Search PubMed⌕ Search

Biomedical subjects

J M Davy

Publications and source records attributed to J M Davy.

At least 55 records · Page 3Linked to original sources
PubMed1993

Reproducibility of the model of induced ventricular tachycardia in conscious dogs with infarction.

The canine model of ventricular tachycardias (VT) induced by programmed stimulation is used routinely in several laboratories to test antiarrhythmic drugs. The aim of the present study was to determine the rate of success and reproducibility of this model. We analyzed a group of 58 dogs that underwent a 2-hr occlusion and were submitted to programmed electrical stimulation at least 4 days after the surgery. Only 29 dogs (50%) were inducible and included in the study, as 22 dogs died following myocardial infarction, and seven dogs were never inducible. Out of 130 trials, 92 (70%) performed on inducible dogs were positive with 11% of nonsustained ventricular tachycardias, 63% of sustained monomorphic ventricular tachycardias, and 26% of ventricular fibrillation. Inducibility decreased over time in a subgroup of 19 dogs that was submitted to four trials during the first month after the infarction (68% of inducible dogs versus 46% in trials 1 and 4, respectively). Ventricular effective refractory period decreased significantly from 146 +/- 7 msec at trial 1 to 114 +/- 6 msec at trial 4, and the severity of the induced ventricular tachycardias increased. This variability should be considered when planning studies on antiarrhythmic drugs in this model.

Animals↗
PubMed1993

Experimental models of torsades de pointes.

Torsades de pointes is the most typical ventricular tachycardia involving QT-interval prolongation. It is a rather unusual but potentially lethal ventricular tachycardia with a distinctive morphology favored by bradycardia, antiarrhythmic drugs and hypokalemia and requires specific treatment. Torsades de pointes has been shown to be related to bradycardia-dependent early afterdepolarizations (EAD) and/or increased dispersion of repolarization. However, although EAD can be obtained relatively easily in vitro with quinidine or sotalol, torsades de pointes are very difficult to reproduce in animal models. The models of torsades de pointes which have been proposed can be categorized as morphological, EAD-related or pharmacological models. The purpose of the 'morphological' models was to reproduce the twisting of QRS axis typical of torsades de pointes, with no consideration of other aspects such as long QT or bradycardia. These models were produced by epicardial electrical or chemical (aconitine) stimulation at two distant ventricular sites or by overdosing of quinidine in dogs with acute myocardial infarction. The second type of model focused on the conditions producing EAD in vitro. Ventricular tachycardias were obtained in anesthetized dogs using toxics such as cesium or anthopleurine, both producing EAD in vitro. These ventricular tachycardias were shown to be sensitive to magnesium, heart rate and autonomic tone, but torsades de pointes remained rare, at least after cesium injections. The pharmacological models that could be used to study the QT-dependent proarrhythmic effects of drugs are the anesthetized rabbit with alpha-adrenergic stimulation, and the conscious dog model with chronic AV-block and diuretic-induced hypokalemia. Methoxamine-treated anesthetized rabbits develop ventricular tachycardias during clofilium infusions. These ventricular tachycardias, although appearing at very high heart rates, have typical torsades de pointes aspects and are often associated with giant QT waves. The specificity of the model remains to be tested. In our conscious bradycardic and hypokalemic dogs, quinidine and sotalol but not flecainide, propranolol or lidocaine induced QT-dependent arrhythmogenic effects and torsades de pointes. Efficacy of high rate stimulations and magnesium were repeatedly observed. This demanding model, especially designed for qualitative drug comparisons, is also well suited to studies on the mechanisms of initiation of torsades de pointes. The pertinence of these models for estimating the risk of QT-dependent proarrhythmias associated with non-antiarrhythmic agents remains to be tested.

Animals↗
PubMed1993

Antiarrhythmic effect of a sotalol-mexiletine combination on induced ventricular tachycardia in dogs.

