Changes In Refractory Period Research Articles

Ventricular repolarization time, location of pacing stimulus and current pulse amplitude conspire to determine arrhythmogenicity in mice.

In this study, we investigate the impact of altered action potential durations (APD) on ventricular repolarization time and proarrhythmia in mice with and without genetic deletion of the K+ -channel-interacting protein 2 (KChIP2-/- and WT respectively). Moreover, we examine the interrelationship between the dispersion of repolarization time and current pulse amplitude in provoking ventricular arrhythmia. Intracardiac pacing in anesthetized mice determined refractory periods and proarrhythmia susceptibility. Regional activation time (AT), APD and repolarization time (=AT+APD) were measured in isolated hearts using floating microelectrodes. Proarrhythmia in WT and KChIP2-/- was not sensitive to changes in refractory periods. Action potentials were longer in KChIP2-/- hearts compared to WT hearts. Isolated WT hearts had large apico-basal dispersion of repolarization time, whereas hearts from KChIP2-/- mice had large left-to-right ventricular dispersion of repolarization time. Pacing from the right ventricle in KChIP2-/- mice invivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice. Large heterogeneity of repolarization time is proarrhythmic when pacing is delivered from the location of earlier repolarization time. Ventricular repolarization time, location of the pacing stimulus and theamplitude of the stimulating current pulse are critical parameters underlying arrhythmia vulnerability.

Selective Ablation of the Ligament of Marshall Reduces the Prevalence of Ventricular Arrhythmias Through Autonomic Modulation in a Cesium-Induced Long QT Canine Model.

The goal of this study was to investigate the effect of selective ablation of the ligament of Marshall (LOM) on ventricular arrhythmias (VAs). Previous studies have shown that selective stimulation of sympathetic elements of the LOM, the distalsegment of the ligament of Marshall that extends beyond the left superior pulmonary vein (LOMLSPV), might induceVAs. In protocol 1, the blood pressure and ventricular effective refractory period changes as a response to LOMLSPV stimulation and left stellate ganglion (LSG) stimulation were measured before and after LOMLSPV ablation in 8anesthetized dogs. In protocol 2, a total of 24 dogs were randomly divided into group 1 (cesium alone, n= 8), group 2 (cesium combined with LSG stimulation, n= 8), and group 3 (cesium combined with LSG stimulation after LOMLSPV ablation, n= 8). Early afterdepolarization amplitude, VA prevalence, and the tachycardia threshold (measured according to the dose of cesium administered) were compared among the groups. In protocol 1, both LOMLSPV stimulation and LSG stimulation significantly increased blood pressure and shortened the ventricular effective refractory period, both of which were significantly attenuated by LOMLSPV ablation. Inprotocol 2, compared with group 1, the prevalence of VAs and the early afterdepolarization amplitudes were significantly augmented in group 2 and were maintained at a comparable level in group 3. Furthermore, the tachycardia threshold in group 2 (0.625 mmol/kg) was significantly lower than that noted in groups 1 and 3 (both 1.000 mmol/kg; p< 0.05). LOMLSPV ablation reduced the prevalence of the VAs induced by cesium in combination with LSG stimulation, and the antiarrhythmic effect may involve the blockade of the sympathetic conduit between the LSG and the ventricles.

High frequency stimulation extends the refractory period and generates axonal block in the rat hippocampus.

The therapeutic mechanisms of deep brain stimulations (DBS) are not fully understood. Axonal block induced by high frequency stimulation (HFS) has been suggested as one possible underlying mechanism of DBS. To investigate the mechanism of the generation of HFS-induced axonal block. High frequency pulse trains were applied to the fiber tracts of alveus and Schaffer collaterals in the hippocampal CA1 neurons in anaesthetized rats at 50, 100 and 200Hz. The amplitude changes of antidromic-evoked population spikes (APS) were measured to determine the degree of axonal block. The amplitude ratio of paired-pulse evoked APS was used to assess the changes of refractory period. There were two distinct recovery stages of axonal block following the termination of HFS. One frequency-dependent faster phase followed by another frequency-independent slower phase. Experiments with specially designed temporal patterns of stimulation showed that HFS produced an extension of the duration of axonal refractory period thereby causing a fast recovery phase of the axonal block. Thus, prolonged gaps inserted within HFS trains could eliminate the axonal block and induced large population spikes and even epileptiform activity in the upstream or downstream regions. Extension of refractory period plays an important role on HFS induced axonal block. Stimulation pattern with properly designed pauses could be beneficial for different requirements of excitation or inhibition in DBS therapies.

