Model Of Sudden Cardiac Death Research Articles

Effect of interventions that increase cyclic AMP levels on susceptibilty to ventricular fibrillation in unanesthetized dogs

Although the autonomic nervous system has been implicated in the formation of ventricular fibrillation, the precise mechanism by which this is mediated remains undetermined. In particular, the role of second messengers, generated by β-adrenoceptor activation, has been postulated to mediate the pro-arrhythmic effects of the sympathetic nervous system. Thus, a 2 min occlusion of the left circumflex coronary artery was initiated during the last minute of exercise in canines with healed myocardial infarctions (produced by ligation of left anterior descending artery). Fifteen dogs were found to be susceptible to the formation of ventricular fibrillation while 17 animals were resistant. Nine resistant dogs were treated with the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX,1 mg/kg) in combination with an infusion of 8-bromo-cAMP (100–150 μg/kg/min beginning 45 min prior to exercise). Heart rate and left ventricular d P/d t max significantly increased, but failed to elicit, arrhythmias during the exercise and ischemia test. Nine resistant animals were also treated with the adenylate cyclase activator forskolin, (100 μg/kg), which provoked the same hemodynamic changes as the cyclic AMP infusion but also failed to induce ventricular fibrillation. Both forskolin ( n = 3) and IBMX ( n = 3) induced large increases in myocardial cAMP levels (control 5.2 ± 0.5, forskolin 8.1 ± 0.8 pmol/mg non-collagen protein; control 5.0 ± 0.8, IBMX 6.8 ± 0.3 pmol/mg non-collagen protein). Ten resistant animals were treated with the β-adrenoceptor agonist isoproterenol (1–10 μg/kg/min), which failed to cause ventricular fibrillation despite significant increases in the hemodynamic parameters described above. Finally, experiments were repeated after 8-bromo-cAMP infusion and IBMX pretreatment in 8 susceptible animals with pharmacologic denervation (atropine + propranolol + prazosin). In spite of hemodynamic increases indicative of an increase in myocardial cyclic AMP levels, arrhythmias were not re-introduced. These data suggest that changes in cAMP may not be responsible for ventricular fibrillation in this model of sudden cardiac death.

Lipids and cardiac arrhythmia

In any discussion of lipids and heart disease it is beneficial from the outset to recognise that at least three different pathological processes may be involved. The first of these is atherosclerosis which involves the deposition of "fat" in the coronary vessels, another is thrombogenesis which describes the formation of blood clots in the coronary vessels, and the third is arrhythmia which refers to disorders in the beating of the heart which may become sufficiently serious to cause sudden cardiac death (SCD). Also it is this disturbance in the rhythmic beating of the heart which is responsible for much of the mortality from 'heart attacks' which occur 'outside-of-hospital' in societies like U.S.A., U.K. and Australia. It is this latter condition of cardiac arrhythmia which is the major concern of this review. Because it is often difficult to differentiate the role of lipids in 'heart disease' in man, it has frequently been assumed that all dietary fatty acids have similar effects on the different processes involved, and many unwarranted generalisations have been made which have led to conflicts of opinion amongst physicians and confusion in the lay public. From the animal studies discussed in this review, it is apparent that dietary fatty acids have an important role to play in determining the vulnerability of the myocardium to develop serious ventricular fibrillation (VF) and potentially lethal cardiac arrhythmia. In general, diets rich in saturated fatty acids promote a state of myocardial vulnerability, whilst diets rich in PUFA significantly diminish the probability of developing lethal disorders in cardiac rhythm when the heart is placed under pharmacological (or emotional) stress, or deprived of sufficient blood flow and supply of oxygen. Very recent experiments with the monounsaturated fatty acid (MUFA) oleic acid clearly demonstrate that, at least in rats subjected to ligation of their coronary artery, this acid is not 'neutral' as has been suggested by some for its role in atherosclerosis, but in fact is indistinguishable from saturated fatty acids in its effect in promoting arrhythmia during either regional ischaemia or reperfusion arrhythmia in this animal model of SCD.(ABSTRACT TRUNCATED AT 400 WORDS)

Protection against programmed electrical stimulation-induced ventricular tachycardia and sudden cardiac death by NE-10064, a class III antiarrhythmic drug.

