Biomedical subjects
Publications and source records attributed to J F Aupetit.
A patient with bronchiectasis had an inferolateral myocardial infarction. Coronary arteriography revealed a large anastomosis from the left circumflex artery to the left lower lobe bronchial arteries. The relationship between the patient's myocardial infarction and possible "coronary steal" is discussed.
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The effects of Bay k 8644 were studied in the canine in situ heart under vagal influence and out of this influence on sinus rate and sinus recovery time, conduction time and effective refractory period (ERP) in the atrioventricular (AV) node and ERP of the atrial muscle. Bay k 8644, intravenously infused at the 2 micrograms X kg-1 X min-1 rate for 30 min, enhanced the inhibition of the atrial specialized tissue as well as the shortening of the atrial muscle ERP during vagal activity, elicited by the injection of dextromoramide into the cisterna magna. It did not develop any atrial action in the absence of vagal activity, suppressed by atropine. The reflex increase of vagal tone, in response to a small increase in blood pressure produced by Bay k 8644, is not the only cause of the phenomena observed in the former case. The observations can be explained primarily in terms of an interaction between Bay k 8644 and acetylcholine (ACh):ACh intraaortically injected near the coronary ostia, in a dose just sufficient to slow down sinus rate before Bay k 8644, reduced the rate by 50% at the end of a 60 min infusion of Bay k 8644 and the ACh threshold dose necessary to elicit a short third degree AV block before Bay k 8644 was reduced by 50% at the end of a 30 min infusion of Bay k 8644. Therefore, ACh appeared to be capable of enhancing the effects of a calcium channel activator as well as the effects of hypercalcaemia, as earlier reported.
Increase in heart rate may be detrimental to atrioventricular conduction. The effects of such an increase were investigated in the paced intact dog heart, by measuring the conduction time in the atrioventricular node (obtained from the His bundle potential recording) and the effective refractory period in this node as determined by the extrastimulus method. Investigations on atrioventricular nodal conduction were performed with and without vagal influence. After central restoration of vagal tone by dextromoramide in anesthetized animals, both parameters appeared to lengthen as the heart rate rose. This lengthening became considerable at the highest rates. After blockade of cholinergic receptors by atropine, no significant change occurred when the heart rate was raised. The prolongation observed under vagal tone was enhanced by the rise in the plasma calcium concentration to 3.10 mmol X l-1 and reduced by a calcium influx inhibitor, verapamil, in 0.2 mg X kg-1 dose. These effects are related to the calcium intracellular concentration, since the rise in this concentration beyond an optimum has been demonstrated to inhibit the calcium and potassium channel.
Forty-eight patients (25 M, 23 F) age range 25 to 83 years were admitted for treatment of deep vein thrombosis (DVT) of lower limbs confirmed by phlebocavography. Lesions were sural in 6 cases (Gr. 1), subcrural in 28 (Gr. 2) and supracrural in 13 (Gr. 3). Rheoplethysmography with venous occlusion (ORP) was performed and repeated every four months until (possible) recovery of normal emptying parameters (EI). Mean observation period was 25 +/- 8 months. In group 1, ORP indices were always restored to normal values within 4 months. In groups 2 and 3, normal values of IDV were observed in 23/38 patients within a median period of 10 months. Actuarial analysis of changes in EI values showed normalization in 65% of patients within 12 to 16 months with lack of significant differences between values for groups 2 and 3. Beyond this period of time any recovery of normal emptying indices is more aleatory, the residual obstructive syndrome appearing to be established definitely. Antivitamin K therapy (AVK) was instituted in 44 patients, and discontinuation was a function of normalization of EI. Good long-term results (clinical and ORP) were noted in 26/28 cases: one patient had recurrence of DVT with regional extension of thrombus and another a thrombosis on a Mobin-Uddin filter. Restoration of normal EI values during the 16 months following onset of DVT of lower limbs constitutes a valuable index for cessation of AVK therapy. After this period, recovery from the obstructive syndrome is more aleatory and decision to continue therapy must be based on other criteria.
