Role of NADPH oxidase and xanthine oxidase in mediating inducible VT/VF and triggered activity in a canine model of myocardial ischemia.

BACKGROUND: Ventricular tachycardia or fibrillation (VT/VF) of focal origin due to triggered activity (TA) from delayed afterdepolarizations (DADs) is reproducibly inducible after anterior coronary artery occlusion. Both VT/VF and TA can be blocked by reducing reactive oxygen species (ROS). We tested the hypothesis that inhibition of NADPH oxidase and xanthine oxidase would block VT/VF. METHODS: 69 dogs received apocynin (APO), 4 mg/kg intraveneously (IV), oxypurinol (OXY), 4 mg/kg IV, or both APO and OXY (BOTH) agents, or saline 3 h after coronary occlusion. Endocardium from ischemic sites (3-D mapping) was sampled for Rac1 (GTP-binding protein in membrane NADPH oxidase) activation or standard microelectrode techniques. Results (mean±SE, * p<0.05): VT/VF originating from ischemic zones was blocked by APO in 6/10 *, OXY in 4/9 *, BOTH in 5/8 * or saline in 1/27; 11/16 VT/VFs blocked were focal. In isolated myocardium, TA was blocked by APO (10(-6) M) or OXY (10(-8) M). Rac1 levels in ischemic endocardium were decreased by APO or OXY. CONCLUSION: APO and OXY suppressed focal VT/VF due to DADs, but the combination of the drugs was not more effective than either alone. Both drugs inhibited ischemic Rac1 with inhibition by OXY suggesting ROS-induced ROS. The inability to totally prevent VT/VF suggests that other mechanisms also contribute to ischemic VT.

Novel indices for left-ventricular dyssynchrony characterization based on highly automated segmentation from real-time 3-d echocardiography.

Cardiac resynchronization therapy (CRT) using a biventricular pacemaker is an invasive and expensive treatment option for left ventricular mechanical dyssynchrony (LVMD). The CRT candidate selection is a crucial issue due to the unreliability of the current standard CRT indicators. Real-time three-dimensional (3-D) echocardiography (RT3DE) provides four-dimensional (4-D) (3-D+time) information about the LV and is suitable for LVMD assessment. In this article, the complex left ventricle (LV) shape and motion of 50 RT3DE datasets are represented by novel 4-D descriptors - 4-D sphericity, volume and shape, from which novel indices were derived by principal component analysis (PCA) and subsequently analyzed by a support vector machine (SVM) classifier to assess their capability of LVMD characterization and CRT outcome prediction. These novel indices outperformed clinical indices and have promising capabilities in disease characterization and great potential in CRT outcome prediction. To enable efficient quantitative RT3DE analysis, a segmentation method was developed to combine the powers of active shape models and optimal graph search. Various aspects of the method were designed to handle varying RT3DE image quality among datasets and LV segments. An application with graphical user interface was developed to provide the user with simple and intuitive control. The developed method was robust to inter-observer variability and produced very good accuracy - 3.2±1.1 mm absolute surface positioning error, <1 mm mean signed error and <5% mean volume difference. The computer method's classification performance was compared with the independent standard, showing that the 4-D shape modal indices were not only the most capable of all tested options when employed for disease characterization but also the least sensitive to segmentation imperfections.

Association among intracardiac T-wave alternans, ischemia, and spontaneous ventricular arrhythmias after coronary artery occlusion in a canine model.

