Decrease In Ventricular Fibrillation Threshold Research Articles

Functional selectivity of cardiac preganglionic sympathetic neurones in the rabbit heart

BackgroundStudies have shown regional and functional selectivity of cardiac postganglionic neurones indicating there might exist a similar heterogeneity in spinal segmental preganglionic neurones, which requires further investigation. MethodsRight and left sympathetic chains were electrically stimulated from T6 to T1 in the innervated isolated rabbit heart preparation (n = 18). Sinus rate, left ventricular pressure, retrograde ventriculo-atrial conduction, monophasic action potential duration, effective refractory period, ventricular fibrillation threshold and electrical restitution were measured. ResultsRight sympathetic stimulation had a greater influence on heart rate (T1-T2: right; 59.9 ± 6.0%, left; 41.1 ± 5.6% P < 0.001) and left stimulation had greater effects on left ventricular pressure (T1-T2: right; 20.7 ± 3.2%, left; 40.3 ± 5.4%, P < 0.01) and ventriculo-atrial conduction (T1-T2: right; −6.8 ± 1.1%, left; −15.5 ± 0.2%) at all levels, with greater effects at rostral levels (T1-T3). Left sympathetic stimulation caused shorter monophasic action potentials at the base (T4-T5: right; 119.3 ± 2.7 ms, left; 114.7 ± 2.5 ms. P < 0.05) and apex (T4-T5: right; 118.8 ± 1.2 ms, left; 114.6 ± 2.6 ms. P < 0.05), greater shortening of effective refractory period (T4-T5: right; −3.6 ± 1.3%, left; −7.7 ± 1.8%. P < 0.05), a steeper maximum slope of restitution (T4-T5 base: right; 1.3 ± 0.2, left; 1.8 ± 0.2. P < 0.01. T4-T5 apex: right; 1.0 ± 0.2, left; 1.6 ± 0.3. P < 0.05) and a greater decrease in ventricular fibrillation threshold (T4-T5: right; −22.3 ± 6.8%, left;-39.0 ± 1.7%), with dominant effects at caudal levels (T4-T6). ConclusionsThe preganglionic sympathetic efferent axons show functionally distinct pathways to the heart. The caudal segments (T4-T6) of the left sympathetic chain had a greater potential for arrhythmia generation and hence could pose a target for more focused clinical treatments for impairments in cardiac function.

Altered thyroid status affects myocardial expression of connexin-43 and susceptibility of rat heart to malignant arrhythmias that can be partially normalized by red palm oil intake.

We aimed to study the impact of altered thyroid status on myocardial expression of electrical coupling protein connexin-43 (Cx43), the susceptibility of rats to ventricular fibrillation (VF) and the effects of antioxidant-rich red palm oil (RPO). Adult male and female euthyroid, hyperthyroid (treated with T3/T4), hypothyroid (treated with methimazole) Wistar rats supplemented or not with RPO for 6weeks were used. Function of isolated perfused heart and VF threshold were determined. Left ventricular tissue was used for assessment of mRNA and protein levels of Cx43, its phosphorylated forms and topology. Protein kinase C signaling (PKC) and gene transcripts of some proteins related to cardiac arrhythmias were assessed. Hyperthyroid state resulted in decrease of total and phosphorylated forms of Cx43 and suppression of PKC-ε expression in males and females, decrease of Cx43 mRNA in females, decrease of VF threshold and increase of functional parameters in male rat hearts. In contrast, hypothyroid status resulted in the increase of total and phosphorylated forms of Cx43, enhancement PKC-ε expression in males and females, increase of Cx43 mRNA in females, increase of VF threshold and decrease of functional parameters in male rat hearts. Function of the heart was partially normalized by RPO intake, which also enhanced myocardial Cx43 and PKC-ε expression as well as increased VF threshold in hyperthyroid male rats. We conclude that there is an inverse relationship between myocardial expression of Cx43, including its functional phosphorylated forms, and susceptibility of male rat hearts to VF in condition of altered thyroid status. RPO intake partly ameliorated adverse changes caused by excess of thyroid hormones.

