Pierre Voisine

Publications (80)406.73 Total impact

• Article: Endovascular treatment of a blunt thoracic aortic laceration due to thoracolumbar spine fracture.

  François Dagenais, Geneviève Nadeau, Jean-Pierre Normand, Roc Turcotte, Patrick Mathieu, Pierre Voisine
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  ABSTRACT: A 36-year-old woman sustained an aortic laceration at the level of the diaphragmatic hiatus owing to a displaced thoracolumbar spine fracture (TLS). We herein report the first case of aortic trauma secondary to a TLS fracture treated with a thoracic stent-graft.
  Innovations Technology and Techniques in Cardiothoracic and Vascular Surgery 01/2006; 1(3):123-5.
• Article: Effects of L-arginine on fibroblast growth factor 2-induced angiogenesis in a model of endothelial dysfunction.

  Pierre Voisine, Jian Li, Cesario Bianchi, Tanveer A Khan, Marc Ruel, Shu-Hua Xu, Jun Feng, Audrey Rosinberg, Tamer Malik, Yasunari Nakai, Frank W Sellke
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  ABSTRACT: Nitric oxide availability, which is decreased in advanced coronary artery disease associated with endothelial dysfunction, is an important mediator of fibroblast growth factor-2 (FGF-2)-induced angiogenesis. This could explain the disappointing results of FGF-2 therapy in clinical trials despite promising preclinical studies. We examined the influence of L-arginine supplementation to FGF-2 therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. Eighteen pigs were fed either a normal (NORM, n=6) or high cholesterol diet, with (HICHOL-ARG, n=6) or without (HICHOL, n=6) L-arginine. All pigs underwent ameroid placement on the circumflex artery and 3 weeks later received surgical FGF-2 treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by immunohistochemistry. FGF-2, fibroblast growth receptor-1, endothelial-derived nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and syndecan-4 levels were determined by immunoblotting. Pigs from the HICHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. FGF-2 treatment was ineffective in the HICHOL group (circumflex/left anterior descending blood flow ratios: 1.01 (rest) and 1.01 (pace), after and before treatment). Addition of L-arginine improved myocardial perfusion in response to FGF-2 at rest (ratio 1.13, P=0.02 versus HICHOL) but not during pacing (ratio 0.94, P=NS), and was associated with increased protein levels of iNOS and eNOS. L-arginine supplementation can partially restore the normal response to endothelium-dependent vasorelaxants and myocardial perfusion in response to FGF-2 treatment in a swine model of hypercholesterolemia-induced endothelial dysfunction. These findings suggest a role for L-arginine in combination with FGF-2 therapy for end-stage coronary artery disease.
  Circulation 09/2005; 112(9 Suppl):I202-7. · 14.74 Impact Factor
• Article: Effects of L-arginine on the endogenous angiogenic response in a model of hypercholesterolemia.

  Yasunari Nakai, Pierre Voisine, Cesario Bianchi, Shu-Hua Xu, Jun Feng, Tamer Malik, Audrey Rosinberg, Frank W Sellke
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  ABSTRACT: The angiogenic properties of vascular endothelial growth factor and fibroblast growth factor-2 are mediated in part through nitric oxide release, whose availability is decreased in endothelial dysfunction associated with advanced coronary artery disease. We examined the influence of L-arginine supplementation on the endogenous angiogenic response to ischemia in a porcine model of hypercholesterolemia. Eighteen Yucatan pigs were fed either a normal (NORM, n=6) or a high-cholesterol diet, with (CHOL-ARG, n=6) or without (CHOL, n=6) L-arginine (100 mg/kg/day), throughout the experiment. All pigs underwent ameroid constrictor placement on the circumflex artery (LCx). Seven weeks later, endothelium-dependent coronary microvascular responses to fibroblast growth factor-2 and vascular endothelial growth factor were assessed by videomicroscopy. Perfusion was assessed with radioactive microspheres; angiogenesis was evaluated by platelet-endothelial cell adhesion molecule-1 (CD-31) staining. Regional myocardial function was assessed by sonomicrometry. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase was measured by Western blot analyses. Pigs from the CHOL group showed significant endothelial dysfunction in the LCx territory. The dysfunction was normalized partially by L-arginine supplementation, which restored the response in the LCx territory to the level of the nonischemic anterior wall. L-arginine supplementation resulted in increases of perfusion, density of capillary endothelial, and level of endothelial nitric oxide synthase in the ischemic region. Despite these findings, no improvement in myocardial regional function was found. L-arginine supplementation can partially restore endothelium-dependent vasorelaxation and improve myocardial perfusion in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with growth factor therapy for end-stage coronary artery disease.
  Surgery 09/2005; 138(2):291-8. · 3.10 Impact Factor
• Article: Aprotinin preserves cellular junctions and reduces myocardial edema after regional ischemia and cardioplegic arrest.