T-wave alternans (TWA) has been investigated as a marker for susceptibility to lethal ventricular arrhythmia. In this article, we studied intracardiac TWA and ischemia as predictors of spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) in a canine model of coronary artery occlusion (CAO). Anesthetized, open-chest dogs were studied. Electrograms from intracardiac bipolar electrodes (IBEs) were assessed for TWA and spontaneous VT or VF. TWA was defined on IBE as T wave voltage change on every other complex. In each heart, we examined 62 electrograms measured in the risk zone and surrounding normal sites, filtered from 3 to 1300 Hz. Ischemia was measured as percent of all IBE recorded that had QRS voltage drop >45%. Mapping localized the three-dimensional origin of spontaneous VT or VF. The data from dogs with VF (n = 5), VT (n = 8), or controls (no VT or VF, n = 8) were analyzed before left CAO, at the 20th min after CAO and times immediately preceding VT and VF. We found a correlation between intracardiac TWA and ischemia. More importantly, increases in intracardiac TWA peaked immediately preceding spontaneous VF and VT and were significantly higher compared to controls at comparable times. At VT/VF origins and adjacent sites, the mean TWA magnitude and discordance of TWA distinguished between VT/VF and controls at comparable times but not between VT and VF or between reentry and focal mechanisms. TWA was more common than ischemia at VT/VF origins. In summary, changes in intracardiac TWA and ischemia correlate with impending spontaneous VT/VF in a clinically applicable canine model of CAO.

Catecholamine-independent heart rate increases require Ca2+/calmodulin-dependent protein kinase II.

BACKGROUND: Catecholamines increase heart rate by augmenting the cAMP-responsive hyperpolarization-activated cyclic nucleotide-gated channel 4 pacemaker current (I(f)) and by promoting inward Na(+)/Ca(2+) exchanger current (I(NCX)) by a "Ca(2+) clock" mechanism in sinoatrial nodal cells (SANCs). The importance, identity, and function of signals that connect I(f) and Ca(2+) clock mechanisms are uncertain and controversial, but the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is required for physiological heart rate responses to ß-adrenergic receptor (ß-AR) stimulation. The aim of this study was to measure the contribution of the Ca(2+) clock and CaMKII to cardiac pacing independent of ß-AR agonist stimulation. METHODS AND RESULTS: We used the L-type Ca(2+) channel agonist Bay K8644 (BayK) to activate the SANC Ca(2+) clock. BayK and isoproterenol were similarly effective in increasing rates in SANCs and Langendorff-perfused hearts from wild-type control mice. In contrast, SANCs and isolated hearts from mice with CaMKII inhibition by transgenic expression of an inhibitory peptide (AC3-I) were resistant to rate increases by BayK. BayK only activated CaMKII in control SANCs but increased L-type Ca(2+) current (I(Ca)) equally in all SANCs, indicating that increasing I(Ca) was insufficient and suggesting that CaMKII activation was required for heart rate increases by BayK. BayK did not increase I(f) or protein kinase A-dependent phosphorylation of phospholamban (at Ser16), indicating that increased SANC Ca(2+) by BayK did not augment cAMP/protein kinase A signaling at these targets. Late-diastolic intracellular Ca(2+) release and I(NCX) were significantly reduced in AC3-I SANCs, and the response to BayK was eliminated by ryanodine in all groups. CONCLUSIONS: The Ca(2+) clock is capable of supporting physiological fight-or-flight responses, independent of ß-AR stimulation or I(f) increases. Complete Ca(2+) clock and ß-AR stimulation responses require CaMKII.

I(f) and SR Ca(2+) release both contribute to pacemaker activity in canine sinoatrial node cells.

