Curtis A. Anderson

Substrate-Specific Derangements in Mitochondrial Metabolism and Redox Balance in the Atrium of the Type 2 Diabetic Human Heart

OBJECTIVES The aim of this study was to determine the impact of diabetes on oxidant balance and mitochondrial metabolism of carbohydrate- and lipid-based substrates in myocardium of type 2 diabetic patients. BACKGROUND Heart failure represents a major cause of death among diabetic patients. It has been proposed that derangements in cardiac metabolism and oxidative stress may underlie the progression of this comorbidity, but scarce evidence exists in support of this mechanism in humans. METHODS Mitochondrial oxygen (O(2)) consumption and hydrogen peroxide (H(2)O(2)) emission were measured in permeabilized myofibers prepared from samples of the right atrial appendage obtained from nondiabetic (n = 13) and diabetic (n = 11) patients undergoing nonemergent coronary artery bypass graft surgery. RESULTS Mitochondria in atrial tissue of type 2 diabetic individuals show a sharply decreased capacity for glutamate and fatty acid-supported respiration, in addition to an increased content of myocardial triglycerides, as compared to nondiabetic patients. Furthermore, diabetic patients show an increased mitochondrial H(2)O(2) emission during oxidation of carbohydrate- and lipid-based substrates, depleted glutathione, and evidence of persistent oxidative stress in their atrial tissue. CONCLUSIONS These findings are the first to directly investigate the effects of type 2 diabetes on a panoply of mitochondrial functions in the human myocardium using cellular and molecular approaches, and they show that mitochondria in diabetic human hearts have specific impairments in maximal capacity to oxidize fatty acids and glutamate, yet increased mitochondrial H(2)O(2) emission, providing insight into the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of heart failure in diabetic patients.

Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways

Progressive energy deficiency and loss of cardiomyocyte numbers are two prominent factors that lead to heart failure in experimental models. Signals that mediate cardiomyocyte cell death have been suggested to come from both extrinsic (e.g., cytokines) and intrinsic (e.g., mitochondria) sources, but the evidence supporting these mechanisms remains unclear, and virtually nonexistent in humans. In this study, we investigated the sensitivity of the mitochondrial permeability transition pore (mPTP) to calcium (Ca(2+)) using permeabilized myofibers of right atrium obtained from diabetic (n = 9) and nondiabetic (n = 12) patients with coronary artery disease undergoing nonemergent coronary revascularization surgery. Under conditions that mimic the energetic state of the heart in vivo (pyruvate, glutamate, malate, and 100 μM ADP), cardiac mitochondria from diabetic patients show an increased sensitivity to Ca(2+)-induced mPTP opening compared with nondiabetic patients. This increased mPTP Ca(2+) sensitivity in diabetic heart mitochondria is accompanied by a substantially greater rate of mitochondrial H(2)O(2) emission under identical conditions, despite no differences in respiratory capacity under these conditions or mitochondrial enzyme content. Activity of the intrinsic apoptosis pathway mediator caspase-9 was greater in diabetic atrial tissue, whereas activity of the extrinsic pathway mediator caspase-8 was unchanged between groups. Furthermore, caspase-3 activity was not significantly increased in diabetic atrial tissue. These data collectively suggest that the myocardium in diabetic patients has a greater overall propensity for mitochondrial-dependent cell death, possibly as a result of metabolic stress-imposed changes that have occurred within the mitochondria, rendering them more susceptible to insults such as Ca(2+) overload. In addition, they lend further support to the notion that mitochondria represent a viable target for future therapies directed at ameliorating heart failure and other comorbidities that come with diabetes.

Renal artery fibromuscular dysplasia: Results of current surgical therapy

PURPOSE This retrospective review describes current surgical management of renal artery (RA) fibromuscular dysplasia (FMD) to define contemporary clinical characteristics and surgical results in patients over the age of 21 years. METHODS From January 1987 through March 1994, 40 consecutive adults with hypertension had operative RA repair of FMD at our center and form the basis of this report. From histologic and angiographic appearance, FMD was classified with regard to specific type, noting the presence of RA dissections, RA macroaneurysms and branch RA involvement. Associations between blood pressure response to operation and patient age, duration of hypertension, presence of extrarenal atherosclerosis, presence of branch renal artery disease, and primary or secondary procedure were examined. Clinical characteristics and blood pressure response in these contemporary patients were compared with the results reported from an earlier surgical series. RESULTS Unilateral RA repair was performed in 34 patients, and bilateral procedures were required in six patients. Branch renal artery repair was performed in 28 instances, including ex vivo RA repair in 11 patients. There were no perioperative or follow-up deaths; however, three RA grafts (7%) failed within 30 days of operation. Initial blood pressure response was considered cured in 33%, improved in 57%, and failed in 10%. Analysis demonstrated that patients older than 45 years of age had a significantly decreased rate of hypertension cure compared with younger patients; among patients younger than 45 years of age, duration of hypertension was inversely related to cure. Compared with earlier surgical series, our current group of patients was significantly older, with more frequent branch renal artery involvement and extrarenal atherosclerosis, and demonstrated decreased rate of hypertension cure. CONCLUSION A beneficial blood pressure response is currently observed in most selected patients after surgical correction of RA-FMD. Compared with earlier series, however, the present day patient differs in many respects, including a significantly decreased chance for hypertension cure after surgical repair.

