Publications by authors named "Yves Cottin"

207 Publications

Coronary lesion complexity in patients with heterozygous familial hypercholesterolemia hospitalized for acute myocardial infarction: data from the RICO survey.

Lipids Health Dis 2021 May 4;20(1):45. Epub 2021 May 4.

PEC2, EA 7460, UFR Health Sciences, University of Bourgogne Franche Comté, Dijon, France.

Background: Although patients with familial heterozygous hypercholesterolemia (FH) have a high risk of early myocardial infarction (MI), the coronary artery disease (CAD) burden in FH patients with acute MI remains to be investigated.

Methods: The data for all consecutive patients hospitalized in 2012-2019 for an acute MI and who underwent coronary angiography were collected from a multicenter database (RICO database). FH (n = 120) was diagnosed using Dutch Lipid Clinic Network criteria (score ≥ 6). We compared the angiographic features of MI patients with and without FH (score 0-2) (n = 234) after matching for age, sex, and diabetes (1:2).

Results: Although LDL-cholesterol was high (208 [174-239] mg/dl), less than half of FH patients had chronic statin treatment. When compared with non-FH patients, FH increased the extent of CAD (as assessed by SYNTAX score; P = 0.005), and was associated with more frequent multivessel disease (P = 0.004), multiple complex lesions (P = 0.022) and significant stenosis location on left circumflex and right coronary arteries. Moreover, FH patients had more multiple lesions, with an increased rate of bifurcation lesions or calcifications (P = 0.021 and P = 0.036, respectively). In multivariate analysis, LDL-cholesterol levels (OR 1.948; 95% CI 1.090-3.480, P = 0.024) remained an independent estimator of anatomical complexity of coronary lesions, in addition to age (OR 1.035; 95% CI 1.014-1.057, P = 0.001).

Conclusions: FH patients with acute MI had more severe CAD, characterized by complex anatomical features that are mainly dependent on the LDL-cholesterol burden. Our findings reinforce the need for more aggressive preventive strategies in these high-risk patients, and for intensive lipid-lowering therapy as secondary prevention.
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http://dx.doi.org/10.1186/s12944-021-01467-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094609PMC
May 2021

Impact of Platelet Reactivity in ACS Patients on Clinical Outcomes with Triple Antithrombotic Therapy.

J Clin Med 2021 Apr 8;10(8). Epub 2021 Apr 8.

Department of Cardiology, ARCHANTEC, School of Medicine, Aix Marseille University, 13007 Marseille, France.

Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) in patients on oral anticoagulants (OAC) remains a clinical conundrum. In fact, combining an OAC with dual antiplatelet therapy (triple antithrombotic therapy, TAT) increases the risk of bleeding. Clopidogrel is the only thienopyridine recommended in TAT patients. Whether its response plays a relevant role in this setting remains uncertain. We aimed to evaluate the level of platelet reactivity inhibition (PRI) achieved by oral TAT in Acute Coronary Syndrome (ACS) patients undergoing PCI and its relationship with outcomes. We performed a multicenter prospective observational study and assessed PRI by vasodilator-stimulated phosphoprotein (VASP) index following a loading dose of clopidogrel. The primary endpoint was the incidence of major adverse cerebral or cardiovascular events (MACCE) at six months based on High on Treatment Platelet Reactivity (HTPR, VASP > 50%). The secondary endpoint was the incidence of bleeding at six months based on Low on Treatment Platelet Reactivity (LTPR, VASP < 16%). 491 patients were followed up for six months: 7.7% experienced MACCE and 17.3% experienced bleeding. There was no significant relationship between HTPR and MACCE, neither between LTPR and bleeding. Vitamin-K antagonist (VKA) treatment was associated with more MACCE and bleeding events, and the majority of events occurred within the first months. VASP index failed to predict outcomes in post-ACS patients with TAT. We confirm that direct acting OAC should be prioritized over VKA in TAT regimen.
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http://dx.doi.org/10.3390/jcm10081565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068113PMC
April 2021

Detection of Myocardial Infarction by Cardiac Magnetic Resonance in Embolic Stroke Related to First Diagnosed Atrial Fibrillation.

J Stroke Cerebrovasc Dis 2021 Jun 10;30(6):105753. Epub 2021 Apr 10.

Department of Cardiology, Dijon University Hospital, 21000 Dijon, France. Electronic address:

Introduction: Elevated troponin levels are found in a significant number of patients who are diagnosed with acute embolic stroke (AES) after first diagnosed atrial fibrillation (AF). These myocardial injuries, which are known as cardiocerebral infarction (CCI), are potentially caused by coronary embolism and correspond to simultaneous cardiac and cerebral embolisms. However, this severe condition remains poorly understood. In this prospective study, we aimed to investigate the prevalence and the cardiac magnetic resonance (CMR) characteristics of CCI.

Materials And Methods: Consecutive patients with first diagnosed AF hospitalized for AES in a neurovascular intensive care unit from 2019 to 2020 were included. Troponin Ic kinetic were measured <72 h, MRI and coronary angiography or CT scan were performed <7 days after admission. Patients with significant coronary lesions were excluded.

Results: During the study period, 1150 patients with strokes were hospitalized in the neurovascular intensive care unit (ICU). Of these patients, 955 had an ischemic stroke and 97 had a transient ischemic attack. Among the 44 patients with AES and with first diagnosed AF, 34 patients underwent CMR and CMR analysis identified 12 MI. A significant rise in troponin (>0.10 µg/L) was observed in 35% of the total population (12/34 patients). More specifically, a rise was seen in 23% of the AES without MI group, 58% of the AES with MI. In addition, coronary embolism was identified in 3 patients who underwent coronary angiography (3/12) and MI was often (30%) localized in infero-latero-medial and infero-apical segments. Most AES were localized in the superficial sylvian territory.

