INSERM E9920

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Presentation of the research group

 

The research group, located in Rouen, France. Experimental research takes place in the Medical School, while clinical studies are conducted in the University Hospital

The group includes researchers from the national medical research institute (INSERM), from the Medical and Pharmacy Schools, and from several departments of the University Hospital (Cardiology, Histology, Nephrology, Pharmacology, Vascular surgery and intensive care)

Endothelial function, as well as endothelial dysfunction and its treatment, are evaluated both in experimental models and in humans.

Experimental models involve studies in isolated large and small arteries, performed either in organs chambers or in perfused/pressurized systems. With these systems, we have especially evaluated:

• Coronary endothelial dysfunction after cardiac ischemia and reperfusion (MPEG movie on induction of ischemia/reperfusion). In these experiments, our group was the first to extend the concept of endogenous adaptation to ischemia (i.e. ischemic preconditioning), previously described in cardiac myocytes, to the coronary endothelial cells. These studies have been performed not only in isolated coronary arteries, but also in cultured endothelial cells submitted to anoxia, and now extend to other pathological situations in which tissue ischemia is an important component.
• Vascular endothelial dysfunction in hypertension 
• Endothelial dysfunction (i.e. altered flow – mediated vasodilation) in peripheral resistance arteries in experimental heart failure. In this model, we have characterized various protective treatments, e.g. chronic physical exercise and ACE inhibitors.
• Endothelial dysfunction and other determinants of systemic inflammatory response in hemorrhagic shock

In humans, endothelial function is assessed at the level of peripheral large arteries (especially the radial artery), using flow-mediated vasodilatation as a model for nitric oxide release from the endothelium. Initially performed in healthy volunteers to characterise the role of NO,  the technique is now routinely used to assess the effects of treatments on endothelial dysfunction in hypertension and in congestive heart failure, in parallel to the experimental studies performed in these diseases.

Again, cardiac function, as well as cardiac dysfunction and its treatment, are evaluated both in experimental models and in humans

Experimental models are designed :

• to assess the effect of various treatments in chronic heart failure induced by coronary artery ligation, usually in rats. Treatments evaluated include ACE inhibitors, calcium channel blockers, or endothelin antagonists, and involve measurements of systemic and cardiac hemodynamics (using micromanometers and echocardiography), cardiac remodeling and structural changes (echocardiography, histology and immunohistochemistry), measurements of circulating neuro-hormones, and ultimately long term survival (over periods of 9-12 months)
• to develop and validate new echocardiographic criteria (especially using Doppler Tissue Imaging, DTI) to detect early early abnormalities in contractile function. Initially performed in experimental models of ischemia / reperfusion, early contractile dysfunction is now evaluated in models of physiologic (e.g. exercise) and pathologic (e.g. pressure or volume overload) hypertrophy.

Clinical studies also are designed to validate new echocardiographic criteria in the early detection of contractile abnormalities in various situations, including cardiac hypertrophy, or cardiac grafting. These studies now concentrate on heart failure and its treatment, and run in parallel to the experimental studies, testing the same treatments both in animal models and in humans.

In vivo techniques

Coronary artery ligation in rats (models of ischemia, infarction or heart failure) (MPEG movie on induction of ischemia/reperfusion - 9Mo)
Aortic Stenosis (pressure – overload hypertrophy)
Aorta-cava Fistula (volume overload hypertrophy)
Renal artery stenosis (renal hypertension)
Vascular grafts
Hemorrhagic shock
Aortic clamping
Hemodynamic measurements
Arterial pressure in conscious rats (plethysmography)
Continuous measurements of blood pressure in chronically implanted rats (telemetry)
Ventricular pressures (Millar micromanometer)
Regional blood flows (Doppler probes and microspheres)
Left ventricular function and remodeling (echocardiography)
Regional cardiac contractility and contractility gradients (Tissue Doppler Imaging)

Measurements in isolated arteries

Vasomotor responses in large arteries (rat aorta, human mammary arteries, , ...) in organ chambers
Vasomotor responses in small arteries (200-300 mm) using a small vessel myograph
Vasomotor responses to changes in pressure or flow in small arteries (200-300 mm), using an arteriograph coupled to a video camera
Isolated perfused heart.

