Ischemia-induced Conduction Delay Research Articles

J wave dynamicity during coronary angiography and intracoronary acetylcholine administration.

J-waves may be observed during coronary angiography (CAG) or intracoronary acetylcholine (ACh) administration, but their significance is unknown. Forty-nine patients, 59.1±11.5 years old and 59% male, were studied on suspicion of vasospastic angina, and J wave dynamicity was compared between CAG and Ach administration. Diagnostic (≥0.1mV) or nondiagnostic (<0.1mV) J waves in 9 and 3 patients, respectively, were augmented, and J waves were newly observed in 2 patients during CAG and Ach administration. Similar changes in the J-wave amplitude were observed: from 0.10±0.09mV to 0.20±0.15mV (p<.002) and from 0.10±0.10mV to 0.20±0.16mV (p<.001) during CAG and Ach administration, respectively. J waves were located in the inferior leads and changed only during the right coronary interventions. In the remaining 35 patients, J waves were absent before and during the coronary interventions. Augmentation of J waves was found when the RR interval was shortened in some patients. Injection of anoxic media into the coronary artery might induce a conduction delay from myocardial ischemia that manifests as augmentation or new occurrence of J waves. Both CAG and intracoronary Ach administration affected J waves similarly in the same individuals. A myocardial ischemia-induced conduction delay may be responsible for the changes in J waves, but further studies are needed.

Malignant arrhythmias and acute myocardial ischemia: Interaction between flecainide and the autonomic nervous system

The antiarrhythmic and proarrhythmic effects of flecainide were assessed in 21 anesthetized cats. Ventricular arrhythmias can be reproducibly induced in cats by the combination of acute myocardial ischemia and sympathetic stimulation. Premature ventricular contractions (PVCs), sustained (sVT) and nonsustained (nsVT) ventricular tachycardia (VT), or ventricular fibrillation (VF) may be induced by a 1-minute left stellate ganglion stimulation during a 3-minute coronary artery occlusion. After three trials yielding consistent results, flecainide (2 mg/kg intravenous bolus plus 2 mg · kg −1 · hr −1 intravenous infusion) was injected and two additional trials performed. Eight cats also underwent two trials after propranolol (0.2 mg/kg) administered while flecainide infusion was maintained. Flecainide decreased heart rate and blood pressure and slightly prolonged JTc (9%, p < 0.05). It markedly augmented QRS duration (61%, p < 0.0001), which was increased by an additional 61% ( p < 0.0001) during sympathetic stimulation. VF was observed in 8 animals and never after flecainide ( p < 0.05). However, after drug administration all cats had VT (2 nsVT and 6 sVT), and 5 required cardiac massage. Flecainide did not prevent the occurrence of nsVT in 6 cats, and it worsened arrhythmias by inducing VT (4 nsVT and 2 sVT) in 6 cats with only PVCs or without arrhythmias in the control trials. Propranolol, administered while flecainide infusion was maintained, prevented the increase in heart rate and the marked QRS prolongation during sympathetic stimulation (4 ± 3 vs 52 ± 16 msec, p < 0.05) and abolished the proarrhythmic effect of flecainide in 4 of 5 animals. Thus flecainide, despite an antifibrillatory effect, does not prevent and actually may favor the occurrence of sVT during acute myocardial ischemia and enhanced sympathetic activity. Propranolol, by countering the increase in heart rate during sympathetic stimulation, prevented the rate-dependent conduction delay and abolished the proarrhythmic effect of flecainide. The exacerbation, whenever a transient ischemic episode is accompanied by elevated sympathetic activity, of the ischemia-induced conduction delay caused by flecainide may in part explain the mortality data in the Cardiac Arrhythmia Suppression Trial.

