[Multidisciplinary research on cardiac arrhythmias and their pharmacological or surgical treatment].
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Biomedical subjects
Publications and source records attributed to R Cardinal.
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We investigated the possibility that the prolongation of the ventricular effective refractory period (VERP) by amiodarone might be mediated, at least in part, by inhibition of thyroid influence on the heart. VERP values were measured in vitro in isolated septal preparations obtained from control, thyroidectomized and thyroxine (tetraiodothyronine; T4)- or triiodothyronine (T3)-treated rats. Differences in thyroid influence on the heart between these groups were assessed by changes in the myosin isozyme (V1, V2, V3) pattern. VERP measurements were also done in similar groups treated with amiodarone for 7 days (50 mg/kg/day i.p.). VERP tended to be increased by thyroidectomy and was significantly reduced by T4 or T3 treatment when compared with the control group. Amiodarone treatment significantly prolonged VERP in control (33.4 +/- 1.9 to 45.0 +/- 4.5 msec), thyroidectomized (39.9 +/- 1.7 to 48.3 +/- 2.8 msec), T4-treated (26.2 +/- 1.0 to 37.4 +/- 1.3 msec) and T3-treated rats (25.6 +/- 1.1 to 34.3 +/- 1.3 msec). However, the magnitudes of the VERP prolongation by amiodarone were not significantly different among the four groups. The action of amiodarone on action potential duration was similar to its action on VERP. The myocardial concentrations of amiodarone and desethylamiodarone were not significantly different among the four groups. Amiodarone treatment produced a significant reduction of serum T3 levels in the control and in the T4-treated groups and an increase in reverse T3 levels. Thus, the class III action of amiodarone was not affected, in the present model, by experimental modification of thyroid influence on the heart.
The relation between electrical alternans recorded in acutely ischaemic myocardium, ventricular arrhythmias, and changes in the activation sequence was studied. Sixty three unipolar electrograms, simultaneously recorded from the epicardial surface of the in situ porcine heart during 6 min periods of coronary occlusion, were converted to a digital format and analysed by computer. The time integrals of the electrograms during their QRS complex, ST segment, and T wave were measured. Unipolar waveform alternation was then quantified by subtracting the values obtained for two consecutive beats showing alternans. The spatial distribution of unipolar waveform alternation was illustrated by isoarea difference maps. Isochronal maps of the local excitation detected on each electrogram were constructed. Of 52 occlusions in 27 preparations, unipolar waveform alternation was detected in 42 and was promptly followed by ventricular arrhythmias in 37. The magnitude of unipolar waveform alternation increased from the margin to the inner portion of the ischaemic zone but its correlation with activation delay was poor, and there was no change in the activation sequence. These results suggest that beat to beat alternation of the unipolar waveform is related to changes in the action potential configuration rather than to changes in the activation sequence. Furthermore, unipolar waveform alternation appears to be associated with the development of early post-occlusion ventricular arrhythmias.
To investigate ventricular tachycardias produced in healthy canine myocardium by stimulation of sympathetic ganglia or cardiac nerves, we simultaneously recorded a surface ECG and 63 ventricular electrograms in anesthetized open-chest dogs. Isochronal and isopotential maps were generated off-line by computer. Ventricular tachycardia with uniform beat-to-beat morphology was induced in 13 or 22 dogs by electrical stimulation of the left stellate ganglion (five experiments), the left middle cervical ganglion (four experiments), the left caudal pole cardiopulmonary nerve (two experiments), or the ventrolateral cardiac nerve (eight experiments). It was not inducible by stimulation of the right-sided major cardiopulmonary nerves or ganglia. In most instances the earliest measured electrical excitation occurred on the posterior aspect of the ventricles. Isochronal maps demonstrated a radial spread of the impulse away from the area of earliest excitation. Changes in the region of earliest excitation and (or) activation pattern were accompanied by changes in QRS morphology. The potential gradients measured between areas displaying positive and negative T waves on the anterior and left lateral aspects of the ventricles were significantly increased by ventrolateral cardiac nerve stimulation. However, the ventricular regions where these potential gradients existed differed from the regions of earliest excitation during ventricular tachycardia. These results demonstrate that the thoracic autonomic nervous system can induce repetitive ventricular excitation originating from consistent loci.