Cell cultures

Isolation and culture of rat aortic and coronary endothelial cells
Culture in static conditions or in the presence of shear stress (roller)

Histology, Immunohistochemistry

Histomorphometry, image analysis
Immunoperoxydase
Immunofluorescence
Apoptosis

Biochemistry, molecular biology

Gene expression by RT-PCR
Western Blot
ELISA (endothelin, cytokines, ...)
NO Measurements (chemiluminescence)
HPLC (catecholamines, ...)
Spectrophotometry (anti-oxidant enzymes)

Cardiac Function

Left ventricular function and remodeling (echocardiography)
Regional cardiac contractility and contractility gradients (Tissue Doppler Imaging)

Vascular / endothelial function

Regional blood flows (Doppler)
Cardiac output (bioimpedance)
Noninvasive arterial pressure (photoplethysmography)
Noninvasive measurements of arterial diameter and wall thickness
Evaluation of endothelium – dependent vasomotor responses (NIUS 02, wall track system)
Intima/media thickness

Drug assays / measurements of circulating mediators

HPLC
HPLC MS-MS

 

1. Laude K, Richard V, Henry JP, Lallemand F, Thuillez C. Evidence against a role of inducible nitric oxide synthase in the endothelial protective effects of delayed preconditioning . Br J Pharmacol, 2000, 130: 1547-1552
2. Mulder P, Richard V, Richard V, Derumeaux G, Henry JP, Renet S, Opgenorth T, Thuillez C. Selective ET_A vs. combined ET_A-ET_B blockade in rat chronic heart failure. Circulation, 2000, 102: 491-493
3. Varin R, Mulder P, Tamion F, Richard V, Henry JP, Lallemand F, Lerebours G, Thuillez C. Improvement of endothelial function by chronic ACE inhibition in heart failure: Role of NO, prostanoids, oxidant stress and bradykinin. Circulation, 2000, 102:351-356
4. Ben Driss A, Devaux C, Henrion D, Duriez M, Thuillez C, Levy BI, Michel J-B. Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure. Circulation, 2000, 101:2764-2770
5. Artigues C, Richard V, Roussel C, Lallemand F, Henry JP, Thuillez C. Increased endothelium--monocyte interactions in salt-sensitive hypertension: effect of L-arginine. J Cardiovasc Pharmacol 2000;35:468-473.
6. Derumeaux G, Ovize M, Loufoua J, Pontier G, Andre-Fouet X, Cribier A. Assessment of nonuniformity of transmural myocardial velocities by color-coded tissue doppler imaging : characterization of normal, ischemic, and stunned myocardium . Circulation 2000;101:1390-1395.
7. Richard V, Hogie M, Thuillez C. Angiotensin II receptor blockade unmasks a depressor response to endothelin antagonists in rats. Fundam.Clin.Pharmacol. 2000;14:101-106.
8. Safar ME, Thuillez C, Richard V, Benetos A. Pressure-independent contribution of sodium to large artery structure and function in hypertension . Cardiovasc.Res. 2000;46:269-276.
9. Beauchamp P, Richard V, Tamion F, Lallemand F, Lebreton JP, Vaudry H, Daveau M, Thuillez C. Protective effects of preconditioning in cultured rat endothelial cells: effects on neutrophil adhesion and expression of ICAM-1 after anoxia and reoxygenation. Circulation 1999;100:541-546.
10. Cribier A, Eltchaninoff H, Koning R, Rath PC, Arora R, Imam A, El-Sayed M, Dani S, Derumeaux G, Benichou J, Tron C, Janorkar S, Pontier G, Letac B. Percutaneous mechanical mitral commissurotomy with a newly designed metallic valvulotome: immediate results of the initial experience in 153 patients. Circulation 1999;99:793-799.
