Lethal Ventricular Fibrillation Research Articles

The myocardial infarct size-limiting and antiarrhythmic effects of acyl-CoA:Cholesterol acyltransferase inhibitor VULM 1457 protect the hearts of diabetic–hypercholesterolaemic rats against ischaemia/reperfusion injury both in vitro and in vivo

The study was designed to characterise the influence of a novel acyl-CoA:cholesterol acyltransferase inhibitor, VULM 1457, on the severity of myocardial ischaemia–reperfusion injury in a model of diabetes mellitus and hypercholesterolaemia induced by co-administration of streptozotocin and a high fat-cholesterol diet. We used Langendorff-perfused rat hearts to measure the size of myocardial infarction after 30 min of regional ischaemia, followed by a 2-h reperfusion period, and open-chest rats were exposed to 6 min of ischaemia and 10 min of reperfusion to analyse ventricular arrhythmias. In addition to the high fat-cholesterol diet, VULM 1457 was administered to the diabetic–hypercholesterolaemic rats for 5 days. Decreased plasma and liver cholesterol levels and a significantly reduced occurrence of ventricular fibrillation (29% vs. 100%, P < 0.01), determined via the mean number and duration of episodes (0.6 ± 0.4 and 2.1 ± 1.4 s vs. 2.8 ± 0.8 and 53.5 ± 14.4 s in diabetic–hypercholesterolaemic rats, both P < 0.01), were observed in these animals. Lethal ventricular fibrillation was suppressed, and arrhythmia severity was also significantly decreased in these animals as compared to the non-treated animals (2.9 ± 0.6 vs. 4.9 ± 0.2; P < 0.05). A smaller infarct size, normalised to the size of area at risk, was observed in the treated diabetic–hypercholesterolaemic group as compared to the non-treated group (16.3 ± 1.9% vs. 37.3 ± 3.1%; P < 0.01). Aside from remarkable hypolipidaemic activity, VULM 1457 improved the overall myocardial ischaemia–reperfusion injury outcomes in the diabetic–hypercholesterolaemic rats by suppressing arrhythmogenesis as well as by reducing myocardial necrosis.

Identification of a Potent hERG Channel Activator with a Novel Mechanism of Action

hERG potassium channels are an important component of cardiac action potential repolarization, and loss of function mutations of hERG channels prolong the cardiac ECG QT interval. Long QT Syndrome is associated with cardiac rhythm disorders, including torsades de pointes, which can degenerate into lethal ventricular fibrillation. In this study, we report the discovery of a potent hERG activator (Compound 1). Using whole cell patch-clamp studies of recombinant hERG expressed in HEK293 cells, we found that 3 μM Compound 1 increased hERG current amplitude more than 10-fold. This increase was reversed by the hERG blocker E4031(1 μM). Enhancement of hERG was steeply concentration dependent (EC50 0.5 ± 0.1 μM, Hill slope 3.3 ± 0.2). The observed increase in amplitude was primarily due to removal of channel inactivation. The compound also produced a hyperpolarizing shift in the voltage dependence of channel activation at high concentrations and a modest slowing of deactivation. In isolated guinea pig ventricular myocytes, Compound 1 produced a concentration-dependent shortening of action potential duration (>70%, 3 μM) that was prevented by pre-incubation with E4031. In conclusion, we have identified a novel activator of hERG potassium channels. This compound may provide a useful tool for further biophysical characterization of hERG channels and investigation of cardiac electrophysiology.

Pravastatin Inhibits Arrhythmias Induced by Coronary Artery Ischemia in Anesthetized Rats

We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P<0.05) decreased MPO activities, but only pravastatin decreased the incidence of ischemia-induced lethal VF. Both statins had no significant effects on body weight, blood pressure, heart rate, and QT interval as we reported earlier. Our results prove further that pravastatin has benefits to decrease cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in prevention of arrhythmias. A decrease in the neutrophil infiltration may be partly involved in the inhibitory effect of pravastatin on the ischemia-induced VF.

Vagal nerve–mediated vasospasm–induced lethal ventricular fibrillation

We report a case of variant angina complicated by lethal ventricular fibrillation. Serial ambulatory electrocardiogram monitoring revealed high-frequency spectra reflecting augmented vagal nerve activity preceding the vasospastic episodes. Our case suggests that heart rate variability analysis can help identify potential unexpected sudden cardiac death in patients with variant angina.