The electrophysiologic and antifibrillatory properties of NE-10064 were studied in vivo in a conscious canine model of sudden cardiac death. Purpose bred male mongrel dogs weighing 14.5-21.5 kg were anesthetized, and surgical anterior myocardial infarction (MI) was induced by a 2-h occlusion, with reperfusion, of the left anterior descending coronary artery (LAD). Three to 5 days after induction of anterior wall MI, animals were subjected to testing by programmed electrical stimulation (PES). As compared with predrug incidence (12 of 12), NE-10064 (10 mg/kg intravenously, i.v.) reduced (p < 0.05) the incidence (8 of 12) of PES-induced ventricular tachycardia (VT). All but 1 control animal remained inducible after vehicle (5% dextrose in water). The cycle length of induced VT was not prolonged by NE-10064 (0.245 +/- 0.046 s predrug vs. 0.301 +/- 0.060 s postdrug). NE-10064 increased ventricular effective refractory period (VERP 166 +/- 5 ms predrug vs. 194 +/- 13 ms postdrug, p = 0.013), prolonged QTc interval (310 +/- 12 ms predrug vs. 350 +/- 16 ms postdrug, p = 0.004) and prolonged the effective refractory period (ERP) of noninfarcted myocardium (p = 0.045). The drug did not affect ECG-indexes of conduction velocity: QRS and P-R intervals were not affected, nor were activation delay and conduction time of noninfarcted and infarcted myocardium. In the sudden cardiac death protocol, NE-10064 protected (p = 0.018) against ischemia-induced ventricular fibrillation (VF, 75% survival with drug vs. 25% survival without drug). NE-10064 afforded protection (p = 0.040) throughout 14 h posterolateral ischemia in the presence of the previous anterior infarct.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The Anatomic Matrix as a Factor in Susceptibility to Lethal Arrhythmias in a Canine Model of Sudden Cardiac Death

In a previously reported canine model of sudden cardiac death, its authors heavily weighted the role of the autonomic nervous system in determining whether or not a combined stress of submaximal exercise and ischemia would produced a fatal arrhythmia the setting of a healed anterior wall myocardial infarction. This morphologic study of that model reveals that anatomic factors are also relevant to vulnerability to sudden death: dogs who developed ventricular fibrillation in response to such a stress (susceptible) had significantly more of the left ventricle (LV) infarcted than dogs who survived the stress (resistant): 13.14% (± 2.67 S.E.M) as compared with 4.01% (± 2.11 S.E.M.). Moreover, areas of fibrosis were spread more widely throughout the ventricle and septum in susceptible as compared with resistant animals, which consistently showed more homogeneous areas of infarct largely confined to the apical portion of the LV. While the autonomic nervous system may well be relevant to survival to stress in an animal which has survived a myocardial infarction, we conclude that there are important anatomic factors which determine vulnerability.

Sudden Cardiac Death: Future Approaches Based on Identification and Control of Transient Risk Factors

Sudden Cardiac Death. Future progress in the ability to control the problem of sudden cardiac death will require new approaches in applied epidemiology, methods of accurately evaluating therapeutic outcome, and techniques to identify and control those transient risk factors that are responsible for the initiation of fatal arrhythmias. In regard to the latter, transient risk factors are distinguished from classical risk factors in two ways: (1) they are not present continuously over time, thus confounding sampling techniques among a population; and (2) their dynamic nature suggests a proximate role in the initiation of potentially fatal arrhythmias in contrast to the role of classical risk factors in the genesis of the underlying diseases. Transient risk factors derive from the structure/function model of sudden cardiac death, which places structural abnormalities in a conditioning role, establishing the sensitivity to a transient destabilizing influence. In contrast, functional abnormalities are those conditions immediately responsible for destabilizing the system, establishing vulnerability to potentially fatal arrhythmias. They include four categories of risk: (1) transient ischemia and reperfusion; (2) systemic abnormalities, such as hemodynamic dysfunction and fluid and electrolyte imbalance; (3) autonomic fluctuations, both central and cardiac; and (4) cardiac toxic states, including proarrhythmic effects of antiarrhythmic drugs and arrhythmogenic effects of other substances. Sudden cardiac death is a dynamic problem, and its pathogenesis contains dynamic features. The ability to identify transient risk factors and to control them before they exert their influence on a conditioned electrophysiologic system will provide new inroads into the problem of sudden cardiac death.

