Ischemia-induced Ventricular Tachycardia Research Articles

Canine Model of Ischemia-Induced Ventricular Tachycardia

IntroductionDespite advances in antiarrhythmia therapies, ventricular tachycardia (VT) is a leading cause of sudden cardiac death. Investigation into the characteristics and new treatments for this arrhythmia is required to improve outcomes and a reproducible model of VT would be useful in these endeavors. We therefore created a canine model of ischemia-induced VT. Materials and methodsA pacing lead was implanted in the right ventricle in canines (n = 13) and the left anterior descending artery was occluded in two locations for 2 h and subsequently released to create an ischemia-reperfusion injury. In the 10 dogs that survived the first 48 h following the initial study, a terminal study was conducted 4-7 d later and VT was induced using premature stimulation or burst pacing through the right ventricle lead. The arrhythmia was terminated using either antitachycardia pacing or a defibrillatory shock. Multiple inductions into sustained VT were attempted. ResultsSustained VT was induced in eight of 10 dogs with an average cycle length of 335 ± 70 bpm. Multiple episodes of VT were induced. Episodes of VT exhibited different electrocardiogram morphologies and cycle lengths in individual animals. ConclusionsThis canine model provides a consistent technique for inducing multiple episodes of sustained VT. It may be useful for investigating VT mechanisms and testing novel therapeutics and treatments for patients with VT.

No evidence of association between habitual physical activity and ECG traits: Insights from the electronic Framingham Heart Study

No evidence of association between habitual physical activity and ECG traits: Insights from the electronic Framingham Heart Study

Effects of antiarrhythmic peptide 10 on acute ventricular arrhythmia.

To observe the effects antiarrhythmic peptide 10 (AAP10) aon acute ventricular arrhythmia and the phosphorylation state of ischemic myocardium connexin. Acute total ischemia and partial ischemia models were established by ceasing perfusion and ligating the left anterior descending coronary artery in SD rats. The effects of AAP10 (1 mg/L) on the incidence rate of ischemia-induced ventricular arrhythmia were observed. The ischemic myocardium was sampled to detect total-Cx43 and NP-Cx43 by immunofluorescent staining and western blotting. the total-Cx43 expression was detected through image analysis system by semi-quantitative analysis. AAP10 could significantly decrease the incidence of ischemia-induced ventricular tachycardia and ventricular fibrillation. During ischemic stage, total ischemia (TI) and AAP10 total ischemia (ATI) groups were compared with partial ischemia (PI) and AAP10 partial ischemia (API) groups. The rates of incidence for arrhythmia in the ATI and API groups (10% and 0%) were lower than those in the TI and PI groups (60% and 45%). The difference between the two groups was statistically significant (P=0.019, P=0.020). The semi-quantitative analysis results of the ischemic myocardium showed that the total-Cx43 protein expression distribution areas for TI, ATI, PI and API groups were significantly decreased compared with the control group. On the other hand, the NP-Cx43 distribution areas of TI, ATI, PI and API groups were significantly increased compared with the control group (P>0.05). AAP10 could increase the total-Cx43 expression in the ischemic area and decrease the NP-Cx43 expression. Western blot results were consistent with the results of immunofluorescence staining. AAP10 can significantly decrease the rate of incidence of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. Acute ischemic ventricular arrhythmias may have a relationship with the decreased phosphorylation of Cx43 induced by ischemia. AAP10 may stimulate the phosphorylation of Cx43 by increasing the total-Cx43 expression and decreasing the NP-Cx43 expression in the ischemic area, so as to decrease ventricular arrhythmia.

Dyscholesterolemia Alters L-Type Calcium Current Which Protects against Ischemia-Induced Ventricular Tachycardia and Ventricular Fibrillation