11. Garot J, Derumeaux GA, Monin JL, Duval-Moulin AM, Simon M, Pascal D, Castaigne A, Dubois-Rande JL, Diebold B, Gueret P. Quantitative systolic and diastolic transmyocardial velocity gradients assessed by M-mode colour Doppler tissue imaging as reliable indicators of regional left ventricular function after acute myocardial infarction. Eur Heart J 1999;20:593-603.
12. Habib G, Derumeaux G, Avierinos JF, Casalta JP, Jamal F, Volot F, Garcia M , Lefevre J, Biou F, Maximovitch-Rodaminoff A, Fournier PE, Ambrosi P, Velut JG, Cribier A, Harle JR, Weiller PJ, Raoult D, Luccioni R. Value and limitations of the Duke criteria for the diagnosis of infective endocarditis. J Am Coll Cardiol 1999;33:2023-2029.
13. Joannides R, Moore N, de la Gueronniere V, Thuillez C. Effect of water on arteries [letter; comment]. Lancet 1999;354:516.
14. Lafitte S, Dos SP, Derumeaux G, Perron JM, Garrigue S, Kerouani A, Roudaut R. Can power motion imaging mode combined with contrast agent assess myocardial contraction and perfusion? In vitro and in vivo studies. J Am Soc Echocardiogr. 1999;12:941-950.
15. Michoux N, Joannides R, Gouesbet G, Thuillez C, Maheun B, Le Sceller L. Physical determinism in human arterial dynamics. Eur Phys J AP 1999;8:265-268.
16. Richard V, Danielou E, Kaeffer N, Thuillez C. Delayed endothelial protective effects of monophosphoryl lipid A after myocardial ischemia and reperfusion in rats. J Mol.Cell Cardiol 1999;31:1117-1123.
17. Tamion F, Richard V, Lyoumi S, Hiron M, Bonmarchand G, Leroy J, Daveau M, Thuillez C, Lebreton JP. Induction of haem oxygenase contributes to the synthesis of pro-inflammatory cytokines in re-oxygenated rat macrophages: role of cGMP. Cytokine. 1999;11:326-333.
18. Varin R, Mulder P, Richard V, Tamion F, Devaux C, Henry JP, Lallemand F , Lerebours G, Thuillez C. Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress. Circulation 1999;99:2951-2957.
19. Derumeaux G, Ovize M, Loufoua J, Andre-Fouet X, Minaire Y, Cribier A, Letac B. Doppler tissue imaging quantitates regional wall motion during myocardial ischemia and reperfusion. Circulation 1998;97:1970-1977.
20. Derumeaux G, Redonnet M, Soyer R, Cribier A, Letac B. Assessment of the progression of cardiac allograft vasculopathy by dobutamine stress echocardiography. J Heart Lung Transplant. 1998;17:259-267.
21. Garot J, Diebold B, Derumeaux GA, Monin JL, Bosio P, Duval-Moulin AM, Castaigne A, Dubois-Rande JL, Gueret P. Comparison of regional myocardial velocities assessed by quantitative 2-dimensional and M-mode color Doppler tissue imaging: influence of the signal-to-noise ratio of color Doppler myocardial images on velocity estimators of the Doppler tissue imaging system. J Am Soc Echocardiogr. 1998;11:1093-1105.
22. Joannides R, Moore N, Iacob M, Compagnon P, Bacri AM, Thuillez C. Divergent effects of verapamil and amlodipine at rest and during exercise. J Hypertens Suppl 1998;16:S25-S29.
23. Mulder P, Richard V, Thuillez C. Different effects of calcium antagonists in a rat model of heart failure. Cardiology 1998;89 Suppl 1:33-37.
24. Mulder P, Richard V, Bouchart F, Derumeaux G, Munter K, Thuillez C. Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure. Cardiovasc Res 1998;39:600-608.
