Biomedical subjects
Publications and source records attributed to C Fisch.
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OBJECTIVES: The purpose of this review is to assemble the widely dispersed information about cardiac alternans and to categorize the types and mechanisms of alternans, their clinical manifestations and possible therapeutic implications. BACKGROUND: The phenomena of mechanical and electrical alternans have been of continuing interest to both physiologists and clinicians. Recent studies have enhanced this interest because of the reported association of alternans with experimental myocardial ischemia and cardiac arrhythmias. METHODS: The review formulates concepts based on extensive review of published studies and personal observations. RESULTS: Cardiac alternans has been subdivided into the following four categories: 1) mechanical, 2) electrical, 3) in association with myocardial ischemia, and 4) in association with cardiac motion. Mechanical alternans can be explained by hemodynamic or inotropic alterations, or both. Mechanical alternans in the ventricular muscle is accompanied by alternans of action potential shape. In the Purkinje fibers, action potential duration alternates without change in shape and is determined by the duration of the preceding diastolic interval. However, in ventricular muscle fiber, alternans can occur in the presence of constant diastolic intervals. T wave alternans reflects changes in action potential duration and is frequently associated with a long QT interval. Electrocardiographic manifestations of conduction alternans occur at many different sites within the conducting system and myocardium. During myocardial ischemia, additional mechanisms of repolarization alternans have been proposed. Alternans occurring in the presence of a large pericardial effusion is attributed to swinging motion of the heart maintaining two-beat periodicity. CONCLUSIONS: Since its origin as "pulsus alternans" described by Traube in 1872, the definition of alternans has evolved into a term encompassing multiple physiologic and pathologic phenomena that, although united by the term cardiac alternans, diverge widely with respect to etiology, mechanism and clinical significance.
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The nitroaromatic drug nilutamide has been shown previously to undergo redox cycling in aerobic rat liver microsomes, being reduced by NADPH-cytochrome P-450 reductase to a nitro anion-free radical which reacts with oxygen, to regenerate the parent drug, and form a superoxide anion dismuted to hydrogen peroxide. In the present study, the effects of nilutamide on isolated rat hepatocytes have been determined. After 6 and 8 hr of incubation with 0.5 mM nilutamide, lactate dehydrogenase was released in the incubation medium, and cell viability was decreased markedly. Consistent with a redox cycle producing reactive oxygen species, nilutamide increased nonmitochondrial (cyanide-resistant) oxygen consumption; the toxicity of nilutamide occurred sooner and was more extensive in the presence of sodium azide (an inhibitor of catalase). Consistent with an oxidative stress, the toxicity of nilutamide was associated with depletion of reduced glutathione, increased levels of glutathione disulfide, increased Ca(++)-dependent phosphorylase a activity, oxidation and accumulation of cytoskeleton-associated proteins and formation of blebs; toxicity was prevented by glutathione precursors, thiol reductants and/or antioxidants, such as L-cystine, L-cysteine, N-acetyl-L-cysteine, dithiothreitol, N,N'-diphenyl-p-phenylene-diamine and alpha-tocopherol. Feeding the animals with a diet supplemented with 2% L-cystine increased the initial glutathione stores of hepatocytes and prevented nilutamide toxicity. It is concluded that nilutamide is toxic to isolated rat hepatocytes, as a probable consequence of an oxidative stress due to the redox cycling of this nitroaromatic compound.
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Wide QRS tachycardia is a diagnostic challenge when confronted on a 12-lead electrocardiogram. The differential diagnosis includes: ventricular tachycardia; supraventricular tachycardia with aberration; and Wolff-Parkinson-White syndrome. Confronted with a wide QRS tachycardia, one must determine whether the origin is ventricular or supraventricular because the therapy will differ. The electrocardiographic findings of capture beats, fusion beats and atrioventricular dissociation are highly specific for ventricular tachycardia but not very sensitive. After careful assessment of the 12-lead electrocardiogram following selected diagnostic features, the correct diagnosis of the cause of wide QRS tachycardia can be made in about 90 percent of patients. This article contains a brief discussion of the diagnostic features of wide QRS tachycardia.
