Topic: Journal Club Selection

Abstract

Diastolic Function and Clinical Outcomes After Transcatheter Aortic Valve Replacement: PARTNER 2 SAPIEN 3 Registry.

Ong G, Pibarot P, Redfors B, Weissman NJ, ... Douglas PS, Hahn RT
Background
Few studies have evaluated if diastolic function could predict outcomes in patients with aortic stenosis.
Objectives
The authors aimed to assess the association between diastolic dysfunction (DD) and outcomes in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR).
Methods
Baseline, 30-day, and 1- and 2-year transthoracic echocardiograms from the PARTNER (Placement of Aortic Transcatheter Valves) 2 SAPIEN 3 registry were analyzed by a consortium of core laboratories and divided into the American Society of Echocardiography DD groups.
Results
Among the 1,750 included, 682 (54.4%) had grade 1 DD, 352 (28.1%) had grade 2 DD, 168 (13.4%) had grade 3 DD, and 51 (4.1%) had indeterminate DD grade. Incremental baseline grades of DD were associated with an increase in combined 1- and 2-year cardiovascular (CV) death/rehospitalization (all p < 0.002) and all-cause death at 2 years (p = 0.01) but not at 1 year. Improvement in DD grade/grade 1 DD at 30 days post-TAVR was seen in 70.8% patients. Patients with improvement in ≥1 grade of DD/grade 1 DD had reduced 1-year CV death/rehospitalization (p < 0.001) and increased 2-year survival (p = 0.01). Baseline grade 3 DD was a predictor of 1-year CV death/rehospitalization (hazard ratio: 2.73; 95% confidence interval: 1.07 to 6.98; p = 0.04). Improvement in DD grade/grade 1 DD at 30 days was protective for 1-year CV death/rehospitalizations (hazard ratio: 0.39; 95% confidence interval: 0.19 to 0.83; p = 0.01).
Conclusions
In the PARTNER 2 SAPIEN 3 registry, baseline DD was a predictor of up to 2 years clinical outcomes in patients who underwent TAVR. Improvement in DD grade at 30 days was associated with improvement in short-term clinical outcomes. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - PARTNER II - PARTNERII - S3 Intermediate [PARTNERII S3i]; NCT03222128; PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - High Risk and Nested Registry 7 [PII S3HR/NR7]; NCT03222141).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Dec 2020; 76:2940-2951
Ong G, Pibarot P, Redfors B, Weissman NJ, ... Douglas PS, Hahn RT
J Am Coll Cardiol: 21 Dec 2020; 76:2940-2951 | PMID: 33334422
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Abstract

Evolution of antithrombotic therapy in patients undergoing percutaneous coronary intervention: a 40-year journey.

Cao D, Chandiramani R, Chiarito M, Claessen BE, Mehran R

Since its introduction in 1977, percutaneous coronary intervention has become one of the most commonly performed therapeutic procedures worldwide. Such widespread diffusion, however, would have not been possible without a concomitant evolution of the pharmacotherapies associated with this intervention. Antithrombotic agents are fundamental throughout the management of patients undergoing coronary stent implantation, starting from the procedure itself to the long-term prevention of cardiovascular events. The last 40 years of interventional cardiology have seen remarkable improvements in both drug therapies and device technologies, which largely reflected a progressive understanding of the pathophysiological mechanisms of coronary artery disease, as well as procedure- and device-related adverse events. The purpose of this article is to provide an overview of the important milestones in antithrombotic pharmacology that have shaped clinical practice of today while also providing insights into knowledge gaps and future directions.

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

Eur Heart J: 25 Dec 2020; epub ahead of print
Cao D, Chandiramani R, Chiarito M, Claessen BE, Mehran R
Eur Heart J: 25 Dec 2020; epub ahead of print | PMID: 33367641
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Abstract

Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission.

Wei AH, Döhner H, Pocock C, Montesinos P, ... Roboz GJ,
Background
Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.
Methods
We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.
Results
A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.
Conclusions
CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 23 Dec 2020; 383:2526-2537
Wei AH, Döhner H, Pocock C, Montesinos P, ... Roboz GJ,
N Engl J Med: 23 Dec 2020; 383:2526-2537 | PMID: 33369355
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Abstract

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome.

Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Aims 
Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.
Methods and results 
Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.
Conclusion 
Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

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

Eur Heart J: 22 Dec 2020; epub ahead of print
Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Eur Heart J: 22 Dec 2020; epub ahead of print | PMID: 33355356
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Abstract

Calcium-Induced Autonomic Denervation in Patients With Post-Operative Atrial Fibrillation.

