Richard C. Cook

Functional Analysis of the Chromosome 9p21.3 Coronary Artery Disease Risk Locus

Objectives—We have investigated the functional significance of conserved sequences within the 9p21.3 risk locus for coronary artery disease (CAD) and determined the relationship of 9p21.3 to expression of ANRIL and to whole genome gene expression. Methods and Results—We demonstrate that a conserved sequence within the 9p21.3 locus has enhancer activity and that the risk variant significantly increases reporter gene expression in primary aortic smooth muscle cells. Whole blood RNA expression of the short variants of ANRIL was increased by 2.2-fold whereas expression of the long ANRIL variant was decreased by 1.2-fold in healthy subjects homozygous for the risk allele. Expression levels of the long and short ANRIL variants were positively correlated with that of the cyclin-dependent kinase inhibitor, CDKN2B (p15) and TDGF1 (Cripto), respectively. Relevant to atherosclerosis, genome-wide expression profiling demonstrated upregulation of gene sets modulating cellular proliferation in carriers of the risk allele. Conclusion—These findings are consistent with the hypothesis that the 9p21.3 risk allele contains a functional enhancer, the activity of which is altered in carriers of the risk allele. 9p21.3 may promote atherosclerosis by regulating expression of ANRIL, which in turn is associated with altered expression of genes controlling cellular proliferation pathways.

Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation

Three patients with diffuse large B-cell type of post-transplant lymphoproliferative disease after lung transplantation were treated with rituximab, an anti-CD20 monoclonal antibody. Treatment resulted in two complete remissions and one non-response.

Prophylactic Intravenous Magnesium Sulphate in Addition to Oral β-Blockade Does Not Prevent Atrial Arrhythmias After Coronary Artery or Valvular Heart Surgery

Background— Atrial arrhythmias (AA) are an important cause of morbidity after cardiac surgery. Efforts at prevention of postoperative AA have been suboptimal. Perioperative beta-blocker administration is the standard of care at many centers. Although prophylactic administration of magnesium sulfate (MgSO4) has been recommended, review of all previously published trials of MgSO4 reveals conflicting results. This study was designed to address methodological shortcomings from previous studies and is the largest randomized, placebo-controlled trial of intravenous (IV) MgSO4 for the prevention of AA after coronary artery bypass grafting or cardiac valvular surgery. Methods and Results— A total of 927 nonemergent cardiac surgery patients were stratified into 2 groups: isolated coronary artery bypass grafting (n=694), or valve surgery with or without coronary artery bypass grafting (n=233), and randomized to receive either 5g IV MgSO4 or placebo on removal of the cross-clamp, followed by daily 4-hour infusions, from postoperative day 1 until postoperative day 4. All patients were treated according to an established oral &bgr;-blocker protocol. Postoperative serum Mg levels were checked and standard of care was to administer IV MgSO4 for low serum levels. The primary end point was AA lasting ≥30 minutes or requiring treatment for hemodynamic compromise. There were no differences in the incidence of AA between patients who received IV MgSO4 or placebo (26.4% versus 24.3%, respectively). The results were similar when broken down according to stratified groups. Conclusions— In patients treated with a protocol for postoperative oral &bgr;-blocker after nonemergent cardiac surgery, the addition of prophylactic IV MgSO4 did not reduce the incidence of AA.

Traction injury during minimally invasive harvesting of the saphenous vein is associated with impaired endothelial function

