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EFFECTS OF ANGIOTENSIN-II AND CAPTOPRIL ON INDUCIBLE SUSTAINED VENTRICULAR-TACHYCARDIA 2 WEEKS AFTER MYOCARDIAL-INFARCTION IN THE PIG

The effects of angiotensin II (AII) and captopril (C) on the inducibility of ventricular tachyarrhythmias were investigated 14 days after infarction in pigs. In 27 pigs, ischemia was induced by 60-min occlusion of the left coronary artery. Four pigs died of ventricular fibrillation during ischemia, and six others died within 24 h due to pump failure. Of the 17 survivors, eight pigs developed a sustained (>30 s) monomorphic ventricular tachycardia (sVT) after programmed electrical stimulation. In nine noninducible pigs, an AII infusion (0.6 μg/kg/min) caused inducible sVT in three animals and nonsustained VT in two animals (>10 reentrant beats). In two of the remaining four animals, spontaneous premature ventricular beats appeared during the infusion. In a group of five healthy pigs, the electrophysiological effects of AII were evaluated. Infusion of AII caused a rapid and sustained increase in arterial blood pressure to 161 ± 6.4% (p < 0.001). The sinus cycle length decreased to 74 ± 5.2% (p < 0.02). The effective refractory period of the right ventricle decreased significantly to 82 ± 5.5% (p < 0.05). These results show that modulation of the renin-angiotensin system after myocardial infarction influences the inducibility of malignant ventricular tachyarrhythmias, as shown by the increased inducibility of sustained ventricular tachycardia. This may be related to a decreased ventricular refractoriness. Therefore, it is suggested that C can reduce malignant ventricular tachycardia late after myocardial infarction by preventing the deleterious arrhythmogenic effects of AII.

In vivo effect of bradykinin during ischemia and reperfusion: improved electrical stability two weeks after myocardial infarction in the pig.

In this study, the effect of brady kinn on saline infusion during isehemia and reperfusion on electrical stability 2 weejs after nt icarcra, infaction, was assessed Acute mvocardial infarction was increced in 23 Pigs by at transiummal occlusion of the left coronary artery with of catheter balloon, intlated for 48 min. Bradskinn was administered by a 30 min infustion that started after 30 min of coronary occlusion adn was continued and 15 min after reperfusion. Although creatine kinase levels in bradykinn-treated annuals were signticantly lower (p 0.001) 2 week survival was not different between groups In survivors the filtered QRS ventricular deflection ducation detected asing signal-ever aged electrocardiographys was significantly prolonged in Saline-treated pags. whereas in bradskinn- treated pigs this prolongasion was prevented. The terminal voltage of the QRS complex was significantly lower in dline-treated pigs than in bradvkinin treated pigs. These two parameters signify an improved electrical stability after bradykinin treatment. Refractory periods in Sahne-treated hearts were longer than in bradskimn-treated hearts (106 ± 10) vs 95 ± 13% (p 0.05) Also. current thresholds in the intaret border zones showed a greater varianc e in saline-treated hearts (p 0.001) pointing toward mor tissue beterogeneity of the infared border zone. Programmed electrical stimulation showed a trend toward reduced inducibility of sustained ventricular tachycardia in bradykinin treated hearts. Therefore, bradvkinin improves electrical stability 2 weeks after expermental myocardial infarction.

Rate-dependent effects of the class III antiarrhythmic drug almokalant on refractoriness in the pig

The electrophysiologic effects of intravenously administered almokalant, a new class III antiarrhythmic drug, in 7 isoflurane-anesthetized pigs after low and high dose were investigated. Low-dose almokalant included bolus infusion of 0.05 mumol/kg/min for 5 min followed by a continuous infusion of 0.0025 mumol/kg/min for 40 min. Thereafter, a high dose of 0.2 mumol/kg/min for 5 min and 0.01 mumol/kg/min for 40 min was given. PR, QRS, AH, and HV intervals did not change during almokalant administration. The QT interval increased dose dependently from 337 +/- 17 to 442 +/- 20 ms at high dose (p < 0.05). Atrial refractory periods (AERP) were prolonged dose dependently at a 500-ms pacing cycle length from 178 +/- 15 at baseline to 227 +/- 27 and 253 +/- 23 ms during low- and high-dose almokalant infusion, respectively. For pacing cycle lengths of 400 and 300 ms, these values were 180 +/- 11, 207 +/- 25, and 259 +/- 34 and 157 +/- 12, 193 +/- 21, and 234 +/- 28 ms, respectively. At a pacing cycle length of 500 ms, mean ventricular effective refractory period (VERP) was 270 +/- 25 ms as compared with 306 +/- 24 and 337 +/- 17 during low and high dose, respectively. A similar pattern of VERP changes during both low- and high-dose infusion was noted at the shorter pacing cycle lengths, with an increase from 240 +/- 23 to 274 +/- 22 and 279 +/- 24 ms during a 400-ms cycle length and from 210 +/- 17 to 235 +/- 19 and 234 +/- 21 ms during a 300-ms cycle length. The ratio of the VERP and ventricular monophasic action potential duration (VAPD) did not change significantly. The Wenckebach cycle length increased by 36 +/- 36 and 83 +/- 37 ms with low- and high-dose almokalant infusion, respectively. The percent increase of AERP at pacing cycle lengths of 500, 400, and 300 ms during high-dose almokalant was 42, 44, and 49%, respectively; these increases for VERP were 25, 16, and 11%, respectively. In conclusion, prolongation of refractoriness by almokalant was more pronounced at the atrial than the ventricular level. Prolongation of refractoriness was maintained at short pacing cycle lengths especially in the atrium, indicating absence of reverse-use dependence of almokalant in the porcine heart. The marked atrial effects, paralleled by atrioventricular conduction slowing, and the absence of reverse use-dependence all contribute to the feasibility of use of almokalant, in particular in the treatment of supraventricular tachyarrhythmias.