Monoamine Oxidase is a Major Determinant of Redox Balance in Human Atrial Myocardium and is Associated With Postoperative Atrial Fibrillation

Background Onset of postoperative atrial fibrillation (POAF) is a common and costly complication of heart surgery despite major improvements in surgical technique and quality of patient care. The etiology of POAF, and the ability of clinicians to identify and therapeutically target high‐risk patients, remains elusive. Methods and Results Myocardial tissue dissected from right atrial appendage (RAA) was obtained from 244 patients undergoing cardiac surgery. Reactive oxygen species (ROS) generation from multiple sources was assessed in this tissue, along with total glutathione (GSHt) and its related enzymes GSH‐peroxidase (GPx) and GSH‐reductase (GR). Monoamine oxidase (MAO) and NADPH oxidase were observed to generate ROS at rates 10‐fold greater than intact, coupled mitochondria. POAF risk was significantly associated with MAO activity (Quartile 1 [Q1]: adjusted relative risk [ARR]=1.0; Q2: ARR=1.8, 95% confidence interval [CI]=0.84 to 4.0; Q3: ARR=2.1, 95% CI=0.99 to 4.3; Q4: ARR=3.8, 95% CI=1.9 to 7.5; adjusted Ptrend=0.009). In contrast, myocardial GSHt was inversely associated with POAF (Quartile 1 [Q1]: adjusted relative risk [ARR]=1.0; Q2: ARR=0.93, 95% confidence interval [CI]=0.60 to 1.4; Q3: ARR=0.62, 95% CI=0.36 to 1.1; Q4: ARR=0.56, 95% CI=0.34 to 0.93; adjusted Ptrend=0.014). GPx also was significantly associated with POAF; however, a linear trend for risk was not observed across increasing levels of the enzyme. GR was not associated with POAF risk. Conclusions Our results show that MAO is an important determinant of redox balance in human atrial myocardium, and that this enzyme, in addition to GSHt and GPx, is associated with an increased risk for POAF. Further investigation is needed to validate MAO as a predictive biomarker for POAF, and to explore this enzymes potential role in arrhythmogenesis.

Clinical Outcomes in Patients With Prolonged Intensive Care Unit Length of Stay After Cardiac Surgical Procedures

BACKGROUND Advances in critical care medicine have allowed for improved care of patients requiring prolonged intensive care unit length of stay (prICULOS) after cardiac operations, yet little is known regarding their eventual outcomes. The purpose of this study was to examine short- and long-term outcomes in patients undergoing cardiac operations with prICULOS. METHODS All cases of coronary artery bypass grafting (CABG), aortic valve, mitral valve, and combined CABG/valve surgical procedures performed at a single institution from July 2002 to July 2007 were identified. All-cause mortality in patients discharged alive from the hospital was determined until December 2007 through linkage with the Social Security Death Index. Patients who experienced intraoperative death or those with missing or invalid social security numbers were excluded. The definition of prICULOS was total ICULOS greater than 7 days. RESULTS A total of 3,478 patients met inclusion criteria. One hundred thirty-seven of three thousand four hundred seventy-eight patients (3.9%) experienced prICULOS. These patients were more likely to be older than 70 years (55.5% versus 30.5%; p<0.0001) and to have had recent myocardial infarction (28.5% versus 20.1%; p=0.02), previous cardiac operation (18.3% versus 6.9%; p<0.0001), and emergent status (9.5% versus 1.6%; p<0.0001). They experienced greater in-hospital mortality (37.2% versus 1.7%; p<0.0001) and those who were discharged alive had worse long-term survival (log-rank, p<0.0001). After risk adjustment, prICULOS emerged as a significant predictor of in-hospital death (odds ratio [OR] 20.9; 95% confidence interval [CI], 12.9-33.7) and decreased long-term survival (hazard ratio [HR] 2.9; 95% CI, 2.0-4.3). CONCLUSIONS Patients with prICULOS after cardiac operations have worse overall outcomes. These data may be used to inform these patients and their families of realistic expectations regarding their clinical course.

