Publications by authors named "Christophe Beauloye"

104 Publications

Prevalence and Disease Spectrum of Extracoronary Arterial Abnormalities in Spontaneous Coronary Artery Dissection.

JAMA Cardiol 2021 Nov 24. Epub 2021 Nov 24.

Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom.

Importance: Spontaneous coronary artery dissection (SCAD) has been associated with fibromuscular dysplasia (FMD) and other extracoronary arterial abnormalities. However, the prevalence, severity, and clinical relevance of these abnormalities remain unclear.

Objective: To assess the prevalence and spectrum of FMD and other extracoronary arterial abnormalities in patients with SCAD vs controls.

Design, Setting, And Participants: This case series included 173 patients with angiographically confirmed SCAD enrolled between January 1, 2015, and December 31, 2019. Imaging of extracoronary arterial beds was performed by magnetic resonance angiography (MRA). Forty-one healthy individuals were recruited to serve as controls for blinded interpretation of MRA findings. Patients were recruited from the UK national SCAD registry, which enrolls throughout the UK by referral from the primary care physician or patient self-referral through an online portal. Participants attended the national SCAD referral center for assessment and MRA.

Exposures: Both patients with SCAD and healthy controls underwent head-to-pelvis MRA (median time between SCAD event and MRA, 1 [IQR, 1-3] year).

Main Outcome And Measures: The diagnosis of FMD, arterial dissections, and aneurysms was established according to the International FMD Consensus. Arterial tortuosity was assessed both qualitatively (presence or absence of an S curve) and quantitatively (number of curves ≥45%; tortuosity index).

Results: Of the 173 patients with SCAD, 167 were women (96.5%); mean (SD) age at diagnosis was 44.5 (7.9) years. The prevalence of FMD was 31.8% (55 patients); 16 patients (29.1% of patients with FMD) had involvement of multiple vascular beds. Thirteen patients (7.5%) had extracoronary aneurysms and 3 patients (1.7%) had dissections. The prevalence and degree of arterial tortuosity were similar in patients and controls. In 43 patients imaged with both computed tomographic angiography and MRA, the identification of clinically significant remote arteriopathies was similar. Over a median 5-year follow-up, there were 2 noncardiovascular-associated deaths and 35 recurrent myocardial infarctions, but there were no primary extracoronary vascular events.

Conclusions And Relevance: In this case series with blinded analysis of patients with SCAD, severe multivessel FMD, aneurysms, and dissections were infrequent. The findings of this study suggest that, although brain-to-pelvis imaging allows detection of remote arteriopathies that may require follow-up, extracoronary vascular events appear to be rare.
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http://dx.doi.org/10.1001/jamacardio.2021.4690DOI Listing
November 2021

Increased Collagen Turnover Is a Feature of Fibromuscular Dysplasia and Associated With Hypertrophic Radial Remodeling: A Pilot, Urine Proteomic Study.

Hypertension 2021 Nov 17:HYPERTENSIONAHA12118146. Epub 2021 Nov 17.

Division of Cardiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium (M.P.,C.B., A.P.).

Fibromuscular dysplasia (FMD), a nonatherosclerotic, noninflammatory disease of medium-sized arteries, is an underdiagnosed disease. We investigated the urinary proteome and developed a classifier for discrimination of FMD from healthy controls and other diseases. We further hypothesized that urinary proteomics biomarkers may be associated with alterations in medium-sized, but not large artery geometry and mechanics. The study included 33 patients with mostly multifocal, renal FMD who underwent in depth arterial exploration using ultra-high frequency ultrasound. The cohort was separated in a training set of 23 patients with FMD from Belgium and an independent test set of 10 patients with FMD from Italy. For each set, controls matched 2:1 were selected from the Human Urinary Proteome Database. The specificity of the classifier was tested in 700 additional controls from general population studies, patients with chronic kidney disease (n=66) and coronary artery disease (n=31). Three hundred thirty-five urinary peptides, mostly related to collagen turnover, were identified in the training cohort and combined into a classifier. When applying in the test cohort, the area under the receiver operating characteristic curve was 1.00, 100% specificity at 100% sensitivity. The classifier maintained a high specificity in additional controls (98.3%), patients with chronic kidney (90.9%) and coronary artery (96.8%) diseases. Furthermore, in patients with FMD, the proteomic score was positively associated with radial wall thickness and wall cross-sectional area. In conclusion, a proteomic score has the potential to discriminate between patients with FMD and controls. If confirmed in a wider and more diverse cohort, these findings may pave the way for a noninvasive diagnostic test of FMD.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.18146DOI Listing
November 2021

Reduction of Lipid-Core Burden Index in Nonculprit Lesions at Follow-Up after ST-Elevation Myocardial Infarction: A Randomized Study of Bioresorbable Vascular Scaffold versus Optimal Medical Therapy.

J Interv Cardiol 2021 1;2021:5590093. Epub 2021 Jul 1.

Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium.

Background: Non-flow-limiting nonculprit lesions (NCL) that contain a large lipid-rich necrotic core (nonculprit lipid-rich plaques (NC-LRP)) are most likely to cause recurrent acute coronary syndrome after ST-elevation myocardial infarction (STEMI). Near-infrared spectroscopy (NIRS) detects LRPs using the maximum 4 mm lipid-core burden index (maxLCBI). Few data are available regarding NIRS-guided therapy of these NC-LRPs, which are a potential target for preventive stenting. Bioresorbable vascular scaffold (BVS) provides local drug delivery and could facilitate plaque passivation after resorption. This study sought to assess the safety of BVS implantation in NC-LRPs and its efficacy in reducing maxLCBI at 2-year follow-up after STEMI.

