Saint-Herblain, France
Saint-Herblain, France

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Obadia J.-F.,Service de Chirurgie Cardiothoracique et Transplantation | Obadia J.-F.,French Institute of Health and Medical Research | Armoiry X.,Hospices Civils de Lyon | Armoiry X.,University Claude Bernard Lyon 1 | And 15 more authors.
EuroIntervention | Year: 2015

Aims: Percutaneous mitral valve repair (pMVR) is a new therapeutic option for mitral valve regurgitation. Positive preliminary results in non-randomised studies have been published supporting the use of the MitraClip system in patients with secondary mitral regurgitation (MR) and poor left ventricular (LV) function contraindicated to surgery. The aim of the MITRA-FR study is to provide a higher level of evidence for the efficacy of the MitraClip device in this setting. Methods and results: The MITRA-FR study is a national, multicentre, investigator-initiated, open-label, randomised trial to evaluate the benefits and safety of pMVR using the MitraClip system plus optimal medical therapy (OMT) compared with OMT alone (control) in patients with severe symptomatic secondary MR contraindicated to surgical repair. The trial aims to enrol 144 MitraClip-treated subjects and 144 control (OMT alone) patients. The primary endpoint is a composite of all-cause mortality and unplanned hospitalisations for heart failure at 12 months after randomisation. Conclusions: MITRA-FR is a randomised controlled national trial designed to evaluate the performance of pMVR in comparison to OMT in patients with severe symptomatic secondary MR contraindicated to cardiac surgery. © Europa Digital & Publishing 2015. All rights reserved.


Cariou B.,Nantes University Hospital Center | Cariou B.,LInstitut du Thorax
Diabetes and Metabolism | Year: 2012

The management of type 2 diabetes continues to evolve as new data emerge. Although glycaemic control is still important, other risk factors - such as hypertension, dyslipidaemia and obesity - must also be addressed in order to reduce the long-term risks of cardiovascular complications and mortality. In this context, targeting the incretin system, and glucagon-like peptide-1 (GLP-1) in particular, has generated much interest. GLP-1 is released from the gut in response to food ingestion and plays a crucial role in glucose homeostasis. GLP-1 receptors are expressed in the heart and vasculature, prompting evaluation of their physiological role and pharmacological stimulation, both in healthy and disease states. These studies indicate that GLP-1 and GLP-1-based therapies appear to have direct, beneficial effects on the cardiovascular system, in addition to their glucose-lowering properties, such as modulation of blood pressure, endothelial function, and myocardial contractility. Intriguingly, some of these effects appear to be independent of GLP-1 receptor signalling. Data from clinical studies of the GLP-1 receptor agonists, exenatide and liraglutide on cardiovascular risk factors, in patients with type 2 diabetes are also promising and the results from prospective studies to assess cardiovascular outcomes are eagerly awaited. © 2012 Elsevier Masson SAS.


Le Quang K.,Montreal Heart Institute | Le Quang K.,Laval University | Benito B.,Montreal Heart Institute | Benito B.,Hospital Del Mar | And 10 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2013

Background-When complete atrioventricular block (AVB) occurs, infranodal escape rhythms are essential to prevent bradycardic death. The role of T-type Ca2+ channels in pacemaking outside the sinus node is unknown. We investigated the role of T-type Ca2+ channels in escape rhythms and bradycardia-related ventricular tachyarrhythmias after AVB in mice. Methods and Results-Adult male mice lacking the main T-type Ca2+ channel subunit Cav3.1 (Cav3.1-/-) and wild-type (WT) controls implanted with ECG telemetry devices underwent radiofrequency atrioventricular node ablation to produce AVB. Before ablation, Cav3.1-/- mice showed sinus bradycardia (mean±SEM; RR intervals, 148±3 versus 128±2 ms WT; P<0.001). Immediately after AVB, Cav3.1-/- mice had slower escape rhythms (RR intervals, 650±75 versus 402±26 ms in WT; P<0.01) but a preserved heart-rate response to isoproterenol. Over the next 24 hours, mortality was markedly greater in Cav3.1-/- mice (19/31; 61%) versus WT (8/26; 31%; P<0.05), and Torsades de Pointes occurred more frequently (73% Cav3.1-/- versus 35% WT; P<0.05). Escape rhythms improved in both groups during the next 4 weeks but remained significantly slower in Cav3.1 -/-. At 4 weeks after AVB, ventricular tachycardia was more frequent in Cav3.1-/- than in WT mice (746±116 versus 214±78 episodes/24 hours; P<0.01). Ventricular function remodeling was similar in Cav3.1-/- and WT, except for smaller post-AVB fractional-shortening increase in Cav3.1-/-. Expression changes were seen post-AVB for a variety of genes; these tended to be greater in Cav3.1-/- mice, and overexpression of fetal and profibrotic genes occurred only in Cav3.1 -/-. Conclusions-This study suggests that T-type Ca2+ channels play an important role in infranodal escape automaticity. Loss of T-type Ca2+ channels worsens bradycardia-related mortality, increases bradycardia-associated adverse remodeling, and enhances the risk of malignant ventricular tachyarrhythmias complicating AVB. © 2013 American Heart Association, Inc.


