Antiarrhythmic properties of tetrodotoxin against occlusion-induced arrhythmias in the rat: a novel approach to the study of the antiarrhythmic effects of ventricular sodium channel blockade

Blockade of ventricular sodium conductance (gNa) is believed to play an important role in the beneficial antiarrhythmic effects of class I antiarrhythmic agents. The present study was undertaken to examine the importance of ventricular gNa blockade by assessing the antiarrhythmic profile of tetrodotoxin (TTX), a selective sodium channel blocker. Experiments were performed in pentobarbital-anesthetized and artificially ventilated rats. Two doses of TTX were tested for antiarrhythmic action: a low dose (low TTX, 10 micrograms/kg of bolus + infusion of 10 micrograms/kg/hr) which blocked only neuronal activity, and a high dose (TTXh, 50 micrograms/kg of bolus + infusion of 50 micrograms/kg/hr) which also produced signs of ventricular gNa blockade in normal hearts. To control for the decreases in blood pressure and heart rate caused by TTX, hexamethonium, nitroprusside and propranolol were also used. Only TTXh possessed antiarrhythmic activity in rats subjected to myocardial ischemia (produced by ligation of the left anterior descending coronary artery). Arrhythmia scores (mean, n = 9) were: saline, 3.8; hexamethonium, 3.8; nitroprusside, 3.2; nitroprusside + propranolol, 4.3; low TTX, 3.9; and TTXh, 0.9. Only TTXh reduced dV/dt max. of the action potential (recorded in vivo by means of 3 M KCl filled microelectrodes) as well as action potential height, and concomitantly prolonged the P-R and QRS intervals of normal hearts. In conclusion, our study demonstrated that drugs which produced hypotension, bradycardia and loss of autonomic function were not antiarrhythmic. On the other hand, the marked antiarrhythmic activity of TTXh appeared to depend upon ventricular gNa blockade. Thus, TTX provides a useful tool for examining the antiarrhythmic properties of ventricular gNa blockade.     

Effects of rotigaptide, a gap junction modifier, on defibrillation energy and resuscitation from cardiac arrest in rabbits

The gap junction modifier Rotigaptide (ZP123), which promotes cellular coupling, was hypothesized to decrease defibrillation thresholds during prolonged ventricular fibrillation (VF). Thirty-two New Zealand white rabbits were randomized to receive saline (control, n = 16) or Rotigaptide (n = 16). Following 4 min of untreated VF, biphasic defibrillation shocks were applied through chest wall patches, starting either at 300 volts (V) (n = 16) or 500 V (n = 16), with 200 V increasing steps to 900 V in case of shock failure. Rotigaptide significantly decreased defibrillation voltage requirements (average cumulative voltage of all shocks: 1206 +/- 709 V in control group vs. 844 +/- 546 V in treated group, P = .002). Rotigaptide had no effect on heart rate, QRS duration, QT interval, ventricular effective refractory period, monophasic action potential duration or on connexin 43 density using immunofluorescence. Rotigaptide improves the ability to defibrillate after untreated VF.     

Endogenous prostaglandin endoperoxides and prostacyclin modulate the thrombolytic activity of tissue plasminogen activator. Effects of simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/prostaglandin H2 receptors in a canine model of coronary thrombosis.

We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation, the animals received saline (controls, n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion), a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion), a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion), a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then, all dogs received heparin (200 U/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 +/- 5 vs. 56 +/- 7 min, respectively, P = NS), but it was significantly shortened by R 68070 and dazoxiben (11 +/- 2 and 25 +/- 6 min, respectively, P less than 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P less than 0.01). Reocclusion was observed in eight of eight control dogs, five of seven SQ 29548-treated dogs, seven of nine dazoxiben-treated dogs, and zero of eight R 68070-treated animals (P less than 0.001). TxB2 and 6-keto-PGF1 alpha, measured in blood samples obtained from the coronary artery distal to the thrombus, were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels, whereas 6-keto-PGF1 alpha levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either intervention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.     