Trimetazidine demonstrated cardioprotective effects through mitochondrial pathway in a model of acute coronary ischemia

Myocardial ischemia affects mitochondrial function leading to ionic imbalance and susceptibility to ventricular fibrillation. Trimetazidine (TMZ), a metabolic agent, is clinically used as an anti-anginal therapy. This study was conducted to compare the effect of TMZ 20mg immediate release (IR) and TMZ 35mg modified release (MR), two bioequivalent marketed formulations of TMZ, on cardioprotection during acute ischemia in pigs. A 4-day oral treatment with TMZ 20mg IR (800mg, tid) or TMZ 35mg MR (1,400mg, bid) had no effect on ventricular fibrillation threshold (VFT) prior to ischemia but significantly prevented the decrease in VFT observed in placebo-treated groups after a 1-min left anterior descending coronary artery occlusion. This effect occurred without modifying cardiac hemodynamic and conduction parameters. In both TMZ-treated groups, a significant reduction of the ischemic area as well as a protection of cardiomyocytes were observed. Cardiac enzymatic activity (phosphorylase, succinate dehydrogenase, ATPase) was increased in TMZ-treated groups. Both formulations preserved mitochondrial structure and improved mitochondrial function as demonstrated by a twofold increase of oxidative phosphorylation, by a reduction of reactive oxygen species (ROS) production (>30%) and by a trend to increase the mitochondrial calcium retention capacity. In this model of ischemia, both TMZ formulations, leading to equivalent TMZ plasma exposures, demonstrated similar cardioprotective effects. This protection could be attributed to a preservation of mitochondrial structure and function, which plays a central role in ATP and ROS production and consequently could be considered as a target of cardioprotection.

Electrophysiological effect of rotigaptide in rabbits with heart failure.

IntroductionRotigaptide is a new anti-arrhythmic peptide, which has recently been found to increase junctional conductance and prevent ischemia-induced ventricular tachycardia. In this study, we attempted to investigate the effects and mechanisms of rotigaptide on the vulnerability to ventricular arrhythmias in rabbits with heart failure (HF).Material and methodsChronic volume-pressure overload was used to induce HF. After rotigaptide infusion, an electrophysiological study was performed to record monophasic action potential (MAP), determine the effective refractory period (ERP) and ventricular fibrillation threshold (VFT), and assess the susceptibility to ventricular arrhythmia. Finally, real-time PCR was used to detect the changes of connexin 43 (Cx43) mRNA expression.ResultsHF rabbits exhibited significant down-regulation of Cx43 mRNA, increase of effective refractory period (ERP) and decrease of VFT (p < 0.05, respectively). These changes resulted in an increase of vulnerability to ventricular tachyarrhythmias (VT/VF). Rotigaptide administration shortened ERP (113.3 ±8.6 ms vs. 131.7 ±12.5 ms, p < 0.05), restored VFT (15.0 ±2.0 V vs. 6.3 ±1.4 V, p < 0.05), and decreased the vulnerability to VT/VF. However, short-term rotigaptide treatment had no significant effect on MAP duration (MAP duration at 90% repolarization: 169.3 ±6.0 ms vs. 172.7 ±6.2 ms, p > 0.05) or connexin 43 mRNA expression (p > 0.05).ConclusionsRotigaptide decreases the ERP, elevates VFT, and reduces the vulnerability to ventricular arrhythmias without changing Cx43 expression in rabbits with HF. It may be a promising antiarrhythmic drug for preventing ventricular arrhythmia in HF.

11 Trimetazidine demonstrated cardioprotective effects through mitochondrial pathway in a model of acute coronary ischaemia in pig

Myocardial ischaemia affects mitochondrial function leading to ionic imbalance and susceptibility to ventricular fibrillation. Trimetazidine (TMZ), a metabolic agent, is clinically used as an anti-anginal therapy. This study was conducted...

Inhibition of NADPH oxidase up-regulates connexin 43 and ameliorates electrical remodeling in rabbits with heart failure

