Comparison of the effect of beta adrenergic antagonists with different ancillary properties on isolated canine and human coronary arteries.

Experiments were performed on canine and human isolated coronary arteries to characterise human coronary beta adrenoceptors and to determine whether or not beta blocking agents with different ancillary properties unmask the alpha adrenergic effect of noradrenaline in a similar way. The inhibitory effects of atenolol (a beta1 selective antagonist), epanolol (a beta1 selective antagonist with modest intrinsic sympathetic activity), and propranolol (a non-selective antagonist) were assessed on isoproterenol concentration-response curves. Regression analysis provided slopes not significantly different from unity and similar pA2 values for each agent in both preparations. In a second group of experiments, the effects of noradrenaline (10 mumol.litre-1) were assessed in the absence and presence of beta blockade. At equipotent doses (1 log or 2 log units from the pA2 values) each beta blocking agent unmasked the alpha effect of noradrenaline in the same way. This alpha effect of noradrenaline (10 mumol.litre-1) was completely abolished by prazosin 1 mumol.litre-1 in canine coronary arteries but only partially antagonised in human coronary arteries. Thus the property of a beta blocking agent to unmask the alpha adrenergic effect of adrenaline is mainly related to its affinity for the coronary smooth muscle beta adrenoceptors. These beta adrenoceptors were very similar in both preparations and appear to be mainly beta1. The alpha adrenoceptors seem, nevertheless, to be different and resistant to prazosin in human preparations.

Comparison of responses to acetylcholine and serotonin on isolated canine and human coronary arteries.

Canine and human coronary arteries were studied in organ baths to compare the responses to acetylcholine and serotonin in the two species. The human coronary rings were isolated from seven patients without cardiac disease (mean age 15 years, range 7-20). In one set of experiments canine and human preparations were incubated with phentolamine, propranolol and ketanserin (all at 1 mumol.litre-1 concentration) and precontracted with prostaglandin F2 alpha (PGF2 alpha 1-2 mumol.litre-1). Acetylcholine (0.1-10 mumol.litre-1) and serotonin (0.1-100 mumol.litre-1) relaxed canine preparations dose dependently, the maximum responses (expressed as % of depression of PGF2 alpha response) being 84 (SEM 6)% (n = 9) and 51(5)% (n = 6) respectively. In the same experimental conditions, acetylcholine and serotonin failed to relax the human coronary rings (n = 11) while substance P and bradykinin induced relaxations of 72(4)% (n = 11) and 66(7)% (n = 11) of PGF2 alpha response respectively. In another set of experiments, dose-contraction curves were constructed for acetylcholine or serotonin (in presence of phentolamine and propranolol). On human rings with endothelium, methylene blue (10 mumol.litre-1), a non-specific inhibitor of endothelium derived relaxing factor (EDRF), potentiated these dose-contraction curves: markedly for serotonin, the EC50 decreasing from 1.2(0.2) to 0.22(0.08) mumol.litre-1 (n = 11, p less than 0.01) with a significant increase in the maximal response); and slightly for acetylcholine, EC50 decreasing from 0.84(0.11) to 0.40(0.13) mumol.litre-1 (n = 10, p less than 0.05) without significant change in the maximal response.(ABSTRACT TRUNCATED AT 250 WORDS)

Does cardiac denervation affect the short-term blood pressure variability in humans?

OBJECTIVE: To explore the repercussion of cardiac denervation on the short-term blood pressure variability in humans, in order to assess the extent to which the variability of blood pressure is linked to the variability of heart rate. METHODS: Beat-to-beat blood pressure and RR interval time were recorded in 16 heart-transplanted patients and were compared with those of 10 healthy control subjects in the resting supine, sitting and standing positions. Blood pressure and RR interval variabilities were assessed by spectral analysis. RESULTS: The total blood pressure power and the sitting very low-frequency, low-frequency, low-frequency and high-frequency blood pressure variability were similar in the heart-transplanted patients and in the controls, despite a marked reduction in the RR interval variability in the heart-transplanted patients. However, the heart-transplanted patients had lower standing low-frequency blood pressure variability than the control subjects. Moreover, very low-frequency and low-frequency RR interval variabilities reappeared in the long-term heart-transplanted patients but not in the short-term heart-transplanted patients (range of time after transplantation 53-124 and 3-25 months, respectively). CONCLUSIONS: Short-term RR interval fluctuations are not mandatory for the maintenance of normal blood pressure variability in the supine and sitting positions, but may contribute to the increase in the low-frequency blood pressure variability which occurs normally in the standing position. Moreover, the long-term heart-transplanted patients had increased RR interval variability, which may have been caused by the reappearance of limited autonomic cardiac modulation. However, this increased RR interval variability did not affect the corresponding blood pressure variability.

