Ranolazine depresses conduction of rapid atrial depolarizations in a beating rabbit heart model.

PURPOSE: Previous clinical studies have shown that ranolazine (RAN) added to amiodarone (AMIO) might accelerate the termination of recent-onset atrial fibrillation. This study was undertaken to delineate possible mechanisms that contribute to the enhancement of the antiarrhythmic efficacy of RAN-AMIO coadministration. METHODS: Ten rabbits were anesthetized and two monophasic action potential (MAP) catheters were sequentially inserted into the right atrium. One MAP electrode was used to pace and record; the other electrode was used only for recording MAP from an adjacent atrial region. Intraatrial conduction time (IACT), 2:1 intraatrial conduction block (IACB), and atrial post-repolarization refractoriness (aPRR) were consecutively determined by high-rate atrial burst pacing and programmed stimulation, respectively. All parameters were evaluated during baseline and following AMIO (3 mg/kg iv) or AMIO+RAN (2.4 mg/kg iv bolus +0.134 mg/kg/min maintenance infusion). RESULTS: The IACT remained unchanged post AMIO compared with baseline (37.6 ± 3.8 vs 36.4 ± 2.4 ms), whereas the addition of RAN to AMIO significantly prolonged IACT (50.4 ± 3.6 ms, p < .001). The pacing cycle length producing 2:1 IACB was 101.2 ± 21.7 ms at baseline , 117.5 ± 15 ms after AMIO (p = 0.265), and 150 ± 14 ms after AMIO+RAN (p < .001). Baseline aPRR was longer following AMIO treatment (35 ± 5 vs 50 ± 9 ms, p < .01) but remarkably prolonged with RAN supplementation (105 ± 11 ms, p < .001). CONCLUSIONS: RAN significantly prolonged the propagation time of rapid atrial depolarizations and potentiated the AMIO-induced moderate increases in aPRR. These mechanisms possibly contribute to the earlier termination of atrial fibrillation when RAN is co-administered with AMIO.

Effectiveness of aldosterone antagonists for preventing atrial fibrillation after cardiac surgery in patients with systolic heart failure: a retrospective study.

Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery. There exist consistent experimental and clinical data suggesting that aldosterone antagonists (AAs) may exert beneficial effects regarding electrical and structural remodeling in failing myocardium. Recently, eplerenone (EPL) has been found to reduce the incidence of nonsurgical AF when added to guideline-recommended therapy in patients with systolic heart failure. Based on these findings, we primarily aimed to evaluate by retrospective analysis the impact of the two AAs, EPL and spironolactone (SPL), given at standard therapeutic doses in preventing new-onset POAF in patients the majority of which had a preoperative ejection fraction (EF) below 40%. A total of 332 patients (298 men/34 women, mean age 64.3 ± 9 years) without history of AF were included in this analysis; 132 of these patients received long-term EPL or SPL in addition to beta-blockade/statins therapy and 200 patients received neither EPL nor SPL. All patients underwent on-pump coronary artery bypass graft (80%) and/or valvular surgery (20%). In the nonAA group (EF = 35.8 ± 6%) 90/200 patients (45%) had POAF, while in the AA group (EF = 36.2 ± 5%) only 40/132 patients (30.3%) developed POAF (P < 0.01, χ (2) test). Multivariate logistic regression analysis revealed that only AAs and left atrial diameter significantly affected the development of POAF even when adjusted for other clinical variables (P < 0.05). In conclusion, AAs significantly reduced the incidence of POAF when added to standard heart failure therapy in patients undergoing on-pump cardiac surgery.

Occurrence of a terminal vascularisation after experimental myocardial infarction.