Background: Hypercholesterolemia is associated with alteration of the lipid composition of the sarcolemma which may cause augmentation of the L-type calcium current (ICaL) and appears to be protective against ventricular fibrillation in patients with myocardial infarction.Hypothesis: Hypercholesterolemia increases ICaL resulting in action potential (AP) prolongation which protects against ischemia induced arrhythmias.Methods: ECG was measured in LDL-receptor knockout (LDLr-/-) mice with elevated LDL cholesterol and wild type mice (WT). AP, ICaL and calcium handling were determined in left ventricular myocytes. In perfused hearts the left anterior descending artery was ligated. Arrhythmia inducibility was tested every 30s by three premature stimuli with a coupling interval of 10ms longer than the refractory period followed by a 500ms pause. Area at risk (AAR) was determined with Evans Blue.Results: Cholesterol concentration in left ventricular myocytes was higher in LDLr-/- mice than WT (34.4±2.8 vs 25.5±0.4 μmol/gr protein) resulting in AP and QTc prolongation (APD90 102±4 vs 84.4±3.1, QTc 50.9±1.3 vs 43.8±1.18ms and increased ICaL (12.1±1.1, and 9.4±0.7 pA/pF) and calcium transient amplitude (74±4 vs 35±3 nM). The incidence of induced premature beats was not significantly different. In 7/7 LDLr-/- and 8/9 WT hearts arrhythmias could be provoked. In LDLr-/- hearts, only 5/412 induction attempts resulted in VT/VF whereas in WT hearts 30/477 induction attempts resulted in VT/VF. (p<0.05) The AAR was not different between LDLr-/- and WT mice.Conclusion: Hypercholesterolemia protects against the occurrence of re-entrant arrhythmias during myocardial ischemia by QTc and AP prolongation due to increased ICaL.

Electrophysiological effect of rotigaptide in rabbits with heart failure.

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

Arrhythmogenic Effect of Sympathetic Histamine in Mouse Hearts Subjected to Acute Ischemia

The role of histamine as a newly recognized sympathetic neurotransmitter has been presented previously, and its postsynaptic effects greatly depended on the activities of sympathetic nerves. Cardiac sympathetic nerves become overactivated under acute myocardial ischemic conditions and release neurotransmitters in large amounts, inducing ventricular arrhythmia. Therefore, it is proposed that cardiac sympathetic histamine, in addition to norepinephrine, may have a significant arrhythmogenic effect. To test this hypothesis, we observed the release of cardiac sympathetic histamine and associated ventricular arrhythmogenesis that was induced by acute ischemia in isolated mouse hearts. Mast cell-deficient mice (MCDM) and histidine decarboxylase knockout (HDC(-/-)) mice were used to exclude the potential involvement of mast cells. Electrical field stimulation and acute ischemia-reperfusion evoked chemical sympathectomy-sensitive histamine release from the hearts of both MCDM and wild-type (WT) mice but not from HDC(-/-) mice. The release of histamine from the hearts of MCDM and WT mice was associated with the development of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. The incidence and duration of induced ventricular arrhythmias were found to decrease in the presence of the selective histamine H(2) receptor antagonist famotidine. Additionally, the released histamine facilitated the arrhythmogenic effect of simultaneously released norepinephrine. We conclude that, under acute ischemic conditions, cardiac sympathetic histamine released by overactive sympathetic nerve terminals plays a certain arrhythmogenic role via H(2) receptors. These findings provided novel insight into the pathophysiological roles of sympathetic histamine, which may be a new therapeutic target for acute ischemia-induced arrhythmias.

Loss of Anti-Arrhythmic Effect of Vagal Nerve Stimulation on Ischemia-Induced Ventricular Tachyarrhythmia in Aged Rats

Reduced vagal activity is associated with increased risk for life-threatening arrhythmia during myocardial ischemia (MI); conversely, the increase in vagal tone may provide protective effect against ventricular arrhythmias. In fact, vagal nerve stimulation (VNS) exerted an anti-arrhythmic effect by preserving connexin 43 (Cx43), a gap junction protein in ventricles, in a rat model of MI. We investigated the effects of VNS on ventricular tachyarrhythmia during acute MI and the expression of Cx43 in aged rats. Both adult (3-4 months) and aged (≥ 24 months) male rats were subjected to ischemia of 30 min. VNS was applied before ischemia either alone or in combination with atropine (0.5 mg/kg) or carbenoxolone, a gap junction inhibitor (10 mg/kg). During the 30-min ischemia, the incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) was higher in aged rats compared with adult rats. VNS significantly suppressed VT and VF in adult rats and these effects were eliminated by atropine or carbenoxolone. In contrast, VNS did not suppress VT and VF in the aged rats. Moreover, ischemia did not change the expression levels of total Cx43 protein in adult and aged rat ventricles. However, the expression level of total Cx43 protein was two times lower in sham-operated aged rats than that in sham-operated adult rats. Thus, in aged rats, loss of anti-arrhythmic effect of VNS is associated with reduced expression of Cx43 protein. These findings suggest that Cx43 may be an important target for inhibiting ischemia-induced VT in adult patients but not in aged patients.