Amlodipine, a long-acting calcium antagonist drug reduces ischemia-induced ventricular conduction delay in pig hearts

The effects of amlodipine, a novel, long-lasting calcium channel blocking agent, on ischemia-induced myocardial conduction delay was studied in anesthetized pigs paced at a constant heart rate. Acute coronary occlusion (3 minutes) significantly lengthened time to onset, time to peak and duration of bipolar electrograms recorded from both subendocardial and subepicardal left ventricular sites. After intravenous injection of amlodipine (0.3 mg/kg, n = 6), subsequent periods of ischemia greatly reduced (p < 0.01) all indexes of subepieardial conduction delay. In the subendocardium, amlodpine decreased only time to onset (−25 ± 4%, p < 0.01) within the ischemie zone. Significant delays in all indexes were present during repeated ischemic periods in the placebo-treated control group (n = 5). Amlodpine also Increased regional myocardial blood flow within the nonischemic myocardium by 25 ± 10% and deceased mean aortic pressure by 7 ± 2% without altering flow in the ischemic region. Left atrial pressure remained unchanged. Indexes of ischemia-induced conduction delay were more rapidly restored after reperfusion in amlodipine-pretreated than in control animals. In conclusion, amlodipine produced a beneficial blood flow-independent effect on ischemia-induced injury potentials. This effect may help to reduce the likelihood of development of lethal ventricular arrhythmias in the early stage of myocardial ischemia in the clinical setting.

Ischemia-Induced Conduction Delay and Ventricular Arrhythmias

Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180-200 min-1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 +/- 35 vs. 262 +/- 34 s control, mean +/- SEM, p less than 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.

P-230 - Effect of gallopamil on ischemia-induced conduction delay in the isolated dog heart

P-230 - Effect of gallopamil on ischemia-induced conduction delay in the isolated dog heart

The relationship between ventricular arrhythmias and ischemia-induced conduction delay in closed-chest animals within 24 hours of myocardial infarction

To investigate the myocardial conduction characteristics of premature impulses during the first 24 hours following coronary ligation and its relationship to late infarction ventricular arrhythmias, transmural electrodes were positioned in the normal and ischemic myocardium in nine dogs. Cardiac conduction in ischemic myocardium was delayed 15 minutes post coronary occlusion both in the epicardium and endocardium, both in the anterograde (base to apex) and retrograde (apex to base) direction, and was maintained at the same level throughout the experiment. Conduction across the border of ischemic myocardium from ischemic to the normal segment was also delayed, especially in the endocardium. Spontaneous ventricular arrhythmias recorded on Holter tapes showed significant increase in the number of premature ventricular complexes and ventricular tachyarrhythmias 9 hours after infarction. Thus our findings suggest that spontaneous arrhythmias occurring in the late phase of acute myocardial infarction (AMI) are independent of the ischemia-induced conduction delay and an alternate mechanism such as abnormal automaticity may be responsible for late ventricular arrhythmias.

Comparative study of the effect of slow channel inhibiting agents on ischemia-induced conduction delay as relevant to the genesis of ventricular fibrillation

Conduction delay has been shown to be an important factor in the genesis of ventricular fibrillation (VF). We evaluated the relationship between conduction delay and (1) initiation of VF and (2) the effects of Ca ++ blockers on conduction delay in 41 dogs: eight control (nontreated, non-VF); nine ischemic VF; eight verapamil-treated (0.15 mg/kg bolus followed by 7.5 μg/kg/min); eight diltiazem-treated (20 μg/kg/min); and eight nifedipine-treated (0.1 mg/kg bolus). Propagation of electrically-induced premature impulses from the midmyocardial bipole of one transmural electrode was recorded at epicardial and endocardial bipoles of other electrodes before and 5, 15, and 30 minutes after coronary ligation. Conduction delay (i.e., conduction times compared to preligation levels) of VF, verapamil, diltiazem, and nifedipine groups were compared to control group in normal and in the center and border of ischemic zones in both base to apex (anterograde) and apex to base (retrograde) directions. Results showed that there was no change in conduction delay in the normal zone between control and VF groups or the treated groups, but both in the center and border of ischemic zone VF was quantitatively related to conduction delay and Ca ++ blockers, except that nifedipine significantly reduced conduction delay. We conclude that our model provides a new approach to the assessment of anti-VF intervention. Further, verapamil and diltiazem appear to be useful agents in reducing the risk of ischemia-induced reentrant ventricular tachyarrhythmias.

