Topic: Journal Club Selection

Abstract

Diseases of the Aorta and Kidney Disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Sarafidis P, Martens S, Saratzis A, Kadian-Dodov D, ... Johansen K, for Conference Participants
Chronic kidney disease (CKD) is an independent risk factor for the development of abdominal aortic aneurysm (AAA), as well as for cardiovascular and renal events and all-cause mortality following surgery for AAA or thoracic aortic dissection. In addition, the incidence of acute kidney injury (AKI) after any aortic surgery is particularly high, and this AKI per se is independently associated with future cardiovascular events and mortality. On the other hand, both development of AKI after surgery and the long-term evolution of kidney function differ significantly depending on the type of AAA intervention (open surgery vs. the various subtypes of endovascular repair). Current knowledge regarding AAA in the general population may not be always applicable to CKD patients, as they have a high prevalence of co-morbid conditions and an elevated risk for periprocedural complications. This summary of a Kidney Disease: Improving Global Outcomes Controversies Conference group discussion reviews the epidemiology, pathophysiology, diagnosis, and treatment of Diseases of the Aorta in CKD and identifies knowledge gaps, areas of controversy, and priorities for future research.

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

Cardiovasc Res: 20 Sep 2022; 118:2582-2595
Sarafidis P, Martens S, Saratzis A, Kadian-Dodov D, ... Johansen K, for Conference Participants
Cardiovasc Res: 20 Sep 2022; 118:2582-2595 | PMID: 34469520
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Abstract

PLX3397, a CSF1 receptor inhibitor, limits allotransplantation-induced vascular remodelling.

Almonte VM, Uriyanghai U, Egaña-Gorroño L, Parikh D, ... Riascos-Bernal DF, Sibinga NES
Aims
Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular pathways. While occlusive intimal lesions are composed predominantly of smooth-muscle-like cells (SMLCs), the origin of these cells and the stimuli leading to their accumulation in GVD are uncertain. Macrophages have recently been identified as both potential drivers of intimal hyperplasia and precursors that undergo transdifferentiation to become SMLCs in non-transplant settings. Colony-stimulating factor-1 (CSF1) is a well-known regulator of macrophage development and differentiation, and prior preclinical studies have shown that lack of CSF1 limits GVD. We sought to identify the origins of SMLCs and of cells expressing the CSF1 receptor (CSF1R) in GVD, and to test the hypothesis that pharmacologic inhibition of CSF1 signalling would curtail both macrophage and SMLC activities and decrease vascular occlusion.
Methods and results
We used genetically modified mice and a vascular transplant model with minor antigen mismatch to assess cell origins. We found that neointimal SMLCs derive from both donor and recipient, and that transdifferentiation of macrophages to SMLC phenotype is minimal in this model. Cells expressing CSF1R in grafts were identified as recipient-derived myeloid cells of Cx3cr1 lineage, and these cells rarely expressed smooth muscle marker proteins. Blockade of CSF1R activity using the tyrosine kinase inhibitor PLX3397 limited the expression of genes associated with innate immunity and decreased levels of circulating monocytes and intimal macrophages. Importantly, PLX3397 attenuated the development of GVD in arterial allografts.
Conclusion
These studies provide proof of concept for pharmacologic inhibition of the CSF1/CSF1R signalling pathway as a therapeutic strategy in GVD. Further preclinical testing of this pathway in GVD is warranted.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2718-2731
Almonte VM, Uriyanghai U, Egaña-Gorroño L, Parikh D, ... Riascos-Bernal DF, Sibinga NES
Cardiovasc Res: 20 Sep 2022; 118:2718-2731 | PMID: 34478521
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Abstract

Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart.