Mexiletine was recently shown to antagonize the effects of sotalol on repolarization of canine Purkinje fibers. The significance of this interaction for the antiarrhythmic properties of these drugs remains unknown. The antiarrhythmic effects of sotalol and mexiletine alone and in combination on induced ventricular tachycardias (VTs) were assessed in 20 conscious dogs with chronic infarction. Electrophysiological measurements and programmed stimulation were performed before and after the infusion of sotalol (4 mg/kg) or mexiletine (4 mg/kg), and after infusion of the combination. The electrophysiological parameters didn't change after mexiletine. Sotalol alone and the combination both similarly prolonged the QT interval and VERP. Induction of VT by programmed stimulation was not prevented by mexiletine, but the cycle length of monomorphic VT was increased in 7 of 10 dogs. The induction of VT was prevented by sotalol (11/16 dogs), but VTs were not slowed significantly. Sotalol plus mexiletine prevented VT as did sotalol alone (11/16 dogs). The combination also increased the cycle length of VT in all eight dogs with monomorphic VT. Thus, the antagonism shown in vitro appears to have no consequences in this model. On the contrary, the sotalol-mexiletine combination showed some additive antiarrhythmic effects on induced VT in dogs.

Animals↗
PubMed1992

[Experimental models of torsades de pointes].

Several experimental models of torsades de pointes have been proposed these last years. They can be classified in 2 categories: morphological models designed to reproduce the ECG features of "torsade", with in vivo ventricular stimulations or with computer ECG stimulations and pharmacological models designed to obtain in vivo early after depolarizations, with toxic agents such as cesium chloride and anthopleurine, or with commercialized or new pharmaceutical drugs. These models improved electrophysiologic and pharmacologic knowledge of torsades de pointes. The respective roles of early after depolarizations in torsades initiation and of reentry in the following beats of the salvos is now recognized. Induction protocols were described, which appeared to involve an inotropic potentiation following burst or repetitive extrastimuli. A more accurate evaluation of arrhythmogenic risk associated with new drugs could be developed.

Animals↗
PubMed1991

Methods and limitations of an experimental model of long QT syndrome.

An experimental model of the long QT syndrome has been developed in conscious dogs. This report discusses the methods used in its preparation and the strengths and weaknesses of the model. This new model is suitable for screening the bradycardia-dependent proarrhythmic effects of drugs and for studying the electrophysiology of "torsades de pointes." Permanent bradycardia (RR: 1558 +/- 83 ms) was obtained in 37 dogs by chemically-induced complete atrioventricular block. A 10% further increase of ventricular repolarization (QT: 306 +/- 7.0 ms to 331 +/- 5.5 ms) was obtained in 28 of these dogs by diuretic-induced hypokalemia. Diuretics, despite saline replacement, induced some degree of functional renal failure and extracellular volume losses. The QT interval increased although ventricular cycle length decreased slightly. These biological and electrophysiological parameters were reproducible except for a slow increase in plasma creatinine. Cardiac failure and sudden death rarely occurred. The most severe, but reversible, renal failure occurred in some dogs given the highest diuretic doses. Hypokalemia resulted in ventricular arrhythmias in only 6 dogs, 2 of them exhibiting runs of ventricular tachycardia and even "torsade de pointes" as their potassium levels fell below 2 mmol/L. The results of studies with several drugs using the model, with or without hypokalemia, or with bradycardia worsened by propranolol are analysed.

Animals↗
PubMed1991

Complete atrioventricular block following mediastinal irradiation: a report of six cases.