Methods And Results: In total, 33 non-flow-limiting NCLs from 29 STEMI patients were included in this study. Of these, 15 were LRPs and were randomly assigned to either the BVS + optimal medical therapy (OMT) arm (group 1;  = 7) or the OMT arm (group 2;  = 8). At baseline, there were no differences in plaque characteristics between groups (fractional flow reserve: 0.85 ± 0.04 vs. 0.89 ± 0.06; diameter stenosis (DS): 43.4 ± 8 vs. 40.1 ± 10.7%; plaque burden 54.98 ± 5.8 vs. 49.76 ± 8.31%; and maxLCBI 402 [348; 564] vs. 373 [298; 516]; = for all comparisons between groups 1 and 2, respectively). Seven BVSs were implanted 3 ± 1 days after STEMI in six patients, without complications. At angiographic follow-up (712 [657; 740] days), a significant and similar reduction of maxLCBI was observed in both groups, with a median change of 306 [257; 377] in group 1 vs. 300 [278; 346] in group 2 (=0.44). DS was significantly lower in group 1 vs. group 2 (19.8 ± 7 vs. 41.7 ± 13%, =0.003), while plaque burden remained unchanged in both groups. Overall survival was 100%, target lesion failure was 13%, and stent thrombosis was 0%.

Conclusions: BVS + OMT and OMT appear as similarly safe and effective in reducing maxLCBI in NC-LRPs at 2-year follow-up after STEMI.
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http://dx.doi.org/10.1155/2021/5590093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266479PMC
October 2021

Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK.

Sci Rep 2021 07 1;11(1):13700. Epub 2021 Jul 1.

Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), 55, Avenue Hippocrate B1.55.03.1322, 1200, Brussels, Belgium.

Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad's integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.
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http://dx.doi.org/10.1038/s41598-021-93156-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249425PMC
July 2021

Sex Differences of the Diabetic Heart.

Front Physiol 2021 27;12:661297. Epub 2021 May 27.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Type 2 diabetes is a chronic disease associated with micro- and macro-vascular complications, including myocardial ischemia, and also with a specific and intrinsic cardiac dysfunction called diabetic cardiomyopathy (DCM). Both clinical and animal studies demonstrate significant sex differences in prevalence, pathophysiology, and outcomes of cardiovascular diseases (CVDs), including those associated with diabetes. The increased risk of CVDs with diabetes is higher in women compared to men with 50% higher risk of coronary artery diseases and increased mortality when exposed to acute myocardial infarction. Clinical studies also reveal a sexual dimorphism in the incidence and outcomes of DCM. Based on these clinical findings, growing experimental research was initiated to understand the impact of sex on CVDs associated with diabetes and to identify the molecular mechanisms involved. Endothelial dysfunction, atherosclerosis, coagulation, and fibrosis are mechanisms found to be sex-differentially modulated in the diabetic cardiovascular system. Recently, impairment of energy metabolism also emerged as a determinant of multiple CVDs associated with diabetes. Therefore, future studies should thoroughly analyze the sex-specific metabolic determinants to propose new therapeutic targets. With current medicine tending toward more personalized care of patients, we finally propose to discuss the importance of sex as determinant in the treatment of diabetes-associated cardiac diseases to promote a more systemic inclusion of both males and females in clinical and preclinical studies.
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http://dx.doi.org/10.3389/fphys.2021.661297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192974PMC
May 2021

A new degree of complexi(n)ty in the regulation of GLUT4 trafficking.

Biochem J 2021 04;478(7):1315-1319

Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.

Loss of the insulin-stimulated glucose uptake in muscle is a crucial event participating in the defect of whole-body metabolism in type 2 diabetes. Therefore, identification by Pavarotti et al. (Biochem. J (2021) 478 (2): 407-422) of complexin-2 as an important contributor to glucose transporter 4 (GLUT4) translocation to muscle cell plasma membrane upon insulin stimulation is essential. The present commentary discusses the biological importance of the findings and proposes future challenges and opportunities.
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http://dx.doi.org/10.1042/BCJ20210008DOI Listing
April 2021

AMP-activated protein kinase: A remarkable contributor to preserve a healthy heart against ROS injury.

Free Radic Biol Med 2021 04 4;166:238-254. Epub 2021 Mar 4.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium; Division of Cardiology, Cliniques universitaires Saint Luc, Brussels, Belgium. Electronic address:

Heart failure is one of the leading causes of death and disability worldwide. Left ventricle remodeling, fibrosis, and ischemia/reperfusion injury all contribute to the deterioration of cardiac function and predispose to the onset of heart failure. Adenosine monophosphate-activated protein kinase (AMPK) is the universally recognized energy sensor which responds to low ATP levels and restores cellular metabolism. AMPK activation controls numerous cellular processes and, in the heart, it plays a pivotal role in preventing onset and progression of disease. Excessive reactive oxygen species (ROS) generation, known as oxidative stress, can activate AMPK, conferring an additional role of AMPK as a redox-sensor. In this review, we discuss recent insights into the crosstalk between ROS and AMPK. We describe the molecular mechanisms by which ROS activate AMPK and how AMPK signaling can further prevent heart failure progression. Ultimately, we review the potential therapeutic approaches to target AMPK for the treatment of cardiovascular disease and prevention of heart failure.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.02.047DOI Listing
April 2021

Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort.

Cardiovasc Diabetol 2021 02 19;20(1):48. Epub 2021 Feb 19.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc and Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Cardiovascular Division, Université Catholique de Louvain, Avenue Hippocrate, 10, 1200, Brussels, Belgium.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C).

Methods: We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves.

Results: Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m, p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m, p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients. Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1-2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1-4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels).

Conclusion: Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.
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http://dx.doi.org/10.1186/s12933-021-01242-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893869PMC
February 2021

AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.

Basic Res Cardiol 2021 02 9;116(1):10. Epub 2021 Feb 9.

Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium.

We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.
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http://dx.doi.org/10.1007/s00395-021-00846-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873123PMC
February 2021

New insight in understanding the contribution of SGLT1 in cardiac glucose uptake: evidence for a truncated form in mice and humans.

