Ischemia-induced and reperfusion-induced arrhythmias: Importance of heart rate

Abstracts From the Literature-Physiology Selected

by David

Tumor Necrosis Factor and the Acute Metabolic Response to Tissue Injury in Man. Starnes HF Jr, Warren RS,

Jeevanandam

M, et al.

R. Dantzker Role of Xanthine Oxidase fleperfusion Injury. Granger

ture and Intestinal LaMont

Toxin

A Perturbs

Cytoskeletal

Struc-

Tight Junction Permeability of Cultured Human Epithelial Monolayers. Hecht G, Pothoulakis C,

JT, et al.

J Clin Invest 82:1516, 1988.

Toxin A of Clostridium dificile causes severe inflammatory enterocolitis in man and animals that appears to be mediated in part by acute inflammatory cells that migrate into the toxin A-exposed mucosa. To determine the direct effects of toxin A on intestinal epithelial permeability and structure in the absence of other modulating factors, we used cultured monolayers of a human intestinal epithelial cell line (T,,). A toxin A concentration of 7 x 10-l fig/ml (3 x 10w9M) nearly abolished monolayer transepithelial resistance within 6-8 h. This marked permeability defect occurred while the monolayers were still confluent. Dual sodium-mannitol flux studies localized the permeability defect to the intercellular tight junction. Cytotoxicity assays and morphological evaluation using Nomarski optics and electron microscopy failed to demonstrate any evidence of cell damage at the time the maximum resistance response was observed. Fluorescent staining for F actin, however, revealed a marked decrease in fluorescent intensity in toxintreated monolayers versus controls. These data show that toxin A can directly affect the barrier function of this model intestinal epithelium and initially does so by selectively enhancing tight junction permeability. Furthermore, cytoskeletal structure is markedly altered over the same time course, although the integrity of individual cells is maintained. Because the cytoskeleton of intestinal epithelial cells is known to be capable of regulating tight junction permeability, we speculate that the above effects of toxin A on epithelial barrier function result from alterations of the cytoskeleton. (Reprinted with permission.) Journal

of Critical

Care, Vol4,

No 3 (September),

1989:

in Ischemia-

Am J Physiol 255Hl269,

In this lecture, evidence is presented to support the following hypothesis regarding the roles of xanthine oxidasederived oxidants and granulocytes in ischemia-reperfusioninduced microvascular injury. During the ischemic period, ATP is catabolized to yield hypoxanthine. The hypoxic stress also triggers the conversion of NAD-reducing xanthine dehydrogenase to the oxygen radical-producing xanthine oxidase. During reperfusion, molecular oxygen is reintroduced into the tissue where it reacts with hypoxanthine and xanthine oxidase to produce a burst of superoxide anion and hydrogen peroxide. In the presence of iron, superoxide anion and hydrogen peroxide react via the Haber-Weiss reaction to form hydroxyl radicals. This highly reactive and cytotoxic radical then initiates lipid peroxidation of cell membrane components and the subsequent release of substances that attract, activate, and promote the adherence of granulocytes to microvascular endothelium. The adherent granulocytes then cause further endothelial cell injury via the release of superoxide and various proteases. (Reprinted with permission.) Temporal

difici/e

Granulocytes

DN.

1988.

J Clin Invest 82:1321,1988.

Tumor necrosis factor (cachectin), a protein produced by monocytes and macrophages, has been implicated as an important mediator of the lethal effects of endotoxic shock and the cachexia of chronic infection. Recombinant human tumor necrosis factor (Y (rTNF) was given intravenously to patients as part of an antineoplastic trial. Fever, tachycardia, and at higher doses, hypotension occurred after a single injection of rTNF. Metabolic effects after rTNF administration were dose related and included enhanced energy expenditure with elevated CO, production, increased whole body protein metabolism and peripheral amino acid efflux from the forearm, and decreased total arterial amino acid levels associated with a significant increase in plasma cortisol. Elevated serum triglycerides, as well as increased glycerol and free fatty acid turnover were seen, suggesting increased whole body lipolysis and fat utilization after rTNF. These findings indicate that administration of TNF in man reproduces many of the acute physiologic and metabolic responses to tissue injury, including energy substrate mobilization (Reprinted with permission.) Clostridium

and

pp 225-238

Myocardial

Bugelski,

Relation

Between

Reperfusion

PJ, et al.