Lecour S, Du Pré BC, Bøtker HE, Brundel BJJM, ... Young ME, Van Laake LW
Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2566-2581
Lecour S, Du Pré BC, Bøtker HE, Brundel BJJM, ... Young ME, Van Laake LW
Cardiovasc Res: 20 Sep 2022; 118:2566-2581 | PMID: 34505881
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Abstract

Left atrial appendage thrombus and cerebrovascular events post-transcatheter aortic valve implantation.

van Wiechen MP, Faure ME, Hokken TW, Ooms JF, ... Budde RPJ, Van Mieghem NM
Aims
To elucidate the frequency and clinical impact of left atrial appendage thrombus (LAAT) in patients set for transcatheter aortic valve implantation (TAVI).
Methods and results
All patients undergoing TAVI between January 2014 and June 2020 with analysable multislice computed tomography (MSCT) for LAAT were included. Baseline and procedural characteristics were collected, pre-procedural MSCT\'s were retrospectively analysed for LAAT presence. The primary endpoint was defined as the cumulative incidence of any cerebrovascular event (stroke or transient ischaemic attack) within the first year after TAVI. A Cox proportional hazards model was used to identify predictors.A total of 1050 cases had analysable MSCT. Median age was 80 [interquartile range (IQR) 74-84], median Society of Thoracic Surgeons\' Predicted Risk Of Mortality (STS-PROM) was 3.4% (IQR 2.3-5.5). Thirty-six percent were on oral anticoagulant therapy for atrial fibrillation (AF). LAAT was present in 48 (4.6%) of cases. Patients with LAAT were at higher operative risk [STS-PROM: 4.9% (2.9-7.1) vs. 3.4% (2.3-5.5), P = 0.01], had worse systolic left ventricular function [EF 52% (35-60) vs. 55% (45-65), P = 0.01] and more permanent pacemakers at baseline (35% vs. 10%, P < 0.01). All patients with LAAT had a history of AF and patients with LAAT were more often on vitamin K antagonist-treatment than patients without LAAT [43/47 (91%) vs. 232/329 (71%), P < 0.01]. LAAT [hazard ratio (HR) 2.94 (1.39-6.22), P < 0.01] and the implantation of more than one valve [HR 4.52 (1.79-11.25), P < 0.01] were independent predictors for cerebrovascular events.
Conclusion
Patients with MSCT-identified LAAT were at higher risk for cerebrovascular events during the first year after TAVI.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1345-1353
van Wiechen MP, Faure ME, Hokken TW, Ooms JF, ... Budde RPJ, Van Mieghem NM
Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1345-1353 | PMID: 34322706
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Abstract

Clinical impact of left atrial appendage filling defects in patients undergoing transcatheter aortic valve implantation.

Okuno T, Lanz J, Stortecky S, Heg D, ... Windecker S, Pilgrim T
Aims
Incidental detection of left atrial appendage (LAA) filling defects is a common finding on multi-detector computed tomography in aortic stenosis patients under evaluation for transcatheter aortic valve implantation (TAVI). We aimed to investigate the incidence of LAA filling defects before TAVI and its impact on clinical outcomes.
Methods and results
In a prospective registry, LAA filling defects were retrospectively evaluated and categorized into one of four sub-types: thrombus-like, heterogeneous, horizontal, and Hounsfield Unit (HU)-run-off. The primary endpoint was the composite of cardiovascular death or disabling stroke up to 1-year follow-up. Among 1621 patients undergoing TAVI between August 2007 and June 2018, LAA filling defects were present in 177 patients (11%), and categorized as thrombus-like in 22 (1.4%), heterogeneous in 37 (2.3%), horizontal in 80 (4.9%), and HU-run-off in 38 (2.4%). Compared to patients with normal LAA filling, patients with LAA filling defects had greater prevalence of atrial fibrillation (84.7% vs. 26.4%, P < 0.001) and history of cerebrovascular events (16.4% vs. 10.9%, P = 0.045). The primary endpoint occurred in 131 patients (9.2%) with normal LAA filling and in 36 patients (21.2%) with LAA filling defects (P < 0.001). Subgroup analysis suggested that the risk of disabling stroke was greatest in the thrombus-like pattern (23.0%), followed by the HU-run-off (8.0%), the heterogeneous (6.2%), and the horizontal pattern (1.2%).
Conclusion
LAA filling defects were observed in 11% of aortic stenosis patients undergoing TAVI and associated with an increased risk of cardiovascular death and disabling stroke up to 1 year following TAVI.
Trial registration
https://www.clinicaltrials.gov. NCT01368250.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1354-1364
Okuno T, Lanz J, Stortecky S, Heg D, ... Windecker S, Pilgrim T
Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1354-1364 | PMID: 34463717
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Abstract

