058 The ongoing MESAMI translational research program

PurposeDespite the improvement of pharmacological and surgical therapies, the mortality related to ischemic heart failure remains high. During the last years, bone marrow-mesenchymal stem cell (BM-MSC) therapy has been proposed as a novel approach for the prevention and therapy of heart failure. Intramyocardial injection allows concentration of grafted cells within the injured zone. However, a major problem of with intraparenchymal route of administration is the early death of most of grafted cells. The goal of the MESAMI program is to evaluate the effect of intramyocardial administration of BM-MSC preconditioned or not with the pineal hormone melatonin in ischemic cardiomyopathy.Methods and ResultsOur preclinical investigations have designed a preconditioning strategy of BM-MSCs with the melatonin that significantly increases survival and efficacy of grafted cells in animal models of myocardial ischemia. Melatonin treatment significantly ameliorates the beneficial effects of BM-MSC on the recovery of cardiac function. In the mean time, we started a phase I clinical trial in patients with severe ischemic cardiomyopathy and no option of revascularization, using the NOGA XP system to guide injections into the myocardium. Based on our basic research results, we are developing a multicenter phase II trial on the effects of intramyocardial administration of melatonin-preconditioned BM-MSC in patients with chronic ischemic cardiomyopathy.ConclusionThe ongoing MESAMI program is representative of a translational research program in France

092 VO2 max to measure the functional status of obese heart failure patients

BackgroundObesity has been described as an independent risk factor for heart failure (HF). However, B-type natriuretic peptide (BNP) failed in evaluation of the severity of HF in obese patient because: i) Obese patients suffer dyspnoea earlier than non obese which leads to an earlier diagnosis an could explain lower BNP rates, and ii) BNP receptors were found on adipocytes suggesting a higher clearance of BNP in obese patients.PurposeOur aim was to explore the relationship between functional status of obese HF patients and BNP levels.Method and resultsIn our HF registry, 249 patients with dilated cardiomyopathy (DCM) were included in 3 groups regarding their body mass index: 112 normal weighted <25kg/m2 (NW), 88 overweighted 25–29.9kg/m2 (OW), and 49 obese 30kg/m2 or greater (Ob) patients. We analyzed NYHA status, the 6 minutes walk test (6MWT) a simple and reliable way to assess the exercise capacity of DCM patients, and measured the peak oxygen consumption during incremental exercise (VO2 max).There was no significant difference between the 3 groups for baseline characteristics and ejection fraction was comparable (NW: 27+/−9%; OW: 27+/−9%; Ob: 29+/−10%; p=0.26))BNP levels were lower in the obese group (962+/−1166 in NW, 757+/−204 in OW, 353+/−608 in Ob; p=0.02). There was no significant difference between groups in distance covered in the 6MWT (NW: 370+/−98m; OW: 392+/−125m; Ob: 388m; p=0.27) and NYHA scores (NM: 2.3+/−0.7; OW: 2.3+/−0.6; Ob: 2.4+/−0.7; p=0.32), however, VO2 max was significantly lower in the Ob patients (NW: 17.4+/−7.7ml/min/kg; OW: 16.1+/−5.0ml/min/kg; Ob: 14.8+/−6.9ml/min/kg; p=0.04).ConclusionThese results show that VO2 max is more useful to discriminate functional status in obese patients with DCM compared to 6MWT, NYHA scores and BNP levels. BNP in the obese likely underestimates severity of HF

Tonic chemoreflex activation contributes to increased sympathetic nerve activity in heart failure-related anemia.