In order to determine the interaction between diltiazem and digoxin, plasma digoxin concentrations and the principal ECG parameters (24 hour Holter monitoring) were measured in 10 healthy volunteers under basal conditions (P0), with 0.375 mg/day of digoxin (P1 = 17 days), during association with 240 mg/day of diltiazem (P2 = 17 days) and then again on digoxin alone (P3 = 10 days). The addition of diltiazem was associated with a 20.4% rise in plasma digoxin concentrations (0.59 ng/ml vs 0.49 ng.ml). There was no significant variation of plasma digoxin after withdrawal of diltiazem; in some cases it remained unchanged, in others it fell or continued to rise. During the administration of digoxin and diltiazem, the mean RR period and the duration of the maximal pauses increased (p less than 0.05); the RR interval also increased (p less than 0.01) but the mean QRS duration and the QTc interval did not change significantly with respect to their values on digoxin alone. After withdrawal of diltiazem, the PR interval was the only parameter to decrease significantly (p less than 0.05). These results suggest that patients receiving this drug association should be followed up carefully.
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The effects of the calcium channel modulators, Bay k 8644, infused i.v. at a rate of 2.5 micrograms/kg/min, and diltiazem, injected i.v. in a dose of 0.5 mg/kg, on the susceptibility to fibrillation induced by ischaemia, were investigated in anaesthetized, open-chest pigs. Ischaemia was produced, under ventricular pacing at constant high rate (180 beats/min), by transient complete occlusion of the left anterior descending coronary artery, near its origin. It was maintained till the triggering of fibrillation. The propensity to fibrillation was judged from the time elapsing between the onset of occlusion and the onset of fibrillation (time to fibrillation). In addition to the surface electrocardiogram, conduction time and monophasic action potential were recorded in the ventricular contractile fibres, as were dP/dtmax in the left ventricle and blood pressure in the carotid artery. At the end of a 10 min infusion, Bay k 8644 lowered to a large extent (about 40%) the time to fibrillation, which returned to its control values within the following 20 min. Conversely, diltiazem increased the time to fibrillation by a factor 4 or 5 at 5 min after its administration. This time to fibrillation remained substantially increased 25 min later. These changes were not associated with alterations in conduction time or monophasic action potential duration in the absence of ischaemia, but with significant alterations in myocardial contractility and blood pressure: in the direction of an increase with Bay k 8644 and of a decrease with diltiazem. These results are in agreement with the enhancement by Bay k 8644 and the prevention by diltiazem of cell calcium overload which is at present recognized as being the essential determinant of the fibrillatory process.
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Heart failure, a frequent disease in the elderly, has a pejorative prognosis. Clinical diagnosis is complicated by atypical or difficult-to-interpret symptoms and by the concomitant presence of other diseases, particularly cognitive impairment, neurological disorders and diseases of the musculoskeletal system. Among the additional investigations, echocardiography remains underused. Impairment of diastolic left ventricular function is frequent. The usual laboratory tests must include calculation of the creatinine clearance, which is indispensable for dosage adjustment of certain drugs (ACE inhibitors, digoxin, spironolactone). The value of plasma natriuretic peptide assays as diagnostic tools has not been determined in elderly or very elderly populations and the plasma B-type natriuretic peptide increases with age. Comprehensive geriatric assessment is essential in order to screen for concomitant diseases and determine the patient's degree of dependence. The general objectives of treatment remain applicable to the elderly subject: improvement in the quality of life, reduction of mortality and the number and duration of hospitalisations, and slowing disease progression. In the frail elderly subject, symptom alleviation is to be the primary objective. In the absence of specific studies on elderly or very elderly subjects, most of the recommendations have been extrapolated from the data based on the evidence generated in younger populations. The dietary rules are to be more flexible than those used for younger subjects, particularly in order to prevent the risk of denutrition induced by strict salt-free diets. Special precautions for the use of heart failure drugs are due to comorbidities and the pharmacokinetic and pharmacodynamic changes related to aging. Drugs dosage increase is to be cautious and carefully monitored for adverse reactions. The therapeutic programmes in which multidisciplinary teams are involved reduce the number and duration of hospitalisations and the costs generated by the disease.