Am J Physiol Heart Circ Physiol 2021 02 8;320(2):H838-H853. Epub 2021 Jan 8.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Although sodium glucose cotransporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidence using phlorizin, the most common inhibitor of SGLTs, has suggested its role in glucose transport. However, phlorizin could also affect classical facilitated diffusion via glucose transporters (GLUTs), bringing into question the relevance of SGLT1 in overall cardiac glucose uptake. Accordingly, we assessed the contribution of SGLT1 in cardiac glucose uptake using the SGLT1 knockout mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1-knockout (KO) and control littermate (WT) mice either under basal state, insulin, or hyperglycemia. Similarly, in vivo basal and insulin-stimulated cardiac glucose transport measured by micro-PET scan technology did not differ between WT and KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT or KO-derived cardiomyocytes. However, higher concentrations (1 mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation independently from cardiomyocyte genotype. Interestingly, we discovered that mouse and human hearts expressed a shorter transcript, leading to SGLT1 protein lacking transmembrane domains and residues involved in glucose and sodium bindings. In conclusion, cardiac SGLT1 does not contribute to overall glucose uptake, probably due to the expression of transcript variant. The inhibitory effect of phlorizin on cardiac glucose uptake is SGLT1-independent and can be explained by GLUT transporter inhibition. These data open new perspectives in understanding the role of SGLT1 in the heart. Ever since the discovery of its expression in the heart, SGLT1 has been considered as similar as the intestine and a potential contributor to cardiac glucose transport. For the first time, we have demonstrated that a transcript variant is present in the heart that has no significant impact on cardiac glucose handling.
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http://dx.doi.org/10.1152/ajpheart.00736.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082801PMC
February 2021

Myocardial glucotoxicity: Mechanisms and potential therapeutic targets.

Arch Cardiovasc Dis 2020 Nov 12;113(11):736-748. Epub 2020 Nov 12.

Pole of cardiovascular research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, B-1200 Brussels, Belgium; WELBIO, B-1300 Wavre, Belgium. Electronic address:

Besides coronary artery disease, which remains the main cause of heart failure in patients with diabetes, factors independent of coronary artery disease are involved in the development of heart failure in the onset of what is called diabetic cardiomyopathy. Among them, hyperglycaemia - a hallmark of type 2 diabetes - has both acute and chronic deleterious effects on myocardial function, and clearly participates in the establishment of diabetic cardiomyopathy. In the present review, we summarize the cellular and tissular events that occur in a heart exposed to hyperglycaemia, and depict the complex molecular mechanisms proposed to be involved in glucotoxicity. Finally, from a more translational perspective, different therapeutic strategies targeting hyperglycaemia-mediated molecular mechanisms will be detailed.
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http://dx.doi.org/10.1016/j.acvd.2020.06.006DOI Listing
November 2020

Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide.

Sci Transl Med 2020 10;12(564)

Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KULeuven, 3000 Leuven, Belgium.

Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but strategies using systemic antioxidants have generally failed to prevent it. We sought to identify key regulators of oxidant-mediated cardiac hypertrophy amenable to targeted pharmacological therapy. Specific isoforms of the aquaporin water channels have been implicated in oxidant sensing, but their role in heart muscle is unknown. RNA sequencing from human cardiac myocytes revealed that the archetypal is a major isoform. expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalized with NADPH oxidase-2 and caveolin-3. We show that hydrogen peroxide (HO), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of HO through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by HO Deletion of or selective blockade of the AQP1 intrasubunit pore inhibited HO transport in mouse and human cells and rescued the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. Treatment of mice with a clinically approved AQP1 inhibitor, Bacopaside, attenuated cardiac hypertrophy. We conclude that cardiac hypertrophy is mediated by the transmembrane transport of HO by the water channel AQP1 and that inhibitors of AQP1 represent new possibilities for treating hypertrophic cardiomyopathies.
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http://dx.doi.org/10.1126/scitranslmed.aay2176DOI Listing
October 2020

Adherence to quality indicators for ST-elevation myocardial infarction and its relation to mortality: a hospital network analysis from the Belgian STEMI database.

Eur Heart J Qual Care Clin Outcomes 2021 Oct;7(6):601-607

Department of Cardiology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium.

Aims: To assess the adherence to established quality indicators (QIs) for ST-elevation myocardial infarction (STEMI) at the hospital-network level and its relation to outcome.

Methods And Results: The data of 7774 STEMI patients admitted to 32 STEMI networks during the period 2014-18 were extracted from the Belgian STEMI database. Five QIs [primary percutaneous coronary intervention use, diagnosis-to-balloon time (DiaTB) <90 min, door-to-balloon time (DoTB) <60 min, P2Y12 inhibitor and statin prescription at discharge, and a composite QI score ranging from 0 to 10] were correlated with in-hospital mortality adjusted for differences in baseline risk profile (TIMI risk score). The median composite QI score was 6.5 [interquartile range (IQR) 6-8]. The most important gaps in quality adherence were related to time delays: the recommended DiaTB and DoTB times across the different networks were achieved in 68% (IQR 53-71) and 67% (IQR 50-78), respectively. Quality adherence was better in networks taking care of more high-risk STEMI patients. The median in-hospital mortality among the STEMI networks was 6.4% (IQR 4.1-7.9%). There was a significant independent inverse correlation between the composite QI score and in-hospital mortality (partial correlation coefficient: -0.45, P = 0.013). Stepwise regression analysis revealed that among the individual QIs, prolonged DiaTB was the most important independent outcome predictor.

Conclusion: Among established STEMI networks, the time delay between diagnosis and treatment was the most variable and the most relevant prognostic QI, underscoring the importance of assessing quality of care throughout the whole network.
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http://dx.doi.org/10.1093/ehjqcco/qcaa067DOI Listing
October 2021

Glucose transporters in cardiovascular system in health and disease.

Pflugers Arch 2020 09 18;472(9):1385-1399. Epub 2020 Aug 18.

Institut de Recherche Expérimentale et Clinique, Pole of Cardiovascular Research, Université catholique de Louvain, Avenue Hippocrate 55, B1.55.05, B-1200, Brussels, Belgium.