Paraplegia increased cardiac NGF content, sympathetic tonus, and the susceptibility to ischemia-induced ventricular tachycardia in conscious rats

Midthoracic spinal cord injury is associated with ventricular arrhythmias that are mediated, in part, by enhanced cardiac sympathetic activity. Furthermore, it is well known that sympathetic neurons have a lifelong requirement for nerve growth factor (NGF). NGF is a neurotrophin that supports the survival and differentiation of sympathetic neurons and enhances target innervation. Therefore, we tested the hypothesis that paraplegia is associated with an increased cardiac NGF content, sympathetic tonus, and susceptibility to ischemia-induced ventricular tachyarrhythmias. Intact and paraplegic (6-9 wk posttransection, T(5) spinal cord transection) rats were instrumented with a radiotelemetry device for recording arterial pressure, temperature, and ECG, and a snare was placed around the left main coronary artery. Following recovery, the susceptibility to ventricular arrhythmias (coronary artery occlusion) was determined in intact and paraplegic rats. In additional groups of matched intact and paraplegic rats, cardiac nerve growth factor content (ELISA) and cardiac sympathetic tonus were determined. Paraplegia, compared with intact, increased cardiac nerve growth factor content (2,146 +/- 286 vs. 180 +/- 36 pg/ml, P < 0.05) and cardiac sympathetic tonus (154 +/- 4 vs. 68 +/- 4 beats/min, P < 0.05) and decreased the ventricular arrhythmia threshold (3.6 +/- 0.2 vs. 4.9 +/- 0.2 min, P < 0.05). Thus altered autonomic behavior increases the susceptibility to ventricular arrhythmias in paraplegic rats.

Identification of ischemia-regulated phosphorylation sites in connexin43: A possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123)

Previous studies suggest that dephosphorylation of connexin43 (Cx43) is related to uncoupling of gap junction communication, which plays an important role in the genesis of ischemia-induced ventricular tachycardia. We studied changes in Cx43 phosphorylation during global ischemia in the absence and presence of the antiarrhythmic peptide analogue rotigaptide (formerly known as ZP123). Phosphorylation analysis was performed on Cx43 purified from isolated perfused rat hearts using matrix-assisted laser desorption/ionization mass spectrometry and liquid chromatography electrospray ionization tandem mass spectrometry. Thirteen different serine phosphorylation sites were identified in Cx43 during non-ischemic conditions, three of which had not previously been described. Within the first 7 min of ischemia, Ser306 became fully dephosphorylated whereas Ser330 became phosphorylated. Between 15 and 30 min of ischemia, the critical time interval where gap junction uncoupling occurs, Ser297 and Ser368 also became fully dephosphorylated. During the same time period, all untreated hearts developed asystole. Treatment with rotigaptide significantly increased the time to ischemia-induced asystole and suppressed dephosphorylation of Ser297 and Ser368 at 30 min of ischemia. Our results suggest that phosphorylation of Ser297 and Ser368 may be involved in functional gating of Cx43 during ischemia and may be possible downstream targets for rotigaptide signaling.