Wang H, Zhang Y, Xin F, Jiang H, ... Wang Q, Po SS
Background
Post-operative atrial fibrillation (POAF) is associated with worse long-term cardiovascular outcomes.
Objectives
This study hypothesized that injecting calcium chloride (CaCl) into the major atrial ganglionated plexi (GPs) during isolated coronary artery bypass grafting (CABG) can reduce the incidence of POAF by calcium-induced autonomic neurotoxicity.
Methods
This proof-of-concept study randomized 200 patients undergoing isolated, off-pump CABG to CaCl (n = 100) or sodium chloride (sham, n = 100) injection. Two milliliters of CaCl (5%) or sodium chloride (0.9%) was injected into the 4 major atrial GPs during CABG. All patients received 7-day continuous telemetry and Holter monitoring. The primary outcome was incidence of POAF (≥30 s) in 7 days. Secondary outcomes included length of hospitalization, POAF burden, average ventricular rate during AF, plasma level of inflammatory markers, and actionable antiarrhythmic therapy to treat POAF.
Results
The POAF incidence was reduced from 36% to 15% (hazard ratio: 0.366; 95% confidence interval: 0.211 to 0.635; p = 0.001). Length of hospitalization did not differ between the 2 groups. POAF burden (first 7 post-operative days), the use of amiodarone or esmolol, and the incidence of atrial couplets and nonsustained atrial tachyarrhythmias were significantly reduced in the CaCl group. Heart rate variability data showed a decrease in both high-frequency and low-frequency power in the CaCl group with a preserved low-frequency/high-frequency ratio, suggesting that the sympathetic/parasympathetic balance was not perturbed by CaCl injection.
Conclusions
Injection of CaCl into the 4 major atrial GPs reduced the POAF hazard by 63%. Inhibition of GP function by Ca-mediated neurotoxicity may underlie the therapeutic effect. (Calcium Autonomic Denervation Prevents Postoperative Atrial Fibrillation; ChiCTR1800019276).

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

J Am Coll Cardiol: 04 Jan 2021; 77:57-67
Wang H, Zhang Y, Xin F, Jiang H, ... Wang Q, Po SS
J Am Coll Cardiol: 04 Jan 2021; 77:57-67 | PMID: 33413942
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Abstract

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

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

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

Eur Heart J: 21 Dec 2020; epub ahead of print
Abraham WT, Lindenfeld J, Ponikowski P, Agostoni P, ... Salsali A, Anker SD
Eur Heart J: 21 Dec 2020; epub ahead of print | PMID: 33351892
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Abstract

Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes.

Csengeri D, Sprünker NA, Di Castelnuovo A, Niiranen T, ... Iacoviello L, Schnabel RB
Aims 
There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts.
Methods and results 
In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF.
Conclusions 
In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.

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

Eur Heart J: 12 Jan 2021; epub ahead of print
Csengeri D, Sprünker NA, Di Castelnuovo A, Niiranen T, ... Iacoviello L, Schnabel RB
Eur Heart J: 12 Jan 2021; epub ahead of print | PMID: 33438022
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Abstract

Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial.

Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M,
Aims
In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction.
Methods and results
Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains.
Conclusion
Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.

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

Eur Heart J: 08 Jan 2021; epub ahead of print
Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M,
Eur Heart J: 08 Jan 2021; epub ahead of print | PMID: 33420498
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Abstract

Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study.

Holt A, Blanche P, Zareini B, Rajan D, ... Gislason GH, Lamberts M

Listen to the audio abstract of this contribution at https://doi.org/10.1093/eurheartj/ehaa1058.
Aims
We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in stable, optimally treated myocardial infarction (MI) patients without heart failure (HF).
Methods and results
Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive, free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differences (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26% sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age 61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD (95% confidence intervals)] correspondingly; 0.1% (-0.3% to 0.5%), 0.2% (-0.7% to 1.2%), and 1.2% (-0.2% to 2.7%).
Conclusions
In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.

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: 10 Jan 2021; epub ahead of print
Holt A, Blanche P, Zareini B, Rajan D, ... Gislason GH, Lamberts M
Eur Heart J: 10 Jan 2021; epub ahead of print | PMID: 33428707
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Abstract

VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration.