International audienceSympathetic activation contributes to both the initiation and progression of heart failure. The role of anemia in determining sympathetic overactivity in chronic heart failure (CHF) patients is unknown. We tested the hypothesis that, in CHF patients, anemia could lead to increased sympathetic activity through tonic activation of excitatory chemoreceptor afferents. We conducted a double-blind, randomized, vehicle-controlled study to examine the effect of chemoreflex deactivation on muscle sympathetic nerve activity in CHF patients with and without anemia. We compared the effect of breathing 100% oxygen for 15 minutes in 18 stable CHF patients with anemia and 18 control CHF patients matched for age, sex, blood pressure, and body mass index. Baseline muscle sympathetic nerve activity was significantly elevated in CHF patients with anemia compared with patients with CHF alone (56.0+/-3.2 versus 45.5+/-3.1 bursts per minute; P<0.0237). Administration of 100% oxygen led to a significant decrease in muscle sympathetic nerve activity in CHF patients with anemia (from 56.0+/-3.4 to 50.9+/-3.2 bursts per minute; P<0.0019). In contrast, neither room air nor 100% oxygen changed muscle sympathetic nerve activity or hemodynamics in patients with CHF alone. We report for the first time direct evidence of increased sympathetic nerve traffic in patients with CHF-related anemia. Sympathetic hyperactivity in patients with CHF and anemia is partially chemoreflex mediated and could explain how anemia contributes to the progression of CHF and increases morbidity and mortality in these patients

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

International audienceBackground: 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

Cardiac macrophage subsets differentially regulate lymphatic network remodeling during pressure overload

International audienceAbstract The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking. We observed a remodeling of the cardiac lymphatic vessels and a reduced lymphatic efficiency during heart hypertrophy and failure induced by transverse aortic constriction. The lymphatic endothelial cell number of the failing hearts was positively correlated with cardiac function and with a subset of cardiac macrophages. This macrophage population distinguished by LYVE-1 (Lymphatic vessel endothelial hyaluronic acid receptor-1) and by resident macrophage gene expression signature, appeared not replenished by CCR2 mediated monocyte infiltration during pressure overload. Isolation of macrophage subpopulations showed that the LYVE-1 positive subset sustained in vitro and in vivo lymphangiogenesis through the expression of pro-lymphangiogenic factors. In contrast, the LYVE-1 negative macrophage subset strongly expressed MMP12 and decreased the endothelial LYVE-1 receptors in lymphatic endothelial cells, a feature of cardiac lymphatic remodeling in failing hearts. The treatment of mice with a CCR2 antagonist during pressure overload modified the proportion of macrophage subsets within the pathological heart and preserved lymphatic network from remodeling. This study reports unknown and differential functions of macrophage subpopulations in the regulation of cardiac lymphatic during pathological hypertrophy and may constitute a key mechanism underlying the progression of heart failure

Mesenchymal Stem Cells Promote Matrix Metalloproteinase Secretion By Cardiac Fibroblasts And Reduce Cardiac Ventricular Fibrosis After Myocardial Infarction.

International audienceRecent studies showed that mesenchymal stem cells (MSCs) transplantation significantly decreased cardiac fibrosis. However, the mechanisms involved in these effects are still poorly understood. In this work, we investigated whether the antifibrotic properties of MSCs involve the regulation of matrix metalloproteinases (MMPs) and matrix metalloproteinase endogenous inhibitor (TIMPs) production by cardiac fibroblasts.In vitro experiments showed that conditioned medium from MSCs decreased viability, alpha-SMA expression and collagen secretion of cardiac fibroblasts. These effects were concomitant to the stimulation of MMP-2/MMP-9 activities and MT1-MMP expression. Experiments performed with fibroblasts from MMP2-/- mice demonstrated that MMP2 plays a preponderant role in preventing collagen accumulation upon incubation with conditioned-medium from MSCs. Interestingly, we found that MSC-conditioned medium also decreased the expression of TIMP2 in cardiac fibroblasts. In vivo studies showed that intracardiac injection of MSCs in a rat model of post-ischemic heart failure induced a significant decrease in ventricular fibrosis. This effect was associated with the improvement of morphological and functional cardiac parameters.In conclusion, we showed that MSCs modulate the phenotype of cardiac fibroblasts and their ability to degrade extracellular matrix. These properties of MSCs open new perspective for understanding of the mechanisms of action of MSCs and anticipate their potential therapeutic or side effects