Isolated Heart Function after Ischemia and Reperfusion in Sucrose-Fed Rats: Influence of Gender and Treatment

Sucrose-fed rats (HTG) develop hypertension, hypertriglyceridemia, and other features of the metabolic syndrome. This condition, nowadays a world epidemic, is more prevalent in males and increases the risk of cardiovascular diseases. Weanling male and female rats were given either tap water in control (C) or 30% sucrose solution in HTG groups and commercial rat chow for 3, 5, or 8 months. We studied possible variations in cardiac function, due to gender and length of treatment, in isolated heart after ischemia-reperfusion, since an impaired performance may be more easily detected under stress. Together, sucrose treatment and age affected all cardiac variables. Gender had significant effect on coronary vascular resistance and postischemic levels of the enzyme CK-MB; the percentages of retained cardiac enzymes after ischemia were higher in C and HTG females. C and HTG males had a higher incidence of arrhythmias than females, but only HTG males suffered lethal ventricular fibrillation.

Isolated heart function during ischemia and reperfusion in sucrose-fed rats. Effect of insulin infusion

In myocardial damage due to ischemia–reperfusion, the administration of insulin together with glucose and potassium may be protective, although in some patients and animal models, it is ineffective. In a rat model (HTG) with characteristics of the metabolic syndrome, induced by sucrose feeding, ischemia–reperfusion of the isolated heart evidences a less favorable outcome than in control animals, particularly males. We investigated the effect of insulin infusion during the reperfusion period in isolated hearts from control and HTG male and female rats. Weanling Wistar rats were given commercial rat chow and tap water (C rats) or 30% sucrose solution (HTG rats) for 8 months. They developed moderate hypertension and hyperinsulinemia, central adiposity, nephropathy, and hypertriglyceridemia. Cardiac function was recorded in a Langendorff preparation subjected to 25 min ischemia and 15 min reperfusion. The handicapped functionality of HTG hearts is more apparent under conditions of stress. Insulin administration improved particularly mechanical work and +d p/d t max variables. The effect of sex was observed on the type of arrhythmias developed during reperfusion: Only the males showed lethal ventricular fibrillation, which disappeared after insulin administration. Females had lower levels of cardiac enzymes creatine kinase (CKMB) and lactic dehydrogenase (LDH), but their performance was not hindered, probably on account of protective factors such as estrogens. Summing up, the pathological features of the HTG model did not prevent insulin from exerting some of its beneficial effects in HTG hearts. Sex differences in the outcome were more apparent in the type of arrhythmias after reperfusion; they were lethal in HTG males only, but insulin prevented their onset.

Selective potentiation of L-type calcium channel currents by cocaine in cardiac myocytes.

Cocaine use poses a major health problem not only because of the dependence it causes but also because of the generation of life-threatening cardiac arrhythmias following overdose. Elucidating the molecular mechanisms of action of cocaine, therefore, remains a critical step in developing treatment for cocaine addiction and preventing cardiac complications. Although the neurotransmitter transporters are suggested to be primary targets for cocaine, the continued drug-seeking behavior of transporter knock-out mice suggests the involvement of additional mechanisms. Several studies have shown that voltage-gated calcium channel blockers can prevent the behavioral and reinforcing effects of the drug and also cocaine-induced cardiac events, including lethal ventricular fibrillation. However, the role of voltage-gated calcium channels in cocaine-induced responses is not clear. Herein, I show that cocaine, in pharmacological doses, selectively and potently enhances L-type calcium channel currents in isolated rat ventricular myocytes. This potentiation by cocaine is due to an increase and decrease, respectively, in the calcium channel opening and closing rates, with no apparent effects on voltage-dependence or single-channel conductance. The effects of cocaine are rapidly reversible and unaffected by prior ATPgammaS-induced channel phosphorylation. These results suggest that cocaine directly binds and facilitates the opening of L-type calcium channels. Importantly, elevated intracellular calcium levels via this mechanism triggering second messenger pathways and gene activation may contribute to many of the cardiovascular and central nervous system effects of cocaine.

Cariporide, a highly selective Na+/H+ exchange inhibitor, suppresses the reperfusion-induced lethal arrhythmias and "overshoot" phenomenon of creatine phosphate in situ rat heart.