Neutrophil

Injury.

Smith

Accumulation

EF

Am J Physiol255:H1060,

and

ZZZ, Egan

JW,

1988.

Infiltration of polymorphonuclear leukocytes (PMN) is associated with the progression of myocardial infarction and reperfusion injury. However, little is known about the time course of cellular infiltration. To investigate this issue, rats were subjected to 30 min of coronary artery occlusion followed by reperfusion for ~96 h. Myocardial injury was determined by measuring the depletion of myocardial creatine phosphokinase activity, and PMN infiltration was assessed by measuring myeloperoxidase (MPO) activity. MPO activity increased from 0.7 U/g tissue in non-operated animals, to a peak of 6.7 + 0.8 and 6.4 + 1.4 U/g at 6 and 24 h after coronary artery reperfusion, respectively. MPO activity decreased to 3.3 f 0.8 U/g at 48 h and 1.1 + 0.4 U/g at 96 h, suggesting diminished PMN accumulation. Histological examination confirmed the accumulation and resolution of PMN over the 96-h period. At 24 h, there was a signifficant linear correlation between infarct size and MPO act,ivity, whereas at 96 h no relationship was found. These data indicate that PMN infiltration occurs early in response to reperfusion injury and persists for only 24 h after initiation of reperfusion. These findings suggest that attempts to moderate inflammatory cell responses to myocardial injury should be administered early after coronary artery reperfusion to limit the accumulation of potentially deleterious inflammatory cells. (Reprinted with permission.) Ischemia-Induced and reperfusion-Induced Importance of Heart Rate. Bernier M,

DJ.

Am J Physiol256:H21,

Arrhythmias:

Curtis

MJ.

Hearse

1989.

The relationship between heart rate and ischemia-induced and reperfusion-induced arrhythmias was studied using 573 225

226

ABSTRACTS

isolated rat hearts. Hearts (12/group), subjected to 7 min of coronary occlusion and 10 min reperfusion, were paced at 300,330,360,390,420,480, or 540 beats/mm. Pacing either throughout the experiment or during ischemia alone led to a rate-dependent increase in the incidence of reperfusioninduced ventricular fibillation (VF) from 25% in the unpaced hearts to >90% when the rate was 420 beats/min or higher. However, pacing during reperfusion alone did not increase the incidence of reperfusion-induced VF. In separate hearts, the right atrium was removed to permit examination of both low and high rates (167 + 2,240,336 2 3, or 480 beats/min throughout the experiment) over a wide range of durations of occlusion (3,5,7,10,15,20, or 40 min). Ischemia-induced VF incidence was critically dependent on heart rate, low rates being protective. Duuring reperfusion, the incidence of VF was also highly rate dependent if reperfusion was initiated within 10 min of the onset of ischemia (ranging from 8% when rate was 167 + 2 beats/min to 100% when rate was 480 beats/min) but was unrelated to heart rate when reperfusion occurred at later times (ranging from 33 to 50% when ischemia duration was 40 min). Heart rate can therefore influence susceptibility to ischemia- and reperfusion-induced arrhythmias, probably as a result of an effect on the rate of development of ischemic injury. (Reprinted with permission.) Prophylaxis Acylcarnitine

KA,

of Early

Ventricular

Accumulation.

Fibrillation

Corr

PB, Creer

by inhibition

MH,

of

Yamada

er al. .I Clin Invest 83:927, 1989.