Omega-3 PUFA's reduce the vulnerability of the rat heart to ischaemic arrhythmia in the presence of a high intake of saturated animal fat

The effect of dietary lipids upon the development of cardiac arrhythmias has been studied in an animal model of Sudden Cardiac Death. Ischaemic arrhythmia in mature male rats was induced by occlusion of the coronary artery. After 44 weeks of feeding various lipid modified diets, it was demonstrated that complete substitution of omega-6 polyunsaturated fatty acids (PUFA's) for saturated animal fat produced great benefits in cardiac function; as the number of ventricular premature beats (VPB), and the incidence (%) and severity (duration in seconds) of both ventricular tachycardia (VT) and ventricular fibrillation (VF) were markedly reduced. However, when mixed diets containing additional saturated fat (SF) plus either sunflower seed oil (SSO) rich in omega-6 PUFA or fish oil (FO) containing omega-3 PUFA's were compared, it was apparent that the inclusion of a relatively small proportion of omega-3 PUFA's in the diet was of great benefit as no VF was recorded in this group, whereas a similar proportion of omega-6 PUFA added to a saturated fatty acid rich diet was without significant effect. As the mixed SF/PUFA diets were constructed to contain essentially similar proportions of both saturated and monounsaturated fatty acids, but with contrasting amounts of either omega-6 or omega-3 PUFA's, the benefits observed by the inclusion of omega-3 PUFA's in the diet were direct and not due to coincidental changes in other fatty acid components of the diets.

Dietary fats and oils in cardiac arrythmia in rats

The effect of long-term feeding of various dietary fats and oils on cardiac arrhythmia was studied in an animal model of sudden cardiac death. After confirmation that a dietary supplement of saturated animal fat (SF) increased the animals' susceptibility to develop cardiac arrhythmia under ischemic stress whereas the polyunsaturated fatty acids of sunflower seed oil (SSO) reduced this susceptibility, we found that diets supplemented with either chemically refined palm oil (PO-I) or physically refined palm oil (PO-II) gave results that were generally intermediate in value between the SF and the SSO groups. However, during reperfusion of a previously ischemic heart, both PO-I- and PO-II-supplemented diets appeared to be as effective as SSO in reducing ventricular premature beats. In addition, the incidence of animals displaying severe ventricular fibrillation was much less after palm-oil feeding than it was after SF feeding. These preliminary results warrant further investigation of the potential antiarrhythmic effects of commercial palm oil.

Heart rate variability before and after myocardial infarction in conscious dogs at high and low risk of sudden death

Heart rate variability has been demonstrated both experimentally and clinically to be of prognostic importance in determining mortality after myocardial infarction. However, no paired studies have been reported to examine heart rate variability before and after myocardial infarction. The hypothesis was tested that low values of heart rate variability provided risk assessment both before and after myocardial infarction with use of an established canine model of sudden cardiac death. Risk for sudden death was assessed 1 month after myocardial infarction by a protocol in which exercise and myocardial ischemia were combined; dogs that developed ventricular fibrillation were classified at high risk for sudden death (susceptible) and the survivors were considered low risk (resistant). In resistant dogs, myocardial infarction did not affect any measure of heart rate variability: 1) mean RR interval, 2) standard deviation of the mean RR interval, and 3) the coefficient of variance (standard deviation/RR interval). By contrast, after myocardial infarction, susceptible dogs showed significant decrease in all measures of heart rate variability. Before myocardial infarction, no differences were seen between susceptible and resistant dogs. However, 30 days after infarction, epidemiologic analysis of the coefficient of variance showed high sensitivity and specificity (88% and 80%, respectively), predicting susceptibility. Therefore, results of analysis of 30 min of beat to beat heart period at rest 30 days after myocardial infarction are highly predictive for increased risk of sudden death.