Glucose transporters are essential for the heart to sustain its function. Due to its nature as a high energy-consuming organ, the heart needs to catabolize a huge quantity of metabolic substrates. For optimized energy production, the healthy heart constantly switches between various metabolites in accordance with substrate availability and hormonal status. This metabolic flexibility is essential for the maintenance of cardiac function. Glucose is part of the main substrates catabolized by the heart and its use is fine-tuned via complex molecular mechanisms that include the regulation of the glucose transporters GLUTs, mainly GLUT4 and GLUT1. Besides GLUTs, glucose can also be transported by cotransporters of the sodium-glucose cotransporter (SGLT) (SLC5 gene) family, in which SGLT1 and SMIT1 were shown to be expressed in the heart. This SGLT-mediated uptake does not seem to be directly linked to energy production but is rather associated with intracellular signalling triggering important processes such as the production of reactive oxygen species. Glucose transport is markedly affected in cardiac diseases such as cardiac hypertrophy, diabetic cardiomyopathy and heart failure. These alterations are not only fingerprints of these diseases but are involved in their onset and progression. The present review will depict the importance of glucose transport in healthy and diseased heart, as well as proposed therapies targeting glucose transporters.
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http://dx.doi.org/10.1007/s00424-020-02444-8DOI Listing
September 2020

α1AMP-Activated Protein Kinase Protects against Lipopolysaccharide-Induced Endothelial Barrier Disruption via Junctional Reinforcement and Activation of the p38 MAPK/HSP27 Pathway.

Int J Mol Sci 2020 Aug 4;21(15). Epub 2020 Aug 4.

Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.

Vascular hyperpermeability is a determinant factor in the pathophysiology of sepsis. While, AMP-activated protein kinase (AMPK) is known to play a role in maintaining endothelial barrier function in this condition. Therefore, we investigated the underlying molecular mechanisms of this protective effect. α1AMPK expression and/or activity was modulated in human dermal microvascular endothelial cells using either α1AMPK-targeting small interfering RNA or the direct pharmacological AMPK activator 991, prior to lipopolysaccharide (LPS) treatment. Western blotting was used to analyze the expression and/or phosphorylation of proteins that compose cellular junctions (zonula occludens-1 (ZO-1), vascular endothelial cadherin (VE-Cad), connexin 43 (Cx43)) or that regulate actin cytoskeleton (p38 MAPK; heat shock protein 27 (HSP27)). Functional endothelial permeability was assessed by in vitro Transwell assays, and quantification of cellular junctions in the plasma membrane was assessed by immunofluorescence. Actin cytoskeleton remodeling was evaluated through actin fluorescent staining. We consequently demonstrate that α1AMPK deficiency is associated with reduced expression of CX43, ZO-1, and VE-Cad, and that the drastic loss of CX43 is likely responsible for the subsequent decreased expression and localization of ZO-1 and VE-Cad in the plasma membrane. Moreover, α1AMPK activation by 991 protects against LPS-induced endothelial barrier disruption by reinforcing cortical actin cytoskeleton. This is due to a mechanism that involves the phosphorylation of p38 MAPK and HSP27, which is nonetheless independent of the small GTPase Rac1. This results in a drastic decrease of LPS-induced hyperpermeability. We conclude that α1AMPK activators that are suitable for clinical use may provide a specific therapeutic intervention that limits sepsis-induced vascular leakage.
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http://dx.doi.org/10.3390/ijms21155581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432762PMC
August 2020

Impact of COVID-19-related public containment measures on the ST elevation myocardial infarction epidemic in Belgium: a nationwide, serial, cross-sectional study.

Acta Cardiol 2021 Oct 30;76(8):863-869. Epub 2020 Jul 30.

Department of Cardiology, Catholic University Hospital Mont-Godinne, Brussels, Belgium.

Aims: The current study assessed the impact of COVID-19-related public containment measures (i.e. lockdown) on the ST elevation myocardial infarction (STEMI) epidemic in Belgium.

Methods And Results: Clinical characteristics, reperfusion therapy modalities, COVID-19 status and in-hospital mortality of consecutive STEMI patients who were admitted to Belgian hospitals for percutaneous coronary intervention (PCI) were recorded during a three-week period starting at the beginning of the lockdown period on 13 March 2020. Similar data were collected for the same time period for 2017-2019. An evaluation of air quality revealed a 32% decrease in ambient NO concentrations during lockdown (19.5 µg/m³ versus 13.2 µg/m³,  < .001). During the three-week period, there were 188 STEMI patients admitted for PCI during the lockdown versus an average 254 STEMI patients before the lockdown period (incidence rate ratio = 0.74,  = .001). Reperfusion strategy was predominantly primary PCI in both time periods (96% versus 95%). However, there was a significant delay in treatment during the lockdown period, with more late presentations (>12 h after onset of pain) (14% versus 7.6%,  = .04) and with longer door-to-balloon times (median of 45 versus 39 min,  = .02). Although the in-hospital mortality between the two periods was comparable (5.9% versus 6.7%), 5 of the 7 (71%) COVID-19-positive STEMI patients died.

Conclusion: The present study revealed a 26% reduction in STEMI admissions and a delay in treatment of STEMI patients. Less exposure to external STEMI triggers (such as ambient air pollution) and/or reluctance to seek medical care are possible explanations of this observation.
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http://dx.doi.org/10.1080/00015385.2020.1796035DOI Listing
October 2021

Early thrombogenicity of coronary stents: comparison of bioresorbable polymer sirolimus-eluting and bare metal stents in an aortic rat model.

Am J Cardiovasc Dis 2020 15;10(2):72-83. Epub 2020 Jun 15.

Pole de Recherche Cardiovasculaire, Institut de Recherche Experimentale et Clinique (IREC), Universite Catholique de Louvain (UCLouvain) Brussels, Belgium.

Background: Although 1-month dual antiplatelet therapy (DAPT) in patients treated with bare metal stents (BMS) is well established, the optimal duration of DAPT after implantation of a drug-eluting stent (DES) is still a matter of debate. The safety of shortened DAPT is under investigation due to concern about the risk of stent thrombosis. Data on platelet activation and prothrombotic response in vivo following bioresorbable polymer sirolimus-eluting stent (BP-SES) implantation are scarce.

