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Background Chemokines and platelet activation are both important in atherogenesis. Platelet inhibitors are widely used in coronary artery disease (CAD), and we hypothesized that the platelet inhibitor clopidogrel could modify chemokines in CAD patients. Objectives We sought to investigate the effect of clopidogrel on the expression of chemokines and chemokine receptors in peripheral blood mononuclear cells (PBMC) in CAD patients. Patients/methods Thirty-seven patients with stable angina were randomized to clopidogrel (n = 18) or placebo (n = 19). PBMC, blood platelets and plasma were collected at baseline and after 7-10 days in the patients, and in 10 healthy controls. mRNA levels of chemokines and chemokine receptors in PBMC were analyzed by ribonuclease protection assays and real-time reverse transcriptase polymerase chain reaction. Platelet activation was studied by flow cytometry. Results (i) At baseline, the gene expression of the regulated on activation normally T-cell expressed and secreted (RANTES) chemokines and macrophage inflammatory peptide (MIP)-1beta in PBMC, the expression of CD62P and CD63 on platelets and the levels of platelet-derived microparticles (PMP) were elevated in angina patients comparing healthy controls; (ii) markers of platelet activation were either reduced (CD63) or unchanged (CD62P, PMP, beta-thromboglobulin) during clopidogrel therapy; (iii) in contrast, clopidogrel significantly up-regulated the gene expression of RANTES and MIP-1beta in PBMC, while no changes were found in the placebo group; (iv) a stable adenosine 5'-diphosphate metabolite attenuated the release of MIP-1beta, but not of RANTES, from activated PBMC in vitro. Conclusions Even if we do not argue against a beneficial role for clopidogrel in CAD, our findings may suggest potential inflammatory effects of clopidogrel in CAD.

This article presents the results of a retrospective analysis of the use of beta-blockers and current dosing of these agents in patients with coronary artery disease. While 70 to 78% of patients admitted to Norwegian university hospitals during 1990-1997 for angiographic evaluation of chest pain used beta-blockers, only 43-60% of patients with stable coronary artery disease enrolled in the 4S study in Norway received such treatment. High risk groups such as diabetics and patients with peripheral artery disease were less likely to receive beta-blockers during the early period, but were not treated differentially compared to low risk patients during recent years. Only 15% of patients with congestive heart failure received oral beta-blockers, and only 10.5% intravenous beta-blockade during acute myocardial infarction. The dosing of the most common beta-blockers were low, approximately 50% of doses shown to improve survival after acute myocardial infarction.

During the years 1985 to 1987 a total number of 388 patients from the Norwegian health region 1 were transferred from Ullevål Hospital to heart centres abroad for heart operation because of the low operating capacity in our own hospital. The operative mortality in pure coronary bypass operations was 6.0%. Six out of 34 patients (17.6%) died postoperatively following valvular replacements. A questionnaire was sent to all survivors in November, 1989 and July, 1996. The clinical condition was judged to be very good or good by 95% and 83% of the patients, respectively. A self-evaluation of quality of life on a visual analog scale indicated a significant improvement after the operation.

The procainamide plasma concentration was followed during maintenance therapy with a new procainamide retard tablet preparation in 23 hospitalized patients suffering from acute or chronic coronary heart disease with complicating ventricular arrhythmias. After initial individually adjusted treatment with Pronestyl every third hour, either orally or intramuscularly, for at least eight dose intervals, the retard tablets were given at 6 hour intervals for 2 to 12 days, or more. In 19 patients with no major fluctuations in their circulatory or renal state, adequate and relatively stable plasma procainamide concentration was obtained upon a constant dose of the retard preparation. On an average, the difference from minimum to maximum concentration was 55 per cent within the 6 hour dose intervals. In four patients with unstable circulation and/or renal function, procainamide therapy had to be disrupted in two because of severe side effects and toxic concentrations, and the dose was adjusted in the remaining two. It is concluded that the formulation of procainamide tablet preparations has simplified procainamide therapy within and outside hospital and improved our possibilities to perform short-and long-term studies on the risk/ benefit ratio of procainamide treatment in patients with severe ventricular arrhythmias.

