Menachem Matsa

Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion

OBJECTIVES The purpose of this study was to examine whether tumor necrosis factor-alpha (TNF-alpha) is released directly from the ischemic myocardium undergoing reperfusion. BACKGROUND Tumor necrosis factor-alpha is a protein hormone produced by systemic leukocytes (primarily by activated macrophages). It has been implicated as a systemic mediator in the development of septic shock and other pathologic conditions. Serum TNF-alpha has also been detected in a variety of cardiac disease states and after myocardial ischemia-reperfusion injury. METHODS Nine isolated rat hearts undergoing 30 min of perfusion, followed by warm cardioplegic arrest, 1 h of global ischemia and 30 min of reperfusion, were investigated using the modified Langendorff model. RESULTS Significant amounts of TNF-alpha (752 +/- 212 pmol/ml) were detected in the effluent during the first minute of reperfusion. Tumor necrosis factor-alpha levels correlated with postischemic deterioration in peak systolic pressures (r = 0.7882, p = 0.012), dP/dt max (r = 0.6795, p = 0.044), time-pressure integral (r = 0.7661, p = 0.0016) and postischemic creatine kinase levels (r = 0.8367, p = 0.005). The deterioration in coronary flow, however, was inversely correlated with TNF-alpha levels (r = -0.7581, p = 0.018). CONCLUSIONS To our knowledge, this study is the first to suggest that the isolated rat myocardium synthesizes and releases TNF-alpha in response to ischemia and reperfusion, which directly correlates with the postischemic deterioration in myocardial mechanical performance and the amount of cellular necrosis.

Anti–Tumor Necrosis Factor-Alpha Improves Myocardial Recovery After Ischemia and Reperfusion ☆

OBJECTIVES This study sought to assess the importance of locally released or paracrine myocardial tumor necrosis factor-alpha (TNF-alpha) in the evolution of postischemic myocardial dysfunction and to use immunohistochemical studies to localize TNF-alpha within the myocardium. BACKGROUND TNF-alpha is implicated as a systemic mediator in the development of myocardial ischemia-reperfusion injury by promoting leukocyte myocardial infiltration, and it has been shown to originate from noncardiac peripheral mononuclear cells. We have recently documented in a blood-free environment the release of TNF-alpha from the ischemic-reperfused myocardium. METHODS Isolated rat hearts undergoing 1 h of global cardioplegia-induced ischemia and 30 min of reperfusion were investigated with use of the modified Langendorff model. Hearts were randomly divided into three subgroups: group A, control group; and groups B and C, isolated hearts receiving cardioplegic solution containing monoclonal hamster antimurine TNF-alpha antibodies (group B) or hamster IgG (group C). RESULTS Significant amounts of TNF-alpha were detected in group A and group C effluent on 1 min of reperfusion (752 +/- 212 and 958 +/- 409 pmol/ml, respectively). However, in group B, TNF-alpha was below detectable levels. In this group, postischemic left ventricular peak systolic pressures, first derivative of the rise in left ventricular pressure (dP/dtmax), pressure-time integral, coronary flow and O2 consumption improved (analysis of variance [ANOVA] p < 0.0001 for all variables) compared with values in groups A and C; creatine kinase levels decreased (p < 0.005); and myocardial structure was preserved. Immunohistochemical staining localized TNF-alpha to cardiac myocytes and to endothelial cells. CONCLUSIONS Anti-TNF-alpha neutralizes local TNF-alpha release from cardiac myocytes after ischemia and improves myocardial recovery during reperfusion, indicating that postischemic paracrine TNF-alpha release plays an active role in myocardial dysfunction.

Sternal wound infections in patients after coronary artery bypass grafting using bilateral skeletonized internal mammary arteries.

