Biomedical subjects

Marc Ruel

Publications and source records attributed to Marc Ruel.

47 records · Page 3Linked to original sources

PubMed2003

Vascular growth factors and angiogenesis in cardiac surgery.

Therapeutic angiogenesis, in the form of growth factor protein administration or gene therapy, has emerged as a new method of treatment for patients with severe, inoperable coronary artery disease. Improved myocardial perfusion and function after administration of angiogenic growth factors has been demonstrated in animal models of chronic myocardial ischemia. Recently, preliminary clinical trials using growth factor proteins or genes encoding these angiogenic factors have demonstrated clinical and other objective evidence of relevant angiogenesis. A recent study reported beneficial long-term effects of therapeutic angiogenesis using fibroblast growth factor (FGF)-2 protein in terms of freedom from angina and perfusion on single-photon emission computed tomographic imaging. Thus, therapeutic angiogenesis has the potential to extend treatment options to patients who are not optimal candidates for conventional methods of myocardial revascularization. However, endogenous antiangiogenic influences, intrinsic lack of response of patients with severe endothelial dysfunction, and other limitations will need to be overcome before angiogenesis becomes a standard therapy for the treatment of patients with severe coronary disease.

Angiogenesis Inducing Agents↗

PubMed2003

Activation of pulmonary mitogen-activated protein kinases during cardiopulmonary bypass.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Animals↗

PubMed2003

Gene expression profile after cardiopulmonary bypass and cardioplegic arrest.

OBJECTIVE: This study examines the cardiac and peripheral gene expression responses to cardiopulmonary bypass and cardioplegic arrest. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Aged↗

PubMed2003

Internal thoracic artery flow competition: studies in a canine H-graft model.

OBJECTIVE: Internal thoracic artery (ITA) flow competition is a diversion of graft flow through intact ITA branches with a net decrease in perfusion to the grafted coronary. Although a widely acknowledged phenomenon, the conditions under which flow competition occurs have not been established. This is examined in a canine H-graft model. METHODS: Eight dogs had a right ITA segment interposed (H-graft) between their in situ left ITA (LITA) and the snared left anterior descending (LAD) coronary artery. Proximal LITA and H-graft flows were measured at baseline and during pacing-induced tachycardia, phenylephrine-induced hypertension, and nitroprusside-induced hypotension. Flows were measured with the distal LITA open and occluded. Two additional animals were subjected to eight separate 2-min periods of LAD ischemia, after which post-ischemic H-graft flow measurements were obtained with and without distal LIMA occlusion. RESULTS: During baseline conditions, proximal LITA flow was greater when the distal LITA was open rather than occluded (46+/-15 versus 35+/-12 ml/min, respectively; P=0.002), but H-graft flow did not change significantly (32+/-18 versus 35+/-18 ml/min, respectively; P=0.21). Similarly, occlusion of the distal LITA had no impact on H-graft flow during tachycardia, hypertension, or hypotension. Only in animals subjected to transient LAD ischemia did H-graft flow increase with distal LITA occlusion, albeit marginally (65+/-7-70+/-9 ml/min, occluded versus open, respectively; P=0.04). CONCLUSIONS: Mild diversion of flow from the LAD was demonstrated during immediate post-ischemic coronary reperfusion only, and could not be elicited under any other physiologic condition. These data suggest that flow competition is unlikely to constitute a clinically significant limitation to the use of H-grafts or other modalities that leave ITA branches patent.

Animals↗

PubMed2003

Angiogenic protein therapy.

Therapeutic angiogenesis, in the form of growth factor protein administration or gene therapy, has emerged as a new method of treatment for patients with severe, inoperable coronary artery disease. Improved myocardial perfusion and function after the administration of angiogenic growth factors has been demonstrated in animal models of chronic myocardial ischemia. A recent clinical study reported beneficial long-term effects of therapeutic angiogenesis using FGF-2 protein in terms of freedom from angina and myocardial perfusion on nuclear imaging and suggested that protein angiogenic therapy has the potential to extend treatment options to patients who are not optimal candidates for conventional methods of myocardial revascularization. The ultimate role that angiogenesis will play in the treatment of ischemic heart disease will, however, be determined from adequately powered, randomized, double-blind, placebo-controlled trials. It is likely that endogenous antiangiogenic influences, intrinsic lack of response of patients with severe endothelial dysfunction, and other limitations will have to be overcome before angiogenesis becomes standard therapy for the treatment of coronary artery disease.

Adult↗

PubMed2003

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

BACKGROUND: 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). STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Animals↗

PubMed2003

Cardiopulmonary bypass reduces peripheral microvascular contractile function by inhibition of mitogen-activated protein kinase activity.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Aged↗

PubMed2002

Intracardiac ultrasonic suture welding for knotless mitral valve replacement.

OBJECTIVE: The difficulty in tying multiple knots with endoscopic instruments constitutes a technical obstacle to the development of closed-chest valve surgery. The following set of experiments was undertaken to ascertain the in-vivo feasibility of using an intracardiac ultrasonic welding device for knotless suture fixation during mitral valve replacement (MVR). METHODS: Five adult sheep weighing 48-52 kg underwent MVR with a commercially available mechanical prosthesis, using pledgetted interrupted polypropylene sutures. An ultrasonic suture welder designed for intracardiac use was used to adjust suture tension and fuse strands together without knots. Echocardiographic assessment of the mitral prosthesis was carried out at baseline and after maintenance of supraphysiologic arterial pressures for 60 min. Subsequently, the animals' explanted hearts were assessed under sustained left ventricular (LV) pressurization to 180 mmHg in an ex-vivo pressure-loop system. RESULTS: MVR was successfully performed in all animals and welds reliably completed in less than 1 s. One sheep could not successfully be weaned off cardiopulmonary bypass; however, a normal prosthetic valve implant was confirmed at post-mortem examination. Echocardiographic assessment prior to and during LV pressurization revealed normal seating and function of the prosthesis in all cases. At post-mortem examination all valves were adequately implanted, suture tails laid flat on the surface of the prosthesis' sewing ring, welded suture strands were intact and accurately point-fused together, and no evidence of perivalvular leak was found around any of the prostheses despite sustained LV pressurization. CONCLUSIONS: This new modality proved reliable in an acute sheep model of MVR and could constitute a promising avenue towards facilitation of total endoscopic valve procedures in humans.