Vagal denervation and reinnervation after ablation of ganglionated plexi

Surgical ablation of ganglionated plexi has been proposed to increase efficacy of surgery for atrial fibrillation. This experimental canine study examined electrophysiologic attenuation and recovery of atrial vagal effects after ganglionated plexi ablation alone or with standard surgical lesion sets for atrial fibrillation. Dogs were divided into 3 groups: group 1 (n = 6) had focal ablation of the 4 major epicardial ganglionated plexi fat pads, group 2 (n = 6) had pulmonary vein isolation with ablation, and group 3 (n = 6) had posterior left atrial isolation with ablation. All fat pads were ablated. Sinus and atrioventricular interval changes during bilateral vagosympathetic trunk stimulation were examined before and both immediately and 4 weeks after ablation. Vagally induced effective refractory period changes and mean QRST area changes (index of local innervation) were examined in 5 atrial regions. Sinus and atrioventricular interval changes and heart rate variability decreased immediately after ablation, but only sinus interval changes were restored significantly after 4 weeks in all groups. Ablation-modified vagal effects on effective refractory period or QRST area changed heterogeneously in groups 1 and 2. In group 3, regional vagal effects were attenuated extensively postablation in both atria. Posterior left atrial isolation with ablation incrementally denervated the atria. In the long term, vagal stimulation increased QRST area changes relative to control values in all groups. Heart rate variability was also assessed. Ganglionated plexi ablation significantly reduced atrial vagal innervation. Restoration of vagal effects at 4 weeks suggests early atrial reinnervation.

Electrophysiologic measures of diabetic neuropathy: Mechanism and meaning

Whole nerve electrophysiologic procedures afford a battery of measures that can provide a noninvasive and objective index of the onset and progression of diabetic polyneuropathy (DPN). Advances in physiologic procedures, digital hardware, and mathematical models have allowed assessment of activity in slower conducting fibers, as well as measures that reflect changes in refractory periods and threshold excitability. These expanded options can augment standard measures of maximal conduction velocity and compound amplitude and greatly enhance the sensitivity of whole nerve measure to both structural (e.g. demyelination) and "nonstructural" (e.g. redistribution of ion channels) deficits associated with DPN. The mechanisms underlying the physiologic events in DPN are multifactorial and their sequence in complex, with different mechanisms contributing to change at overlapping, but distinct points in the progression. Factors influencing early change in velocity may differ from those contributing to chronic deficits and these mechanisms may also differ in their response to various putative therapies. This review attempts to summarize the pattern of whole nerve electrophysiologic change associated with DPN, outlines the strengths and limitations of the various measures that are feasible, and discusses the specific impact of know pathophysiologic mechanisms on these end points.

Efficacy of bretylium tosylate for ventricular tachycardia

In 20 patients with inducible ventricular tachycardia (VT), intravenous bretylium tosylate infused as a 10-mg/kg bolus followed by 2 mg/min caused no change in refractory periods and did not suppress inducibility of VT. The use of bretylium for the treatment of VT should be reexamined.

Differences in refractory-period response of canine subendocardium and subepicardium to bunazosin, an alpha1-adrenoceptor antagonist, and propranolol during myocardial ischemia.

Our objective was to investigate the effects of alpha1- or beta-adrenoceptor blockers on endocardial and epicardial refractory-period changes during myocardial ischemia in alpha-chloralose-anesthetized dogs. The first and second diagonal branches of the left anterior descending coronary artery were ligated. The refractory period was determined by an S1-S2 extrastimulus method. Dogs were treated with the alpha1-blocker bunazosin (0.1-0.2 mg/kg, i.v.; n = 16), the beta-blocker propranolol (0.2 mg/kg, i.v.; n = 15), or saline (n = 11). Dogs that developed ventricular tachycardia/fibrillation (VT/VF) during the experiment were excluded from the statistical assessment in refractory periods. In all groups, coronary ligation produced a significant shortening of the refractory period of ischemic epicardial tissue (p < 0.05) but only minimal shortening of ischemic endocardial refractory periods, resulting in an increased difference in repolarization time between the endo- and epicardial sites. Treatment with bunazosin ameliorated this ischemia-related shortening of refractory periods at both the endo- and epicardial sites, with a greater effect seen epicardially (p < 0.05), resulting in values similar to those in the nonischemic tissue. Treatment with propranolol prolonged refractory periods more in the epicardial (p < 0.01) than in endocardial sites, exacerbating the disparity in the refractory period between the endo- and epicardial sites (p < 0.05). Propranolol also prolonged the refractory period of nonischemic tissue (p < 0.05 and p < 0.01 in endo- and epicardial sites, respectively), resulting in a significant difference between the ischemic and normal myocardium at the endocardial site (p < 0.05). Results suggest that the alpha1-blocker bunazosin reduces the refractory-period disparity between the ischemic and normal myocardium without increasing the disparity between the endo- and epicardial surfaces, whereas propranolol produces a greater disparity.