  Tanveer A Khan, Cesario Bianchi, Eugenio Araujo, Pierre Voisine, Shu-Hua Xu, Jun Feng, Jian Li, Frank W Sellke
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  ABSTRACT: Cardiac surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest has been associated with myocardial edema attributable to vascular permeability, which is regulated in part by thrombin-induced alterations in cellular junctions. Aprotinin has been demonstrated to prevent activation of the thrombin protease-activated receptor, and we hypothesized that aprotinin preserves myocardial cellular junctions and prevents myocardial edema in a porcine model of regional ischemia and cardioplegic arrest. Fourteen pigs were subjected to 30 minutes of regional ischemia, followed by 60 minutes of CPB, with 45 minutes of crystalloid cardioplegia, then 90 minutes of post-CPB reperfusion. The treatment group (n=7) was administered aprotinin (40,000 kallikrein inhibitor units [KIU]/kg loading dose, 40,000 KIU/kg pump prime, and 10,000 KIU/kg per hour continuous infusion). Control animals (n=7) received normal saline. Myocardial vascular endothelial (VE)-cadherin, beta-catenin and gamma-catenin, and associated mitogen-activated protein kinase (MAPK) pathways were assessed by immunoblot and immunoprecipitation. Histologic analysis of the cellular junctions was done by immunofluorescence. Myocardial tissue water content was measured. VE-cadherin, beta-catenin, and gamma-catenin levels were significantly greater in the aprotinin group (all P<0.05). Immunfluorescence confirmed that aprotinin prevented loss of coronary endothelial adherens junction continuity. Aprotinin reduced tyrosine phosphorylation in myocardial tissue sections. Phospho-p38 activity was approximately 30% lower in the aprotinin group (P=0.007). The aprotinin group demonstrated decreased myocardial tissue water content (81.2+/-0.5% versus 83.5+/-0.3%; P=0.01) and reduced intravenous fluid requirements (2.9+/-0.2 L versus 4.0+/-0.4 L; P=0.03). Aprotinin preserves adherens junctions after regional ischemia and cardioplegic arrest through a mechanism potentially involving the p38 MAPK pathway, resulting in preservation of the VE barrier and reduced myocardial tissue edema.
  Circulation 09/2005; 112(9 Suppl):I196-201. · 14.74 Impact Factor
• Article: Giant pseudoaneurysm after proximal aortic surgery treated by means of redo axillary artery cannulation and use of an Endoclamp device.

  Francois Dagenais, Pierre Voisine, Patrick Mathieu
  Journal of Thoracic and Cardiovascular Surgery 08/2005; 130(1):208-9. · 3.41 Impact Factor
• Article: Normalization of coronary microvascular reactivity and improvement in myocardial perfusion by surgical vascular endothelial growth factor therapy combined with oral supplementation of l-arginine in a porcine model of endothelial dysfunction.

  Pierre Voisine, Cesario Bianchi, Tanveer A Khan, Marc Ruel, Shu-Hua Xu, Jun Feng, Jian Li, Tamer Malik, Audrey Rosinberg, Frank W Sellke
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  ABSTRACT: Vascular endothelial growth factor acts in part through nitric oxide release, the availability of which is decreased in endothelial dysfunction associated with advanced coronary artery disease. This could explain the relatively disappointing results of vascular endothelial growth factor therapy in clinical studies compared with animal studies. We examined the influence of L-arginine supplementation to vascular endothelial growth factor therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. Twenty-four pigs were fed either a normal (NORM, n = 8) or high-cholesterol diet with (CHOL-ARG, n = 8) or without (CHOL, n = 8) L-arginine. All pigs underwent ameroid placement on the circumflex artery and then 3 weeks later received surgical vascular endothelial growth factor treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by means of immunohistochemistry. Vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt levels were determined by means of immunoblotting. Pigs from the CHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. Vascular endothelial growth factor treatment was ineffective in the CHOL group (circumflex/left anterior descending coronary artery blood flow ratios: 0.95 [rest] and 0.74 [pace] before-after treatment; P < .05 compared with the NORM group). Addition of L-arginine restored the angiogenic effect of vascular endothelial growth factor (ratios: 1.13 [rest] and 1.20 [pace]; P < .05) and was associated with increased endothelial cell density, as well as vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt protein levels in the ischemic territory. L-Arginine supplementation can restore normal endothelium-dependent vasorelaxation and angiogenic response to vascular endothelial growth factor in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with vascular endothelial growth factor therapy for end-stage coronary artery disease.
  Journal of Thoracic and Cardiovascular Surgery 07/2005; 129(6):1414-20. · 3.41 Impact Factor
• Article: Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity.