Role of alpha-adrenergic coronary tone in exercise-induced angina pectoris.

To provide more insight into the role of alpha-adrenergic coronary tone in exercise-induced angina, 9 patients with chronic stable angina underwent after coronary angiography a symptom-limited supine exercise test on a cyclo-ergometer. After recovery, phentolamine was directly injected into the most diseased vessel (2 mg in 5 minutes), and immediately thereafter the same exercise (identical workloads and exercise duration) was repeated. During exercise 1, heart rate (HR), mean blood pressure and cardiac index increased 51% (p less than 0.001), 23% (p less than 0.01) and 33% (p less than 0.01), respectively, and pulmonary artery wedge pressure (PA wedge) increased from 9 +/- 1 to 26 +/- 2 mm Hg (p less than 0.001). After intracoronary injection of phentolamine, control values (including PA wedge) at rest did not change significantly. During exercise 2, HR, mean blood pressure and cardiac index increased in a similar way--50% (p less than 0.001), 25% (p less than 0.01) and 40% (p less than 0.01), respectively; however the increase in PA wedge was less (p less than 0.01). ST-segment depression at the end of exercise 2 was smaller for identical workloads and double products: 1.5 +/- 0.3 mm vs 2.5 +/- 0.3 mm (p less than 0.01). ST/HR slope in exercise 2 also decreased 51% (p less than 0.01). These results show a less severe ischemic response after intracoronary alpha blockade and argue for an improvement in coronary blood supply.

Oral sustained-release nitroglycerin in chronic stable angina: a multicenter, double-blind, randomized crossover trial.

Forty-six patients with stable angina pectoris were randomized to receive either oral sustained-release nitroglycerin (SRNG, 6.5 mg) or placebo (P) 3 times a day for a 2-week double-blind trial. They were investigated for the frequency of anginal episodes, for sublingual nitroglycerin consumption and for exercise tolerance. There was a slight but significant decrease in the number of anginal episodes (6.4 +/- 1.5 episodes/week with P, 4.9 +/- 1.7 with SRNG, p less than 0.005) and sublingual nitroglycerin consumption (3.9 +/- 1 tablets/week with P, 2.7 +/- 1 with SRNG, p less than 0.005). The patients performed 3 upright multistage (increments of 30 W every 3 minutes) exercise tests on a bicycle ergometer before the start of the study and 1 hour after the intake of SRNG or P, at the end of each double-blind phase. Exercise capacity, expressed as exercise duration, increased from 8.9 +/- 3.8 minutes with P to 10.2 +/- 3.8 minutes with SRNG (14.6%; p less than 0.001). At symptom-limited exercise, ST depression was significantly reduced (p less than 0.05) during the SRNG phase. Thirty-four patients (74%) reached a higher peak heart rate (139 beats/min with P, 145 beats/min with SRNG; p less than 0.001) and 35 patients (76%) a higher rate-pressure product (+6%; p less than 0.001). These changes in exercise tolerance are relatively modest and at least 11 patients would have benefited from larger doses of nitrates.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous diltiazem versus nitroglycerin for silent and symptomatic myocardial ischemia in unstable angina pectoris.

For 18 patients consecutively admitted to the coronary care unit for unstable angina, 48-hour electrocardiographic Holter monitoring was performed after they were randomly assigned in a single-blind fashion to 1 of 2 treatment groups. The first group was treated with acetylsalicylic acid (ASA) and intravenous nitroglycerin, the second with ASA and intravenous diltiazem. All of the patients treated with nitroglycerin still had ischemic episodes after 48 hours (33% were symptomatic), in contrast with 11% of the diltiazem group (11% asymptomatic). Maximal ST-segment depressions of symptomatic and asymptomatic episodes were significantly different; and no significant increases in heart rate were observed either during the 15 seconds before ischemia began or during the ischemic episode. During the 48 hours, the diltiazem group had significantly fewer ischemic episodes (17) than did the nitroglycerin group (145). We concluded that "on-line" ST-segment observation is of prime importance for monitoring unstable angina; that the majority of the ischemic episodes associated with unstable angina are silent; and that intravenous diltiazem could be an effective pretreatment for patients who must undergo mechanical or surgical therapy.