Electrophysiological effects of diltiazem, nifedipine and Ni2+ on the subepicardial muscle cells of canine heart under the condition of combined hypoxia, hyperkalemia and acidosis.

Using microelectrode techniques, we examined the effects of the slow channel blockers diltiazem, nifedipine and Ni2+ on the tissue deterioration induced by a modified superfusion solution imitating some of the metabolic changes in acute myocardial ischemia (pO2 = 4.0--5.1 kPa, [K+] = 8 mmol/l, pH = 6.80) in the isolated right ventricular subepicardial muscles of canine heart. Resting membrane potential (RMP), action potential amplitude (APA), action potential duration and maximum upstroke velocity of action potential (V max) were reduced, and conduction time was prolonged during superfusion with the modified solution. In the presence of diltiazem (6.7 mumol/l), nifedipine (2.9 mumol/l) and Ni2+ (1.0 mmol/l), the degree of the reductions of APA and V max, and of the prolongation of conduction time induced by the modified solution was significantly reduced. However, none of the three slow channel blockers affected the change in RMP. These results suggest that decreasing calcium influx reduces the deteriorating effect of the modified solution on the sodium channels, and this action can partly explain the reduction of ischemia-induced conduction delay by slow channel blockers.

Flow-independent improvement by diltiazem of ischemia-induced conduction delay in porcine hearts

The calcium channel blocking agent, diltiazem, improves ischemia-induced conduction delays in the canine heart. It is not known, however, if the improvement of myocardial blood flow caused by diltiazem participates in this response. Accordingly, ischemia-induced conduction delay was measured during brief coronary artery occlusion before and after administration of diltiazem in nine anesthetized pigs with fixed heart rate. Acute coronary occlusion prolonged subendocardial (mean +/- standard error of the mean, 39.9 +/- 3.9 ms) and subepicardial (41.6 +/- 4.1 ms) conduction times (time to peak of the bipolar electrogram in each region) by 51 +/- 4 and 58 +/- 5%, respectively. Regional myocardial blood flow at the ischemic electrode sites was 0.006 +/- 0.002 ml/min per g and was unaffected by diltiazem. Intravenous diltiazem pretreatment (0.01, 0.1, 0.3 and 1.0 mg/kg) 5 minutes before coronary occlusion significantly reduced the ischemia-induced conduction delay in both subendocardial and subepicardial regions during coronary occlusion. The pigs in which ventricular fibrillation occurred within 10 minutes showed a significantly longer conduction delay than that observed in pigs in which ventricular fibrillation occurred later (greater than 10 minutes). Thus, the data suggest that the reduction of ischemia-induced conduction delay produced by diltiazem is independent of blood flow changes and, therefore, that diltiazem may have a beneficial antiarrhythmic action.

Effects of verapamil and lidocaine on changes in action potential characteristics and conduction time induced by combined hypoxia, hyperkalemia, and acidosis in canine ventricular myocardium.

We examined the effects of verapamil and lidocaine on changes in action potential characteristics and conduction time in the isolated right ventricular myocardium of canine hearts during superfusion with altered Tyrode's solution imitating some of metabolic alterations that occur in acute myocardial ischemia (Po2 less than 50 mm Hg, KCl 8 mM, pH 6.80). Altered Tyrode's solution produced loss of resting membrane potential (RMP), action potential amplitude (APA), action potential duration, and upstroke velocity of action potential (Vmax), and prolonged conduction time (CT). In the presence of lidocaine (5 mg/L), altered Tyrode's solution aggravated the reductions of APA and Vmax and the prolongation of CT in both endocardial and epicardial muscle cells. On the other hand, in the presence of verapamil (1 mg/L), the degree of the reductions of APA and Vmax and of the prolongation of CT induced by altered Tyrode's solution was reduced in epicardial muscle cells, but not in endocardial ones. Neither verapamil nor lidocaine affected change in RMP. These results suggest that the improving effect of verapamil on ischemia-induced conduction delay can be partly explained by its salutary effect on the depressed fast channel.

