Nicolas Noiseux

Gait Speed as an Incremental Predictor of Mortality and Major Morbidity in Elderly Patients Undergoing Cardiac Surgery

OBJECTIVES The purpose of this study was to test the value of gait speed, a clinical marker for frailty, to improve the prediction of mortality and major morbidity in elderly patients undergoing cardiac surgery. BACKGROUND It is increasingly difficult to predict the elderly patients risk posed by cardiac surgery because existing risk assessment tools are incomplete. METHODS A multicenter prospective cohort of elderly patients undergoing cardiac surgery was assembled at 4 tertiary care hospitals between 2008 and 2009. Patients were eligible if they were 70 years of age or older and were scheduled for coronary artery bypass and/or valve replacement or repair. The primary predictor was slow gait speed, defined as a time taken to walk 5 m of ≥ 6 s. The primary end point was a composite of in-hospital post-operative mortality or major morbidity. RESULTS The cohort consisted of 131 patients with a mean age of 75.8 ± 4.4 years; 34% were female patients. Sixty patients (46%) were classified as slow walkers before cardiac surgery. Slow walkers were more likely to be female (43% vs. 25%, p = 0.03) and diabetic (50% vs. 28%, p = 0.01). Thirty patients (23%) experienced the primary composite end point of mortality or major morbidity after cardiac surgery. Slow gait speed was an independent predictor of the composite end point after adjusting for the Society of Thoracic Surgeons risk score (odds ratio: 3.05; 95% confidence interval: 1.23 to 7.54). CONCLUSIONS Gait speed is a simple and effective test that may identify a subset of vulnerable elderly patients at incrementally higher risk of mortality and major morbidity after cardiac surgery.

Off-Pump or On-Pump Coronary-Artery Bypass Grafting at 30 Days

BACKGROUND The relative benefits and risks of performing coronary-artery bypass grafting (CABG) with a beating-heart technique (off-pump CABG), as compared with cardiopulmonary bypass (on-pump CABG), are not clearly established. METHODS At 79 centers in 19 countries, we randomly assigned 4752 patients in whom CABG was planned to undergo the procedure off-pump or on-pump. The first coprimary outcome was a composite of death, nonfatal stroke, nonfatal myocardial infarction, or new renal failure requiring dialysis at 30 days after randomization. RESULTS There was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (9.8% vs. 10.3%; hazard ratio for the off-pump group, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P=0.59) or in any of its individual components. The use of off-pump CABG, as compared with on-pump CABG, significantly reduced the rates of blood-product transfusion (50.7% vs. 63.3%; relative risk, 0.80; 95% CI, 0.75 to 0.85; P<0.001), reoperation for perioperative bleeding (1.4% vs. 2.4%; relative risk, 0.61; 95% CI, 0.40 to 0.93; P=0.02), acute kidney injury (28.0% vs. 32.1%; relative risk, 0.87; 95% CI, 0.80 to 0.96; P=0.01), and respiratory complications (5.9% vs. 7.5%; relative risk, 0.79; 95% CI, 0.63 to 0.98; P=0.03) but increased the rate of early repeat revascularizations (0.7% vs. 0.2%; hazard ratio, 4.01; 95% CI, 1.34 to 12.0; P=0.01). CONCLUSIONS There was no significant difference between off-pump and on-pump CABG with respect to the 30-day rate of death, myocardial infarction, stroke, or renal failure requiring dialysis. The use of off-pump CABG resulted in reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

Effects of Off-Pump and On-Pump Coronary-Artery Bypass Grafting at 1 Year

BACKGROUND Previously, we reported that there was no significant difference at 30 days in the rate of a primary composite outcome of death, myocardial infarction, stroke, or new renal failure requiring dialysis between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report results on quality of life and cognitive function and on clinical outcomes at 1 year. METHODS We enrolled 4752 patients with coronary artery disease who were scheduled to undergo CABG and randomly assigned them to undergo the procedure off-pump or on-pump. Patients were enrolled at 79 centers in 19 countries. We assessed quality of life and cognitive function at discharge, at 30 days, and at 1 year and clinical outcomes at 1 year. RESULTS At 1 year, there was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (12.1% and 13.3%, respectively; hazard ratio with off-pump CABG, 0.91; 95% confidence interval [CI], 0.77 to 1.07; P=0.24). The rate of the primary outcome was also similar in the two groups in the period between 31 days and 1 year (hazard ratio, 0.79; 95% CI, 0.55 to 1.13; P=0.19). The rate of repeat coronary revascularization at 1 year was 1.4% in the off-pump group and 0.8% in the on-pump group (hazard ratio, 1.66; 95% CI, 0.95 to 2.89; P=0.07). There were no significant differences between the two groups at 1 year in measures of quality of life or neurocognitive function. CONCLUSIONS At 1 year after CABG, there was no significant difference between off-pump and on-pump CABG with respect to the primary composite outcome, the rate of repeat coronary revascularization, quality of life, or neurocognitive function. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