Coronary vasomotility and myocardial blood flow early after heart transplantation.

Serotonin constricts coronary arteries with endothelial dysfunction, a common abnormality in cardiac transplant recipients. To assess whether endothelial dysfunction is associated with myocardial blood flow (MBF) abnormalities, 24 patients were studied 1 to 12 months after transplantation. Serotonin in increasing doses (1, 10, and 20 micrograms/min for 2.5 min each) was infused into the coronary circulation. Diameters were measured by quantitative angiography. Fourteen patients (group A) had a pronounced artery constriction (diameter reduction > 40%), while in 10 other patients (group B), such a constriction was never reached. No patient had evidence of rejection and all had angiographically normal coronary arteries. MBF was measured at rest and after intravenous dipyridamole with dynamic nitrogen-13 ammonia positron emission tomography (PET). The resting MBF was higher in group A than in group B (94 +/- 12 vs 74 +/- 15 ml/min/100 g of tissue; p < 0.05). During dipyridamole, MBF was not significantly different (191 +/- 53 vs 184 +/- 64 ml/min/100 g; p = NS). Coronary flow reserve (the ratio of perfusion after dipyridamole to perfusion at rest) was significantly lower in group A than in group B (2.08 +/- 0.54 vs 2.66 +/- 0.57; p < 0.05). Thus, coronary hypersensitivity to serotonin in cardiac transplant recipients is associated with elevated resting MBF and reduced coronary flow reserve. Immune mechanisms inducing endothelial injuries and inflammation-related hyperemia may account for these abnormalities.

Effect of oral sustained-release nitroglycerin on exercise capacity in angina pectoris: dose-response relation and duration of action during double-blind crossover randomized acute therapy.

Ten men with documented coronary artery disease and stable exertional angina underwent a double-blind crossover study to examine the benefit and the duration of action on their symptom-limited exercise capacity of 2 doses (2.5 and 6.5 mg) of sustained-release nitroglycerin (SRNG). A multistage bicycle test was performed in the sitting position by steps of 30 W each 3 minutes until the onset of typical angina pectoris. It was performed 24 hours before the start of the study; 1 and 5 hours after administration of placebo, and repeated after 2.5 and 6.5 mg of SRNG administered in a double-blind crossover study according to a 4 successive days protocol. No differences appeared between administration of placebo (1 and 5 hours) and the results obtained at the first exercise test. The dose of 2.5 mg of SRNG was effective on the symptom-limited working capacity but only at 1 hour (+9%; p less than 0.01). The dose of 6.5 mg was more effective both at 1 hour (+25%; p less than 0.001) and at 5 hours (+27%; p less than 0.001). All patients had angina at a higher heart rate (+5 to 8%; p = NS [not significant] and p less than 0.01), whereas systolic blood pressure and double product tended to be slightly but insignificantly increased. S-T depression at the onset of angina was insignificantly changed with placebo, and 2.5 and 6.5 mg of SRNG. It is concluded that 6.5 mg of orally administered SRNG is effective during at least 5 hours, and that the magnitude of the benefit and its duration are dose-related.

Early alterations of myocardial blood flow reserve in heart transplant recipients with angiographically normal coronary arteries.

