Marc Ruel

Skeletonized Internal Thoracic Artery Harvest Reduces Pain and Dysesthesia and Improves Sternal Perfusion After Coronary Artery Bypass Surgery: A Randomized, Double-Blind, Within-Patient Comparison

Background— Observational studies suggest that skeletonization of the internal thoracic artery (ITA) can improve conduit flow and length and reduce deep sternal infections and postoperative pain. We performed a randomized, double-blind, within-patient comparison of skeletonized and nonskeletonized ITAs in patients undergoing coronary surgery. Methods and Results— Patients (n=48) undergoing bilateral ITA harvest were randomized to receive 1 skeletonized and 1 nonskeletonized ITA. Intraoperatively, ITA flow was assessed directly and with a Doppler flow probe before and after topical application of papaverine. ITA harvest time and conduit length were recorded. A blinded assessment of pain (visual analog scale) and dysesthesia (physical examination) was performed at discharge, at 2 weeks, and at a 3-month follow-up. Sternal perfusion was assessed with nuclear imaging (n=7). Skeletonization required longer ITA harvest times (27±1 versus 24±1 minutes; P=0.04). There was a trend toward increased ITA length in the skeletonized group (18.2±0.3 versus 17.7±0.3 cm; P=0.09). In situ ITA flow was lower in skeletonized arteries (7.4±0.9 versus 10.1±1.0 mL/min; P=0.01) and increased significantly after ITA division and papaverine application. Postanastomotic flows were similar between groups. Skeletonization was associated with decreased pain at the 3-month follow-up and a reduction in major sensory deficits at the 4-week and 3-month (17% versus 50%; P=0.002) follow-ups. Baseline adjusted sternal perfusion was significantly greater by 17±6% (P=0.03) on the skeletonized side. Conclusions— Skeletonization results in reduced postoperative pain and dysesthesia and increased sternal perfusion at follow-up but does not produce increased conduit flow. ITA skeletonization may be a strategy for reducing morbidity after CABG.

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.

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.

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.

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.

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.

Endogenous myocardial angiogenesis and revascularization using a gastric submucosal patch

BACKGROUND The gastrointestinal submucosa physiologically produces angiogenic proteins. We examined whether these properties could lead to endogenous myocardial angiogenesis in a swine model of chronic ischemia. METHODS Fifteen Yorkshire swine underwent ameroid constrictor placement around the circumflex artery and either lateral epicardial abrasion, creation of a gastroepiploic artery (GEA) based gastric patch, mucosal avulsion, transdiaphragmatic transfer, and apposition of the patch against the circumflex myocardial territory (number = 8; test animals), or lateral epicardial abrasion alone (number = 7; controls). Seven weeks later, lateral myocardial perfusion, endothelial cell density, and expression of VEGFR-1 and VE-cadherin were determined using isotope-labeled microsphere assays, immunohistochemistry, and immunoblotting, respectively. RESULTS Microsphere assays showed equivalent lateral/anterior myocardial perfusion indices at rest (1.10 +/- 0.49 vs 0.95 +/- 0.23, test vs control animals; p = 0.54), but higher perfusion in test animals versus controls during pacing (1.05 +/- 0.29 vs 0.69 +/- 0.09, test vs controls; p = 0.02). Increased myocardial endothelial cell density (42.6 +/- 8.5 vs 26.1 +/- 11.6 cells per 3850 microm2, test vs controls; p = 0.02) and expression of VE-cadherin (3.10 +/- 0.60-fold change, test vs controls; p = 0.001) were also observed in the lateral territory of test animals versus controls. Reconstitution of the proximally occluded circumflex artery from patch collaterals was demonstrated on gastroepiploic arteriography in a subset of test animals. CONCLUSIONS This model results in an angiogenic process of significantly greater magnitude than that resulting from chronic myocardial ischemia alone, without the need for exogenous angiogenic agents.

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.

HOW DURABLE IS REPAIR OF DEGENERATIVE MITRAL REGURGITATION IN THE YOUNG

Introduction: The purpose of this study was to determine the performance of mitral repair in young patients with degenerative disease. Some have described a linear rate of valve repair failure, which, if accurate, would predict inevitable valve reoperation for young patients. This study was performed to determine the durability of repair of degenerative MR according to patient age. Hypothesis: Failure of mitral valve repair is non-linear and is not influenced by the age of the patient presenting to surgery. Methods: Between 2001-2016, 894 patients underwent repair of degenerative MR. Of these, 40 were <40 years of age at the time of surgery; 87 were between 40-50 years; 187 were between 51-60 years; 263 were between 61-70 years and 317 were ?70 at the time of surgery. Patients were assessed in a dedicated valve clinic and follow-up was for 5.0±3.8 years (extended to 13.8 years). Results: Perioperative mortality was 0.3%. Younger patients were more likely to present to surgery with bileaflet prolapse compa...

IGF-1 ENGINEERED HUMAN CARDIAC STEM CELLS PROMOTE REPAIR OF ISCHEMIC MYOCARDIUM BY IMPROVING TRANSPLANT CELL SURVIVAL AND REDUCING MYOCARDIAL APOPTOSIS

the need for comprehensive long-term follow up studies. METHODS: The Canadian Registry of Atrial Fibrillation (CARAF) enrolled patients from 7 centres in Canada at the time of first electrocardiographic diagnosis of AF. Comprehensive clinical and echocardiographic data were collected and patients were followed annually, documenting clinical outcomes, recurrence of PAF, and progression to CAF. Univariate and multivariable Cox proportionate hazards analyses were performed to model the association between baseline clinical, electrocardiographic, and echocardiographic variables and outcomes of stroke and death in patients with AF. RESULTS: A total of 897 patients with non-surgical paroxysmal AF (PAF) were included in the analysis. The medial follow-up time was 8.89 years (interquartile range of 5 to 9.12 years). A total of 268 deaths and 84 strokes occurred during the follow-up period. Univariate analyses identified 13 risk factors that were independently associated with risk of death and 9 risk factors that were independently associated with risk of stroke. Of these risk factors, history of cardiomyopathy, presence of congestive heart failure (CHF), severe mitral regurgitation (MR) and older age had the highest hazard ratios (HR) for occurrence of death (HR 1⁄42.74, 2.61, 2.11 and 2.10, respectively (p<0.001)). The factors were also statistically associated with death in multivariate analysis. Presence of moderate to severe mitral stenosis (MS), cardiomyopathy, increase in left ventricular (LV) posterior wall dimension, CHF and age were highly associated with occurrence of stroke (HR1⁄4 3.99, 3.23, 2.51, 1.94 and 1.73, respectively (p<0.03)). In multivariable analysis, MS, age, And LV posterior wall dimension were associated with stroke. CONCLUSION: In patients with diagnosis of PAF, there are various clinical and echocardiographic risk factors that are independently associated with higher risk of poor outcomes such as death and stroke.