Physiological data indicate a residual vascularisation within ischemic myocardial regions where necrosis of most cells have been reported to occur after myocardial infarction. We therefore studied, by means of immunohistochemistry, computer-assisted morphometry, and electron microscopy, the terminal vascularisation in correlation to cardiomyocytes in ten canine hearts 1 and 3 weeks after occlusion of the left anterior descending (LAD) coronary artery. In comparison to non-infarcted myocardium we found the following alterations in infarcted myocardium: (1) the area density of cardiomyocytes decreased from 98% (control) to 7.9% (1 week after occlusion) and to 2.7% (3 weeks after occlusion); (2) the number of capillaries was diminished to 11.6% and to 2.6%; respectively; (3) smooth muscle alpha-actin was induced in endothelial (EC) cells of the microvessels; and (4) terminal resistance vessels increased 11-fold and 20-fold in number, respectively. Our findings confirm the necrosis of the vast majority of cardiomyocytes and capillaries within the first 3 weeks after myocardial infarction. Besides a small number of capillaries, many terminal resistance vessels, however, seem to persist in the scarring infarcted tissue. The occurrence of these microvessels is supposed to be important for the granulation tissue as well as for the control and regulation of a residual blood supply during scar formation.

Electropharmacology of the bradycardic agents alinidine and zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion.

Myocardial infarction was produced in 27 anesthetized dogs by ligating the left anterior descending (LAD) coronary artery proximal to the septal branch. Nineteen of these animals survived the operation and were studied by programmed stimulation in a random sequence between the third and seventh days after the infarct. Complete electrophysiologic testing was implemented in each animal prior to and after single doses of either alinidine (1 mg/kg IV) or zatebradine (0.5 mg/kg IV). Alinidine prevented reinduction of sustained ventricular tachycardia (SVT) in only 2 of 9 dogs and zatebradine in 1 of 8 dogs. The SVT cycle length was not significantly changed in all cases in which it was still inducible despite drug administration (p > 0.05). Alinidine lengthened the effective refractory period (ERP) in the AV node (p < 0.01), whereas zatebradine did not induce a statistically significant prolongation. Conversely, zatebradine increased the left ventricular ERP, while alinidine left it almost unchanged. The rate-corrected QT interval (QTc) did not significantly differ from control values after the administration of either agents. Also, the duration and the ERP of infarctzone potentials, defined as late potentials, remained unaltered. The results indicate that the bradycardic agents alinidine and zatebradine do not exert antiarrhythmic efficacy against SVT induced during subacute myocardial infarction in conscious dogs. None of these drugs substantially changed ventricular electrophysiology or showed a drug-specific proarrhythmic effect.

Electrophysiological mechanisms of action of ethmozine that explain its antiarrhythmic efficacy in the late stage of experimental myocardial infarction in dogs.

The effects of intravenous ethmozine (3 mg.kg-1) on electrophysiological parameters of ischaemically damaged myocardium and induced ventricular tachyarrhythmias were studied by programmed stimulation in 17 conscious dogs with 4 to 8 day-old ligation of the left anterior descending coronary artery. Ethmozine showed a beneficial effect on sustained ventricular tachycardia by suppressing its inducibility in five of 14 animals or by slowing its rate in six of 14 animals. Ethmozine prolonged the ventricular effective refractory period in normal and infarcted myocardium, and impaired depressed conduction in ischaemically damaged tissue. The latter was indicated by significant lengthening of late potentials recorded from the infarction zone. The QT interval was only slightly increased with ethmozine. Our findings indicate an antiarrhythmic action of ethmozine in the late stage of myocardial infarction. Major mechanisms accounting for its efficacy may predominantly be associated with marked depression of slow conduction in the infarction zone, as well as with prolongation of ventricular refractoriness without significant changes of ventricular repolarization.

Electrophysiological mechanisms of action of the levorotatory isomer of sotalol in a canine infarct model of inducible ventricular tachycardia: comparison with the beta-1 receptor antagonist bisoprolol.