Conclusion: We found a high prevalence of CMR-confirmed double embolization sites in the acute phase of an embolic stroke. Further studies are required to better characterize the pathophysiology, clinical course and prognostic value of CCI. Moreover, optimal management strategies, including antiplatelet therapy, remain to be determined.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105753DOI Listing
June 2021

Antitumor Activity of Protons and Molecular Hydrogen: Underlying Mechanisms.

Cancers (Basel) 2021 Feb 20;13(4). Epub 2021 Feb 20.

PEC2 (EA7460), Faculty of Health Sciences, University Bourgogne-Franche Comte, 7 Bd Jeanne d'Arc, 21000 Dijon, France.

Understanding the structure and dynamics of the various hydrogen forms has been a subject of numerous studies. Protons (H) and molecular hydrogen (H) in the cell are critical in a wide variety of processes. A new cancer treatment uses H, a biologically inactive gas. Due to its small molecular weight, H can rapidly penetrate cell membranes and reach subcellular components to protect nuclear DNA and mitochondria. H reduces oxidative stress, exerts anti-inflammatory effects, and acts as a modulator of apoptosis. Exogenous H, administered by inhalation, drinking H-rich water, or injecting H-rich saline solution, is a protective therapy that can be used in multiple diseases, including cancer. In particle therapy, cyclotrons and synchrotrons are the accelerators currently used to produce protons. Proton beam radiotherapy (PBT) offers great promise for the treatment of a wide variety of cancers due to the sharp decrease in the dose of radiation at a defined point. In these conditions, H and different types of H donors may represent a novel therapeutic strategy in cancer treatment.
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http://dx.doi.org/10.3390/cancers13040893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924327PMC
February 2021

Letter by Putot et al Regarding Article, "Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction".

Circulation 2021 Feb 22;143(8):e250-e251. Epub 2021 Feb 22.

Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires, Université de Bourgogne Franche Comté, Dijon, France (A.P., Y.C., M.Z.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051103DOI Listing
February 2021

Myocardial infarction during giant cell arteritis: A cohort study.

Eur J Intern Med 2021 Feb 17. Epub 2021 Feb 17.

Department of Internal Medicine and Clinical Immunology, Dijon University Hospital, Dijon, France; Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-21000 Dijon, France. Electronic address:

Background: Cardiovascular risk is increased in giant cell arteritis (GCA). We aimed to characterize myocardial infarction (MI) in a GCA cohort, and to compare the GCA and non-GCA population affected by MI.

Methods: In patients with a biopsy-proven diagnosis of GCA between 1 January 2001 and 31 December 2016 in Côte D'Or (France), we identified patients with MI by crossing data from the territorial myocardial infarction registry (Observatoire des Infarctus de Côte d'Or) database. Five controls (non-GCA + MI) were paired with one case (GCA + MI) after matching for age, sex, cardiovascular risk factors and prior cardiovascular disease. MI were characterized as type 1 MI (T1MI), resulting from thrombus formation due to atherothrombotic disease, or type 2 MI (T2MI), due to a myocardial supply/demand mismatch. GCA-related MI was defined as MI occurring within 3 months of a GCA flare (before or after).

Results: Among 251 biopsy-proven GCA patients, 13 MI cases were identified and paired with 65 controls. MI was GCA-related in 6/13 cases, accounting for 2.4% (6/251) of our cohort. T2MI was more frequently GCA-related than GCA-unrelated (80% vs. 16.7%, p = 0.080), and GCA diagnosis was the only identified triggering factor in 75% of GCA-related T2MI. GCA-unrelated MI were more frequently T1MI and occurred in patients who had received a higher cumulative dose of prednisone (p = 0.032). GCA was not associated with poorer one-year survival.

Conclusions: GCA-related MI are mainly T2MI probably caused by systemic inflammation rather than coronaritis. GCA-unrelated MI are predominantly T1MI associated with atherothrombotic coronary artery disease.
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http://dx.doi.org/10.1016/j.ejim.2021.02.001DOI Listing
February 2021

Decongestant use and the risk of myocardial infarction and stroke: a case-crossover study.

Sci Rep 2021 Feb 18;11(1):4160. Epub 2021 Feb 18.

Normandie Université, Université Caen Normandie, CHU Caen Normandie, Inserm U1237, Caen, France.

Pharmacovigilance reports of cerebral and cardiovascular events in those who use decongestants have triggered alerts related to their use. We aimed to assess the risk of stroke and myocardial infarction (MI) associated with the use of decongestants. We conducted a nested case-crossover study of patients with incident stroke and MI identified in France between 2013 and 2016 in two systematic disease registries. Decongestant use in the three weeks preceding the event was assessed using a structured telephone interview. Conditional logistic multivariable models were used to estimate the odds of incident MI and stroke, also accounting for transient risk factors and comparing week 1 (index at-risk time window, immediately preceding the event) to week 3 (reference). Time-invariant risk factors were controlled by design. In total, 1394 patients with MI and 1403 patients with stroke, mainly 70 years old or younger, were interviewed, including 3.2% who used decongestants during the three weeks prior to the event (1.0% definite exposure in the index at-risk time window, 1.1% in the referent time window; adjusted odds ratio (aOR), 0.78; 95%CI, 0.43-1.42). Secondary analysis yielded similar results for individual events (MI/stroke). We observed no increased risk of MI or stroke for patients 70 years of age and younger without previous MI or stroke who used decongestants.
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http://dx.doi.org/10.1038/s41598-021-83718-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893034PMC
February 2021

Triglycerides and risk of atherosclerotic cardiovascular disease: An update.

Arch Cardiovasc Dis 2021 Feb 3;114(2):132-139. Epub 2021 Feb 3.

PEC2, EA 7460, University of Bourgogne Franche-Comté, 21000 Dijon, France; Cardiology Department, University Hospital Centre of Dijon Bourgogne, 21000 Dijon, France.