The effect of magnesium sulfate on action potential duration and cardiac arrhythmias

To evaluate the electrophysiologic and antiarrhythmic effects, Mg was infused at 15 mg/h (n = 5) or an equal volume of saline (1.2 mL/h) (n = 5) and electrocardiogram and action potential duration (APD) recorded every 15 minutes. Rats were anesthetized with 70 mg/kg pentobarbital intraperitoneally. Mg increased QT 15 +/- 6% on average compared with 1 +/- 4 for saline P < 0.01. Mg increased QT, 0, 0, 6 +/- 4, 13 +/- 5, 16 +/- 4, 23 +/- 5, 29 +/- 8, and 32 +/- 5% over baseline after a 2 hours infusion (P < 0.01). APD increased by 0, 6 +/- 3, 8 +/- 8, 14 +/- 4, 16 +/- 12, 21 +/- 4, 25 +/- 5% change from baseline (P < 0.05). The mean percentage of increase was 12 +/- 8 for the Mg group and 1 +/- 3 for the saline group (P < 0.05). The JT interval also increased after Mg (P < 0.01). After Mg loading, coronary occlusion of the left anterior descending coronary artery was performed. Ventricular premature contractions (VPCs), ventricular tachycardia (VT), and ventricular fibrillation (VF) were frequent in the saline control group, with 2 dying in VF; with only scattered VPCs and short runs of nonsustained VT in the Mg group. The results of these findings indicate that infusion of MgSO4 can prolong the QRS, QT, and JT intervals in the rat and these changes correlate well with arrhythmia suppression.     

Hemodynamic and sedative effects of dexmedetomidine in dog.

This study investigated hemodynamic and sedative effects of a single dose of the selective alpha-2 adrenoceptor agonist dexmedetoimidine (DMED) in isoflurane-anesthetized dogs. DMED (20 micrograms/kg i.v. 2-min infusion) was given to all dogs. In Group 1 the effects of DMED (time control; N = 10) were studied over 4 hr. In Group 2 (N = 11) glycopyrrolate (40 micrograms/kg initial dose followed by 20 micrograms/kg repeated every 30 min) was used to modulate the DMED-induced vagally mediated changes in heart rate. In Group 3 (N = 8), two doses of nifedipine were used to offset the DMED-induced increase in arterial blood pressure, low dose nifedipine = 10 micrograms/kg bolus followed by 2.5 micrograms/kg/min infusion for 20 min, high dose nifedipine = 20 micrograms/kg bolus followed by 5 micrograms/kg/min infusion for 20 min. DMED administration reduced isoflurane anesthetic requirements by 89% at 30 min and by 50% at 4 hr. Maximum increase in mean arterial blood pressure (MABP) +67 mm Hg occurred 1 min after DMED. MABP remained significantly elevated throughout the 4 hr studied (about +20%). Concomitant with the transient peak in MABP, heart rate (129 +/- 6 to 60 +/- 8 bpm) and cardiac output (3.5 +/- 0.3 to 0.9 +/- 0.1 l/min) decreased, whereas systemic vascular resistance (2460 +/- 210 to 14,700 +/- 1330 dynes.sec.cm-5) and left ventricular end diastolic pressure (4 +/- 1 to 27 +/- 4 mm Hg) increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Results of Electrophysiological Testing and Long-Term Follow-Up in Patients Sustaining Cardiac Arrest Only While Receiving Type IA Antiarrhythmic Agents