Measurement of compensatory arterial remodelling over time with serial coronary computed tomography angiography and 3D metrics.

van den Hoogen IJ, van Rosendael AR, Lin FY, Gianni U, ... Shaw LJ, Bax JJ
Aims
The magnitude of alterations in which coronary arteries remodel and narrow over time is not well understood. We aimed to examine changes in coronary arterial remodelling and luminal narrowing by three-dimensional (3D) metrics from serial coronary computed tomography angiography (CCTA).
Methods and results
From a multicentre registry of patients with suspected coronary artery disease who underwent clinically indicated serial CCTA (median interscan interval = 3.3 years), we quantitatively measured coronary plaque, vessel, and lumen volumes on both scans. Primary outcome was the per-segment change in coronary vessel and lumen volume from a change in plaque volume, focusing on arterial remodelling. Multivariate generalized estimating equations including statins were calculated comparing associations between groups of baseline percent atheroma volume (PAV) and location within the coronary artery tree. From 1245 patients (mean age 61 ± 9 years, 39% women), a total of 5721 segments were analysed. For each 1.00 mm3 increase in plaque volume, the vessel volume increased by 0.71 mm3 [95% confidence interval (CI) 0.63 to 0.79 mm3, P < 0.001] with a corresponding reduction in lumen volume by 0.29 mm3 (95% CI -0.37 to -0.21 mm3, P < 0.001). Serial 3D arterial remodelling and luminal narrowing was similar in segments with low and high baseline PAV (P ≥ 0.496). No differences were observed between left main and non-left main segments, proximal and distal segments and side branch and non-side branch segments (P ≥ 0.281).
Conclusions
Over time, atherosclerotic coronary plaque reveals prominent outward arterial remodelling that co-occurs with modest luminal narrowing. These findings provide additional insight into the compensatory mechanisms involved in the progression of coronary atherosclerosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1336-1344
van den Hoogen IJ, van Rosendael AR, Lin FY, Gianni U, ... Shaw LJ, Bax JJ
Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1336-1344 | PMID: 34468717
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Abstract

Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascular remodelling.

Luo L, Cai Y, Zhang Y, Hsu CG, ... Berk BC, Yan C
Aims
Intimal hyperplasia is a common feature of vascular remodelling disorders. Accumulation of synthetic smooth muscle cell (SMC)-like cells is the main underlying cause. Current therapeutic approaches including drug-eluting stents are not perfect due to the toxicity on endothelial cells and novel therapeutic strategies are needed. Our preliminary screening for dysregulated cyclic nucleotide phosphodiesterases (PDEs) in growing SMCs revealed the alteration of PDE10A expression. Herein, we investigated the function of PDE10A in SMC proliferation and intimal hyperplasia both in vitro and in vivo.
Methods and results
RT-qPCR, immunoblot, and in situ proximity ligation assay were performed to determine PDE10A expression in synthetic SMCs and injured vessels. We found that PDE10A mRNA and/or protein levels are up-regulated in cultured SMCs upon growth stimulation, as well as in intimal cells in injured mouse femoral arteries. To determine the cellular functions of PDE10A, we focused on its role in SMC proliferation. The anti-mitogenic effects of PDE10A on SMCs were evaluated via cell counting, BrdU incorporation, and flow cytometry. We found that PDE10A deficiency or inhibition arrested the SMC cell cycle at G1-phase with a reduction of cyclin D1. The anti-mitotic effect of PDE10A inhibition was dependent on cGMP-dependent protein kinase Iα (PKGIα), involving C-natriuretic peptide (CNP) and particulate guanylate cyclase natriuretic peptide receptor 2 (NPR2). In addition, the effects of genetic depletion and pharmacological inhibition of PDE10A on neointimal formation were examined in a mouse model of femoral artery wire injury. Both PDE10A knockout and inhibition decreased injury-induced intimal thickening in femoral arteries by at least 50%. Moreover, PDE10A inhibition decreased ex vivo remodelling of cultured human saphenous vein segments.
Conclusions
Our findings indicate that PDE10A contributes to SMC proliferation and intimal hyperplasia at least partially via antagonizing CNP/NPR2/cGMP/PKG1α signalling and suggest that PDE10A may be a novel drug target for treating vascular occlusive disease.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2703-2717
Luo L, Cai Y, Zhang Y, Hsu CG, ... Berk BC, Yan C
Cardiovasc Res: 20 Sep 2022; 118:2703-2717 | PMID: 34550322
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Abstract