1 Binding of propranolol in vitro was determined in sera from 38 non-fasting patients 4-6 days after an acute myocardial infarction. The binding of propranolol was significantly lower in 12 patients receiving a subcutaneous heparin injection than in 26 patients receiving warfarin. 2 The binding of propranolol in sera from 9 geriatric patients without any acute diseases and 10 young, healthy subjects was similar to that of patients with acute myocardial infarction receiving heparin. 3 Mean serum concentration of α1-acid glycoprotein was similar in the four different groups of individuals. 4 For all subjects, the binding of propranolol was positively correlated to serum concentrations of α1-acid glycoprotein. 5 In the patients with myocardial infarction the binding was negatively correlated to serum concentrations of non-esterified fatty acids. Mean serum concentrations of non-esterified fatty acids was significantly higher in the patients receiving heparin than those receiving warfarin. 6 Addition of heparin and palmitic acid to serum in vitro did not affect the binding of propranolol. 7 The effect of heparin on binding variations was observed more closely in three non-fasting patients with myocardial infarction. Serum binding of propranolol and concentrations of chylomicrons and pre-β-lipoproteins were significantly reduced after a subcutaneous heparin injection of 5,000 iu, while serum concentrations of non-esterified fatty acids increased threefold. Concentrations of α1-acid glycoprotein and albumin were unchanged. Changes in binding of propranolol was closely correlated to concomitant changes in the triglyceride-rich lipoproteins. 8 These observations indicate that propranolol is bound to both triglyceride-rich lipoproteins and α1-acid glycoprotein in serum. Even smaller doses of heparin activate lipoprotein lipase and decrease binding of propranolol to lipoproteins in non-fasting subjects.

A randomized, double-blind, placebo-controlled trial of propranolol was carried out in 560 high-risk survivors of myocardial infarction enrolled at 12 Norwegian hospitals. The main purpose of the study was to determine the effect of propranolol, 160 mg/day, on the incidence of sudden cardiac death over 12 months. The patients were randomized 4-6 days after the acute event. A statistically significant reduction in sudden cardiac deaths of 52% was noted (11 deaths in the propranolol group and 23 in the placebo group). Four placebo patients and one propranolol patient were successfully resuscitated from ventricular fibrillation. In addition, less severe ventricular arrhythmias were significantly more common among the placebo-treated patients. Twenty-five patients in the treatment group and 37 in the control group died (p = 0.11). Severe adverse effects of the drug were uncommon in this high-risk population. The findings support the results of the Beta-Blocker Heart Attack Trial and other long-term beta-blocker trials in survivors of myocardial infarction.

This paper presents the long-term results of 221 thrombendarterectomy operations during the period 1955-61, and of 86 femoro-popliteal venous bypass operations during the period 1961-64. The indication for surgery was in the majority of the patients disabling claudication. When pain at rest or ulceration was present, arterial reconstruction was performed even when the outlook for a lasting result was poor. Preoperatively a major amputation seemed inevitable in 31 limbs. Thirteen of these are considered to have been saved by the operation. After aortoiliac thrombendarterectomy patent arteries were found in 80% of the extremities after one year and in 48% after 10 years. Forty-five per cent of the extremities were patent on re-examination or remained patent until death. After fermoro-popliteal thrombendarterectomy, 61% of the arteries were patent after one year and 26% after 10 years. Thirty-nine per cent of the arteries were patent on re-examination or remained patent until death. After femoro-popliteal venous bypass, 88% of the grafts were patent after one year and 58% after 5 years. Forty-nine per cent of the grafts were patent on re-examination or remained patent until death. The postoperative mortality was small (4.4% after aortoiliac surgery and 2.0% after femoro-popliteal surgery), and mostly caused by widespread atherosclerosis in other parts of the arterial system. On re-examination 8 to 16 years after the operation, 63% of the patient were dead. Almost 50% of the deaths were caused by coronary heart disease, 17% by cerebrovascular catastrophes, and 13% by other manifestations of atherosclerotic disease. The results are discussed, and it is concluded that long-term results after vascular surgery may be favourable. Peripheral atherosclerosis is, however, a local manifestation of a generalized disease. The indications for reconstructive arterial surgery should therefore be relatively restricted.

