Dezhi Xing

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.

Bradycardia Stimulates Vascular Growth During Gradual Coronary Occlusion

Objective—In cultured endothelium, stretch induces release of growth factors that contribute to angiogenesis. We tested the hypothesis that bradycardia, which prolongs ventricular diastolic filling time and volume, promotes collateral vessel growth. Methods and Results—An ameroid occluder was placed on coronary arteries of dogs with normal heart rates (AM) or bradycardia (55 bpm; AM+BC). A third group had normal heart rates and no ameroid (control [CON]). Four weeks after occluder placement, myocardial blood flow at rest and maximal vasodilation (adenosine) at equivalent heart rates and vascular morphometry of hearts were measured. In AM dogs, conductance (myocardial flow/diastolic pressure) of collateral-dependent myocardium was similar to collateral-independent myocardium during rest but increased to only one third of CON during maximal vasodilation. In contrast, in AM+BC dogs, conductance was similar in collateral-dependent and -independent regions during maximal vasodilation. Arteriolar length density in collateral-dependent myocardium was 80% greater in AM+BC than AM dogs. Capillary length density in collateral-dependent region of AM dogs was lower than CON but normal in AM+BC dogs. The angiopoietin receptor Tie-2 increased in collateral-dependent regions of AM and AM+BC groups, whereas vascular endothelial growth factor increased in collateral-dependent and -independent regions only in AM+BC dogs. Conclusion—Chronic bradycardia during gradual coronary artery occlusion facilitates angiogenesis/arteriogenesis in collateral-dependent myocardium and preserves maximal perfusion.

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 α-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 α-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 α-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 VT was 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 α-2 adrenoceptors on Purkinje fibers.

Angiotensin II effects on ischemic focal ventricular tachycardia are predominantly mediated through myocardial AT2 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.

71 LOVASTATIN IS ANTIARRHYTHMIC IN ISCHEMIC HEART TISSUE BY BLOCKING TRIGGERED ACTIVITY

Background AVID and MADIT-II trials showed that patients with coronary artery disease taking HMG-CoA reductase inhibitors have fewer ICD shocks suggesting anti-arrhythmic effects. Our aim was to analyze the effects of acutely administered lovastatin (LOVA): 1) on ICD defibrillation threshold (DFT) since antiarrhythmics can worsen DFT, and 2) on triggered activity (TA) recorded from ischemic endocardium excised from the anterior wall of anesthetized dogs with anterior descending coronary occlusion. Methods and Results Dogs received LOVA dissolved in DMSO. DMSO alone produced no effect on DFT. LOVA 10 mg IV did not alter effective refractory period and tended to improve defibrillation success (from 20 ± 3 to 17 ± 3 J, P = 0.09 vs control). Ischemic endocardium was studied using standard microelectrode techniques with normal Tyrodes solution. There were no delayed afterdepolarizations (DADs) or TA at baseline in this depolarized tissue (-71 ± 4 mV). Isoproterenol (5 × 10-7 M) superfusion, produced sustained TA with DAD amplitudes of 4.2 ± 1 mV. LOVA (10-7 M) produced no change in resting membrane potential (-70 ± 4 mV), action potential duration at 90% (from 231 ± 11 to 229 ± 8 msec, ns), action potential duration at 50% (168 ± 7 to 166 ± 6 msec, ns), action potential amplitude (89 ± 5 to 85 ± 5 mV, ns), overshoot (11 ± 1 to 10 ± 1 mV) or DAD amplitude (4.0 ± 1 mV, ns). Interestingly, TA was attenuated to 1-5 complexes with LOVA (p<0.05) and not with DMSO alone. Reversibility to sustained TA also occurred after LOVA washout (20 min) as well as with co-superfusion with mevalonic acid (10-7 M, n = 4), which also did not change action potentials or DADs. Conclusions These results are consistent with the possibility that a prenylated protein down-stream from the mevalonic acid pathway may underlie this effect. Thus LOVA in concentrations achievable in human plasma may be antiarrhythmic for TA without a deleterious effect on DFT.