Electrophysiological Remodeling of the Heart Owing to Rate

Although damage to the heart from inflammation and infarction are well-established stimuli that trigger major cardiac remodeling, it has been known since 1954 that a persistent supraventricular tachycardia also can alter cardiac structure and function.1 This clinical observation was exploited 8 years later when it was demonstrated that rapid stimulation of the normal heart could produce reversible congestive heart failure.2 Since then, rapid pacing has been used frequently to create an investigational animal model of heart failure. The effects of prolonged pacing-induced tachycardia, in the range of 250 bpm for 3 or 4 weeks, has been studied in depth in several animal species and has been shown to cause extensive myocardial remodeling. Biventricular enlargement with reduced wall thickness and no increase in muscle mass, reduced cross-sectional myocyte area and increased length, disarray of myofibril alignment and cytoarchitecture, increases in contractile protein degradation, and destruction of the supporting myocardial collagen matrix represent some of the structural changes contributing to reduced ventricular function.3 Diminished responsiveness to β-adrenoceptor stimulation caused by a reduction in β-receptor density and a variety of alterations in the adrenergic signaling processes also occur.4 Replacement fibrosis, loss of cells, and reactive hypertrophy of the remaining cells have been noted recently.5 mRNA levels for specific cytoskeletal proteins increase, along with alterations in cytoskeletal architecture6 and abnormalities in phospholamban.7 In pigs subjected to 3 weeks of a tachycardia-induced cardiomyopathy, myocyte action potential showed reduced membrane resting potential, reduced amplitude and upstroke velocity, and prolonged duration at 90% repolarization. Peak L-type Ca2+ current density was reduced because of an absolute reduction in L-type Ca2+ current flow into the myocyte possibly caused by reduced open probability of the channel.8 However, in dogs that had rapid ventricular pacing for 3 to 4 weeks, action …

Effect of altered activation sequence on epicardial QRST area and refractory period in dogs.

We investigated the effects of activation sequence on cardiac surface QRST areas and refractory periods in experiments on dogs. Right and left ventricular pacings were performed, and the pacing site was altered every 6 minutes. After 4 minutes of a given pacing, 54 unipolar electrograms distributed over the entire cardiac surface were recorded. Next, refractory periods at electrode sites near pacing electrodes were measured. Paired right ventricular/left ventricular (RV/LV) pacing data were obtained six or seven times in each sample. Although the QRST isoarea maps during the two activation orders were qualitatively similar, it was recognized consistently from the right ventricle-left ventricle difference map that leads around the RV free wall had positive values and that leads around the LV free wall and apex had negative values. Compared with the same leads at RV and LV pacing, QRST areas were larger when pacing sites were near the leads. The local QRST areas of individual leads at which we measured local refractory period were consistently larger during drive from proximal pacing sites than during drive from distant pacing sites. Refractory periods were consistently longer during proximal pacing than during distal pacing, and there was a positive correlation between change in local QRST area and change in refractory period (r = 0.64) during altered activation sequence, whereas there was an inverse correlation between change in QRST area and change in refractory period (r = -0.91) during localized myocardial warming. Both local QRST areas and local refractory periods were dependent on the activation sequence, and there was a positive correlation between QRST areas and refractory periods during various activation sequences compared with localized myocardial warming.

Effects of postural changes versus exercise on the electrophysiologic parameters of the accessory pathway