The effects of two novel antiarrhythmic drugs, cibenzoline and flecainide, known to exert potent inhibitory effects on sodium channel, were investigated on intraventricular conduction in anaesthetized, closed-chest dogs. During this study, in which the heart was electrically stimulated, the pacing period was gradually reduced in the 500-200 msec range, and the pacing rate was abruptly altered (2 sec) or sustained (8 to 10 sec) in order to study the possible frequency- and time-dependency of the depression of conduction. In addition to the electrocardiogram, the conduction time was recorded in the ventricular contractile tissue between an electrode advanced to the apex and the pacing electrode positioned near the base. Effective refractory period (ERP) was concurrently measured according to the extrastimulus method, and the monophasic action potential (MAP) recorded. The drugs were infused at a rate of 0.2 mg/kg/min over a 10 min period after a 4.0 mg/kg loading dose. Conduction time was lengthened by approximately 50% at low frequencies and 100% at high frequencies. Widening of the ORS complexes paralleled this lengthening, whereas the drugs tended only to prolong ERP, without preventing its shortening induced by acceleration. Cardiac disorders were aggravated when high pacing rates were maintained for 8 to 10 sec.
In recent clinical studies, certain class I antiarrhythmic drugs (flecaïnide, lidocaïne) appeared to be responsible for an increase in mortality, when used to treat ventricular arrhythmias occurring after or during infarction. Experimentally, in pigs whose rate of ventricular beats was kept constant by pacing, all the studied class I antiarrhythmic drugs, disopyramide, lidocaïne and flecaïnide, proved to be to a variable degree capable of shortening time to onset of fibrillation (TOF) elicited by controlled myocardial ischemia. Fibrillation occurred at the end of the decline, under the influence of ischemia, of electrical fibrillation threshold (EFT) down to near 0 mA. The fall of EFT to this level was checked by ischemias of increasing duration to be hastened by the cited antiarrhythmic drugs. In other words, these drugs exert a profibrillatory effect in the ischemic heart.
A comparative evaluation of beta-blockers and calcium antagonists as protective agents against ventricular fibrillation related to myocardial ischaemia, was attempted in the pig heart in situ of anaesthetized, open-chest animals, subjected to a temporary complete occlusion of the left anterior descending coronary artery near its origin. This occlusion resulted in fibrillation occurring after a time depending on the vulnerability to the fibrillatory process. As this time to onset of fibrillation does normally not exceed a few minutes, its determination could be achieved repeatedly in the course of an experiment, in the absence and presence of drugs such as beta-blockers and calcium antagonists. When propranolol (0.05 mg/kg, i.v.) and verapamil (0.05 mg/kg, i.v.) abolished tachycardia produced by isoproterenol (0.25 micrograms/kg/min), the triggering of fibrillation was delayed in either case: in animals under atrial pacing at a rate close to the sinus rate on each determination, time to fibrillation was prolonged from about 160 to 400 sec by propranolol and from 160 to 640 sec by verapamil, with a return to control values within 60 min. Under ventricular pacing at a constant high rate (180 beats/min), no change was observed in time to fibrillation after propranolol (0.025 or 0.050 mg/kg), whereas verapamil, in the same conditions and in the same doses, multiplied this time by about 4 and 6, respectively. Consequently, propranolol and verapamil are likely to protect against fibrillation immediately after i.v. injection, but the protection due to propranolol is only indirect and a consequence of bradycardia which tends to increase the polarization of the muscular fibres, whereas verapamil adds to the same influence a direct preventive action by avoiding a cellular calcium overload in these fibres, which is responsible for the depolarization and fluctuations of their membrane potential.
A comparative study of the various classes of antiarrhythmic drugs as agents protecting against ischaemia-induced ventricular fibrillation was undertaken in the pig in situ heart, in anaesthetized animals which were subjected to complete temporary occlusion of the left anterior descending coronary artery. This occlusion resulted in fibrillation after a time which varied in inverse ratio to vulnerability to fibrillation. However, as this time did not exceed a few minutes, time to onset of fibrillation could be repeatedly measured in the course of an experiment, in the absence or in the presence of an antiarrhythmic drug. Under ventricular pacing at a constant rate, 180 beats/min, all the class I antiarrhythmic drugs, flecainide, disopyramide and lidocaine, in clinical dose range, reduced time to fibrillation to a large extent (25 to 50%) at the maximum of their action, with gradual return to control values within less than one hour. The enhancement of vulnerability to fibrillation was accompanied by reduction in intraventricular conduction velocity and fibrillation rate. With the same ventricular pacing, no change was observed in time to fibrillation under the influence of propranolol or amiodarone. As for verapamil, it lengthened this time considerably, up to 600%. However, bradycardia produced in usual circumstances ensures a real protection against ischaemic fibrillation with propranolol and amiodarone and enhances protection directly exerted by verapamil.
