Publications by authors named "Christophe Piot"

65 Publications

Myocardial Injury After Balloon Predilatation Versus Direct Transcatheter Aortic Valve Replacement: Insights From the DIRECTAVI Trial.

J Am Heart Assoc 2020 12 10;9(24):e018405. Epub 2020 Dec 10.

Department of Cardiology Montpellier University Hospital Montpellier France.

Background Myocardial injury is associated with higher mortality after transcatheter aortic valve replacement (TAVR) and might be increased by prior balloon aortic valvuloplasty (BAV). We aimed to evaluate the impact of prior BAV versus direct prosthesis implantation on myocardial injury occurring after (TAVR) with balloon-expandable prostheses. Methods and Results The DIRECTAVI (Direct Transcatheter Aortic Valve Implantation) trial, an open-label randomized study, demonstrated noninferiority of TAVR without BAV (direct TAVR group) compared with systematic BAV (BAV group) with the Edwards SAPIEN 3 valve. High-sensitivity troponin was assessed before and the day after the procedure. Incidence of myocardial injury after the procedure (high-sensitivity troponin elevation >15× the upper reference limit [14 ng/L]) was the main end point. Impact of myocardial injury on 1-month adverse events (all-cause mortality, stroke, major bleeding, major vascular complications, transfusion, acute kidney injury, heart failure, pacemaker implantation, and aortic regurgitation) was evaluated. Preprocedure and postprocedure high-sensitivity troponin levels were available in 211 patients. The mean age of patients was 83 years (78-87 years), with 129 men (61.1%). Mean postprocedure high-sensitivity troponin was 124.9±81.4 ng/L in the direct TAVR group versus 170.4±127.7 ng/L in the BAV group (=0.007). Myocardial injury occurred in 42 patients (19.9%), including 13 patients (12.2%) in the direct TAVR group and 29 (27.9%) in the BAV group (=0.004). BAV increased by 2.8-fold (95% CI, 1.4-5.8) myocardial injury probability. Myocardial injury was associated with 1-month adverse events (=0.03). Conclusions BAV increased the incidence and magnitude of myocardial injury after TAVR with new-generation balloon-expandable valves. Myocardial injury was associated with 1-month adverse events. These results argue in favor of direct SAPIEN 3 valve implantation. Registration URL: https://www.Clinicaltrials.gov; Unique identifier: NCT02729519.
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http://dx.doi.org/10.1161/JAHA.120.018405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955361PMC
December 2020

Anti-apoptotic peptide for long term cardioprotection in a mouse model of myocardial ischemia-reperfusion injury.

Sci Rep 2020 10 22;10(1):18116. Epub 2020 Oct 22.

IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France.

Reperfusion therapy during myocardial infarction (MI) leads to side effects called ischemia-reperfusion (IR) injury for which no treatment exists. While most studies have targeted the intrinsic apoptotic pathway to prevent IR injury with no successful clinical translation, we evidenced recently the potent cardioprotective effect of the anti-apoptotic Tat-DAXXp (TD) peptide targeting the FAS-dependent extrinsic pathway. The aim of the present study was to evaluate TD long term cardioprotective effects against IR injury in a MI mouse model. TD peptide (1 mg/kg) was administered in mice subjected to MI (TD; n = 21), 5 min prior to reperfusion, and were clinically followed-up during 6 months after surgery. Plasma cTnI concentration evaluated 24 h post-MI was 70%-decreased in TD (n = 16) versus Ctrl (n = 20) mice (p***). Strain echocardiography highlighted a 24%-increase (p****) in the ejection fraction mean value in TD-treated (n = 12) versus Ctrl mice (n = 17) during the 6 month-period. Improved cardiac performance was associated to a 54%-decrease (p**) in left ventricular fibrosis at 6 months in TD (n = 16) versus Ctrl (n = 20). In conclusion, targeting the extrinsic pathway with TD peptide at the onset of reperfusion provided long-term cardioprotection in a mouse model of myocardial IR injury by improving post-MI cardiac performance and preventing cardiac remodeling.
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http://dx.doi.org/10.1038/s41598-020-75154-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582178PMC
October 2020

Use and outcomes of the PK Papyrus covered stent in France: SOS PK Papyrus Registry.

Catheter Cardiovasc Interv 2020 Oct 21. Epub 2020 Oct 21.

Cardiology Department, Rangueil University Hospital, Toulouse, France.

Objectives: To evaluate the rate of procedural success and long-term outcomes of the PK Papyrus (PKP) covered stent (CS).

Background: CS are essential in the treatment of coronary artery perforation (CAP). They have also been used to treat coronary artery aneurysms. Limited evidence is available on clinical outcomes with the PKP.

Methods: This was a multicenter, observational, retrospective, and prospective study. Consecutive patients undergoing intentional PKP implantation in 22 centers in France were included. The primary endpoint was the rate of procedural success. Secondary endpoints included rates of death, myocardial infarction (MI), target lesion revascularization (TLR), in-stent restenosis (ISR), and stent thrombosis (ST).

Results: Data from 130 patients were analyzed (mean age 72.5 ± 10.5 years; 71% men). The main indication for PKP was CAP, in 84 patients (65%). Delivery success was achieved in 95% and procedural success in 91%. During the in-hospital stay, 15 patients died (12%) and 7 (5%) presented with ST. Data from 127 patients were available at 19.2 ± 12.8 month follow-up. Thirty-three patients died (26%), 15 (12%) had an MI and 21 (17%) presented with TLR. TLR was due to ISR in 12 patients (9%), 10 had definite ST (8%) and 1 patient for stent under-expansion.

Conclusions: The principal indication for PKP was CAP. PKP had high rates of delivery and procedural success. At long-term follow-up, there was a high rate of TLR, mainly due to ISR and ST. These results are consistent with previously reported data in these clinical settings.
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http://dx.doi.org/10.1002/ccd.29328DOI Listing
October 2020

Routine CYP2C19 Genotyping to Adjust Thienopyridine Treatment After Primary PCI for STEMI: Results of the GIANT Study.

JACC Cardiovasc Interv 2020 03;13(5):621-630

Sorbonne Université-Université Paris 6, ACTION Study Group, Groupe Hospitalier Pitié-Salpêtrière (Assistance Publique Hôpitaux de Paris), INSERM UMRS 1166, Paris, France.

Objectives: The aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary percutaneous coronary intervention.

Background: Response to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms.

Methods: CYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment.

Results: Detection of LOF alleles resulted in adjustment of P2Y inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups.

Conclusions: In a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment [GIANT]; NCT01134380).
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http://dx.doi.org/10.1016/j.jcin.2020.01.219DOI Listing
March 2020

Unrestricted use of polymer-free sirolimus eluting stents in routine clinical practice.

Medicine (Baltimore) 2020 Feb;99(8):e19119

Städtische Kliniken Esslingen, Esslingen, Germany.

Stent designs with ultrathin struts may further increase the procedural success of challenging lesion subsets. The objective of this study was to assess the safety and efficacy of ultrathin strut, polymer-free sirolimus eluting stent (PF-SES) implantations in a large scale, unselected patient population.Adult patients underwent percutaneous coronary interventions (PCI) with a thin-strut PF-SES. Data from two all-comers observational studies having the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled. The accumulated target lesion revascularization (TLR) rate at 9-12 months was the primary endpoint. All dual antiplatelet therapy strategies according to the applicable guidelines were permissible.In total, 7243 patients were prospectively enrolled for PCI with PF-SES in stable coronary artery disease or acute coronary syndrome (ACS). Major risk factors in the overall cohort were diabetes (37.3%), ST elevation myocardial infarction (18.1%) and non-ST myocardial infarction (24.6%). The follow-up rate was 88.6% in the overall population. The TLR rate in the overall cohort was 2.2% whereas definite/probable stent thrombosis (ST) occurred in 0.7%. In patients with in-stent restenosis lesions, the major adverse cardiac events rate was 6.4% whereas the corresponding rate for isolated left main coronary artery (LMCA) disease was highest with 6.7% followed by patients with culprit lesions in vein bypasses (VB, 7.1%). The mortality rate in patients treated in VB lesions was highest with 5.4%, followed by the isolated LMCA subgroup (3.4%) and ACS (2.6%).PCI with PF-SES in an unselected patient population, is associated with low clinical event and ST rates. Furthermore, PF-SES angioplasty in niche indications demonstrated favorable safety and efficacy outcomes with high procedural success rates.
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http://dx.doi.org/10.1097/MD.0000000000019119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034709PMC
February 2020

Polymer-free sirolimus-eluting stent use in Europe and Asia: Ethnic differences in demographics and clinical outcomes.

