Steven C. Hendrickson

Free fatty acid metabolism during myocardial ischemia and reperfusion.

Long chain free fatty acids (FFA) are the preferred metabolic substrates of myocardium under aerobic conditions. However, under ischemic conditions long chain FFA have been shown to be harmful both clinically and experimentally. Serum levels of free fatty acids frequently are elevated in patients with myocardial ischemia. The proposed mechanisms of the detrimental effects of free fatty acids include: (1) accumulation of toxic intermediates of fatty acid metabolism, such as long chain acyl-CoA thioesters and long chain acylcarnitines, (2) inhibition of glucose utilization, particularly glycolysis, during ischemia and/or reperfusion, and (3) uncoupling of oxidative metabolism from electron transfer. The relative importance of these mechanisms remains controversial. The primary site of FFA-induced injury appears to be the sarcolemmal and intracellular membranes and their associated enzymes. Inhibitors of free fatty acid metabolism have been shown experimentally to decrease the size of myocardial infarction and lessen postischemic cardiac dysfunction in animal models of regional and global ischemia. The mechanism by which FFA inhibitors improve cardiac function in the postischemic heart is controversial. Whether the effects are dependent on decreased levels of long chain intermediates and/or enhancement of glucose utilization is under investigation. Manipulation of myocardial fatty acid metabolism may prove beneficial in the treatment of myocardial ischemia, particularly during situations of controlled ischemia and reperfusion, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. (Mol Cell Biochem 166: 85-94, 1997)

Sternal plating for the treatment of sternal nonunion

BACKGROUND Sternal nonunion, defined as sternal pain with clicking, instability, or both for more than 6 months in the absence of infection, is an uncommon complication of median sternotomy. Nonunion is frequently complicated by the presence of multiple transverse fractures, which make simple rewiring inadequate. METHODS Six patients with debilitating pain secondary to sternal nonunion were treated with the technique of sternal plating between 1989 and 1995. RESULTS Sternal plating corrected sternal instability and provided excellent pain relief in all 6 patients. All patients reported an improved quality of life and were able to resume recreational activities. Two patients have had plate removal for late bursa formation. Sternal healing was complete in both instances. CONCLUSIONS Sternal plating, which is based on the tension-band principle, is an effective treatment of sternal nonunion. The technique is applicable to both simple and complex nonunions. The stainless steel plates resist bending stresses, and the cortical bone resists compressive forces. The technique requires minimal dissection of the posterior sternal border, is not circumferential, and provides secure sternal approximation.

Intraoperative identification of cardiac patients at risk to develop postoperative atrial fibrillation.

Postoperative atrial fibrillation (AF) is a complication occurring in 11% to 36% of patients after cardiac operations, which results in increased morbidity and hospital costs. A new electrophysiologic screening test was developed to identify those patients at risk for development of postoperative AF. The test was validated in 50 patients (43 men and 7 women) with a mean age of 59.6 +/- 1.3 years who underwent coronary artery bypass grafting with or without other cardiac surgical procedures. After aortic and venous cannulation, but before initiation of bypass, the mid-right atrium was stimulated with a bipolar probe at 25 microA for 3 seconds. Alternating current was increased by 25 microA until AF was induced or up to a maximum of 200 microA. Postoperative AF occurred in 18 patients (36%), 17 of whom had inducible AF (sensitivity = 0.94). Of the remaining 32 AF-free patients, 13 had negative tests (specificity = 0.41). Age and sex were not factors affecting inducibility, although patients who developed AF were older than those who were AF free (63.6 versus 57.3 years, p = 0.02). Length of stay in the intensive care unit was longer for those with postoperative AF than for AF-free patients (3.6 versus 1.9 days, p = 0.02). The negative predictive value of the test was 0.93, and the positive value was 0.47. These data show that this new intraoperative technique may be used to identify patients at risk for postoperative AF. Prophylactic therapy can therefore be directed to only those patients at risk for postoperative AF.

A Method for Perfusion of the Leg During Cardiopulmonary Bypass via Femoral Cannulation

Minimally invasive approaches for cardiac operations currently are gaining increasing attention. Some of these approaches require cannulation of the femoral vessels for cardiopulmonary bypass. A potential complication of femoral cannulation is ischemic injury to the lower extremity in some cases that require long bypass times. To minimize this risk we have begun cannulating the common femoral artery distally, as well as proximally. This technique perfuses the leg for the duration of cardiopulmonary bypass, and it can be accomplished with minimal increases in cost and operative time.