Ten male patients with chronic stable angina pectoris completed a randomized, double-blind cross-over study, with matched placebo run-in period (P), to compare the effects of a long-acting preparation of propranolol (LA, 160 mg once a day) with that of conventional propranolol (CP, 40 mg four times a day) each given for 14 days. Response was assessed by symptom-limited bicycle ergometry, degree of ST segment depression, daily anginal attack rate and glyceryl trinitrin consumption (GTN). Heart rate and ventricular extra-systolic frequency (VES) were recorded by 24 h Holter monitor. Bicycle ergometry was performed and a trough blood sample taken for propranolol estimation on day 14 prior to the morning dose. Both formulations increased total work capacity (P 3412, LA 4095, CP 3697 kpm/min), reduced rate-pressure product (P 21896, LA 16011, CP 15609 mm Hg beats/min), and degree of ST segment depression (P 4.53, LA 2.48, CP 2.43), but without differences between the formulations. Daily anginal attack rate was reduced from 30 (placebo) to 7.5 (CP) and 14.5 (LA) (P less than 0.05 between treatment groups). There was a reduction in daily GTN consumption by both treatments. The heart rate and total number of VESs during 24 h was similar in the two treatment groups and was reduced in comparison with placebo. Both formulations were well tolerated. Long-acting propranolol is an effective and well-tolerated alternative to conventional propranolol in the treatment of chronic stable and stress-induced angina, and in reducing VES frequency.

A prospective, randomised, double-blind study was performed to compare the effects of propranolol and placebo on sudden cardiac death in a high-risk group of patients who survived acute myocardial infarction. Altogether 4929 patients with definite acute myocardial infarction were screened for inclusion: 574 (11.6%) died before randomisation, and 3795 (77%) were excluded. Five hundred and sixty patients aged 35 to 70 years were stratified into two risk groups and randomly assigned treatment with propranolol 40 mg four times a day or placebo. Treatment started four to six days after the infarction. By one year there had been 11 sudden deaths in the propranolol group and 23 in the placebo group (p less than 0.038, two-tailed test analysed according to the "intention-to-treat" principle). Altogether there were 25 deaths in the propranolol group and 37 in the placebo group (P less than 0.12), with 16 and 21 non-fatal reinfarctions respectively. A quarter of the patients were withdrawn from each group. Withdrawal because of heart failure during the first two weeks of treatment was significantly more common among propranolol-treated patients than among the controls, but thereafter the withdrawal rate was the same. The significant reduction in sudden death was comparable with that after alprenolol, practolol, and timolol, which suggests that the mechanism of prevention is beta-blockade rather than any other pharmacological property of the individual drugs.

During a 5-year period, 1969-1973, 451 patients with acute severe pulmonary diseases were admitted to the three medical intensive care units (MICU) at Ullevaal Hospital. In 39% of the patients a major cardiac arrhythmia was recorded in the units during a mean observation time of 24 h. The subsequent mortality in the hospital was 31% in patients with arrhythmias in the MICU, and 8% in patients without arrhythmias. The association between arrhythmias and mortality was significant (P less than 0.004) in patients with a diagnosis of pneumonia. There was also an association (P less than 0.04) between arrhythmias and the severity of lung disease. Continuous electrocardiographic monitoring of patients with severe pneumonia or acute exacerbations of obstructive lung disease is recommended.

The hemodynamic effect of 5 mg propranolol intravenously was studied during permanent endocardial pacing in nine patients with complete atrioventricular heart block. The heart rate was constant at a preset pacemaker frequency. After the injection of propranolol the cardiac output was reduced in all patients and a fall in maximal arterial dp/dt was found. Atrial retardation occurred in all patients. The atrial contractility, as judged from the maximal atrial systolic pressure, was not reduced. It is concluded that the reduction of cardiac performance after propranolol in patients with constant ventricular rate is a result only of the negative inotropic effect on the ventricular myocardium.