PLoS One 2020 13;15(1):e0226606. Epub 2020 Jan 13.

Gachon University Gil Medical Center, Incheon, South Korea.

Background: The objective of this study was to assess regional and ethnic differences in an unselected patient population treated with polymer-free sirolimus-eluting stents (PF-SES) in Asia and Europe.

Methods: Two all-comers observational studies based on the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were combined for data analysis to assure sufficient statistical power. The primary endpoint was the accumulated target lesion revascularization (TLR) rate at 9-12 months.

Results: Of the total population of 7243 patients, 44.0% (3186) were recruited in the Mediterranean region and 32.0% (2317) in central Europe. The most prominent Asian region was South Korea (17.6%, 1274) followed by Malaysia (5.7%, 413). Major cardiovascular risk factors varied significantly across regions. The overall rates for accumulated TLR and MACE were low with 2.2% (140/6374) and 4.4% (279/6374), respectively. In ACS patients, there were no differences in terms of MACE, TLR, MI and accumulated mortality between the investigated regions. Moreover, dual antiplatelet therapy (DAPT) regimens were substantially longer in Asian countries even in patients with stable coronary artery disease as compared to those in Europe.

Conclusions: PF-SES angioplasty is associated with low clinical event rates in all regions. Further reductions in clinical event rates seem to be associated with longer DAPT regimens.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226606PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957170PMC
April 2020

A multicentre, randomised controlled clinical study of drug-coated balloons for the treatment of coronary in-stent restenosis.

EuroIntervention 2020 Jul 17;16(4):e328-e334. Epub 2020 Jul 17.

Universität Giessen, Giessen, Germany.

Aims: Treatment of in-stent restenosis of coronary stents is challenging. The use of drug-coated balloons (DCB) is a promising technique to treat in-stent restenosis without adding another metal layer. The aim of the AGENT ISR randomised trial is to evaluate angiographic and clinical outcomes in patients with ISR of a previously treated lesion who were treated with either a DCB with a new coating formulation (Agent) or a standard DCB (SeQuent Please).

Methods And Results: AGENT ISR is a multicentre, randomised, open-label, non-inferiority study comparing the Agent and SeQuent Please DCB. A total of 125 patients (mean age ~68 years, 18% female) with in-stent restenosis of a previously treated lesion <28 mm in length were randomised at 11 sites in Europe to Agent (n=65) or SeQuent Please (n=60). The primary endpoint, six-month in-stent late lumen loss, in the Agent group (0.397±0.43 mm [n=51]) was non-inferior to that of the SeQuent Please group (0.393±0.536 mm [n=49]), as the two-sided upper 95% confidence boundary for the difference between groups was less than the pre-specified non-inferiority margin of 0.20 (difference 0.004, 95% CI [-0.189, 0.196]; pnon-inferiority=0.046). At one year, mortality was 3.1% in Agent and 1.7% in SeQuent Please patients (p>0.99), target lesion revascularisation 7.7% versus 10.0% (p=0.89), and stent thrombosis 0% versus 3.3% (p=0.44). Similar improvements in quality of life were seen in the two groups.

Conclusions: In this head-to-head comparison of two DCB, Agent proved to be non-inferior to SeQuent Please for in-stent late lumen loss at six months.

Clinical Trials Registration: NCT02151812 (http://clinicaltrials.gov/).
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http://dx.doi.org/10.4244/EIJ-D-19-00051DOI Listing
July 2020

Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years.

Eur J Heart Fail 2019 12 18;21(12):1619-1627. Epub 2019 Nov 18.

Lyon, France; Université Lyon 1, Villeurbanne, France; CNRS, UMR5558, Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Service de Biostatistique - Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Villeurbanne, France.

Aims: The MITRA-FR trial showed that among symptomatic patients with severe secondary mitral regurgitation, percutaneous repair did not reduce the risk of death or hospitalization for heart failure at 12 months compared with guideline-directed medical treatment alone. We report the 24-month outcome from this trial.

Methods And Results: At 37 centres, we randomly assigned 304 symptomatic heart failure patients with severe secondary mitral regurgitation (effective regurgitant orifice area >20 mm or regurgitant volume >30 mL), and left ventricular ejection fraction between 15% and 40% to undergo percutaneous valve repair plus medical treatment (intervention group, n = 152) or medical treatment alone (control group, n = 152). The primary efficacy outcome was the composite of all-cause death and unplanned hospitalization for heart failure at 12 months. At 24 months, all-cause death and unplanned hospitalization for heart failure occurred in 63.8% of patients (97/152) in the intervention group and 67.1% (102/152) in the control group [hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.77-1.34]. All-cause mortality occurred in 34.9% of patients (53/152) in the intervention group and 34.2% (52/152) in the control group (HR 1.02, 95% CI 0.70-1.50). Unplanned hospitalization for heart failure occurred in 55.9% of patients (85/152) in the intervention group and 61.8% (94/152) in the control group (HR 0.97, 95% CI 0.72-1.30).

Conclusions: In patients with severe secondary mitral regurgitation, percutaneous repair added to medical treatment did not significantly reduce the risk of death or hospitalization for heart failure at 2 years compared with medical treatment alone.
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http://dx.doi.org/10.1002/ejhf.1616DOI Listing
December 2019

A novel therapeutic peptide targeting myocardial reperfusion injury.

Cardiovasc Res 2020 03;116(3):633-644

IGF, Univ. Montpellier, CNRS, INSERM, F-34094 Montpellier, France.

Aims: Regulated cell death is a main contributor of myocardial ischaemia-reperfusion (IR) injury during acute myocardial infarction. In this context, targeting apoptosis could be a potent therapeutical strategy. In a previous study, we showed that DAXX (death-associated protein) was essential for transducing the FAS-dependent apoptotic signal during IR injury. The present study aims at evaluating the cardioprotective effects of a synthetic peptide inhibiting FAS:DAXX interaction.

Methods And Results: An interfering peptide was engineered and then coupled to the Tat cell penetrating peptide (Tat-DAXXp). Its internalization and anti-apoptotic properties were demonstrated in primary cardiomyocytes. Importantly, an intravenous bolus injection of Tat-DAXXp (1 mg/kg) 5 min before reperfusion in a murine myocardial IR model decreased infarct size by 48% after 24 h of reperfusion. In addition, Tat-DAXXp was still efficient after a 30-min delayed administration, and was completely degraded and eliminated within 24 h thereby reducing risks of potential side effects. Importantly, Tat-DAXXp reduced mouse early post-infarction mortality by 67%. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, and an improvement of myocardial functional recovery as evidenced in ex vivo experiments.

Conclusions: Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to a strong cardioprotection in vivo by inhibiting IR injury validating Tat-DAXXp as a promising candidate for therapeutic application.
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http://dx.doi.org/10.1093/cvr/cvz145DOI Listing
March 2020

Hemodynamic Performances and Clinical Outcomes in Patients Undergoing Valve-in-Valve Versus Native Transcatheter Aortic Valve Implantation.