Administration of either aspirin or salicylic acid (3 mmol.kg-1 b.wt. i.p.) decreased by 50 and 65%, respectively, the in vivo oxidation of [U-14C]palmitic acid to [14C]CO2 in mice; after salicylic acid administration, exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 87, 33 and 38%, respectively. Inhibition lasted 9 hr. It was associated with markedly decreased blood glucose concentrations and increased plasma ketone bodies. Repeated administration of salicylic acid (2 mmol.kg-1 i.p. every 8 hr) tripled hepatic triglycerides and produced mild microvesicular steatosis of the liver at 22 hr in fasted mice. In vitro, salicylic acid (1.5 mM) had no or little effect on the formation of beta-oxidation products from [1-14C]octanoic or [1-14C]palmitoyl-L-carnitine, in the presence of ATP, carnitine (40 microM) and coenzyme A (40 microM), but decreased by 51% that from [1-14C]palmitic acid. In the latter system, increasing the concentrations of coenzyme A and carnitine to 200 microM suppressed the inhibitory effect of salicylic acid. Salicylic acid (1.5 mM) decreased by 80% the in vitro mitochondrial formation of palmitoyl-coenzyme A from [1-14C]palmitic acid and 10 microM coenzyme A; again, increasing the concentration of coenzyme A prevented inhibition. We conclude that salicylic acid decreases the mitochondrial activation and thus beta-oxidation of long chain fatty acids, presumably by sequestering extramitochondrial coenzyme A and possibly carnitine.
Any attempt to group clinical states according to those in which EPS is indicated and those in which EPS is contraindicated is difficult because of a considerable overlap. With this one reservation in mind, indications for EPS can be classified in three general groups. These include a group in which the procedure is helpful and frequently indicated, a group in which the procedure is occasionally of benefit but more often there is a difference of opinion among investigators as to its utility, and a third group in which EPS is rarely helpful, often contraindicated, and on occasion harmful. The clinical states and the utility of the EPS in each are summarized in Table 1.
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The effects of amiodarone on the respiration of isolated mouse liver mitochondria have been determined. Amiodarone (200 microM) had a biphasic effect on state 4 respiration supported by either glutamate plus malate or succinate. Initially, the respiratory rate was increased. This stimulatory effect was not prevented by oligomycin (an inhibitor of ATP synthase). It was associated with marked accumulation of amiodarone in the mitochondria, and with collapse of the mitochondrial membrane potential. This initial uncoupling effect was followed by a progressive decrease in the state 4 respiration rate, leading eventually to marked inhibition. Preincubation for 5 min with amiodarone (200 microM) also decreased markedly ADP-stimulated (state 3) respiration, ATP production and dinitrophenol-stimulated (uncoupled) respiration supported by glutamate plus malate (which donate electrons to complex I), and respiration supported by succinate (which donate electrons to complex II), but did not affect respiration supported by duroquinol (donating electrons to complex III) or by ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine (donating electrons to cytochrome c). Preincubation with amiodarone (150-200 microM) decreased markedly respiration mediated by fatty acids of various chain length and respiration mediated by citrate, a tricarboxylic acid cycle substrate. We conclude that amiodarone has a dual effect on mitochondrial respiration. The initial uncoupling effect is probably due to the entry of protonated amiodarone, releasing a proton in the matrix. Accumulation of amiodarone soon leads to inhibition of the respiratory chain at the levels of complex I and complex II and to decreased ATP formation.
Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from [U-14C]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of [14C]CO2 from [U-14C]palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of [U-14C]palmitic acid. One hour after 100 mg.kg-1, the exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of [14C]CO2 from [1-14C]palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.
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