The effects of a highly selective Na+/H+ exchange inhibitor cariporide on the reperfused in situ heart were assessed. Male Sprague-Dawley (SD) rats weighing 200-300 g were anesthetized with pentobarbital sodium (60 mg/kg, i.p.) and divided into four groups; sham-operated (n = 6), vehicle (n = 15), 0.1 mg/kg (n = 15), and 1.0 mg/kg (n = 15) groups. The left coronary artery was ligated for 5 min and then released with ECG and blood pressure monitoring. Cariporide was intravenously given as a bolus 2 min before the reperfusion. The heart was rapidly excised and frozen 3 min after the onset of ventricular fibrillation, otherwise 10 min after the reperfusion. The adenosine triphosphate (ATP), creatine phosphate (CP), and glycogen contents were measured in the reperfused ischemic myocardium by using an enzymatic fluorometric assay technique. The incidence of the lethal ventricular fibrillation was 53% in the vehicle, 27% in the low-dose and 7% in the high-dose group. The concentrations (mean+/-SEM) of ATP, CP (nmol/mg protein), and glycogen (nmol as glucose/mg protein) were 74+/-4, 255+/-19, and 164+/-21 in the sham, 23+/-4, 763+/-70, and 61+/-7 in the vehicle, 27+/-4, 180+/-16, and 104+/-14 in the low-dose, and 32+/-4, 178+/-24, and 108+/-8 in the high-dose groups, respectively, indicating that cariporide significantly blunted CP overshoot as well as glycogenolysis during reperfusion. Thus cariporide can be expected to depress arrhythmogenesis and protect the metabolic status of the heart.

Gender does not influence acute myocardial infarction in adult dogs

Mechanisms responsible for the well-documented “protection” against myocardial ischemia and infarction in young women and subsequent loss of protection after menopause remain speculative. One possibility is that gender-related variables (such as endogenous hormone levels or regular loss of stored iron) alter the susceptibility of the heart to ischemia: if so, then premenopausal women when compared with men may manifest endogenous protection against acute myocardial ischemic injury. Using the canine model we therefore sought to determine whether gender influences acute myocardial ischemia and infarction. Retrospective analysis was performed on data compiled from 60 mature adult dogs subjected to 1 hour of coronary artery occlusion and ≥4 hours of reperfusion. We first compared the incidence of lethal ventricular fibrillation in the male and female cohorts and then for survivors compared collateral blood flow during coronary occlusion (by injection of radioactive microspheres), infarct size (assessed by tetrazolium staining and expressed as a percentage of the myocardium at risk), and regional wall motion (by somomicrometry) in the infarct-related area. The incidence of lethal ventricular fibrillation was 23% in the male dogs and 19% in the female dogs ( p = 0.70, difference not significant). For survivors, the area at risk of infarction was comparable in males and females (23 ± 2% and 22% ± 1% of the total left ventricular weight), and the groups were equally ischemic during coronary occlusion, with collateral blood flow to the ischemic subendocardium averaging 0.05 ± 0.02 and 0.07 ± 0.01 ml/min/g tissue. There was no difference in infarct size between the two cohorts: area of necrosis was 17% ± 6% and 18% ± 3% of the myocardium at risk in the males and females, respectively. In addition, the groups were equally dyskinetic during occlusion and equally hypokinetic after reperfusion. We conclude that gender does not influence acute myocardial ischemia and infarction in the canine model.

Antiarrhythmic versus antifibrillatory actions: Inference from experimental studies

Pathophysiology of the coronary circulation is a major contributor to altering the myocardial substrate, rendering the heart susceptible to the onset of arrhythmias associated with sudden cardiac death. Antiarrhythmic drug therapy for the prevention of sudden cardiac death has been provided primarily on the basis of trial and error and in some instances based on ill-suited preclinical evaluations. The findings of the Cardiac Arrhythmia Suppression Trial (CAST) requires a reexamination of the manner in which antiarrhythmic drugs are developed before entering into clinical testing. The major deficiency in this area of experimental investigation has been the lack of animal models that would permit preclinical studies to identify potentially useful or deleterious therapeutic agents. Further, CAST has emphasized the need to distinguish between pharmacologic interventions that suppresses nonlethal disturbances of cardiac rhythm as opposed to those agents capable of preventing lethal ventricular tachycardia or ventricular fibrillation. Preclinical models for the testing of antifibrillatory agents must consider the fact that the superimposition of transient ischemic events on an underlying pathophysiologic substrate makes the heart susceptible to lethal arrhythmias. Proarrhythmic events, not observed in the normal heart, may become manifest only when the myocardial substrate has been altered. We describe a model of sudden cardiac death that may more closely simulate the clinical state in humans who are at risk. The experimental results show a good correlation with clinical data regarding agents known to reduce the incidence of lethal arrhythmias as well as those showing proarrhythmic actions.