Am J Cardiol 2019 07 18;124(1):90-97. Epub 2019 Apr 18.

Department of Cardiology, Montpellier University hospital, Montpellier University, France; PhyMedExp, University of Montpellier, Montpellier, France. Electronic address:

Valve-in-valve (ViV) transcatheter aortic valve implantation (TAVI) emerged has a less invasive treatment than surgery for patients with degenerated bioprosthesis. However, few data are currently available regarding results of ViV versus TAVI in native aortic valve. We aimed to compare hemodynamic performances and 1-year outcomes between patients who underwent ViV procedure and patients who underwent non-ViV TAVI. This bicentric study included all patients who underwent aortic ViV procedure for surgical bioprosthetic aortic failure between 2013 and 2017. All patients who underwent TAVI were included in the analysis during the same period. ViV and non-ViV patients were matched with 1:2 ratio according to size, type of TAVI device, age (±5 years), sex, and STS score. Primary end point was hemodynamic performance including mean aortic gradient and aortic regurgitation at 1-year follow-up. A total of 132 patients were included, 49 in the ViV group and 83 in the non-ViV group. Mean age was 82.8 ± 5.9 years, 55.3% were female. Mean STS score was 5.2% ± 3.1%. Self-expandable valves were implanted in 78.8% of patients. At 1-year follow-up, aortic mean gradient was significantly higher in ViV group (18.1 ± 9.4 mm Hg vs 11.4 ± 5.4 mm Hg; p < 0.0001) and 17 (38.6%) patients had a mean aortic gradient ≥20 mm Hg vs 6 (7.8%) in the non-ViV group (p = 0.0001). Aortic regurgitation > grade 2 were similar in both groups (p = 0.71). In the ViV group, new pacemaker implantation was less frequent (p = 0.01) and coronary occlusions occurred only in ViV group (n = 2 [4.1%]). At 1-year follow-up, 3 patients (2.3%) died from cardiac cause, 1 (2.1%) in the ViV group vs 2 (2.4%) in the non-ViV group (p = 0.9). There was no stroke. In conclusion, compared with TAVI in native aortic stenosis, ViV appears as a safe and feasible strategy in patients with impaired bioprosthesis. As 1-year hemodynamic performances seem better in native TAVI procedure, long-term follow-up should be assessed to determinate the impact of residual stenosis on outcomes and durability.
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http://dx.doi.org/10.1016/j.amjcard.2019.04.009DOI Listing
July 2019

Paclitaxel Drug-Coated Balloon After Bare-Metal Stent Implantation, an Alternative Treatment to Drug-Eluting Stent in High Bleeding Risk Patients (The Panelux Trial).

J Invasive Cardiol 2019 04;31(4):94-100

Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse Rangueil 1, Avenue Jean Poulhès TSA50032, 31059 Toulouse Cedex 9, France. Email:

Background: Prolonged dual-antiplatelet therapy (DAPT) in high bleeding risk (HBR) patients undergoing percutaneous coronary intervention can be challenging. We assessed the clinical safety of bare-metal stent (BMS) implantation followed by drug-coated balloon (DCB) treatment in HBR patients for whom drug-eluting stent implantation could be problematic in maintaining low ischemic event rate without increasing hemorrhagic events.

Methods: The study included patients with at least 1 de novo lesion who were either under long-term anticoagulant treatment or required semi-urgent non-coronary intervention. The strategy consisted of PRO-Kinetic Energy BMS stent (Biotronik AG) implantation followed by Pantera Lux DCB (Biotronik AG) and patients were followed for up to 12 months in 37 French centers.

Results: Between October 2013 and April 2015, a total of 432 patients with 623 de novo lesions who were either under long-term anticoagulant treatment (n = 300) or required semi-urgent non-cardiac surgery (n = 132) were treated by BMS plus DCB. Mean patient age was 74.1 ± 9.1 years, 76.4% were men, and 38% were diabetic. The composite primary endpoint rate (defined as target-lesion failure at 12 months) was 5.6% (95% confidence interval, 3.3-7.9). Median duration for DAPT treatment was 33 days. Hemorrhagic events, as defined by the Bleeding Academic Research Consortium, occurred in 31 patients (7.2%) and definite stent thrombosis occurred in 5 patients (1.3%).

Conclusions: The combination of BMS plus DCB intervention is safe even with a short duration of DAPT. This strategy might be an alternative to DES implantation in HBR patients if future randomized trials support this approach.
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April 2019

Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation.

N Engl J Med 2018 12 27;379(24):2297-2306. Epub 2018 Aug 27.

From Hopital Cardiovasculaire Louis Pradel, Chirurgie Cardio-Vasculaire et Transplantation Cardiaque (J.-F.O.), Pharmacy Department and Laboratoire Mateis (X.A.), and Hopital Cardiovasculaire Louis Pradel, Clinical Investigation Center and Heart Failure Department, INSERM 1407 (C.B., G.S., N. Mewton), Hospices Civils de Lyon and Claude Bernard University, Lyon, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Bichat (D.M.-Z., B.I., A.V.), and APHP, Hôpital Européen Georges Pompidou (N.K.), Paris, Centre Hospitalier Universitaire (CHU) Rennes, Hôpital Pontchaillou, Rennes (G.L., E.D.), Assistance Publique-Hôpitaux de Marseille (APHM), Hôpital de la Timone (G.B.), and Hôpital Saint Joseph (N. Michel), Marseille, CHU Nantes, Hôpital Guillaume et René Laennec, Nantes (N.P., J.-N.T., P.G.), Institut Jacques Cartier, Massy (T.L., B.C.), Clinique du Millénaire (C.P.) and CHU Montpellier, Hôpital Arnaud-de-Villeneuve (F.L.), Montpellier, CHU Angers, Angers (F.R.), CHU Toulouse, Hôpital Rangueil, Toulouse (D.C.), Centre Cardiologique du Nord, Saint-Denis (M.N.), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg (P.O.), Centre Hospitalier Régional Universitaire (CHRU) de Tours, Hôpital Trousseau, Tours (C.S.E.), APHP, Hôpital Henri Mondor, Créteil (E.T.), CHU Bordeaux, Hôpital Haut-Lévêque, Pessac (L.L.), CHRU Brest, Hôpital de La Cavale Blanche, Brest (M.G.), and Service de Biostatistique-Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Centre National de la Recherche Scientifique (CNRS), and Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Villeurbanne (F.B., D.M.-B.) - all in France; and the University of Ottawa Heart Institute, Division of Cardiology, Ottawa, Canada (D.M.-Z.).

Background: In patients who have chronic heart failure with reduced left ventricular ejection fraction, severe secondary mitral-valve regurgitation is associated with a poor prognosis. Whether percutaneous mitral-valve repair improves clinical outcomes in this patient population is unknown.

Methods: We randomly assigned patients who had severe secondary mitral regurgitation (defined as an effective regurgitant orifice area of >20 mm or a regurgitant volume of >30 ml per beat), a left ventricular ejection fraction between 15 and 40%, and symptomatic heart failure, in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group; 152 patients) or to receive medical therapy alone (control group; 152 patients). The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 12 months.

Results: At 12 months, the rate of the primary outcome was 54.6% (83 of 152 patients) in the intervention group and 51.3% (78 of 152 patients) in the control group (odds ratio, 1.16; 95% confidence interval [CI], 0.73 to 1.84; P=0.53). The rate of death from any cause was 24.3% (37 of 152 patients) in the intervention group and 22.4% (34 of 152 patients) in the control group (hazard ratio, 1.11; 95% CI, 0.69 to 1.77). The rate of unplanned hospitalization for heart failure was 48.7% (74 of 152 patients) in the intervention group and 47.4% (72 of 152 patients) in the control group (hazard ratio, 1.13; 95% CI, 0.81 to 1.56).