Objectives: The aim of our study was to compare the early thrombogenicity of BP-SES with that of BMS in an aortic rat model.

Methods And Results: Overall, 30 rats underwent stent implantation in the abdominal aorta: BMS (Pro-Kinetic Energy; N=15) and BP-SES (Ultimaster Tansei; N=15) were compared in terms of their early thrombogenicity. CD62P exposure at the platelet surface and fibrinogen binding at the integrin receptor were not different between BMS and BP-SES over time. The thrombus coverage of the scaffold (0 vs. 0.1%, P=0.84) was similarly low in both groups at Day 28; thrombotic deposits had totally disappeared at Day 84. The endothelial strut coverage was similarly high at 1 month (90 vs. 95%, P=0.64) and 3 months (87 vs. 97%, P=0.99) following BMS and BP-SES implantation, respectively.

Conclusions: This study demonstrates the low early thrombogenicity of a BP-SES implanted in an aortic rat model, which did not differ from a BMS. These data could be helpful to support the safety of a shortened 1-month DAPT duration following BP-SES implantation in the human coronary artery.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364276PMC
June 2020

Heart failure with preserved ejection fraction in Belgium: characteristics and outcome of a real-life cohort.

Acta Cardiol 2021 Sep 17;76(7):697-706. Epub 2020 Jul 17.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc and Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.

Background: Due to aging of the population and the increase of cardiovascular risk factors, heart failure and preserved ejection fraction (HFpEF) is a rising health issue. Few data exist on the phenotype of HFpEF patients in Belgium and on their prognosis.

Objectives: We describe clinical characteristics and outcomes of Belgian HFpEF patients.

Methods: We prospectively enrolled 183 HFpEF patients. They underwent clinical examination, comprehensive biological analysis and echocardiography, and were followed for a combined outcome of all-cause mortality and first HF hospitalisation.

Results: Belgian patients with HFpEF were old (78 ± 8 years), predominantly females (62%) with multiple comorbidities. Ninety-five per cent were hypertensive, 38% diabetic and 69% overweight. History of atrial fibrillation was present in 63% of population, chronic kidney disease in 60% and anaemia in 58%. Over 30 ± 9 months, 55 (31%) patients died, 87 (49%) were hospitalised and 111 (63%) reached the combined outcome. In multivariate Cox analysis, low body mass index (BMI), NYHA class III and IV, diabetes, poor renal function and loop diuretic intake were independent predictors of the combined outcome ( < .05). BMI and renal function were also independent predictors of mortality, as were low haemoglobin, high E/e' and poor right ventricular function.

Conclusion: Belgian patients with HFpEF are elderly patients with a high burden of comorbidities. Their prognosis is poor with high rates of hospitalisation and mortality. Although obesity is a risk factor for developing HFpEF, low BMI is the strongest independent predictor of mortality in those patients.
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http://dx.doi.org/10.1080/00015385.2020.1770460DOI Listing
September 2021

Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction.

ESC Heart Fail 2020 10 24;7(5):2494-2507. Epub 2020 Jun 24.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc, Avenue Hippocrate, 10, Brussels, 1200, Belgium.

Aims: Besides regulating calcium-phosphate metabolism, fibroblast growth factor 23 (FGF-23) has been associated with incident heart failure (HF) and left ventricular hypertrophy. However, data about FGF-23 in HF and preserved ejection fraction (HFpEF) remain limited. The aim of this study was to assess the association between FGF-23 levels, clinical and imaging characteristics, particularly diffuse myocardial fibrosis, and prognosis in HFpEF patients.

Methods And Results: We prospectively included 143 consecutive HFpEF patients (78 ± 8 years, 61% female patients) and 31 controls of similar age and gender (75 ± 6 years, 61% female patients). All subjects underwent a complete two-dimensional echocardiography and cardiac magnetic resonance with extracellular volume (ECV) assessment by T1 mapping. FGF-23 was measured at baseline. Among the patients, differences in clinical and imaging characteristics across tertiles of FGF-23 levels were analysed with a trend test across the ordered groups. Patients were followed over time for a primary endpoint of all-cause mortality and first HF hospitalization and a secondary endpoint of all-cause mortality. Median FGF-23 was significantly higher in HFpEF patients compared with controls of similar age and gender (247 [115; 548] RU/mL vs. 61 [51; 68] RU/mL, P < 0.001). Among HFpEF patients, higher FGF-23 levels were associated with female sex, higher incidence of atrial fibrillation, lower haemoglobin, worse renal function, and higher N terminal pro brain natriuretic peptide levels (P for trend < 0.05 for all). Regarding imaging characteristics, patients with higher FGF-23 levels had greater left atrial volumes, worse right ventricular systolic function, and more fibrosis estimated by ECV (P for trend < 0.05 for all). FGF-23 was moderately correlated with ECV (r = 0.46, P < 0.001). Over a mean follow-up of 30 ± 8 months, 43 patients (31%) died and 69 patients (49%) were hospitalized for HF. A total of 87 patients (62%) reached the primary composite endpoint of all-cause mortality and/or first HF hospitalization. In multivariate Cox regression analysis for the primary endpoint, FGF-23 (HR: 3.44 [2.01; 5.90], P < 0.001) and E wave velocities (HR: 1.01 [1.00; 1.02], P = 0.034) were independent predictors of the primary composite endpoint. In multivariate Cox regression analysis for the secondary endpoint, ferritin (HR: 1.02 [1.01; 1.03], P < 0.001), FGF-23 (HR: 2.85 [1.26; 6.44], P = 0.012), and ECV (HR: 1.26 [1.03; 1.23], P = 0.008) were independent predictors of all-cause mortality.