Background We hypothesized that inhibition of NADPH oxidase by apocynin can ameliorate electrical remodeling and exert antiarrhythmogenic effect by up-regulating connexin 43 (Cx43) in rabbits with heart failure (HF). Methods HF was induced by volume overload plus pressure overload. Rabbits with HF or sham operation were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for eight weeks. Eight weeks after surgery, QRS duration, monophasic action potential duration (MAPD), effective refractory period (ERP), the inducibility of ventricular arrhythmia and ventricular fibrillation threshold (VFT) were evaluated by in vivo electrophysiological study. The Cx43 expression was examined by Real-time PCR and Western blot. Results Apocynin treatment reduced QRS duration, shortened MAPD at 90% repolarization (MAPD 90) and ERP in rabbits with HF. The vulnerability for ventricular arrhythmias was increased in HF hearts, and this increased vulnerability to arrhythmias was reversed by apocynin. The HF rabbits exhibited a marked decrease in VFT compared with sham rabbits, but this decrease was ameliorated by apocynin. Compared with sham-operated rabbits, the total Cx43 mRNA and protein expression and the phosphorylated Cx43 protein were decreased in the HF rabbits, but the reduction was reversed by apocynin. Conclusion Inhibition of NADPH oxidase increases Cx43 expression, ameliorates electrical remodeling and exerts antiarrhythmogenic effect in rabbits with HF. Inhibition of NADPH oxidase could have the potential to become a new antiarrhythmic preventive therapy for HF.

Carvedilol Ameliorates the Decreases in Connexin 43 and Ventricular Fibrillation Threshold in Rats with Myocardial Infarction

Connexin 43 (Cx43) is the most prominent connexin in the mammalian ventricular myocardium and forms gap junctions that are essential for normal conduction of action potential. Carvedilol, a nonselective beta-blocker, is widely used to prevent ventricular arrhythmias after myocardial infarction (MI). Here, we examined the effect of carvedilol on the expression of Cx43 protein and ventricular fibrillation threshold (VFT) using a rat MI model. VFT is defined as the lowest voltage, at which ventricular fibrillation is induced by electrical stimulation. Adult male Wister rats were divided into sham-operated group (n = 20) and MI groups treated with intragastric administration of saline (control, n = 30) or carvedilol (2.5 mg/kg, n = 30) twice a day for 7 days immediately after ligation of the left coronary artery. Compared with sham group (100%), total Cx43 protein and phosphorylated Cx43 protein were decreased in the MI rats to 60 +/- 21% and 52 +/- 19% (both P < 0.05), respectively. Treatment with carvedilol prevented the MI-induced decrease in total and phosphorylated Cx43 levels (91 +/- 17% and 80 +/- 20%, both P < 0.05), respectively, which were similar to the levels of sham animals. Moreover, the MI rats exhibited a marked decrease in VFT compared with the sham group (7.2 +/- 1.30 vs. 13.0 +/- 2.12 V, P < 0.05), but the decrease was abolished by carvedilol (11.0 +/- 2.65 V). In conclusion, carvedilol might prevent the ischemia-induced ventricular arrhythmias by restoring Cx43 protein and VFT to the basal levels.

Activation of peripheral δ opioid receptors eliminates cardiac electrical instability in a rat model of post-infarction cardiosclerosis via mitochondrial ATP-dependent K + channels

The effects of the selective delta-1 (δ 1) opioid receptor agonist, DPDPE, and the selective δ 2 opioid receptor agonist, DSLET, have been studied on the ventricular fibrillation threshold (VFT) in rats with an experimental post-infarction cardiosclerosis (CS). It has been found that CS induced a significant decrease in VFT. This CS-induced decrease in VFT was significantly reversed by intravenous administration of DPDPE (0.1 mg/kg) 10 min before VFT measurement. On the contrary, intravenous injection of DSLET (0.5 mg/kg) exacerbated the CS-induced cardiac electrical instability. Pretreatment with the selective δ opioid receptor antagonist, ICI 174,864 (0.5 mg/kg), completely abolished the changes in VFT produced by both DPDPE and DSLET. Previous administration of a nonselective peripherally acting opioid receptor antagonist, naloxone methiodide (5 mg/kg) also completely reversed the antifibrillatory action of DPDPE. Naloxone methiodide and ICI 174,864 alone had no effect on VFT. Pretreatment with the nonselective K ATP channel blocker, glibenclamide (0.3 mg/kg), or with the mitochondrial selective K ATP channel blocker, 5-hydroxydecanoic acid (5-HD, 5 mg/kg), completely abolished the DPDPE-induced increase in cardiac electrical stability. Glibenclamide and 5-HD alone had no effect on VFT. These results demonstrate that the δ opioid receptor plays an important role in the regulation of electrical stability in rats with post-infarction cardiosclerosis. We propose that peripheral δ 1 opioid receptor stimulation reverses CS-induced electrical instability via mitochondrial K ATP channels. On the contrary, δ 2 opioid receptor stimulation may exacerbate the CS-induced decrease in VFT. Further studies are necessary to determine the δ opioid receptor subtype which mediates the antifibrillatory effect of DPDPE and pro-fibrillatory effect of DSLET.