Increasing evidence suggests that cardiac pacemaking is the result of two sinoatrial node (SAN) cell mechanisms: a 'voltage clock' and a Ca(2+) dependent process, or 'Ca(2+) clock.' The voltage clock initiates action potentials (APs) by SAN cell membrane potential depolarization from inward currents, of which the pacemaker current (I(f)) is thought to be particularly important. A Ca(2+) dependent process triggers APs when sarcoplasmic reticulum (SR) Ca(2+) release activates inward current carried by the forward mode of the electrogenic Na(+)/Ca(2+) exchanger (NCX). However, these mechanisms have mostly been defined in rodents or rabbits, but are unexplored in single SAN cells from larger animals. Here, we used patch-clamp and confocal microscope techniques to explore the roles of the voltage and Ca(2+) clock mechanisms in canine SAN pacemaker cells. We found that ZD7288, a selective I(f) antagonist, significantly reduced basal automaticity and induced irregular, arrhythmia-like activity in canine SAN cells. In addition, ZD7288 impaired but did not eliminate the SAN cell rate acceleration by isoproterenol. In contrast, ryanodine significantly reduced the SAN cell acceleration by isoproterenol, while ryanodine reduction of basal automaticity was modest ( approximately 14%) and did not reach statistical significance. Importantly, pretreatment with ryanodine eliminated SR Ca(2+) release, but did not affect basal or isoproterenol-enhanced I(f). Taken together, these results indicate that voltage and Ca(2+) dependent automaticity mechanisms coexist in canine SAN cells, and suggest that I(f) and SR Ca(2+) release cooperate to determine baseline and catecholamine-dependent automaticity in isolated dog SAN cells.

Angiotensin II effects on ischemic focal ventricular tachycardia are predominantly mediated through myocardial AT(2) receptor.

Ischemic focal ventricular tachycardia (VT) occurs in animals and humans. Angiotensin-converting enzyme inhibitors and receptor blockers reduce sudden death in patients with ischemic heart disease. In our dog model of coronary artery occlusion (CAO), we tested the hypothesis that angiotensin II (AGII) will selectively promote focal VT and that the specific AT(2) blocker PD-123319 (PD), or AT(1) blocker losartan, will affect this VT. Anesthetized dogs (n = 90) underwent CAO, followed by three-dimensional activation mapping of inducible VT. Dogs without VT in 1-3 h after CAO received AGII, and those with VT received either PD or losartan. Focal endocardium excised from ischemic sites was studied in vitro with standard microelectrode. Of 33 dogs with no inducible VT, AGII infusion resulted in sustained VT of only focal Purkinje origin in 13 (39%) compared with 0 of 20 dogs with saline. Of 26 dogs with inducible VT at baseline, given PD, reinduction was blocked in 8 of 10 (P < 0.05) focal VT, but only 1 of 15 with reentry. In contrast, of 11 dogs given losartan, reinduction of either mechanism was not blocked. In vitro triggered activity in Purkinje was blocked by PD in 13 of 19 (P < 0.05), but not by losartan in 8. Also, triggered activity was promoted by AGII, losartan, or the combination in 9 of 12 tissues. AGII promotes only focal, mainly Purkinje ischemic VT. PD, but not losartan, preferentially blocked focal VT, which is likely due to triggered activity due to delayed afterdepolarizations in Purkinje.

Free radical scavenger specifically prevents ischemic focal ventricular tachycardia.

BACKGROUND: Focal ventricular tachycardia (VT) in acute myocardial ischemia is closely related to triggered activity (TA), which may be blocked by scavenging reactive oxygen species (ROS). OBJECTIVE: This study analyzed effects of acutely administered ROS scavenger-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) on VT in vivo and TA in vitro. METHODS: Forty-three alpha chloralose anesthetized dogs with coronary artery occlusion were studied. Three-dimensional activation mapping helped to locate the origin of focal or reentrant VT. TEMPO (30 mg/kg intravenously) or vehicle was given. Endocardium excised from the site of origin of VT was studied using standard microelectrode techniques and measures of ROS. RESULTS: Reentry and focal VT induction were both highly reproducible. TEMPO blocked focal VT in 6 of 11 dogs (P <.05), but 9 of 9 dogs with reentrant VT continued to have VT re-induced after TEMPO. TEMPO did not alter effective refractory period (168 +/- 3 to 171 +/- 3 ms), mean blood pressure (88 +/- 3 to 81 +/- 3 mm Hg), and size of ischemia (42% +/- 3% vs 40% +/- 4%). In vitro, TEMPO (10(-3) M, n = 14) produced no change in action potentials. Nevertheless, TA was reversibly attenuated from 5.3 +/- 1.1 to 0.4 +/- 0.4 complexes with TEMPO (n = 15, P <.05). Lucigenin-enhanced chemiluminescence and dihydroethidium staining showed increased ROS in ischemic endocardium; TEMPO dramatically reduced ROS in ischemic sites. CONCLUSION: TEMPO, a scavenger of ROS, prevented triggered activity associated with focal VT during myocardial ischemia in areas of increased ROS. Antioxidant therapy may play an important role in blockade of focal VT under the conditions of myocardial ischemia.