Low-density lipoprotein cholesterol is a well-known causal factor for atherosclerotic cardiovascular disease, and is the primary target of lipid-lowering therapy. There is, however, still a substantial risk of atherosclerotic cardiovascular disease events despite intensive statin therapy, and data from clinical trials suggest that an elevated concentration of triglycerides is a marker of residual cardiovascular risk on low-density lipoprotein-lowering therapy. Serum triglycerides are a biomarker for triglyceride-rich lipoproteins, and several lines of evidence indicate that triglyceride-rich lipoproteins and their cholesterol-enriched remnant particles are associated with atherogenesis. Moreover, genetic data in humans strongly suggest that the remnants of triglyceride-rich lipoproteins are a causal cardiovascular risk factor. Although lifestyle changes remain the cornerstone of management of hypertriglyceridaemia, a recent trial with high doses of the omega-3 fatty acid icosapent ethyl showed a significant reduction in cardiovascular events that was not explained by the reduction in triglycerides alone. In patients with elevated triglycerides, several novel drugs are in development to reduce the residual risk on statin therapy linked to an excess of atherogenic triglyceride-rich lipoproteins. In this review, we provide an update on the biology, epidemiology and genetics of triglycerides, and the risk of atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.1016/j.acvd.2020.11.006DOI Listing
February 2021

PCSK9 levels do not predict severity and recurrence of cardiovascular events in patients with acute myocardial infarction.

Nutr Metab Cardiovasc Dis 2021 03 20;31(3):880-885. Epub 2020 Nov 20.

University Hospital Center Dijon Bourgogne, Cardiology Department, Dijon, France.

Background And Aims: It remains unclear whether serum PCSK9 levels can predict the severity of the disease and the risk of future events in patients with coronary artery disease (CAD). We aimed to evaluate the association between PCSK9 levels, metabolic parameters, severity of CAD on coronary angiography (SYNTAX score), and the risk of in-hospital events and at one-year follow-up.

Methods And Results: From September 2015 to December 2016, serum PCSK9 levels were measured on admission in patients not previously receiving statin therapy, and admitted for an acute myocardial infarction (MI), in an intensive care unit from a university hospital. In a total of 648 patients (mean age: 66 years, 67% male), median PCSK9 was 263 ng/ml, higher for females compared with males (270 vs 256 ng/ml, p = 0.009). Serum PCSK9 was associated with LDL cholesterol (r = 0.083, p = 0.036), total cholesterol (r = 0.136, p = 0.001) and triglycerides (r = 0.137, p = 0.001). A positive association was also observed in the subgroup of patients with CRP >10 mg/L (p < 0.001), but not with NT-proBNP, troponin and creatine kinase. PCSK9 levels were similar whatever the SYNTAX score or the number of significant coronary lesions. PCSK9 levels were not associated with in-hospital events (death, recurrent MI and stroke) and events (cardiovascular death, cardiovascular events, recurrent MI) at one-year follow-up.

Conclusions: In this large cohort of patients hospitalized for acute MI and not previously receiving statin therapy, PCSK9 levels was not associated with the severity or the recurrence of cardiovascular events. The clinical utility of measuring PCSK9 levels for this category of patients therefore appears limited.
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http://dx.doi.org/10.1016/j.numecd.2020.11.010DOI Listing
March 2021

Outcomes in patients with acute myocardial infarction and new atrial fibrillation: a nationwide analysis.

Clin Res Cardiol 2021 Jan 28. Epub 2021 Jan 28.

Service de Cardiologie, Centre Hospitalier Universitaire et Faculté de Médecine, Université de Dijon, Dijon, France.

Background: In patients with acute myocardial infarction (AMI), history of atrial fibrillation (AF) and new onset AF during the early phase may be associated with a worse prognosis. Whether both conditions are associated with similar outcomes is a matter of debate.

Methods: We collected information for all patients with AMI seen in French hospitals between 2010 and 2019. Among 797,212 patients seen with STEMI or NSTEMI, 75,701 (9.5%) had history of AF, and 34,768 (4.4%) had new AF diagnosed between day 1 and day 30 after AMI.

Results: Patients with new AF were older and had more comorbidities than those with no AF but were younger and had less comorbidities than those with history of AF. During follow-up [mean (SD) 1.8 (2.4) years, median (interquartile range) 0.7 (0.1-3.1) years], 163,845 deaths and 30,672 ischemic strokes were recorded. Using Cox multivariable analysis, compared to patients with no AF, history of AF was associated with a higher risk of death during follow-up (adjusted hazard ratio HR 1.17, 95% CI 1.16-1.19) and this was also the case for patients with new AF (adjusted HR 2.11, 2.07-2.15). Both history of AF and new AF were associated with a higher risk of ischemic stroke compared to patients with no AF: adjusted HR 1.19 (1.15-1.23) for history of AF, adjusted HR 1.78 (1.68-1.88) for new AF. New AF was associated with a higher risk of death and of ischemic stroke than history of AF: adjusted HR 1.74 (1.70-1.79) and 1.32 (1.23-1.42), respectively.

Conclusions: In a large and systematic nationwide analysis, AF first recorded in the first 30 days after AMI was independently associated with higher risks of death and ischemic stroke than those in patients with no AF or previously known AF.
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http://dx.doi.org/10.1007/s00392-021-01805-2DOI Listing
January 2021

The Multifaceted Interplay between Atrial Fibrillation and Myocardial Infarction: A Review.

J Clin Med 2021 Jan 7;10(2). Epub 2021 Jan 7.

Department of Cardiology, University Teaching Hospital of Dijon Bourgogne, 21000 Dijon, France.