To evaluate the antiarrhythmic efficacy of l-sotalol and bisoprolol on inducible ventricular arrhythmias, conscious dogs with 4- to 8-day-old myocardial infarction were studied by programmed electrical stimulation. Direct recordings from infarcted and adjacent normal subepicardium were made using a specially designed composite electrode. From 18 dogs developing sustained ventricular tachycardia (sVT) during control stimulation, l-sotalol (1.5 mg/kg i.v.) prevented reinducibility of sVT in 10 animals, while in seven other animals it significantly reduced the rate of tachycardia. Bisoprolol (0.2 mg/kg i.v.), tested in a separate group of 10 dogs susceptible to sVT, was mostly ineffective in preventing or slowing the tachycardia. Both agents significantly prolonged conduction time and refractoriness within the atrioventricular conduction system, and decreased heart rate. However, while l-sotalol lengthened ventricular refractoriness and QT interval, bisoprolol exerted only a minor effect on these parameters. Neither of the drugs affected conduction in normal and infarcted myocardium, as indicated by almost unchanged QRS complex width and duration of ventricular late potentials, respectively. The results indicate that acute beta-blockade is ineffective against sVT induced during the subacute stage of myocardial infarction. The antiarrhythmic efficacy of l-sotalol may predominantly be related to its prolonging effect on ventricular refractoriness, supporting the concept of pure class III action.

Lidocaine converts inducible ventricular fibrillation into sustained ventricular tachycardia in conscious dogs with recent myocardial infarction.

The aim of the present study was to investigate the effect of lidocaine (L) on ventricular tachyarrhythmias with special reference to ventricular fibrillation (VF). Myocardial infarction (MI) was created in 39 dogs by doubly ligating the left anterior descending (LAD) coronary artery. All animals surviving the infarction (n = 33) were subjected to programmed ventricular stimulation 7.6 +/- 3.2 days later. Local electrical activity was recorded from the subepicardium of the left ventricular wall by means of a specially designed composite electrode. L (2 and 4 mg/kg i.v.) facilitated the induction of sustained monomorphic ventricular tachycardia (sVT) in 8 dogs with nonsustained polymorphic ventricular tachycardia (nsVT) in the control. In 13 dogs developing sVT during control stimulation, L slowed the rate of tachycardia in 8 animals (first-dose effect), while it abolished arrhythmia induction in 5 animals (second-dose effect). It was interesting that L (2 mg/kg) abolished reproduction of control VF in 12 animals by converting it into sVT. L significantly depressed conduction and prolonged ventricular refractoriness in the infarction zone. The results suggest that L facilitates induction of sVT in conscious dogs with recent MI, thereby decreasing susceptibility of infarcted myocardium to aggressive polymorphic nsVT or VF. The capability of L to exacerbate slow conduction in the infarction zone seems not to favor the development of VF during this stage of MI.

Intraindividual comparison of diltiazem and verapamil on induction of paroxysmal supraventricular tachycardia.

The effects of i.v. diltiazem (0.25 mg/kg) and i.v. verapamil (0.15 mg/kg) were studied in 18 patients with recurrent paroxysmal supraventricular tachycardia (SVT) who underwent serial electrophysiological studies. In 10 of 18 patients with extranodal accessory pathways the effects of diltiazem and verapamil were similar in comparable plasma concentrations. SVT was prevented in 10/10 cases after diltiazem and 9/10 cases after verapamil, furthermore there as an increase in antegrade refractoriness of the normal AV nodal pathway of 22 and 27%, respectively; accessory pathway refractoriness and conduction remained unchanged in both drugs. In 8 of 18 patients with dual AV nodal pathways diltiazem was significantly less effective as compared to verapamil (p < 0.02) regarding prevention ov SVT (3/8 vs. 8/8 cases) and increase in the antegrade refractoriness of the slow AV nodal pathway (+21 vs. +34%). However, both drugs produced equivalent slowing of antegrade AV nodal conduction and a similar increase in antegrade refractoriness of the fast AV nodal pathway. In all 18 patients, the site of action of both drugs was the antegrade limb, regardless of SVT mechanism. The data suggest that the two calcium antagonists are equipotent in AV reentrance but verapamil may offer greater benefit in AV nodal reentrance than diltiazem.

Effects of prenylamine and AQ-A 39 on reentrant ventricular arrhythmias induced during the late myocardial infarction period in conscious dogs.