Therapeutic management of patients sustaining a cardiac arrest while receiving antiarrhythmic agents can be difficult since the role of the drug in possibly facilitating the arrhythmia is often difficult to define. To determine if the response to programmed stimulation could give insight into which patients may have experienced a drug-induced cardiac arrest, we studied 29 patients (61 +/- 9 years) with no prior history of sustained ventricular tachyarrhythmias (VT) who suffered a cardiac arrest only while receiving type Ia antiarrhythmic agents. Patients with documented myocardial infarction, acute ischemia, electrolyte abnormalities, or torsade de pointes were excluded from the study. Twenty-four patients had coronary artery disease with prior myocardial infarction (ejection fraction 28% +/- 9%) and five patients had idiopathic dilated cardiomyopathy (ejection fraction 31% +/- 6%). During baseline electrophysiological testing, 19 patients (66%) had inducible sustained ventricular arrhythmias: uniform VT, n = 14 (group I), polymorphic VT or ventricular fibrillation, n = 5 (group II). Ten patients (group III) had no inducible sustained ventricular arrhythmias. To determine if rechallenge with a type Ia agent could facilitate induction of a sustained ventricular arrhythmia in group III, eight patients underwent ten electrophysiological studies during therapy with either procainamide or quinidine. Only two patients developed sustained VT in response to programmed stimulation. Patients in groups I and II received therapy guided by electrophysiological testing, including antiarrhythmic agents alone (n = 8), subendocardial resection (n = 4), or an implantable cardioverter defibrillator (n = 7). Patients in group III received antiarrhythmic agents empirically (n = 3), or for treatment of atrial tachyarrhythmias (n = 2) or nonsustained VT (n = 1). In addition, four patients in group III received an implantable cardioverter defibrillator. During a mean follow-up of 28 +/- 27 months (range: 1 day-84 months) 13 patients died suddenly or received a defibrillator shock preceded by syncope or presyncope: group I: n = 5; group II: n = 2; group III: n = 6. In conclusion: (1) most patients sustaining a cardiac arrest only in the presence of type Ia antiarrhythmic agents have inducible sustained VT in the absence of antiarrhythmic agents, and (2) the risk of recurrent VT persists in patients without inducible sustained arrhythmias in the drug-free state, regardless of whether they manifest inducible arrhythmias after rechallenge with a type Ia agent.     

Effect of gamma-L-glutamyl-L-dopa on phosphate excretion

gamma-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present study compared the phosphaturic effects of the infusion of equimolar doses of gludopa (n = 8), L-DOPA (n = 8), and gamma-L-glutamyl-L-tyrosine (glutyrosine, n = 6). Glutyrosine was used as a control to evaluate the effect of the glutamyl portion of gludopa on phosphate excretion. Sprague-Dawley rats (350 to 400 g) were anesthetized with 5-sec-butylethyl-2-thyobarbituric acid (Inactin; 100 mg/kg, IP) and underwent thyroparathyroidectomy. Clearances were taken during the infusion of normal saline vehicle, followed by the infusion of gludopa, L-DOPA, or glutyrosine, all infused at the rate of 10 nmol/kg bolus and 0.8 nmol/kg/min (iv). To determine the contribution of glutamyl derivative to phosphate excretion, gludopa or L-DOPA was infused in the presence of SCH23390, a DA-1 receptor antagonist. Gludopa infusion significantly increased dopamine excretion (from 1.9+/-0.2 ng/min to 17.0+/-3.9 ng/min, delta15.0+/-3.9 ng/min, P < .008) and fractional excretion of phosphate (from 2.6%+/-0.6% to 34.8%+/-1.8%, delta32.0%+/-1.6%, P < .001). L-DOPA infusion significantly increased dopamine excretion (from 1.4+/- 0.4 ng/min to 9.7+/-1.6 ng/min, delta8.3+/-1.5 ng/min, P < .001) and fractional excretion of phosphate (from 1.7%+/-0.6% to 8.2%+/-2.0%, delta6.4%+/-1.5%, P < .004). Glutyrosine infusion significantly increased fractional excretion of phosphate (from 2.8%+/-0.8% to 17.5%+/-5.2%, delta14.6%+/-4.8%, P < .03) without changing dopamine excretion (delta0.5+/-0.2 ng/min). Infusion of gludopa in the presence of SCH23390 increased fractional excretion of phosphate (from 5.7%+/-2.5% to 12.6%+/-3.5%, delta6.8%+/-2.3%, n = 6, P < .03), whereas SCH23390 completely blocked the phosphaturic effect of L-DOPA. We conclude that gamma-L-glutamyl-L-DOPA is more phosphaturic than L-DOPA in the rat because of the combined effects of dopamine and the glutamyl moiety.     