The electrophysiologic profile of the accessory pathway was studied in 17 patients (mean age ± standard deviation 32 ± 14 years) with Wolff-Parkinson-White (WPW) syndrome who were either lying down in a supine position, standing, or undergoing isometric or dynamic treadmill exercise. There were significant decreases in the PP interval after isometric exercise, standing and dynamic exercise (supine 764 ± 224, standing 638 ± 146, isometric 60S ± 170, treadmill 455 ± 86 ms; p <O.O5). Both anterograde and retrograde accessory pathway refractory periods were measured after a constant drive of 400 ms during lying down supine, standing and isometric and treadmill exercise (Bruce protocol stage II). There was no significant decrease in the anterograde accessory pathway refractory period during isometric exercise (lying down 26S ± 22 to isometric exercise 256 ± 13 ms, p <O.OS), but there were significant decreases (p <O.OS) during standing (246 ± 24 ms) and treadmill exercise (235 ± 17 ms). The retrograde accessory pathway refractory period also showed a significant decrease (supine 272 ± 16, isometric 267 ± 23, standing 249 ± 15, treadmill 237 ± 17 ms; p <O.O5). The relative change in refractory periods was greater when patients changed from lying down to standing than when they changed from standing to treadmill exercise, despite obvious higher adrenergic neuronal activities during exercise. These findings suggest that testing the accessory pathway during free standing can give a reliable indication of the sensitivity of the accessory pathway to sympathetic stimulation. Further increase in sympathetic stimulation, as judged by increases in the sinus rate, does not cause proportional reduction in the refractoriness of the accessory pathways.

Inhibition of calmodulin and protein kinase C by amiodarone and other class III antiarrhythmic agents

Class III antiarrhythmic agents may prolong refractoriness via modulation of ion channels, which may be sensitive to Ca2+ regulatory proteins or enzymes. Accordingly, the purpose of this study was to quantitate the effects of several structurally diverse class III antiarrhythmic agents on calmodulin-regulated enzymes and protein kinase C activity, and to evaluate the ability of these agents and known calmodulin antagonists to prolong cardiac refractoriness in vivo. The rank order of potency (IC50;microM) of selected class III antiarrhythmic agents and reference calmodulin antagonists as inhibitors of calmodulin-regulated phosphodiesterase activity were: calmidazolium (0.12 microM) greater than amiodarone (0.62 microM) greater than desethylamiodarone (1.5 microM) greater than trifluoperazine (4.3 microM), bepridil (5 microM) greater than W-7 (7.5 microM), clofilium (13 microM). Similar concentration-related inhibition was evident in a second calmodulin-regulated system, inhibition of myosin light-chain phosphorylation and superprecipitation of arterial actomyosin. Sotalol and tetraethylammonium were inactive at 100 microM. Protein kinase C activity was also inhibited by some of these agents; desethylamiodarone (IC50 = 11 microM) was more potent than the reference agent, H-7 (IC50 = 79 microM), or amiodarone (38% inhibition at 100 microM) and clofilium (32% inhibition at 100 microM). In vivo, the minimally effective doses required to increase ventricular effective refractory periods in paced guinea pigs were (in mg/kg) bepridil, sotalol [1] greater than clofilium [3] greater than amiodarone [10] greater than W-7, desethylamiodarone [20]. No changes in refractory period were noted with maximum testable doses of calmidazolium or trifluoperazine. These studies show that some, but not all, class III antiarrhythmic agents are effective and potent calmodulin antagonists or protein kinase C inhibitors. Moreover, some calmodulin antagonists are effective at prolonging refractoriness in vivo. However, a lack of correlation between these agents suggests that these mechanisms are not solely responsible for the prolongation of refractoriness of all class III agents.

Is the adaptation of right ventricular refractoriness to an abrupt increase in heart rate impaired in chronic heart failure?

Chronic heart failure is associated with a high risk of ventricular arrhythmias and sudden death, although the mechanisms leading to these arrhythmias are not fully understood. To determine if the adaptation of ventricular refractoriness to an abrupt increase in heart rate is impaired in heart failure, electrophysiologic findings in 11 patients with structurally normal hearts (group I) were compared to findings in 28 patients with chronic heart failure (mean left ventricular ejection fraction 0.23 ± 0.05). Heart failure was due to coronary artery disease in 14 patients (group II) and to idiopathic dilated cardiomyopathy in 14 patients (group III). The effective refractory period at the right ventricular apex was measured during unipolar cathodal pacing at twice diastolic threshold following a 12-beat ventricular drive at a cycle length of 600 msec. The pacing cycle length was then decreased to 400 msec for one, two, and three beats and the refractory period was determined for each beat at the faster rate. For each beat the mean refractory periods of group II and III patients were similar and were significantly longer than those of group I patients ( p < 0.01). The refractory period progressively shortened at the 400 msec cycle length and the percent decrease for each beat was similar among all three groups ( p > 0.10). In the group II and III patients there was no correlation of the refractory period or change in refractory period with the pulmonary artery, right atrial, and pulmonary capillary wedge pressures. We conclude that chronic heart failure is associated with prolongation of the right ventricular effective refractory period but the ability to adapt to a sudden increase in heart rate by shortening the refractory period is not impaired and is therefore unlikely to contribute to the increased incidence of arrhythmias in heart failure.