Antiarrhythmic actions of tedisamil: Studies in rats and primates

Tedisamil is a new bradycardic agent, previously shown to block transient outward and delayed rectifier potassium currents in cardiac tissue [1,2]. In the present study tedisamil caused bradycardia and Q-Tc widening in rats and primates. Q-Tc widening is indicative of class III antiarrhythmic actions. In keeping with this, tedisamil had antiarrhythmic activity against electrical and ischemia-induced arrhythmias in rats. In rats, 0.5–4 mg/kg IV tedisamil caused parallel and dose-related increases in action-potential duration, “Q-Tc” interval, and refractory period; and decreases in maximum ventricular following frequency. In primates after 0.5–2.0 mg/kg IV, findings were similar for indices of Q-T widening and decreases in maximum ventricular following frequency. Tedisamil did not change QRS width, nor did it increase threshold currents for capture of ventricles, nor for fibrillo-flutter at doses below 4 mg/kg in rats. These findings were consistent with the lack of significant sodium-channel blockade. However, upon increasing the dose to 4 mg/kg, ventricular fibrillo-flutter could not be induced in rats by electrical stimulation; instead, only ventricular tachycardias with slow rates occurred. Ischemia-induced ventricular fibrillation was reduced in a dose-related manner by tedisamil in rats. The overall incidence of ischemia-induced ventricular tachycardia was not markedly reduced, but rates during tachycardic episodes were lower. When pacing was used to overcome tedisamil-induced bradycardia, antiarrhythmic actions during ischemia were more pronounced. These findings are consistent with the hypothesis that tedisamil increased refractoriness, which resulted in extended path lengths for reentry circuits and slower rates during episodes of ventricular tachycardia. High doses of tedisamil increased path lengths so much that the multiple reentry circuits of fibrillation could no longer occur. The limited study in primates suggests similar mechanisms could occur in humans.

R56865, a Potent New Antiarrhythmic Agent, Effective During Ischemia and Reperfusion in the Rat Heart

The antiarrhythmic effects of R56865 were characterized both in vivo and in vitro. Four groups (n = 12 per group) of anesthetized rats, subjected to 5- or 30-min coronary artery ligation and reperfusion, were studied: saline, dimethyl sulfoxide (DMSO) carrier, and R56865 (0.5 or 2 mg/kg) were administered as an intravenous (i.v.) bolus before ligation. After 5 min of ischemia, the incidences of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF), which were high in the saline (100 and 75%, respectively) and DMSO (100 and 82%, respectively) control groups, were abolished with both doses of R56865. With 30 min of ischemia, R56865 (2 mg/kg) significantly reduced the incidences of ischemia-induced VT and VF (from 100 and greater than 50% to 25 and 8%, respectively). For in vitro studies, five groups (n = 12 per group) of isolated rat hearts subjected to 10- or 30-min coronary ligation and reperfusion were studied: unmodified buffer and buffer containing DMSO or R56865 (10(-7), 10(-8), 10(-9) M). After 10 min of ischemia, R56865 (10(-7) M) decreased reperfusion-induced VT and VF (from 100 and 75% in buffer controls to 42 and 8%, respectively) when administered throughout the experiment. With 30 min of ischemia, R5685 (10(-7) M) reduced the incidences of ischemia-induced VT and VF (from 75 and 67% in the buffer controls to 25 and 25%, respectively). Although reperfusion after 30 min of ischemia did not induce VF in any of the groups studied, VT and other arrhythmias did occur and their incidences were reduced significantly by R56865. To investigate whether calcium overload might mediate the effects of R56865, hearts were perfused aerobically with a high-calcium/low-sodium medium. VT and VF occurred in 80% of control hearts; R56865 (10(-7) M) did not prevent these arrhythmias. In conclusion, R56865 exerts a potent effect against ischemia- and reperfusion-induced arrhythmias through a mechanism which appears to operate during ischemia.

Effect of coronary occlusion on arrhythmias and conduction in the ovine heart.

The proximal left circumflex coronary artery was occluded for 1 h in 16 open-chest sheep anesthetized with pentobarbital sodium. Epicardial conduction was monitored at three or four sites within the ischemic zone and one site in the normal zone. Eight of the sheep developed ventricular fibrillation within the first 15 min of occlusion; the remaining sheep survived the 1-h observation period. In the sheep that developed spontaneous ventricular fibrillation, the circumflex perfused a significantly greater amount of the left ventricle (44 +/- 3 vs. 39 +/- 3%; P = 0.008). The occurrence of spontaneous ventricular fibrillation was invariably preceded by a period of sustained (0.5-4 min) ventricular tachycardia. Six of the surviving sheep developed episodes of sustained (2-10 min) tachycardia that were self-terminating. The ischemic zone electrograms showed continuous fractionated electrical activity during both self-terminating tachycardias and tachycardias ending in fibrillation. The continuous epicardial electrical activity did not appear to cause the tachycardias but rather occurred as a result of the tachycardias. The genesis of ventricular tachycardia and fibrillation in this model may involve mechanisms different from ischemia-induced ventricular tachycardia and fibrillation in canine and porcine hearts.