Addition of Frailty and Disability to Cardiac Surgery Risk Scores Identifies Elderly Patients at High Risk of Mortality or Major Morbidity

Background— Cardiac surgery risk scores perform poorly in elderly patients, in part because they do not take into account frailty and disability which are critical determinants of health status with advanced age. There is an unmet need to combine established cardiac surgery risk scores with measures of frailty and disability to provide a more complete model for risk prediction in elderly patients undergoing cardiac surgery. Methods and Results— This was a prospective, multicenter cohort study of elderly patients (≥70 years) undergoing coronary artery bypass and/or valve surgery in the United States and Canada. Four different frailty scales, 3 disability scales, and 5 cardiac surgery risk scores were measured in all patients. The primary outcome was the STS composite end point of in-hospital postoperative mortality or major morbidity. A total of 152 patients were enrolled, with a mean age of 75.9±4.4 years and 34% women. Depending on the scale used, 20–46% of patients were found to be frail, and 5–76% were found to have at least 1 disability. The most predictive scale in each domain was: 5-meter gait speed ≥6 seconds as a measure of frailty (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.17–5.90), ≥3 impairments in the Nagi scale as a measure of disability (OR, 2.98; 95% CI, 1.35–6.56) and either the Parsonnet score (OR, 1.08; 95% CI, 1.04–1.13) or Society of Thoracic Surgeons Predicted Risk of Mortality or Major Morbidity (STS-PROMM) (OR, 1.05; 95% CI, 1.01–1.09) as a cardiac surgery risk score. Compared with the Parsonnet score or STS-PROMM alone, (area under the curve, 0.68–0.72), addition of frailty and disability provided incremental value and improved model discrimination (area under the curve, 0.73–0.76). Conclusions— Clinicians should use an integrative approach combining frailty, disability, and risk scores to better characterize elderly patients referred for cardiac surgery and identify those that are at increased risk.

Kidney Function After Off-Pump or On-Pump Coronary Artery Bypass Graft Surgery A Randomized Clinical Trial

IMPORTANCE Most acute kidney injury observed in the hospital is defined by sudden mild or moderate increases in the serum creatinine concentration, which may persist for several days. Such acute kidney injury is associated with lower long-term kidney function. However, it has not been demonstrated that an intervention that reduces the risk of such acute kidney injury better preserves long-term kidney function. OBJECTIVES To characterize the risk of acute kidney injury with an intervention in a randomized clinical trial and to determine if there is a difference between the 2 treatment groups in kidney function 1 year later. DESIGN, SETTING, AND PARTICIPANTS The Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) enrolled 4752 patients undergoing first isolated coronary artery bypass graft (CABG) surgery at 79 sites in 19 countries. Patients were randomized to receive CABG surgery either with a beating-heart technique (off-pump) or with cardiopulmonary bypass (on-pump). From January 2010 to November 2011, 2932 patients (from 63 sites in 16 countries) from CORONARY were enrolled into a kidney function substudy to record serum creatinine concentrations during the postoperative period and at 1 year. The last 1-year serum creatinine concentration was recorded on January 18, 2013. MAIN OUTCOMES AND MEASURES Acute kidney injury within 30 days of surgery (≥50% increase in serum creatinine concentration from prerandomization concentration) and loss of kidney function at 1 year (≥20% loss in estimated glomerular filtration rate from prerandomization level). RESULTS Off-pump (n = 1472) vs on-pump (n = 1460) CABG surgery reduced the risk of acute kidney injury (17.5% vs 20.8%, respectively; relative risk, 0.83 [95% CI, 0.72-0.97], P = .01); however, there was no significant difference between the 2 groups in the loss of kidney function at 1 year (17.1% vs 15.3%, respectively; relative risk, 1.10 [95% CI, 0.95-1.29], P = .23). Results were consistent with multiple alternate continuous and categorical definitions of acute kidney injury or kidney function loss, and in the subgroup with baseline chronic kidney disease. CONCLUSIONS AND RELEVANCE Use of off-pump compared with on-pump CABG surgery reduced the risk of postoperative acute kidney injury, without evidence of better preserved kidney function with off-pump CABG surgery at 1 year. In this setting, an intervention that reduced the risk of mild to moderate acute kidney injury did not alter longer-term kidney function. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00463294.