Ligands for opioid and σ-receptors improve cardiac electrical stability in rat models of post-infarction cardiosclerosis and stress

The effects of the extremely selective μ-opioid receptor agonist, [D-Arg 2,Lys 4]-dermorphin-(1–4)-amide (DALDA), the μ-opioid receptor agonist morphine, the μ δ agonist D-Ala 2, Leu 5, Arg 6-enkephalin (dalargin), the κ-opioid receptor agonist spiradoline and the σ 1-receptor antagonist DuP 734 on ventricular fibrillation threshold (VFT) was investigated in an experimental post-infarction cardiosclerosis model and an immobilization stress-induced model in rats. Both models produced a significant decrease in VFT. The postinfarction cardiosclerosis-induced decrease in VFT was significantly reversed by intravenous administration of dalargin (0.1 mg kg ), DALDA (0.1 mg kg ), or morphine HCl (1.5 mg kg ). Pretreatment with naloxone (0.2 mg kg ) completely eliminated the increase in cardiac electrical stability produced by DALDA. Both spiradoline (8 mg kg , i.p.) and DuP 734 (1 mg kg , i.p.) produced a significant increase in VFT in rats with postinfarction cardiosclerosis. This effect of spiradoline was blocked by nor-binaltorphimine. The immobilization stress-induced decrease in VFT was significantly reversed by administration of either DALDA, spiradoline or DuP 734. In conclusion, activation of either μ- or κ 1-opioid receptors or blockade of σ 1-receptors reversed the decrease in VFT in both cardiac compromised models. Since DALDA and dalargin essentially do not cross blood brain barriers, their effects on VFT may be mediated through peripheral μ-opioid receptors.

Importance of beta blockade in the therapy of serious ventricular arrhythmias

Beta blockers have traditionally been considered relatively poor antiarrhythmic agents for patients with ventricular arrhythmias. This view is based on the observations that β blockers are less effective in suppressing spontaneous ventricular ectopy or inducible ventricular arrhythmias than are the class I and class III agents. However, there are convincing data that β blockers can have a clinically important antiarrhythmic effect and prevent arrhythmic and sudden death. Beta blockers have multiple potential effects that can contribute to a therapeutic antiarrhythmic action, including an antiadrenergic/vagomimetic effect, a decrease in ventricular fibrillation threshold, and prevention of a catecholamine reversal of concomitant class I/III antiarrhythmic drug effects. Postinfarction trials, recent congestive heart failure studies, and observations in patients who are at risk for sustained ventricular arrhythmias all suggest a potent antiarrhythmic effect of β blockade.

Calcium antagonists and prevention of ventricular fibrillation induced by transient or persistent ischemia.

Experimental studies have shown the limitation by calcium antagonists of the propensity to fibrillation secondary to the occlusion of a large coronary artery. However, this capacity, studied in the acute phase of infarction, is less obvious and still under debate. Ischemia was therefore produced in anesthetized, open-chest pigs by complete occlusion of the left anterior descending coronary artery according to two modes, either near its origin during brief but increasing periods (30, 60, 120, 180 s, etc) or half-way from this origin for a much longer time (60 min). The time course of vulnerability to fibrillation was monitored by ventricular fibrillation threshold (VFT), measured by trains of diastolic stimuli of 100 ms. Verapamil was administered in a 50 micrograms/kg dose followed by 2 micrograms/kg/min infusion. 1) In the case of brief proximal occlusions under pacing at a constant high rate (180 beats/min), verapamil slowed the decline of VFT from 6-8 mA to nearly 0 mA. VFT was 4.4 +/- 0.4 mA after 60 s ischemia, whereas it had already fallen to 1.8 +/- 0.3 mA (p < 0.001) in the absence of the drug. Accordingly, the onset of spontaneous fibrillation which depends on the decrease in VFT to about 0 mA was prolonged from 2-3 to 6-9 min. Bradycardia, concurrently produced by verapamil, is a factor which enhances these alterations. 2) In the case of a persistent midportion occlusion of the artery under sinus rate, fibrillations were similarly delayed by verapamil from 14-25 to 23-49 min after occlusion, but they were more numerous. VFT was lowered to critical values later, but also for a longer time. The period propitious to fibrillation was prolonged because the return of VFT to higher values reflecting hypoexcitability subsequent to the first cell injury was substantially delayed. Consequently, calcium antagonists should often prevent ventricular fibrillation when transient ischemia disappears before VFT falls to the vicinity of 0 mA. In contrast, a real benefit could not be expected from these drugs when ischemia is persistent since they then only delay fibrillations, the number of which is increased.

