Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes.

BACKGROUND: The CD40 ligand (CD40L) on activated T cells and platelets may be activating matrix metalloproteinases, inducing procoagulant activity, and be involved in the pathogenesis of acute coronary syndromes by promoting plaque rupture in atheroma. METHODS AND RESULTS: To study the role of CD40L-CD40 interaction in coronary disease, we analyzed levels of soluble (s) and membrane-bound CD40L in the peripheral blood from 29 patients with stable angina, 26 with unstable angina, and 19 controls. Our main findings follow. (1) Patients with unstable angina had significantly raised serum levels of sCD40L when compared with patients with stable angina and controls. (2) Platelets could release large amounts of sCD40L when stimulated ex vivo with the thrombin receptor-agonist peptide SFLLRN in both patients and controls. (3) Platelets in patients with unstable angina were characterized ex vivo by decreased intracellular levels and decreased SFLLRN-stimulated release of sCD40L, which may possibly represent a higher percentage of degranulated platelets in these patients. (4) T cells in patients with unstable angina had enhanced surface expression of CD40L and increased release of sCD40L on anti-CD3/anti-CD28 stimulation in vitro when compared with patients with stable angina and controls. (5) Recombinant CD40L and serum from patients with unstable angina who had high sCD40L levels induced enhanced release of monocyte chemoattractant peptide-1 from mononuclear cells, a CC-chemokine involved in the pathogenesis of atherosclerosis. CONCLUSIONS: This first demonstration of enhanced levels of soluble and membrane-bound forms of CD40L in angina patients, with particularly high levels in patients with unstable angina, suggests that CD40L-CD40 interaction may play a pathogenic role in both the long-term atherosclerotic process and in the triggering and propagation of acute coronary syndromes.

Late medical complications and fatigue in Hodgkin's disease survivors.

PURPOSE: Long-term medical complications, such as cardiac, pulmonary, and thyroid dysfunction, are frequent among Hodgkin's disease survivors (HDSs). Chronic fatigue is also highly prevalent among HDSs. Few studies have explored possible etiologic explanations for fatigue. The aim of this study was to explore whether late cardiac, pulmonary, and thyroid complications after curative treatment for Hodgkin's disease (HD) may explain the high level of fatigue among HDSs. PATIENTS AND METHODS: Four-hundred fifty-nine patients treated for HD at the Norwegian Radium Hospital from 1971 to 1991 were included in a cross-sectional, follow-up study of subjective health status. Fatigue (physical [PF] and mental), was measured by the Fatigue Questionnaire. A subcohort of the HDSs (116 patients) treated from 1980 to 1988 were included in a separate study in which long-term cardiac, pulmonary, and thyroid complications were assessed. All patients had received radiotherapy, and 63 patients had received additional chemotherapy. The present study comprised 92 patients (mean age, 37 years; range, 23 to 56 years) who participated in both studies. RESULTS: HDSs with pulmonary dysfunction were more fatigued than HDSs with normal pulmonary function (PF 10.9 v 8.9; P <.05). Gas transfer impairment was the most prevalent pulmonary dysfunction, and three times as many patients with gas transfer impairment reported chronic fatigue (duration, 6 months or longer), compared with patients without pulmonary dysfunction (48% v 17%, P <.01). No associations were found between cardiac sequelae or hypothyroidism and fatigue. CONCLUSION: Pulmonary dysfunction is associated with fatigue in HDSs. Cardiac sequelae was not associated with fatigue in HDSs. We question the absence of an association between thyroid complications and fatigue.

Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris. Clinical results from the Norwegian randomized trial.