Renal hemodynamic and excretory responses to renin inhibition induced by A-64662

Experiments were conducted in sodium-depleted anesthetized monkeys to determine the effects of the primate-selective renin inhibitor A-64662 on renal function. Five groups of monkeys were examined with each group receiving an i.v. infusion of vehicle or A-64662 at doses (bolus plus continuous infusion) of 0.1 + 0.01, 1.0 + 0.1, 10 + 1.0 or 100 micrograms/kg + 10 micrograms/kg/min (n = 6/dose). Plasma renin activity was inhibited (P less than .05) at all infusion doses ranging from 33 +/- 8% at the lowest dose to 95 +/- 3% at the highest dose. Inhibition of plasma renin activity was accompanied by renal vasodilation as renal blood flow (RBF) increased (P less than .05) in a dose-dependent manner beginning at the dose of 1.0 microgram/kg + 0.1 micrograms/kg/min. RBF increased 36 +/- 7% at the highest dose of A-64662 examined. Associated with the increments in RBF, renal vascular resistance progressively decreased (P less than .05) by 12 +/- 3, 31 +/- 3 and 40 +/- 6%, respectively, with increasing doses of A-64662. Glomerular filtration rate was unchanged at all doses of A-64662. As a result, a significant (P less than .05) fall in the filtration fraction was observed as the dose of A-64662 increased. Mean arterial pressure was unaffected by the two lowest doses of A-64662, but decreased (P less than 0.05) by 13 +/- 1 and 18 +/- 4 mm Hg, respectively, at the two highest doses of A-64662 infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of different dosages and modes of sodium bicarbonate administration during cardiopulmonary resuscitation.

Systemic acidosis occurs during cardiac arrest and cardiopulmonary resuscitation (CPR). The present study investigated the effect of different modes of sodium bicarbonate administration on blood gas parameters during CPR. Arterial and venous blood gases were obtained during 10 minutes of CPR which was preceded by 3 minutes of unassisted ventricular fibrillation in 36 dogs. Following 1 minute of CPR, the animals received one of four treatments in a randomized and blinded manner: normal saline (NS), sodium bicarbonate bolus dose 1 mEq/kg (B), sodium bicarbonate continuous infusion 0.1 mEq/kg/min (I), and sodium bicarbonate bolus dose (0.5 mEq/kg) plus continuous infusion 0.1 mEq/kg/min (L+I). Eleven dogs completed NS, 8 B, 8 I, and 9 L+I protocol. Following NS infusion, both arterial and venous pH declined consistently over time. Significant differences compared with NS treatment in venous pH were observed at 12 minutes of ventricular fibrillation (L+I, 7.27 +/- 0.05; NS, 7.15 +/- 0.05; B, 7.20 +/- 0.05; I, 7.24 +/- 0.04, each bicarbonate treatment versus NS, and L+I versus B, (P < .05). The B group had an elevated venous PCO2 (mm Hg) concentration following 6 minutes of ventricular fibrillation compared with NS, L+I, and I groups (81 +/- 14 versus 69 +/- 10 versus 68 +/- 10 versus 71 +/- 8, respectively, (P = .07). Arterial pH and PCO2 values showed a similar trend as the venous data with the L+I group demonstrating arterial alkalosis (pH > 7.45) at 12 minutes of ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic effects of E-4031, a class III antiarrhythmic agent, on re-entrant ventricular arrhythmias in a canine 7-day-old myocardial infarction model

Effects of E-4031, a class III antiarrhythmic agent, on re-entrant ventricular arrhythmias were studied in eight dogs with a 7-day-old myocardial infarction. Epicardial mapping and local refractory periods were obtained using 47-channel bipolar electrodes attached to the epicardium. The induction of sustained ventricular tachycardia by programmed electrical stimulation was not suppressed by i.v. infusion of E-4031 at 1 microgram/kg/min, but was suppressed markedly by infusion at 10 micrograms/kg/min in six of seven dogs. During the infusion of E-4031 at 10 micrograms/kg/min, epicardial conduction velocity in the normal ventricle did not change (0.7 +/- 0.12 to 0.71 +/- 0.13 m/sec, n = 6), whereas slowed conduction in the infarct zone improved (0.58 +/- 0.10 to 0.77 +/- 0.13 m/sec, n = 6). E-4031 at 10 micrograms/kg/min prolonged effective refractory periods (ERP) in the normal zone (139 +/- 8 to 164 +/- 18 msec, P less than .01, n = 8), nontransmural infarct zone (145 +/- 7 to 177 +/- 15 msec, P less than .01, n = 8) and transmural infarct zone (156 +/- 14 to 191 +/- 22 msec, P less than .01, n = 8). The degrees of ERP prolongation were almost equal in all zones. On epicardial mapping, the areas of longer ERP and delayed conduction were observed to become inexcitable after the administration of E-4031. These results demonstrated that E-4031 effectively prevented the induction of re-entrant ventricular tachycardia in canine myocardial infarction model, and suggested that E-4031 rendered re-entrant circuits inexcitable by marked ERP prolongation in both normal and infarct zones.     