Epidermal Growth Factor and Perlecan Fragments Produced by Apoptotic Endothelial Cells Co‐Ordinately Activate ERK1/2‐Dependent Antiapoptotic Pathways in Mesenchymal Stem Cells

Mounting evidence indicates that mesenchymal stem cells (MSC) are pivotal to vascular repair and neointima formation in various forms of vascular disease. Yet, the mechanisms that allow MSC to resist apoptosis at sites where other cell types, such as endothelial cells (EC), are dying are not well defined. In the present work, we demonstrate that apoptotic EC actively release paracrine mediators which, in turn, inhibit apoptosis of MSC. Serum‐free medium conditioned by apoptotic EC increases extracellular signal‐regulated kinases 1 and 2 (ERK1/2) activation and inhibits apoptosis (evaluated by Bcl‐xL protein levels and poly (ADP‐ribose) polymerase cleavage) of human MSC. A C‐terminal fragment of perlecan (LG3) released by apoptotic EC is one of the mediators activating this antiapoptotic response in MSC. LG3 interacts with β1‐integrins, which triggers downstream ERK1/2 activation in MSC, albeit to a lesser degree than medium conditioned by apoptotic EC. Hence, other mediators released by apoptotic EC are probably required for induction of the full antiapoptotic phenotype in MSC. Adopting a comparative proteomic strategy, we identified epidermal growth factor (EGF) as a novel mediator of the paracrine component of the endothelial apoptotic program. LG3 and EGF cooperate in triggering β1‐integrin and EGF receptor‐dependent antiapoptotic signals in MSC centering on ERK1/2 activation. The present work, providing novel insights into the mechanisms facilitating the survival of MSC in a hostile environment, identifies EGF and LG3 released by apoptotic EC as central antiapoptotic mediators involved in this paracrine response. STEM CELLS 2010;28:810–82028:810–820

One-Year Safety Analysis of the COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133 Bone Marrow Stem Cells to Placebo in Patients after Acute Myocardial Infarction and Left Ventricular Dysfunction.

Bone marrow stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium. Despite initial excitement, recent clinical trials using non-homogenous stem cells preparations showed variable and mixed results. Selected CD133+ hematopoietic stem cells are candidate cells with high potential. Herein, we report the one-year safety analysis on the initial 20 patients enrolled in the COMPARE-AMI trial, the first double-blind randomized controlled trial comparing the safety, efficacy, and functional effect of intracoronary injection of selected CD133+ cells to placebo following acute myocardial infarction with persistent left ventricular dysfunction. At one year, there is no protocol-related complication to report such as death, myocardial infarction, stroke, or sustained ventricular arrhythmia. In addition, the left ventricular ejection fraction significantly improved at four months as compared to baseline and remained significantly higher at one year. These data indicate that in the setting of the COMPARE-AMI trial, the intracoronary injection of selected CD133+ stem cells is secure and feasible in patients with left ventricle dysfunction following acute myocardial infarction.

Preoperative Anxiety as a Predictor of Mortality and Major Morbidity in Patients Aged >70 Years Undergoing Cardiac Surgery