OBJECTIVES: The purpose of the study was to evaluate clinical effects, exercise performance and effect on maximal oxygen consumption (MVO2) of transmyocardial revascularization with CO2-laser (TMR) in patients with refractory angina pectoris. BACKGROUND: Transmyocardial laser revascularization is a new method to treat patients with refractory angina pectoris not eligible for conventional revascularization. Few randomized studies comparing TMR with conventional treatment have been published. METHODS: One hundred patients with refractory angina not eligible for conventional revascularization were block-randomized in a 1:1 ratio to receive continued optimal medical treatment (MT) or TMR in addition to MT. The patients were evaluated at baseline and at three and 12 months with end points to symptoms, exercise capacity and MVO2. RESULTS: Transmyocardial laser revascularization resulted in significant relief in angina symptoms after three and 12 months compared to baseline. Time to chest pain during exercise increased from baseline by 78 s after three months (p = NS) and 66 s (p < 0.01) after 12 months in the TMR group, whereas total exercise time and MVO2 were unchanged. No significant changes were observed in the MT group. Perioperative mortality was 4%. One year mortality was 12% in the TMR group and 8% in the MT group (p = NS.) CONCLUSIONS: Transmyocardial laser revascularization was performed with low perioperative mortality and caused significant symptomatic improvement, but no improvement in exercise capacity.

Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the Coronary AngioPlasty Amlodipine REStenosis Study (CAPARES).

OBJECTIVES: Our intent was to investigate the effect of the dihydropyridine calcium channel blocker amlodipine on restenosis and clinical outcome in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Amlodipine has sustained vasodilatory effects and relieves coronary spasm, which may reduce luminal loss and clinical complications after PTCA. METHODS: In a prospective, double-blind design, 635 patients were randomized to 10 mg of amlodipine or placebo. Pretreatment with the study drug started two weeks before PTCA and continued until four months after PTCA. The primary angiographic end point was loss in minimal lumen diameter (MLD) from post-PTCA to follow-up, as assessed by quantitative coronary angiography (QCA). Clinical end points were death, myocardial infarction, coronary artery bypass graft surgery and repeat PTCA (major adverse clinical events). RESULTS: Angioplasty was performed in 585 patients (92.1%); 91 patients (15.6%) had coronary stents implanted. Follow-up angiography suitable for QCA analysis was done in 236 patients in the amlodipine group and 215 patients in the placebo group (per-protocol group). The mean loss in MLD was 0.30 +/- 0.45 mm in the amlodipine group versus 0.29 +/- 0.49 mm in the placebo group (p = 0.84). The need for repeat PTCA was significantly lower in the amlodipine versus the placebo group (10 [3.1%] vs. 23 patients [7.3%], p = 0.02, relative risk ratio [RR]: 0.45, 95% confidence interval [CI]: 0.22 to 0.91), and the composite incidence of clinical events (30 [9.4%] vs. 46 patients (14.5%), p = 0.049, RR: 0.65, CI: 0.43 to 0.99) within the four months follow-up period (intention-to-treat analysis). CONCLUSIONS: Amlodipine therapy starting two weeks before PTCA did not reduce luminal loss, but the incidence of repeat PTCA and the composite major adverse clinical events were significantly reduced during the four-month follow-up period after PTCA with amlodipine as compared with placebo.

Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes.

OBJECTIVES: We sought to study the relationships between chemokines and oxidative stress in acute coronary syndrome. BACKGROUND: In view of existing knowledge on the participation of leukocytes and oxidative stress in the pathogenesis of acute coronary syndrome, we hypothesized that chemokines may play a role in recruiting and activating leukocytes in this disorder. METHODS: The levels of chemokines and oxidative stress were studied in 38 patients with stable and 38 with unstable angina and in 20 controls. In separate in vitro experiments the effect of chemokines on reactive oxygen species in monocytes and the effect of antioxidants on chemokine levels in these cells were also studied. RESULTS: 1) Angina patients had raised serum levels of chemokines in both cross-sectional and longitudinal testing, with particularly high levels of interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory peptide (MIP)-1-alpha in unstable disease. 2) T cells, and particularly monocytes, seem to contribute to the raised IL-8, MCP-1 and MIP-1-alpha levels in unstable angina. 3) Concomitantly, and significantly correlated with MCP-1 and IL-8 levels, stable and particularly unstable angina patients had decreased plasma levels of antioxidants and increased lipid peroxidation, suggesting enhanced oxidative stress. 4) Monocyte chemoattractant protein-1 enhanced the generation of O2- in monocytes from unstable angina patients, and the antioxidant glutathione-monoethyl ester suppressed the production of IL-8 and MCP-1 in these cells. CONCLUSIONS: Our findings suggest an interaction between chemokines and oxidative stress in unstable angina. This interaction may represent a vicious circle involved in the pathogenesis of acute coronary syndromes.

