Louis P. Perrault

Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation

BACKGROUND Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited. METHODS We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank. RESULTS At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, -6.6 and -6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P=0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months. CONCLUSIONS We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes. (Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.).

Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation

BACKGROUND In a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. METHODS We randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. RESULTS At 2 years, the mean (±SD) LVESVI was 41.2±20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2±20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, -14.1 ml per square meter and -14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-procedure group (hazard ratio in the combined-procedure group, 0.90; 95% confidence interval, 0.45 to 1.83; P=0.78). There was no significant between-group difference in the rank-based assessment of the LVESVI (including death) at 2 years (z score, 0.38; P=0.71). The 2-year rate of moderate or severe residual mitral regurgitation was higher in the CABG-alone group than in the combined-procedure group (32.3% vs. 11.2%, P<0.001). Overall rates of hospital readmission and serious adverse events were similar in the two groups, but neurologic events and supraventricular arrhythmias remained more frequent in the combined-procedure group. CONCLUSIONS In patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not lead to significant differences in left ventricular reverse remodeling at 2 years. Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.).

Comparative study of cyclosporine and tacrolimus vs newer immunosuppressants mycophenolate mofetil and rapamycin on coronary endothelial function

BACKGROUND Endothelial dysfunction contributes to the development of intimal hyperplasia in transplanted hearts by decreasing the protective effects of endothelial-derived nitric oxide. Immunosuppressive drugs may increase the dysfunction caused by rejection and further accelerate the development of graft coronary vasculopathy. This study compares the effect of cyclosporine and tacrolimus vs two newer immunosuppressive drugs, mycophenolate mofetil and rapamycin, on coronary endothelial function. METHODS An in vitro model of drug incubation in Krebs-bicarbonate solution (4(o)C, 48 hours) using porcine epicardial coronary arteries was developed. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4), 10(-7) mol/liter), tacrolimus (10(-4), 10(-7) mol/liter), mycophenolate mofetil (10(-4), 10(-7) mol/liter), rapamycin (10(-7), 10(-11) mol/liter), and their vehicles to assess effects on G-protein-mediated vasorelaxations leading to the release of nitric oxide. RESULTS Exposure to cyclosporine and mycophenolate mofetil was associated with a dose-dependent decrease in endothelium-dependent relaxations to serotonin (an agonist that binds to 5-HT1D receptors coupled to Gi-protein) but no impairment of relaxations to bradykinin (an agonist that binds to B2 receptors coupled to Gq-proteins). Exposure to tacrolimus and rapamycin caused severe impairment of relaxations to serotonin and a lesser one to bradykinin. We observed alterations of relaxations to the calcium ionophore A23187 after exposure to mycophenolate mofetil and rapamycin. Exposure to rapamycin and mycophenolate mofetil vehicles impaired relaxation to all agonists. CONCLUSIONS These results suggest that cyclosporine and mycophenolate mofetil induce a dysfunction of the vasorelaxing properties of the endothelium that may lead to a decrease in the protective effects of nitric oxide on the vascular wall but that these drugs still have a more favorable vascular profile than do tacrolimus and rapamycin. Decreased endothelial function after mycophenolate mofetil and rapamycin exposure could be caused by their vehicles.

Effect of clopidogrel on bleeding and transfusions after off-pump coronary artery bypass graft surgery: impact of discontinuation prior to surgery

OBJECTIVE The use of antiplatelet drugs to treat acute myocardial infarction, unstable angina, acute coronary syndrome and secondary prevention following percutaneous coronary interventions is well accepted. However, it constitutes a serious risk of bleeding for patients undergoing coronary artery bypass grafting surgery (CABG). We evaluated the effect of aspirin and clopidogrel (CPDG), both irreversible platelet aggregation inhibitors, on operative bleeding and determined the optimal timing for their discontinuation before surgery. METHOD Between July 2001 and December 2004, we reviewed our experience with 453 patients undergoing off-pump CABG surgery (OPCAB) who received CPDG (n=101) or not (n=352) preoperatively, and compared the intraoperative and postoperative bleeding to determine risks factors associated with blood or platelet transfusions. RESULTS Clopidogrel in OPCAB surgery is associated with higher intraoperative (702.24 ml vs 554.13 ml, p=0.03) and postoperative bleeding (864.93 ml vs 603.75 ml, p=0.03). The mean operative blood loss is higher in patients still on CPDG at the time of surgery compared to patients off CPDG at least 72 h before surgery (802 ml vs 554.13 ml, p<0.0001). Blood loss in the later subgroup of patients is comparable to the control group without CPDG (p=NS). Clopidogrel is associated with more platelet transfusions (OR=11.79, [1.48; 93.86]). CONCLUSION Blood loss is higher in OPCAB patients receiving clopidogrel before surgery. However, discontinuation of clopidogrel three days (72 h) prior to the operation demonstrated a similar blood loss pattern compared to a control group. Clopidogrel is associated with more platelets, but not red blood cell transfusions following OPCAB surgery.

Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers.

Age-associated telomere shortening leads to replicative senescence of human endothelial cells (EC). Risk factors for cardiovascular disease (CVD) accelerate ageing, while there is a concomitant rise in oxidative stress known to promote stress-induced senescence (SIS) in vitro. Of all risk factors for CVD, smoking is most associated with the development of inflammation and accelerated atherosclerosis due to a prooxidant-antioxidant imbalance. We tested the hypothesis that SIS predominates in EC isolated from chronic smokers with premature atherosclerosis undergoing coronary artery bypass graft surgery (CABG). We isolated and cultured EC from segments of internal mammary arteries from smoker, former smoker, and nonsmoker coronary patients. Senescence of EC was induced by serial passage and quantified by the measurement of telomere length and senescence-associated beta-galactosidase activity. Compared with nonsmokers, smoker patients were 10 years younger at the time of CABG, evidence of premature atherosclerosis. Cellular senescence was independent of telomere length and directly related to oxidative damage. EC exhibited higher expression levels of markers of oxidative stress (lipid peroxydation level and caveolin-1 mRNA), inflammation (angiopoietin-like 2 mRNA), hypoxia (vascular endothelial growth factor (VEGF)-A mRNA), and cell damage (p53 mRNA). In conclusion, a high oxidative stress environment in EC isolated from atherosclerotic chronic smokers predisposes to SIS rather than replicative senescence.

Management practices and major infections after cardiac surgery.

BACKGROUND Infections are the most common noncardiac complication after cardiac surgery, but their incidence across a broad range of operations, as well as the management factors that shape infection risk, remain unknown. OBJECTIVES This study sought to prospectively examine the frequency of post-operative infections and associated mortality, and modifiable management practices predictive of infections within 65 days from cardiac surgery. METHODS This study enrolled 5,158 patients and analyzed independently adjudicated infections using a competing risk model (with death as the competing event). RESULTS Nearly 5% of patients experienced major infections. Baseline characteristics associated with increased infection risk included chronic lung disease (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.21 to 2.26), heart failure (HR: 1.47; 95% CI: 1.11 to 1.95), and longer surgery (HR: 1.31; 95% CI: 1.21 to 1.41). Practices associated with reduced infection risk included prophylaxis with second-generation cephalosporins (HR: 0.70; 95% CI: 0.52 to 0.94), whereas post-operative antibiotic duration >48 h (HR: 1.92; 95% CI: 1.28 to 2.88), stress hyperglycemia (HR: 1.32; 95% CI: 1.01 to 1.73); intubation time of 24 to 48 h (HR: 1.49; 95% CI: 1.04 to 2.14); and ventilation >48 h (HR: 2.45; 95% CI: 1.66 to 3.63) were associated with increased risk. HRs for infection were similar with either <24 h or <48 h of antibiotic prophylaxis. There was a significant but differential effect of transfusion by surgery type (excluding left ventricular assist device procedures/transplant) (HR: 1.13; 95% CI: 1.07 to 1.20). Major infections substantially increased mortality (HR: 10.02; 95% CI: 6.12 to 16.39). CONCLUSIONS Major infections dramatically affect survival and readmissions. Second-generation cephalosporins were strongly associated with reduced major infection risk, but optimal duration of antibiotic prophylaxis requires further study. Given practice variations, considerable opportunities exist for improving outcomes and preventing readmissions. (Management Practices and Risk of Infection Following Cardiac Surgery; NCT01089712).