Alpha-2 adrenergic antagonism enhances risk of ventricular tachycardia during acute ischemia.

OBJECTIVE: In this study we tested the hypothesis that alpha-2 adrenergic antagonism could facilitate induction of previously non-inducible ventricular tachycardia (VT) during acute ischemia. Previous reports suggest that VT during ischemia may be modulated by (alpha-2 adrenergic agonists. DESIGN: The left anterior descending artery was occluded after instrumentation of the ischemic risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Three dimensional mapping characterized the mechanism of VT induced with extrastimuli. RESULTS: Of 16 non-inducible dogs included, eight which were given the alpha-2 adrenergic antagonist yohimbine all had inducible VT, while all eight in the control group remained non-inducible (p < 0.05). Six of the VTs were of focal Purkinje origin. The cycle length of the VTwas 119 +/- 4 ms. Mean arterial pressure (81+/- 8 to 82 +/- 8 mmHg, p = ns), ventricular effective refractory period (146 +/- 6 to 144 +/- 5 ms, p = ns) and ischemic zone size (55 +/-6% vs. 61 +/- 4%, p = 0.45) were not altered by yohimbine indicating minimal central or pre-junctional effects of the drug. CONCLUSIONS: Yohimbine facilitates induction of VT, especially those with focal Purkinje fiber origin, suggestive of an effect mediated through antagonism of post-junctional alpha-2 adrenoceptors on Purkinje fibers.

Lovastatin specifically prevents focal ischemic ventricular tachycardia due to triggered activity.

BACKGROUND: Use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor has been associated with reduced implantable defibrillator shocks in several multicenter trials, suggesting an antiarrhythmic effect. OBJECTIVE: The purpose of this study was to determine if lovastatin had an antiarrhythmic effect in a canine model of ischemic and inducible ventricular tachycardia (VT). METHODS: Forty-seven alpha-chloralose anesthetized dogs underwent left anterior descending coronary occlusion. Three-dimensional activation mapping identified the mechanism of reinducible VT and the response to lovastatin (0.5 mg/kg IV). The endocardium was excised from foci and studied using standard microelectrode techniques with Tyrode's solution. RESULTS: Lovastatin blocked focal VT in 8 of 13 dogs (P <.01) compared with only 1 of 12 saline-treated dogs with focal VT. Lovastatin had no effect on reentrant VT. Lovastatin did not alter the effective refractory period, arterial pressure, or percentage of ischemic electrograms. Effective plasma concentration of lovastatin hydroxy acid ranged from 21-157 ng/mL (0.8-3.7 x 10(-7) M). In vitro rapid pacing, mostly with isoproterenol (5 x 10(-7) M) superfusion, produced delayed afterdepolarizations and triggered activity (9 +/- 2 action potentials). Lovastatin (10(-7) M) produced no change in action potentials or delayed afterdepolarizations. However, triggered activity was attenuated to 2 +/- 1 action potentials with lovastatin (P <.05, n = 13) but not with vehicle alone. Triggered activity returned to control after lovastatin washout (20 minutes) as well as with co-superfusion with mevalonic acid (10(-6) M, n = 5). 2,2,6,6-Tetramethylpiperidine-N-oxyl, an antioxidant that enters tissues (10(-3) M, n = 8), prevented triggered activity in a fashion similar to lovastatin. CONCLUSION: Lovastatin, in concentrations achievable in human plasma, specifically suppresses triggered activity and focal VT due to ischemia. A prenylated protein downstream from mevalonic acid may act as an antioxidant, producing the antiarrhythmic effect.