This review was conducted to emphasize the complex interplay between atrial fibrillation (AF) and myocardial infraction (MI). In type 1 (T1) MI, AF is frequent and associated with excess mortality. Moreover, AF after hospital discharge for T1MI is not rare, suggesting the need to improve AF screening and to develop therapeutic strategies for AF recurrence. Additionally, AF is a common trigger for type 2 MI (T2MI), and recent data have shown that tachyarrhythmia or bradyarrhythmia could be a causal factor in, respectively, 13-47% or 2-7% of T2MI. In addition, AF is involved in T2MI pathogenesis as a result of severe anemia related to anticoagulants. AF is also an underestimated and frequent cause of coronary artery embolism (CE), as a situation at risk of myocardial infarction with non-obstructive coronary arteries. AF-causing CE is difficult to diagnose and requires specific management. Moreover, patients with both AF and chronic coronary syndromes represent a therapeutic challenge because the treatment of AF include anticoagulation, depending on the embolic risk, and ischemic heart disease management paradoxically includes antiplatelet therapy.
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http://dx.doi.org/10.3390/jcm10020198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826531PMC
January 2021

The Crosstalk of Adipose-Derived Stem Cells (ADSC), Oxidative Stress, and Inflammation in Protective and Adaptive Responses.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Faculté des Sciences de Santé, Université de Bourgogne, Franche Comté, 7 Bd Jeanne d'Arc, 21000 Dijon, France.

The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties.
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http://dx.doi.org/10.3390/ijms21239262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730805PMC
December 2020

Wearable cardioverter-defibrillator in patients with a transient risk of sudden cardiac death: the WEARIT-France cohort study.

Europace 2021 Jan;23(1):73-81

Department of Cardiology, General Hospital of Cannes, 06150 Cannes, France.

Aims : We aimed to provide contemporary real-world data on wearable cardioverter-defibrillator (WCD) use, not only in terms of effectiveness and safety but also compliance and acceptability.

Methods And Results : Across 88 French centres, the WEARIT-France study enrolled retrospectively patients who used the WCD between May 2014 and December 2016, and prospectively all patients equipped for WCD therapy between January 2017 and March 2018. All patients received systematic education session through a standardized programme across France at the time of initiation of WCD therapy and were systematically enrolled in the LifeVest Network remote services. Overall, 1157 patients were included (mean age 60 ± 12 years, 16% women; 46% prospectively): 82.1% with ischaemic cardiomyopathy, 10.3% after implantable cardioverter-defibrillator explant, and 7.6% before heart transplantation. Median WCD usage period was 62 (37-97) days. Median daily wear time of WCD was 23.4 (22.2-23.8) h. In multivariate analysis, younger age was associated with lower compliance [adjusted odds ratio (OR) 0.97, 95% confidence interval (CI) 0.95-0.99, P < 0.01]. A total of 18 participants (1.6%) received at least one appropriate shock, giving an incidence of appropriate therapy of 7.2 per 100 patient-years. Patient-response button allowed the shock to be aborted in 35.7% of well-tolerated sustained ventricular arrhythmias and in 95.4% of inappropriate ventricular arrhythmia detection, finally resulting in an inappropriate therapy in eight patients (0.7%).

Conclusion: Our real-life findings reinforce previous studies on the efficacy and safety of the WCD in the setting of transient high-risk group in selected patients. Moreover, they emphasize the fact that when prescribed appropriately, in concert with adequate patient education and dedicated follow-up using specific remote monitoring system, compliance with WCD is high and the device well-tolerated by the patient.
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http://dx.doi.org/10.1093/europace/euaa268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842091PMC
January 2021

Comment on: Revascularization Versus Medical Therapy in Patients Aged 80 Years and Older with Acute Myocardial Infarction.

J Am Geriatr Soc 2021 Jan 12;69(1):274-275. Epub 2020 Nov 12.

Geriatrics Internal Medicine Department, University Hospital of Dijon Bourgogne, France.

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http://dx.doi.org/10.1111/jgs.16938DOI Listing
January 2021

Impact of COVID-19 Pandemic on Mechanical Reperfusion for Patients With STEMI.

J Am Coll Cardiol 2020 11;76(20):2321-2330

Division of Cardiology, Ospedale "Sant'Anna", Ferrara, Italy.

Background: The fear of contagion during the coronavirus disease-2019 (COVID-19) pandemic may have potentially refrained patients with ST-segment elevation myocardial infarction (STEMI) from accessing the emergency system, with subsequent impact on mortality.

Objectives: The ISACS-STEMI COVID-19 registry aims to estimate the true impact of the COVID-19 pandemic on the treatment and outcome of patients with STEMI treated by primary percutaneous coronary intervention (PPCI), with identification of "at-risk" patient cohorts for failure to present or delays to treatment.

Methods: This retrospective registry was performed in European high-volume PPCI centers and assessed patients with STEMI treated with PPPCI in March/April 2019 and 2020. Main outcomes are the incidences of PPCI, delayed treatment, and in-hospital mortality.

Results: A total of 6,609 patients underwent PPCI in 77 centers, located in 18 countries. In 2020, during the pandemic, there was a significant reduction in PPCI as compared with 2019 (incidence rate ratio: 0.811; 95% confidence interval: 0.78 to 0.84; p < 0.0001). The heterogeneity among centers was not related to the incidence of death due to COVID-19. A significant interaction was observed for patients with arterial hypertension, who were less frequently admitted in 2020 than in 2019. Furthermore, the pandemic was associated with a significant increase in door-to-balloon and total ischemia times, which may have contributed to the higher mortality during the pandemic.

Conclusions: The COVID-19 pandemic had significant impact on the treatment of patients with STEMI, with a 19% reduction in PPCI procedures, especially among patients suffering from hypertension, and a longer delay to treatment, which may have contributed to the increased mortality during the pandemic. (Primary Angioplasty for STEMI During COVID-19 Pandemic [ISACS-STEMI COVID-19] Registry; NCT04412655).
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http://dx.doi.org/10.1016/j.jacc.2020.09.546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834750PMC
November 2020

Insights Into Mechanisms of GDF15 and Receptor GFRAL: Therapeutic Targets.