Propranolol blocks ventricular refractory period changes with orthostatic stress in humans

The purpose of this study was to test the hypothesis that orthostatic stress shortens the right ventricular effective refractory period by reflex activation of beta-adrenergic receptors. Twelve patients undergoing electrophysiologic testing for standard clinical indications were studied. After a full electrophysiologic study, patients underwent graded lower body negative pressure before and after administration of either propranolol (0.2 mg/kg intravenously) in Group I or atropine (0.035 mg/kg intravenously) in Group II. Before the addition of drugs, lower body negative pressure produced decreases in systolic blood pressure and significant increases in sinus rate. The effective refractory period shortened from 214 +/- 8 (mean +/- SEM) to 206 +/- 7 ms at -40 cm H2O and to 197 +/- 4 ms at -60 cm H2O lower body negative pressure. After propranolol, Group I patients had no change in right ventricular effective refractory period despite similar changes in sinus rate and systolic blood pressure. In group II patients, atropine did not alter effective refractory period responses to lower body negative pressure. Thus, reflex adjustments to orthostatic stress result in shortening of right ventricular effective refractory period mediated by way of beta-adrenergic mechanisms. These findings constitute the first evidence that sympathetic influences mobilized by the body can directly modulate ventricular electrophysiologic changes.

Procainamide, disopyramide and quinidine: Discordant antiarrhythmic effects during crossover comparison in patients with inducible ventricular tachycardia

A crossover comparison of intravenous procainamide, disopyramide and quinidine was made in 32 patients. All three drugs had dosage-related effects on electrocardiographic intervals, refractory periods and cycle length of ventricular tachycardia. Significant linear relations between serum drug levels and changes in refractory periods and ventricular tachycardia cycle length were also observed. Ventricular tachycardia was no longer inducible on at least one drug in 11 patients but concordance of this effect on both of the others was 36% and on either of the others it was 45%. Ventricular tachycardia remained inducible on at least one drug in 28 patients and concordance of this effect on both of the others was 75% and on either of the others was 79%. Continued inducibility on quinidine, the drug producing the greatest electrophysiologic effects, was the best individual predictor of continued inducibility on the others. Subdivision of continued inducibility into easier to induce, inducibility unchanged, or harder to induce dramatically decreased concordance of this effect. Thus the antiarrhythmic effects of these drugs are discordant in individual patients despite electrophysiologic similarities. Nevertheless, continued inducibility after high dosages of any one of these drugs is clinically useful for screening for continued inducibility on the others and this is dose-related rather than drug specific.

The effect of cycle length on the atrial refractory period.

The effect of cycle length upon refractory period of the atria was measured in 34 patients. The effect of abrupt change in paced cycle length on atrial refractory period was measured by introducing after every eighth paced cycle (CLP) a test cycle (CLT) at an interval which was either 100 ms longer (CLT = CLP + 100 ms) or shorter (CLT = CLP - 100 ms) than the paced cycle. These findings confirm that: (1) atrial refractory periods shorten with decreasing cycle length during steady state pacing; (2) an abrupt change in paced cycle length results in a change in refractory period. This change is similar in direction but smaller in magnitude than the change which occurs in response to steady state pacing; and (3) there is no correlation between intraatrial conduction time and refractoriness.

Distribution of local repolarization changes produced by efferent vagal stimulation in the canine ventricles

The purpose of this study was to compare the distribution of effects of right and left efferent vagal stimulation on ventricular recovery properties in the in situ heart. To measure these effects in many areas simultaneously, local repolarization changes (local QT intervals) were recorded with bipolar electrodes in nine ventricular sites from 38 anesthetized dogs. In initial experiments, this method was shown to correlate with effective refractory period changes measured in the same test site after QT recording; vagal nerve stimulation prolonged the local QT interval by 1 ms for each 0.82 ms prolongation in effective refractory period (r = 0.87). Simultaneous local QT recordings during vagal nerve stimulation demonstrated uniform prolongation with two exceptions. First, left vagal efferent stimulation prolonged local QT interval in the posterior left ventricular base more than did right vagal stimulation (5.9 +/- 1.0 mean +/- standard error of the mean versus 3.7 +/- 0.9%, p less than 0.05). This probably resulted from an interaction with the left sympathetic nerves because left stellate ganglionectomy or norepinephrine infusion eliminated differences between effects of right and left vagal stimulation. Second, it was also found that vagal stimulation from either side did not prolong local QT interval time in the anterior right ventricle despite attempts to augment vagal effects with bilateral vagal stimulation alone or during isoproterenol or physostigmine administration. These regional differences in ventricular repolarization exhibited in response to efferent vagal nerve stimulation in the dog may provide a basis for understanding how autonomic influences could contribute to the genesis of ventricular arrhythmias.

