[Platelet antiaggregants in other pathologies]. / Antiagrégants plaquettaires dans les autres pathologies.

Platelet aggregation inhibitors are used in numerous clinical situations on the basis of claims that platelets are involved. As a result of controlled clinical trials, some of these situations have become formal indications for some of these drugs. The situations in which platelet aggregation inhibitors are used include: arteritis of the lower limb at the intermittent claudication stage, leg ulcers of arterial origin, emboligenic arteritis with focus of platelet hyperfixation, progression of atherosclerosis as assessed by angiography, implantation of vascular surfaces, diabetic retinopathy, retinal venous thrombosis, cycle cell anaemia and perhaps thrombocythaemia. Other, more discussed indications of antiplatelet drugs are mentioned.

[Calcium channel blockers in ischemic cardiopathies]. / Les inhibiteurs du canal calcique lent dans les cardiopathies ischémiques.

Calcium-entry blockers are the drugs of choice in coronary spasm, unstable angina, and when patients do not have any effort limitation. However, beta-blockers, without sympathomimetic activity, remain the treatment of angina pectoris. When clinical situation is difficult to control, association calcium blockers and bêta-blockers are more efficient than monotherapy. In myocardial infarction, results are controversial: calcium channel blockers should be administered only with beta-blockers.

Evaluation of 10 QT prediction formulas in 881 middle-aged men from the seven countries study: emphasis on the cubic root Fridericia's equation.

In 881 middle-aged men from one Italian cohort of the Seven Countries Study, QT and RR intervals were measured in lead 2 from resting ECGs (25 mm/sec) and fitted separately with 10 mathematically different QT prediction formulas. The relative accuracy of fit to data was assessed from the minimum mean-squared residual and the minimum Akaike Information Criterion values. Using the Minnesota code, 588 men had normal (group 1) and 293 had abnormal (group 2) ECGs. A better fit to QT-RR data by all formulas was observed in group 1, compared with group 2. Among one-parameter equations in both groups, the cubic root Fridericia's formula is better suited to fit the data than the Bazett's square root or other formulas. The former compares favorably with multiparameter equations or with the inverse relation and gives the best fit in group 2. Thus the cubic root equation might be more accurate than the square root or several complex formulas for correcting measured QT intervals for cardiac cycle length in middle-aged men.

[Prevalence of arterial hypertension and its treatment in 2,595 adults]. / Prévalence de l'hypertension artérielle et de son traitement chez 2,595 adultes.

The prevalence of arterial hypertension, as defined by the W.H.O. (systolic BP greater than 160 mmHg and/or diastolic BP greater than 95 mmHg), and the prevalence of its treatment were studied in 2595 local government employees of Marseilles, aged from 20 to 65 years. The prevalence of hypertension was 17.96 p. 100 (466/2595, including 222 men and 244 women). The prevalence of normal tension was 57.50 p. 100 (1492/2595, including 802 men and 690 women). The prevalence of treated hypertension was 37.98 p. 100 (177/466) divided into 29.27 p. 100 (65/222) in men and 45.90 p. 100 (112/244) in women (p less than 0.0001). Blood pressure was controlled by treatment in 32.30 p. 100 (21/65) of treated men and in 36.61 p. 100 (41/112) of treated women (NS). 81.14 p. 100 (198/244) of hypertensive women and 57/82 p. 100 (399/690) of normotensive women were active (managers, executives). In treated men, the plasma level of apoprotein A1 was decreased and that of apoprotein B was increased. Among men, the global score at Bortner questionnaire was significantly lower in the group of 175 untreated hypertensive patients (176 +/- 46) than in the group of treated hypertensive patients (192 +/- 48, p less than 0.05) and in the group of normotensive subjects (186 +/- 41, p less than 0.05). This indicated that untreated hypertensive men have a tendency to type B pattern and suggested a line of research aimed at a better understanding of the relative failure of anti-hypertensive treatments in the prevention of coronary disease.

Prevention of postischemic ventricular fibrillation late after right or left stellate ganglionectomy in dogs.