Change in opioid peptide level in the heart and blood plasma during acute myocardial ischaemia complicated by ventricular fibrillation.

1. The influence of acute myocardial ischaemia (AMI) complicated by ventricular fibrillation (VF) on opioid peptide level in myocardium and blood plasma of rats has been studied. 2. Leu-enkephalin level in myocardium of rats with AMI and VF has been found to be significantly lower than in animals with AMI but without VF. 3. Met-enkephalin level has been found to be significantly increased in both animals with VF and without it. We have not found a significant difference in met-enkephalin level in myocardium of animals with VF and without it. 4. AMI was induced to increase the enkephalin and beta-endorphin level in blood plasma of all the animals, whether VF had occurred or not. 5. Preliminary administration of D-Ala2,Leu5,Arg6-enkephalin, a synthetic analogue of leu-enkephalin, has prevented a decrease of ventricular fibrillation threshold in experimental coronary occlusion. 6. The obtained results allow us to conclude that enkephalins of myocardium but not opioid peptides of blood plasma play an important role in VF occurrence.

Preconditioning reduces infarct size but accelerates time to ventricular fibrillation in ischemic pig heart

Preconditioning protects the rat heart from ventricular arrhythmias. However, the mechanism of this beneficial effect and its existence in large animal models remain unknown. We submitted 49 pigs to 40 min of left anterior descending coronary occlusion and 2 h of reperfusion and assessed the incidence of ventricular fibrillation (VF) and time to VF. Monophasic action potential duration (MAPD) and ventricular fibrillation threshold (VFT) were measured throughout the experiment. Preconditioning significantly reduced infarct size but failed to reduce the incidence of VF either during the 40-min ischemic insult or the following reperfusion. Moreover, preconditioning accelerated the onset of VF during the prolonged ischemia; time to VF averaged 8 +/- 2 min in the preconditioned group vs. 18 +/- 2 min in the control group (P < 0.05). This premature peak of VF in preconditioned hearts was associated with a significant decrease of VFT and shortening of MAPD. This suggests that preconditioning does not limit the incidence of VF in the pig model. Rather, preconditioning decreases the time to VF in this species, likely through lowering of the VFT and shortening of the action potential duration.

Contrasting effects of cyclic AMP increase caused by beta-adrenergic stimulation or by adenylate cyclase activation on ventricular fibrillation threshold of isolated rat heart.

Increased myocardial tissue cyclic AMP has been associated with both a positive inotropic and a proarrhythmic effect. We wished to determine whether two agents that increase myocardial cyclic AMP levels by different mechanisms would induce comparable changes in vulnerability of the heart to ventricular fibrillation (VF) and in the inotropic status. Using an isolated perfused rat heart model, we studied the effects of beta-adrenoceptor stimulation by isoproterenol (ISO) and direct activation of adenylate cyclase by forskolin. The ventricular fibrillation threshold (VFT) was taken as an index of the vulnerability to VF and peak left ventricular systolic pressure (LVSP) as a measure of the force of LV contraction. ISO resulted in a dose-related increase in tissue cyclic AMP with a corresponding decrease in VFT and a marked increase in LVSP. Forskolin produced a delayed but exponential increase in cyclic AMP at concentrations greater than 3 x 10(-7) M with relatively small increases in LVSP. With forskolin, the VFT decreased only at extremely high cyclic AMP levels, suggesting that the drug had increased cyclic AMP in a compartmentalized manner. The discrepant effects of ISO and forskolin on VFT could not be explained by changes in heart rate (HR). These results show that an increase in tissue cyclic AMP can have markedly different arrhythmogenic effects depending on the mechanism by which cyclic AMP is increased.

