02036450.

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

Eur Heart J: 06 Oct 2021; 42:3979-3988
Bonnesen MP, Frodi DM, Haugan KJ, Kronborg C, ... Svendsen JH, Diederichsen SZ
Eur Heart J: 06 Oct 2021; 42:3979-3988 | PMID: 34471928
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Abstract

Assessing Microvascular Dysfunction in Angina With Unobstructed Coronary Arteries: JACC Review Topic of the Week.

Jansen TPJ, Konst RE, Elias-Smale SE, van den Oord SC, ... van Royen N, Damman P
Coronary microvascular dysfunction is a highly prevalent condition of both structural and functional coronary disorders in patients with angina and nonobstructive coronary artery disease (ANOCA). Current diagnostic modalities to assess microvascular function are related to prognosis, but these modalities have several technical shortcomings and lack the opportunity to determine true coronary blood flow and microvascular resistance. Intracoronary continuous thermodilution assessment of absolute coronary flow (Q) and microvascular resistance (R) was recently shown to be safe and feasible in ANOCA. Further exploration and implementation could lead to a better understanding and treatment of patients with ANOCA. This review discuss the coronary pathophysiology of microvascular dysfunction, provides an overview of noninvasive and invasive diagnostics, and focuses on the novel continuous thermodilution method. Finally, how these measurements of absolute Q and R could be integrated and how this would affect future clinical care are discussed.

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

J Am Coll Cardiol: 04 Oct 2021; 78:1471-1479
Jansen TPJ, Konst RE, Elias-Smale SE, van den Oord SC, ... van Royen N, Damman P
J Am Coll Cardiol: 04 Oct 2021; 78:1471-1479 | PMID: 34593129
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Abstract

Stress Cardiac Magnetic Resonance Myocardial Perfusion Imaging: JACC Review Topic of the Week.

Patel AR, Salerno M, Kwong RY, Singh A, Heydari B, Kramer CM
Stress cardiovascular magnetic resonance imaging (CMR) is a cost-effective, noninvasive test that accurately assesses myocardial ischemia, myocardial viability, and cardiac function without the need for ionizing radiation. There is a large body of literature, including randomized controlled trials, validating its diagnostic performance, risk stratification capabilities, and ability to guide appropriate use of coronary intervention. Specifically, stress CMR has shown higher diagnostic sensitivity than single-photon emission computed tomography imaging in detecting angiographically significant coronary artery disease. Stress CMR is particularly valuable for the evaluation of patients with moderate to high pretest probability of having stable ischemic heart disease and for patients known to have challenging imaging characteristics, including women, individuals with prior revascularization, and those with left ventricular dysfunction. This paper reviews the basics principles of stress CMR, the data supporting its clinical use, the added-value of myocardial blood flow quantification, and the assessment of myocardial function and viability routinely obtained during a stress CMR study.

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

J Am Coll Cardiol: 18 Oct 2021; 78:1655-1668
Patel AR, Salerno M, Kwong RY, Singh A, Heydari B, Kramer CM
J Am Coll Cardiol: 18 Oct 2021; 78:1655-1668 | PMID: 34649703
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Abstract

Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review.

Del Buono MG, Montone RA, Camilli M, Carbone S, ... Niccoli G, Crea F
Coronary microvascular dysfunction (CMD) encompasses several pathogenetic mechanisms involving coronary microcirculation and plays a major role in determining myocardial ischemia in patients with angina without obstructive coronary artery disease, as well as in several other conditions, including obstructive coronary artery disease, nonischemic cardiomyopathies, takotsubo syndrome, and heart failure, especially the phenotype associated with preserved ejection fraction. Unfortunately, despite the identified pathophysiological and prognostic role of CMD in several conditions, to date, there is no specific treatment for CMD. Due to the emerging role of CMD as common denominator in different clinical phenotypes, additional research in this area is warranted to provide personalized treatments in this \"garden variety\" of patients. The purpose of this review is to describe the pathophysiological mechanisms of CMD and its mechanistic and prognostic role across different cardiovascular diseases. We will also discuss diagnostic modalities and the potential therapeutic strategies resulting from recent clinical studies.

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

J Am Coll Cardiol: 27 Sep 2021; 78:1352-1371
Del Buono MG, Montone RA, Camilli M, Carbone S, ... Niccoli G, Crea F
J Am Coll Cardiol: 27 Sep 2021; 78:1352-1371 | PMID: 34556322
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Abstract

Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.