  Patrick Mathieu, Pierre Voisine, Andrée Pépin, Rahoul Shetty, Nadia Savard, François Dagenais
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  ABSTRACT: The calcification of heart valves is associated with valve degeneration and failure, but the mechanisms involved are poorly understood. The presence of lamellar bone has been demonstrated in calcified aortic valves. Since osseous calcification is closely associated with alkaline phosphatase (ALP) activity, it was hypothesized that ALP activity might be implicated in the calcification of isolated leaflet interstitial cells (ICs). Human valve leaflet ICs were isolated from transplant-explanted hearts at the time of transplantation (n = 12). Isolated leaflet ICs expressed the fibroblast-specific antigen (100% of cells) and smooth muscle (SM) alpha-actin (70-80% of cells), but osteoblastic markers were not expressed. Cultured ICs did not calcify spontaneously, however when the growth medium was supplemented with beta-glycerophosphate (an organic phosphate) it induced the formation of calcified nodules that expressed osteonectin and ALP, but not SM alpha-actin. Beta-glycerophosphate-induced calcification of ICs showed a time-dependent effect on the calcium content of treated cells over a 14-day period. ALP activity was considerably increased in beta-glycerophosphate-treated ICs, and this correlated with the calcium content (r = 0.5: p = 0.01). Levamisol (an ALP inhibitor) inhibited the beta-glycerophosphate-induced calcification process, as well as the expression of osteoblastic differentiation markers. Isolated and cultured leaflet ICs did not calcify spontaneously, though organic phosphate induced the formation of calcified nodules that expressed osteoblastic markers. The calcification of isolated ICs was seen to be dependent on ALP activity.
  The Journal of heart valve disease 06/2005; 14(3):353-7. · 0.81 Impact Factor
• Article: Aprotinin inhibits protease-dependent platelet aggregation and thrombosis.

  Tanveer A Khan, Cesario Bianchi, Pierre Voisine, Jennifer Sandmeyer, Jun Feng, Frank W Sellke
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  ABSTRACT: Hemostatic effects of the protease inhibitor aprotinin in cardiac surgery are well described, and recent evidence suggests an antithrombotic mechanism of aprotinin through inhibition of thrombin-mediated platelet activation. We hypothesized that aprotinin provides hemostasis while reducing vascular thrombosis by attenuating protease-dependent platelet function. Rabbits (3 to 4 kg) underwent carotid artery thrombosis induced by electrical current. Treatment animals (n = 8) received aprotinin by a 100,000-KIU bolus followed by a continuous infusion (25,000 KIU/h). Control animals (n = 8) received crystalloid solution. Thrombus weight and time to thrombotic occlusion were determined. Platelet aggregation was examined in response to protease-dependent (thrombin) and protease-independent (adenosine diphosphate, ADP) platelet agonists. Platelet thrombin protease-activated receptor (PAR) expression was analyzed by Western blot. Ear bleeding time and abdominal incisional bleeding were measured at baseline and serially. Thrombus weight was decreased by aprotinin (6.1 +/- 1.1 mg versus 10.8 +/- 1.5 mg, aprotinin versus control, p < 0.05). Time to thrombotic occlusion was prolonged in the aprotinin group (17.4 +/- 1.0 minutes versus 8.3 +/- 1.3 minutes, p < 0.001). Rabbit platelet expression of thrombin PARs was demonstrated by Western blot analysis, and was not altered by aprotinin therapy. Platelet aggregation due to thrombin was decreased by aprotinin therapy (59.2% +/- 3.0% versus 95.8% +/- 1.5%, p < 0.001), whereas protease-independent, ADP-induced platelet aggregation was unchanged with aprotinin. Incisional bleeding was not different between groups. In the aprotinin group, bleeding time was unchanged at baseline and then reduced for the duration of the experiment (35.0 +/- 4.7 seconds versus 76.8 +/- 6.4 seconds, p < 0.05). While providing hemostatic effects, aprotinin attenuates vascular thrombosis in part by inhibition of PAR activation, resulting in the prevention of thrombin-induced platelet aggregation.
  The Annals of thoracic surgery 06/2005; 79(5):1545-50. · 3.74 Impact Factor
• Article: Vasomotor dysfunction after cardiac surgery.

  Marc Ruel, Tanveer A Khan, Pierre Voisine, Cesario Bianchi, Frank W Sellke
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  ABSTRACT: Cardiopulmonary bypass and cardioplegic arrest, which allow for support of the circulation and stabilization of the heart during cardiac procedures, are still used for the vast majority of cardiac operations worldwide. However, in addition to a well-recognized systemic inflammatory response, cardiopulmonary bypass and cardioplegic arrest elicit complex, multifactorial vasomotor disturbances that vary according to the affected organ bed, with reduced vascular resistances in the skeletal muscle and peripheral circulation, and increased propensity to spasm in the cardiac, pulmonary, mesenteric and cerebral vascular beds. This article outlines the nature, mechanistic basis, and clinical correlates of the vasomotor alterations encountered in patients undergoing cardiac surgery using cardiopulmonary bypass and cardioplegic arrest.
  European Journal of Cardio-Thoracic Surgery 12/2004; 26(5):1002-14. · 2.55 Impact Factor
• Article: Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest.