Complete atrioventricular block (AVB) following radiotherapy has been reported rarely, usually after high dose mediastinal irradiation for Hodgkin's disease or lung or breast carcinoma. We report six new cases of episodic complete infranodal AVB, requiring permanent pacemaker implantation. The mean age was 48-years old (ranging from 25-60) at the first Adams Stokes attack, mean delay was 12 years after irradiation (10-18), and mean radiation dose was 5,200 rads (4,000-6,500). All patients had abnormal interval electrocardiograms (right bundle branch block in two, left bundle branch block in three, alternating left and right bundle branch block in one). Electrocardiograms during the episode of AVB or Holter recordings were consistent with infranodal block in all patients; electrophysiological study performed in five patients confirmed infranodal AVB in four, and one was normal. Pericardial disease was constant, which included pericardial constriction in four patients. Two patients died after failure of pericardiectomy to improve congestive heart failure, due to epicardial, myocardial, and endocardial involvement. Noncardiac mediastinal lesions were present in four cases. Since this delayed complication may occur in patients of such age that the relation between the AVB and the chest irradiation is questionable, we propose the following etiologic criteria; high radiation dose (over 4,000 rads); delay of 10 years or more; abnormal interval tracings; pericardial involvement; and associated cardiac or mediastinal radiation-induced lesions.

Adult↗
PubMed1991

Arrhythmogenic activities of antiarrhythmic drugs in conscious hypokalemic dogs with atrioventricular block: comparison between quinidine, lidocaine, flecainide, propranolol and sotalol.

In order to create and evaluate a model sensitive to QT-dependent proarrhythmic effects of drugs, a long QT syndrome was produced in chronically instrumented dogs with bradycardia and hypokalemia. Bradycardia (mean cycle length: 1495 +/- 78 msec) was provided by permanent atrioventricular block and hypokalemia (K+ = 2.6 +/- 0.05 mmol/l) by high doses of diuretics. To evaluate that model, six of these conscious dogs were subjected to quinidine, flecainide, lidocaine, propranolol and sotalol infusions. In crossover design, drugs were infused i.v. at rates allowing stable and nontoxic drug plasma levels during the experiment. Four-lead ECGs were recorded for arrhythmias for 30 min before (base line) and 75 min after onset of infusion. Ventricular cycle length was increased dramatically by sotalol, lidocaine and propranolol (+618 +/- 192, +388 +/- 125 and +329 +/- 114 msec, respectively) and QT interval was increased by sotalol, quinidine and flecainide (+56 +/- 8, +31 +/- 7.9 and +20 +/- 5.7 msec, respectively). Quinidine and sotalol, but not flecainide, propranolol or lidocaine, exhibited significant arrhythmogenic activities. During quinidine infusion, most dogs exhibited some ventricular arrhythmias whose most severe forms were runs of ventricular tachycardia. These arrhythmias were suppressed by pacing at high rates. During sotalol infusion, five out of six dogs exhibited typical "torsades de pointes." This incidence was not related to the slowing effects of sotalol on idioventricular pacemakers, because a similar incidence was obtained in five complementary dogs paced at 40 bpm. It could be related to dose, because torsades de pointes occurred only once in another group of five dogs receiving half the dose used in the controlled study. Only quinidine and sotalol, but not propranolol, flecainide or lidocaine, are clinically associated to torsades de pointes. They were also the only drugs associated with proarrhythmic events in the present study, a fact suggesting that QT-dependent arrhythmogenic effects of drugs can be reliably evaluated in conscious hypokalemic dogs with complete atrioventricular block.

Animals↗
PubMed1990

Comparison of the cardiac electrophysiological effects of flecainide and hydroquinidine in anesthetized dog: concentration-response relationship.