Effects of verapamil on conduction delay and potassium efflux induced by global ischemia in isolated rabbit hearts

The effects of verapamil on the conduction delay and potassium efflux induced by global ischemia were evaluated in 40 isolated Langendorff-perfused rabbit hearts under constant ventricular pacing. Global ischemia of 7 min duration, which was produced by stopping the perfusion flow, prolonged the intramyocardial conduction time by 86.5 ± 9.6% of the pre-ischemic values in 10 non-treated control hearts. Verapamil, when perfused in various concentratiins (10–1000 ng/ml) in Tyrode solution for 15 min prior to the global ischemia, significantly and concentration-dependently reduced the ischemia-induced conduction delay. However, the increased potassium content of the coronary effluents collected during ischemia and 1 min after reperfusion, which was assumed to reflect the extracellularly accumulated potassium during ischemia, was not significantly reduced by verapamil. These results suggest that the favorable effect of verapamil on the ischemia-induced conduction delay is a direct action on the ischemic myocardial cells, being independent of its vasodilating action. It also seems unlikely to be mediated by reduction of extracellular potassium accumulation in the ischemic myocardium.

Electrophysiologic effects of diltiazem in canine myocardium, with special reference to conduction delay during ischemia

Three sets of experiments investigated hemodynamic and electrophysiologic effects of diltiazem in dogs. The first set compared electrophysiologic and hemodynamic effects of varying dosages. The second set assessed the effect of diltiazem on ventricular myocardial conduction delay during ischemia and reperfusion, and the third compared the effects of diltiazem on myocardial conduction delay with those of verapamil and nifedipine. Hemodynamic and electrophysiologic effects were studied in 10 anesthetized closed chest dogs, by standard techniques under control conditions and after 30 minute infusions of diltiazem at doses of 0.01, 0.02, 0.04 and 0.08 mg/kg per min. Atrioventricular nodal refractory periods were prolonged significantly at a dose of 0.02 mg/kg per min; however, systemic vascular resistance and blood pressure decreased significantly only at a dose of 0.04 mg/kg per min. In a separate group of 16 dogs (8 control and 8 treated with diltiazem at a dose of 0.02 mg/kg per min), conduction delays of induced premature impulses were recorded in the normal, ischemic and reperfused endocardium after left anterior descending coronary arterial occlusion and reperfusion. Significantly less conduction delay was seen in the treated animals, in both the ischemic endocardium and its border. In another group of 16 dogs, the effect of diltiazem on ischemia-induced conduction delay was then compared with those of verapamil (n = 8) and nifedipine (n = 8) after identical experimental protocols. The effects of diltiazem were comparable with those seen with verapamil, whereas nifedipine failed to alter conduction times consistently. We conclude (1) that the electrophysiologic effects of diltiazem are apparent at small doses (0.02 mg/kg per min), whereas hemodynamic variables are significantly altered only at larger doses; (2) that this hemodynamically tolerated dose of diltiazem offers significant protection from ischemia-induced reentrant ventricular arrhythmias, because we have previously shown in our model that conduction delay is statistically related to the genesis of spontaneous ischemic ventricular fibrillation; and that the effects of diltiazem on ischemia-induced conduction delay are comparable with those of verapamil but not those of nifedipine.