Ventricular fibrillation threshold is influenced by left ventricular stretch and mass in the absence of ischaemia

Ischaemic heart disease is known to contribute to the development of ventricular arrhythmias. However, the role of non-ischaemic variables has been less well defined. We therefore studied the effect of myocardial stretch and ventricular mass on the vulnerability of the rat heart to ventricular fibrillation. DESIGN AND EXPERIMENTAL MATERIAL: Two groups of rat hearts were studied in an isolated buffer perfused apparatus: group I, mature female animals with an average dry left ventricular weight of 73 mg and group II, a group of retired breeders with an average left ventricular weight of 122 mg. Hearts performed isovolumetric work at either low (0 mm Hg) or high (20 mm Hg) left ventricular end diastolic pressures. Ventricular fibrillation was provoked by trains of ventricular extrastimuli delivered at increasing current until development of the arrhythmia. The current required to provoke ventricular fibrillation decreased in both groups at the high left ventricular end diastolic pressure and the larger hearts in group II were more vulnerable to ventricular fibrillation than those in group I. The decrease in ventricular fibrillation threshold occurred in the absence of an increase in myocardial lactate production or a decrease in endocardial to epicardial flow ratios. This study thus identified two variables, myocardial stretch and ventricular mass, which influence the development of ventricular fibrillation and which are independent of myocardial ischaemia in this animal model. These observations may be relevant to an understanding of the increased incidence of lethal arrhythmias which occur in patients with dilated cardiomyopathies.

Comparative Antifibrillatory Effects of d- and dl-Sotalol in Normal and Ischaemic Ventricular Muscle of the Cat

The aim of this study was to compare the effects of d- and dl-sotalol on the ventricular fibrillation threshold (VFT) and the effective refractory period (VERP) in anaesthetized cats subjected to coronary artery occlusion. Occlusion of the left anterior descending coronary artery caused a decrease in VFT (measured in mA) (1.40 +/- 0.1 to 0.6 +/- 0.1). dl-Sotalol (1 and 5 mg kg-1) increased VFT before the induction of ischaemia (1.7 +/- 0.1 to 33.8 +/- 1.0 and 38, respectively), and the higher dose prevented the ischaemia-induced fall in VFT. d-Sotalol (1 and 5 mg kg-1) caused only small increases in VFT in normal (1.9 +/- 0.3 to 2.3 +/- 0.3 and 2.6 +/- 0.3) and ischaemic (0.8 +/- 0.1 to 1.2 +/- 0.2 and 1.3 +/- 0.2) myocardium. Both d- and dl-sotalol increased VERP measured in normal myocardium. The % changes observed with 1 and 5 mg kg-1 of the racemate (17 +/- 1 and 57 +/- 4) were significantly greater than those with the d-isomer (8 +/- 3 and 16 +/- 2). dl-Sotalol, but not d-sotalol, prevented the haemodynamic responses to 50 ng kg-1 isoprenaline. These results suggest that VFT in anaesthetized cats is markedly increased by beta-adrenoceptor blockade and only marginally increased by the direct class III antiarrhythmic action of d-sotalol.

Electrical alternans and cardiac electrical instability.

We investigated the relationship between electrical alternans and cardiac electrical stability in a series of 20 dog experiments and in a pilot clinical study. Electrical alternans was detected in both the QRS complex and the ST-T wave by use of a novel multidimensional spectral technique. The magnitude of the alteration was expressed as the alternating electrocardiographic morphology index (AEMI), expressed as parts per million of waveform energy. Electrical stability in the dog preparations was assessed via the ventricular fibrillation threshold measurement, and in the clinical studies via programmed stimulation. In 10 dog experiments, systemic hypothermia resulted in a 60% decrease in ventricular fibrillation threshold (VFT) (p less than .0001) and a significant increase in both AEMI(QRS) form 3.7 +/- 3.0 to 1448 +/- 548 (p less than .0001) and AEMI(ST-T) from 43.9 +/- 18.4 to 19,178 +/- 5579 (p less than .0001). In 10 dog experiments, transient coronary artery ligation also resulted in a 60% decrease in VFT (p less than .0001), an increase from 76.3 +/- 46.5 to 245 +/- 11 in AEMI(QRS) (p less than .05), and an increase from 842 +/- 505 to 1365 +/- 392 in AEMI(ST-T) (p less than .002). In 119 observations in 20 animal experiments, the rank correlation between VFT and AEMI(QRS) was -.30 (p less than .001), with that between VFT and AEMI(ST-T) being -.55 (p less than .0001). In a double-blind pilot clinical trial consisting of 23 studies in 19 patients, the result of electrophysiologic testing was used as an independent measure of cardiac electrical stability. Alternation in waveform morphology identified the inducible patient population with a sensitivity of 92%, a positive predictivity of 70%, and a specificity of 50% (p less than .05). We conclude that analysis of subtle beat-to-beat variability in electrocardiographic morphology may provide a noninvasive measure of cardiac electrical stability.