The effects of prenylamine (PNL) and AQ-A 39 on sustained ventricular tachycardia (SVT) were studied by programmed stimulation in conscious dogs 4-10 days after ligation of the left anterior descending (LAD) coronary artery. In 8 of 16 dogs developing SVT in the control, PNL (3 mg/kg intravenously, i.v.) suppressed inducibility of SVT and slowed the rate of tachycardia in 6 other animals. In a separate group of 10 dogs with inducible SVT, AQ-A 39 (4 mg/kg i.v.) abolished elicitation of tachycardia in 3 dogs and decreased its rate in 6 other dogs. Neither drug affected normal conduction significantly, but PNL impaired slow conduction in the infarct zone, as indicated by prolongation of late potential. Both agents increased the effective refractory period (ERP) of infarcted and normal ventricular myocardium and prolonged the corrected QT interval. PNL and AQ-A 39 exert notable efficacy in preventing infarcted heart from severe ventricular arrhythmias. Prolongation of ventricular refractoriness and repolarization, as well as decreased slow conduction in ischemically damaged myocardium, are major mechanisms accounting for the effectiveness of these drugs against ventricular arrhythmias.

Significance of cardiac innervation on spontaneous ventricular arrhythmias elicited by left stellate ganglion stimulation in dogs 4 days after myocardial infarction: comparison of two experimental models.

The effects of cardiac sympathetic overactivity on spontaneous arrhythmias and transmural left ventricular effective refractory period (LVERP) were assessed by left stellate stimulation (LSS) in 16 anesthetized dogs. The experiments were performed 4 days after proximal occlusion of the left anterior descending (LAD) coronary artery produced by either ligation (9 dogs) or embolization with histoacryl (7 dogs). The innervation of left ventricular myocardium was studied by light and electron microscopies. Synaptophysin (SYN)- and neuropeptide Y (NPY)-immunoreactive nerve fibers and terminals were thereby detected. In dogs subjected to ligation, LSS elicited negligible arrhythmias in spite of a decrease in LVERP by 6.9 +/- 2.2% (mean +/- SD, p < 0.001). However, dogs with intravascular occlusion were more susceptible to LSS, as indicated by development of sustained ventricular rhythms. In these animals, the LVERP decreased with LSS by 14.6 +/- 3.4% (p < 0.001). The innervation of the anterior left ventricular wall distal to the place of occlusion revealed a higher reduction of SYN- and NPY-immunoreactive nerves in infarcted myocardium and a more heterogeneous distribution of nerves in undamaged regions after ligation, compared to intravascular occlusion. Ultrastructurally, nerve terminals containing small agranular and large dense-core vesicles were found innervating ischemically damaged myocardiocytes. Our findings indicate a higher preservation of nerves in infarcted and noninfarcted myocardium of animals subjected to embolic occlusion of the LAD. Because LSS apparently elicited more arrhythmias in these animals, we suggested a proarrhythmic effect of intact myocardial innervation after infarction.

Cardiac sympathetic nervous activity during myocardial ischemia, reperfusion and ventricular fibrillation in the dog--effects of intravenous lidocaine.

In 12 open-chest dogs, cardiac sympathetic nervous activity (CSNA) was recorded before and after occlusion of the left anterior descending coronary artery as well as during reperfusion and ventricular fibrillation (VF). In 7 control animals, CSNA did not significantly differ from preocclusion levels when determined 20 min after occlusion (+3.5 +/- 1.5%, mean +/- SEM) and up to 15 min following reperfusion (+1.5 +/- 0.6%). However, VF was associated with a potential increase in CSNA by 106 +/- 15.5% (p less than 0.001). The effect of lidocaine (6 mg/kg) on cardiac sympathetic tone was examined in 5 additional animals. Lidocaine reduced control CSNA by 23 +/- 4.7% (p less than 0.001); subsequent ischemia and reperfusion did not substantially change the level of preocclusion activity. CSNA decreased significantly also during VF (52 +/- 4.2%, p less than 0.001). In conclusion, efferent CSNA was slightly altered in the course of acute myocardial ischemia and reperfusion, but significantly increased during VF. Lidocaine produced marked attenuation of CSNA in anesthetized dogs.

Heart innervation after ligation of the left anterior descending coronary artery (LAD).