The concentration-dependent effects of flecainide and hydroquinidine were studied in closed-chest anesthetized dogs. The electrophysiological effects of three doses (i.v. infusions followed by an appropriate perfusion to plateau the plasma levels) of flecainide (1, 2, and 3.9 mg/kg) and hydroquinidine (2, 4, 7.5 mg/kg) were tested. Sinus cycle length, QRS duration, His-Purkinje and AV nodal conduction times, Wenckebach period, atrial, nodal, and ventricular refractory periods, and corrected QT interval were measured before and 30 min after the beginning of each bolus infusion. Both hydroquinidine and flecainide increased the sinus cycle length, and slowed cardiac conduction to different degrees. Hydroquinidine and flecainide prolonged ventricular conduction; flecainide had a greater effect at the His-Purkinje level. Hydroquinidine exhibited only a weak and nonsignificant effect at the AV node, whereas flecainide dramatically prolonged conduction and refractoriness. The two drugs increased AERP equally. The QT interval and ventricular refractoriness were similarly prolonged to the same extent by both drugs (32 and 35% after the third doses of hydroquinidine and flecainide, respectively). The high plasma flecainide levels reached in our study (1.47 and 2.9 micrograms/ml after the second and third doses, respectively) may explain these effects, which are unexpected for a class Ic agent. These results suggest that flecainide could increase the QT interval, like a class Ia drug when its plasma level exceeds the therapeutic range.

Anesthesia↗
PubMed1989

[Clinical electrophysiologic properties of magnesium and correlations with its anti-arrhythmia efficacy in acquired torsade de pointes].

Recently, intravenous administration of low doses of magnesium has proved remarkably effective in the treatment of acquired torsade de pointe, but its electrophysiologic effects remain poorly understood. Three clinical cases are reported in three distinct situations (quinidine treatment, hypokalemia, bradycardia with complete atrioventricular block). These cases confirm the efficacy of magnesium, which acts without notable modification of ventricular cycles or the duration of repolarization. In ten patients undergoing intracavitary exploration, the electrophysiologic parameters were analyzed before and after injection of magnesium sulfate (35 mg/kg). Only three parameters were significantly altered; the corrected sinusal recovery time (increase from 245 +/- 92 ms to 296 +/- 96 ms), the effective nodal refractory period (increase from 333 +/- 98 ms to 346 +/- 93 ms), and the Wenckebache period (decrease from 157 +/- 28/min to 144 +/- 21/min). No changes were noted in other parameters, notably ventricular (QT interval, QRS duration, HV interval, and effective ventricular refractory period). The arrhythmic action on the ventricle is therefore remarkable and is not accompanied by patent electrophysiologic effects. The efficacy of magnesium in torsade de pointe may suggest action on calcium currents.

Aged↗
PubMed1988

Effects of magnesium on ischemic and reperfusion arrhythmias in the rat heart and electrophysiologic effects of hypermagnesemia in the anesthetized dog.

Magnesium sulfate, reportedly clinically effective against some ventricular arrhythmias, has not been extensively studied for its effects on experimental ischemic and reperfusion arrhythmias. We evaluated the effects of three high extracellular concentrations of magnesium (Mg2+) 1.19, 2.38, and 4.76 mM in 70 isolated perfused rat hearts following coronary artery ligation and reperfusion, at each of three different perfusate ionized calcium (Ca2+) concentrations (0.9, 1.25, and, 2.5 mM), where 1.25 mM is close to physiologic. At 0.9 mM Ca2+, higher concentrations of Mg2+ increased the sinus node cycle length (p less than 0.02) and virtually abolished ischemic ventricular tachycardia (VT) and reperfusion ventricular fibrillation (VF) (p less than 0.01), otherwise consistently found in this model. At 1.25 and 2.5 mM Ca2+ increasing Mg2+ had no effect on the incidence of ischemic or reperfusion arrhythmias, although at 1.25 mM Ca2+ ischemic VT had longer cycle lengths and VT appeared after a longer delay (p less than 0.01). In the nonischemic dog heart, marked increases of serum Mg2+ progressively prolonged the A-H, H-V, and QR S intervals, the ventricular effective refractory period, and the sinus cycle length, while the arterial blood pressure fell. Because of its relatively modest electrophysiologic and hemodynamic effects, it is inferred that intravenous magnesium may be given therapeutically with relative safety.

Anesthesia↗
PubMed1988

Mode of action of antiarrhythmic drugs and the implicated arrhythmogenic risk.