Nitric oxide inhalation in the treatment of primary graft failure following heart transplantation

BACKGROUND Primary graft failure from right or left ventricular insufficiency remains a serious cause of early death following heart transplantation. Inhaled nitric oxide (NO) is a potent pulmonary vasodilator that could decrease pulmonary pressure and improve right ventricular function. METHODS Two cases of early graft failure following orthotopic heart transplantation were treated with NO inhalation. The treatment consisted of inhalation of 20 ppm of NO, introduced 4 to 6 hours following transplantation, in 2 patients supported with high doses of inotropic agents and vasopressors in addition to the intra-aortic balloon pump. RESULTS In the first and second cases, NO inhalation resulted in a decrease in pulmonary artery pressure, in a decrease in pulmonary vascular resistance and in an increase in cardiac index. In the second patient, systemic oxygenation improved markedly 30 minutes after initiation of NO. In the 2 patients, NO inhalation, mechanical ventilation and the intra-aortic balloon pump were weaned 4 days following transplantation. CONCLUSION Primary graft failure from donor ischemic damage, reperfusion injury or pulmonary hypertension remains a serious complication. The use of an intra-aortic balloon pump, inotropic agents and of inhaled NO appears to offer the best support for recovery of donor heart function. Primary graft failure from right or left ventricular insufficiency remains a serious cause of early mortality following heart transplantation. Ischemic damage of donor heart, reperfusion injury or pulmonary hypertension are the main causes of early graft failure. Although the cause is multifactorial, treatment of primary organ failure remains difficult with dismal results. The objective of the present study was to review the result of 2 patients with donor right heart failure following heart transplantation treated with inhaled nitric oxide (NO).

The Paracrine Effect: Pivotal Mechanism in Cell-Based Cardiac Repair

Cardiac cell therapy has emerged as a controversial yet promising therapeutic strategy. Both experimental data and clinical applications in this field have shown modest but tangible benefits on cardiac structure and function and underscore that transplanted stem–progenitor cells can attenuate the postinfarct microenvironment. The paracrine factors secreted by these cells represent a pivotal mechanism underlying the benefits of cell-mediated cardiac repair. This article reviews key studies behind the paracrine effect related to the cardiac reparative effects of cardiac cell therapy.

Improved preservation of coronary endothelial function with Celsior compared with blood and crystalloid solutions in heart transplantation

BACKGROUND Endothelial injury from preservation solutions has been implicated in acute coronary vasospasm and pathologic activation of the endothelium, which can contribute to the development of graft coronary vasculopathy after heart transplantation. Preservation solutions with a powerful antioxidant capacity may decrease the occurrence of these complications. MATERIALS AND METHODS This study was designed to evaluate the effect of Celsior (an anti-oxidant solution specifically designed for cardiac preservation) in a model of heart preservation (4 hours at 4 degrees C to reproduce the situation encountered in clinical heart transplantation) compared two commonly used cardioplegic and preservation strategies on coronary endothelial function. Endothelium-dependent relaxation of normal porcine epicardial coronary arteries to serotonin (5-HT, an agonist that activates 5-HT(1d) receptors coupled to Gi proteins) and bradykinin (BK, which activates B2 receptors coupled to Gq proteins) was studied in standard organ chamber experiments in the following groups: a control group was submitted to immediate excision without cardioplegia and preserved in saline solution (0.9% NaCl) for 4 hours (Group 1); two groups had cardioplegia induced with a crystalloid solution and were stored for 4 hours in saline (Group 2) or 4 hours in Celsior solution (Group 3); and two groups had cardioplegia induced with normothermic blood cardioplegia and were stored for 4 hours in the saline (Group 4), or 4 hours in Celsior solution (Group 5). Finally, two groups underwent cardioplegia with Celsior and were stored for 4 hours in saline (Group 6), or 4 hours in the Celsior solution (Group 7). All cardioplegia solutions were at 4 degrees C (except blood cardioplegia at 37 degrees C) and all preservations solutions were at 4 degrees C. RESULTS Endothelium-dependent relaxations to serotonin were significantly decreased in all groups except the Celsior + Celsior group compared with the control group. There were no significant differences in relaxation to bradykinin except in one group. Use of the Celsior solution for induction of cardioplegia and storage better preserved endothelium-dependent G-protein-mediated relaxation compared with the other arrest and preservation strategies. CONCLUSIONS The observed effect may be associated with an improvement in both short- and long-term outcome in heart transplantation, especially because these alterations may be further compounded by reperfusion.

Focused Review on Transthoracic Echocardiographic Assessment of Patients with Continuous Axial Left Ventricular Assist Devices

Left ventricular assist devices (LVADs) are systems for mechanical support for patients with end-stage heart failure. Preoperative, postoperative and comprehensive followup with transthoracic echocardiography has a major role in LVAD patient management. In this paper, we will present briefly the hemodynamics of axial-flow LVAD, the rationale, and available data for a complete and organized echocardiographic assessment in these patients including preoperative assessment, postoperative and long-term evaluation.