Conclusions: Among patients with severe secondary mitral regurgitation, the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone. (Funded by the French Ministry of Health and Research National Program and Abbott Vascular; MITRA-FR ClinicalTrials.gov number, NCT01920698 .).
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http://dx.doi.org/10.1056/NEJMoa1805374DOI Listing
December 2018

Acute and long-term cardioprotective effects of the Traditional Chinese Medicine MLC901 against myocardial ischemia-reperfusion injury in mice.

Sci Rep 2017 10 31;7(1):14701. Epub 2017 Oct 31.

IGF, CNRS, INSERM, Univ Montpellier, Montpellier, France.

MLC901, a traditional Chinese medicine containing a cocktail of active molecules, both reduces cerebral infarction and improves recovery in patients with ischemic stroke. The aim of this study was to evaluate the acute and long-term benefits of MLC901 in ischemic and reperfused mouse hearts. Ex vivo, under physiological conditions, MLC901 did not show any modification in heart rate and contraction amplitude. However, upon an ischemic insult, MLC901 administration during reperfusion, improved coronary flow in perfused hearts. In vivo, MLC901 (4 µg/kg) intravenous injection 5 minutes before reperfusion provided a decrease in both infarct size (49.8%) and apoptosis (49.9%) after 1 hour of reperfusion. Akt and ERK1/2 survival pathways were significantly activated in the myocardium of those mice. In the 4-month clinical follow-up upon an additional continuous per os administration, MLC901 treatment decreased cardiac injury as revealed by a 45%-decrease in cTnI plasmatic concentrations and an improved cardiac performance assessed by echocardiography. A histological analysis revealed a 64%-decreased residual scar fibrosis and a 44%-increased vascular density in the infarct region. This paper demonstrates that MLC901 treatment was able to provide acute and long-term cardioprotective effects in a murine model of myocardial ischemia-reperfusion injury in vivo.
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http://dx.doi.org/10.1038/s41598-017-14822-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665902PMC
October 2017

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke.

N Engl J Med 2017 09;377(11):1011-1021

From the Department of Neurology, Sainte-Anne Hospital, INSERM 894, Département Hospitalo-Universitaire (DHU) NeuroVasc Sorbonne Paris-Cité (J.-L.M., G.T.), and the Department of Neurology, Saint-Joseph Hospital (M.Z.), Paris Descartes University, the Department of Neurology and Stroke Unit (C.G.) and the Department of Cardiology (J.-M.J.), Bichat Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM 1148, DHU FIRE (Fibrosis Inflammation and Remodeling in Cardiovascular, Renal, and Respiratory Diseases) Sorbonne Paris-Cité, the Department of Neurology, Saint-Antoine Hospital, AP-HP, Pierre et Marie Curie University (P.F.), the Department of Neurology, Lariboisière Hospital, DHU NeuroVasc Sorbonne Paris-Cité, Paris Diderot University (P.R.), and the Epidemiology and Clinical Research Unit, Georges Pompidou European Hospital, AP-HP, INSERM Centre d'Investigation Clinique 1418 (A.C.-N., G.C.), Paris, the Departments of Physiology (G.D.), Neurology (H.H.), and Cardiology (J.-L.D.-R.), Henri Mondor Hospital, AP-HP, University Paris Est Creteil, Creteil, the Departments of Neurology (B.G.) and Cardiology (P. Guérin), Centre Hospitalier Universitaire (CHU) Nantes, Nantes, the Department of Neurology, University Hospital, Rouen (E.M.), the Stroke Department (L.M.) and the Departments of Interventional Cardiology (R.R.) and Cardiovascular Investigations (M.B.), Pierre Wertheimer and Louis Pradel Hospitals, Lyon University, Lyon, the Department of Neurology, Gui de Chauliac Hospital, INSERM 894 (C.A.), and the Department of Interventional Cardiology, Clinique du Millénaire, INSERM 1191 (C.P.), Montpellier University, Montpellier, the Department of Neurology, Dijon Stroke Registry, EA 7460 (Y.B.), and the Department of Cardiology (J.-C.E.), University Hospital, Burgundy University, Dijon, the Departments of Neurology (F.V., T.M.) and Cardiology (N.M.), Jean Minjoz University Hospital, Franche-Comté University, Besançon, the Departments of Neurology (O.D.) and Cardiology (B.B.), Michallon Hospital, Grenoble Alpes University, Grenoble, the Department of Neurology and Stroke Unit (S.C.) and the Department of Cardiology (L.L.), University Hospital, Jules Verne Picardie University, Amiens, the Department of Neurology, Yves le Foll Hospital, Saint Brieuc (C.V.), the Department of Neurology and Stroke Unit (N.D.-P.) and the Department of Cardiology and Congenital Heart Disease (F.G.), Centre Hospitalier Régional Universitaire (CHRU) Lille, Lille Nord de France University, Lille, the Department of Neurology and Stroke Unit (I.S.) and the Department of Congenital Cardiac Diseases (J.-B.T.), CHU Bordeaux, Bordeaux University, Bordeaux, the Department of Neurology, University Hospital, INSERM 1059, Lyon University, Saint-Etienne (P. Garnier), the Departments of Neurology (A.F.) and Cardiology (J.-R.L.), University Hospital, Clermont-Ferrand, the Department of Neurology and Stroke Unit, Cavale Blanche Hospital, INSERM 1078, University of Western Brittany, Brest (S.T.), the Department of Neurology, La Timone Hospital, Aix-Marseille University, Marseille (E.R.-B.), the Department of Neurology, Saint-Jean Hospital, Perpignan (D.S.), the Department of Neurology and Stroke Unit, Central Hospital, Nancy (J.-C.L.), the Departments of Neurology (J.-F.P.) and Cardiology and Vascular Diseases (J.-M.S.), Pontchaillou Hospital, Rennes University, Rennes, the Department of Neurology, Caen University Hospital, Caen (M.A.), the Department of Neurology, Docteur Schaffner Hospital, Lens (C.L.) - all in France; the Stroke Center, Department of Neurology, Vaudois University Hospital, Lausanne University, Lausanne, Switzerland (P.M.); the Department of Cardiology, CHU Sart Tilman, Liege University, Liege, Belgium (L.P.); and the Department of Neurology, University Hospital, Duisburg-Essen University, Duisberg-Essen, Germany (C.W.).

Background: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy.

Methods: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3.

Results: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone.

Conclusions: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).
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http://dx.doi.org/10.1056/NEJMoa1705915DOI Listing
September 2017

Cardiac mGluR1 metabotropic receptors in cardioprotection.

Cardiovasc Res 2017 May;113(6):644-655

IGF, CNRS, INSERM, Univ. Montpellier, F-34094 Montpellier, France.

Aims: In a previous study using a genome-wide microarray strategy, we identified metabotropic glutamate receptor 1 (mGluR1) as a putative cardioprotective candidate in ischaemic postconditioning (PostC). In the present study, we investigated the role of cardiac mGluR1 receptors during cardioprotection against myocardial ischaemia-reperfusion injury in the mouse myocardium.

Methods And Results: mGluR1 activation by glutamate administered 5 min before reperfusion in C57Bl/6 mice subjected to a myocardial ischaemia protocol strongly decreased both infarct size and DNA fragmentation measured at 24 h reperfusion. This cardioprotective effect was mimicked by the mGluR1 agonist, DHPG (10 μM), and abolished when glutamate was coinjected with the mGluR1 antagonist YM298198 (100 nM). Wortmannin (100 nM), an inhibitor of PI3-kinase, was able to prevent glutamate-induced cardioprotection. A glutamate bolus at the onset of reperfusion failed to protect the heart of mGluR1 knockout mice subjected to a myocardial ischaemia-reperfusion protocol, although PostC still protected the mGluR1 KO mice. Glutamate-treatment improved post-infarction functional recovery as evidenced by an echocardiographic study performed 15 days after treatment and by a histological evaluation of fibrosis 21 days post-treatment. Interestingly, restoration of functional mGluR1s by a PostC stimulus was evidenced at the transcriptional level. Since mGluR1s were localized at the surface membrane of cardiomyocytes, they might contribute to the cardioprotective effect of ischaemic PostC as other Gq-coupled receptors.