Monophasic action potentials in patients with coronary artery disease: reproducibility and electrical restitution and conduction at different stimulation rates.

Monophasic action potentials were recorded in the outflow tract of the right ventricle in patients with coronary artery disease during ventricular pacing at different basic cycle lengths and programmed stimulation. During continuous pacing (basic cycle length 600 ms) the time for 90% repolarisation (MAP90) and the QTa interval decreased exponentially during the first 1.5-2 min of pacing to 90% of control values. The reproducibility of the monophasic action potential signals and the ventricular effective refractory period were assessed as good when studied after repetitive trains of 8 beats for more than 1.5 min. The reproducibility of conduction, however, was less good. Electrical restitution of MAP90 duration of the premature beats determined at three different basic cycle lengths was different from that in single muscle preparations. The curves showed two phases with unchanged MAP90 durations despite longer coupling intervals. The first phase was close to the ventricular effective refractory period, probably because subnormal conduction left the diastolic interval constant for the earliest premature beats. This indicates that subnormal conduction may influence the premature dispersion of repolarisation.

Effect of percutaneous transluminal coronary angioplasty on exercise in patients with and without previous myocardial infarction.

Improvement in exercise capacity is an important clinical effect of percutaneous transluminal coronary angioplasty (PTCA), and was assessed in patients with and without previous myocardial infarction (MI) undergoing PTCA. We prospectively followed patients with exercise testing before and 2 weeks after angioplasty in 415 patients, 170 (41%) of whom had a previous MI. A third exercise test was performed 20 +/- 2 weeks after PTCA in 403 patients. From left ventricular angiography obtained before PTCA, regional dyskinesia was classified into anterior or posterior locations. Both patients with and without previous MI had a significant increase in exercise capacity from before to 2 and 20 weeks after PTCA (previous MI: 31.9% and 29.3%; no MI: 50.7% and 38.2%; p <0.0001 [analysis of variance]). In patients with MI and anterior dyskinesia, in whom lesions on the left anterior descending artery were dilated or posterior dyskinesia in whom lesions on the right coronary artery were dilated, exercise capacity increased significantly from before to 2 and 20 weeks after PTCA (left anterior descending artery: 53.1% and 39.7%, p <0.0001; right coronary artery: 16.9% and 27.6%, p = 0.01 [analysis of variance]). Multivariate regression analysis revealed that male sex, no previous MI, and dilation of left anterior descending artery were significantly associated with increased exercise capacity after angioplasty adjusted for age and smoking habits, whereas left ventricular ejection fraction and end-diastolic pressure were not associated with increased exercise capacity.

Impairment in right ventricular performance after left ventricular aneurysm surgery.

To study the effect of operation for left ventricular (LV) aneurysm on right ventricular (RV) performance, we studied 50 patients before operation with right heart catheterization, RV angiography, and radionuclide ventriculography. Forty patients were followed up and underwent the same investigations 10 +/- 4 months after operation. At baseline, regional RV dysfunction was observed in 89% of the patients whereas global RV dysfunction was present in approximately a third. After operation, no changes in RV regional dysfunction or RV pressures were observed. However, a significant increase in RV end-diastolic (p less than 0.03) and end-systolic volume indices (p less than 0.02) along with a significant decrease in resting and exercise RV ejection fractions (p less than 0.05) was found. We were unable to demonstrate any significant relationship between preoperative RV dysfunction and surgical outcome. We conclude that RV dysfunction is common in patients with LV aneurysm. Current techniques of operative intervention for this type of aneurysm seem to be followed by RV dilatation and impairment in RV function.

Increased risk of heart valve regurgitation after mediastinal radiation for Hodgkin's disease: an echocardiographic study.