Percent right ventricular pacing predicts outcomes in the DAVID trial.

BACKGROUND: The Dual-Chamber and VVI Implantable Defibrillator (DAVID) trial demonstrated a worse outcome in patients with implantable cardioverter-defibrillators (ICDs) programmed to DDDR at 70 bpm compared with patients who had ICDs programmed to VVI backup pacing at 40 bpm. Pacing was more frequent in the DDDR group. OBJECTIVES: The purpose of this study was to determine whether right ventricular pacing (RV) is an independent predictor of outcome in the DAVID trial. METHODS: We evaluated the relationship of percent RV pacing to the composite endpoint of death or hospitalization for congestive heart failure. Patients who had a 3-month follow-up and who had not yet reached an endpoint were included in the study. Using Cox regression analysis (VVI group N = 195; DDDR group N = 185), we examined multiple factors, including percent RV pacing at 3-month follow-up, that might be associated with adverse outcomes. RESULTS: Percent RV pacing as a continuous variable was correlated with the primary endpoint. As a dichotomous variable, the best separation for predicting endpoints occurred with DDDR RV pacing > 40% vs DDDR RV pacing < or = 40% (P = .025). Patients with DDDR RV pacing < or = 40% had similar or better outcomes to the VVI backup group (P = .07). Correction for baseline variables predictive of the composite outcome in the (nonpaced) VVI group (use of nitrates, increased heart rate, and increased age) did not change the findings for RV pacing (P = .008). In contrast, atrial pacing was not predictive of worse outcomes. CONCLUSION: These results suggest, but do not prove, a causal relationship between frequent RV pacing and adverse outcomes in patients with left ventricular ejection fraction < or = 40%.

Overdrive pacing of early ischemic ventricular tachycardia: evidence for both reentry and triggered activity.

Entrainment can be a useful method to identify reentry as a mechanism of ventricular tachycardia (VT). In this study, we evaluated the effect of gradually decreasing cycle lengths of overdrive pacing for stable VT induced in a canine model 1-3 h after coronary occlusion. Intact dogs underwent anterior descending coronary artery occlusion after instrumentation of the risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Overdrive pacing was attempted if the animals had sustained hemodynamically stable VT, looking for evidence of entrainment. Subsequent three-dimensional mapping determined the mechanism of VT. Fifteen of the 21 dogs studied demonstrated entrainment with overdrive pacing by progressive QRS fusion alone (1), the first nonpaced QRS entrained to the paced cycle length only (7), or both (7). Five of these 15 dogs also had postpacing acceleration of the VT at a subsequent faster pacing cycle length. The mechanism of acceleration in four was a change to a VT with a focal origin. The prepacing mechanism in all 15 dogs was subsequently mapped to reentry. Regarding the six VTs, which demonstrated no evidence for entrainment, the site of earliest activity was mapped to a focal origin in all. These data showing entrainment of inducible reentrant VTs and lack of such for focal VTs support that the focal VTs seen in this study are unlikely the result of microreentry but possibly a mechanism as triggered activity.

Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs.

The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in alpha-chloralose-anesthetized, open-chest dogs 1-4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 +/- 0.1 nM, 77 vs. 75%; 7.8 +/- 0.4 nM, 86 vs. 77%; and 78.8 +/- 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.

Triggered activity due to delayed afterdepolarizations in sites of focal origin of ischemic ventricular tachycardia.