Conclusion: This study provides the first demonstration that mGluR1 activation at the onset of reperfusion induces cardioprotection and might represent a putative strategy to prevent ischaemia-reperfusion injury.
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http://dx.doi.org/10.1093/cvr/cvx024DOI Listing
May 2017

Assessment of the area at risk after acute myocardial infarction using 123I-MIBG SPECT: Comparison with the angiographic APPROACH-score.

J Nucl Cardiol 2018 04 22;25(2):572-580. Epub 2016 Aug 22.

Department of Nuclear Medicine, Montpellier University Hospital, 34295, Montpellier Cedex 5, France.

Background: Assessment of the area at risk (AAR) associated with an acute myocardial infarction is crucial for evaluating prevention and revascularization strategies. The aim of this study was to evaluate whether I-metaiodobenzylguanidine (I-MIBG) single-photon emission computed tomography (SPECT) provides a more widely available assessment of anatomical AAR than the established anatomical angiographic methods.

Methods: Seventy patients with ST-segment elevation acute myocardial infarction (STEMI) underwent coronary angiography with percutaneous coronary intervention and subsequent I-MIBG myocardial scintigraphy with left myocardial relative radiotracer uptake evaluation 12 ± 10 days after STEMI. Patients were divided into two groups depending on whether the culprit artery was occluded (50 patients) or sub-occluded (20 patients). Two scores were calculated as a percentage of the left ventricular myocardium surface, the first using a standard 17-segment summed rest score derived from the relative quantitative evaluation of I-MIBG myocardial uptake (MAR) and the second using the modified APPROACH-score (ApAR).

Results: For the patients with occluded artery, this study showed a high correlation between MAR and the angiographic score (Pearson r = .762 and P < .0001). For the patients with sub-occluded artery, for which the ApAR is not reliable, this study showed no correlation between MAR and the angiographic score (Pearson r = .18 and P = 0.45).

Conclusions: I-MIBG myocardial scintigraphy provides ARR assessment similar to that of ApAR in patients with a single occluded coronary artery. However, MAR differs from ApAR when angiographic scores are known to be inaccurate (sub-occluded culprit artery) or impossible to use. Further studies are needed to evaluate the potential clinical interest of I-MIBG SPECT as an alternative for area at risk assessment after STEMI even when the culprit artery is sub-occluded or when the angiographic scores cannot be used.
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http://dx.doi.org/10.1007/s12350-016-0644-7DOI Listing
April 2018

Sustained quality of life improvement after intracoronary injection of autologous bone marrow cells in the setting of acute myocardial infarction: results from the BONAMI trial.

Qual Life Res 2017 01 20;26(1):121-125. Epub 2016 Jul 20.

INSERM, UMR1087, CNRS, UMR 6291, l'institut du thorax, CIC-thorax, Université de Nantes, CHU de Nantes, Nantes, 44000, France.

Purpose: Cardiac cell therapy is a promising treatment for acute myocardial infarction (AMI), leading to cardiac function improvement. However, whether it translates into quality of life (QoL) improvement is unclear. We hypothesized that administration of bone marrow cells (BMC) to patients with AMI improves QoL.

Methods: In the multicenter BONAMI trial (NCT00200707), patients with reperfused AMI and decreased myocardial viability were randomized to intracoronary autologous BMC infusion (n = 52) or state-of-the-art therapy (n = 49). QoL data, derived from the Minnesota Living with Heart Failure questionnaire (MLHFQ), were obtained 1, 3, and 12 months after AMI and analyzed using a Rasch-family model.

Results: Using this model, QoL improved over time in the BMC group (p = 0.025) but not in the control group. Furthermore, the BMC-group patients displayed a better QoL than the control-group patients at 3 and 12 months post-AMI (p = 0.034 and p = 0.003, respectively). These findings were not detected when analyzing MLHFQ data using a standard method. Cardiac function, myocardial viability, mortality, and number of major adverse cardiac events did not differ between treatment groups.

Conclusion: Our results suggest that BMC therapy can improve QoL, stressing the need for confirmation trials and for systematic QoL assessment in cardiac cell therapy trials .
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http://dx.doi.org/10.1007/s11136-016-1366-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591380PMC
January 2017

close: Closure of patent foramen ovale, oral anticoagulants or antiplatelet therapy to prevent stroke recurrence: Study design.

Int J Stroke 2016 08 7;11(6):724-32. Epub 2016 Apr 7.

Department of Neurology, Annecy-Genevois Hospital, Annecy, France.

Rationale: Currently available data do not provide definitive evidence on the comparative benefits of closure of patent foramen ovale, oral anticoagulants and antiplatelet therapy in patients with patent foramen ovale-associated cryptogenic stroke

Aim: To assess whether transcatheter patent foramen ovale closure plus antiplatelet therapy is superior to antiplatelet therapy alone and whether oral anticoagulant therapy is superior to antiplatelet therapy, for secondary stroke prevention in patients aged 16 to 60 years with a large patent foramen ovale or a patent foramen ovale associated with an atrial septal aneurysm, and an otherwise unexplained ischaemic stroke or retinal ischaemia.

Sample Size: Six hundred and sixty-four patients were included in the study.

Methods And Design: CLOSE is an academic-driven, multicentre, randomized, open-label, three-group, superiority trial with blinded adjudication of outcome events. The trial has been registered with Clinical Trials Register (Clinicaltrials.gov, NCT00562289). Patient recruitment started in December 2007. Patient follow-up will continue until December 2016. Expected mean follow-up = 5.6 years.

Study Outcomes: The primary efficacy outcome is the occurrence of fatal or nonfatal stroke. Safety outcomes include fatal, life-threatening or major procedure- or device-related complications and fatal, life-threatening or major haemorrhagic complications.

Discussion: CLOSE is the first specifically designed trial to assess the superiority of patent foramen ovale closure over antiplatelet therapy alone and the superiority of oral anticoagulants over antiplatelet therapy to prevent stroke recurrence in patients with patent foramen ovale-associated cryptogenic stroke.
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http://dx.doi.org/10.1177/1747493016643551DOI Listing
August 2016

Editor's Choice-Medically managed patients with non-ST-elevation acute myocardial infarction have heterogeneous outcomes, based on performance of angiography and extent of coronary artery disease.

Eur Heart J Acute Cardiovasc Care 2017 Apr 12;6(3):262-271. Epub 2016 Jan 12.

4 French Alliance for Cardiovascular Clinical Trials (FACT), France.

Background: Medically managed individuals represent a high-risk group among patients with non-ST-elevation acute myocardial infarction (NSTE-AMI). We hypothesized that prognosis in this group is heterogeneous, depending on whether medical management was decided with or without coronary angiography (CAG).

Methods: Using data from the French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction (FAST-MI), we analysed data from 798 patients with NSTE-AMI who were medically managed (i.e. without revascularization during the index hospitalization). Patients were categorized according to the performance of CAG and, if performed, to the extent of coronary artery disease (CAD).

Results: There were marked differences in baseline demographics, according to whether CAG was performed and to the extent of CAD. While the overall mortality rate at five years was high (56.2%), it differed greatly between groups, with patients who did not undergo CAG having a higher mortality rate (77.4%) than patients who underwent CAG (36.7%, p<0.001), and a higher mortality rate even than patients with multivessel CAD (54.2%, p<0.001). By multivariable analysis, non-performance of CAG was an independent predictor of all-cause mortality among medically managed NSTE-AMI patients (adjusted hazard ratios (95% confidence intervals) 3.19 (1.79-5.67) at 30 days, 2.28 (1.60-3.26) at one year, and 1.63 (1.28-2.07) at five years; all p<0.001).