25. Bellissant E, Chau NP, Thuillez C, Gerbeau C, Richard C, Giudicelli JF. Pharmacokinetic-pharmacodynamic model relating spiraprilat plasma concentrations to systemic and regional hemodynamic effects in congestive heart failure. J Cardiovasc Pharmacol 1997;30:253-260.
26. Bouchart F, Derumeaux G, Mouton-Schleifer D, Bessou JP, Redonnet M, Soyer R. Conventional and total orthotopic cardiac transplantation: a comparative clinical and echocardiographical study. Eur J Cardiothorac.Surg. 1997;12:555-559.
27. Elhage R, Bayard F, Richard V, Holvoet P, Duverger N, Fievet C, Arnal JF. Prevention of fatty streak formation of 17beta-estradiol is not mediated by the production of nitric oxide in apolipoprotein E- deficient mice. Circulation 1997;96 :3048-3052.
28. Eltchaninoff H, Cribier A, Tron C, Derumeaux G, Koning R, Hecketsweiller B, Letac B. Adaptation to myocardial ischemia during coronary angioplasty demonstrated by clinical, electrocardiographic, echocardiographic, and metabolic parameters. Am Heart J 1997;133:490-496.
29. Godin M, Fillastre JP, Simon P, Francois A, Roy FL, Morin JP. Is ochratoxin a nephrotoxic in human beings? Adv.Nephrol Necker.Hosp. 1997;26:181-206.
30. Joannides R, Richard V, Haefeli WE, Benoist A, Linder L, Luscher TF, Thuillez C. Role of nitric oxide in the regulation of the mechanical properties of peripheral conduit arteries in humans. Hypertension 1997;30:1465-1470.
31. Joannides R, Bakkali e, Richard V, Benoist A, Moore N, Thuillez C. Evaluation of the determinants of flow-mediated radial artery vasodilatation in humans. Clin Exp Hypertens 1997;19:813-826.
32. Joannides R, Bakkali EH, Le RF, Rivault O, Godin M, Moore N, Fillastre JP, Thuillez C. Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis. Nephrol Dial.Transplant. 1997;12:2623-2628.
33. Kaeffer N, Richard V, Thuillez C. Delayed coronary endothelial protection 24 hours after preconditioning: role of free radicals. Circulation 1997;96:2311-2316.
34. Mulder P, Richard V, Derumeaux G, Hogie M, Henry JP, Lallemand F, Compagnon P, Mace B, Comoy E, Letac B, Thuillez C. Role of endogenous endothelin in chronic heart failure: effect of long- term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. Circulation 1997;96:1976-1982.
35. Mulder P, Devaux B, Richard V, Henry JP, Wimart MC, Thibout E, Mace B, Thuillez C. Early versus delayed angiotensin-converting enzyme inhibition in experimental chronic heart failure. Effects on survival, hemodynamics, and cardiovascular remodeling. Circulation 1997;95:1314-1319.
36. Mulder P, Richard V, Compagnon P, Henry JP, Lallemand F, Clozel JP, Koen R , Mace B, Thuillez C. Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure. J Am Coll Cardiol 1997;29:416-421.
37. Mulder P, Compagnon P, Devaux B, Richard V, Henry JP, Elfertak L, Wimart MC, Thibout E, Comoy E, Mace B, Thuillez C. Response of large and small vessels to alpha and beta adrenoceptor stimulation in heart failure: effect of angiotensin converting enzyme inhibition. Fundam.Clin Pharmacol 1997;11:221-230.
38. Tamion F, Richard V, Lyoumi S, Daveau M, Bonmarchand G, Leroy J, Thuillez C, Lebreton JP. Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic or endotoxic shock. Am J Physiol 1997;273:G314-G321.