Conclusions: Fibroblast growth factor 23 (FGF-23) levels were significantly higher in HFpEF patients compared with controls of similar age and gender. FGF-23 was correlated with fibrosis evaluated by ECV. High levels of FGF-23 were significantly associated with signs of disease severity such as worse renal function, larger left atrial volumes, and right ventricular dysfunction. Moreover, FGF-23 was a strong predictor of poor outcome (mortality and first HF hospitalization).
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http://dx.doi.org/10.1002/ehf2.12816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524237PMC
October 2020

Pulmonary hypertension due to left heart disease: diagnostic value of pulmonary artery distensibility.

Eur Radiol 2020 Nov 16;30(11):6204-6212. Epub 2020 Jun 16.

Division of Radiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Avenue Hippocrate 10, 1200, Brussels, Belgium.

Objectives: To evaluate how pulmonary artery (PA) distensibility performs in detecting pulmonary hypertension due to left heart disease (PH-LHD) in comparison with parameters from ungated computed tomography (CT) and echocardiography.

Methods: One hundred patients (79 men, mean age = 63 ± 17 years) with either severe heart failure with reduced ejection fraction (HFrEF), aortic stenosis, or primary mitral regurgitation prospectively underwent right heart catheterization, ungated CT, ECG-gated CT, and echocardiography. During the ECG-gated CT, the right PA distensibility was calculated. In ungated CT, dPA, dPA/AA, the ratio of dPA to the diameter of the vertebra, segmental PA diameter, segmental PA-to-bronchus ratio, and the main PA volume were measured; the egg-and-banana sign was recorded. During echocardiography, the tricuspid regurgitation (TR) gradient was measured. The areas under the ROC curves (AUC) of these signs were computed and compared with DeLong test. Correlation between PA distensibility and PA pressure (PAP) was investigated through Pearson's coefficient.

Results: PA distensibility was lower in patients with PH than in those without PH (11.4 vs. 21.2%, p < 0.001) and correlated negatively with mean PAP (r = - 0.72, p < 0.001). Age, PA size, and mean PAP were independent predictors of PA distensibility. PA distensibility < 18% detected PH-LHD with 96% sensitivity and 73% specificity; its AUC was 0.92, larger than that of any other sign at ungated CT and TR gradient (AUC ranging from 0.54 to 0.83, DeLong: p ranging from 0.020 to < 0.001).

Conclusion: PA distensibility on an ECG-gated CT can detect PH-LHD better than the parameters reflecting PA dilatation in ungated CT or TR gradient in the echocardiography of patients with severe HFrEF, aortic stenosis, or mitral regurgitation.

Key Points: • In left heart disease, pulmonary artery distensibility is lower in patients with PH than in those without pulmonary hypertension (11.4 vs. 21.2%, p < 0.001). • In left heart disease, pulmonary artery distensibility detects pulmonary hypertension with an area under the receiver operating curve of 0.92. • In left heart disease, the area under the receiver operating curve of pulmonary artery distensibility for detecting pulmonary hypertension is larger than that of all other signs at ungated CT (p from 0.019 to < 0.001) and tricuspid regurgitation gradient at echocardiography (p = 0.020).
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http://dx.doi.org/10.1007/s00330-020-06959-7DOI Listing
November 2020

Safe use of hydroxychloroquine and its combination with azithromycin in the context of Sars-CoV-2 outbreak: Clinical experience in a Belgian tertiary center.

Travel Med Infect Dis 2020 Jul - Aug;36:101788. Epub 2020 Jun 12.

Department of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

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http://dx.doi.org/10.1016/j.tmaid.2020.101788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290202PMC
September 2020

Right Ventricular Global Longitudinal Strain and Outcomes in Heart Failure with Preserved Ejection Fraction.

J Am Soc Echocardiogr 2020 08 7;33(8):973-984.e2. Epub 2020 May 7.

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc, Brussels, Belgium. Electronic address:

Background: Right ventricular (RV) strain has emerged as an accurate tool for RV function assessment and is a powerful predictor of survival in patients with heart failure with reduced ejection fraction. However, its prognostic impact in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. The aim of this study was to compare the prognostic value of RV global longitudinal strain (RVGLS) by two-dimensional speckle-tracking echocardiographic (STE) imaging in patients with HFpEF against conventional RV function parameters.

Methods: Patients with HFpEF were prospectively recruited, and 149 of 183 (81%) with analyzable STE RVGLS images constituted the final study population (mean age, 78 ± 9 years; 61% women), compared with 28 control subjects of similar age and sex. All control subjects and 120 patients also underwent cardiac magnetic resonance imaging. Patients were followed up for a primary end point of all-cause mortality and first heart failure hospitalization, and Cox regression analysis was performed.

Results: Mean STE RVGLS was significantly altered in patients with HFpEF compared with control subjects (-21.7 ± 4.9% vs -25.9 ± 4.2%, P < .001). STE RVGLS correlated well with RV ejection fraction by cardiac magnetic resonance (r = -0.617, P < .001). Twenty-eight patients with HFpEF (19%) had impaired STE RVGLS (>-17.5%). During a mean follow-up period of 30 ± 9 months, 91 patients with HFpEF (62%) reached the primary end point. A baseline model was created using independent predictors of the primary end point: New York Heart Association functional class III or IV, hemoglobin level, estimated glomerular filtration rate, and the presence of moderate or severe tricuspid regurgitation. Impaired STE RVGLS provided significant additional prognostic value over this model (χ to enter = 7.85, P = .005). Impaired tricuspid annular plane systolic excursion and fractional area change, however, did not.

Conclusions: In patients with HFpEF, impaired RVGLS has strong prognostic value. STE RVGLS should be considered for systematic evaluation of RV function to identify patients at high risk for adverse events.
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http://dx.doi.org/10.1016/j.echo.2020.02.016DOI Listing
August 2020

Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function.