Räsänen M, Sultan I, Paech J, Hemanthakumar KA, ... Kivelä R, Alitalo K
Background
Recent discoveries have indicated that, in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. Here we set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B (VEGF-B) in the heart and the effect of VEGF-B on recovery from myocardial infarction.
Methods
We used mice and rats expressing a VEGF-B transgene, VEGF-B-gene-deleted mice and rats, apelin-CreERT, and natriuretic peptide receptor 3-CreERT recombinase-mediated genetic cell lineage tracing and viral vector-mediated VEGF-B gene transfer in adult mice. Left anterior descending coronary vessel ligation was performed, and 5-ethynyl-2\'-deoxyuridine-mediated proliferating cell cycle labeling; flow cytometry; histological, immunohistochemical, and biochemical methods; single-cell RNA sequencing and subsequent bioinformatic analysis; microcomputed tomography; and fluorescent- and tracer-mediated vascular perfusion imaging analyses were used to study the development and function of the VEGF-B-induced vessels in the heart.
Results
We show that cardiomyocyte overexpression of VEGF-B in mice and rats during development promotes the growth of novel vessels that originate directly from the cardiac ventricles and maintain connection with the coronary vessels in subendocardial myocardium. In adult mice, endothelial proliferation induced by VEGF-B gene transfer was located predominantly in the subendocardial coronary vessels. Furthermore, VEGF-B gene transduction before or concomitantly with ligation of the left anterior descending coronary artery promoted endocardium-derived vessel development into the myocardium and improved cardiac tissue remodeling and cardiac function.
Conclusions
The myocardial VEGF-B transgene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in subendocardial myocardium in adult mice, and structural and functional rescue of cardiac tissue after myocardial infarction. VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue.



Circulation: 04 Jan 2021; 143:65-77
Räsänen M, Sultan I, Paech J, Hemanthakumar KA, ... Kivelä R, Alitalo K
Circulation: 04 Jan 2021; 143:65-77 | PMID: 33203221
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Abstract

Redox-Resistant SERCA [Sarco(endo)plasmic Reticulum Calcium ATPase] Attenuates Oxidant-Stimulated Mitochondrial Calcium and Apoptosis in Cardiac Myocytes and Pressure Overload-Induced Myocardial Failure in Mice.

Goodman JB, Qin F, Morgan RJ, Chambers JM, ... Cohen RA, Colucci WS
Background
SERCA [sarco(endo)plasmic reticulum calcium ATPase] is regulated by oxidative posttranslational modifications at cysteine 674 (C674). Because sarcoplasmic reticulum (SR) calcium has been shown to play a critical role in mediating mitochondrial dysfunction in response to reactive oxygen species, we hypothesized that SERCA oxidation at C674 would modulate the effects of reactive oxygen species on mitochondrial calcium and mitochondria-dependent apoptosis in cardiac myocytes.
Methods
Adult rat ventricular myocytes expressing wild-type SERCA2b or a redox-insensitive mutant in which C674 is replaced by serine (C674S) were exposed to HO (100 µmol/Lμ). Free mitochondrial calcium concentration was measured in adult rat ventricular myocytes with a genetically targeted fluorescent probe, and SR calcium content was assessed by measuring caffeine-stimulated release. Mice with heterozygous knock-in of the SERCA C674S mutation were subjected to chronic ascending aortic constriction.
Results
In adult rat ventricular myocytes expressing wild-type SERCA, HO caused a 25% increase in mitochondrial calcium concentration that was associated with a 50% decrease in SR calcium content, both of which were prevented by the ryanodine receptor inhibitor tetracaine. In cells expressing the C674S mutant, basal SR calcium content was decreased by 31% and the HO-stimulated rise in mitochondrial calcium concentration was attenuated by 40%. In wild-type cells, HO caused cytochrome c release and apoptosis, both of which were prevented in C674S-expressing cells. In myocytes from SERCA knock-in mice, basal SERCA activity and SR calcium content were decreased. To test the effect of C674 oxidation on apoptosis in vivo, SERCA knock-in mice were subjected to chronic ascending aortic constriction. In wild-type mice, ascending aortic constriction caused myocyte apoptosis, LV dilation, and systolic failure, all of which were inhibited in SERCA knock-in mice.
Conclusions
Redox activation of SERCA C674 regulates basal SR calcium content, thereby mediating the pathologic reactive oxygen species-stimulated rise in mitochondrial calcium required for myocyte apoptosis and myocardial failure.



Circulation: 21 Dec 2020; 142:2459-2469
Goodman JB, Qin F, Morgan RJ, Chambers JM, ... Cohen RA, Colucci WS
Circulation: 21 Dec 2020; 142:2459-2469 | PMID: 33076678
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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

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.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.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).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

PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36.