Animals↗

PubMed2002

Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein.

OBJECTIVE: The long-term effects of surgical fibroblast growth factor 2 therapy are examined. METHODS: In a randomized, double-blind study, fibroblast growth factor 2 (10 microg or 100 microg) or placebo (n = 8 each) was delivered in the ungraftable myocardial territory of patients concomitantly undergoing coronary artery bypass grafting. Patients were followed up to 32.2 +/- 6.8 months postoperatively with clinical assessment and nuclear perfusion imaging. RESULTS: Baseline patient characteristics were similar between the 3 groups. There were 2 late deaths, one of pancreatic cancer and one of undetermined cause (both in the 100-microg fibroblast growth factor 2 group). Two patients (both in the control group) underwent a total of 6 repeat cardiac catheterizations for recurrent coronary events. Mean Canadian Cardiovascular Society angina class improved at late follow-up from baseline in all groups (P < or = .02); however, patients treated with either dose of fibroblast growth factor 2 had significantly more freedom from angina recurrence than those treated with placebo (P =.03). Late nuclear perfusion scans revealed a persistent reversible or a new, fixed perfusion defect in the ungraftable territory of 4 of 5 patients who received placebo versus only 1 of 9 patients treated with fibroblast growth factor 2 (P =.02). The overall sum of left ventricular stress perfusion defect scores was also lower in fibroblast growth factor 2-treated patients than in control subjects (1.3 +/- 1.4 vs 3.9 +/- 2.1, respectively; P =.04). A trend toward a higher late left ventricular ejection fraction was noted in fibroblast growth factor 2-treated patients (55.1% +/- 14.6% vs 44.3% +/- 6.5%, fibroblast growth factor 2-treated patients versus control subjects; P =.12). CONCLUSIONS: These data suggest that surgical angiogenic therapy with sustained-release fibroblast growth factor 2 may result in a prolonged myocardial revascularization effect that could translate into clinical benefit.

Coronary Artery Bypass↗

PubMed2002

A new and simplified method for coronary and graft imaging during CABG.

BACKGROUND: Improvements in percutaneous catheter interventions and new technical demands in the practice of coronary surgery have increased the need for an accurate and easy-to-use imaging modality for validating the quality of bypass grafts in the operating room. This report examines the initial clinical use of fluorescent cardiac imaging, a technology that uses indocyanine green (ICG) with a portable imaging device to visualize coronary anatomy and grafts intraoperatively. METHODS: The modality was evaluated at two institutions in 20 patients undergoing non-emergent CABG or MIDCAB with respect to safety, feasibility of use, and image quality. Images were generated and acquired with a portable laser diode/infrared camera device after injection of 0.5 ml of ICG (0.5-5.0 mg/ml) either intravenously, via the antegrade cardioplegia cannula, or via the cardiopulmonary bypass circuit. RESULTS: There were no ICG- or imaging device-related complications. The technology was easy-to-use during conventional CABG as well as MIDCAB and adequately demonstrated coronary anatomy, filling of the grafts, and graft patency in all but two patients. In one patient, the use of the modality resulted in the intraoperative recognition and revision of a non-functioning graft. CONCLUSION: This technology is user-friendly in the operating room, appears to be safe, provides good-quality images of coronary anatomy and grafts, and holds promise as an intraoperative graft validation tool for conventional and minimally invasive CABG.

Aged↗

PubMedDate not supplied

CD117-positive cells and mast cells in adult human cardiac valves--observations and implications for the creation of bioengineered grafts.

BACKGROUND: There is no report to date of stem cells in human cardiac valves. We examined their possible presence, number, and distribution in valves removed at cardiac surgery from patients with a variety of underlying valve pathologies. METHODS: Grossly normal aortic and mitral valves were obtained from live heart transplant patients. Surgically excised valves with rheumatic mitral stenosis, aortic valve age-related degeneration, aortic valve changes of aortoannular ectasia, and mitral valves with myxomatous degeneration were studied. Immunohistochemical and histochemical studies were performed on sequential valve sections, including hematoxylin and eosin, hematoxylin phloxine saffron, Movat pentachrome, toluidine blue, CD31, CD34, and CD117. RESULTS: There were small clusters of CD117-positive cells in the fibrosa and spongiosa of mitral and aortic valves from all groups of valves. Sequential sectioning and staining showed that almost all of these cells were mast cells. However, in the mitral myxomatous valves and the mitral rheumatic valves, there were rare CD117-positive cells that did not have corresponding toluidine blue staining and thus could be valve mesenchymal stem cells. CONCLUSIONS: Most of the CD117-positive cells in normal and diseased adult heart valves are mast cells. These valve cells could play a role in valve pathology and injury. A very small number of possible valve stem cells were also identified. It is unlikely that these valve stem cells are sufficient in number to allow isolation and expansion for tissue engineering purposes.

Bioprosthesis↗