Results obtained in the prevention of ventricular fibrillation secondary to myocardial ischaemia are unexpected. Profibrillatory properties might be manifested by Class I antiarrhythmic drugs, normally antifibrillatory. Clear antifibrillatory properties might be manifested by calcium channel blockers, the antifibrillatory effects of which are normally questionable. Therefore, the action of a Class I antiarrhythmic drug, flecainide, and of a calcium channel blocker, verapamil, on the vulnerability to ischaemic ventricular fibrillation was assessed in anaesthetized, open-chest pigs by ventricular fibrillation threshold. Ventricular fibrillation threshold was determined with trains of diastolic stimuli of 100 msec duration, delivered at a rate of 180 beats/min (near that of the ventricular tachycardia), by a subepicardial electrode inserted into the area that could be subjected to ischaemia. Before determining this threshold, ventricles were paced at the same rate, particularly during the ischaemic periods. Ischaemia was produced by complete occlusion of the left anterior descending coronary artery, either at its origin or half-way from it, over increasing periods. The monophasic action potential and conduction time were recorded in the ischaemic area. Before ischaemia, flecainide was adapted to rais the ventricular fibrillation threshold, in spite of a lengthening of the conduction time. Verapamil was devoid of any influence on these parameters. The antifibrillatory effect of flecainide disappeared with ischaemia, which reduced the ventricular fibrillation threshold down to near 0 mA, with triggering of the spontaneous fibrillation at this level: this reduction was no longer counteracted and even hastened by flecainide, becomes finally profibrillatory. Verapamil, on the contrary, delayed the fall in ventricular fibrillation threshold, maintained far from 0 mA, with prevention of fibrillation, unless the occlusion was maintained over a much longer period. Verapamil similarly delayed the shortening of the monophasic action potential duration and the lengthening of the conduction time, preceding fibrillation and leading to it. Consequently, ischaemic depolarization is apparently responsible for the loss of antifibrillatory activity in a sodium blocker, such as flecainide, and the development of antifibrillatory activity in a calcium blocker, since the sodium channel is activated only at high potentials, whereas the calcium channel is activated at lower potentials.
Class I antiarrhythmic drugs do not decrease, but increase, the risk of ventricular fibrillation in the ischemic myocardium. On the contrary, vulnerability to fibrillation related to ischemia appears to be substantially reduced by calcium antagonists. We assessed whether the calcium antagonist diltiazem (0.50 mg/kg bolus plus 0.02 mg/kg/min infusion) could prevent the profibrillatory effect or even partially restore the antifibrillatory effect of a class I antiarrhythmic drug, flecainide (1 mg/kg bolus plus 0.04 mg/kg/min infusion) in the ischemic myocardium of anesthetized, open-chest pigs. Ischemia was obtained by completely occluding the left anterior descending coronary artery near its origin. Vulnerability to fibrillation was assessed by electrical fibrillation threshold (EFT), measured with diastolic impulses of 100 msec duration delivered at a rate of 180 beats/minute. Diltiazem did not oppose the rise in EFT induced by flecainide in the absence of ischemia (6.8 +/- 1.2 to 9.9 +/- 0.9 mA, p<0.001). It limited the fall in EFT observed under the dual influence of ischemia and flecainide (4.2 +/- 0.9 vs 1.3 +/- 0.6 mA, p<0.001). By reducing calcium entry into myocardial fibers, diltiazem delayed ischemic depolarization, as evidenced by reduced shortening of the monophasic action potential duration from 215 +/- 7 to 200 +/- 4 msec, instead of 178 +/- 6 (p<0.001), and reduced lengthening of intraventricular conduction time from 33 +/- 5 to 43 +/- 4 msec, instead of 53 +/- 4 (p<0.01). Therefore, diltiazem is likely to prevent the loss and even the reversal of the antifibrillatory properties of flecainide due to myocardial ischemia in dosages that do not adversely affect myocardial contractility or atrioventricular conduction to a large extent.