Qi Z, Hu L, Zhang J, Yang W, ... Ding Z, Ge J
Background
PCSK9 (proprotein convertase subtilisin/kexin 9), mainly secreted by the liver and released into the blood, elevates plasma low-density lipoprotein cholesterol by degrading low-density lipoprotein receptor. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, and the underlying mechanisms, as well, still remain unclear.
Methods
We detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, α-granule release, spreading, and clot retraction. These studies were complemented by in vivo analysis of FeCl-injured mouse mesenteric arteriole thrombosis. We also investigated the underlying mechanisms. Using the myocardial infarction (MI) model, we explored the effects of PCSK9 on microvascular obstruction and infarct expansion post-MI.
Results
PCSK9 directly enhances agonist-induced platelet aggregation, dense granule ATP release, integrin αIIbβ3 activation, P-selectin release from α-granules, spreading, and clot retraction. In line, PCSK9 enhances in vivo thrombosis in a FeCl-injured mesenteric arteriole thrombosis mouse model, whereas PCSK9 inhibitor evolocumab ameliorates its enhancing effects. Mechanism studies revealed that PCSK9 binds to platelet CD36 and thus activates Src kinase and MAPK (mitogen-activated protein kinase)-extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase, increases the generation of reactive oxygen species, and activates the p38MAPK/cytosolic phospholipase A2/cyclooxygenase-1/thromboxane A signaling pathways downstream of CD36 to enhance platelet activation, as well. Using CD36 knockout mice, we showed that the enhancing effects of PCSK9 on platelet activation are CD36 dependent. It is important to note that aspirin consistently abolishes the enhancing effects of PCSK9 on platelet activation and in vivo thrombosis. Last, we showed that PCSK9 activating platelet CD36 aggravates microvascular obstruction and promotes MI expansion post-MI.
Conclusions
PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, and MI expansion post-MI, as well, by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors or aspirin abolish the enhancing effects of PCSK9, supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications.



Circulation: 04 Jan 2021; 143:45-61
Qi Z, Hu L, Zhang J, Yang W, ... Ding Z, Ge J
Circulation: 04 Jan 2021; 143:45-61 | PMID: 32988222
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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: 04 Jan 2021; epub ahead of print
Chowdhary A, Garg P, Das A, Nazir MS, Plein S
Heart: 04 Jan 2021; epub ahead of print | PMID: 33402364
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Abstract

Influence of Chronic Obstructive Pulmonary Disease on Atrial Mechanics by Speckle Tracking Echocardiography in Patients with Atrial Fibrillation.

Goedemans L, Leung M, van der Bijl P, Abou R, ... Delgado V, Bax JJ

The present study aimed to examine differences in left- and right atrial characteristics between atrial fibrillation (AF) patients with and without chronic obstructive pulmonary disease (COPD). For this, 420 patients (mean age 68±10 years, 73% female) with first diagnosis of AF and baseline echocardiography were included. Of these, 143 COPD patients were compared with 277 patients without COPD matched by age, gender and body surface area. Additionally 38 healthy controls without cardiovascular risk factors, matched for age, were included. For all 3 groups, left atrial (LA) volumes and diameter, LA reservoir strain (LASr), left ventricular ejection fraction (LVEF), right atrial (RA) area and diameter, RA reservoir strain (RASr) and tricuspid annular plane systolic excursion (TAPSE) were evaluated on transthoracic echocardiography. Baseline characteristics were similar in patients with and without COPD except for smoking and a history of heart failure (42% vs. 11%, p<0.001 and 48% vs 37%, p=0.036 for COPD and non-COPD patients, respectively). Also, COPD patients less often used β-blockers (63% vs.75%, p=0.017). There were no significant differences in LVEF, LA volume and RA area between COPD and non-COPD patients. Compared to the controls, AF patients had impaired LVEF, LASr and RASr. Only RASr was significantly worse in COPD patients as compared to non-COPD patients (15.3% [9.0 - 25.1] vs. 19.6% [11.8 - 28.5], p=0.013). Additionally, a trend towards worse RASr was observed with increasing COPD severity. In conclusion, AF patients with concomitant COPD have more impaired RA function compared to patients without COPD but with similar atrial size and LA function.

Copyright © 2020. Published by Elsevier Inc.

Am J Cardiol: 21 Dec 2020; epub ahead of print
Goedemans L, Leung M, van der Bijl P, Abou R, ... Delgado V, Bax JJ
Am J Cardiol: 21 Dec 2020; epub ahead of print | PMID: 33359195
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Abstract

Basal Segmental Longitudinal Strain: A Marker of Subclinical Myocardial Involvement in Anderson-Fabry Disease.