  Tanveer A Khan, Cesario Bianchi, Pierre Voisine, Jun Feng, Jeralyn Baker, Melanie Hart, Minoru Takahashi, Greg Stahl, Frank W Sellke
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  ABSTRACT: Surgical coronary revascularization with cardiopulmonary bypass and cardioplegia has been associated with reperfusion injury. The serine protease inhibitor aprotinin has been suggested to reduce reperfusion injury, yet a clinically relevant study examining regional ischemia under conditions of cardiopulmonary bypass and cardioplegia has not been performed. Pigs were subjected to 30 minutes of regional myocardial ischemia by distal left anterior descending coronary artery occlusion, followed by 60 minutes of cardiopulmonary bypass with 45 minutes of cardioplegic arrest and 90 minutes of post-cardiopulmonary bypass reperfusion. The treatment group (n = 6) was administered aprotinin systemically (40,000 kallikrein-inhibiting units [KIU]/kg intravenous loading dose, 40,000 KIU/kg pump prime, and 10,000 KIU x kg(-1) x h(-1) intravenous continuous infusion). Control animals (n = 6) received crystalloid solution. Global and regional myocardial functions were analyzed by the left ventricular+dP/dt and the percentage segment shortening, respectively. Left ventricular infarct size was measured by tetrazolium staining. Tissue myeloperoxidase activity was measured. Myocardial sections were immunohistochemically stained for nitrotyrosine. Coronary microvessel function was studied by videomicroscopy. Myocardial infarct size was decreased with aprotinin treatment (27.0% +/- 3.5% vs 45.3% +/- 3.0%, aprotinin vs control; P <.05). Myocardium from the ischemic territory showed diminished nitrotyrosine staining in aprotinin-treated animals versus controls, and this was significant by grade (1.3 +/- 0.2 vs 3.2 +/- 0.2, aprotinin vs control; P <.01). In the aprotinin group, coronary microvessel relaxation improved most in response to the endothelium-dependent agonist adenosine diphosphate (44.7% +/- 3.2% vs 19.7% +/- 1.7%, aprotinin vs control; P <.01). No significant improvements in myocardial function were observed with aprotinin treatment. Aprotinin reduces reperfusion injury after regional ischemia and cardioplegic arrest. Protease inhibition may represent a molecular strategy to prevent postoperative myocardial injury after surgical revascularization with cardiopulmonary bypass.
  Journal of Thoracic and Cardiovascular Surgery 10/2004; 128(4):602-8. · 3.41 Impact Factor
• Article: Differences in gene expression profiles of diabetic and nondiabetic patients undergoing cardiopulmonary bypass and cardioplegic arrest.

  Pierre Voisine, Marc Ruel, Tanveer A Khan, Cesario Bianchi, Shu-Hua Xu, Isaac Kohane, Towia A Libermann, Hasan Otu, Alan R Saltiel, Frank W Sellke
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  ABSTRACT: Diabetes mellitus is an independent risk factor for early postoperative mortality and complications after coronary artery bypass grafting (CABG). We sought to compare the cardiac gene expression responses to cardiopulmonary bypass (CPB) and cardioplegic arrest (C) in patients with and without diabetes. Twenty atrial myocardium samples were harvested from 5 type II insulin-dependent diabetic and 5 matched nondiabetic patients undergoing CABG, before and after CPB/C. Oligonucleotide microarray analyses of 12625 genes were performed on the 10 sample pairs using matched pre-CPB tissues as controls. Array results were validated with Northern blotting and immunoblotting. Compared with pre-CPB/C, post-CPB/C myocardial tissues revealed 851 upregulated and 480 downregulated genes with a threshold P< or =0.025 (signal-to-noise ratio, 4.04) in the diabetic group, compared with 480 upregulated and 626 downregulated genes (signal-to-noise ratio, 3.04) in the nondiabetic group (P<0.001). There were 18 genes that were upregulated >4-fold in diabetic and nondiabetic patients (including inflammatory/transcription activators FOS, CYR 61, and IL-6, apoptotic gene NR4A1, stress gene DUSP1, and glucose-transporter gene SLC2A3). However, 28 genes showed such marked upregulation in the diabetic group exclusively (including inflammatory/transcription activators MYC, IL8, IL-1beta, growth factor vascular endothelial growth factor, amphiregulin, and glucose metabolism-involved gene insulin receptor substrate 1), and 27 genes in the nondiabetic group only, including glycogen-binding subunit PPP1R3C. Gene expression profile after CPB/C is quantitatively and qualitatively different in patients with diabetes. These results have important implications for the design of tailored myocardial protection and operative strategies for diabetic patients undergoing CPB/C.
  Circulation 09/2004; 110(11 Suppl 1):II280-6. · 14.74 Impact Factor
• Source

  Available from: Frank W Sellke

  Article: Inhibition of the cardiac angiogenic response to exogenous vascular endothelial growth factor.