39. Bellissant E, Annane D, Pussard E, Thuillez C, Giudicelli JF. Systemic, pulmonary, brachial, renal and hepato-splanchnic hemodynamic effects of spirapril in severe congestive heart failure. Fundam.Clin Pharmacol 1996; 10:127-135.
40. Compagnon P, Thiberville L, Moore N, Thuillez C, Lacroix C. Simple high-performance liquid chromatographic method for the quantitation of 5-fluorouracil in human plasma. J Chromatogr.B.Biomed.Appl. 1996;677:380-383.
41. Dhib M, Prieur AM, Courville S, Niaudet P, Francois A, Godin M, Fillastre JP. Crescentic glomerulonephritis in juvenile chronic arthritis. J Rheumatol. 1996;23:1636-1640.
42. Fillastre JP, Godin M, Legallicier B, Chretien P, Bidault R, Gillotin C, Wooton R, Posner J, Peck RW. Pharmacokinetics of netivudine, a potent anti-varicella zoster virus drug, in patients with renal impairment. J Antimicrob.Chemother. 1996;37:965-974.
43. Fillastre JP, Baguet JC, Dubois D, Vauquier J, Godin M, Legallicier B, Luus HG, de lR, Carcone N, Genthon R. Kinetics, safety, and efficacy of ramipril after long-term administration in hemodialyzed patients. J Cardiovasc Pharmacol 1996;27:269-274.
44. Godin M, Francois A, Le RF, Morin JP, Creppy E, Hemet J, Fillastre JP. Karyomegalic interstitial nephritis [letter; comment]. Am J Kidney Dis. 1996;27:166.
45. Kaeffer N, Richard V, Francois A, Lallemand F, Henry JP, Thuillez C. Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats. Am J Physiol 1996;271:H842-H849.
46. Kolb F, Heudes D, Mandet C, Plissonnier D, Osborne-Pellegrin M, Bariety J, Michel JB. Presensitization accelerates allograft arteriosclerosis. Transplantation 1996;62:1401-1410.
47. Laurent S, Vanhoutte P, Cavero I, Chabrier PE, Dupuis B, Elghozi JL, Hamon G, Janiak P, Juillet Y, Kher A, Koen R, Madonna O, Maffrand JP, Pruneau D, Thuillez C. The arterial wall: a new pharmacological and therapeutic target. Fundam.Clin Pharmacol 1996;10:243-257.
48. Le RF, Godin M, Legallicler B, Fillastre JP, Bidault R, Posner J, Peck RW. Pharmacokinetics of netivudine in haemodialysis patients [letter]. J Antimicrob.Chemother. 1996;38:913-915.
49. Lefebvre H, Compagnon P, Contesse V, Hamel C, Delarue C, Thuillez C, Vaudry H, Kuhn JM. Production and metabolism of serotonin (5-HT) by the human adrenal gland. Endocr.Res 1996;22:851-853.
50. Misset B, Timsit JF, Chevret S, Renaud B, Tamion F, Carlet J. A randomized cross-over comparison of the hemodynamic response to intermittent hemodialysis and continuous hemofiltration in ICU patients with acute renal failure. Intensive Care Med. 1996;22:742-746.
51. Mulder P, Elfertak L, Richard V, Compagnon P, Devaux B, Henry JP, Scalbert E, Desche P, Mace B, Thuillez C. Peripheral artery structure and endothelial function in heart failure: effect of ACE inhibition. Am J Physiol 1996;271:H469-H477.
52. Richard V, Joannides R, Henry JP, Mulder P, Mace B, Guez D, Schiavi P, Thuillez C. Fixed-dose combination of perindopril with indapamide in spontaneously hypertensive rats: haemodynamic, biological and structural effects. J Hypertens 1996;14:1447-1454.
53. Richard V, Kaeffer N, Thuillez C. Delayed protection of the ischemic heart--from pathophysiology to therapeutic applications. Fundam.Clin Pharmacol 1996;10:409-415.
54. Simon P, Godin M, Fillastre JP. Ochratoxin a: a new environmental factor which is toxic for the kidney? [editorial]. Nephrol Dial.Transplant. 1996;11:2389-2391.