To gain insight into the differences in antiarrhythmic potential of right vs left stellate ganglionectomy, 72 dogs were randomized to either unilateral stellectomy or second intercostal space thoracotomy and left circumflex coronary arteriovenous pedicle occlusion was performed, without vagotomy, a mean of 8 weeks later under anesthesia. The type and timing of ventricular ectopic beats, including both nonsustained and sustained ventricular tachycardia and ventricular fibrillation, were investigated. Several covariates, including postischemic electrocardiographic changes, were considered. Both right and left stellate ganglionectomy reduced the incidence of early (0 to 10 min) (p = .004 and p = .001, respectively) and total (0 to 60 min) (p = .009 and p = .008, respectively) ischemia-induced ventricular fibrillation, and improved outcome (p = .0013 and p = .0012, respectively). Early sustained ventricular tachycardia was similarly reduced (p = .02) in both stellectomized groups. By contrast, neither the type nor the time distribution of the other forms of ventricular arrhythmias differed significantly among the randomized groups. The multivariate Cox's regression model showed that ST segment elevation at 3 min postocclusion, unilateral stellate ganglionectomy (either right or left), sex, and weight were significant independent predictors of the incidence of ventricular fibrillation during the occlusion period. Lower ST segment elevation and reduced incidence of sustained ventricular tachycardia in the early postischemic period might explain improved outcome in stellectomized dogs by Cox analysis. The side of intervention (either stellectomy or sham operation) did not influence survival; however, left-sided interventions were more effective than right-sided ones. These results confirm the previously reported antifibrillatory effect of left and indicate like effects of right stellate ganglionectomy in a randomized experimental study.

Effects of cicletanine in the left circumflex coronary artery occlusion-reperfusion canine model of sudden death: analysis of 107 experiments using Cox's proportional hazards model.

Multivariate analysis of survival using Cox's proportional hazards model demonstrates that several clinically measurable covariates are determinants of life-threatening arrhythmias following left circumflex coronary artery occlusion-reperfusion in 107 dogs. These are heart rate, ST segment elevation and mean aortic pressure immediately (3 min) following occlusion, and the presence of early (0-10 min) post-occlusion sustained ventricular tachycardia. The risk of occlusion-reperfusion ventricular fibrillation was determined according to Cox's solution based on ST segment elevation, thus enabling quantification of the role of cicletanine. Since cicletanine-treated dogs had reduced mean ST segment elevation at 3 min post-occlusion, lower incidence of early post-occlusion (0-10 min) sustained ventricular tachycardia, and increased endogenous production of prostacyclin, and the latter was inversely correlated with the level of ST segment elevation, it is concluded that such favourable effects on the ischaemic myocardium were contributory to the improved outcome in these experiments. These effects on the ischaemic myocardium obtained in spite of a hypotensive action in the experimental setting might be regarded as desirable and it is therefore suggested that they should be further investigated by pharmacodynamic studies in human subjects.

Prevention of postischaemic ventricular fibrillation by long term beta adrenoceptor blockade with acebutolol in the anaesthetised dog.

Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment underwent the same procedure. Coronary ligations in the randomised study were performed during seven consecutive days, and four dogs were operated on each day. This schedule was chosen in order to measure acebutolol plasma concentrations just before ligation from 60 to 540 min after the last dose of the drug. Long term oral treatment with acebutolol protected against postischaemic ventricular fibrillation and significantly reduced the incidence of both early phase (0-10 min postocclusion) ventricular arrhythmias and ventricular fibrillation. As a result the outcome was significantly improved after 60 min of ischaemia in acebutolol compared with placebo treated animals. The results in the control animals were similar to those in the placebo treated dogs. The protective effect of long term oral treatment with acebutolol lasted for nine hours and was apparently independent of the plasma concentrations of the drug. These data show that improved outcome in this canine model is due to the prevention of ischaemia induced ventricular fibrillation by long term beta adrenoceptor blockade, which is able to overcome the effect, if any, of partial agonist activity of acebutolol. A direct myocardial anti-ischaemic effect might explain the effectiveness of long term oral treatment, which is independent of plasma concentrations of the drug.

Molsidomine prevents post-ischaemic ventricular fibrillation in dogs.

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

Experimental and clinical pharmacology of bretylium tosylate in acute myocardial infarction: a 15-year journey.