Regulation of carbohydrate and fatty acid utilization by L-carnitine during cardiac development and hypoxia

This study is designed to investigate whether substrate preference in the myocardium during the neonatal period and hypoxia-induced stress is controlled intracellularly or by extracellular substrate availability. To determine this, the effect of exogenous L-carnitine on the regulation of carbohydrate and fatty acid metabolism was determined during cardiac stress (hypoxia) and during the postnatal period. The effect of L-carnitine on long chain (palmitate) and medium chain (octonoate) fatty acid oxidation was studied in cardiac myocytes isolated from less than 24 h old (new born; NB), 2 week old (2 week) and hypoxic 4 week old (HY) piglets. Palmitate oxidation was severely decreased in NB cells compared to those from 2 week animals (0.456 ± 0.04 vs. 1.207 ± 0.52 nmol/mg protein/30 min); surprisingly, cells from even older hypoxic animals appeared shifted toward the new born state (0.695 ± 0.038 nmol/mg protein/30 min). Addition of L-carnitine to the incubation medium, which stimulates carnitine palmitoyl-transferase I (CPTI) accelerated palmitate oxidation 3 fold in NB and approximately 2 fold in HY and 2 week cells. In contrast, octanoate oxidation which was greater in new born myocytes than in 2 week cells, was decreased by L-carnitine suggesting a compensatory response. Furthermore, oxidation of carbohydrates (glucose, pyruvate, and lactate) was greatly increased in new born myocytes compared to 2 week and HY cells and was accompanied by a parallel increase in pyruvate dehydrogenase (PDH) activity. The concentration of malonyl-CoA, a potent inhibitor of CPTI was significantly higher in new born heart than at 2 weeks. These metabolic data taken together suggest that intracellular metabolic signals interact to shift from carbohydrate to fatty acid utilization during development of the myocardium. The decreased oxidation of palmitate in NB hearts probably reflects decreased intracellular L-carnitine and increased malonyl-CoA concentrations. Interestingly, these data further suggest that the cells remain compliant so that under stressful conditions, such as hypoxia, they can revert toward the neonatal state of increased glucose utilization.

Experimental aortocoronary saphenous vein graft function after mechanical cardiac massage with the Anstadt Cup

Direct mechanical ventricular actuation (DMVA) using the Anstadt Cup can achieve total circulatory support by massaging the fibrillating, asystolic, or failing heart. The device does not contact the blood or cause significant myocardial trauma. The purpose of this study was to assess the functional integrity of saphenous vein grafts (SVGs) subjected to DMVA vs cardiopulmonary bypass (CPB). Human SVGs were used to bypass the ligated left anterior descending coronary artery in 11 dogs. Animals then received 2 hrs of either DMVA (n=5) or CPB (n=6) during sustained ventricular fibrillation. Grafted and non grafted (control) SVG segments were then studied in vitro. SVG patency was confirmed by radiolabeled microspheres and pathologic evaluation. Matched SVG specimens (control) were not exposed to circulatory support. All SVGs were subjected to isometric tension studies. SVG contractile responses to norepinephrine, bradykinin, serotonin, and histamine were assessed. Maximal response to all agonists were similar between control SVG segments compared to either CPB or DMVA support (p=NS, ANOVA). All cumulative dose response curves were similar after DMVA vs CPB support. In conclusion, the smooth muscle function of SVGs in this study was not significantly altered by DMVA support. Therefore, short-term DMVA support does not impair patency or adversely effect the functional integrity of smooth muscle within SVGs.

Regulation of glucose utilization by inhibition of mitochondrial fatty acid uptake in cardiac cells.

In order to investigate the mechanism by which fatty acid oxidation inhibitors regulate cardiac metabolism, the effects of 2-tetradecylglycidic acid (2-TDGA), and 2-bromopalmitic acid (2-BPA) on the oxidation of [1-14C]palmitate, [1-14C]octanoate and [U-14C]glucose were studied in isolated rat myocytes. Fifty per cent inhibition of palmitate oxidation was achieved at 20 microM 2-TDGA and 60 microM 2-BPA. Octanoate oxidation was also inhibited by 2-BPA. In contrast to their effect on palmitate oxidation, fatty acid inhibitors significantly stimulated the oxidation of glucose in a concentration-dependent manner. Moreover, the oxidation of [2-14C]pyruvate was increased two-fold by these compounds. The rate of uptake of [U-14C]-2-deoxyglucose was also stimulated two-fold by these inhibitors. These studies suggest that the stimulation of glucose utilization via the inhibition of fatty acid oxidation may be mediated through the stimulation of both glucose transport and the oxidation of pyruvate by the pyruvate dehydrogenase complex.