BACKGROUND: The evaluation of the coronary reserve provides valuable information on the status of coronary vessels. Therefore, we studied with positron emission tomography (PET) and 13N-ammonia the myocardial blood flow (MBF) reserve in heart transplant recipients free of allograft rejection and with angiographically normal coronary arteries early after heart transplantation (HTx). The MBF reserve was calculated as the ratio between MBF after dipyridamole injection and basal MBF normalized for the rate-pressure product. METHODS: Patients were studied within 3 months (group A, n = 12) or more than 9 months (group B, n = 12) after HTx. Five patients have been studied both during the early and late period after HTx. Results were compared to those obtained in 7 normal volunteers (NL). RESULTS: Group A recipients had a significantly lower dipyridamole MBF (in ml/min/100 gr of tissue) than that of group B recipients (142+/-34 vs 195+/-59, p<0.05). This resulted in a significant decrease in MBF reserve early after HTx (group A: 1.82+/- 0.33) and a restoration to normal values thereafter (group B: 2.52+/- 0.53 vs NL: 2.62+/-0.51, p = ns). Separate analysis of 5 patients studied twice is consistent with these results. CONCLUSION: This study shows that in heart transplant recipients free of allograft rejection and with normal coronary angiography, MBF reserve is impaired early after HTx. Restoration within one year suggests that this abnormality does not represent an early stage of cardiac allograft vasculopathy.

Increased platelet aggregability and prostacyclin biosynthesis induced by intense physical exercise.

Changes in platelet aggregability during maximal bicycle ergometry were studied in healthy untrained subjects. Ex vivo platelet aggregation in response to ADP and collagen was measured in whole blood by impedance aggregometry or by direct electronic counting in an Ultra-Flo 100 platelet counter. This last method revealed that the platelet aggregation induced by low concentration of ADP (0.5 - 1.0 microM) was significantly enhanced during exercise. The plasma level of beta-thromboglobulin and the urinary excretion of 2,3--dinor-6-keto prostaglandin F1 alpha were also increased. These data indicate that an intense physical exercise enhances the aggregability of human platelets and induces a compensatory increase in prostacyclin biosynthesis.

Physical fitness does not reflect physical activity patterns in middle-aged workers.

Questionnaires and a sub-maximal exercise test were used to assess occupational and leisure time physical activity as well as physical fitness in a standardized prospective study in 2,565 Belgian and Slovakian middle-aged healthy workers. Less than 5% of the subjects engaged in strenuous work requiring an energy expenditure above 31.5 kJ.min-1. One-third of the Belgians and 50% of the Slovakians reported no heavy leisure time activity during the preceding 12 months. Physical fitness, defined as the workload at heart rate 150 beats.min-1 (standardized for body weight), was significantly higher in Slovakians as compared to Belgians (1.52 +/- 0.28 W.kg-1 and 1.48 +/- 0.28 W.kg-1; P less than 0.001). Occupational physical activity in Belgians and heavy leisure time activity in Slovakians were independently related to fitness levels. However, each activity score explained less than 1% of the variance of physical fitness. We conclude that in these mainly sedentary, middle-aged subjects, fitness levels are independent from the usual physical activity patterns.

Abnormal placentation and selective embolization of the uterine arteries.

OBJECTIVE: Abnormal placentation accounts for more than 50% of uterine artery embolization failure. The authors report their experience in this situation. STUDY DESIGN: Seven women presented with abnormal placentation. Uterine artery embolization was carried out in emergency or prophylactic control of postpartum bleeding. RESULTS: In five patients, control of postpartum hemorrhage was obtained without hysterectomy. In two cases with no placental removal and prophylactic procedures, hysterectomy and blood transfusion were not necessary. The manual removal of the placenta was achieved secondarily, respectively on the 25th and the 12th day. CONCLUSIONS: The success rate of uterine artery embolization for postpartum bleeding appears to be lower with abnormal placentation. In none of the cases with the placenta present was it possible to leave the residual placenta in place. However, embolization may permit a safe waiting period and spontaneous migration of the placenta. When the diagnosis is made before delivery, prophylactic uterine artery embolization without placental removal should be considered to reduce blood transfusion and preserve fertility.

Thrombophilia and fetal growth restriction.