Böhm M, Anker SD, Butler J, Filippatos G, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Background
Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known.
Objectives
The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods
Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin\'s effects and significance on SBP.
Results
Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension.
Conclusions
Empagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (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: 27 Sep 2021; 78:1337-1348
Böhm M, Anker SD, Butler J, Filippatos G, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
J Am Coll Cardiol: 27 Sep 2021; 78:1337-1348 | PMID: 34556320
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Abstract

Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca-ATPase Expression in Cardiomyocytes.

Korf-Klingebiel M, Reboll MR, Polten F, Weber N, ... Wang Y, Wollert KC
Background
Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation\'s potential benefits. Inflammatory cells secrete MYDGF (myeloid-derived growth factor) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload.
Methods
We defined the cellular sources and function of MYDGF in wild-type (WT), Mydgf-deficient (Mydgf-/-), and Mydgf bone marrow-chimeric or bone marrow-conditional transgenic mice with pressure overload-induced heart failure after transverse aortic constriction surgery. We measured MYDGF plasma concentrations by targeted liquid chromatography-mass spectrometry. We identified MYDGF signaling targets by phosphoproteomics and substrate-based kinase activity inference. We recorded Ca2+ transients and sarcomere contractions in isolated cardiomyocytes. Additionally, we explored the therapeutic potential of recombinant MYDGF.
Results
MYDGF protein abundance increased in the left ventricular myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While Mydgf-/- mice had no apparent phenotype at baseline, they developed more severe left ventricular hypertrophy and contractile dysfunction during pressure overload than WT mice. Conversely, conditional transgenic overexpression of MYDGF in bone marrow-derived inflammatory cells attenuated pressure overload-induced hypertrophy and dysfunction. Mechanistically, MYDGF inhibited G protein-coupled receptor agonist-induced hypertrophy and augmented SERCA2a (sarco/endoplasmic reticulum Ca2+-ATPase 2a) expression in cultured neonatal rat ventricular cardiomyocytes by enhancing PIM1 (Pim-1 proto-oncogene, serine/threonine kinase) expression and activity. Along this line, cardiomyocytes from pressure-overloaded Mydgf-/- mice displayed reduced PIM1 and SERCA2a expression, greater hypertrophy, and impaired Ca2+ cycling and sarcomere function compared with cardiomyocytes from pressure-overloaded WT mice. Transplanting Mydgf-/- mice with WT bone marrow cells augmented cardiac PIM1 and SERCA2a levels and ameliorated pressure overload-induced hypertrophy and dysfunction. Pressure-overloaded Mydgf-/- mice were similarly rescued by adenoviral Serca2a gene transfer. Treating pressure-overloaded WT mice subcutaneously with recombinant MYDGF enhanced SERCA2a expression, attenuated left ventricular hypertrophy and dysfunction, and improved survival.
Conclusions
These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure.



Circulation: 11 Oct 2021; 144:1227-1240
Korf-Klingebiel M, Reboll MR, Polten F, Weber N, ... Wang Y, Wollert KC
Circulation: 11 Oct 2021; 144:1227-1240 | PMID: 34372689
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Abstract

Interferon-gamma Impairs Human Coronary Artery Endothelial Glucose Metabolism via Tryptophan Catabolism and Activates Fatty Acid Oxidation.

Lee LY, Oldham WM, He H, Wang R, ... Handy DE, Loscalzo J
Background: Endothelial cells depend on glycolysis for much of their energy production. Impaired endothelial glycolysis has been associated with various vascular pathobiologies, including impaired angiogenesis and atherogenesis. Interferon-gamma (IFN-γ)-producing CD4+ and CD8+ T-lymphocytes have been identified as the predominant pathologic cell subsets in human atherosclerotic plaques. While the immunological consequences of these cells have been extensively evaluated, their IFN-γ-mediated metabolic effects on endothelial cells remain unknown. The purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine, IFN-γ, on human coronary artery endothelial cells (HCAEC).
Methods:
The metabolic effects of IFN-γ on primary HCAEC were assessed by unbiased transcriptomic and metabolomic analyses combined with real-time extracellular flux analyses and molecular mechanistic studies. Cellular phenotypic correlations were made by measuring altered endothelial intracellular cyclic guanosine monophosphate (cGMP) content, wound healing capacity, and adhesion molecule expression.
Results:
IFN-γ exposure inhibited basal glycolysis of quiescent primary HCAEC by 20% through the global transcriptional suppression of glycolytic enzymes resulting from decreased basal hypoxia inducible factor 1α (HIF1α) nuclear availability in normoxia. The decrease in HIF1α activity was a consequence of IFN-γ-induced tryptophan catabolism resulting in ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF1β sequestration by the kynurenine-activated aryl hydrocarbon receptor (AHR). Additionally, IFN-γ resulted in a 23% depletion of intracellular NAD+ in HCAEC. This altered glucose metabolism was met with concomitant activation of fatty acid oxidation, which augmented its contribution to intracellular ATP balance by over 20%. These metabolic derangements were associated with adverse endothelial phenotypic changes, including decreased basal intracellular cGMP, impaired endothelial migration, and a switch to a pro-inflammatory state. Conclusions: IFN-γ impairs endothelial glucose metabolism via altered tryptophan catabolism destabilizing HIF1, depletes NAD+, and results in a metabolic shift toward increased fatty acid oxidation. This work suggests a novel mechanistic basis for pathologic T-lymphocyte-endothelial interactions in atherosclerosis mediated by IFN-γ, linking endothelial glucose, tryptophan, and fatty acid metabolism with NAD(H) and ATP generation, and their adverse endothelial functional consequences.