EFFECTS OF EARLY ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IN A PIG MODEL OF MYOCARDIAL-ISCHEMIA AND REPERFUSION

Summary: In a blind, randomized study, the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were compared with those of placebo in a closed-chest pig model of myocardial infarction. In anesthetized pigs, myocardial ischemia and reperfusion were induced by inflation and deflation of a catheter balloon in the left anterior descending coronary artery (LAD), respectively. Thirty minutes after induction of ischemia and 15 min before reperfusion, a bolus injection of 0.06 mg/kg perindoprilat (n = 12), the active compound of perindopril, or placebo (n = 12) was administered in the pulmonary artery of these animals. After the acute phase of myocardial infarction, treatment with 12 mg/day perindopril or placebo was continued orally for 2 weeks. During the entire treatment period, 7 of 12 animals died in the placebo group versus 2 of 12 animals in the perindopril group (Fishers exact test p < 0.04). This beneficial effect of perindopril on mortality could not be attributed to salvage of myocardial tissue because the increases in creatine phosphokinase and coronary venous purine levels were similar in perindopriland placebo-treated animals. Neither were there any significant between-treatment differences in the hemodynamic and (neuro)humoral parameters during the acute phase of myocardial infarction. The difference in mortality was observed within 24 h after myocardial infarction. Prevention of acute pump failure and, especially, life-threatening ventricular arrhythmias may explain this improvement in survival by perindopril. Retrospectively, logistic regression analysis showed that, irrespective of treatment, survival was inversely correlated to plasma renin activity (PRA) before induction of ischemia (r = −0.33; p < 0.02). High initial PRA levels most likely reflected increased angiotensin II (ANGII) activity, which might have been beneficially influenced by perindopril. In addition, during the acute phase of myocardial infarction, prostaglandin E2 (PGE2) levels were significantly higher in animals that survived than in animals that died, but to establish the role of these humoral parameters to mortality in myocardial infarction definitively prospective studies are needed.

Effects of Bradykinin on Inducible Sustained Ventricular Tachycardia Two Weeks After Myocardial Infarction in Pigs

Summary: We studied the in vivo effect of bradykinin infusion on inducible sustained ventricular tachycardia (VT) 2 weeks after myocardial infarction in pigs, based on the assumption that the antiarrhythmic effect of angiotensin-converting enzyme (ACE) inhibitors may, apart from their angiotensin-II lowering effect, also be due to elevation of endogenous bradykinin levels. Of the six pigs with inducible VT in the control state, four were noninducible during subsequent bradykinin infusion (p < 0.05). The ventricular effective refractory period (VERP) did not change during bradykinin infusion (from 237 × 37 to 239 × 42 ms), nor did intraventricular conduction change (filtered QRS duration was 45 × 17 ms before and 43 × 19 ms during infusion). Bradykinin caused both a significant systolic blood pressure (SBP) decrease (from 79 × 14 to 49 × 4 mm Hg, p < 0.001) and diastolic BP (DBP) decrease (from 41 × 10 to 27 × 4 mm Hg, p < 0.01). In conclusion, exogenous bradykinin reduced the inducibility of sustained VT 2 weeks after myocardial infarction. Because refractory periods or conduction velocity were not affected, the mechanism of action might be associated with the BP decrease, which can decrease wall stress. The previously reported antiarrhythmic effect of ACE inhibitors may he due in part to elevation of endogenous bradykinin levels.