Effects of diltiazem on conduction of premature impulses during acute myocardial ischemia and reperfusion

The effect of diltiazem on conduction of cardiac impulses was studied using premature impulses. Conduction times were measured in the epicardium and endocardium in both anterograde and retrograde directions during ischemia and reperfusion of the left ventricular anterior wall. In 16 dogs (8 control and 8 treated with diltiazem), the left anterior descending artery was occluded initially below the second diagonal branch and 30 minutes later below the first diagonal branch. Infusion of diltiazem (0.02 mg/kg per min) was begun at the time of the first ligation in the treated dogs. Conduction delay in normal, ischemic and reperfused myocardium and at the border of ischemia or reperfusion was compared in the two groups. In addition, treated and nontreated ischemic zones were analyzed in the diltiazem-treated group. Results showed significantly less ischemia-induced conduction delay in the diltiazem-treated group in both ischemic myocardium and at the border of ischemia. This beneficial effect was seen in the ischemic segment in the treated dogs whether or not the medication was given before or after coronary ligation. Further, the effect of the drug on epicardial and endocardial conduction did not differ significantly. These data suggest that diltiazem may have potential value in the treatment of ventricular reentrant arrhythmias associated with acute ischemia over and above the well recognized hemodynamic and metabolic effects of calcium channel blocking agents.

Effect of verapamil on conduction delay produced by myocardial ischemia and reperfusion

Changes in conduction times induced by ischemia (ΔCT) have been shown to be quantitatively related to genesis of spontaneous ischemic ventricular fibrillation (VF). We studied conduction delay encountered by premature impulses in epicardium and endocardium in both anterograde and retrograde directions during ischemia and reperfusion in eight control and in eight verapamil treated dogs. Acute myocardial ischemia was produced by single-stage ligation of left anterior descending artery below second diagonal initially, and 30 minutes later below first diagonal branch. In treated dogs, verapamil was given, 0.15 mg/kg intravenous bolus, immediately after first ligation and was followed by an infusion of 7.5 μg/kg/min. Thus post-treated segment and pretreated segment were obtained in the same animal. ΔCT was compared between control and treated dogs in four myocardial zones: (1) normal, (2) ischemic including pre- and post-treated segments, (3) reperfused, and (4) border of reperfusion or ischemia. Results showed that ischemia-induced conduction delay was significantly less in verapamil treated dogs throughout period of ischemia and reperfusion, both in epicardium and endocardium. In addition, in the border of ischemia retrograded conduction showed significantly less depression during ischemia and reperfusion. The protective effect of verapamil was impressive both in pretreated and post-treated segments of ischemic myocardium. We conclude that verapamil offers significant protective action with regard to ischemia-induced conduction delay. Since ΔCT is quantitatively related to ischemic VF, verapamil can be antiventricular fibrillatory in myocardial ischemia.

Effects of calcium antagonists on coronary circulation and conduction delay induced by myocardial ischemia in dogs: A comparative study with other coronary vasodilators

The effects of calcium antagonists on coronary circulation and ischemia-induced conduction delay were compared with those of other coronary vasodilating drugs in 41 anesthetized dogs. Pretreatment with verapamil (0.3 mg/kg), diltiazem (0.4 mg/kg), nifedipine (3 μg/kg, 30 μg/kg), nitroglycerin+phenylephrine and dipyridamole (0.5 mg/kg) increased both coronary flow and regional myocardial blood flow in the pre-ischemic period, whereas nitroglycerin alone (10 μg/kg + 10μg/kg/min) decreased and isosorbide dinitrate (0.15 mg/kg) hardly affected them. Nevertheless, only drugs possessing a slow channel blocking action, i.e., verapamil, diltiazem, and nifedipine in a large dose improved the conduction delay produced by coronary occlusion under constant atrial pacing. These results suggest that the coronary vasodilating action of the calcium antagonists is unlikely to play an essential role in reducing the conduction delay in the ischemic myocardium.