Circulation: 11 Oct 2021; epub ahead of print
Lee LY, Oldham WM, He H, Wang R, ... Handy DE, Loscalzo J
Circulation: 11 Oct 2021; epub ahead of print | PMID: 34636650
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Abstract

Contraction Patterns of the Right Ventricle Associated with Different Degrees of Left Ventricular Systolic Dysfunction.

Surkova E, Kovács A, Tokodi M, Lakatos BK, ... Parati G, Badano LP
Background
The functional adaptation of the right ventricle (RV) to the different degrees of left ventricular (LV) dysfunction remains to be clarified. We sought to (1) assess the changes in RV contraction pattern associated with the reduction of LV ejection fraction (EF) and (2) analyze whether the assessment of RV longitudinal, radial, and anteroposterior motion components of total RVEF adds prognostic value.
Methods
Consecutive patients with left-sided heart disease who underwent clinically indicated transthoracic echocardiography were enrolled in a single-center prospective observational study. Adverse outcome was defined as heart failure hospitalization or cardiac death. Cross-sectional analysis using the baseline 3-dimensional echocardiography studies was performed to quantify the relative contribution of the longitudinal, radial, and anteroposterior motion components to total RVEF.
Results
We studied 292 patients and followed them for 6.7±2.2 years. In patients with mildly and moderately reduced LVEF, the longitudinal and the anteroposterior components of RVEF decreased significantly, while the radial component increased resulting in preserved total RVEF (RVEF: 50% [46%-54%] versus 47% [44%-52%] versus 46% [42%-49%] in patients with no, mild, or moderate LV dysfunction, respectively; data presented as median and interquartile range). In patients with severe LV systolic dysfunction (n=34), a reduction in all 3 RV motion components led to a significant drop in RVEF (30% [25%-39%], P<0.001). In patients with normal RVEF (>45%), the anteroposterior component of total RVEF was a significant and independent predictor of outcome (hazard ratio, 0.960 [CI, 0.925-0.997], P<0.001).
Conclusions
In patients with left-sided heart disease, there is a significant remodeling of the RV associated with preservation of the RVEF in patients with mild or moderate LV dysfunction. In patients with normal RVEF, the measurement of the anteroposterior component of RV motion provided independent prognostic value.



Circ Cardiovasc Imaging: 29 Sep 2021:CIRCIMAGING121012774; epub ahead of print
Surkova E, Kovács A, Tokodi M, Lakatos BK, ... Parati G, Badano LP
Circ Cardiovasc Imaging: 29 Sep 2021:CIRCIMAGING121012774; epub ahead of print | PMID: 34587749
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Abstract

Pulmonary percutaneous valve implantation in large native right ventricular outflow tract with 32 mm Myval transcatheter heart valve.

Rodríguez Ogando A, Ballesteros F, Martínez JLZ
Pulmonary percutaneous valve implantation (PPVI) is feasible with satisfactory mid-term results in patients with native right ventricular outflow tract (RVOT) and has been increasingly used instead of surgically implantable pulmonary valves. Creating a stable landing zone with a diameter less than the largest commercially available valve (previously available 29 mm and currently available 32 mm) is crucial for technical success of the procedure, limiting the number of suitable candidates for PPVI. We report the case of PPVI with a 32 mm Myval transcatheter heart valve in a patient with a large native RVOT (pre-stented with AndraStent XXL mounted on a 35 × 60 mm valve balloon catheter) lesion who had Tetralogy of Fallot surgically corrected. The post-procedural outcomes of this case were satisfactory with no complications reported during the hospital stay.