Electrophysiologic effects of beta blockers in ventricular arrhythmias

β-adrenergic receptor blocking agents are effective antiarrhythmic drugs in patients with ventricular arrhythmias. However, these agents exert little or no measurable electrophysiologic effect on normal Purkinje and ventricular muscle fibers when administered acutely. They prevent catecholamine-induced increases in Purkinje fiber automaticity and may interfere with catecholamine-dependent slow responses. β-adrenergic blocking drugs also prevent the decrease in ventricular fibrillation threshold induced by catecholamines. In the acutely ischemic ventricle, some β blockers selectively depress conduction within the ischemic zone. The long-term administration of some β blockers has, in contrast to their short-term effects, been shown to prolong action potential duration and effective refractory period in the ventricle. Which of these observed electrophysiologic effects, either alone or in combination, contributes to the ventricular antiarrhythmic effects of β-blocking drugs in man is at present unknown.

Effect of thromboxane synthetase inhibition on vulnerability to ventricular arrhythmia following coronary occlusion

Release of thromboxane (TXA 2) during acute myocardial infarction may be an important contributing factor in the genesis of ventricular fibrillation (VF). We assessed the effect of selective TXA 2 inhibition on vulnerability to VF after total occlusion of the anterior descending coronary artery in chloralose-anesthetized cats. Animals were pretreated with vehicle or with CGS-13080, a TXA 2 synthetase inhibitor, 3.0 or 9.0 mg/kg intravenously. There was an apparent dose-dependent protective effect following CGS-13080 administration, in which the decrease in VF threshold following coronary occlusion was attenuated. Also, the incidence of spontaneous ventricular arrhythmia in the first 30 minutes after occlusion was reduced by two thirds in the 9.0 mg/kg CGS-13080 group compared to the vehicle-treated animals. This protective effect does not appear to be due to a change in hemodynamics, effective refractory periods, or extent of ischemia. TXA 2 released during coronary occlusion appears to be arrhythmogenic, and inhibiting its synthesis may be protective.

Effect of coronary vasodilation on ventricular fibrillation threshold: Role of exogenous vasodilators and perfusion conditions

Even without myocardial ischemia, coronary blood flow (CBF) constitutes a major determinant of ventricular fibrillation threshold (VFT). To clarify whether abnormal distribution of normal or increased CBF plays any additional role, 14 open-chest chloralose-anesthetized dogs with fixednormalized heart rate, cardiac output, and systemic arterial pressure and separate servocontrolled left main coronary artery perfusion were studied as follows: VFT was determined first with coronary perfusion pressure (CPP) set at systemic level (80 mm Hg). Then CBF index was fixed at control levels (134.0 ± 9.5 ml/min · 100 gm −1 LV) and coronary vasodilation was induced by intracoronary infusion of adenosine until CPP decreased to 49.0 ± 2.0 mm Hg. Myocardial O 2 consumption, LV pressure, LV dp dt , and surface ECG remained unchanged. However, VFT decreased in all trials by about 45% ( p < 0.001). When CPP was reset to 80 mm Hg while maintaining vasodilation, CBF index increased by 90% to 255.4 ± 15.4 ml/min · 100 gm −1 LV and VFT by 26% ( p < 0.005) from control. Yet these VFT increases in response to intraluminal pharmacologic vasodilation were about 19% ( p < 0.002) lower than expected for similar CBF index increases occurring physiologically. We conclude that intraluminal coronary vasodilation not matched by appropriate CBF increase results in substantial decrease of VFT. Moreover, at comparable increase of CBF, spontaneous physiologic vasodilation is more effective than intraluminal pharmacologic coronary vasodilation in increasing VFT.