55. Soyer R, Bouchart F, Bessou JP, Redonnet M, Mouton-Schleifer D, Derumeaux G, Arrignon J, Letac B. Aortic valve replacement after aortic valvuloplasty for calcified aortic stenosis. Eur J Cardiothorac.Surg. 1996;10:977-982.
56. Derumeaux G, Habib G, Schleifer DM, Ambrosi P, Bessou JP, Metras D, Cribier A, Luccioni R, Soyer R, Letac B. Standard orthotopic heart transplantation versus total orthotopic heart transplantation. A transesophageal echocardiography study of the incidence of left atrial thrombosis. Circulation 1995;92:II196-II201.
57. Derumeaux G, Redonnet M, Mouton-Schleifer D, Bessou JP, Cribier A, Saoudi N, Koning R, Soyer R, Letac B . Dobutamine stress echocardiography in orthotopic heart transplant recipients. J Am Coll Cardiol 1995;25:1665-1672.
58. Derumeaux G, Mouton-Schleifer D, Soyer R, Saoudi N, Cribier A, Letac B. High incidence of left atrial thrombus detected by transoesophageal echocardiography in heart transplant recipients. Eur Heart J 1995;16:120-125.
59. Joannides R, Richard V, Haefeli WE, Linder L, Luscher TF, Thuillez C. Role of basal and stimulated release of nitric oxide in the regulation of radial artery caliber in humans. Hypertension 1995;26:327-331.
60. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Luscher TF. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 1995;91:1314-1319.
61. Joannides R, Richard V, Moore N, Godin M, Thuillez C. Influence of sympathetic tone on mechanical properties of muscular arteries in humans. Am J Physiol 1995;268:H794-H801.
62. Mulder P, Devaux B, el FL, Compagnon P, Richard V, Henry JP, Scalbert E, Desche P, Mace B, Thuillez C. Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure. Am J Cardiol 1995;76:28E-33E.
63. Redonnet M, Derumeaux G, Mouton-Schleifer D, Litzler PY, Segond G, Bouchart F, Bessou JP, Letac B, Soyer R. Noninvasive detection of cardiac graft vascular disease. Transplant.Proc. 1995;27:2530-2531.
64. Richard V, Murry CE, Reimer KA. Healing of myocardial infarcts in dogs. Effects of late reperfusion. Circulation 1995;92:1891-1901.
65. Richard V, Blanc T, Kaeffer N, Tron C, Thuillez C. Myocardial and coronary endothelial protective effects of acetylcholine after myocardial ischaemia and reperfusion in rats: role of nitric oxide. Br J Pharmacol 1995;115:1532-1538.
66. Richard V, Tron C, Blanc T, Thuillez C. Infarct size-limiting properties of Ro 40-5967, a novel nondihydropyridine calcium channel, in anesthetized rats: comparison with verapamil. J Cardiovasc Pharmacol 1995;25:552-557.
67. Richard V, Hogie M, Clozel M, Loffler BM, Thuillez C. In vivo evidence of an endothelin-induced vasopressor tone after inhibition of nitric oxide synthesis in rats. Circulation 1995;91:771-775.
68. Thuillez C, Mulder P, Elfertak L, Blaysat G, Compagnon P, Henry JP, Richard V, Scalbert E, Desche P. Prevention of endothelial dysfunction in small and large arteries in a model of chronic heart failure. Effect of angiotensin converting enzyme inhibition. Am J Hypertens 1995;8:7S-12S.

Dernière MAJ: 23/11/01
[ Accueil ] [ Composition de l'E9920 ] [ Objectifs de recherche ] [ Matériel et équipement de recherche ] [ Accueil stagiaires ] [ Principaux résultats ] [ Publications ] [ English Version ]