The mode of antiarrhythmic action of drugs usually cannot be extrapolated from their electrophysiologic properties despite extensive in vitro and in vivo assessment: in most cases, the mechanism of arrhythmias remains uncertain and cannot be established by clinical evaluation including electrophysiologic study; in specific cases where the arrhythmia substrate is fully described, the exact origin of antiarrhythmic action is unknown, especially when chronic preventive treatment is considered where triggering events are probably important. Nevertheless, the profound electrophysiologic changes resulting from antiarrhythmic drugs alter several delicate balances, at the cellular level (repolarizing and depolarizing currents) and at the tissue level (refractory period/conduction time ratio). Some afterdepolarizations can be elicited, especially when repolarization is delayed by long cycle lengths and K+ current inhibition; reentry is enhanced when conduction impairment occurs without similar change in refractoriness. Proarrhythmic effects of drugs seem to relate to these alterations and caution should be exerted when ECG shows drug-induced QT or QRS prolongations.

Animals↗
PubMed1988

Effects of amiodarone therapy on thyroid iodine content as measured by x-ray fluorescence.

Thyroid iodine content (TIC) was measured by x-ray fluorescence in 68 patients who had received amiodarone treatment for varying intervals (1 g/week for 1-120 months). Thirty-six patients were euthyroid; the mean TIC of the patients (n = 15), who had been treated for less than 12 months was 30 +/- 19 (+/- SD) mg, twice the normal mean value (14.6 +/- 5.0 mg), and it was 39 +/- 17 mg in those (n = 16) who had been treated for 12-60 months and 29 +/- 6 mg in those (n = 5) who had been treated longer (greater than 60 months). Nineteen patients were hyperthyroid and had elevated TIC values. Of them, 6 patients had a goiter; their TIC (50 +/- 19 mg) was not significantly different from that of the hyperthyroid patients with no goiter (55 +/- 29 mg), but they became hyperthyroid more rapidly. Thirteen patients were hypothyroid; none had TIC values above the normal range, and it was below 2.5 mg in 5 patients. A sequential study was undertaken in 11 euthyroid patients who had no detectable antithyroid antibodies. TIC did not increase during treatment in 2 patients; both developed hypothyroidism, which was transient in 1 despite continuation of amiodarone treatment. The TIC initially increased during amiodarone treatment in the other 9 patients, leveling off at the end of the first year. The TIC rose well above the upper limit of the normal range in 4 patients, of whom 2 became hyperthyroid during the second year of treatment. TIC remained within the normal range in the other 5 patients, of whom 3 became hypothyroid after 12-24 months of treatment (1 subclinical, 2 overt). Although the TIC was significantly higher in the patients with hyperthyroidism than in the patients who remained euthyroid, the TIC test cannot be used to predict the occurrence of hyperthyroidism. The latter must be diagnosed on the basis of clinical symptoms and a frank elevation of serum thyroid hormone levels. Conversely, patients whose TIC values do not increase during treatment or remain within the normal range should be considered at risk for hypothyroidism.

Adult↗
PubMed1988

[Sotalol-induced torsades de pointe in the conscious dog with atrioventricular block. Role of hypokalemia].