OBJECTIVE Many methods of minimally invasive surgical harvesting of the great saphenous vein have been developed because of the morbidity related to the long skin incision after traditional (open) great saphenous vein harvesting. One such method involves the use of multiple small incisions separated by 10- to 15-cm skin bridges through which the saphenous vein is harvested. We hypothesized that this method of saphenous vein harvesting might subject the saphenous vein to considerable traction forces, resulting in impaired endothelial cell function. METHODS Four-millimeter great saphenous vein segments were obtained from patients undergoing elective coronary artery bypass graft surgery. Group A (minimally invasive surgery) consisted of 23 rings from 20 patients (age, 65.8 +/- 11.1 years, mean +/- SD). Group B (open harvesting) consisted of 33 rings from 8 patients (age, 69.8 +/- 8.6 years). All great saphenous vein segments were undistended and were used within 24 hours of harvesting. Isometric tension experiments were performed on each ring of the great saphenous vein by using a force-displacement transducer to measure the force of contraction in grams. Measurements included developed force after exposure to high-potassium depolarizing solution and 50 micromol/L phenylephrine and decrease in force of contraction (relaxation) after exposure to 1 and 10 micromol/L acetylcholine. RESULTS There were no differences between the minimally invasive surgery and open harvesting groups in their responses to high-potassium depolarizing solution or phenylephrine: high-potassium depolarizing solution, contractions of 4.26 +/- 0.72 g (mean +/- SEM) and 3.95 +/- 0.38 g, respectively (P =.70); phenylephrine, contractions of 3.49 +/- 0.63 g and 2.73 +/- 0.39 g, respectively (P =.41). There was no net relaxation in segments from the minimally invasive surgery group after exposure to 1.0 or 10 micromol/L acetylcholine. In contrast, rings from the open harvesting group demonstrated relaxation of -0.41 +/- 0.07 g and -0.32 +/- 0.09 g after exposure to 1.0 and 10 micromol/L acetylcholine, respectively. CONCLUSIONS In undistended saphenous vein segments isolated from patients undergoing minimally invasive surgical and open techniques of harvesting, there was no acetylcholine-mediated endothelium-dependent relaxation in the minimally invasive surgery group. Therefore harvesting of the great saphenous vein through multiple small incisions might result in endothelial dysfunction, possibly caused by traction injury.

Effect of Immunosuppressive Therapy, Serum Creatinine, and Time After Transplant on Plasma Total Homocysteine in Patients Following Heart Transplantation

OBJECTIVES To determine the prevalence of hyperhomocysteinemia in heart transplant recipients, and to assess the effect of renal function and immunosuppressive medication on total plasma homocysteine (tHcy) levels. BACKGROUND Elevated plasma tHcy levels have been associated with increased risk of mortality in patients with established coronary artery disease. Graft coronary disease is the major cause of morbidity and mortality in long-term survivors of heart transplantation. The tHcy has been found to be elevated in heart and kidney transplant patients, however, the etiologic factors have not been clearly delineated. METHODS The study group consisted of 70 heart transplant recipients (56 males, 14 females, mean age 53+/-13 years [range 17 to 69 years]). The parameters evaluated were fasting tHcy level, cumulative cyclosporine (CyA) dose, cumulative prednisone dose, serum creatinine, and time from transplantation. RESULTS The mean fasting tHcy level was 20.5+/-10.2 micromol/L (range 5.2 to 59.0 micromol/L). Sixty-one (87%) had fasting tHcy levels greater than the seventy-fifth percentile of the general population (>12.2 micromol/L in males, and >10.1 micromol/L in females). There was no difference in mean post-transplant tHcy level between patients with and without coronary artery disease before transplantation (21.0+/-11.4 vs. 19.3+/-6.7 micromol/L, p = NS). There were significant relationships between the tHcy level and the serum creatinine (r = 0.76, p<0.001), and cumulative exposure to CyA (r = 0.31, p<0.01). There were no significant relationships between tHcy levels and cumulative prednisone dose, or time from transplantation. CONCLUSIONS Fasting tHcy levels are markedly elevated in the majority of patients following heart transplantation, and are correlated to serum creatinine. Further studies are needed to determine other etiologic factors of elevated tHcy following heart transplantation, and to examine the impact of elevated tHcy on clinical outcomes.