New simplified technique for 3D mapping and ablation of right ventricular outflow tract tachycardia

OBJECTIVE: To evaluate the safety and efficacy of using a circular multielectrode catheter for mapping and ablation of ventricular tachycardia (VT) or premature ventricular complexes (PVCs) from the right ventricular outflow tract (RVOT). BACKGROUND: Three-dimensional (3D) mapping systems are commonly used for mapping and ablation of RVOT VT and PVCs. Newer catheters that are circular with multiple electrodes, such as the Lasso catheter, are capable of simultaneously recording from multiple points within a circumferential plane. Given the tubular structure of the RVOT, these catheters could be used for mapping tachycardias from the RVOT. METHODS: A retrospective cohort study of patients undergoing radiofrequency (RF) ablation of RVOT VT or PVCs was performed. In group 1 (n = 7), mapping was performed with a single ablation catheter and fluoroscopy. In group 2 (n = 10), 3D mapping using ESI (n = 9) or CARTO (n = 1) was performed. In group 3 (n = 12), mapping was performed with a circular multielectrode catheter (n = 12). All ablations were performed with 4-mm tip catheters using RF energy. RESULTS: Catheter ablation for RVOT VT (n = 15) or PVCs (n = 14) was performed on 29 cases in 26 patients, 9 males. Mean age was 35.9 years. In groups 1, 2, and 3, the mean number of lesions was 17.7 +/- 7.7, 13.6 +/- 7.7, and 18.2 +/- 22.7 and the median number of lesions was 20, 13, and 5, respectively. There were no significant differences in the number of lesions, RF time, fluoroscopy time, procedure time, and acute success rate among the three techniques. There were three complications in group 2 and one in group 3. CONCLUSION: The use of a circular multielectrode catheter is as effective as the other standard available 3D mapping techniques, both in terms of procedural success and procedural characteristics. Additionally, because of the lower cost associated with using the circular multielectrode catheter approach, further evaluation should be performed to determine whether this is the most cost-effective approach to 3D mapping and ablation of RVOT tachycardias.     

Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel

Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n=15) or ranolazine (2 mg/kg i.v. bolus plus 60 microg/kg/min i.v. infusion; n=15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42+/-0.02 versus 0.33+/-0.02; p<0.007) and stroke volume (1.05+/-0.08 versus 0.78+/-0.07 ml; p<0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23+/-0.03 versus 0.34+/-0.03 in vehicle-treated group; p<0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44+/-5 versus 57+/-4% vehicle; p<0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis.     

Effects of intravenous magnesium in a prolonged QT interval model of polymorphic ventricular tachycardia focus on transmural ventricular repolarization

BACKGROUND: This study was performed to clarify the antiarrhythmic effects of magnesium sulfate (Mg(++)) in a prolonged QT interval canine model of polymorphic ventricular tachyarrhythmia (VTA). METHODS: In six experiments in a canine model of prolonged QT by anthopleurin-A, Mg(++) was administered in boluses of 0.2 mL/kg during repetitive episodes of self-terminating polymorphic VTA or frequent premature ventricular complexes (PVCs). The distribution of ventricular repolarization across the left ventricular(LV) wall and dispersion of transmural repolarization were analyzed before, and 30 and 120 seconds after Mg(++) administration, during ventricular pacing at 100 bpm. Transmural unipolar electrograms were recorded from multipolar needle electrodes, and local activation-recovery intervals (ARI) were measured. RESULTS: Mg(++) rapidly eliminated self-terminating polymorphic VTA and all isolated PVCs. During ventricular pacing at 100 bpm, Mg(++) caused modest shortening of ARI at all recording sites. Since the magnitude of ARI shortening was greater at mid-myocardial sites than at other ventricular sites, mean transmural ARI dispersion decreased from 80 +/- 22 to 45 +/- 18 ms within 30 seconds after Mg(++) injection. However, this effect was transient, and, at 120 seconds after Mg(++) administration, ARI had increased all sites and transmural ARI dispersion lengthened to 65 +/- 18 ms. Besides suppression of triggered premature activity, homogenization of transmural ventricular repolarization was associated with the antiarrhythmic effects of intravenous Mg(++) in this model. CONCLUSION: Since these effects were transient, a continuous intravenous infusion of Mg(++) is preferred to prevent recurrences of VTA.     