The QRST deflection area of electrograms duringglobal alterations of ventricular repolarization

Changes of refractory period and QRST deflection area in cardiac electrograms due to localized myocardial warming and altered cycle length were determined. Localized myocardial warming consistently resulted in increased QRST deflection area which was highly correlated with reduction of refractory period. Similar reductions of refractory period by decreased cycle length were associated with insignificant changes of small QRST areas and significant reductions of larger QRST areas. The different effect of local thermal alteration of repolarization and global alteration due to cycle length changes is experimental evidence that QRST deflection area depends on differences in duration of ventricular repolarization properties. The finding of decreased deflection area with decreased cycle length is also evidence of decreased disparity of repolarization properties of normal myocardium at rapid heart rates.

Sympathetic neural effects on regional atrial recovery properties and cardiac rhythm

The functional distribution of the cardiac sympathetic nerves to the atria and their arrhythmiogenic effects were determined in 16 open-chest pentobarbital-anesthetized dogs. Shortening of refractory periods at four right and two left atrial sites during stimulation of the nerves was taken as a criterion of their distribution. Stimulation of right stellate ganglion, craniovagal, and right stellate cardiac nerves produced localized shortening on the right atrium, particularly at the sinus node area, and invariably induced sinus tachycardia. The recurrent cardiac nerve produced little shortening at all sites and less arrhythmiogenic effect. The left stellate ganglion and ventrolateral cardiac nerve affected only left atrial sites and induced atrioventricular junctional rhythm. The ventromedial cardiac nerve affected all sites and had no consistent arrhythmiogenic effect. The innominate nerve had no substantial effect. We concluded that the functional distribution of the cardiac sympathetic nerves is localized, and that rate, rhythm, and refractory period changes induced by stimulation of these nerves are characteristic of the area of distribution.

Ventricular recovery properties and QRST deflection area in cardiac electrograms.

We measured QRST deflection areas in cardiac surface electrograms of dogs and determined their relation to changes of refractory period induced by localized myocardial warming. Refractory period changes and QRST deflection areas were highly correlated with an average correlation of 0.95 over multiple activation sequences. For a single activation sequence, refractory period change was also highly correlated with ST-T deflection area, but over multiple activation sequences this correlation was reduced and the pooled variance of ST-T deflection areas was over 18 times greater than that of QRST area. No relation between QRST deflection area and the absolute value of refractory period over various cardiac sites was evident. Findings suggest that a particular set of ventricular recovery properties cannot be defined on the basis of QRST deflection areas, but that changes of recovery properties can be recognized on that basis.

Changes in myocardial refractory periods following ischemia in the porcine heart

Summary The purpose of this study was to utilize computer technique to analyze the time course of changes in myocardial refractory periods following coronary ligation in the porcine model in order to: o 1) compare these changes with those in the canine heart, a model with extensive coronary collateral circulation; 2) correlate alterations in refractory periods with spontaneous ventricular arrhythmias; and 3) correlate changes in refractory periods with the ability to initiate a repetitive ventricular rhythm by a premature stimulus applied near the effective refractory period. An on-line microprocessor with a real-time clock was interfaced with a sensing-stimulating unit to provide continuous determination of refractory period changes in 14 pigs in which the heart was exposed via a thoracotomy. The results were compared with the number of premature ventricular contractions (PVCs) and the ability to precipitate ventricular fibrillation by a premature ventricular stimulus. The results showed that: o 1) refractory periods in ischemic tissue were significantly reduced (p 2) both the number of PVCs per minute and changes in refractory periods increased to minute 3–4, however, the frequency of PVCs had declined significantly by minute 8–9 (20.4±16.55 vs. 1.60±2.51; p 3) the ability to initiate ventricular fibrillation was proportional to the reduction in refractory periods in ischemic tissue with fibrillation in only two of 14 animals stimulated at 0–20% vs. four of six at refractory period reductions of 20–40% (p These studies establish the distinctive time course of changes in refractory periods following ischemia in an animal without significant pre-existing coronary collateral circulation, and correlate these changes with spontaneous and induced ventricular arrhythmias.