Experimental and clinical studies demonstrate the antifibrillatory effectiveness of bretylium tosylate: Experimental ventricular fibrillation induced either by electrical stimulation or by ischemia is prevented by bretylium. In 2,000 acute myocardial infarction patients who received bretylium prophylactically primary ventricular fibrillation occurred in less than 1% of cases. In a randomized hemodynamic study in acute myocardial infarction patients bretylium induced a significant decrease in heart rate, systolic and mean left ventricular pressures, and in systolic and mean aortic pressures. In addition, a parallel and significant decrease in total pulmonary and systemic resistances was seen, accompanied by decreases in tension time and left ventricular (delta P/delta V) indexes. Bretylium tosylate induces stabilization of electrical systole duration (QTc) in acute myocardial infarction patients. The conclusions of the present review strongly support those of the United States Food and Drug Administration, approving bretylium for prophylaxis and treatment of ventricular fibrillation.

The circumflex coronary artery occlusion canine model of sudden death: methodology and electrocardiographic observations.

This study deals with a left circumflex coronary artery occlusion-reperfusion canine model of sudden death using multiple electrocardiographic leads to define a subgroup of animals at high risk of ventricular fibrillation. Occlusion was followed by ventricular fibrillation in 15 of 30 animals (50%). In the 15 dogs surviving 60 min postocclusion, reperfusion gave rise to ten cases of ventricular fibrillation (66.7%). Thus, the total incidence of occlusion-reperfusion ventricular fibrillation was 25 of 30 (83.3%). Electrocardiographic delta R% changes greater than or equal to 25% in leads 2 and 3 at both 3 and 5 min postocclusion predicted the occurrence of postocclusion ventricular fibrillation with 80% specificity and 56% sensitivity. However, ST segment elevation greater than or equal to 0.5 mV in the same leads at the same times predicted postocclusion ventricular fibrillation with 67% specificity and 100% sensitivity. When only dogs with ST segment elevation greater than or equal to 0.5 mV in leads 2 and 3 at both 3 and 5 min postocclusion were considered, ventricular fibrillation postocclusion was seen in 15 of 20 dogs (75%) and ventricular fibrillation after reperfusion occurred in four of the remaining five animals (80%). Thus, in the subgroup of animals presenting with ST segment elevation greater than or equal to 0.5 mV in leads 2 and 3 at both 3 and 5 min postocclusion, the overall incidence of occlusion-reperfusion ventricular fibrillation was 19 of 20 (95%). These data may be useful in studies aimed at testing the effectiveness of drugs or other interventions in a canine model of sudden death.

Cicletanide improves outcome after left circumflex coronary artery occlusion-reperfusion in the dog.

The possible antifibrillatory effect of cicletanide, a new diuretic antihypertensive drug, was investigated at random in 50 anesthetized dogs subjected to left circumflex coronary artery ligation for 60 min and later reperfused. In this model, standard electrocardiographic leads 2 and 3 were continuously registered to measure delta R wave percent changes, to count the number of ventricular premature beats, and to document the onset of ventricular fibrillation; aortic pressure was recorded; 6-keto PGF1 alpha and TXB2 plasma levels were determined. Cicletanide significantly reduced early (Phase 1a) postischemic ventricular fibrillation (5 of 25 vs. 12 of 25, p = 0.036) but failed to reduce the incidence of global ischemia-induced ventricular fibrillation. On the other hand, the incidence of postreperfusion ventricular fibrillation was lower in the cicletanide group (1 of 14 vs. 5 of 9, p = 0.04). In addition, the total survival rate was improved in cicletanide treated dogs (p = 0.0257). While the rate-pressure product was lowered by the drug independent of the presence of ischemia, delta R% changes after occlusion were less in treated dogs than in controls. Moreover, the drug reduced significantly the number of ventricular premature beats in the early (Phase 1a) postischemic period. Finally, the drug increased (mean two-fold) the plasma levels of 6-keto PGF1 alpha as compared with controls; however, this increase was less than that achieved (mean 20-fold) after 100 ng/kg/min epoprostenol (prostacyclin) given in a further series of animals. Thus, improved outcome follows 10 mg/kg i.v. cicletanide administration in this model.

[Eicosanoids, vascular function and atherosclerosis]. / Icosanoïdes, fonction vasculaire et athérosclérose.

Icosanoides (prostaglandins, leukotrienes) seem to play an essential part in cardiovascular pathology. A range of experimental data obtained both in vitro and in vivo has resulted in a rapid progression of our understanding of their biochemical and functional properties and has opened up new fields of pharmacological research. However, a clear cut demonstration of their clinical relevance remains difficult. Improved methodology will no doubt provide more information about the importance of these compounds. For the present, we recommend reexamination of previously reported results.

[Eicosanoids, myocardial ischemia and sudden death]. / Icosanoïdes, ischémie myocardique et mort subite.