Sotalol is a beta-blocking agent endowed with class III electrophysiological properties. It has proved clinically effective in the treatment of arrhythmia, but episodes of torsades de pointe have been observed, particularly (though not exclusively) in the presence of hypokalaemia. The effect of sotalol with or without hypokalaemia was studied on a recently developed model for experimental torsades de pointe. Conscious dogs with complete atrioventricular block (ventricular cycle RR = 1530 +/- 170 ms) and provided with permanent atrial and ventricular epicardial electrodes were given sotalol intravenously either as a 4.5 mg/kg bolus injection or as a 1.5 mg/kg/h infusion. Group I dogs (n = 8) had normal blood potassium levels (4.3 +/- 0.1 mEq/1); following sotalol (plasma concentration 3.7 +/- 0.2 micrograms/ml) the ventricular rhythm was electrically driven to 25/min (RR = 240 ms) and QT was increased by 68 +/- 11 ms; torsades de pointe occurred in 5/8 animals (62 p. 100). Group II dogs (n = 6) had diuretic-induced hypokalaemia (2.6 +/- 0.1 mEq/1); following sotalol (plasma concentrations 3.8 +/- 0.3 micrograms/ml) the ventricular rhythm also depended on an external pacemaker to reach 25/min (in all but 1 dog) and QT increased by 46 +/- 11 ms; torsades de pointes were obtained in 5/6 animals (83 p. 100). These torsades de pointe were prevented in every case by rapid ventricular pacing (100-120/min). Thus, the pro-arrhythmic effects of sotalol were very frequent on this experimental model, but hypokalaemia was not necessary for torsades de pointe to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Phase mapping of radionuclide gated biventriculograms in patients with sustained ventricular tachycardia or Wolff-Parkinson-White syndrome.

Accuracy of Fourier phase mapping of radionuclide gated biventriculograms in detecting the origin of abnormal ventricular activation was studied during ventricular tachycardia or preexcitation. Group I included six patients suffering from clinical recurrent VT; 3 gated blood pool studies were acquired for each patient: during sinus rhythm, right ventricular pacing, and induced sustained VT-Group II included seven patients with Wolff-Parkinson-White syndrome and recurrent paroxysmal tachycardia; 3 gated blood pool studies were acquired for each patient: during sinus rhythm, right atrial pacing and orthodromic reciprocating tachycardia. Each acquisition lasted 5 min, in 30 degrees-40 degrees left anterior oblique projection. In Group I, the Fourier phase mapping was consistent with QRS morphology and axis during VT (5/6), except in one patient with LV aneurysm and LBBB electrical pattern during VT. Origin of VT on phase mapping was located in the right ventricle (n = 2) or in left ventricle (n = 4), at the border of wall motion abnormalities each time they existed (5/6). In Group II, the phase advance correlated with the location of the accessory pathway determined by ECG and endocardial mapping (n = 6) and per-operative epicardial mapping (n = 1). Discrimination between anterior and posterior localisation of paraseptal pathways and location of intermittent preexcitation was not possible. We conclude that Fourier phase mapping is an accurate method for locating the origin of VT and determining its etiology. It can help locate the site of ventricular preexcitation in patients with only one accessory pathway; its accuracy in locating multiple accessory pathways remains unknown.

Adult↗
PubMed1987

The relationship between successful defibrillation and delivered energy in open-chest dogs: reappraisal of the "defibrillation threshold" concept.

The traditional assessment of the energy required for successful ventricular defibrillation involves the measurement of a "defibrillation threshold" (DFT), implying a clear-cut distinction between effective and ineffective energies. We examined the relationship between delivered energy and the likelihood of successful defibrillation in 10 open-chest pentobarbital anesthetized dogs, with the use of an internal spring/patch electrode system. An initial DFT was determined by decreasing the energy discharged until a failure first occurred (10.3 +/- 3.4 J). Six energy levels in 1 to 2 J increments were then selected surrounding this value and each was administered eight times in balanced random order (total 48 trials). The relationship between energy and percent success in defibrillation exhibited a shallow slope, with a gradual increase in success from 0% to 100% over several energy increments. The initial DFTs showed actual success rates varying from 25% to 87.5% (mean 71 +/- 26%). The results were fitted to a sigmoidal dose-response curve by logistic regression analysis and the energy associated with 50% success (E50) and 80% success (E80) was determined, as no single value for DFT could be defined in any animal. In 12 other dogs, a defibrillation curve was similarly constructed at baseline and was repeated after 90 minutes. No significant change in E50 (5.0 +/- 2.1 J vs 5.2 +/- 2.7 J) or E80 (6.3 +/- 2.5 J vs 6.6 +/- 3.2 J) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