OBJECTIVE: Genetic thrombophilia may represent a new risk factor for obstetrical complications. The aim of the study was to determine which subgroups may be associated with genetic thrombophilia for small for gestational age infants (SGA). METHODS: A case-control study was performed in three different maternity wards in Normandy. Cases (n=203) were women who had pregnancies complicated by unexplained SGA infants defined as a birth weight below the 3rd centile and control subjects (n=203) were women who had infants with birth weight > or =10th centile. Patients were tested in the immediate postpartum period and 2 months later for factor V Leiden mutation, and prothrombin 20210A mutation. Frequencies of these mutations were observed in different subgroups of SGA infants depending on pregnancy or neonatal outcomes usually associated with intrauterine growth restriction (IUGR), and were then compared with the overall prevalence for these mutations detected in the control group. RESULTS: Prevalences for factor V Leiden mutation (or=2.58; 95% confidence interval: 0.83-8.04), prothrombin 20210A mutation (or=2.03; 95% confidence interval: 0.51-8.01), were comparable between cases and controls (4.9% versus 1.9% and 2.9% versus 1.4%, respectively). Frequencies for these two polymorphisms significantly increased in subgroups of SGA infants with a normal Pourcelot index (13/133 versus 7/203; P=0.04), a gestational age > or =37 weeks of gestation (15/143 versus 7/203; P=0.01), a vaginal delivery (11/117 versus 7/203; P=0.04), a birth weight > or =2000 g (12/121 versus 7/203; P=0.03), no admission to paediatric ward (11/116 versus 7/203; P=0.01), a low Ponderal index <2.5(e) centile (6/45 versus 7/203; P=0.04), and normal head circumference >10th centile (7/53 versus 7/203; P=0.01) in comparison with the control group. CONCLUSIONS: An association was found between polymorphisms for factor V Leiden and prothrombin, and asymmetrical intrauterine growth restriction with immediate favourable neonatal outcomes.

Ankle/arm pressure index in asymptomatic middle-aged males: an independent predictor of ten-year coronary heart disease mortality.

PURPOSE OF THE STUDY: to evaluate the predictive power of a reduced ankle/brachial pressure index (ABPI) (< or = .90) in an asymptomatic middle-aged male working population free of coronary heart disease. MATERIALS AND METHODS: 2023 subjects forty to fifty-five years old were screened at their work place. Standard techniques were used. Blood was drawn in the fasting state. Ankle and brachial blood pressures were measured by Doppler signals and all measures were done by one observer, duly trained in epidemiologic methodology. RESULTS: in univariate analysis, an ABPI < or = .90 was significantly associated with age, total serum cholesterol, body mass index, smoking, and awareness of diabetes. In multivariate analysis, it was associated with awareness of diabetes, age, Ln triglycerides (P = .073), and smoking (P = .088). Relative risks for reduced versus normal ABPI are 2.77 (P = .010), 4.16 (P = .011) and 4.97 (P = .006) for ten-year all causes, cardiovascular, and coronary mortality, respectively. In a multiple logistic regression analysis, the following variables were significant independent predictors of coronary mortality: smoking (odds ratio [OR] = 4.84), reduced ABPI (OR = 3.63), and low density lipoprotein cholesterol (OR for 1 SD = 1.69). Reduced ABPI is also an independent predictor of cardiovascular mortality. CONCLUSION: a reduced ABPI is an independent risk factor for coronary and cardiovascular mortality in asymptomatic middle-aged Belgian males.

Long-term follow-up of heart transplant patients.

The present study was designated to assess long term functional capacity, blood pressure and renal function at 12 and 60 months after heart transplantation. The data of sixty heart transplant recipients were retrospectively reviewed. At rest, radionuclide ejection fraction and cardiac index measured by thermodilution were within normal range, demonstrating normal left systolic function. In all patients, exercise tests were performed sitting on a bicycle. Peak oxygen uptake decreased from 23 +/- 6 to 19 +/- 6 ml/kg/min (mean +/- S.D.) respectively at 12 and 60 months after surgery (p < 0.01), which represent a 17% diminution in functional capacity. This decrease is nevertheless only related with a 10 kg increase in total body weight (69 +/- 9; 79 +/- 12 kg; p < 0.001) and thus absolute peak oxygen uptake remained unchanged. Blood pressure rised significantly since the first month after transplantation. Sixty-seven percent of recipients had systemic hypertension at 60 months, despite medical therapy. A decline in renal function was observed in all patients, beginning after the first year of transplantation.

From physical capacity to fitness to work in coronary patients.

The authors studied the energetic expenditures of 15 coronary patients during work. The subjects with reduced physical capacity tolerated a high fraction of their VO2 SL during their work with activity peaks close to their maximal capacity.