Hypoxia in isolated myocytes results in accumulation of long-chain acylcarnitines (LCA) in sarcolemma. Inhibition of carnitine acyltransferase I (CAT-I) with sodium 2-[S(4-chlorophenyl)-pentyll-oxirane-2 carboxylate (POCA) prevents both the accumulation of LCA in the sarcolemma and the initial electrophysiologic derangements associated with hypoxia. Another amphiphilic metabolite, lysophosphatidylcholine (LPC), accumulates in the ischemic heart in vivo, in part because of inhibition of its catabolism by accumulating LCA. It induces electrophysiologic alterations in vitro analogous to early changes induced by ischemia in vivo. The present study was performed to determine whether POCA could prevent accumulation of both LCA and LPC induced by ischemia in vivo and if so, whether attenuation of early arrhythmogenesis would result. LAD coronary artery occlusions were induced for 5 min in chloralose-anesthetized cats. Coronary occlusion in untreated control animals elicited prompt, threefold increases of LCA (73 f 8 to 286 + 60 pmol/mg protein) and twofold increase of LPC (3.3 + 0.4 to 7.5 + 0.9 nmol/mg protein) selectively in the ischemic zone, associated with ventricular tachycardia (VT) or ventricular fibrillation (VF) occurring within the 5-min interval before acquisition of myocardial samples in 64% of the animals. POCA prevented the increase of both LCA and LPC. It also prevented the early occurrence of VT or VF (within 5 min of occlusion) in all animals studied. The antiarrhythmic effect of POCA was not attributable to favorable hemodynamic changes or to changes in myocardial perfusion measured with radiolabeled microspheres. Thus, inhibition of CAT-I effectively reduced the incidence of lethal arrhythmias induced early after the onset of ischemia. Accordingly, pharmacologic inhibition of this enzyme provides a promising approach for

prophylaxis of sudden cardiac death, that typically occurs very soon after the onset of acute ischemia, in man. (Reprinted with permission.) Decreased Acute and

Rathat

Cardiac Chronic

Response Hypoxia.

to

lsoproterenol

Richalet

Infusion

J-P,

C, et al. J Appl Physiol65:1957,

Larmignat

in

P,

1988.

The hypothesis of a blunted chronotropic response of cardiac fl-adrenergic receptors in altitude hypoxia was tested in nine subjects at sea level (SL) by infusion of isoproterenol. Observations were made at SL, in acute hypoxia (2 days at 4,350 m, condition Hl), in more prolonged hypoxia [13 days between 850 and 4,800 m, condition HZ] and in chronic hypoxia [21 days at 4,800 m, condition H3]. Resting heart rate was higher in all hypoxic conditions. Resting norepinephrine concentrations were found to be significantly higher in conditions HZ (1.64 + 0.59) and H3 (1.74 + 0.76) than at SL (0.77 r 0.18 rig/ml). Isoproterenol, diluted in saline, was infused at increasing doses of 0.0, 0.02, 0.04, and 0.06 fig - kg-‘, min-‘. For the highest dose, there was a significantly smaller increase in heart rate in conditions HI (35 f 9), N2 (33 + ll), and H3 (31 f 11) than at SL (45 + 8 min-‘). The increase in pulse (systolic/diastolic) pressure, considered as the vascular response to isoproterenol infusion, was smaller in condition H3 (29 + 16) than at SL (51 ? 24 mmHg). There was a significant increase in the dose of isoproterenol required to increase heart rate by 25 min-’ and decrease in slope of heart rate increase vs. log(dose) relationship in conditions H2 and H3. Thus an hypoxia-related attenuated response of P-adrenergic receptors to exogenous stimulation was found in humans. In the first days of exposure, this effect was limited and might be explained by a competitive action of endogenous adrenergic activity, thereafter a downregulation mechanism of the @receptor function may take place as a consequence of chronically elevated sympathetic activity. (Reprinted with permission.) lnotropic Sepsis.

Sensitivity

Smith

to fl-Adrenergic

LW,

McDonough

Stimulation

KH.

in Early

Am J Physiol

255:H699,1988. In early sepsis, maintenance of in vivo cardiovascular performance is at least partly dependent on sympathetic support to hearts with intrinsic contractile defects. Yet prolonged sympathetic stimulation, as occurs in sepsis, would be expected to alter the heart’s ability to respond to this stimulation. We have investigated myocardial inotropic sensitivity to P-adrenergic stimulation in a model of sepsis in which animals, at the time studied, exhibited bacteremia, normal arterial blood pressure and cardiac output, elevated heart rate, and elevated plasma catecholamines. Intrinsic myocardial contractile function, as assessedby the maximal rate of left ventricular pressure development (LV dP/d&) in an isovolumically contracting heart preparation, was significantly depressed in septic animals. To determine whether hearts from septic animals could respond normally to @adrenergic stimulation, we studied inotropic response to a bolus of isoproterenol in these isolated hearts. With maximal isoproterenol stimulation, hearts from septic animals were able to attain the same dP/dt, as were hearts from control