OBJECTIVES This study evaluated the risks of sternal wound infections in patients undergoing myocardial revascularization using bilateral skeletonized internal mammary arteries (IMAs). BACKGROUND The skeletonized IMA is longer than the pedicled one, thus providing the cardiac surgeon with increased versatility for arterial myocardial revascularization without the use of vein grafts. It is isolated from the chest wall gently with scissors and silver clips, and no cauterization is employed. Preservation of collateral blood supply to the sternum and avoidance of thermal injury enable more rapid healing and decrease the risk of sternal wound infection. METHODS From April 1996 to August 1997, 545 patients underwent arterial myocardial revascularization using bilateral skeletonized IMAs. The right gastroepiploic artery was used in 100 patients (18%). The average age of the patients was 65 years; 431 (79%) were men and 114 (21%) were women; 179 (33%) were older than 70 years of age; 166 (30%) were diabetics. The average number of grafts was 3.2 per patient. RESULTS The 30-day operative mortality rate was 2% (n = 11). There were six perioperative infarcts (1.1%) and six strokes (1.1%); 9 patients had sternal infection (1.7%) and 15 (2.8%) had superficial infection. Risk factors for sternal infection were chronic obstructive pulmonary disease and emergency operation. Superficial sternal wound infections were more common in women and in patients with chronic obstructive pulmonary disease, renal failure, or peripheral vascular disease. The 1-year actuarial survival rate was 97%. Two of the six late deaths were not cardiac-related. Late dehiscence occurred in three patients (0.6%). The death rate (early and late) of patients with any sternal complication was higher than that of patients without those complications (33% vs. 2.7%). CONCLUSIONS Routine arterial myocardial revascularization using bilateral skeletonized IMAs is safe, and postoperative morbidity and mortality rates are low, even in elderly patients and those with diabetes. Chronic obstructive pulmonary disease and emergency operations were found to be associated with an increased risk of sternal infections, and the authors recommend avoiding the use of bilateral skeletonized IMAs in patients with these preoperative risk factors.

Technical aspects of double-skeletonized internal mammary artery grafting

BACKGROUND Bilateral internal mammary artery (IMA) grafting is performed to provide complete arterial myocardial revascularization with the intention of decreasing postoperative return of angina and the need for reoperation. We present here technical views of double-skeletonized IMA grafting, and evaluate its clinical outcome. METHODS Skeletonized IMA is harvested gently with scissors and silver clips, without use of cauterization, and embedded in a small syringe filled with papaverine. Three strategies for arterial revascularization were employed in 762 consecutive patients: (1) the cross arrangement (242 patients, 32%), where the in situ right internal mammary artery (RIMA) is used for the left anterior descending artery (LAD), in situ left internal mammary artery (LIMA) to circumflex marginal branches and the gastroepiploic artery for the right coronary artery (RCA); (2) the composite arrangement (476 patients, 62%), where free IMA is attached end-to-side to the other in situ IMA; and (3) the natural arrangement (44 patients, 6%), where the in situ RIMA is connected to the RCA and in situ LIMA to LAD. Mean age was 66 years (range 30 to 92). Two hundred ninety-two patients (38%) were older than 70, and 229 (30%) were diabetic. RESULTS Operative mortality was 2.5% (n = 19). The mortality of urgent and elective cases was 1.2% (8 of 663), and that of emergency operation was 11% (11 of 99). There were 9 (1.2%) perioperative myocardial infarctions, and 10 patients (1.3%) sustained strokes. Sternal wound infection occurred in 14 (1.8%). CONCLUSIONS The three strategies described here provide the surgeon with the versatility required for arterial revascularization with bilateral IMAs in most patients referred for coronary artery bypass grafting.

Emergency myocardial revascularization for acute myocardial infarction: survival benefits of avoiding cardiopulmonary bypass

OBJECTIVE Emergency coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI) is associated with increased operative mortality. It has been suggested that this mortality might be reduced by performing the operation without cardiopulmonary bypass (CPB). METHODS Between January 1992 and April 1998, 77 patients underwent emergency CABG within 48 h of AMI. Thirty seven were operated on with CPB, and 40 without CPB. The two groups were similar regarding age, gender, left-ventricular ejection fraction (EF) and preoperative use of intra-aortic balloon pump (IABP; 50%). The mean number of grafts/patient was 3 in the CPB group, and 1.9 in the No-CPB group (P<0.0001). RESULTS Operative mortality in the CPB group was 24% (nine of 37) compared to 5% (two of 40) without CPB (P=0.015). Follow-up ranged between 6 and 66 months. There were no late deaths in the CPB group compared to nine (22%) in the No-CPB group (P<0.0066). Patients operated on with CPB had lower rates of recurrent angina (0 versus 15%; P=0.04) and re-interventions (0 versus 15%; P=0.04). CONCLUSIONS Our experience suggests that CABG without CPB is the preferred method of myocardial revascularization, due to the fact that it carries lower mortality than CABG with CPB. The trade-off includes increased rates of recurrent angina, re-interventions and late mortality.

Arterial myocardial revascularization with in situ crossover right internal thoracic artery to left anterior descending artery.