An activation of the arachidonic acid cascade has long been reported in coronary artery diseases. However, no clear-cut connection has been demonstrated between this activation and the clinical manifestations of myocardial ischemia. Controlled trials with the available cyclooxygenase inhibitory drugs support the view that these agents might be useful in subgroups of patients. However, these are not known. The peculiar pharmacologic properties of prostacyclin and PGE1 have been documented to improve experimental and clinical acute myocardial ischemia. Further efforts are needed to elucidate the usefulness of some PGs in the management of patients with ischemic heart disease and their contributory role to the disease.

Epoprostenol (PGI2) prevents postischemic ventricular fibrillation and improves outcome in a canine model of sudden death.

In a left circumflex coronary artery occlusion-reperfusion canine model of sudden death the hemodynamic, antiplatelet, antiischemic and antifibrillatory activities of 100 ng.kg-1.min-1 infusion of epoprostenol (Prostacyclin, Flolan, Wellcome Foundation, London, UK) were investigated at random in 40 animals. Significant changes were observed on epoprostenol infusion for mean arterial blood pressure (80 +/- 4 vs 93 +/- 7 mmHg, p less than 0.01), systemic vascular resistance (2379 +/- 769 vs 3290 +/- 768 dynes.s.cm-5, p less than 0.01) and rate-pressure product (10800 +/- 1200 vs 13450 +/- 2500 mmHg.beat.min-1, p less than 0.01) while heart rate did not change. In addition platelet aggregation intensity to ADP decreased by 50% (p less than 0.001). On occlusion treated animals presented with lower systemic vascular resistance (3132 +/- 895 vs 4931 +/- 1079 dynes.s.cm-5, p less than 0.05), rate-pressure product (9950 +/- 850 vs 12168 +/- 1980 mmHg.beat.min-1, p less than 0.01) and mean heart rate (145 +/- 10 vs 169 +/- 10 beats.min-1, p less than 0.01) while the anti-platelet activity persisted. A lower D2-3 mean ST segment elevation occurred at 3 min postocclusion in epoprostenol treated dogs (7.7 +/- 5 vs 14 +/- 8.7 mm, p less than 0.02). The incidence of postischemic ventricular fibrillation was significantly reduced (5/20 i.e. 25% vs 12/20 i.e. 60%, p less than 0.05) in the epoprostenol treated dogs. At the end of the occlusion-reperfusion period treated animals showed an improvement of outcome (10/20 i.e. 50% vs 2/20 i.e. 10%, p less than 0.01). It is suggested that the hemodynamic effect of the drug may provide guidelines for the clinical management of patients with acute myocardial ischemia, when a concomitant antiarrhythmic effect is looked for.

[Evaluation of the effectiveness of medical treatment of intermittent claudication]. / Evaluation de l'efficacité des traitements médicaux de la claudication intermittente.

The effectiveness of drugs to improve the walking distance in intermittent claudication patients is looked into five points: pathophysiology, drugs, methodology of clinical trials, sample survey among the members of the hemodynamic section of the French College of Vascular Diseases and biometric aspects. Finally, some important points of a clinical trial in this field are presented.

[An anesthetic technic in dogs for studying the arrhythmogenic effects of acute coronary occlusion]. / Une technique d'anesthésie du chien pour l'étude des effets arythmogènes de l'occlusion coronaire aiguë.

Intramuscular injection of levomepromazine (0.5 mg/kg) 30 min before intravenous injection of 10 mg/kg pentobarbital sodium induces a good surgical anaesthesia in dogs artificially ventilated with 50% N2O and 50% O2 and given 0.01 mg/kg atropine and 0.1 mg/kg pancuronium intravenously before left thoracotomy. This protocol is suitable for the study of the arrhythmogenic effects of acute one-stage coronary artery ligation in anaesthetized dogs. In fact, minor interference with the autonomic nervous system appears to be involved since heart rate is maintained slow and mean aortic pressure is kept within normal limits, as pH, PaO2, anc PaCO2 during subsequent periods. Acute circumflex coronary arterio-venous pedicle ligation close to the left main trunk division resulted in this model in a high incidence of ventricular fibrillation (10 out of 15 dogs) early (7 +/- 4 min) after occlusion. Specific interventions aimed at reducing the incidence of early post-ischemic life-threatening ventricular arrhythmias might be tested in this model.