© 2021 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 20 Oct 2021; epub ahead of print
Rodríguez Ogando A, Ballesteros F, Martínez JLZ
Catheter Cardiovasc Interv: 20 Oct 2021; epub ahead of print | PMID: 34674370
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Impact:
Abstract

The evolving role of cardiac imaging in patients with myocardial infarction and non-obstructive coronary arteries.

Montone RA, Jang IK, Beltrame JF, Sicari R, ... Bucciarelli-Ducci C, Crea F
Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) represents a heterogeneous clinical conundrum accounting for about 6%-8% of all acute MI who are referred for coronary angiography. Current guidelines and consensus documents recommend that these patients are appropriately diagnosed, uncovering the causes of MINOCA, so that specific therapies can be prescribed. Indeed, there are a variety of causes that can result in this clinical condition, and for this reason diagnostic cardiac imaging has an emerging critical role in the assessment of patients with suspected or confirmed MINOCA. In last years, different cardiac imaging techniques have been evaluated in this context, and the comprehension of their strengths and limitations is of the utmost importance for their effective use in clinical practice. Moreover, recent evidence is clearly suggesting that a multimodality cardiac imaging approach, combining different techniques, seems to be crucial for a proper management of MINOCA. However, great variability still exists in clinical practice in the management of patients with suspected MINOCA, also depending on the availability of diagnostic tools and local expertise. Herein, we review the current knowledge supporting the use of different cardiac imaging techniques in patients with MINOCA, underscoring the importance of a comprehensive multimodality cardiac imaging approach and proposing a practical diagnostic algorithm to properly identify and treat the specific causes of MINOCA, in order to improve prognosis and the quality of life in these patients.

Copyright © 2018. Published by Elsevier Inc.

Prog Cardiovasc Dis: 29 Sep 2021; epub ahead of print
Montone RA, Jang IK, Beltrame JF, Sicari R, ... Bucciarelli-Ducci C, Crea F
Prog Cardiovasc Dis: 29 Sep 2021; epub ahead of print | PMID: 34600948
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Abstract

Right-left ventricular shape variations in tetralogy of Fallot: associations with pulmonary regurgitation.

Mauger CA, Govil S, Chabiniok R, Gilbert K, ... Zhong L, Young AA
Background
Relationships between right ventricular (RV) and left ventricular (LV) shape and function may be useful in determining optimal timing for pulmonary valve replacement in patients with repaired tetralogy of Fallot (rTOF). However, these are multivariate and difficult to quantify. We aimed to quantify variations in biventricular shape associated with pulmonary regurgitant volume (PRV) in rTOF using a biventricular atlas.
Methods
In this cross-sectional retrospective study, a biventricular shape model was customized to cardiovascular magnetic resonance (CMR) images from 88 rTOF patients (median age 16, inter-quartile range 11.8-24.3 years). Morphometric scores quantifying biventricular shape at end-diastole and end-systole were computed using principal component analysis. Multivariate linear regression was used to quantify biventricular shape associations with PRV, corrected for age, sex, height, and weight. Regional associations were confirmed by univariate correlations with distances and angles computed from the models, as well as global systolic strains computed from changes in arc length from end-diastole to end-systole.
Results
PRV was significantly associated with 5 biventricular morphometric scores, independent of covariates, and accounted for 12.3% of total shape variation (p < 0.05). Increasing PRV was associated with RV dilation and basal bulging, in conjunction with decreased LV septal-lateral dimension (LV flattening) and systolic septal motion towards the RV (all p < 0.05). Increased global RV radial, longitudinal, circumferential and LV radial systolic strains were significantly associated with increased PRV (all p < 0.05).
Conclusion
A biventricular atlas of rTOF patients quantified multivariate relationships between left-right ventricular morphometry and wall motion with pulmonary regurgitation. Regional RV dilation, LV reduction, LV septal-lateral flattening and increased RV strain were all associated with increased pulmonary regurgitant volume. Morphometric scores provide simple metrics linking mechanisms for structural and functional alteration with important clinical indices.

© 2021. The Author(s).

J Cardiovasc Magn Reson: 06 Oct 2021; 23:105
Mauger CA, Govil S, Chabiniok R, Gilbert K, ... Zhong L, Young AA
J Cardiovasc Magn Reson: 06 Oct 2021; 23:105 | PMID: 34615541
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This program is still in alpha version.