The present study examined the association between patient-reported anxiety and postcardiac surgery mortality and major morbidity. Frailty Assessment Before Cardiac Surgery was a prospective multicenter cohort study of elderly patients undergoing cardiac surgery (coronary artery bypass surgery and/or valve repair or replacement) at 4 tertiary care hospitals from 2008 to 2009. The patients were evaluated a mean of 2 days preoperatively with the Hospital Anxiety and Depression Scale, a validated questionnaire assessing depression and anxiety in hospitalized patients. The primary predictor variable was a high level of anxiety, defined by a Hospital Anxiety and Depression Scale score of ≥ 11. The main outcome measure was all-cause mortality or major morbidity (e.g., stroke, renal failure, prolonged ventilation, deep sternal wound infection, or reoperation) occurring during the index hospitalization. Multivariable logistic regression analysis examined the association between high preoperative anxiety and all-cause mortality/major morbidity, adjusting for the Society of Thoracic Surgeons predicted risk, age, gender, and depression symptoms. A total of 148 patients (mean age 75.8 ± 4.4 years; 34% women) completed the Hospital Anxiety and Depression Scale. High levels of preoperative anxiety were present in 7% of patients. No differences were found in the type of surgery and Society of Thoracic Surgeons predicted risk across the preoperative levels of anxiety. After adjusting for potential confounders, high preoperative anxiety was remained independently predictive of postoperative mortality or major morbidity (odds ratio 5.1, 95% confidence interval 1.3 to 20.2; p = 0.02). In conclusion, although high levels of anxiety were present in few patients anticipating cardiac surgery, this conferred a strong and independent heightened risk of mortality or major morbidity.

Functional Activity of the Carboxyl‐Terminally Extended Oxytocin Precursor Peptide During Cardiac Differentiation of Embryonic Stem Cells

The hypothalamic post‐translational processing of oxytocin (OT)‐neurophysin precursor involves the formation of C‐terminally extended OT forms (OT‐X) that serve as intermediate prohormones. Despite abundant expression of the entire functional OT system in the developing heart, the biosynthesis and implication of OT prohormones in cardiomyogenesis remain unknown. In the present work, we investigated the involvement of OT‐X in cardiac differentiation of embryonic stem (ES) cells. Functional studies revealed the OT receptor‐mediated cardiomyogenic action of OT‐Gly‐Lys‐Arg (OT‐GKR). To obtain further insight into the mechanisms of OT‐GKR‐induced cardiac effects, we generated ES cell lines overexpressing the OT‐GKR gene and enhanced green fluorescent protein (EGFP). The functionality of the OT‐GKR/EGFP construct was assessed by fluorescence microscopy and flow cytometry, with further confirmation by radioimmunoassay and immunostaining. Increased spontaneously beating activity of OT‐GKR/EGFP‐expressing embryoid bodies and elevated expression of GATA‐4 and myosin light chain 2v cardiac genes indicated an inductive effect of endogenous OT‐GKR on ES cell‐derived cardiomyogenesis. Furthermore, patch‐clamp experiments demonstrated induction of ventricular phenotypes in OT‐GKR/EGFP‐transfected and in OT‐GKR‐treated cardiomyocytes. Increased connexin 43 protein in OT‐GKR/EGFP‐expressing cells further substantiated the evidence that OT‐GKR modifies cardiac differentiation toward the ventricular sublineage. In conclusion, this report provides new evidence of the biological activity of OT‐X, notably OT‐GKR, during cardiomyogenic differentiation.

Transcatheter Aortic Valve Implantation: Recommendations for Practice Based on a Multidisciplinary Review Including Cost-Effectiveness and Ethical and Organizational Issues

Transcatheter aortic valve implantation (TAVI) is a relatively new technology for the treatment of severe and symptomatic aortic valve stenosis. TAVI offers an alternative therapy for patients unable to be treated surgically because of contraindications or severe comorbidities. It is being rapidly dispersed in Canada, as it is worldwide. The objective of this article is to present our recommendations for the use of TAVI, based on a multidisciplinary evaluation of recently published evidence. We systematically searched and summarized published data (2008-2011) on benefits, risks, and cost-effectiveness of TAVI. We also examined ethical issues and organizational aspects of delivering the intervention. We discussed the soundness and applicability of our recommendations with clinical experts active in the field. The published TAVI results for high-risk and/or inoperable patients are promising in terms of survival, function, quality of life, and cost-effectiveness, although we noted large variability in the survival rates at 1 year and in the frequency of important adverse outcomes such as stroke. Until more data from randomized controlled trials and registries become available, prudence and discernment are necessary in the choice of patients most likely to benefit. Patients need to be well-informed about gaps in the evidence base. Our recommendations support the use of TAVI in the context of strict conditions with respect to patient eligibility, the patient selection process, organizational requirements, and the tracking of patient outcomes with a mandatory registry.