95 WHAT IS THE MECHANISM OF ENDOTHELIN 1'S EFFECT ON ISCHEMIC VENTRICULAR TACHYCARDIA?

Background Endothelin (ET), one of the most potent vasoconstrictors, is known to influence ventricular tachycardia (VT). The mechanism thought to be involved includes triggered activity (TA). We investigated effects of ET-1 and the ET-1A receptor blocker BQ123 in a canine model of focal and reentrant VT in a combined in vivo and in vitro study to test the hypothesis that focal VT and TA were selectively affected. Methods Thirty-eight alpha-chloralose-anesthetized dogs with 1 to 3 hours of coronary artery occlusion were studied. Three-dimensional activation mapping identified the mechanism of VT. If VT was not inducible at baseline, incremental doses of ET-1 were given until the VT was induced. If VT was reproducibly induced at baseline, BQ123 was given (2.5 μg/kg, IV), and then induction was repeated. The effect of these agents on action potentials (APs), delayed and early afterdepolarizations (DADs and EADs), and TA measured from ischemic endocardium were studied in vitro by standard microelectrode techniques. Results Of 15 dogs with no VT inducible, ET-1 (0.2 μg/kg, IV) produced sustained VT of mixed reentrant and focal origin in five dogs (p < .05 [*] vs saline alone). ET-1 did not change effective refractory period (ERP), pacing threshold, mean arterial pressure (MAP), or infarct size (37 ± 3% [SEM] to 39 ± 4%). Of 12 dogs with reproducible reentrant VT in control, only 1 had no VT inducible after saline. Of 11 dogs given BQ123, reentrant VT was prevented in 4 of 6*; surface ECG and intracardiac T-wave alternans was blocked in all experiments. Zero of five dogs with focal origin of VT was prevented. BQ123 did not change ERP, threshold, MAP, or infarct size. In vitro APs were not substantially changed by ET-1 until rapid pacing produced AP alternans facilitated by ET-1 in 8 of 15 tissues; however, ET-1 (10-10-10-8 M) did not facilitate EADs, DADs, or TA. Conclusion ET-1 promotes focal and reentrant VT under conditions of myocardial ischemia; however, in vitro tissues do not show TA as we expected. The specific ET-1A receptor blocker BQ123 significantly blocked only reentrant VT. Endothelin plays a major role in reentrant VTs in the dog model of myocardial ischemia probably by promoting AP alternans.

78 ADRENOCEPTOR BLOCKERS AND FOCAL VENTRICULAR TACHYCARDIA DURING CORONARY ARTERY OCCLUSION.

Background Ventricular tachycardia (VT) of focal endocardial and Purkinje origin occurs in humans. Pharmacological blockade of adrenoceptors on endocardial tissues may selectively prevent the induction of focal VT. We tested the hypothesis that alpha adrenoceptor blocker WB4101(WB), beta-1 receptor blocker metoprolol (Met), and beta-2 receptor blocker ICI 118,511(ICI) prevent the induction of focal ischemic VT and evaluated possible mechanisms. Methods Fifty alpha chloralose anesthetized dogs with 1 to 4 hours of coronary artery occlusion (CAO) were involved. Twenty-three multipolar plunge electrodes were placed in and surrounding the risk zone of anterior descending coronary artery. three-dimensional activation mapping off-line helped to identify the origin of VT. If VT was reproducibly induced, WB (0.3 μg/kg, IV), Met (1 mg/kg), or ICI (0.2 mg/kg, IV) was given. The effects of blockers on delayed afterdepolarizations (DADs) and triggered activity (TA) recorded from endocardium and Purkinje tissue excised from the focal origin of VT were studied in vitro by standard microelectrode techniques. Results Eleven dogs were given WB; two had VTs blocked with the same or more extrastimuli. Twelve dogs were received ICI; only 3 had VT blocked, which were no different compared to focal endocardial or Purkinje VT in dogs with saline treatment, of which 1 of 12 had apparent block (p = ns). However, 7 of 15 dogs given Met had focal VT blocked, which was different from the saline treated (p < .05). Of tissues at the origin of VT, excised and studied in vitro, all foci showed DADs and TA with ISO, which were were blocked by WB (10-7 M, in 2 of 6, p = ns), ICI (10-7 M, in 0 of 4, p = ns) and Met (10-7 M, in 6 of 8, p < .05 vs control). Conclusions Pharmacological blockade of beta-1 adrenoceptor in acute ischemia selectively prevents induction of focal VT due to DADs and TA but alpha adrenoceptor and beta-2 receptor blockade does not.