This study for the first time systematically evaluated the site of origin of focal ventricular tachycardia (VT) induced 1-3 h after acute coronary artery ligation in dogs. We determined whether delayed afterdepolarizations (DADs) and triggered activity (TA) are more often recorded from ischemic endocardium excised from focal sites of VT origin. A total of 145 alpha-chloralose-anesthetized dogs were studied: in 54 dogs without inducible VT, normal or ischemic endocardium was investigated in vitro; in 91 dogs, inducible VT was studied by three-dimensional activation mapping, with in vitro study of 51 endocardial foci compared with 40 endocardial ischemic sites not of VT origin. Incidence of DADs (71% vs. 33%, P <0.05) and TA (32% vs. 11%, P <0.05) was greater in ischemic than in normal Purkinje tissues. Purkinje sites of origin of focal VT demonstrated the greatest frequency of DADs (92%, P <0.05) and TA (75%, P <0.05), with repetitive TA predominating. Similar results were obtained in endocardial sites of origin. Action potentials were mildly depolarized and prolonged in the focal sites of origin. These abnormalities were stable up to 2.5 h of recording. This study demonstrated that DADs and TA may underlie a majority of focal VTs in ischemic endocardium and Purkinje tissue.

Increased susceptibility to ventricular arrhythmias in a rodent model of experimental depression.

Depression is an important public health problem and is considered to be an independent risk factor for coronary artery disease. The pathophysiological mechanisms that link depression with adverse cardiovascular events (e.g., myocardial ischemia, myocardial infarction, and sudden death) are not well established. It is possible that an increased susceptibility to life-threatening cardiac arrhythmias in depressed patients influences the risk of morbidity and mortality in coronary artery disease. This idea was tested with the use of an experimental model of depression that was developed to induce anhedonia, the reduced responsiveness to pleasurable stimuli observed in human depressed patients. Rats exposed to 4 wk of chronic mild stress (e.g., paired housing, strobe light, and white noise) displayed anhedonia, which was operationally defined by the reduced intake of a palatable sucrose solution relative to an established baseline and to control animals. Furthermore, compared with control rats, the anhedonic rats showed increased basal heart rate and decreased heart rate variability. In response to an intravenously infused chemical challenge, aconitine, anhedonic rats exhibited an increased vulnerability to ventricular arrhythmias, as indicated by a reduced threshold for premature ventricular complexes, salvos, and ventricular tachycardia. These findings suggest that the presence of depressive symptoms is associated with a lower threshold for ventricular arrhythmias, which may contribute to the increased risk for adverse cardiovascular events in patients with depression.

Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial.

INTRODUCTION: The implantable cardioverter defibrillator (ICD) is commonly used to treat patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Arrhythmia recurrence rates in these patients are high, but which patients will receive a therapy and the forms of arrhythmia recurrence (VT or VF) are poorly understood. METHODS AND RESULTS: The therapy delivered by the ICD was examined in 449 patients randomized to ICD therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. Events triggering ICD shocks or antitachycardia pacing (ATP) were reviewed for arrhythmia diagnosis, clinical symptoms, activity at the onset of the arrhythmia, and appropriateness and results of therapy. Both shock and ATP therapies were frequent by 2 years, with 68% of patients receiving some therapy or having an arrhythmic death. An appropriate shock was delivered in 53% of patients, and ATP was delivered in 68% of patients who had ATP activated. The first arrhythmia treated in follow-up was diagnosed as VT (63%), VF (13%), supraventricular tachycardia (18%), unknown arrhythmia (3%), or due to ICD malfunction or inappropriate sensing (3%). Acceleration of an arrhythmia by the ICD occurred in 8% of patients who received any therapy. No physical activity consistently preceded arrhythmias, nor did any single clinical factor predict the symptoms of the arrhythmia. CONCLUSION: Delivery of ICD therapy in AVID patients was common, primarily due to VT. Inappropriate ICD therapy occurred frequently. Use of ICD therapy as a surrogate endpoint for death in clinical trials should be avoided.

ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs.