Growth hormone decreases phase II ventricular tachyarrhythmias during acute myocardial infarction in rats

GH (growth hormone) administration during acute MI (myocardial infarction) ameliorates subsequent LV (left ventricular) dysfunction. In the present study, we examined the effects of such treatment on arrhythmogenesis. A total of 53 Wistar rats (218+/-17 g) were randomized into two groups receiving two intraperitoneal injections of either GH (2 international units/kg of body weight; n=26) or normal saline (n=27), given at 24 h and 30 min respectively, prior to MI, which was generated by left coronary artery ligation. A single-lead ECG was recorded for 24 h post-MI, using an implanted telemetry system. Episodes of VT (ventricular tachyarrhythmia) and VF (ventricular fibrillation) during the first hour (phase I) and the hours following (phase II) MI were analysed. Monophasic action potential was recorded from the lateral LV epicardium at baseline and 24 h post-MI, and APD90 (action duration at 90% of repolarization) was measured. Infarct size was calculated 24 h post-MI. Infarct size and phase I VT+VF did not differ significantly between groups, but phase II hourly duration of VT+VF episodes was 82.8+/-116.6 s/h in the control group and 18.3+/-41.2 s/h in the GH group (P=0.0027), resulting in a lower arrhythmic (P=0.016) and total (P=0.0018) mortality in GH-treated animals. Compared with baseline, APD90 was prolonged significantly 24 h post-MI in the control group, displaying an increased beat-to-beat variation, but remained unchanged in the GH group. We conclude that GH decreases phase II VTs during MI in the rat. This finding may have implications in cardiac repair strategies.     

Evaluation of Patients with Bundle Branch Block and "Unexplained" Syncope: A Study Based on Comprehensive Electrophysiologic Testing and Ajmaline Stress

Thirty-five patients with bundle branch block (BBB) and unexplained syncope underwent electrophysiologic study (EPS) including programmed ventricular stimulation and ajmaline administration (1 mg/kg, IV) to induce infra-His block. A prolonged HV interval (greater than 55 ms) was present in 16 of the 35 patients. Ajmaline-induced HV block occurred in 12 patients (complete HV block in 10, and 2:1 HV block in two). Monomorphic ventricular tachycardia (VT) was inducible in nine (25.7%) and polymorphic VT in two patients (5.7%). Left ventricular ejection fraction (LVEF) was less than 40% in five patients (45.5%) with inducible VT. Two patients had an unexpected co-existence of inducible HV block and VT. The remaining 14 patients (40%) had no detectable abnormality. The incidence of inducible VT was higher (45% vs 13.3%), and the presence of negative studies was lower (30% vs 53.3%) in patients with structural heart disease (n = 20), when compared to those with no significant heart disease (n = 15) (differences not significant [NS]). During a mean follow-up period of 16.5 +/- 9.2 months, all the patients with inducible HV block have been asymptomatic after having received permanent pacemakers. Patients with inducible monomorphic VT (except one with poor left ventricular function who died suddenly) have also been asymptomatic on antiarrhythmic drugs. Of the remaining patients, seven with normal EPS, two with prolonged HV intervals but no inducible HV block (despite being given permanent pacemakers) and one patient with polymorphic VT on antiarrhythmic drugs continue to have recurrent syncope. Approximately 60% of patients with BBB and unexplained syncope have clinically significant electrophysiologic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of two new PBN-derived phosphorylated nitrones against postischaemic ventricular dysrhythmias