  Pierre Voisine, Cesario Bianchi, Marc Ruel, Tamer Malik, Audrey Rosinberg, Jun Feng, Tanveer A Khan, Shu-Hua Xu, Jennifer Sandmeyer, Roger J Laham, Frank W Sellke
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  ABSTRACT: The angiogenic effects of vascular endothelial growth factor (VEGF) are mediated by the stimulation of endothelial nitric oxide synthase (eNOS) and nitric oxide release. Nitric oxide availability is decreased in patients with coronary disease, a possible explanation for the humble results of VEGF in clinical trials. We sought to examine the effects of exogenous VEGF in a model of endothelial dysfunction. Miniswine fed either a regular (N = 6, group NORM) or hypercholesterolemic diet (N = 6, HICHOL) underwent ameroid placement on the circumflex artery. Three weeks later, baseline myocardial perfusion was assessed by microsphere injections, and all pigs were treated with VEGF. Four weeks later, microsphere injections were repeated and the hearts harvested. Endothelial-dependent coronary microvascular reactivity, and VEGF and eNOS expression were assessed. HICHOL pigs showed significant endothelial dysfunction in the ischemic territory. Post-treatment myocardial blood flow in the circumflex territory was significantly higher in the NORM compared to the HICHOL group. VEGF and eNOS levels were increased in the ischemic territory in the NORM group but decreased in the HICHOL group. The cardiac angiogenic response to VEGF was markedly inhibited in a hypercholesterolemia-induced porcine model of endothelial dysfunction. Coronary endothelial dysfunction could be an obstacle to the efficacy of clinical angiogenesis protocols and a putative therapeutic target.
  Surgery 09/2004; 136(2):407-15. · 3.10 Impact Factor
• Article: Mitogen-activated protein kinase pathways and cardiac surgery.

  Tanveer A Khan, Cesario Bianchi, Marc Ruel, Pierre Voisine, Frank W Sellke
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  ABSTRACT: Mitogen-activated protein kinases are serine-threonine protein kinases that are involved in several processes important to cardiac surgery such as vascular permeability, cytokine production, vasomotor function, and reperfusion injury. Mitogen-activated protein kinases are expressed in multiple cell types including cardiomyocytes, vascular endothelial cells, and vascular smooth muscle cells. Mitogen-activated protein kinases function in cellular signal transduction cascades and are activated by a diverse range of stimuli including ischemia, shear stress, and vasoactive agents. Three major mitogen-activated protein kinase families were identified as the extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases, and p38 kinases. Extensive investigation has established roles for extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases, and p38 kinases in cardiovascular signal transduction pathways. Activity of these signal cascades may contribute to the increased pulmonary vascular permeability and myocardial reperfusion injury observed after cardiac surgery with cardioplegia and cardiopulmonary bypass. Recent findings from our laboratory suggest that alterations in the activity of myocardial extracellular signal-regulated kinase pathways occur as a result of cardioplegia-cardiopulmonary bypass in humans. In addition, these differences in extracellular signal-regulated kinase activity were shown to mediate coronary microcirculatory dysfunction associated with cardioplegia-cardiopulmonary bypass. The resulting deficit in coronary microcirculatory regulation may potentially lead to detrimental effects on organ perfusion and function. As mitogen-activated protein kinase pathways are further characterized, our potential to develop methods to prevent morbidity associated with cardiac surgery and cardiopulmonary bypass may be greatly improved.
  Journal of Thoracic and Cardiovascular Surgery 04/2004; 127(3):806-11. · 3.41 Impact Factor
• Article: Gene expression profile after cardiopulmonary bypass and cardioplegic arrest.