Amiodarone is a potent class III antiarrhythmic agent that has a slow onset of action in patients (ca. 20 days). To determine if myocardial accumulation of desethylamiodarone (DEA), its main metabolite, influences its antiarrhythmic activity, three groups of six Wistar rats were given amiodarone, 50 mg/kg/day i.p. (A groups), and three groups received the same dose of amiodarone in combination with 80 mg/kg/day of phenobarbital to induce hepatic biotransformation (AP groups). After 3, 7 or 21 days, the rats were sacrificed and the ventricular effective refractory period (VERP) was determined by the extrastimulus technique in endocardial preparations superfused in the tissue bath. Control measurements of VERP were done in untreated rats. Myocardial concentrations of DEA measured by high-performance liquid chromatography were significantly higher in the AP groups than in the A groups (7.5 +/- 0.83 vs. 2.27 +/- 0.11 micrograms/g at 3 days, 6.09 +/- 0.70 vs. 2.82 +/- 0.30 micrograms/g at 7 days and 11.93 +/- 1.22 vs. 4.79 +/- 1.84 micrograms/g at 21 days: mean +/- S.E.). Control VERP value was 33.4 +/- 1.2 msec and was increased by 9, 35 and 42% after 3, 7 and 21 days in the A groups, and by 9, 38 and 39% in the AP groups. After 7 days of DEA administration yielding myocardial concentrations similar to those obtained after amiodarone treatment, there was a slight but nonsignificant prolongation of the VERP (12%). Thus, the prolongation of VERP after amiodarone administration did not appear to depend on myocardial DEA accumulation, suggesting that the slow onset of amiodarone class III action may not be related to DEA disposition.
In anesthetized dogs, 60-min occlusions of either the proximal (n = 14), distal (n = 8) left circumflex (LCX), or left anterior descending (LAD, n = 10) arteries were followed by reperfusion. Coronary sinus and aortic norepinephrine and epinephrine plasma concentrations were measured. The ventricular arrhythmias were ventricular premature depolarizations (VPDs), unsustained ventricular tachycardia (VT) (greater than or equal to 3 and less than 20 VPDs), sustained VT (greater than or equal to 20 VPDs), and ventricular fibrillation (VF). A gradual twofold increase (p less than 0.05) in myocardial norepinephrine overflow followed occlusion in all three groups. The increases in the amounts of norepinephrine released in the coronary sinus blood during reperfusion were significant and proportional to the size of the occluded area: proximal LCX, from 0.236 +/- 0.038 to 1.528 +/- 0.490 ng/mL of plasma (p less than 0.001); LAD, from 0.180 +/- 0.027 to 0.795 +/- 0.286 ng/mL (p less than 0.05); distal LCX, from 0.215 +/- 0.039 to 0.404 +/- 0.110 ng/mL (p less than 0.05). Aortic epinephrine concentrations were significantly increased only by LAD occlusion; at 15 min, the value had increased to 0.187 +/- 0.053 ng/mL from an initial value of 0.069 +/- 0.029 ng/mL (p less than 0.001). Two phases of ventricular arrhythmias followed both occlusion and reperfusion. Phase 1 postocclusion was characterized by VPDs and phase 2 by VPDs and unsustained VT. Sustained VT was seen only in phase 1 postreperfusion, whereas unsustained VT was seen in phase 2. VF was seen in 50, 35, and 25% of the dogs with proximal LCX, LAD, and distal LCX occlusion and reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
To investigate the mechanism of uniform ventricular tachycardia induced by programmed stimulation, we recorded His bundle electrograms and unipolar electrograms from 64 subepicardial, subendocardial, and intramural sites in dogs. Isochronal maps were generated off-line by computer. Two groups of dogs were studied 3 days after occlusion of their left anterior descending coronary arteries; one group underwent reperfusion after 2 to 2.5 hr of occlusion and the other methylprednisolone treatment before permanent occlusion. In the former, subepicardial sequences presented either a pattern suggesting circus movement or a radial pattern in which excitation at intramural sites could precede earliest subepicardial excitation. In the latter preparations, subepicardial excitation patterns consistently suggested circus movement in the subepicardial muscle layer surviving over necrotic tissue. Assuming complete circus movement, the "missed" time interval, measured as the interval left unaccounted for by actual recording of local excitation between ventricular tachycardia cycles, ranged from 3% to 64% of the cycle length of ventricular tachycardia. While surviving subepicardial and intramural layers appeared to be involved in the mechanism of ventricular tachycardia, a late second breakthrough on the right ventricle, in conjunction with fixed-coupled H deflections on the His bundle electrograms, suggested the involvement of the conducting system in propagation of the impulse.