EFFECT OF METOPROLOL ON ATRIAL FIBRILLATORY RATE, ATRIOVENTRICULAR NODAL CONCEALED CONDUCTION, AND VENTRICULAR RESPONSE DURING ATRIAL-FIBRILLATION IN PIGS

Summary: We wished to elucidate the effect of β-blockade on fibrillatory rate and atrioventricular (AV) nodal concealed conduction during atrial fibrillation (AF). Subsequent to determination of the effect on atrial functional refractoriness with the extrastimulus technique (basic cycle length 400 ms), the effect of metoprolol (0.3 mg/kg) on atrial fibrillatory rate was determined in 8 open-chest pigs with metacholine-facilitated AF. Once stable AF was established, fibrillatory rate was recorded with a bipolar epicardial electrode, together with the ventricular response during 500 ventricular intervals. For each episode of AF, three indexes were calculated to determine the degree of concealed conduction: the ratio of the longest to the shortest ventricular interval, the ratio of the median ventricular interval to the median atrial interval, and the coefficient of variation of the ventricular intervals. Metoprolol decreased fibrillatory rate (571–432 beats/min, p < 0.01), suggesting a proportionate increase ( + 32%) in atrial functional refractoriness during AF that far exceeded the increase ( + 7%) during sinus rhythm (217–233 ms, p < 0.05). None of the indexes of concealed conduction was affected by metoprolol. Metoprolol decreases fibrillatory rate in AF, possibly due in part to its class I effect, causing rate-dependent prolongation of atrial refractoriness. Despite reducing fibrillatory rate, metoprolol does not affect AV nodal concealed conduction measurably. Our results support the assumption that the reducing effect of β-blockers on ventricular rate during AF is due to direct prolongation of AV nodal refractoriness.

Sustained atrial flutter around the tricuspid valve in pigs: differentiation of procainamide (class IA) from flecainide (class IC) and their rate-dependent effects.

The wavelength theory considers two determinants of reentry, i.e., refractoriness and conduction velocity. It does not take excitability into account primarily. We evaluated frequency-dependence of excitability and refractoriness before and after flecainide or procainamide administration in relation to termination of reentrant atrial flutter. After making a Y-shaped lesion in the right atrium, we induced 62 flutters (cycle length 171 ± 15 ms) by electrical stimulation in 15 pigs. Strength-interval curves were determined to assess excitability and refractoriness. Multiple cycle lengths were used to establish rate-dependent changes. Flutter cycle length increased after flecainide (to 290 ± 67 ms) or procainamide (to 295 ± 54 ms). The flutters always terminated abruptly (flecainide dose 103 ± 104 mg, plasma concentration 370 ± 21 ng/ml; procainamide dose 1,150 ± 686 mg, concentration 51 ± 24 mg/1). Flecainide caused an increase in diastolic thresholds from 0.3 ± 0.2 to 0.8 ± 0.5 mA (p < 0.006) and procainamide from 0.5 ± 0.3 to 0.9 ± 0.5 mA (p < 0.02). The increase in threshold was frequency dependent. Procainamide increased refractoriness at longer cycle lengths (≥250 ms), but this effect was abolished at shorter cycle lengths, indicating that only after significant slowing of the rate, prolongation of refractoriness may appear. Thus, both drugs interrupt reentrant flutter mainly by reducing excitability. Subclassification into IA and IC may be less relevant at high rates. Construction of strength-interval curves and assessment of rate-dependent “postrepolarization refractoriness” should be considered when one studies drugs that influence excitability.

Late Potentials in a Porcine Model of Anterior Wall Myocardial Infarction and Their Relation to Inducible Ventricular Tachycardia

In this study, normal values for signal averaged electrocardiographic parameters were assessed in healthy pigs (n = 100) and the development of late potentials after myocardial infarction (n ‐ 41) in relation to inducible ventricular tachycardia was investigated. Normal values are: filtered QHS duration (QRS) ± 78 msec; root mean square voltage of the averaged QRS complex (Vtot) ± 51 μV, and duration of terminal activity below 30 μV (D30) ± 37 msec. The distribution of the root mean square voitage in the last 30 msec (V30) was biphasic. Two weeks after myocardial infarction, QRS was prolonged from 55 ± 10 to 66 ± 19 msec (P < 0.002), D30 was prolonged from 19 ± 6 msec to 28 ± 13 (P < 0.002). V30 was decreased from 107 ± 135 μV to 45 ± 77 (P < 0.02). The total voltage (Vtot) was decreased from 195 ± 78 to 123 ± 61 μV (P < 0.002). In four pigs (19%) late potentials developed. Sustained ventricular tachycardia was inducible in 11 pigs (52%), ventricular fibrillation in two pigs (10%) and eight pigs (38%) were noninducible. Three of 11 inducible pigs and one of the noninducible pigs had a late potential. The incidence of late potentials and their relation to inducibie sustained ventricular tachycardia is comparable to the situation in man. Therefore, this pig model is an attractive alternative to the commonly used dog models.