Conclusion: Medically managed patients with NSTE-AMI are a heterogeneous group in terms of baseline characteristics and outcomes. The highest risk patients are those who do not undergo CAG. Non-performance of CAG is a strong predictor of death. (FAST-MI, NCT00673036).
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http://dx.doi.org/10.1177/2048872615626354DOI Listing
April 2017

Predictors of ventricular remodelling in patients with reperfused acute myocardial infarction and left ventricular dysfunction candidates for bone marrow cell therapy: insights from the BONAMI trial.

Eur J Nucl Med Mol Imaging 2016 Apr 15;43(4):740-8. Epub 2015 Dec 15.

INSERM, UMR1087, l'institut du thorax, Nantes, F-44000, France.

Purpose: Few data are available regarding the relation of left ventricular (LV) mechanical dyssynchrony to remodelling after acute myocardial infarction (MI) and stem cell therapy. We evaluated the 1-year time course of both LV mechanical dyssynchrony and remodelling in patients enrolled in the BONAMI trial, a randomized, multicenter controlled trial assessing cell therapy in patients with reperfused MI.

Methods: Patients with acute MI and ejection fraction (EF) ≤ 45 % were randomized to cell therapy or to control and underwent thallium single-photon emission computed tomography (SPECT), radionuclide angiography, and echocardiography at baseline, 3 months, and 1 year. Eighty-three patients with a comprehensive 1-year follow-up were included. LV dyssynchrony was assessed by the standard deviation (SD) of the LV phase histogram using radionuclide angiography. Remodelling was defined as a 20 % increase in LV end-systolic volume index (LVESVI) at 1 year.

Results: At baseline, LVEF, wall motion score index, and perfusion defect size were significantly impaired in the 43 patients (52 %) with LV remodelling (all p < 0.001), without significant increase in LV mechanical dyssynchrony. During follow-up, there was a progressive increase in LV SD (p = 0.01). Baseline independent predictors of LV remodelling were perfusion SPECT defect size (p = 0.001), LVEF (p = 0.01) and a history of hypertension (p = 0.043). Bone marrow cell therapy did not affect the time-course of LV remodelling and dyssynchrony.

Conclusions: LV remodelling 1 year after reperfused MI is associated with progressive LV dyssynchrony and is related to baseline infarct size and ejection fraction, without impact of cell therapy on this process.
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http://dx.doi.org/10.1007/s00259-015-3279-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426178PMC
April 2016

Cyclosporine before PCI in Patients with Acute Myocardial Infarction.

N Engl J Med 2015 Sep 30;373(11):1021-31. Epub 2015 Aug 30.

From Centre Hospitalier Universitaire (CHU) Arnaud de Villeneuve (T.-T.C.) and Clinique du Millénaire (C.P.), Montpellier, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg (O.M.), CHU de Nimes, Nimes (G.C.), Hôpital Cardiovasculaire Louis Pradel (G. Rioufol, E.B.-C., C.B., I.B., C.J., G.D., N.M., M.O.), Claude Bernard University (G. Rioufol, E.B.-C., C.B., I.B., C.J., G.D., N.M., M.O.), Centre Hospitalier Saint-Joseph et Saint-Luc (J.-F.A.), Clinique de la Sauvegarde (V.M.), Clinique du Tonkin (P.S.), Clinical Investigation Center and Explorations Fonctionnelles Cardiovasculaires (C.B., I.B., C.J., G.D., N.M., M.O.), Lyon, CHU de Tours (D.A.) and Clinique Saint-Gatien (D.B.), Tours, Hôpital Guillaume et René Laennec, Nantes (P.G.), CHU de Rangueil, Toulouse (M.E.), Centre Hospitalier de Pau, Pau (N.D.), Hôpital Haut Lévèque, Bordeaux (P. Coste), Hôpital A. Michallon-CHU de Grenoble, Grenoble (G.V.), Hôpital Henri Duffau, Avignon (M.M.), Centre Hospitalier du Pays d'Aix, Aix-en-Provence (B.J.), Hôpital Gabriel Montpied, Clermont Ferrand (P.M.), Hôpital Charles Nicolle, Rouen (C.T.), Clinique de la Fourcade, Bayonne (J.-N.L.), Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris (P.G.S.), Hôpital du Bocage, Dijon (Y.C.), Centre Hospitalier General, Chartres (G. Range), Centre Hospitalier de Compiègne, Compiègne (J.C.), CHU d'Angers, Angers (F.P.), CHU de Nancy-Brabois, Vandœuvre-lès-Nancy (F.M.), CHU de Mulhouse (O.R.) and Clinique du Diaconat (O.I.), Mulhouse, Centre Hospitalier d'Annecy, Annecy (L.B.), Polyclinique des Fleurs, Ollioules (P.B.), Hôpital de La Cavale Blanche, Brest (M.G.), Clinique Esquirol, Agen (P. Colin, F.D.P.), Institut Jacques Cartier, Massy (M.-C.M.), Centre Hospitalier Henri Mondor, Créteil (J.-L.D.-R.), Hôpital Claude Galien, Quincy sous Sénat (T.U.), Hôpital Pontchaillou, Rennes (H.L.B.), Clinique de l'Ormeau, Tarbes (T.B.), Hôpital de la Côte de Nacre, Caen (G.G.), and Hôpital Cardi

Background: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling.

Methods: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume.

Results: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups.

Conclusions: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).
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http://dx.doi.org/10.1056/NEJMoa1505489DOI Listing
September 2015

Influence of cardiovascular risk factors on infarct size and interaction with mechanical ischaemic postconditioning in ST-elevation myocardial infarction.

Open Heart 2015;2(1):e000175. Epub 2015 Aug 6.

Cardiology Division , Hôpital Cardiologique Louis Pradel, Centre d'Investigation Clinique, Hospices Civils de Lyon , Lyon , France ; Inserm UMR-1060, CarMeN Unit , Université Claude Bernard Lyon1 , Lyon , France.

Objective: Previous studies have shown that mechanical postconditioning (PostC) significantly reduces infarct size (IS) in patients with acute myocardial infarction. Our objective was to assess the influence of traditional cardiovascular (CV) risk factors on IS and their interaction with ischaemic PostC in patients with acute ST-elevation myocardial infarction (STEMI).

Methods: The study population was constituted from the clinical database pooling of four previously published PostC prospective, multicentre, randomised, open-label controlled trials with identical inclusion criteria. Patients with STEMI, presenting within 12 h of symptoms onset referred for percutaneous coronary intervention, were included. Mechanical ischaemic PostC was performed by four repeated cycles of inflation-deflation of the angioplasty balloon within 1 min of reflow, while the control group underwent no intervention. IS was assessed by measuring total creatine kinase release over 72 h.

Results: 173 patients, aged 58±12 years, 76% males, 48% anterior infarct were included (82 in the PostC group, 91 in the control group). IS was significantly reduced in the PostC compared to the control group (71.7±41.6 vs 88.2±54.5×10(3) arbitrary units; p=0.027). After adjustment for abnormally contracting segments, older patients had smaller IS and smokers had larger IS. Gender, diabetes, hypertension, dyslipidemia and obesity did not have any significant effect on IS. Multivariate regression analysis showed that none of the traditional risk factors had a significant impact on the cardioprotective effect of mechanical ischaemic PostC.

Conclusions: The present analysis suggests that the cardioprotective effect of mechanical PostC is not influenced by traditional CV risk factors that are prevalent in patients with STEMI.
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http://dx.doi.org/10.1136/openhrt-2014-000175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533201PMC
August 2015

Pre-PCI angiographic TIMI flow in the culprit coronary artery influences infarct size and microvascular obstruction in STEMI patients.