Left atrial strain is a predictor of left ventricular systolic and diastolic reverse remodelling in CRT candidates.

Galli E, Oger E, Aalen JM, Duchenne J, ... Smiseth OA, Donal E
Aims
The left atrium (LA) has a pivotal role in cardiac performance and LA deformation is a well-known prognostic predictor in several clinical conditions including heart failure with reduced ejection fraction. The aim of this study is to investigate the effect of cardiac resynchronization therapy (CRT) on both LA morphology and function and to assess the impact of LA reservoir strain (LARS) on left ventricular (LV) systolic and diastolic remodelling after CRT.
Methods and results
Two hundred and twenty-one CRT-candidates were prospectively included in the study in four tertiary centres and underwent echocardiography before CRT-implantation and at 6-month follow-up (FU). CRT-response was defined by a 15% reduction in LV end-systolic volume. LV systolic and diastolic remodelling were defined as the percent reduction in LV end-systolic and end-diastolic volume at FU. Indexed LA volume (LAVI) and LV-global longitudinal (GLS) strain were the main parameters correlated with LARS, with LV-GLS being the strongest determinant of LARS (r = -0.59, P < 0.0001). CRT induced a significant improvement in LAVI and LARS in responders (both P < 0.0001). LARS was an independent predictor of both LV systolic and diastolic remodelling at follow-up (r = -0.14, P = 0.049 and r = -0.17, P = 0.002, respectively).
Conclusion
CRT induces a significant improvement in LAVI and LARS in responders. In CRT candidates, the evaluation of LARS before CRT delivery is an independent predictor of LV systolic and diastolic remodelling at FU.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1373-1382
Galli E, Oger E, Aalen JM, Duchenne J, ... Smiseth OA, Donal E
Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1373-1382 | PMID: 34432006
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Abstract

Adverse right ventricular remodelling, function, and stress responses in obesity: insights from cardiovascular magnetic resonance.