Oskouei B.N.,University of Miami | Lamirault G.,LInstitut du Thorax | Joseph C.,University of Miami | Treuer A.V.,University of Miami | And 7 more authors.
Stem Cells Translational Medicine | Year: 2012

Whereas cardiac-derived c-kit+ stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (MSCs) are undergoing clinical trials testing safety and efficacy as a cell-based therapy, the relative therapeutic and biologic efficacy of these two cell types is unknown. We hypothesized that human CSCs have greater ability than MSCs to engraft, differentiate, and improve cardiac function. We compared intramyocardial injection of human fetal CSCs (36,000) with two doses of adult MSCs (36,000 and 1,000,000) or control (phosphate buffered saline) in nonobese diabetic/severe combined immune deficiency mice after coronary artery ligation. The myocardial infarction-induced enlargement in left ventricular chamber dimensions was ameliorated by CSCs (p <.05 for diastolic and systolic volumes), as was the decline in ejection fraction (EF; p <.05). Whereas 1 × 106 MSCs partially ameliorated ventricular remodeling and improved EF to a similar degree as CSCs, 36,000 MSCs did not influence chamber architecture or function. All cell therapies improved myocardial contractility, but CSCs preferentially reduced scar size and reduced vascular afterload. Engraftment and trilineage differentiation was substantially greater with CSCs than with MSCs. Adult-cultured c-kit+ CSCs were less effective than fetal, but were still more potent than high-dose MSCs. These data demonstrate enhanced CSC engraftment, differentiation, and improved cardiac remodeling and function in ischemic heart failure. MSCs required a 30-fold greater dose than CSCs to improve cardiac function and anatomy. Together, these findings demonstrate a greater potency of CSCs than bone marrow MSCs in cardiac repair. ©AlphaMed Press.


Cariou B.,LInstitut du Thorax | Cariou B.,French Institute of Health and Medical Research
Medecine des Maladies Metaboliques | Year: 2015

Statins are the most widely used lipid lowering drugs due to their proven efficacy to reduce cardiovascular events. Recent post-hoc analyses of randomized controlled trials demonstrated that statins are associated with an increased risk of developing type 2 diabetes (T2D). The risk is higher with high doses of statins and in people with preexisting risk factors for T2D. Whether some statins are more diabetogenic than others remains a controversial issue. The underlying molecular mechanisms sustaining the diabetogenic action of statins remains largely unknown. From a clinical perspective, evidence suggest that the benefits of statins for the reduction of cardiovascular risk far outweigh the risk of developing T2D, especially in patients with higher cardiovascular risk. However, physicians should assess all patients for their T2D risk prior to starting statin therapy in order to reinforce lifestyle changes and to monitor glycemic parameters. © 2014-Elsevier Masson SAS-Tous droits réservés.


Dollet L.,French Institute of Health and Medical Research | Magre J.,French Institute of Health and Medical Research | Cariou B.,French Institute of Health and Medical Research | Cariou B.,LInstitut du Thorax | And 3 more authors.
Biochimie | Year: 2014

Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterized by near absence of adipose tissue and severe insulin resistance. Since the discovery of the gene in 2001, several cellular studies intended to unravel the biological function of seipin and revealed that seipin-deficiency alters adipocyte differentiation and lipid droplet morphology. However, the exact function of the protein remains unclear and the pathophysiology of BSCL in patients carrying BSCL2/seipin mutations is poorly understood. A major breakthrough in the field of seipin came recently, with the demonstration by three independent groups that Bscl2-deficient mice (Bscl2-/-) developed severe lipodystrophy with only residual white and brown fat pads, validating a critical role for seipin in adipose tissue homeostasis. Using in vivo, ex vivo and in vitro methods, these studies demonstrate that seipin plays a key role in adipogenesis, lipid droplet homeostasis and cellular triglyceride lipolysis. In addition to adipose tissue impairment, Bscl2-/- mice are diabetic and display severe hepatic steatosis. Treatment with thiazolidinediones (TZD) in Bscl2-/- mice increases adipose tissue mass and partially rescues the metabolic complications associated with BSCL, highlighting that lipoatrophy is the major cause of the BSCL phenotype. Except an unexpected hypotriglyceridemia, Bscl2-/- mice phenotype represents an almost perfect picture of the human disease. This review analyses how these studies using Bscl2-/- mice brought new insights into seipin function and the mechanisms involved in the pathophysiology of BSCL. We also analyse some of the human data in the light of the mouse phenotyping and discuss the validity of Bscl2-/ - mice model to test pharmaceutical approaches for treating BSCL and its associated metabolic complications. © 2013 Elsevier Masson SAS. All rights reserved.