J Cardiol 2016 Mar;67(3):248-53

Cardiology Division, Centre d'Investigation Clinique de Lyon (CIC), Groupement Hospitalier Est, Hôpital Louis Pradel, 28 avenue Doyen Lépine, 69677 Bron, Hospices Civils de Lyon, France; INSERM UMR-1060, CarMeN Laboratory, Université Claude Bernard Lyon1, Faculté de Médecine Lyon Est, F-69373 Lyon, France.

Objective: The influence of initial-thrombolysis in myocardial infarction (i-TIMI) coronary flow in the culprit coronary artery on myocardial infarct and microvascular obstruction (MVO) size is unclear. We assessed the impact on infarct size of i-TIMI flow in the culprit coronary artery, as well as on MVO incidence and size, by contrast-enhanced cardiac magnetic resonance (ce-CMR).

Methods: In a prospective, multicenter study, pre-percutaneous coronary intervention (PCI) coronary occlusion was defined by an i-TIMI flow ≤1, and patency was defined by an i-TIMI flow ≥2. Infarct size, as well as MVO presence and size, were measured on ce-CMR 72h after admission.

Results: A total of 140 patients presenting with ST-elevated myocardial infarction referred for primary PCI were included. There was no significant difference in final post-PCI TIMI flow between the groups (2.95±0.02 vs. 2.97±0.02, respectively; p=0.44). In the i-TIMI flow ≤1 group, infarct size was significantly larger (32±17g vs. 21±17g, respectively; p=0.002), MVO was significantly more frequent (74% vs. 53%, respectively; p=0.012), and MVO size was significantly larger [1.3 IQR (0; 7.1) vs. 0 IQR (0; 1.6)], compared to in the i-TIMI ≥2 patient group.

Conclusion: Initial angiographic TIMI flow in the culprit coronary artery prior to any PCI predicted final infarct size and MVO size: the better was the i-TIMI flow, the smaller were the infarct and MVO size.
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http://dx.doi.org/10.1016/j.jjcc.2015.05.008DOI Listing
March 2016

Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial).

Am Heart J 2015 Jun 13;169(6):758-766.e6. Epub 2015 Mar 13.

Hôpital de La Cavale Blanche, Brest, France.

Background: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients.

Methods: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction.

Results: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015.

Conclusions: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.
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http://dx.doi.org/10.1016/j.ahj.2015.02.020DOI Listing
June 2015

Comparison of a novel biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent: results of the randomized BIOFLOW-II trial.

Circ Cardiovasc Interv 2015 Feb;8(2):e001441

From the Department of Cardiology, Bern University Hospital, Bern, Switzerland (S.W.); Städtische Kliniken Neuss, Lukaskrankenhaus GmbH, Neuss, Germany (M.H.); Universitäts-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany (F.-J.N.); Charité-Campus Mitte, Berlin, Germany (K.S.); Charité Campus Benjamin Franklin, Berlin, Germany (B.W.); Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (T.S.); Hospital Clínic, Thorax Institute, Barcelona, Spain (M.S.); IDIBAPS, University of Barcelona, Barcelona, Spain (M.S.); Hospital Puerta de Hierro, Madrid, Spain (J.G.); Polyclinique les Fleurs, Ollioules, France (P.B.); Hospital and University Fribourg, Switzerland (S.C.); University of Montpellier, Montpellier Cedex 5, France (C.P.); Segeberger Kliniken, Bad Segeberg, Germany (G.R.); Semmelweis University Heart and Vascular Center, Budapest, Hungary (B.M.); Universitätsklinikum Rostock, Rostock, Germany (H.S.); Klinikum Nürnberg Süd, Nürnberg, Germany (J.B.); Lucerne Canton Hospital, Lucerne, Switzerland (P.E.); MedStar Health Research Institute, Washington, DC (R.W.); Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland (S.Z., P.J.); and ICPS, Massy, France (T.L.).

Background: Biodegradable polymers for release of antiproliferative drugs from drug-eluting stents aim to improve vascular healing. We assessed noninferiority of a novel ultrathin strut drug-eluting stent releasing sirolimus from a biodegradable polymer (Orsiro, O-SES) compared with the durable polymer Xience Prime everolimus-eluting stent (X-EES) in terms of the primary end point in-stent late lumen loss at 9 months.

Methods And Results: A total of 452 patients were randomly assigned 2:1 to treatment with O-SES (298 patients, 332 lesions) or X-EES (154 patients, 173 lesions) in a multicenter, noninferiority trial. The primary end point was in-stent late loss at 9 months. O-SES was noninferior to X-EES for the primary end point (0.10±0.32 versus 0.11±0.29 mm; difference=0.00063 mm; 95% confidence interval, -0.06 to 0.07; Pnoninferiority<0.0001). Clinical outcome showed similar rates of target-lesion failure at 1 year (O-SES 6.5% versus X-EES 8.0%; hazard ratio=0.82; 95% confidence interval, 0.40-1.68; log-rank test: P=0.58) without cases of stent thrombosis. A subgroup of patients (n=55) underwent serial optical coherence tomography at 9 months, which demonstrated similar neointimal thickness among lesions allocated to O-SES and X-EES (0.10±0.04 mm versus 0.11±0.04 mm; -0.01 [-0.04, -0.01]; P=0.37). Another subgroup of patients (n=56) underwent serial intravascular ultrasound at baseline and 9 months indicating a potential difference in neointimal area at follow-up (O-SES, 0.16±0.33 mm(2) versus X-EES, 0.43±0.56 mm(2); P=0.04).

Conclusions: Compared with durable polymer X-EES, novel biodegradable polymer-based O-SES was found noninferior for the primary end point in-stent late lumen loss at 9 months. Clinical event rates were comparable without cases of stent thrombosis throughout 1 year of follow-up.

Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT01356888.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.114.001441DOI Listing
February 2015

Difference in mobilization of progenitor cells after myocardial infarction in smoking versus non-smoking patients: insights from the BONAMI trial.

Stem Cell Res Ther 2013 ;4(6):152

Introduction: Although autologous bone marrow cell (BMC) therapy has emerged as a promising treatment for acute myocardial infarction (AMI), trials reported mixed results. In the BONAMI trial, active smoking reduced cardiac function recovery after reperfused AMI. Therefore, we hypothesized that variability in the functionality of BMCs retrieved from patients with cardiovascular risk factors may partly explain these mixed results. We investigated the characteristics of progenitor cells in active smokers and non-smokers with AMI and their potential impact on BMC therapy efficacy.

Methods: Bone marrow and blood samples from 54 smoking and 47 non-smoking patients enrolled in the BONAMI cell therapy trial were analyzed.

Results: The white BMC and CD45dimCD34+ cell numbers were higher in active smokers (P = 0.001, P = 0.03, respectively). In marked contrast, either bone marrow or blood endothelial progenitor CD45dimCD34 + KDR + cells (EPCs) were decreased in active smokers (P = 0.005, P = 0.04, respectively). Importantly, a multivariate analysis including cardiovascular risk factors confirmed the association between active smoking and lower EPC number in bone marrow (P = 0.04) and blood (P = 0.04). Furthermore, baseline circulating EPC count predicted infarct size decrease at three months post-AMI in non-smokers (P = 0.01) but not in active smokers. Interestingly, baseline circulating EPCs were no longer predictive of cardiac function improvement in the BMC therapy group.

Conclusions: These data suggest that circulating EPCs play an important role in cardiac repair post-AMI only in non-smokers and that active smoking-associated EPC alterations may participate in the impairment of cardiac function recovery observed in smokers after AMI, an effect that was overridden by BMC therapy.
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http://dx.doi.org/10.1186/scrt382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054959PMC
October 2014

The RIPOST-MI study, assessing remote ischemic perconditioning alone or in combination with local ischemic postconditioning in ST-segment elevation myocardial infarction.