Trends Endocrinol Metab 2020 12 7;31(12):939-951. Epub 2020 Nov 7.

Research team, Pathophysiology and Epidemiology of Cerebro-Cardiovascular diseases (PEC2, EA 7460), University of Bourgogne Franche-Comté, UFR des Sciences de Santé, 7 boulevard Jeanne d' Arc, 21079 DIJON, France.

Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily proteins. GDF15 acts as an inflammatory marker, and it plays a role in pathogenesis of tumors, ischemic diseases, metabolic disorders, and neurodegenerative processes. GDF15 is not normally expressed in the tissue; it is prominently induced following 'injury'. GDF15 functions are critical for the regulation of endothelial adaptations after vascular damage. Recently, four research groups simultaneously identified glial-derived neurotrophic factor (GDNF)-family receptor α-like (GFRAL) in the brain, an orphan receptor as the receptor for GDF15, signaling through the coreceptor RET. In this article, new aspects of the biology of GDF15 and receptor GFRAL, and their relationship with various pathologies, are commented on.
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http://dx.doi.org/10.1016/j.tem.2020.10.004DOI Listing
December 2020

Simultaneous cardiocerebral embolization in patients with atrial fibrillation.

Arch Cardiovasc Dis 2020 Dec 3;113(12):821-827. Epub 2020 Nov 3.

Department of Cardiology, CHU de Dijon-Bourgogne, 21000 Dijon, France. Electronic address:

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http://dx.doi.org/10.1016/j.acvd.2020.05.023DOI Listing
December 2020

A case report of an acute coronary syndrome in a 10-year-old boy with homozygous familial hypercholesterolaemia.

Eur Heart J Case Rep 2020 Feb 13;4(1):1-5. Epub 2020 Jan 13.

Department of Cardiology, Dijon University Hospital, 21000 Dijon, France.

Background: Familial hypercholesterolaemia is a well-known disorder, but clinical diagnoses tend to be delayed. Acute coronary syndrome may occur in childhood.

Case Summary: Our patient, a young boy with homozygous familial hypercholesterolaemia, complained of persistent chest pain at rest and suffered a non-ST-elevation myocardial infarction (NSTEMI). The diagnosis of NSTEMI was made on the basis of his clinical features, dynamic electrocardiogram changes, troponin elevation, and cardiac computed tomography findings. The patient was managed surgically by intrathoracic artery (ITA) bypass graft. During post-operative follow-up, the young patient suffered from angina pectoris from unexpected and exceptional atheroma stenosis on the ITA.

Discussion: Familial hypercholesterolaemia needs to be identified quickly in young patients and lipid lowering therapies should be started without delay.
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http://dx.doi.org/10.1093/ehjcr/ytz233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574956PMC
February 2020

Myocardial Infarction after Kidney Transplantation: A Risk and Specific Profile Analysis from a Nationwide French Medical Information Database.

J Clin Med 2020 Oct 19;9(10). Epub 2020 Oct 19.

Department of Cardiology, University Teaching Hospital Burgundy, 21000 Dijon, France.

Introduction: Renal transplant recipients have a high peri-operative risk for cardiovascular events. The post-transplantation period also carries a risk of myocardial infarction (MI). Coronary artery disease (CAD) is a leading cause of death in these patients. We aimed to assess the risk of MI, the specific morbidity profile of MI after transplantation as well as the long-term prognosis after MI in renal transplantation (RT) patients regarding cardiovascular (CV) death and all-cause death.

Methods: From a French national medical information database, all of the patients seen in French hospitals in 2013 with at least 5-years follow-up were retrospectively identified and patients without transplantation but with previous dialysis at baseline were excluded. There were 17,526 patients with RT and 3,288,857 with no RT.

Results: Among these patients, 1020 in the RT group (5.8%), and 93,320 in the non-RT group (2.8%) suffered acute MI during a median follow-up of 5.4 years. After multivariable adjustment, risk of MI was higher in RT patients than in non-RT patients (HR 1.45, IC 95% 1.35-1.55). The mean age was 59.5 years for transplant patients with MI, and 70.6 years for the reference population with MI ( < 0.0001). MI patients with RT (vs. non RT patients) were more likely to have hypertension, diabetes dyslipidemia, and peripheral artery disease (76.0% vs. 48.1%, 38.7% vs. 25.2%, 33.2% vs. 23.2%, and 31.2% vs. 17.3%, respectively, < 0.0001). Incidence of non ST-elevation MI (NSTEMI) was higher in RT patients while incidence of ST-elevation MI (STEMI) was higher in patients without RT. In unadjusted analysis, risk of all-cause death and CV death within the first month after MI were higher in patients without RT (18% vs. 11.1% < 0.0001 and 12.3% vs. 7.8%, < 0.0001, respectively). However, multivariable analysis indicated that risk of all-cause death was higher in patients with RT than in those with no RT (adjusted HR 1.15 IC 95% 1.03-1.28).

Conclusions: MI is not an uncommon complication after RT (incidence of around 5.8% after 5 years). RT is independently associated with a 45% higher risk of MI than in patients without RT, with a predominance of NSTEMI. MI in patients with RT is independently associated with a 15% higher risk of all-cause death than that in patients with MI and no RT.
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http://dx.doi.org/10.3390/jcm9103356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589663PMC
October 2020

Bedside chest ultrasound to distinguish heart failure from pneumonia-related dyspnoea in older COVID-19 patients.

ESC Heart Fail 2020 Oct 13. Epub 2020 Oct 13.

Department of Geriatrics and Internal Medicine, Hospital of Champmaillot, Dijon University Hospital, Dijon, France.

Aims: In the older population, acute heart failure is a frequent, life-threatening complication of COVID-19 that requires urgent specific care. We aimed to explore the impact of point-of-care chest ultrasound (CUS) use in older bedridden inpatients during the COVID-19 pandemic as a tool to distinguish between cardiogenic pulmonary oedema and isolated viral pneumonia-related dyspnoea.