Lewis AJM, Abdesselam I, Rayner JJ, Byrne J, ... Neubauer S, Rider OJ
Aims
We aimed to determine the effect of increasing body weight upon right ventricular (RV) volumes, energetics, systolic function, and stress responses using cardiovascular magnetic resonance (CMR).
Methods and results
We first determined the effects of World Health Organization class III obesity [body mass index (BMI) > 40 kg/m2, n = 54] vs. healthy weight (BMI < 25 kg/m2, n = 49) upon RV volumes, energetics and systolic function using CMR. In less severe obesity (BMI 35 ± 5 kg/m2, n = 18) and healthy weight controls (BMI 21 ± 1 kg/m2, n = 9), we next performed CMR before and during dobutamine to evaluate RV stress response. A subgroup undergoing bariatric surgery (n = 37) were rescanned at median 1 year to determine the effects of weight loss. When compared with healthy weight, class III obesity was associated with adverse RV remodelling (17% RV end-diastolic volume increase, P < 0.0001), impaired cardiac energetics (19% phosphocreatine to adenosine triphosphate ratio reduction, P < 0.001), and reduction in RV ejection fraction (by 3%, P = 0.01), which was related to impaired energetics (R = 0.3, P = 0.04). Participants with less severe obesity had impaired RV diastolic filling at rest and blunted RV systolic and diastolic responses to dobutamine compared with healthy weight. Surgical weight loss (34 ± 15 kg weight loss) was associated with improvement in RV end-diastolic volume (by 8%, P = 0.006) and systolic function (by 2%, P = 0.03).
Conclusion
Increasing body weight is associated with significant alterations in RV volumes, energetic, systolic function, and stress responses. Adverse RV modelling is mitigated with weight loss. Randomized trials are needed to determine whether intentional weight loss improves symptoms and outcomes in patients with obesity and heart failure.

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

Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1383-1390
Lewis AJM, Abdesselam I, Rayner JJ, Byrne J, ... Neubauer S, Rider OJ
Eur Heart J Cardiovasc Imaging: 10 Sep 2022; 23:1383-1390 | PMID: 34453521
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Abstract

Antiplatelet therapy in patients with atrial fibrillation: a systematic review and meta-analysis of randomized trials.

Benz AP, Johansson I, Dewilde WJM, Lopes RD, ... Eikelboom JW, Connolly SJ
Aims
The aim of this study was to systematically assess the effects of antiplatelets on clinical outcomes in patients with atrial fibrillation (AF), treated and not-treated with oral anticoagulation.
Methods and results
We searched MEDLINE, Embase, and CENTRAL from inception until September 2020. From 5446 citations, we selected randomized trials allocating patients with AF to antiplatelet therapy vs. control. We applied random-effects models for meta-analysis and assessed potential effect modification with background anticoagulation use. Eighteen trials including 21 518 participants met our prespecified eligibility criteria. In 10 studies without background anticoagulation, antiplatelets reduced all-cause stroke [486/6165 (events/patients) vs. 621/6061; risk ratio (RR) 0.77, 95% confidence interval (CI) 0.69-0.86, I2 = 0%]. In eight studies with background anticoagulation, there was a signal for an increase in all-cause stroke with antiplatelets (97/4608 vs. 72/4684; RR 1.33, 95% CI 0.98-1.79, I2 = 0%, P-value for interaction <0.001). A similar pattern emerged for ischaemic stroke. Irrespective of background anticoagulation use, antiplatelets increased major bleeding (509/10 402 vs. 328/10 496; RR 1.54, 95% CI 1.35-1.77, I2 = 0%) and intracranial haemorrhage (107/10 221 vs. 65/10 232; RR 1.64, 95% CI 1.20-2.24, I2 = 0%), and reduced myocardial infarction (201/9679 vs. 260/9751; RR 0.79, 95% CI 0.65-0.94, I2 = 0%, all P-values for interaction ≥0.36). Antiplatelets did not affect mortality (1221/10 299 vs. 1211/10 287; RR 1.02, 95% CI 0.89-1.17, I2 = 29%, P-value for interaction = 0.23).
Conclusions
In patients with AF not receiving oral anticoagulation, antiplatelet therapy modestly reduced stroke. There was a corresponding signal for harm when used on top of anticoagulation. Irrespective of background anticoagulation use, antiplatelet therapy significantly increased bleeding, moderately reduced myocardial infarction, and did not affect mortality.

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Eur Heart J Cardiovasc Pharmacother: 29 Sep 2022; 8:648-659
Benz AP, Johansson I, Dewilde WJM, Lopes RD, ... Eikelboom JW, Connolly SJ
Eur Heart J Cardiovasc Pharmacother: 29 Sep 2022; 8:648-659 | PMID: 34142118
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This program is still in alpha version.