BACKGROUND The extra length obtained by skeletonizing the internal thoracic arteries (ITAs) enables versatile use of in situ bilateral ITAs for coronary artery bypass grafting, as the longer skeletonized right ITA more easily reaches the anastomotic site on the left anterior descending coronary artery. METHODS Between April 1996 and November 1999, 365 consecutive patients underwent revascularization with bilateral in situ ITAs (29% of 1,250 grafting procedures performed with both ITAs in our department during this period). The right ITA was routed anterior to the aorta to graft the left anterior descending coronary artery, and the in situ left ITA was used to graft circumflex branches. Right coronary artery branches were grafted with right gastroepiploic artery or saphenous vein graft. The right ITA crossed the midline above the aorta at the most cranial point to avoid damage in case of a repeat sternotomy in the future. RESULTS The operative mortality rate was 2.2% (8 patients). Postoperative morbidity included seven strokes (1.9%), eight sternal wound infections (2.2%), and four perioperative myocardial infarctions (1.1%). Follow-up (6 to 49 months) of 97% of hospital survivors showed a return of angina in 3%. Postoperative coronary angiography (22 patients) revealed a 95% patency rate of both ITAs. One-year and 4-year survival rates (Kaplan-Meier) were 95% and 92.4%, respectively. Important predictors of an early unfavorable event were chronic obstructive pulmonary disease, old age (> or = 70 years), emergency operation, and diabetes. Chronic obstructive pulmonary disease was the only independent predictor of sternal wound infection (odds ratio, 15; 95% confidence interval, 2.8 to 80). It also predicted decreased late survival (hazard ratio, 8.3; 95% confidence interval, 3 to 21.5). CONCLUSIONS With skeletonized dissection of ITAs, the right ITA easily reaches the left anterior descending coronary artery for left-sided arterial revascularization with in situ bilateral ITAs. This procedure is safe, but we recommend avoiding its use in patients with chronic obstructive pulmonary disease.

Routine use of bilateral skeletonized internal mammary arteries for myocardial revascularization

BACKGROUND Complete arterial myocardial revascularization without the use of saphenous veins grafts was primarily performed on selected patient populations such as the young and nondiabetic. In a recently developed surgical technique, the internal mammary artery is dissected gently as a longer skeletonized artery, providing greater versatility for complete arterial revascularization, without saphenous veins grafts. METHODS We prospectively evaluated the impact of the routine use of double skeletonized internal mammary artery in 472 patients who underwent coronary artery bypass grafting between April 1996 and June 1997. Their average age was 65 years (30 to 87 years), 383 (83%) were men, and 89 (17%) women. One hundred sixty-nine (36%) of the patients were older than 70 years, and 145 (31%) were diabetic. The average number of grafts was 3.2 per patient (two to six grafts). RESULTS Operative mortality was 1.7% (n = 8). The mortality of urgent and elective patients was 0.7% (3 of 410 patients), and that of emergency operations was 8.1% (5 of 62 patients; p < 0.01). There were three (0.6%) perioperative infarcts, and 6 patients (1.3%) sustained strokes. Sternal wound infection occurred in 8 patients (1.7%). Postoperative follow-up (1 to 25 months) was available in 462 patients (99%). Two-year actuarial survival was 96.8%, and 92% of the surviving patients are well and free of angina. Neither diabetes mellitus nor old age (>70 years) were significant independent predictors of any early or late untoward events. None of the 70 diabetic patients more than 65 years of age developed sternal wound infection. Chronic lung disease was found to be the only independent predictor for sternal infections. CONCLUSIONS Routine use of bilateral skeletonized internal mammary artery is a safe replacement for the current myocardial revascularization technique even in the old and diabetic patients.

Effects of an Angiotensin II Antagonist on Ischemic and Nonischemic Isolated Rat Hearts