Methods And Results: This prospective series included 16 patients aged 75 or older, hospitalized for acute dyspnoea in an acute geriatric unit of a university hospital and testing positive for a SARS-Cov2 infection. We collected demographic characteristics, medical history, biological screening, clinical symptoms, CUS findings (n = 16) and chest CT-scan conclusions (n = 14). Mean age was 89 years (77-97). All patients presented asthenia and dyspnoea, 56% complained of coughing and diarrhoea, and 50% had fever. Acute heart failure was clinically suspected in seven patients. At CUS, evidence of heart failure was confirmed in three patients (including one without clinical suspicion); interstitial syndrome was confirmed in 12 patients on CUS vs. 9 patients with CT.

Conclusions: In older patients with COVID-19 and acute dyspnoea, the use of point-of-care CUS allowed the clinician to quickly rule out heart failure in nearly half of suspected cases while easily identifying virus-related interstitial syndrome. The use of CUS appears to be suitable for the rapid bedside investigation of dyspnoea in older patients, particularly in the context of the COVID-19 pandemic.
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http://dx.doi.org/10.1002/ehf2.13017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675430PMC
October 2020

Vascular density with optical coherence tomography angiography and systemic biomarkers in low and high cardiovascular risk patients.

Sci Rep 2020 10 7;10(1):16718. Epub 2020 Oct 7.

Laboratoire de Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (EA7460, PEC2), UFR Des Sciences de Santé, Bourgogne Franche-Comté University, Dijon, France.

We aimed to compare retinal vascular density in Optical Coherence Tomography Angiography (OCT-A) between patients hospitalized for acute coronary syndrome (ACS) and control patients and to investigate correlation with angiogenesis biomarkers. Patients hospitalized for an acute coronary syndrome (ACS) in the Intensive Care Unit were included in the "high cardiovascular risk" group while patients without cardiovascular risk presenting in the Ophthalmology department were included as "control". Both groups had blood sampling and OCT-A imaging. Retina microvascularization density in the superficial capillary plexus was measured on 3 × 3 mm angiograms centered on the macula. Angiopoietin-2, TGF-β1, osteoprotegerin, GDF-15 and ST-2 were explored with ELISA or multiplex method. Overall, 62 eyes of ACS patients and 42 eyes of controls were included. ACS patients had significantly lower inner vessel length density than control patients (p = 0.004). A ROC curve found that an inner vessel length density threshold below 20.05 mm was moderately associated with ACS. Significant correlation was found between serum levels of angiopoietin-2 and osteoprotegerin, and retinal microvascularization in OCT-A (R = - 0.293, p = 0.003; R = - 0.310, p = 0.001). Lower inner vessel length density measured with OCT-A was associated with ACS event and was also correlated with higher concentrations of angiopoietin-2 and osteoprotegerin.
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http://dx.doi.org/10.1038/s41598-020-73861-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542456PMC
October 2020

Impact of lockdown on patients with congestive heart failure during the coronavirus disease 2019 pandemic.

ESC Heart Fail 2020 Sep 30. Epub 2020 Sep 30.

PEC2, EA 7460, University of Bourgogne Franche Comté, Dijon, France.

Aims: Cardiovascular co-morbidities like congestive heart failure (CHF) alter the course of coronavirus disease 2019. Factors associated with the outbreak and lockdown can exacerbate CHF.

Methods And Results: We analysed the answers of 124 randomly selected CHF outpatients (mean age 71.0 ± 14.0 years, 60.5% male) interviewed by phone during the sixth and seventh weeks of the lockdown. Most patients were treated for New York Heart Association class II (38.7%) and reduced ejection fraction HF (70.2%). Psychological distress (Kessler 6 score ≥ 5) was common (18.5%), and 21.8% felt worse than before the lockdown. Few patients (n = 10) adjusted their intake of HF medications, always on medical prescription. Decreased physical activity was common (41.9%) and more frequent in women (P = 0.025) and urban dwellers (P = 0.009). Almost half of respondents (46.0%) declared increased screen time, but only few declared more alcohol intake (4.0%). Weight gain was common (27.4%), and 44.4% of current smokers increased tobacco consumption. Adherence to recommended salt or fluid intake restrictions was reduced in 14.5%. Increase in HF symptoms was commonly reported (21.8%) and tended to be higher in women than in men (P = 0.074). Of the 23 patients who had a phone teleconsultation during the pandemic, 16 had initially planned an in-person consultation that they switched for teleconsultation.

Conclusions: During the lockdown, psychological distress and decreased well-being were common in CHF outpatients, and there was an increase in unhealthy lifestyle behaviours. These changes may negatively impact short-term and long-term prognoses. Medication adherence was maintained, and limitations in access to care were partly counterbalanced by use of telehealth.
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http://dx.doi.org/10.1002/ehf2.13016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537025PMC
September 2020

Hospital admissions for acute myocardial infarction before and after lockdown according to regional prevalence of COVID-19 and patient profile in France: a registry study.

Lancet Public Health 2020 10 18;5(10):e536-e542. Epub 2020 Sep 18.

Department of Cardiology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France; French Alliance for Cardiovascular Trials, Paris, France. Electronic address:

Background: The COVID-19 pandemic has had a profound effect on general health care. We aimed to evaluate the effect of a nationwide lockdown in France on admissions to hospital for acute myocardial infarction, by patient characteristics and regional prevalence of the pandemic.