Effects of Combined Thromboxane Synthetase Inhibition/Thromboxane Receptor Antagonism in Two Models of Sudden Cardiac Death in the Canine: Limited Role for Thromboxane

The effects of combined thromboxane synthetase inhibition and thromboxane receptor antagonism (TSI/TRA) were studied in conscious and in anesthetized canine models of sudden cardiac death. Administration of the TSI/TRA, R68070 10 mg/kg intravenously (i.v.), decreased thrombin-stimulated thromboxane synthesis and significantly antagonized platelet aggregation in response to the thromboxane-mimetic U46,619. In the conscious canine model, R68070 did not change ventricular refractoriness, did not prevent induction of ventricular arrhythmias by programmed electrical stimulation, and failed to prevent development of spontaneous ventricular fibrillation (VF) in response to ischemia produced at a site remote from the area of previous myocardial infarction (R68070 mortality = 70%, vehicle = 100%, p = NS). In the anesthetized canine model, R68070 prevented development of ischemia in 7 of 11 animals and reduced mortality significantly (R68070 27% and vehicle 73%; p = 0.038). R68070 inhibited thrombus formation in both models (R68070 conscious 7.0 +/- 2.6 mg and vehicle conscious 15 +/- 7.6 mg, p = NS; R68070 anesthetized 5.9 +/- 1.9 mg and vehicle anesthetized 17.7 +/- 4.3 mg; p less than 0.05). The results suggest that inhibition of thromboxane-dependent activity during acute recovery from infarction was able to protect the myocardium from developing ischemia in response to current-mediated intimal damage in a noninfarct-related artery. In the subacute phase of recovery from infarction, when the underlying myocardial substrate is susceptible to electrical derangement induced by transient ischemia, thromboxane inhibition in itself was unable to prevent ischemia-induced sudden cardiac death. Although R68070 may delay onset of ischemia due to thrombotic occlusion of the coronary artery, there does not appear to be an antiarrhythmic/antifibrillatory action to be derived from interfering with the synthesis or receptor-mediated action of thromboxane. Furthermore, R68070 does not alter the electrophysiologic properties of the heart which would result in an antiarrhythmic or antifibrillatory action.

Current concepts and animal models of sudden cardiac death for drug development

AbstractSudden cardiac death (SCD) or sudden coronary death, occurring in patients with unstable angina (angina at rest), myocardial ischemia with or without myocardial infarction (MI), and congestive heart failure (CHF), emerges as one of the most important challenges in cardiovascular medicine at present. Of the 1.5 million cases of myocardial infarction that occur each year in the U.S., about 540,000 patients will die and more than 300,000 of these will die before they reach a hospital, mostly due to ventricular fibrillation (VF) and/or SCD. About 4.8 million people alive in the U.S. have a history of myocardial infarction, angina pectoris, or both and are prime candidates for SCD. About 3 million people in the U.S. have congestive heart failure (CHF) and about 400,000 new cases are reported each year. One year mortality due to CHF is 33–58% and about 45% of the deaths are sudden. These patients were not those who had deleterious hemodynamic parameters whose demise could be predicted; they were those that died suddenly and unexpectedly of VF. Current pharmacological intervention in patients with a documented myocardial infarction with marketed antiarrhythmic agents has not reduced the overall mortality of SCD significantly. This suggests that an efficacious antiarrhythmic/antifibrillatory agent for the prevention of SCD does not exist at present and that there is an urgent need for such an agent.