INTRODUCTION: The aim of this study was to determine if the stable antiarrhythmic peptide (AAP) analogue ZP123 increases gap junctional intercellular conductance and prevents reentrant ventricular tachycardia (VT) during coronary artery occlusion. METHODS AND RESULTS: Voltage clamp experiments demonstrated that 10 nM ZP123 improved gap junctional intercellular conductance by 69% +/- 20% in pairs of guinea pig ventricular myocytes. VT was induced by programmed stimulation in alpha-chloralose anaesthetized open chest dogs 1 to 4 hours after coronary artery occlusion. Three-dimensional activation mapping was done using six bipolar electrograms on each of 23 multipolar needles in the risk zone. When VT was reproducibly induced, dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (intravenous bolus followed by 30-min infusion per dose). Attempts to induce VT were repeated in each infusion period. Mass spectrometry was used to measure ZP123 plasma concentrations. Twenty-six dogs with reentrant VT were included. ZP123 significantly prevented reentrant VT at all plasma concentrations vs saline: 1.0 +/- 0.2 nM: 6/12 vs 0/12; 7.7 +/- 0.6 nM: 7/13 vs 1/12; and 69.2 +/- 5.4 nM: 9/13 vs 1/13. The preventive effect of ZP123 on reentrant VT was closely correlated to reversal of functional, unidirectional conduction block. ZP123 did not affect effective refractory period, surface ECG parameters, mean arterial pressure, or infarct size. CONCLUSION: The stable AAP analogue ZP123 increased gap junctional intercellular conductance and specifically prevented the induction of reentrant VT during ischemia in a broad dose range without proarrhythmic or hemodynamic side effects. ZP123 is a promising candidate for use in preventing ischemia-induced VT.

Alpha 2-Adrenergic stimulation is protective against ischemia-reperfusion-induced ventricular arrhythmias in vivo.

We previously reported that alpha(2)-adrenergic receptor (alpha(2)-AR) stimulation in Purkinje fibers in vitro prolongs action potential duration and suppresses beta-adrenergic-induced delayed afterdepolarizations and sustained triggered activities. We examined the effects of alpha(2)-AR stimulation on reperfusion-induced ventricular arrhythmias [ventricular tachycardia/ventricular fibrillation (VT/VF)] in vivo. Arterial blood pressure, heart rate, surface electrocardiogram, and renal sympathetic nerve activities were recorded simultaneously in Sprague-Dawley rats. The incidence of VT/VF was 87.5% for controls, 50% for the beta-blocker group, 72% for the alpha(1)-blocker group, and 12.5% for the alpha(1) + beta-blockers group (unopposed alpha(2)-adrenergic activation). Direct alpha(2)-AR stimulation with UK-14304 also prevented VT/VF. These effects were reversed by the alpha(2)-adrenergic antagonist yohimbine. Increases in renal sympathetic nerve activity were associated with left anterior descending coronary artery ligation and reperfusion (33 +/- 1.5 and 62 +/- 1.7% over baseline, respectively) in controls. Similar patterns were observed among all experimental groups irrespective of the incidence of VT/VF on reperfusion. We conclude that alpha(2)-AR stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally mediated.

Purkinje involvement in arrhythmias after coronary artery reperfusion.

Previous studies have indicated that the endocardium may be responsible for a large portion of ventricular tachycardia (VT) seen with reperfusion of ischemic myocardium. To evaluate the role of the Purkinje system in nonreentrant VT arising from the endocardium after reperfusion, the anterior descending coronary artery was occluded for 20 min and then reperfused in 23 dogs after instrumentation of the risk zone with 21 multipolar plunge needles. VT with focal Purkinje origin was defined as a focal endocardial VT with Purkinje potentials recorded before the earliest endocardial myopotential. A total of 19 VTs (mean cycle length 214 +/- 2 ms) were observed with 11 (58%) having focal Purkinje origin. Fifty-eight percent of the VTs degenerated to ventricular fibrillation, with occurrences of two or more independent foci per complex (seen in 7 of 11 compared with 1 of 8 nonsustained VTs). In conclusion, these data show that Purkinje tissue may be important in the genesis of reperfusion VT.