Methods: In this registry study, we collected data from 21 centres participating in the ongoing French Cohort of Myocardial Infarction Evaluation (FRENCHIE) registry, which collects data from all patients admitted for ST segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI) within 48 h of symptom onset. We analysed weekly hospital admissions over 8 weeks: the 4 weeks preceding the institution of the lockdown and the 4 weeks following lockdown. The primary outcome was the change in the number of hospital admissions for all types of acute myocardial infarction, NSTEMI, and STEMI between the 4 weeks before lockdown and the 4 weeks after lockdown. Comparisons between categorical variables were made using χ tests or Fisher's exact tests. Comparisons of continuous variables were made using Student's t tests or Mann-Whitney tests. Poisson regression was used to determine the significance of change in hospital admissions over the two periods, after verifying the absence of overdispersion. Age category, region, and type of acute myocardial infarction (STEMI or NSTEMI) were used as covariables. The FRENCHIE cohort is registered with ClinicalTrials.gov, NCT04050956.

Findings: Between Feb 17 and April 12, 2020, 1167 patients were consecutively admitted within 48 h of acute myocardial infarction (583 with STEMI, 584 with NSTEMI) and were included in the study. Admissions for acute myocardial infarction decreased between the periods before and after lockdown was instituted, from 686 before to 481 after lockdown (30% decrease; incidence rate ratio 0·69 [95% CI 0·51-0·70]). Admissions for STEMI decreased from 331 to 252 (24%; 0·72 [0·62-0·85]), and admissions for NSTEMI decreased from 355 to 229 (35%; 0·64 [0·55-0·76]) following institution of the lockdown, with similar trends according to sex, risk factors, and regional prevalence of hospital admissions for COVID-19.

Interpretation: A marked decrease in hospital admissions was observed following the lockdown, irrespective of patient characteristics and regional prevalence of COVID-19. Health authorities should be aware of these findings, in order to adapt their message if the COVID-19 pandemic persists or recurs, or in case of future major epidemics.

Funding: Recherche Hospitalo-Universitaire en Santé iVasc.
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http://dx.doi.org/10.1016/S2468-2667(20)30188-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498416PMC
October 2020

Impact of COVID-19 lockdown on lifestyle adherence in stay-at-home patients with chronic coronary syndromes: Towards a time bomb.

Int J Cardiol 2021 01 1;323:285-287. Epub 2020 Sep 1.

Cardiology Department, University Hospital, Dijon, France. Electronic address:

Background: We aimed to evaluate the impact of coronavirus disease 2019 (COVID-19)-related lockdown on adherence to lifestyle and drug regimens in stay-at-home chronic coronary syndromes patients living in urban and rural areas.

Methods: A cross-sectional population-based study was perfomed in patients with chronic coronary syndromes. A sample of 205 patients was randomly drawn from the RICO (Observatoire des infarctus de Côte d'Or) cohort. Eight trained interviewers collected data by phone interview during week 16 (April 13 to April 19), i.e. 4 weeks after implementation of the French lockdown (start March 17, 2020).

Results: Among the 195 patients interviewed (of the 205, 3 had died, 1 declined, 6 lost), mean age was 65.5 ± 11.1 years. Only six patients (3%) reported drug discontinuation, mainly driven by media influence or family members. All 166 (85%) patients taking aspirin continued their prescribed daily intake. Lifestyle rules were less respected since almost half (45%) declared >25% reduction in physical activity, 26% of smokers increased their tobacco consumption by >25%, and 24% of patients increased their body weight > 2 kg. The decrease in physical activity and the increase in smoking were significantly greater in urban patients (P < .05).

Conclusions: The COVID-19-related lockdown had a negative impact on lifestyle in a representative sample of stay-at-home CCS patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462445PMC
January 2021

Impact of the COVID-19 lockdown on the management and control of patients with GCA.

Ann Rheum Dis 2020 Aug 7. Epub 2020 Aug 7.

Department of Internal Medicine and Clinical Immunology, University Hospital Centre Dijon, Dijon, France

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http://dx.doi.org/10.1136/annrheumdis-2020-218360DOI Listing
August 2020

Role of humanin, a mitochondrial-derived peptide, in cardiovascular disorders.

Arch Cardiovasc Dis 2020 Aug - Sep;113(8-9):564-571. Epub 2020 Jul 15.

Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne - Franche Comté, Faculté des Sciences de Santé, 7, boulevard Jeanne-d'Arc, 21000 Dijon, France.

The mitochondria produce specific peptides-mitochondrial-derived peptides-that mediate the transcriptional stress response by their translocation into the nucleus and interaction with deoxyribonucleic acid. Mitochondrial-derived peptides are regulators of metabolism. This class of peptides comprises humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides (SHLPs). Humanin inhibits mitochondrial complex 1 activity and limits the level of oxidative stress in the cell. Data show that mitochondrial-derived peptides have a role in improving metabolic diseases, such as type 2 diabetes. Perhaps humanin can be used as a marker for mitochondrial function in cardiovascular disease or as a pharmacological strategy in patients with endothelial dysfunction. The goal of this review is to discuss the newly emerging functions of humanin, and its biological role in cardiovascular disorders.
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http://dx.doi.org/10.1016/j.acvd.2020.03.020DOI Listing
September 2020

Long-term outcomes after acute myocardial infarction in patients with familial hypercholesterolemia: The French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction program.

J Clin Lipidol 2020 May - Jun;14(3):352-360.e6. Epub 2020 Apr 8.

Department of Pharmacology, Hôpital St Antoine, Université Pierre et Marie Curie, Paris, France.

Background: Patients with familial hypercholesterolemia (FH) are prone to develop acute myocardial infarction (AMI) at a younger age.

Objectives: The aim of the present study was to assess 5-year outcomes after AMI according to the presence of FH in a large multicenter cohort of patients.

Methods: The French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction consists of nationwide surveys recruiting patients over a 1- to 2-month period every 5 years. Patients recruited in 2005 and 2010 were followed up to 5 years.