  Marc Ruel, Cesario Bianchi, Tanveer A Khan, Shu Xu, John R Liddicoat, Pierre Voisine, Eugenio Araujo, Helen Lyon, Isaac S Kohane, Towia A Libermann, Frank W Sellke
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  ABSTRACT: This study examines the cardiac and peripheral gene expression responses to cardiopulmonary bypass and cardioplegic arrest. Atrial myocardium and skeletal muscle were harvested from 16 patients who underwent coronary artery bypass grafting before and after cardiopulmonary bypass and cardioplegic arrest. Ten sample pairs were selected for patient similarity, and oligonucleotide microarray analyses of 12,625 genes were performed using matched precardiopulmonary bypass tissues as controls. Array results were validated with Northern blotting, real-time polymerase chain reaction, in situ hybridization, and immunoblotting. Statistical analyses were nonparametric. Median durations of cardiopulmonary bypass and cardioplegic arrest were 74 and 60 minutes, respectively. Compared with precardiopulmonary bypass, postcardiopulmonary bypass myocardial tissues revealed 480 up-regulated and 626 down-regulated genes with a threshold P value of.025 or less (signal-to-noise ratio: 3.46); skeletal muscle tissues showed 560 and 348 such genes, respectively (signal-to-noise ratio: 3.04). Up-regulated genes in cardiac tissues included inflammatory and transcription activators FOS; jun B proto-oncogene; nuclear receptor subfamily 4, group A, member 3; MYC; transcription factor-8; endothelial leukocyte adhesion molecule-1; and cysteine-rich 61; apoptotic genes nuclear receptor subfamily 4, group A, member 1 and cyclin-dependent kinase inhibitor 1A; and stress genes dual-specificity phosphatase-1, dual-specificity phosphatase-5, and B-cell translocation gene 2. Up-regulated skeletal muscle genes included interleukin 6; interleukin 8; tumor necrosis factor receptor superfamily, member 11B; nuclear receptor subfamily 4, group A, member 3; transcription factor-8; interleukin 13; jun B proto-oncogene; interleukin 1B; glycoprotein Ib, platelet, alpha polypeptide; and Ras-associated protein RAB27A. Down-regulated genes included haptoglobin and numerous immunoglobulins in the heart, and factor H-related gene 2, protein phosphatase 1, regulatory subunit 3A, and growth differentiation factor-8 in skeletal muscle. By establishing a profile of the gene-expression responses to cardiopulmonary bypass and cardioplegia, this study allows a better understanding of their effects and provides a framework for the evaluation of new cardiac surgical modalities directly at the genome level.
  Journal of Thoracic and Cardiovascular Surgery 12/2003; 126(5):1521-30. · 3.41 Impact Factor
• Article: Activation of pulmonary mitogen-activated protein kinases during cardiopulmonary bypass.

  Tanveer A Khan, Cesario Bianchi, Eugenio G Araujo, Marc Ruel, Pierre Voisine, Frank W Sellke
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  ABSTRACT: Cardiopulmonary bypass (CPB) produces an inflammatory response associated with pulmonary dysfunction. Mitogen-activated protein kinases (MAPK) have been shown to mediate pulmonary injury. We hypothesized that MAPK are activated during CPB and potentially contribute to lung injury. Pigs were placed on CPB (n = 6) for 90 min, which included 80 min of cardioplegic arrest, followed by 180 min of post-CPB reperfusion. Control animals (n = 6) underwent sternotomy and heparinization only. Lung samples were collected at baseline, during CPB, and during post-CPB reperfusion. Activated forms of extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 were measured by Western blot. Immunohistochemistry was used for tissue localization of activated MAPK. Pulmonary inflammation was determined by histology. Pulmonary edema was estimated by tissue water percentage. Activated ERK1/2 and p38 were increased after 90 min of CPB compared with controls (3.94 +/- 0.61- and 2.49 +/- 0.15-fold increase, respectively; both P < 0.01). At 180 min of post-CPB reperfusion, ERK1/2 activity was increased by nearly 5-fold compared with controls (P < 0.01), whereas p38 activity returned to baseline levels. By immunohistochemistry, activated ERK1/2 and p38 in the CPB group were localized to alveolar epithelial cells, vascular endothelial cells, and bronchial smooth muscle. Histologic signs of lung injury included leukocyte infiltration in the CPB group. Tissue water percentage was increased with CPB (89.9 +/- 1.5% versus 82.5 +/- 1.0%, CPB versus control, P < 0.05). The results of our study demonstrate that CPB increases pulmonary p38 activity and causes sustained activation of ERK1/2. MAPK activation thus may in part mediate the pulmonary inflammatory response and provide a potential site of intervention to prevent pulmonary dysfunction due to CPB.
  Journal of Surgical Research 11/2003; 115(1):56-62. · 2.25 Impact Factor
• Article: Inhibition of the cardiac angiogenic response to surgical FGF-2 therapy in a Swine endothelial dysfunction model.

  Marc Ruel, Gui Fu Wu, Tanveer A Khan, Pierre Voisine, Cesario Bianchi, Jianyi Li, Jian Li, Roger J Laham, Frank W Sellke
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  ABSTRACT: Discrepancy exists between the potent effects of therapeutic angiogenesis in laboratory animals and the marginal results observed in patients with advanced coronary artery disease. In vitro and small animal data suggest that angiogenesis may depend on locally available nitric oxide (NO), but the impact of endothelial dysfunction on therapeutic angiogenesis in the myocardium has been unclear. We compared the effects of clinically applicable angiogenesis methods in swine in which endothelial dysfunction was experimentally induced to that observed in normal swine. Miniswine were fed either a regular (N=13) or hypercholesterolemic diet (N=13) for 20 weeks. Hypercholesterolemic swine showed coronary endothelial dysfunction on videomicroscopy. Animals from both groups received 100 microg of perivascular sustained-release fibroblast growth factor (FGF)-2 in the lateral myocardial territory, previously made ischemic by placement of an ameroid constrictor around the circumflex artery. After 4 weeks of FGF-2 therapy, lateral myocardial perfusion was significantly lower in hypercholesterolemic than in normocholesterolemic swine, both at rest and during pacing (0.44+/-0.04 versus 0.81+/-0.15 mL/min/g at rest, respectively; P=0.006; and 0.50+/-0.06 versus 0.71+/-0.10 mL/min/g during pacing; P=0.02). Hypercholesterolemic swine showed no net increase in perfusion from FGF-2 treatment. Endothelial cell density and FGF receptor-1 expression were significantly lower in the lateral territory of hypercholesterolemic versus normocholesterolemic animals. The cardiac angiogenic response to FGF-2 treatment using clinically applicable methods was markedly inhibited in hypercholesterolemic swine with coronary endothelial dysfunction. These findings suggest that coronary endothelial dysfunction is major obstacle to the efficacy of clinical angiogenesis protocols and constitutes a target toward making angiogenesis more effective in patients with advanced coronary disease.
  Circulation 10/2003; 108 Suppl 1:II335-40. · 14.74 Impact Factor
• Source