Loirand G.,Linstitut du thorax | Loirand G.,University of Nantes | Loirand G.,Nantes University Hospital Center | Pacaud P.,Linstitut du thorax | And 2 more authors.
Small GTPases | Year: 2014

Proper regulation of arterial blood pressure is essential to allow permanent adjustment of nutrient and oxygen supply to organs and tissues according to their need. This is achieved through highly coordinated regulation processes controlling vascular resistance through modulation of arterial smooth muscle contraction, cardiac output, and kidney function. Members of the Rrho family of small GTPases, in particular RrhoAa and Rrac1, have been identified as key signaling molecules playing important roles in several different steps of these regulatory processes. Here, we review the current state of knowledge regarding the involvement of Rho GTPase signaling in the control of blood pressure and the pathogenesis of hypertension. We describe how knockout models in mouse, genetic, and pharmacological studies in human have been useful to address this question. © 2014 Landes Bioscience.


Cariou B.,LInstitut du Thorax | Cariou B.,French Institute of Health and Medical Research
Medecine des Maladies Metaboliques | Year: 2015

Tyrosine kinase inhibitors (TKIs) are targeted therapies which are widely used in clinical oncology. TKIs target common mechanisms of growth, invasion, metastasis, and angiogenesis. However, many TKls are nonselective and their use is associated with important side effects, especially endocrine-related side effects. Consistent data indicate that TKIs influence glucose metabolism. Surprisingly, both increased and decreased plasma glucose levels have been attributed to TKIs. Thus, it is actually recommended to monitor HbA1c and blood glucose levels periodically in patients treated with TKIs. © 2014-Elsevier Masson SAS-Tous droits réservés.


PubMed | Clinique Saint Augustin, lInstitut du Thorax, French Institute of Health and Medical Research, Estaing University Hospital Center and Institute Of Lingenierie Et Of Linformation Of Sante In3S
Type: Comparative Study | Journal: JACC. Cardiovascular interventions | Year: 2015

This study used a fractal bifurcation bench model to compare 6 optimization sequences for coronary bifurcation provisional stenting, including 1 novel sequence without kissing balloon inflation (KBI), comprising initial proximal optimizing technique (POT) + side-branch inflation (SBI) + final POT, called re-POT.In provisional bifurcation stenting, KBI fails to improve the rate of major adverse cardiac events. Proximal geometric deformation increases the rate of in-stent restenosis and target lesion revascularization.A bifurcation bench model was used to compare KBI alone, KBI after POT, KBI with asymmetric inflation pressure after POT, and 2 sequences without KBI: initial POT plus SBI, and initial POT plus SBI with final POT (called re-POT). For each protocol, 5 stents were tested using 2 different drug-eluting stent designs: that is, a total of 60 tests.Compared with the classic KBI-only sequence and those associating POT with modified KBI, the re-POT sequence gave significantly (p < 0.05) better geometric results: it reduced SB ostium stent-strut obstruction from 23.2 6.0% to 5.6 8.3%, provided perfect proximal stent apposition with almost perfect circularity (ellipticity index reduced from 1.23 0.02 to 1.04 0.01), reduced proximal area overstretch from 24.2 7.6% to 8.0 0.4%, and reduced global strut malapposition from 40 6.2% to 2.6 1.4%.In comparison with 5 other techniques, the re-POT sequence significantly optimized the final result of provisional coronary bifurcation stenting, maintaining circular geometry while significantly reducing SB ostium strut obstruction and global strut malapposition. These experimental findings confirm that provisional stenting may be optimized more effectively without KBI using re-POT.


PubMed | linstitut du thorax
Type: Journal Article | Journal: Small GTPases | Year: 2015

Proper regulation of arterial blood pressure is essential to allow permanent adjustment of nutrient and oxygen supply to organs and tissues according to their need. This is achieved through highly coordinated regulation processes controlling vascular resistance through modulation of arterial smooth muscle contraction, cardiac output, and kidney function. Members of the Rho family of small GTPases, in particular RhoA and Rac1, have been identified as key signaling molecules playing important roles in several different steps of these regulatory processes. Here, we review the current state of knowledge regarding the involvement of Rho GTPase signaling in the control of blood pressure and the pathogenesis of hypertension. We describe how knockout models in mouse, genetic, and pharmacological studies in human have been useful to address this question.

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