Basic Res Cardiol 2014 Mar 10;109(2):400. Epub 2014 Jan 10.

Service de Cardiologie, EA 3860, Laboratoire Cardioprotection, Remodelage et Thrombose, Université Angers, CHU Angers, rue Haute de Reculée, 49045, Angers, France,

Local ischemic postconditioning (IPost) and remote ischemic perconditioning (RIPer) are promising cardioprotective therapies in ST-elevation myocardial infarction (STEMI). We aimed: (1) to investigate whether RIPer initiated at the catheterization laboratory would reduce infarct size, as measured using serum creatine kinase-MB isoenzyme (CK-MB) release as a surrogate marker; (2) to assess if the combination of RIPer and IPost would provide an additional reduction. Patients (n = 151) were randomly allocated to one of the following groups: (1) control group, percutaneous transluminal coronary angioplasty (PTCA) alone; (2) RIPer group, PTCA combined with RIPer, consisting of three cycles of 5-min inflation and 5-min deflation of an upper-arm blood-pressure cuff initiated before reperfusion; (3) RIPer+IPost group, PTCA combined with RIPer and IPost, consisting of four cycles of 1-min inflation and 1-min deflation of the angioplasty balloon. The CK-MB area under the curve (AUC) over 72 h was reduced in RIPer, and RIPer+IPost groups, by 31 and 29 %, respectively, compared to the Control group; however, CK-MB AUC differences between the three groups were not statistically significant (p = 0.06). Peak CK-MB, CK-MB AUC to area at risk (AAR) ratio, and peak CK-MB level to AAR ratio were all significantly reduced in the RIPer and RIPer+IPost groups, compared to the Control group. On the contrary, none of these parameters was significantly different between RIPer+IPost and RIPer groups. To conclude, starting RIPer therapy immediately prior to revascularization was shown to reduce infarct size in STEMI patients, yet combining this therapy with an IPost strategy did not lead to further decrease in infarct size.
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http://dx.doi.org/10.1007/s00395-013-0400-yDOI Listing
March 2014

Everolimus-eluting stent for the treatment of bare metal in-stent restenosis: clinical and angiographic outcomes at nine-month follow-up of XERES (Xience Evaluation in bare metal stent REStenosis) trial.

EuroIntervention 2014 Oct;10(6):700-8

Cardiology B, Cardiovascular and Metabolic Pole, Rangueil Hospital, Toulouse, France.

Aims: Restenosis is a frequent complication of coronary stent implantation, especially bare metal stent (BMS) implantation. The everolimus-eluting stent (EES) has previously been shown to be efficacious in the treatment of de novo lesions. We performed this study to evaluate clinical, angiographic and IVUS results after EES implantation for the treatment of BMS ISR. XERES was a prospective, multicentre, nationwide study, enrolling 97 consecutive patients with in-stent restenosis (ISR) after BMS implantation across 20 centres in France. Suitable lesions had a reference vessel diameter between 2.5 mm and 4 mm, a length ≤22 mm and a diameter stenosis between 50 and 100%. The primary endpoint was angiographic in-stent late loss (LL) as determined by quantitative coronary angiography (QCA) at nine-month follow-up. QCA was required to be performed in each included patient and IVUS was performed in a subgroup of 27 patients. At nine-month follow-up, the in-stent late loss was 0.35±0.63 mm. The rate of in-stent binary restenosis was 12.22%, including two complete occlusions. The average volume of neointimal hyperplasia was 15.6±9.9 mm3. The in-stent percent volume obstruction was 8.5±5.2%. The in-segment percent area and diameter obstruction were 32±17% and 27±11%, respectively. Two initial malappositions were persistent and two other patients had late acquired stent malapposition. The cumulative incidence of major adverse cardiac events (MACE) was 10.1%. EES for the treatment of bare metal in-stent restenosis seemed safe and efficacious.
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http://dx.doi.org/10.4244/EIJV10I6A122DOI Listing
October 2014

Postconditioning attenuates no-reflow in STEMI patients.

Basic Res Cardiol 2013 Nov 11;108(6):383. Epub 2013 Sep 11.

Cardiology Division, Centre d'Investigation Clinique de Lyon (CIC), Groupement Hospitalier Est, Hôpital Louis Pradel, Hospices Civils de Lyon, 28 avenue Doyen Lépine, 69677, Bron, France,

After acute myocardial infarction, the presence of no-reflow (or microvascular obstruction: MVO) has been associated with adverse left ventricular (LV) remodeling and worse clinical outcome. This study examined the effects of mechanical ischemic postconditioning on early and late MVO size in acute ST-elevation myocardial infarction (STEMI) patients. Fifty patients undergoing primary coronary angioplasty for a first STEMI with TIMI grade flow 0-1 and no collaterals were randomized to ischemic postconditioning (PC) (n = 25) or control (n = 25) groups. Ischemic PC consisted in the application of four consecutive cycles of a 1-min balloon occlusion, each followed by a 1-min deflation at the onset of reperfusion. Early (3 min post-contrast) and late (10 min post-contrast) MVO size were assessed by contrast-enhanced cardiac-MRI within 96 h after reperfusion. PC was associated with smaller early and late MVO size (3.9 ± 4.8 in PC versus 7.8 ± 6.6% of LV in controls for early MVO, P = 0.02; and 1.8 ± 3.1 in PC versus 4.1 ± 3.9% of LV in controls for late MVO; P = 0.01). This significant reduction was persistent after adjustment for thrombus aspiration, which neither had any significant effect on infarct size, nor on early or late MVO (P = NS for all). Attenuation of MVO was associated to infarct size reduction. Mechanical postconditioning significantly reduces MVO in patients with acute STEMI treated with primary angioplasty.
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http://dx.doi.org/10.1007/s00395-013-0383-8DOI Listing
November 2013

A randomized trial of platelet reactivity monitoring-adjusted clopidogrel therapy versus prasugrel therapy to reduce high on-treatment platelet reactivity.

Int J Cardiol 2013 Oct 2;168(4):4244-8. Epub 2013 Aug 2.

Département de cardiologie, Hôpital universitaire nord, Aix-Marseille Univ., Marseille, France; INSERM UMRS 608, UFR de pharmacie, Marseille, France. Electronic address:

Background: Peri-procedural platelet reactivity (PR) inhibition is critical in patients undergoing percutaneous coronary intervention (PCI). High on-treatment PR (HTPR) was associated with recurrent ischemic events in acute coronary syndrome (ACS) patients undergoing PCI. We aimed to compare a strategy of clopidogrel loading dose-adjustment (CDA) according to PR monitoring with standard prasugrel therapy to reduce the rate of patients exhibiting HTPR.

Methods: We enrolled 177 ACS patients in a prospective multicentre randomized trial comparing CDA according to PR monitoring and prasugrel therapy. The VASP index was used to measure PR and a VASP ≥ 50% defined HTPR. The primary endpoint of the study was the rate of HTPR on discharge.

Results: Baseline characteristics of the CDA group (n = 88) and of the prasugrel group (n = 89) were similar. CDA significantly reduced PR and the rate of HTPR compared to a single LD of clopidogrel (30.9 ± 13.9%; p < 0.0001 and 43 to 2.3%; p < 0.001, respectively). Following CDA the rate of patients with HTPR was significantly lower in the CDA group compared to the prasugrel group on discharge (2.3 vs 15.7%; p = 0.005). In addition fewer patients in the CDA group had a VASP < 16% on discharge (14.7 vs 50.5%; p <0.0001).

Conclusion: In the present study, PR monitoring was superior to standard prasugrel therapy to reduce the rate of HTPR in ACS patients. In addition such strategy reduced the number of patients with very low PR.
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http://dx.doi.org/10.1016/j.ijcard.2013.07.147DOI Listing
October 2013