  Available from: Cesario Bianchi

  Article: Poly(ADP-ribose) polymerase inhibition improves postischemic myocardial function after cardioplegia-cardiopulmonary bypass.

  Tanveer A Khan, Marc Ruel, Cesario Bianchi, Pierre Voisine, Katalin Komjáti, Csaba Szabo, Frank W Sellke
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  ABSTRACT: Poly(ADP-ribose) polymerase activation has been shown to contribute to the pathogenesis of myocardial ischemia-reperfusion injury. We hypothesized that a novel poly(ADP-ribose) polymerase inhibitor, INO-1001, provides myocardial protection and improves cardiac function after regional ischemia and cardioplegia-cardiopulmonary bypass (CPB). Pigs were subjected to 30 minutes of regional ischemia by distal left anterior descending coronary artery ligation followed by CPB (60 minutes) with hyperkalemic cardioplegia (45 minutes). The myocardium then was reperfused post-CPB for 90 minutes. After 15 minutes of ischemia, the treatment group (n = 6) received an INO-1001 bolus (1mg/kg) before a continuous infusion (1mg/kg/hour). Control pigs (n = 6) received vehicle solution. Left ventricular pressure was monitored, from which the maximum, positive first derivative of left ventricular pressure over time (+dP/dt) was calculated. Regional myocardial function in the ischemic area was determined by sonomicrometric analysis. Infarct size was measured as the percent of the ischemic area by tetrazolium staining. Myocardial sections were immunohistochemically stained for poly(ADP-ribose) as a measure of poly(ADP-ribose) polymerase activity and inhibition. Pigs treated with INO-1001 showed improvements in the +dP/dt at 60 and 90 minutes of post-CPB reperfusion (both p = 0.03) and percent segmental shortening at 30, 60, and 90 minutes of post-CPB reperfusion (p = 0.03, 0.009, and 0.03, respectively). Infarct size was decreased in the treatment group (18.5 +/- 5.7% versus 52.0 +/- 7.7%, INO-1001 versus control, p = 0.03). Poly(ADP-ribose) was reduced in myocardial sections from INO-1001-treated animals compared with controls. These results suggest that INO-1001 provides myocardial protection by reducing the extent of infarction and improves cardiac function after regional ischemia and cardioplegia-CPB.
  Journal of the American College of Surgeons 09/2003; 197(2):270-7. · 4.55 Impact Factor
• Article: Cardiopulmonary bypass reduces peripheral microvascular contractile function by inhibition of mitogen-activated protein kinase activity.

  Tanveer A Khan, Cesario Bianchi, Eugenio G Araujo, Marc Ruel, Pierre Voisine, Jianyi Li, John R Liddicoat, Frank W Sellke
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  ABSTRACT: Mitogen-activated protein kinases (MAPK) have been implicated in pathophysiologic responses to cardiopulmonary bypass (CPB). MAPK are deactivated by phosphatases, such as MAPK phosphatase-1 (MKP-1). We hypothesized that MAPK mediate peripheral microvascular contractile dysfunction caused by CPB in humans. Skeletal muscle was harvested before and after CPB. Protein levels of MKP-1 and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 were measured. MKP-1 gene expression was measured. Peripheral microvessel responses to vasopressors were studied by videomicroscopy. Contractile function also was measured after MAPK inhibition with PD98059 (ERK1/2) and SB203580 (p38). ERK1/2, p38, and MKP-1 were localized by immunohistochemistry and in situ hybridization. ERK1/2 and p38 activity was decreased in peripheral tissue after CPB. MKP-1 was increased after CPB. Contractile responses of peripheral arterioles to phenylephrine and vasopressin were decreased after CPB. Microvessel reactivity also was reduced after treatment with PD98059 and SB203580. ERK1/2, p38, and MKP-1 localized to peripheral arterioles in tissue sections. CPB reduces ERK1/2 and p38 activity in peripheral tissue, potentially by MKP-1. Contractile responses of peripheral arterioles to phenylephrine and vasopressin are dependent on ERK1/2 and p38 and are decreased after CPB. These results suggest that alterations in MAPK pathways in part regulate peripheral microvascular dysfunction after CPB in humans.
  Surgery 09/2003; 134(2):247-54. · 3.10 Impact Factor
• Article: Mitogen-activated protein kinase inhibition and cardioplegia-cardiopulmonary bypass reduce coronary myogenic tone.