Cardiovasc Res 2021 01;117(1):43-59

Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Echocardiography is a reliable and reproducible method to assess non-invasively cardiac function in clinical and experimental research. Significant progress in the development of echocardiographic equipment and transducers has led to the successful translation of this methodology from humans to rodents, allowing for the scoring of disease severity and progression, testing of new drugs, and monitoring cardiac function in genetically modified or pharmacologically treated animals. However, as yet, there is no standardization in the procedure to acquire echocardiographic measurements in small animals. This position paper focuses on the appropriate acquisition and analysis of echocardiographic parameters in adult mice and rats, and provides reference values, representative images, and videos for the accurate and reproducible quantification of left ventricular function in healthy and pathological conditions.
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http://dx.doi.org/10.1093/cvr/cvaa110DOI Listing
January 2021

Diabetic Cardiomyopathy and Ischemic Heart Disease: Prevention and Therapy by Exercise and Conditioning.

Int J Mol Sci 2020 Apr 21;21(8). Epub 2020 Apr 21.

Department of Clinical and Biological Science, University of Torino, 10043 Obassano (TO), Italy.

Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. In addition, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.
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http://dx.doi.org/10.3390/ijms21082896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215312PMC
April 2020

The European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI)-clinical phenotypes and their predictors based on a cohort of 1000 patients.

Cardiovasc Res 2021 02;117(3):950-959

Shanghai Institute of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Aims: Since December 2015, the European/International Fibromuscular Dysplasia (FMD) Registry enrolled 1022 patients from 22 countries. We present their characteristics according to disease subtype, age and gender, as well as predictors of widespread disease, aneurysms and dissections.

Methods And Results: All patients diagnosed with FMD (string-of-beads or focal stenosis in at least one vascular bed) based on computed tomography angiography, magnetic resonance angiography, and/or catheter-based angiography were eligible. Patients were predominantly women (82%) and Caucasians (88%). Age at diagnosis was 46 ± 16 years (12% ≥65 years old), 86% were hypertensive, 72% had multifocal, and 57% multivessel FMD. Compared to patients with multifocal FMD, patients with focal FMD were younger, more often men, had less often multivessel FMD but more revascularizations. Compared to women with FMD, men were younger, had more often focal FMD and arterial dissections. Compared to younger patients with FMD, patients ≥65 years old had more often multifocal FMD, lower estimated glomerular filtration rate and more atherosclerotic lesions. Independent predictors of multivessel FMD were age at FMD diagnosis, stroke, multifocal subtype, presence of aneurysm or dissection, and family history of FMD. Predictors of aneurysms were multivessel and multifocal FMD. Predictors of dissections were age at FMD diagnosis, male gender, stroke, and multivessel FMD.

Conclusions: The European/International FMD Registry allowed large-scale characterization of distinct profiles of patients with FMD and, more importantly, identification of a unique set of independent predictors of widespread disease, aneurysms and dissections, paving the way for targeted screening, management, and follow-up of FMD.
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http://dx.doi.org/10.1093/cvr/cvaa102DOI Listing
February 2021

Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP-activated protein kinase and autophagy.

ESC Heart Fail 2020 06 10;7(3):920-932. Epub 2020 Mar 10.

Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH), Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint-Luc, B1.57.04, 57 Avenue Hippocrate, Brussels, 1200, Belgium.

Aims: The abundance of beta 3-adrenergic receptors (β3-ARs) is upregulated in diseased human myocardium. We previously showed that cardiac-specific expression of β3-AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analysed signalling pathways involved in the anti-hypertrophic effect of β3-AR.

Methods And Results: In vitro hypertrophic responses to phenylephrine (PE) were analysed in neonatal rat ventricular myocytes (NRVM) infected with a recombinant adenovirus expressing the human β3-AR (AdVhβ3). We confirmed results in mice with cardiomyocyte-specific moderate expression of human β3-AR (β3-TG) and wild-type (WT) littermates submitted to thoracic transverse aortic constriction (TAC) for 9 weeks. We observed a colocalization of β3-AR with the AMP-activated protein kinase (AMPK) both in neonatal rat and in adult mouse cardiomyocytes. Treatment of NRVM with PE induced hypertrophy and a decrease in phosphorylation of Thr172-AMPK (/2, P = 0.0487) and phosphorylation of Ser79-acetyl-CoA carboxylase (ACC) (/2.6, P = 0.0317), inducing an increase in phosphorylated Ser235/236 S6 protein (×2.5, P = 0.0367) known to be involved in protein synthesis. These effects were reproduced by TAC in WT mice but restored to basal levels in β3-AR expressing cells/mice. siRNA targeting of AMPK partly abrogated the anti-hypertrophic effect of β3-AR in response to PE in NRVM. Concomitant with hypertrophy, autophagy was decreased by PE, as measured by microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio (/2.6, P = 0.0010) and p62 abundance (×3, P = 0.0016) in NRVM or by TAC in WT mice (LC3-II/LC3-I ratio: /5.4, P = 0.0159), but preserved in human β3-AR expressing cells and mice, together with reduced hypertrophy.

Conclusions: Cardiac-specific moderate expression of β3-AR inhibits the hypertrophic response in part through AMPK activation followed by inhibition of protein synthesis and preservation of autophagy. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodelling.
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http://dx.doi.org/10.1002/ehf2.12648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261558PMC
June 2020

Validation of Semiautomated Quantification of Mitral Valve Regurgitation by Three-Dimensional Color Doppler Transesophageal Echocardiography.

J Am Soc Echocardiogr 2020 03;33(3):342-354

Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc, Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium. Electronic address:

Background: The aim of this study was to evaluate the accuracy of mitral regurgitation (MR) volume quantified on three-dimensional (3D) color Doppler transesophageal echocardiography (TEE) using new semiautomated software compared with conventional two-dimensional (2D) proximal isovelocity surface area (PISA) transthoracic echocardiography (TTE) and TEE and cardiac magnetic resonance imaging (CMR).

Methods: Fifty-one patients (mean age, 63 ± 16 years; 35 men) prospectively underwent TTE, TEE, and CMR for MR evaluation. Regurgitant volume (RVol) by 3D MR flow quantification was compared with 2D TTE, TEE, and CMR, and the accuracy of evaluation of severe MR by 3D MR flow quantification was compared against guideline criteria by TEE.