OBJECTIVE: To assess by echocardiography the occurrence and degree of late cardiac sequelae after treatment for Hodgkin's disease by radiation and chemotherapy. PATIENTS AND METHODS: In Norway from 1980 to 1988, 129 patients < 50 years old with Hodgkin's disease had curative treatment with mediastinal radiation, with or without chemotherapy. 116 (90%) of these patients (mean (SD) age 37 (7) years, 67 males) were examined by echocardiography 5-13 years after treatment. 40 healthy individuals (mean (SD) age 40 (11), 20 males) were examined as controls. All those examined were in regular sinus rhythm. RESULTS: Grade > 1 (scale 0-3) aortic and/or mitral valvar regurgitation was found in 24% of the patients (15% aortic, 7% mitral, and 2% aortic+mitral), affecting 46% of the females v 16% of the males (P < 0.001). Female gender was a significant risk factor for aortic and mitral regurgitation (odds ratio 4.7, 95% confidence interval 2.0 to 11.2), whereas age, period of follow up, radiation dose, and chemotherapy were not. Thickened pericardium was diagnosed in 15% of the patients. No risk factors were identified. No cases of pericardial thickening or valvar regurgitation grade > 1 were recorded in the control group. Mean values for measured and calculated indices of systolic and diastolic function were within the normal range for patients and controls. The patients had reduced E/A ratio compared with the healthy controls (E/A 1.1 v 2.0, P < 0.001). CONCLUSIONS: Abnormal left sided valvar regurgitation was detected in one fourth of the patients, affecting the aortic valve in more than half of the cases. Females had an increased risk of valvar regurgitation. Echocardiographic screening after high-dose mediastinal radiation is recommended.

Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study.

OBJECTIVE: To investigate long-term safety and efficacy after intracoronary injection of autologous mononuclear bone marrow cells (mBMCs) in acute myocardial infarction (AMI). DESIGN: Randomised, controlled trial. SETTING: Two university hospitals in Oslo, Norway. PATIENTS: Patients from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) study were re-assessed 3 years after inclusion. INTERVENTIONS: 100 patients with anterior wall ST-elevation myocardial infarction treated with acute percutaneous coronary intervention (PCI) were randomised to receive intracoronary injection of mBMCs (n = 50) or not (n = 50). MAIN OUTCOME MEASURES: Change in left ventricular (LV) ejection fraction (primary). Change in exercise capacity (peak VO(2)) and quality of life (secondary). Infarct size (additional aim), and safety. RESULTS: The rates of adverse clinical events in the groups were low and equal. There were no significant differences between groups in change of global LV systolic function by echocardiography or magnetic resonance imaging (MRI) during the follow-up. On exercise testing, the mBMC-treated patients had larger improvement in exercise time from 2-3 weeks to 3 years (1.5 minutes vs 0.6 minutes, p = 0.05), but the change in peak oxygen consumption did not differ (3.0 ml/kg/min vs 3.1 ml/kg/min, p = 0.75). CONCLUSION: The results indicate that intracoronary mBMC treatment in AMI is safe in the long term. A small improvement in exercise time in the mBMC group was found, but no other effects of treatment could be identified 3 years after cell therapy.

Hemodynamic findings before and after surgery for atrial septal defect of the secundum type in middle-aged patients.

84 patients without concomitant pulmonary or cardiac disease, underwent surgery for atrial septal defect of the secundum type (ASD II) at the age of 40 years or more. Hemodynamics were studied preoperatively at rest, and postoperatively at rest and during exercise during a follow-up investigation which took place 74 months (range 22-174) after surgery. Preoperatively, the pulmonary artery mean pressure (PAMP) exceeded 20 mm Hg in 24 patients (30%). In the patients aged 50 years or more PAMP was significantly higher than in the younger patients, whereas the shunt ratio did not show any increase with age. After surgery, the pressures in right atrium, right ventricle and PA showed significant changes towards normalization. During exercise, a considerable increase of the PA pressures appeared, and this increase correlated significantly with the PA pressures obtained preoperatively at rest.

Governmental steering of highly specialized medical services.