Results: Of 5147 patients discharged alive and in whom FH status could be assessed, 2.8% had probable/definite FH, using an adapted Dutch Lipid Clinic score. They were 12 years younger, on average, than non-FH patients. Before adjustment, their 5-year survival and event-free survival did not differ from non-FH patients. After adjustment, however, both mortality (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.15-2.89; P = .011) and the combined endpoint of death, AMI, or stroke (HR 2.22, 95% CI: 1.51-3.26; P < .001) were higher in FH patients. The higher risk in FH patients was also present in patients receiving high-intensity lipid-lowering therapy at discharge: adjusted HR for mortality 2.29, 95% CI: 1.18 to 4.47, P = .015; HR for cardiovascular events 2.57, 95% CI: 1.48 to 4.48, P = .001. Concordant results were observed in propensity score-marched cohorts.

Conclusions: The risk of long-term mortality and cardiovascular events is twice as high in FH than in non-FH patients, when adjusted on baseline characteristics, even for those receiving high-intensity lipid-lowering therapy. Additional therapeutic measures are needed in these patients.
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http://dx.doi.org/10.1016/j.jacl.2020.03.008DOI Listing
April 2020

Cerebral microbleeds and acute myocardial infarction: Screening and disease progression.

Int J Cardiol Heart Vasc 2020 Jun 29;28:100531. Epub 2020 May 29.

University Hospital Center Dijon Bourgogne, Cardiology Department, Dijon, France.

Introduction: Cerebral microbleeds (CMB) are associated with intracerebral haemorrhage. Therefore they may represent a concern if anticoagulant and/or antiplatelet therapy is needed. The aim of this study was to determine the prevalence of CMB in patients with acute myocardial infarction (AMI), and to follow their progression at 3 months under dual antiplatelet therapy (DAPT).

Methods: This prospective study included patients aged over 60 hospitalized in intensive cardiac care unit in our city for AMI. These patients underwent a first brain Magnetic resonance imaging (MRI) within 72 h of admission, that was repeated 3 months.

Results: 108 patients were included between November 2016 and December 2018. The prevalence of CMB was 21.3%, with a female predominance of 65.2% vs 32.1% (p = 0.004). Diabetes is significantly associated with the presence of CMB, 45.5% vs 21.2% (p = 0.021). Patients with at least one acute CMB had higher haemorrhagic risk as evaluated with CRUSADE score (40.5 ± 13.6 vs 31.2 ± 14.8 (p = 0.004).Multivariate analysis showed that only female sex was associated with the presence of a CMB on the initial MRI. On repeated MRI, an increase in CMB was observed in 6% of patients.Our results suggest that discharge treatment with anticoagulant in combination with antiplatelet therapy may be an independent predictor of early progression of CMB.

Conclusion: Our study confirms the high prevalence of CMB in patients over 60 years with AMI. The association of anticoagulant with DAPT, 3 months after stenting, may be an independent factor of CMB progression.
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http://dx.doi.org/10.1016/j.ijcha.2020.100531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262454PMC
June 2020

Post-Infectious Myocardial Infarction: Does Percutaneous Coronary Intervention Improve Outcomes? A Propensity Score-Matched Analysis.

J Clin Med 2020 May 26;9(6). Epub 2020 May 26.

Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), EA 7460, University of Burgundy and Franche Comté, 21079 Dijon CEDEX, France.

Acute infection is a frequent trigger of myocardial infarction (MI). However, whether percutaneous coronary intervention (PCI) improves post-infectious MI prognosis is a major but unsolved issue. In this prospective multicenter study from coronary care units, we performed propensity score-matched analysis to compare outcomes in patients with and without PCI for post-infectious MI with angiography-proven significant coronary stenosis (>50%). Among 4573 consecutive MI patients, 476 patients (10%) had a concurrent diagnosis of acute infection at admission, of whom 375 underwent coronary angiography and 321 patients had significant stenosis. Among the 321 patients, 195 underwent PCI. Before the matching procedure, patients without PCI had a similar age and sex ratio but a higher rate of risk factors (hypertension, diabetes, chronic renal failure, and prior coronary artery disease), pneumonia, and SYNTAX score than patients without PCI. After propensity score matching, neither in-hospital mortality (13% with PCI vs. 8% without PCI; = 0.4) nor one-year mortality (24% with PCI vs. 19% without PCI, = 0.5) significantly differed between the two groups. In this first prospective cohort of post-infectious MI in coronary care units, PCI might not improve short- and long-term prognosis in patients with angiography-proven significant coronary stenosis. If confirmed, these results do not argue for systematic invasive procedures after post-infectious MI.
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http://dx.doi.org/10.3390/jcm9061608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355802PMC
May 2020

Mitochondrial SLC25 Carriers: Novel Targets for Cancer Therapy.

Molecules 2020 May 22;25(10). Epub 2020 May 22.

Equipe d'Accueil (EA 7460) Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Faculté des Sciences de Santé, Université de Bourgogne-Franche Comté, 7 Bd Jeanne d'Arc, 21000 Dijon, France.

The transfer of metabolites through the mitochondrial membranes is a vital process that is highly controlled and regulated by the inner membrane. A variety of metabolites, nucleotides, and cofactors are transported across the inner mitochondrial membrane (IMM) by a superfamily of membrane transporters which are known as the mitochondrial carrier family (MCF) or the solute carrier family 25 (SLC25 protein family). In humans, the MCF has 53 members encoded by nuclear genes. Members of the SLC25 family of transporters, which is the largest group of solute carriers, are also known as mitochondrial carriers (MCs). Because MCs are nuclear-coded proteins, they must be imported into the IMM. When compared with normal cells, the mitochondria of cancer cells exhibit significantly increased transmembrane potentials and a number of their transporters are altered. SLC25 members were identified as potential biomarkers for various cancers. The objective of this review is to summarize what is currently known about the involvement of mitochondrial SLC25 carriers in associated diseases. This review suggests that the SLC25 family could be used for the development of novel points of attack for targeted cancer therapy.
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http://dx.doi.org/10.3390/molecules25102417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288124PMC
May 2020