Electrophysiologic actions and antifibrillatory efficacy of subacute left stellectomy in a conscious, post-infarction canine model of ischemic ventricular fibrillation

The autonomic nervous system appears to modulate ventricular arrhythmias associated with acute myocardial ischemia. This study investigated the electrophysiologic effects and antifibrillatory actions of subacute left stellectomy in a conscious, post-infarction canine model of sudden cardiac death. Twenty-two dogs with a previous anterior wall myocardial infarction and inducible ventricular arrhythmias were randomized to undergo either left stellectomy ( n = 12) or remain as sham-denervated controls ( n = 10). Five to 7 days post left stellectomy, there were no significant changes in heart rate, electrocardiographic intervals or ventricular refractoriness compared to sham-denervated controls. Acute posterolateral ischemia was produced in left stellectomy and sham-denervated dogs by anodal current-induced thrombosis via a previously positioned electrode in the left circumflex coronary artery. Ventricular fibrillation developed within 1 hour of the onset of ischemia (early ventricular fibrillation) in 3 12 (25%) left stellectomy dogs versus 8 10 (80%) sham-denervated controls ( P < 0.05). However, 24-hour mortality rate was 5 12 (42%) after left stellectomy versus 8 10 (80%) after sham denervation ( P = 0.072). Small differences in regional myocardial norepinephrine content, which is a marker for neuronal integrity, occurred in the mid-posterolateral and mid-anteroseptal regions of the left ventricle after left stellectomy. Overall norepinephrine concentration after left stellectomy was 409.70 ± 9.90 ng/g vs 428.07 ± 10.84 ng/g in sham controls ( P = NS). In summary, subacute left stellectomy significantly reduces the incidence of ventricular fibrillation occurring within 1 hour of the onset of acute posterolateral ischemia at a distance to a previous myocardial infarction in conscious dogs, and tends to reduce the ischemic post-infarction mortality at 24 hours after the onset of ischemia. This protective effect of left stellectomy is not due to any alteration in cardiac electrophysiologic parameters measured prior to the development of acute posterolateral ischemia, nor is it related to regional denervation as determined by myocardial tissue concentration of residual norepinephrine.

Effect of flecainide acetate on prevention of electrical induction of ventricular tachycardia and occurrence of ischemic ventricular fibrillation during the early postmyocardial infarction period: Evaluation in a conscious canine model of sudden death

The antiarrhythmic and antifibrillatory effects of flecainide acetate during the early postinfarction period were evaluated in a conscious canine model of sudden cardiac death. Ventricular tachycardia remained inducible early after infarction in eight of nine dogs receiving an intravenous loading dose of flecainide (2.0 mg/kg body weight) and seven of eight dogs receiving saline vehicle. In both the drug and vehicle groups, there was no significant change in the ventricular refractory period or in the cycle length of the induced ventricular tachycardia. With a maintenance intravenous infusion of flecainide, 1.0 mg/kg per h for 4 hours, the subsequent occurrence of acute posterolateral ischemia resulted in the development of ventricular fibrillation and sudden death in seven of eight flecainide-treated and eight of eight vehicle-treated dogs. Seven additional postinfarction dogs with noninducible tachycardia during pretreatment programmed stimulation, and thereby considered to be at "low risk" for the development of ischemic ventricular fibrillation, were also given flecainide in an intravenous loading and maintenance dosing regimen. The subsequent occurrence of posterolateral ischemia resulted in the development of ventricular fibrillation in three of these seven dogs. These findings suggest that flecainide acetate may not possess pharmacologic properties useful in managing ventricular tachycardia or in preventing ischemic ventricular fibrillation in the presence of recent myocardial damage.