Spin traps might exert antioxidant cardioprotective effects during myocardial ischaemia-reperfusion where free radicals are thought to be responsible for the occurrence of reperfusion injury. The aim of our study was to investigate the effects of two new alpha-phenyl N-tert-butylnitrone (PBN)-derived beta-phosphorylated nitrones: 2-N-oxy-N-[benzylidène amino] diéthyl propyl-2-phosphate (PPN) and 1-diethoxyphosphoryl-1-methyl-N-[(1-oxido-pyridin-1-ium-4-yl) methylidene] ethylamine N-oxide (4-PyOPN) compared with PBN on (1) the evolution of cardiovascular parameters and (2) the postischaemic recovery. Anaesthetized rats were injected with 120 micro mol/kg of the nitrones or 14 micro mol/kg of amiodarone, used as a reference antidysrhythmic drug. Ischaemia was induced in vivo through ligation of the left anterior descending coronary artery for 5 min followed by 15 min of reperfusion after release. Cardiovascular parameters and occurrence of ventricular premature beats (VPB), ventricular tachycardia (VT) and fibrillation (VF) were recorded throughout the experiment. Under nonischaemic conditions, none of the three spin traps was shown to modify cardiovascular parameters during the 25-min measurement period. Solvent-treated (NaCl 0.9%) animals challenged with ischaemia-reperfusion exhibited 39 +/- 10 VPB, 156 +/- 39 s of VT and 60% mortality caused by sustained VF. Nitrones improved slightly postischaemic recovery, reducing the occurrence of VF and mortality to 33% whereas amiodarone injection totally suppressed rhythm disturbances and mortality. Our study has shown only limited antidysrhythmic cardioprotective effects of PBN-derived beta-phosphorylated nitrones during reperfusion after a regional myocardial ischaemia but also minor antioxidant properties of these spin trapping agents.     

Extremely low doses of tissue factor pathway inhibitor decrease mortality in a rabbit model of septic shock

OBJECTIVE: We sought to determine the lowest dose of recombinant human tissue factor pathway inhibitor (TFPI) that can provide protection from lethality in a rabbit model of septic shock. METHODS: Sepsis was induced in New Zealand white rabbits by intraperitoneal implantation of 7.0 ml of a solution containing hemoglobin (4.8 g/dl), porcine mucin (6 g/dl), and 0.8-1.4 x 10(4) viable Escherichia coli (strain O:18 K+). Gentamicin (5 mg/kg) was administered 4 h following surgery, and this dose was repeated every 12 h for 3 days. Beginning 4 h following the induction of sepsis, animals were treated with a bolus (1 ml) plus a continuous infusion (100 ml over 24) of either TFPI (various doses) or its vehicle. Four different doses of TFPI were studied, and each experiment included a contemporaneous control group. The primary outcome parameter was survival time. Results were analyzed using the Wilcoxen log rank test. RESULTS: The average survival time for rabbits treated with the highest dose of TFPI tested (50 microg/kg bolus and 0.5 microg/kg per minute infusion) was 118 h, as compared to 81 h in vehicle-treated controls). The average survival time for septic rabbits treated with a much lower dose of TFPI (100 ng/kg bolus and 1.0 ng/kg per minute infusion) was 119 h as compared to 57 h in surviving vehicle-treated controls. Treatment with an even lower dose of TFPI (10 ng/kg bolus and 0.1 ng/kg per minute infusion) still produced a marginally significant prolongation of average survival time (80 h) relative to contemporaneously studied controls (47 h). When the dose of TFPI was decreased still further (1.0 ng/kg bolus and 0.01 ng/kg per minute infusion), average survival times were not significantly different between TFPI-treated and vehicle-treated rabbits (77 and 51 h, respectively). CONCLUSIONS: Delayed infusion with remarkably low doses of recombinant human TFPI prolongs survival in a rabbit model of antibiotic-treated Gram-negative bacterial sepsis. In planning human trials of TFPI as an adjuvant treatment for sepsis it may be reasonable to use much lower doses of the agent than were heretofore contemplated.     

