Sepsis-induced Myocardial Depression Research Articles

Prevention of early myocardial depression in hyperdynamic endotoxemia in dogs.

In our study the pathomechanism of sepsis-induced early myocardial depression was investigated. We determined the effects of the inducible nitric oxide synthase inhibitor and free radical scavenger mercaptoethylguanidine (MEG) on the myocardial contractility, the endothelial and inducible nitric oxide synthase (eNOS and iNOS) activities, and the activation and tissue accumulation of polymorphonuclear leukocytes in hyperdynamic endotoxemia in dogs. Group 1 served as endotoxemic control. Mean arterial pressure and cardiac output were measured, myocardial contractility was estimated from the end-systolic pressure-diameter relationship. The eNOS, iNOS and myeloperoxidase activities were determined on myocardial biopsy samples, and the free radical-producing capacity of granulocytes was measured from separated cells. The effect of MEG on the in vitro free radical production of isolated granulocytes was measured by chemiluminometry. Endotoxin induced a hyperdynamic circulatory reaction and significant myocardial depression. The myocardial eNOS activity was significantly increased 4 h after induction of endotoxemia and remained elevated, the iNOS activity was increased only 8 h after endotoxemia induction. The free radical-producing capacity and the myocardial accumulation of the granulocytes were significantly increased. In group 2, MEG treatment selectively inhibited the iNOS activity, prolonged the hyperdynamic circulatory reaction, prevented myocardial depression and decreased the activation and tissue accumulation of granulocytes. The compound dose-dependently decreased the in vitro activation of previously resting granulocytes. Our study demonstrates that iNOS do not contribute to the early cardiac failure in endotoxemia. MEG selectively inhibits iNOS in vivo, but its beneficial effects are rather related to the decreases in leukocyte and free radical-mediated myocardial dysfunction during early endotoxemia.

Structure-function relationships in the septic rat heart.

Myocardial edema and histologic changes consistent with tissue injury are reported in association with sepsis-induced myocardial depression. The objective of the present study was to determine whether, in the absence of shock, such changes (assessed by studying microvascular albumin flux, tissue edema, and morphometry) are prerequisites for the development of contractile dysfunction in sepsis. Sprague-Dawley rats were randomized into groups for either cecal ligation and perforation (CLP) or sham study. Twenty-four hours after entry of animals into the study, their myocardial function was assessed with the Langendorff isolated heart technique. Left-ventricular developed pressure (preload: 5 mm Hg) was reduced in CLP animals (34.9 +/- 3.3 mm Hg, n = 10) as compared with time-matched controls (46.4 +/- 4.0 mm Hg, n = 8, p < 0.05, unpaired t test). This was associated with a significant reduction in the maximal rate of increase (+ dP/dt(max)) and decrease (-dP/dt(max)) in left ventricular pressure in the CLP group (sham versus CLP, unpaired t test, p < 0.05). Upon reperfusion, after 30 min of ischemia, left ventricular resting tension was decreased in CLP as compared with sham-treated animals (sham versus CLP, analysis of variance (ANOVA) with repeated measures, p < 0.05). At 24 h, sepsis was not associated with myocardial edema (wet:dry weight ratio, sham = 4.094 +/- 0.098, n = 10; CLP = 4.185 +/- 0.066, n = 7), and tissue albumin flux was reduced (sham = 194 +/- 27 microliters. h-1. g dry wt-1, n = 10; CLP = 100 +/- 14 microliters. h-1. g dry wt-1, n = 7). In tissue processed for electron microscopy, we found no evidence of tissue injury or edema at either 24 or 48 h after CLP. We conclude that polymicrobial normotensive sepsis causes myocardial contractile depression in the absence of changes in myocardial structure.

Myocardial energy metabolism and morphology in a canine model of sepsis

The mechanism responsible for sepsis-induced myocardial depression is not known. To determine if sepsis-induced myocardial depression is caused by inadequate free energy available for work, we studied myocardial energy metabolism in a canine model of sepsis. Escherichia coli-infected (n = 18) or sterile (n = 16) fibrin clots were implanted intraperitoneally into beagles. Myocardial function and structure was assessed using radionuclide ventriculograms, echocardiograms, and light and electron microscopy. The adequacy of energy metabolism was evaluated by comparing catecholamine-induced work increases [myocardial O2 consumption (MVO2) and rate pressure product (RPP)] with a simultaneously obtained estimate of intracellular free energy [phosphocreatine-to-adenosine triphosphate ratio (PCr:ATP)] determined by 31P-magnetic resonance spectroscopy. When compared with control animals, septic animals had a decrease in left ventricular ejection fraction (EF, P < 0.0001) on day 1 and fractional shortening (FS, P < 0.0003) on day 2 after clot implantation. On day 2, neither septic nor control animals had statistically significant decreases in PCr:ATP, despite catecholamine-induced increases in MVO2 and RPP (mean maximal increases in septic animals 135 +/- 31 and 51 +/- 10%, respectively). Light and electron microscopic findings showed that hearts of septic animals, compared with control animals, had a greater degree of morphological abnormalities. Thus, in a canine model of sepsis with alterations in myocyte ultrastructure and documented myocardial depression (decreased EF and FS), intracellular free energy levels (PCr:ATP) were maintained despite catecholamine-induced increases in myocardial work (increased MVO2 and RPP), suggesting high-energy synthetic capabilities are not limiting cardiac function.