Effects of verapamil on conduction delay and potassium efflux induced by global ischemia in isolated rabbit hearts

Abstract The effects of verapamil on the conduction delay and potassium efflux induced by global ischemia were evaluated in 40 isolated Langendorff-perfused rabbit hearts under constant ventricular pacing. Global ischemia of 7 min duration, which was produced by stopping the perfusion flow, prolonged the intramyocardial conduction time by 86.5 ± 9.6% of the pre-ischemic values in 10 non-treated control hearts. Verapamil, when perfused in various concentratiins (10–1000 ng/ml) in Tyrode solution for 15 min prior to the global ischemia, significantly and concentration-dependently reduced the ischemia-induced conduction delay. However, the increased potassium content of the coronary effluents collected during ischemia and 1 min after reperfusion, which was assumed to reflect the extracellularly accumulated potassium during ischemia, was not significantly reduced by verapamil. These results suggest that the favorable effect of verapamil on the ischemia-induced conduction delay is a direct action on the ischemic myocardial cells, being independent of its vasodilating action. It also seems unlikely to be mediated by reduction of extracellular potassium accumulation in the ischemic myocardium.

157 - Effects of several coronary vasodilators on ischemia-induced conduction delay and coronary circulation in dogs.

157 - Effects of several coronary vasodilators on ischemia-induced conduction delay and coronary circulation in dogs.

Effects of Calcium Antagonists and Lidocaine on Conduction Delay Induced by Acute Myocardial Ischemia in Dogs

Effects of calcium antagonists and lidocaine on the conduction delay observed in the ischemic myocardium were studied in 24 open-chest anesthetized dogs. Acute myocardial ischemia was produced by complete occlusion of the left anterior descending coronary artery (LAD) for 5 or 10 minutes. The conduction time was measured from the initial deflection of V waves on the His bundle electrograms to the major deflection of the bipolar electrograms recorded from the ischemic and non-ischemic subepicardium under a constant atrial pacing. LAD occlusion produced conduction delay in the ischemic zone (14.3±2.3 msec, p<0.001) with no effect on the normal zone. This ischemia-induced conduction delay was reversible and rate-dependently increased. Administration of lidocaine (2 mg/kg bolus, 4.3 mg/kg/hr constant infusion) prior to the second occlusion increased conduction delay by 12.9±1.9 msec (p<0.001) whereas diltiazem (0.4 mg/kg i.v.) and verapamil (0.3 mg/kg i.v.) reduced the ischemia-induced conduction delay by 12.7±4.9 msec (p<0.05) and 8.4±1.8 msec (p<0.001), respectively. These results indicate that slow channel blocking agents reduce the conduction delay induced by the myocardial ischemia, in contrast with the prolonging effect of lidocaine.

Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs

The effects of various drugs on delayed activation of the ischemic myocardium and the incidence of ventricular arrhythmias were studied in 34 open-chest anesthetized dogs. The left anterior descending coronary artery was occluded for 6 minutes before and 42 minutes after administration of aprindine (2.85 mg/kg body weight), quinidine (8 mg/kg) and verapamil (0.2 mg/kg) and during infusion of isoproterenol (0.2 microng/min). The time intervals from the onset of the QRS complex to the major deflection of the bipolar electrograms recorded within the normal and ischemic zones were measured at cycle lengths of 500, 400 and 300 msec and were correlated with the development of ventricular arrhythmias. At a cycle length of 500 msec, aprindine increased by 19.5 msec the delay in activation time produced by coronary ligation alone (P less than 0.05), whereas verapamil reduced by 10 msec the extent of ischemia-induced conduction delay (P less than 0.05). The delay in activation time in the ischemic zone was not significantly altered by quinidine or isoproterenol. The incidence of ventricular arrhythmias was increased by aprindine (from 1 in 11 to 8 in 11 dogs), decresed by verapamil (from 3 in 7 to 0 in 7 dogs) and was not changes by quinidine or isoproterenol. Thus, delayed activation of the ischemic myocardium appears to play an important role in the genesis of early arrhythmias due to myocardial ischemia, and drugs that significantly depress conduction in the ischemic myocardium may predispose to the development of ventricular arrhythmia whereas those that improve conduction may be protective. Contrary to their effects on slow channel-dependent conduction, verapamil improved and isoproterenol worsened conduction during ischaemia.