Neurocardiology: Brain Mechanisms Underlying Fatal Cardiac Arrhythmias

Chaos theory may have a widespread application in medicine, from the analysis of protein structure at one end of the spectrum to fetal monitoring and the measurement of aging on the other. This application is especially on firm ground in cardiology, where it is simple and precise for the experimenter, and a primer exists for the clinician. As just presented, the point-correlation-dimension analysis of heartbeat variability is able to characterize the patterns of low-dimensional chaos produced by the heartbeat generator, a mechanism that is a composite of the voltage-dependent, neurotransmitter-dependent, and circulation-dependent ionic conductances that are all located in the myocardium where the heartbeat is formed. Most importantly, this deterministic measure of heartbeat variability is able to predict imminent lethal arrhythmogenesis with an accuracy that the more familiar stochastic measures do not have. This may arise because the PD2 is sensitive to the net degrees of freedom of the heartbeat generator, which, under the influence of the nerves and the coronary circulation, can be shifted so the resulting dynamics cause the initiation of lethal arrhythmogenesis. Application of chaos theory in neurology may be equally fruitful because the deterministic measures can discriminate among neuronal firing patterns, reveal subtle changes in brain waves, and be related to higher cognitive processes. Psychiatry also seems quite likely to benefit more and more from the application because the algorithms can discriminate schizophrenic brain functions from normal ones. Thus it can be expected that future applications will enable observation of biologic processes all along the brain-heart axis by which lethal ventricular fibrillation is regulated and perhaps even caused by its determination of the heartbeat dynamics. The subfield of neurocardiology has come a long way since it was first positively identified as an important research area. It took a lot of experiments to show how lethal cardiac arrhythmogenesis is involved with cerebral activities delivered over autonomic pathways. Although we do not yet fully understand the causal mechanism of lethal arrhythmogenesis, we may be getting close. It will become increasingly imperative for the clinical neurologist, along with the cardiologist, to understand the importance of neurocardiology in medical therapy and for the neurologist, along with the cardiologist and psychiatrist, to understand its importance in preventive treatments.

Experimental Cardiac Trauma—Ballistics of a Captive Bolt Pistol

Cardiac trauma can be experimentally produced by blunt impulsive impact over the cardiac apex in the anesthetized canine. A gradation of myocardial injury, including transient arrhythmia, contusion, and lethal ventricular fibrillation, can be produced by varying the power of the charge in a modified captive bolt pistol. Ballistics experiments were conducted to quantify the velocity, energy, and trajectory of impacts produced by the modified captive bolt pistol using various charges. Correlation of the impact data with the previously reported levels of trauma indicates that a 24 m/s impact with 178 joules of available energy results in lethal ventricular fibrillation with extensive myocardial contusion. Blunt impact at 17 m/s with 102 joules causes serious myocardial injury and at 13 m/s with 67 joules causes minor transient arrhythmia.

Antiarrhythmic activity of the ?2-adrenoblocker alprenolol

Experiments on dogs, cats, and rats with various disturbances of the cardiac rhythm showed that the β2 alfeprol, the Soviet analog of alprenolol, has a marked antiarrhythmic action. The substance abolishes atrial arrhythmias induced by electrical stimulation of the atria or by application of aconitine, it controls ventricular arrhythmias arising as a result of occlusion of a branch of the coronary artery or of ouabain poisoning, and it prevents lethal ventricular fibrillation in rats after calcium chloride poisoning. The antiarrhythmic effect of alprenolol is ascribed not only to blocking of β-adrenoreceptors but also to the quinidine-like action of the compound.

The anti-arrhythmic activity of the tetrabutylamide of EDTA

Experimental models of cardiac fibrillation induced in dogs and rats were used to study the antifibrillatory activity of tetrabutylamide of ethylendiaminetetraacetic acid (TBAEDTA) — a compound devoid of the capacity for complex formation. TBAEDTA in a dose of 5–20 mg/kg repeatedly injected into a vein somewhat decelerated intensified cardiac activity, suppressed the ectopic impulse formation and temporarily restored the correct sinusal rhythm in dogs with experimental myocardial infarction and in dogs intoxicated with oubain. TBAEDTA produced an antifibrillatory effect preventing lethal ventricular fibrillation in rats given a toxic dose of calcium chloride intravenously. The EDTA molecule can apparently be used for the synthesis of substances capable of antifibrillatory activity after the introduction into it of corresponding functional groups, even if this results in the loss of the capacity of the compound for complex formation.

Influence of Induced Hypothermia on Digitalis Toxicity

Toxic doses of ouabain were injected in animals which were subsequently cooled. The mortality- in this group was compared to that of similarly treated controls. Lowering of body- temperature by 8 to 12 C. reduced the arrhythmias produced by the toxic doses of ouabain but did not alter the overall incidence of mortality from ventricular fibrillation when compared to the controls. However, cooled animals survived for considerably longer periods of time than the normothermic controls. It is concluded that subsequently induced hypothermia does not afford an effective protection from digitalis toxicity, even though arrhythmias are reduced and survival is prolonged. These results support the hypothesis that partial protection from ventricular arrhythmias is not necessarily associated with, protection from lethal ventricular fibrillation.