The Effect of Race and Chronic Obstructive Pulmonary Disease on Long-Term Survival after Coronary Artery Bypass Grafting

Background: Chronic obstructive pulmonary disease (COPD) is a known predictor of decreased long-term survival after coronary artery bypass grafting (CABG). Differences in survival by race have not been examined. Methods: A retrospective cohort study was conducted of CABG patients between 2002 and 2011. Long-term survival was compared in patients with and without COPD and stratified by race. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. Results: A total of 984 (20%) patients had COPD (black n = 182; white n = 802) at the time of CABG (N = 4,801). The median follow-up for study participants was 4.4 years. COPD was observed to be a statistically significant predictor of decreased survival independent of race following CABG (no COPD: HR = 1.0; white COPD: adjusted HR = 1.9, 95% CI = 1.7–2.3; black COPD: adjusted HR = 1.6, 95% CI = 1.1–2.2). Conclusion: Contrary to the expected increased risk of mortality among black COPD patients in the general population, a similar survival disadvantage was not observed in our CABG population.

Robotic mitral surgery: current and future roles.

Purpose of review Cardiac surgery, like other surgical fields, is evolving to a more minimally invasive approach. Robotic technology now allows complex mitral valve repairs to be carried out via small incisions with complete avoidance of a sternotomy. The purpose of this review is to assess the current role of robotics in the repair of the mitral valve, and to speculate as to what advances may be forthcoming. Recent findings Several groups have now confirmed that complex mitral valve repairs can be carried out robotically with early results comparable to open repair. Summary Endoscopic mitral repair has become a reality. With further technological advancements and continued clinical experience, this may become the standard approach for mitral valvuloplasty.

The Impact of Prior Percutaneous Coronary Intervention on Long-Term Survival after Coronary Artery Bypass Grafting

BACKGROUND Previous studies examining the influence of prior percutaneous coronary intervention (PCI) on long-term survival after coronary artery bypass grafting (CABG) have reported conflicting results. The purpose of this study was to further examine the influence of prior PCI on long-term survival after CABG at a large tertiary referral heart institute. METHODS Long-term survival between 1992 and 2011 was compared in non-emergent CABG cases with and without prior PCI. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. RESULTS A total of 2532 (19%) patients had prior PCI before CABG (n=13,354). The median follow-up for study participants was 8.1 years. The median survival for patients with and without prior PCI was 15 years and 14 years, respectively (p<0.0001). Long-term survival was similar between patients with and without prior PCI after adjusting for age, sex, race, hypertension, coronary artery disease severity, congestive heart failure, and prior stroke (adjusted HR=0.99, 95%CI=0.91-1.06). CONCLUSION Findings from outcomes research are important in the planning of appropriate postoperative patient care. Our study provides additional evidence that prior PCI is not a significant predictor of long-term survival after CABG.

Preoperative atrial fibrillation and long-term survival after open heart surgery in a rural tertiary heart institute

BACKGROUND Preoperative atrial fibrillation (AF) is associated with increased morbidity and mortality after open heart surgery. However, the impact of preoperative AF on long-term survival after open heart surgery has not been widely examined in rural populations. Patients from rural regions are less likely to receive treatment for cardiac conditions and to have adequate medical insurance coverage. OBJECTIVE To examine the influence of preoperative AF on long-term survival following open heart surgery in rural eastern North Carolina. METHODS Long-term survival was compared in patients with and without preoperative AF after coronary artery bypass grafting (CABG) and CABG plus valve (CABG + V) surgery between 2002 and 2011. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. RESULTS The study population consisted of 5438 patients. A total of 263 (5%) patients had preoperative AF. Preoperative AF was an independent predictor of long-term survival (open heart surgery: adjusted HR = 1.6, 95% CI = 1.3-2.0; CABG: adjusted HR = 1.6, 95% CI = 1.3-2.1; CABG + V: adjusted HR = 1.6, 95% CI = 1.1-2.3). CONCLUSION Preoperative AF is an important predictor of long-term survival after open heart surgery in this rural population.

Three-Dimensional Echocardiographic Features of Unicuspid Aortic Valve Stenosis Correlate with Surgical Findings

A unicuspid aortic valve (UAV) is a rare congenital defect that may manifest clinically as severe aortic stenosis or regurgitation in the third to fifth decade of life. This report describes two cases of UAV stenosis in adult patients diagnosed by transesophageal echocardiography (TEE). The utility of three‐dimensional TEE in confirming valve morphology and its relevance to transcatheter valve replacement are discussed.