Prophylactic Magnesium Does Not Prevent Atrial Fibrillation After Cardiac Surgery: A Meta-Analysis

BACKGROUND Atrial fibrillation (AF) is a common complication after cardiac surgery. Previous meta-analyses have concluded prophylactic magnesium (Mg) prevents postoperative AF, although with a significant degree of heterogeneity among included studies. Recently, the largest randomized, controlled trial published to date (but not included in prior published meta-analyses) concluded that Mg sulfate is not protective against AF after cardiac surgery. The objective of this study was to conduct a new meta-analysis including the results of new Mg trials not included in previous meta-analyses, and to investigate the potential causes and effects of significant heterogeneity observed in previously published meta-analyses. METHODS The MEDLINE, EMBASE, and CENTRAL databases were searched for relevant studies published up to March 31, 2012. Pooled odds ratios of occurrence of AF were calculated using random-effects models. Heterogeneity was assessed as significant using the I(2) statistic. RESULTS Eggers and funnel plots demonstrated biases toward stronger and more positive effects of Mg in smaller studies. When the analysis was restricted to the five double-blind, intention-to-treat studies in which AF was the primary outcome (Mg arm, n = 710; control arm, n = 713), Mg did not prevent postoperative AF (odds ratio, 0.94; p = 0.77), and heterogeneity was no longer significant (I(2) = 40%; p = 0.15). CONCLUSIONS This meta-analysis, restricted to well-conducted trials, does not support the prophylactic use of Mg to prevent AF after cardiac surgery. Prior meta-analyses have drawn conclusions from simple random-effects models with significant heterogeneity. However, this approach leaves important residual heterogeneity and overemphasizes the strongly positive effects of smaller studies.

A debate on the value and necessity of clinical trials in surgery

In the current era of evidence-based medicine there is increasing demand for randomized clinical trials (RCTs) in surgery. Unfortunately, many unique aspects of surgery make RCTs difficult to implement. This article is a debate that explores the motion that clinical trials in surgery are both useful and necessary.

Differences in myocardial PTEN expression and Akt signalling in type 2 diabetic and nondiabetic patients undergoing coronary bypass surgery.

Objective  Patients with diabetes experience increased cardiovascular complications after cardiac surgery. Hyperglycaemia predicts increased mortality after myocardial infarction and may influence cardiovascular risk in humans. Impaired prosurvival phosphatase and tensin homologue on chromosome 10 (PTEN)‐Akt signalling could be an important feature of the diabetic heart rendering it resistant to preconditioning. This study was designed to evaluate for differences and relationships of myocardial PTEN‐Akt‐related signalling and baseline glycaemic control marker in type 2 diabetic and nondiabetic patients undergoing coronary artery bypass surgery.

Modeling the dynamic behavior of a shape memory alloy actuated catheter

In this paper we investigate the transient behavior of a simple active catheter: a central tube actuated by a single nitinol tendon enclosed by an outer sleeve. Dynamic models are developed to characterize the transient behavior and optimize the design of an experimental prototype. The bending mechanics are derived using a circular arc model and are experimentally validated. Nitinol actuation is described using the Seelecke–Muller–Achenbach model for single-crystal shape memory alloys using experimentally determined parameters. The dynamic characteristics of this active catheter system are simulated and compared with experimental results. Joule heating is used to generate tip deflections, which are computed in real time using a dual-camera imaging system. The effects of outer sleeve thickness on heat transfer and transient response characteristics are studied.

A Dynamic Heart System to Facilitate the Development of Mitral Valve Repair Techniques

Objective: The development of a novel surgical tool or technique for mitral valve repair can be hampered by cost, complexity, and time associated with performing animal trials. A dynamically pressurized model was developed to control pressure and flowrate profiles in intact porcine hearts in order to quantify mitral regurgitation and evaluate the quality of mitral valve repair. Methods: A pulse duplication system was designed to replicate physiological conditions in explanted hearts. To test the capabilities of this system in measuring varying degrees of mitral regurgitation, the output of eight porcine hearts was measured for two different pressure waveforms before and after induced mitral valve failure. Four hearts were further repaired and tested. Measurements were compared with echocardiographic images. Results: For all trials, cardiac output decreased as left ventricular pressure was increased. After induction of mitral valve insufficiencies, cardiac output decreased, with a peak regurgitant fraction of 71.8%. Echocardiography clearly showed increases in regurgitant severity from post-valve failure and with increased pressure. Conclusions: The dynamic heart model consistently and reliably quantifies mitral regurgitation across a range of severities. Advantages include low experimental cost and time associated with each trial, while still allowing for surgical evaluations in an intact heart.