Efficacy of diltiazem in two experimental feline models of sudden cardiac death

The potential role of calcium entry blockers in the prevention of life-threatening arrhythmias associated with acute myocardial ischemia and reperfusion is still controversial. In 98 anesthetized cats, the effect of diltiazem was examined in two experimental models. In protocol I, ventricular tachycardia or fibrillation was consistently induced by the interaction between a 2 minute coronary artery occlusion and a 30 second left stellate ganglion stimulation. After three trials under control conditions, if the same pattern of arrhythmia was induced, the drug under study was administered and three additional trials were performed. In 16 animals the administration of saline solution did not modify the pattern of arrhythmias. In contrast, diltiazem (0.1 mg/kg body weight plus 0.2 mg/kg per h) abolished both ventricular tachycardia and fibrillation that had occurred in 64 and 36%, respectively, of the cats in the control state. In protocol II, a 20 minute coronary artery occlusion was released in three groups; one served as the control group, one received diltiazem 15 minutes before occlusion and one received diltiazem 3 minutes before reperfusion. The incidence of reperfusion ventricular fibrillation was 62% (16 of 26) in the control group. It was significantly (p less than 0.05) reduced by diltiazem administered before the occlusion to 25% (4 of 16), whereas it was not affected when diltiazem was administered just before reperfusion (7 [47%] of 15). These results indicate that diltiazem exerts a striking protective effect against the malignant arrhythmias induced by the combination of acute myocardial ischemia and sympathetic hyperactivity. Diltiazem was also effective in reducing the incidence of life-threatening reperfusion arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostacyclin prevents ventricular fibrillation in a canine model of sudden cardiac death.

The antifibrillatory, antithrombotic and hemodynamic properties of intraventricular prostacyclin (PGI2) application were studied in conscious canine model of sudden cardiac death. In anesthetized dogs, a wire electrode was implanted into the left circumflex coronary artery (LCX) and acute myocardial ischemia was produced by 90 min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion. An intracardiac pressure transducer measured ventricular pressure, heart rate, filling pressure and dP/dt. The ECG was obtained from subcutaneous chest needles. Six days later while in ambulatory state, a 180 microA DC current was applied for 4 h to the LCX intimal lining in Tris-HCl (n = 10) and PGI2-treated dogs (50 and 100 ng/kg/min, 11 and 12 dogs, respectively). Myocardial injury and coronary thrombosis induced by electrical stimulation produced ventricular fibrillation in all vehicle-treated dogs at 145 +/- 33 min (mean +/- S.D.). In PGI2-treated hearts only 2 animals fibrillated at 150 +/- 29 min and 180 +/- 52 min following 50 and 100 ng/kg/min of the prostanoid, respectively. Thus, 18/23 PGI2-treated dogs survived 4 h electrical stimulation of the artery. Within the LAD perfusion zone infarction was observed of equal volumes in vehicle and PGI2-treated animals. No ischemia occurred distal to the LCX coronary thrombosis. Ventricular pressure fell in all groups. Heart rate increased in the controls and those animals treated with 50 ng/kg/min PGI2 while 100 ng/kg/min PGI2 increased heart rate by 22 +/- 5% (p less than 0.05). Filling pressure increased in controls but fell in the PGI2-treated hearts. The results indicate that PGI2 can prevent ventricular fibrillation resulting from acute ischemia at a site distant to previous myocardial ischemia with superimposed intimal injury and coronary thrombosis. The PGI2 properties are due to prevention of coronary thrombosis and the occlusion of the artery. Antifibrillatory effects of the prostanoids are suggested.

Experimental model of sudden cardiac death from unexplained cause.

To find a possible explanation for sudden cardiac death from unexplained cause, an experimental model was made with rabbits. The rabbits were fed an atherogenic diet for 2 and 4 months without precordial x-irradiation. Though the coronary sclerosis in the hearts of these rabbits was only slight or not detectable, the ventricular premature contraction threshold (VPCT) and the ventricular fibrillation threshold (VFT) decreased by about 50% and 60% of those in the control animals, respectively. The investigation of isozyme patterns of LDH, GOT, MDH and CPK in the hearts revealed that the changes of these isozyme patterns were almost identical with the results from the human hearts of sudden cardiac death from unexplained cause. From these results, the rabbits fed an atherogenic diet without precordial x-irradiation can be an experimental model of sudden cardiac death from unexplained cause.