  Tanveer A Khan, Cesario Bianchi, Marc Ruel, Pierre Voisine, Jianyi Li, John R Liddicoat, Frank W Sellke
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  ABSTRACT: Cardioplegia-cardiopulmonary bypass (C/CPB) is associated with coronary microcirculatory dysfunction. Regulation of the microcirculation includes myogenic tone. Mitogen-activated protein kinases (MAPK) have been implicated in coronary vasomotor function. We hypothesized that vasomotor dysfunction of the coronary microcirculation is mediated in part by alterations in extracellular signal regulated kinase 1/2 (ERK1/2) activity following C/CPB in humans. Atrial myocardium was harvested from patients (n=15) before and after blood cardioplegia and short-term reperfusion under conditions of CPB. Myogenic tone of coronary arterioles was measured by videomicroscopy. Microvessel tone was determined post-C/CPB and after PD98059, a MAPK/ERK kinase 1/2 (MEK1/2) inhibitor. MAPK phosphatase-1 (MKP-1) and activated ERK1/2 were measured by Western blot. MKP-1 gene expression was determined by Northern blot. In situ hybridization and immunohistochemistry were used to localize myocardial MKP-1 and activated ERK1/2, respectively. Myogenic tone was reduced in coronary arterioles post-C/CPB (-10.5+/-0.9%, P<0.01 versus control/pre-C/CPB, n=5). Myogenic tone was decreased in coronary microvessels after 30 micromol/L (n=5) and 50 micromol/L (n=5) PD98059 treatment (-11.0+/-0.8% and -14.6+/-2.0%, respectively, both P<0.01 versus control/pre-C/CPB). Myocardial levels of activated ERK1/2 were reduced post-C/CPB (0.6+/-0.1, post/pre-C/CPB ratio, P<0.05, n=5) while MKP-1 levels increased (4.2+/-0.6, post/pre-C/CPB ratio, P<0.05, n=5). Myocardial MKP-1 gene expression increased post-C/CPB (3.0+/-0.8, post/pre-C/CPB ratio, P<0.05, n=5). MKP-1 and activated ERK1/2 localized to coronary arterioles in myocardial sections. Coronary myogenic tone is dependent on ERK1/2 and decreased after C/CPB. C/CPB reduces levels of activated ERK1/2, potentially by increased levels of MKP-1. The ERK1/2 signal transduction pathway in part mediates coronary microvascular dysfunction after C/CPB in humans.
  Circulation 09/2003; 108 Suppl 1:II348-53. · 14.74 Impact Factor
• Article: Does the use of stentless aortic valves in a subcoronary position prevent patient-prosthesis mismatch for small aortic annulus?

  Stéphane Lopez, Patrick Mathieu, Philippe Pibarot, Siamak Mohammadi, François Dagenais, Pierre Voisine, Jean Dumesnil, Daniel Doyle
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  ABSTRACT: Freestyle stentless bioprostheses have shown excellent hemodynamic performance. However, small size subcoronary implants have yet to prove their clinical usefulness. The aim of this study was to determine the incidence of patient-prosthesis mismatch [PPM = Indexed Effective Orifice Area (iEOA) < or = 0.85 cm2/m2] after aortic valve replacement (AVR) with 19-mm and 21-mm stentless bioprostheses and to evaluate clinical and hemodynamic outcomes. From January 1993 to December 2000, 419 patients who had undergone Freestyle bioprostheses implantation were prospectively followed. Sixty-eight patients (16%) received a 19-21-mm prosthesis. The EOA was calculated and indexed to the patient's body surface area to obtain the iEOA. Clinical as well as echographic measures were recorded at discharge and at one and five years. PPM was present in 91% and 80% of patients with 19-mm and 21-mm prostheses, respectively. Severe mismatch (iEOA < or = 0.65 cm2/m2) was present in 58% and 17%. Mean gradients at discharge were 22 +/- 11 mmHg for the 19-mm prostheses and 14 +/- 7 mmHg for the 21-mm prostheses. Perioperative mortality was 33% (4/12 pts) for 19-mm prosthesis and 7% (4/56 pts) for 21-mm prostheses. Five-year actuarial survival was 58% for patients with 19-mm prosthesis and 82% for patients with 21-mm prosthesis (p = 0.04). AVR with small size Freestyle subcoronary implants is associated with a high incidence of PPM and high mortality.
  Journal of Cardiac Surgery 23(4):331-5. · 0.87 Impact Factor