BACKGROUND Increasing evidence suggests that a locally integrated or intramyocardial renin-angiotensin system plays a significant role in ischemia-reperfusion injury. We evaluated the effects of losartan, an angiotensin II type 1 receptor blocking agent, on ischemic and nonischemic isolated rat hearts. METHODS Using the modified Langendorff model, hearts were perfused with either low or high doses of losartan (18.2 mmol/L or 182.2 mmol/L, respectively) or with saline added to Krebs-Henseleit solution during phase I of the study. During phase II, hearts were exposed to a 60-minute period of global ischemia. Ischemic arrest was induced with warm cardioplegic solution (KCl, 16 mEq/L) containing either high-dose losartan (182.2 mmol/L) or Krebs-Henseleit solution only. RESULTS During phase I of the study, no statistically significant differences were observed between the low-dose losartan group and the control group. However, hearts treated with high-dose losartan demonstrated an increase in peak systolic pressure, maximum first derivative of pressure, pressure-time integral, coronary flow, and oxygen consumption (p < 0.0001). During phase II, hearts treated with losartan showed a significantly better recovery on reperfusion, as reflected by better contractility (p < 0.001), higher oxygen consumption (p < 0.001), higher coronary flow (p < 0.0001), and lower creatine phosphokinase levels (41.1 +/- 1.7 versus 73.3 +/- 5.6 U/L; p < 0.001). CONCLUSIONS High doses of losartan have a positive inotropic effect on normally perfused hearts. Given in cardioplegic solution, the drug has a significant protective effect on ischemic isolated rat hearts.

Interaction between paracrine tumor necrosis factor-alpha and paracrine angiotensin II during myocardial ischemia.

OBJECTIVES The purpose of this study was to explore interactions between paracrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha) during myocardial ischemia. BACKGROUND Ischemic myocardium releases significant amounts of TNF-alpha. This paracrine release correlated with postischemic myocardial injury. Other studies showed myocardial protection obtained by the use of angiotensin-converting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor antagonist losartan after ischemia. The possibility that these agents decrease TNF-alpha synthesis has not yet been investigated. METHODS Using the modified Langendorff model, isolated rat hearts underwent either 90 min of nonischemic perfusion (control group) or 1 h of global cardioplegic ischemia. In both groups, either captopril (360 micromol/liter) or losartan (182.2 micromol/liter) was added before ischemia. The hearts were assayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-alpha levels. In addition, cardiac myocytes were incubated in cell culture with Ang-II. RESULTS After ischemia, TNF-alpha mRNA expression intensified from 0.63 +/- 0.06 (control group) to 0.92 +/- 0.12 (p < 0.03), and effluent TNF-alpha levels were 711 +/- 154 pg/ml. The TNF-alpha mRNA expression declined to 0.46 +/- 0.07 (p < 0.01) and 0.65 +/- 0.08 (p < 0.02) in captopril- and losartan-treated hearts, respectively. Effluent TNF-alpha was below detectable levels. Concentrations of TNF-alpha in supernatants of incubated cardiac myocytes treated with 10 and 50 nmol/liter of Ang-II were 206.0 +/- 47.0 pg/ml and 810 +/- 130 pg/ml, respectively (p < 0.004). When pretreated with 700 micromol/liter of losartan, TNF-alpha was below detectable levels. CONCLUSIONS This study presents an original explanation for previously reported myocardial protection after ischemia, obtained by the use of captopril and losartan. These drugs reduce TNF-alpha synthesis, providing strong evidence of active interactions between paracrine TNF-alpha and Ang-II in the evolution of the ischemic cascade.

Composite arterial grafting with double skeletonized internal thoracic arteries

OBJECTIVES Composite arterial grafting is a surgical technique for arterial myocardial revascularization, in which free arterial conduits are proximally anastomosed end-to-side to an intact internal thoracic artery (ITA). This report describes technical aspects and results of composite grafting using bilateral skeletonized ITAs. METHODS From April 1996 to February 1999, 1057 patients underwent coronary artery bypass grafting (CABG) using bilateral skeletonized internal thoracic arteries. In 600 of them (57%), composite arterial grafting was performed. There were 452 men and 148 women. The mean age was 69 +/- 7 years. Two-hundred and six patients (34%) were diabetics, 84 (14%) had severe left ventricular dysfunction (ejection fraction of < 35%), and 26 (4.3%) underwent emergency operations. In 574 patients, the right ITA was used as a free graft connected to the in-situ left ITA. In 26, the free left ITA was attached to the in-situ right ITA, and in 38, mini-composite grafts (free distal left ITA on the left ITA, or free distal right ITA on the right ITA) were constructed. The average number of grafts was 3.0/patient (range, 2--6). RESULTS The operative mortality was 2.8% (n = 17), and there were ten (1.7%), deep sternal wound infections. The mean follow-up was 25 months (range, 14--36 months). The 3-year survival was 92.5%. Ninety-seven percent of the surviving patients were angina-free. CONCLUSIONS We currently perform this surgery routinely in most patients referred for CABG, and regard bilateral skeletonized internal thoracic arteries as the most appropriate arterial conduits for the composite technique.