Distribution and amount of neuropeptide Y- and synaptophysin-immunoreactive nervous structures within the heart were investigated in dogs 4 days after ligation of the left anterior descending coronary artery (LAD). In the right atrium and posterior left ventricular regions, which were taken as (non-infarcted) control areas, neuropeptide Y-immunoreactive paravascular nerves and a perivascular nerve plexus running within the adventitia of the coronary arteries and their branches down to the arterioles were observed. Morphometric measurements of the area density revealed 0.099 +/- 0.014% for synaptophysin- and 0.037 +/- 0.0072% for neuropeptide Y-immunoreactivity within the posterior wall of the left ventricular myocardium. Four days after ligation of the LAD only single synaptophysin- and neuropeptide Y-immunoreactive nerve fibers were very rarely detected in the infarcted region of the anterior wall of the left ventricle. Above the ligature larger than normal neuropeptide Y-immunoreactive axons within nerves along the LAD indicated a blockage of the axoplasmic transport of this peptide. When investigating this model of experimental myocardial infarction, mechanical traumatization of peri- and paravascular nerves of the LAD by the ligature has to be considered as a major pathogenetic factor, in addition to ischemia leading to denervation of infarcted as well as non-ischemic myocardium.

Bepridil versus nifedipine for ventricular tachycardia induced in the late postinfarction phase in conscious dogs.

The effects of the two calcium antagonists bepridil and nifedipine on induced ventricular tachyarrhythmias were studied by programmed electrical stimulation in 15 dogs, 4-8 days after myocardial infarction. Recordings from the infarcted and normal anterior wall of the left ventricle were obtained with an epicardial implanted 'composite' electrode. Bepridil (5 mg/kg) or nifedipine (0.025 mg/kg) were administered i.v. on different days and testing was repeated. Sustained ventricular tachycardia was prevented or significantly slowed by bepridil in 11/12 experiments compared with none of 9 experiments with nifedipine. Paradoxically, in 10/15 dogs nifedipine accelerated arrhythmias or even provoked ventricular fibrillation. Bepridil prolonged refractoriness of infarcted myocardium by 15 +/- 4% (mean +/- SD, p less than 0.01), which was greater than the increase it produced in the effective refractory period of normal tissue (9.0 +/- 3.8%) or QTc interval (11 +/- 5.5%). In contrast, nifedipine significantly shortened these parameters. Both drugs did not influence conduction in infarcted and normal zones as indicated by unchanged late potentials, QRS duration and normal-zone electrograms, respectively. The data indicate that the antiarrhythmic action of bepridil was predominantly related to the prolongation of ventricular refractoriness and repolarization (class III effects).

Monoclonal antibodies specific for human cardiac myosin: selection, characterization and experimental myocardial infarct imaging.

Radiolabelled anti-myosin antibodies (AM Ab) specifically accumulate in necrotizing myocytes and, therefore, allow the scintigraphic detection of myocardial infarction. In order to provide a constant supply of myosin-specific antibodies, the somatic cell fusion technique was used for the selection and propagation of AM Ab. Out of 126 antibody producing cell lines, nine were selected for further subcloning, due to their high affinity for purified myosin. For the in vivo imaging, two IgG-antibody molecules appeared particularly useful based on their antigenic specificity as assessed by immunoblotting and indirect immunofluorescence technique. After radiolabelling with iodine-123, undigested antibody molecules or their Fab fragments were injected into 10 dogs with experimental myocardial infarction. The accumulation of radioactivity in myocardial infarction was assessed by in vivo imaging and in vitro scintigraphy of ventricular slices stained by tetrazolium. The use of undigested AM Ab resulted in a high uptake ratio of radioactivity in the infarcted as compared to normal myocardium (20:1). In vivo infarct imaging, however, was not possible due to sustained labelling of the blood pool. The uptake ratio of iodine-123 labelled Fab fragments was only 9:1, but due to a faster plasma clearance of the Fab fragments, uptake in the heart could be visualized 5 h after intravenous injection. Clear differentiation between infarcted and noninfarcted myocardium, however, was limited by accumulation of radioactivity in the thoracotomy wound, in the liver, and in the stomach.