Tricuspid valve prolapse: two-dimensional echocardiographic aspects.

Three patients with prolapse of the mitral and tricuspid valve are presented. The tricuspid valve prolapse was revealed by two-dimensional echocardiography and simultaneous M-mode echocardiogram.

Effects of spironolactone-altizide on left ventricular hypertrophy.

OBJECTIVE: To investigate the effects of the association spironolactone (25 mg)/altizide (15 mg) as monotherapy on left ventricular hypertrophy (LVH) in patients with mild to moderate hypertension. Additionally, to study the correlation between left ventricular mass (LVM) index and electrocardiographic (ECG) criteria for LVH. METHODS AND RESULTS: This was an open, prospective study of 6 months. Patients with mild to moderate essential hypertension were treated with spironolactone/altizide for two months and were included in the study if their blood pressure (BP) at the end of this first treatment period was normalised according to protocol criteria (systolic BP < 160 mm Hg and diastolic BP < 95 mm Hg). Patients then entered a second 4-month treatment period. LVM was determined by echocardiography performed at the beginning of treatment and after 6 months. LVH was defined as LVM > or = 100 g/m2 in women and LVM > or = 131 g/m2 in men. Echocardiograms were interpreted blindly by two echocardiography reading laboratories. Seventy-one patients with a normalised BP after two months of treatment, were enrolled in the study. Changes in LVM index were studied in 31/71 patients with LVH (25 women and 6 men, mean LVM index +/- (SD) 119.9 +/- 16.4 g/m2 in women and 147.8 +/- 10.9 g/m2 in men). Spironolactone/altizide significantly reduced LVM index by 10%, from 125.3 +/- 22.5 to 114.2 +/- 25.1 g/m2 (p < 0.005). Posterior and septal wall thickness decreased by 4% (p = 0.06) and 5% (p = 0.026), respectively. End-diastolic dimension was reduced by 3%, from 50.3 +/- 3.3 to 48.9 +/- 3.4 mm (p = 0.006). The posterior wall thickness to end-diastolic dimension ratio remained unchanged. Complete regression of LVH according to mass criteria occurred in 11 patients out of 31 (34.5%). The observed changes in ECG voltage criteria were in accordance with a decrease of LVM index. CONCLUSION: In this open study, the potassium-sparing diuretic spironolactone/altizide decreases LVM index in hypertensive patients, who were selected for follow-up because they had echocardiographic LVH and because their BP had normalised during an initial 2-month treatment period.

[Cardio-respiratory assistance with the extracorporeal membrane oxygenator for massive pulmonary embolism]. / Assistance cardio-respiratoire par oxygenateur a membrane extracorporel pour embolie pulmonaire massive

A 39 year old pneumectomized patient presents a massive pulmonary embolism, dies within 3 hours and is supported inefficiently by cardiac massage with recurrent mydriasis during 2 hours. At that time, under extracorporeal cardiopulmonary bypass with a membrane oxygenator, the cardiac activity recovers immediatly due to right decompression and coronary perfusion. The patient is conscious within 5 hours. The cardiopulmonary bypass with a membrane oxygenator appears to be the best therapy when the cardiac massage fails to restitute a normal myocardial function. No embolectomy was performed. The patient died when the bypass was stopped after 48 hours. We conclude that the prolonged peripheral extracorporeal bypass followed by embolectomy is the best therapy of pulmonary embolism.

[Physical activity, physical fitness and coronary disease]. / Activité physique, aptitude physique et affections coronariennes.

The relationship between physical activity on and off the job, physical fitness and coronary artery disease was investigated in a prospective study involving 2 363 men, 40 to 55 years old. Sudden death and myocardial infarction occurred in 31 subjects during a 5-year follow-up. Preliminary data are reported. There was no significant correlation between quartiles of physical activity on and off the job and incidence of coronary events. Physical fitness was significantly inversely correlated with incidence of coronary events (p less than 0.05) and was significantly lower in the 31 new cases (p less than 0.03). Multivariate analysis showed that HDL-cholesterol, smoking and physical fitness significantly and independently discriminate between coronary prone patients and healthy subjects. We conclude that physical fitness is an independent, inverse risk indicator of new coronary events.