Programmable External Automatic Antitachycardia Pacing as a Bridge to Definitive Therapy in Patients with Recurrent Sustained Ventricular Tachycardia

The efficacy and safety of external programmable automatic antitachycardia pacemakers (ATPs) used in the critical care setting for recurrent sustained monomorphic ventricular tachycardia (VT) was evaluated. Ten patients who had failed a mean of 4.0 +/- 1.4 antiarrhythmic medications (range 2-7) and who had previously required electrical cardioversion for VT were enrolled. Prior to ATP use, successful overdrive pacing termination of VT was demonstrated in all patients. Intertach (Intermedics, Inc.; n = 9) and Orthocor II (Cordis, Inc.; n = 1) ATPs were attached to temporary bipolar transvenous or epicardial pacing leads. Mean patient age was 66.4 +/- 11.5 years, and mean left ventricular ejection fraction was 22 +/- 7.5%. At the time of initial ATP use, mean VT cycle length was 347 +/- 88 msec (range 280-550 msec). A burst scanning antitachycardia pacing algorithm was used in each patient; one patient was also treated with a fixed rate burst adapted to VT cycle length. The duration of ATP use ranged from 2-25 days (median 5), successfully terminating greater than 3,369 VT episodes (median 3, range 0 to greater than 3,103 episodes per-patient). Two episodes of ATP induced rate acceleration occurred, each successfully terminated by the ATP. Only two patients required external cardioversion during ATP use, one for primary ventricular fibrillation and one for rapid polymorphic VT associated with antiarrhythmic drug withdrawal. ATPs also provided antibradycardia pacing and allowed for serial programmed ventricular stimulation. No complications were associated with transvenous catheter or ATP use.(ABSTRACT TRUNCATED AT 250 WORDS)     

The development and testing of intravenous dosing regimens: application to flecainide for the suppression of ventricular arrhythmias

A two-part pharmacokinetic approach was used to prospectively develop and test intravenous flecainide infusion regimens for the acute therapy for ventricular arrhythmias. Initially, each of nine known responders to oral flecainide was given a rapid flecainide infusion to characterize pharmacokinetic parameters and determine the minimum effective concentration for each patient. These data were used to calculate individually appropriate three-stage flecainide infusions of predetermined durations in eight patients. The three-stage infusions (0.15 +/- 0.02 mg flecainide acetate/kg/min for 5 minutes, 0.046 +/- 0.004 mg/kg/min for 60 minutes, and 0.31 +/- 0.05 mg/kg/hr for 5 to 47 hours; mean +/- SE) resulted in 95% +/- 0.1% suppression of ventricular ectopic depolarizations. Based on these results, six additional patients received a uniform infusion regimen (0.1 mg/kg/min for 5 minutes, 0.025 mg/kg/min for 2 hours, and 0.25 mg/kg/hr for 46 hours). Supplemental doses of 0.25 mg/kg were given (four doses per patient). With this protocol, ventricular ectopic depolarizations were 82.6% +/- 8.5% suppressed. Measured plasma flecainide concentrations were not significantly different from those predicted by pharmacokinetic models. A prompt and sustained antiarrhythmic effect was obtained with an intravenous regimen of flecainide determined by a prospective pharmacokinetic approach. However, the dosages developed in this study may have to be modified for patients with impaired cardiac or renal function.     

Ranolazine—Treatment of Ventricular Tachycardia and Symptomatic Ventricular Premature Beats in Ischemic Cardiomyopathy

Premature ventricular complexes (PVCs) are a frequent occurrence in the presence of ischemic heart disease. A very high PVC load can be symptomatic or occasionally result in a cardiomyopathy (CMP). Treatment options include pharmacologic agents and radiofrequency ablation (RFA). RFA has been successful in treating PVCs in symptomatic patients or in the presence of unexplained CMP. Ranolazine is a piperazine derivative used for treating chronic stable angina. It also has antiarrhythmic properties. We report a patient with ischemic CMP, symptomatic PVCs, and monomorphic ventricular tachycardia (VT) despite attempts to control symptoms with two antiarrhythmic drugs. Initiation of ranolazine led to marked reduction in PVCs along with control of VT and symptoms. (PACE 2010; 33:e119–e120)