In Norway, highly specialized medicine has been under governmental steering since 1991. The Social and Health Department decides at which hospitals certain medical functions should be offered. In the field of cardiovascular medicine this has been experienced as mainly positive. The quality of the work has improved, and cooperation between hospitals has been stimulated.

Natural history of atrial septal defect of secundum type in the middle-aged. Medical versus surgical therapy.

10 middle-aged patients with atrial septal defect of the secundum type (ASD II) were referred to surgery, but for several noncardiological reasons the operation was not performed. 5 patients were reexamined after an interval from 6 1/2 to 15 years. During the follow-up period only relatively minor changes in pulmonary arteriolar resistance had occurred and all patients were still acceptable candidates for surgical treatment. The other 5 patients died after a period of time ranging from 2 weeks to 16 1/2 years from conditions directly or indirectly related to the cardiac malformation. During the same period of time, 84 ASD II patients underwent surgery with a mortality rate of 8.3% after 74 months, including 2 hospital deaths. These results suggest that middle-aged patients with ASD II without obstructive pulmonary hypertension should be operated on without delay, but that in a significant number of cases, long-term conservative treatment is not associated with an increase in pulmonary arteriolar resistance.

Electrocardiographic findings before and after surgery for atrial septal defect of the secundum type in middle-aged patients.

Surgery for atrial septal defect of the secundum type was performed in 84 patients over 40 years of age. Electrocardiograms were studied preoperatively and at a follow-up visit 74 months (range 22-174 months) after surgery. Preoperatively, atrial fibrillation was observed in 13% of the patients, complete right bundle branch block in 30%, and a secondary R wave (R') in lead V1 in 72%. A significant correlation was found between the amplitudes of SV6 and R'V1 and the right ventricular systolic pressure, whereas no significant correlation could be demonstrated between the shunt ratio and any of the QRS parameters. After successful surgery, the mean QRS axis in the frontal plane shifted from +99 degrees to +47 degrees (p less than 0.01), and the following highly significant (p less than 0.001) changes were noticed: increase of the amplitude of SV1, shortening of the QRS duration in V1, increase of the ratio QR'/QRS V1, shortening of the duration of SV6, and diminution of the initial forces of the P wave in V1.

Congenital swallowing-induced symptomatic heart block: a case report of a probably hereditary disorder.

A 15-year-old girl had had syncope induced by swallowing since infancy. An ECG recorded during food intake revealed SA block with very slow junctional and ventricular escape rhythms. No symptoms or signs of other cardiac disorders or gastrointestinal diseases were present. Activation of a strong vagal reflex, able to inhibit impulse formation and propagation in an otherwise normal heart, is the most likely explanation of the disorder in this patient. Furthermore, ECGs of her close relatives which were recorded during food intake as compared with the findings in a reference group (n = 20), indicated that a genetic factor could be involved.

Effects of atenolol and pindolol on the hypokalaemic and cardiovascular responses to adrenaline infusion.

To investigate if the intrinsic sympathomimetic activity of pindolol could modify its beta-blocking effects on the responses to an adrenaline infusion, 10 healthy volunteers were studied. At an interval of 1-4 weeks each subject received pindolol and atenolol in randomized order before the infusion of adrenaline 0.06 microgram.kg-1.min-1. Pindolol prevented hypokalaemia and significantly decreased the heart rate during the adrenaline infusion. These effects were not observed after atenolol. The diastolic blood pressure was slightly increased during the infusion of adrenaline after pindolol, whereas it remained unchanged after atenolol.

[Drug therapy of angina pectoris. Are the possibilities exploited well enough?]. / Medikamentell behandling av angina pectoris. Utnyttes mulighetene godt nok?

A retrospective comparative study of the use of antianginal drugs in 1987 and 1992/93 has been carried out in unselected series of patients admitted for angiographic evaluation. Compared with the patients in 1987 the patients in 1992/93 were treated with approximately 50% of the doses of beta-blockers and isosorbide dinitrate. There was also a considerable reduction of the proportion of patients who received doses of beta-blockers of a similar level as used in large multicentre studies showing improved survival after myocardial infarction. The explanation of this change in therapy may be due, at least partly, to a general fear of side-effects.