Results: Twenty-nine patients had severe MR, 16 had moderate MR, and six had mild MR. Three-dimensional MR flow quantification was feasible in all patients, including prolapse (n = 37), restriction (n = 9), functional MR (n = 5), and eccentric or multiple jects (n = 41). RVol on 3D MR flow quantification correlated well with RVol on 2D PISA TTE (interclass correlation coefficient [ICC] = 0.75, P < .001), quantitatively estimated RVol (ICC = 0.74, P < .001), and 2D PISA TEE (ICC = 0.79, P < .001). Three-dimensional MR flow quantification agreed better with CMR (ICC = 0.86, P < .001) than did RVol on 2D PISA TTE (ICC = 0.66, P < .001) and 2D PISA TEE (ICC = 0.69, P < .001), with narrower limits of agreement on Bland-Altman analysis. Three-dimensional MR flow quantification had high accuracy for diagnosing severe MR using TEE (area under the curve = 0.85, 95% CI 0.74-0.96, P < .001) or CMR (area under the curve = 0.95; 95% CI, 0.89-1.00; P < .001) as the criterion.

Conclusions: The new software enabled semiautomated 3D MR flow quantification in complex MR with multiple and eccentric jets and showed better agreement with CMR than 2D PISA TTE or TEE, suggesting that this method is more accurate than conventional 2D PISA TTE and TEE.
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http://dx.doi.org/10.1016/j.echo.2019.10.013DOI Listing
March 2020

Effect of hyperglycaemia and diabetes on acute myocardial ischaemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols.

Br J Pharmacol 2020 12 9;177(23):5312-5335. Epub 2020 Mar 9.

The Hatter Cardiovascular Institute, University College London, London, UK.

Diabetic patients are at increased risk of developing coronary artery disease and experience worse clinical outcomes following acute myocardial infarction. Novel therapeutic strategies are required to protect the myocardium against the effects of acute ischaemia-reperfusion injury (IRI). These include one or more brief cycles of non-lethal ischaemia and reperfusion prior to the ischaemic event (ischaemic preconditioning [IPC]) or at the onset of reperfusion (ischaemic postconditioning [IPost]) either to the heart or to extracardiac organs (remote ischaemic conditioning [RIC]). Studies suggest that the diabetic heart is resistant to cardioprotective strategies, although clinical evidence is lacking. We overview the available animal models of diabetes, investigating acute myocardial IRI and cardioprotection, experiments investigating the effects of hyperglycaemia on susceptibility to acute myocardial IRI, the response of the diabetic heart to cardioprotective strategies e.g. IPC, IPost and RIC. Finally we highlight the effects of anti-hyperglycaemic agents on susceptibility to acute myocardial IRI and cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.
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http://dx.doi.org/10.1111/bph.14993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680002PMC
December 2020

Platelet Acetyl-CoA Carboxylase Phosphorylation: A Risk Stratification Marker That Reveals Platelet-Lipid Interplay in Coronary Artery Disease Patients.

JACC Basic Transl Sci 2019 Sep 11;4(5):596-610. Epub 2019 Sep 11.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.

Adenosine monophosphate-activated protein kinase (AMPK) acetyl-CoA carboxylase (ACC) signaling is activated in platelets by atherogenic lipids, particularly by oxidized low-density lipoproteins, through a CD36-dependent pathway. More interestingly, increased platelet AMPK-induced ACC phosphorylation is associated with the severity of coronary artery calcification as well as acute coronary events in coronary artery disease patients. Therefore, AMPK-induced ACC phosphorylation is a potential marker for risk stratification in suspected coronary artery disease patients. The inhibition of ACC resulting from its phosphorylation impacts platelet lipid content by down-regulating triglycerides, which in turn may affect platelet function.
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http://dx.doi.org/10.1016/j.jacbts.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872775PMC
September 2019

Vulnerability to cardiac arrest in patients with ST elevation myocardial infarction: Is it time or patient dependent? Results from a nationwide observational study.

Eur Heart J Acute Cardiovasc Care 2020 Nov 27;9(4_suppl):S153-S160. Epub 2019 Aug 27.

Department of Cardiology, University Hospital Antwerp, Belgium.

Aim: Cardiac arrest is a common complication of ST elevation myocardial infarction and is associated with high mortality. We evaluated whether vulnerability to cardiac arrest follows a circadian rhythm and whether it is related to specific patient characteristics.

Methods: A total of 24,164 ST elevation myocardial infarction patients who were admitted to 60 Belgian hospitals between 2008-2017 were analysed. The proportion of patients with cardiac arrest before initiation of reperfusion therapy was calculated for different time periods (hour of the day, months, seasons) and related to patient characteristics using stepwise logistic regression analysis.

Results: Cardiac arrest occurred in 10.8% of the ST elevation myocardial infarction patients at a median of 65 min (interquartile range 33-138 min) after onset of pain. ST elevation myocardial infarction patients with cardiac arrest showed a biphasic pattern with one peak in the morning and one peak in the late afternoon. Multivariate analysis identified the following independent factors associated with cardiac arrest: cardiogenic shock (odds ratio=28), left bundle branch block (odds ratio=3.7), short (<180 min) ischaemic period (odds ratio=2.2), post-meridiem daytime presentation (odds ratio=1.4), anterior infarction (odds ratio=1.3). Overall in-hospital mortality was 30% for cardiac arrest patients versus 3.7% for non-cardiac arrest patients (<0.0001).

Conclusion: In the present study population, cardiac arrest in ST elevation myocardial infarction showed an atypical circadian rhythm with not only a morning peak but also a second peak in the late afternoon, suggesting that cardiac arrest and ST elevation myocardial infarction triggers are, at least partially, different. In addition, specific patient characteristics, such as short ischaemic period, cardiogenic shock and left bundle branch block, increase the vulnerability to cardiac arrest.
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http://dx.doi.org/10.1177/2048872619872127DOI Listing
November 2020
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