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We report our experience with hematin in the treatment of 57 patients in porphyric attacks. The ratio of acute intermittent porphyria: variegate porphyria: hereditary coproporphyria was 43:11:3. More than 90% of the patients showed not only a decline in their porphyrin precursors, but also a favor able clinical response. Hematin was well tolerated and should be considered the treatment of choice in porphyric relapse.
The effect of tocainide on enhanced automaticity if Purkinje fibers was studied under the influence of epinephrine (0.2 microgram/ml) by means of intracellular recordings with microglass electrodes. In the presence of tocainide 5 microgram/ml and 10 microgram/ml cycle length of enhanced automaticity was increased in the range of 10.6% and 34.9% and in the range of 26.3% and 108.7% respectively. Repetitive impulse formation in ventricular myocardium was generated by creating a potential difference in a papillary muscle mounted in a partition chamber. One chamber was connected to ground, the potential of the other chamber could be changed in the range of 0 to 500 mV. By progressively increasing the voltage difference across the papillary muscle repetitive rhythmic impulse formation was induced. The threshold voltage gradient increased in the presence of tocainide (100 microgram/ml) from--285 to--335 mV. The results suggest that tocainide is suitable to suppress arrhythmias due to enhanced automaticity of Purkinje fibers.
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Transitory renal failure occurred in a patient with acute intermittent porphyria in clinical remission following i.v. administration of 1 000 mg hematin. The clinical and biochemical picture suggested "acute tubular necrosis", which was followed by a prompt and complete return of renal function without any late sequelae. The renal failure is thought to have resulted from the presence of circulating free hematin, formed as a result of rapid administration of such a relatively large amount. Such a complication has not occurred in patients given hematin for acute porphyric relapse, in whom much smaller amounts have been infused.
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There is compelling, indirect evidence of hepatic heme deficiency due primarily to the respective genetic errors of the three inducible hepatic porphyrias, acute intermittent porphyria, porphyria variegata, and hereditary coproporphyria. The induction is enhanced by exogenous inducers such as barbiturate, estrogens and other "porphyrogenic" chemicals and factors, including glucose deprivation. The newer knowledge of the induction of delta-aminolevulinic acid synthetase [delta-aminolevulinate synthase; succinyl--CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] in relation to inadequate heme, and repression by heme, stimulated early trials of hematin infusions to overcome the acute relapse in the foregoing inducible porphyrias. Recently this experience has been considerably expanded, 143 infusions of hematin having been given in 22 cases. Studies of the effect on the serum concentrations of delta-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of delta-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum delta-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement.
The effect of temperature on the isometric tetanic myogram was studied in isolated canine tracheal smooth muscle (TSM). At 37 degrees C and 27 degrees C no significant change occurred in maximum tetanic tension (PO). At 17 degrees C a significant reduction was seen Values of Q10 for contraction time (tPO) were almost halved, whereas those for rate of tension development (dP/dt) were almost doubled. The effect of the same temperatures on the force-velocity (F-v) relationships was also studied. All three F-v curves were described by the Hill equation, (P + a) (v + b) = (PO + a)b. Vmax and b decreased with decreased temperature, with Q10's demonstrating they were dependent on active processes. Finally, the decreased dP/dt of the myogram at lower temperatures was felt to be the probable result of decreased contractile element velocity because no decrease in series elastic component stiffness was demonstrable, there being instead an increase in stiffness at lower temperatures.
Early, intravenous administration of hematin in a patient with acute intermittent porphyria and severe quadriparesis may have produced partial but remarkable improvement of neuropathy, and resulted in simultaneous decline of porphyrin precursors in the blood. Intermittent, biweekly hematin infusions given 1 month after the onset of the porphyric relapse had no effect on recovery of the residual neuropathy. We believe hematin may be effective in the treatment of porphyric neuropathy, if administered before irreversible neuronal damage has occured.