Zada M, Lo Q, Boyd AC, Bradley S, ... Tchan MC, Thomas L
Background
Cardiac involvement in Anderson-Fabry disease (AFD) is associated with increased left ventricular (LV) wall thickness. The aim of this study was to evaluate if two-dimensional global and regional strain in patients with AFD can identify early myocardial involvement (when LV wall thickness and function are normal). Additionally, the association of altered strain with adverse cardiovascular events was evaluated.
Methods
In a retrospective cross-sectional study, 43 patients with AFD, before enzyme replacement therapy (mean age, 44 ± 12 years; 58.1% men), were compared with age- and gender-matched healthy control subjects. The mean follow-up duration among patients with AFD for major adverse cardiovascular events (MACE) was 82 months.
Results
LV ejection fraction was similar between groups (patients with AFD vs control subjects, 61 ± 8% vs 61 ± 6%; P = .89). However, global longitudinal strain (LS) was impaired in patients with AFD compared with control subjects (-16.5 ± 3.8% vs -20.2 ± 1.7%, P < .001), with greater impairment in patients with AFD with increased LV wall thickness (-15.4 ± 3.9% vs -18.7 ± 2.3%, P < .006). Additionally, LS was most impaired in the basal segments in patients with AFD (-14.8 ± 3.7% vs -20.3 ± 1.1%, P < .001). MACE occurred in 19 of 43 patients (four women, 15 men), and Kaplan-Meier analysis demonstrated that MACE were associated with impaired basal LS.
Conclusions
In patients with AFD, altered basal LS is present even in those with normal LV wall thickness and is associated with MACE. Therefore, basal LS should be considered when screening for cardiac involvement in AFD, particularly in female patients with AFD with normal LV wall thickness.

Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 23 Dec 2020; epub ahead of print
Zada M, Lo Q, Boyd AC, Bradley S, ... Tchan MC, Thomas L
J Am Soc Echocardiogr: 23 Dec 2020; epub ahead of print | PMID: 33242609
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Abstract

Tricuspid regurgitation in Hypoplastic Left Heart Syndrome: Three-dimensional echocardiography provides additional information in describing jet location.

Mah K, Khoo NS, Tham E, Yaskina M, ... Smallhorn J, Colen T
Background
Twenty-five percent of hypoplastic left heart syndrome (HLHS) patients require tricuspid valve (TV) repair. Location of tricuspid regurgitation (TR) is important in determining the type of repair performed. Three-dimensional echocardiography (3DE) studies report a high incidence of error in 2DE identification of TV leaflets. This study compares 3DE and 2DE assessment of TR in HLHS (jet location, TR grade, reproducibility).
Methods
We performed a retrospective, single center review. Fifty-six HLHS patients with available 2DEs and 3DEs, and mild or greater TR, were included. TR location, grade, vena contracta (VC) area, and TV annulus diameter were measured from 2DE and 3DE. Reproducibility was assessed by blinded reviewers.
Results
3DE identified primary jet location as central (57%), followed by antero-septal (36%). There was poor agreement between 3DE and 2DE findings for jet location (kappa 0.05; CI: -0.08 to 0.19). Interobserver reproducibility for 3DE location was excellent (kappa 0.8), whereas 2DE reproducibility was poor (kappa 0.32). The most common jet location pre-Norwood and pre-Glenn is central (70%); whereas pre-Fontan and post-Fontan the location is central (45%) and anterior-septal (48%). 2DE VC area correlated moderately with 3DE VC area (r = 0.60, p<0.0001). 2DE and 3DE TV annulus diameter for lateral (r = 0.85, p<0.0001) and anterior-posterior (r= 0.74, p= 0.001) dimensions were strongly correlated.
Conclusions
In children with HLHS, 2DE assessment of TR location has poor agreement with 3DE and was poorly reproducible. In contrast, 3DE TR jet location was highly reproducible. Pre-Glenn, a central TR jet was the most common, while post-Glenn central and anteroseptal locations were equal, highlighting the importance of pre-operative identification of TR jet location in HLHS patients.

Copyright © 2020. Published by Elsevier Inc.

J Am Soc Echocardiogr: 25 Dec 2020; epub ahead of print
Mah K, Khoo NS, Tham E, Yaskina M, ... Smallhorn J, Colen T
J Am Soc Echocardiogr: 25 Dec 2020; epub ahead of print | PMID: 33373699
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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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This program is still in alpha version.