Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors.

OBJECTIVES: To examine circadian changes in the sympathovagal balance, the activity of the renin-angiotensin system and hemostatic variables in patients with stable coronary artery disease, and the effects of beta-adrenoceptor blockade and angiotensin-converting enzyme inhibition. BACKGROUND: Sympathovagal balance and key components of the fibrinolytic system show circadian variability. The effects of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors on these autonomic and hemostatic rhythms are not well defined. METHODS: Twenty patients with coronary artery disease underwent 24-h Holter monitoring for heart rate variability and blood sampling (6 hourly for 24 hours) after three consecutive treatment phases, (firstly with placebo, then bisoprolol, and finally quinapril). The effects on sympathovagal balance, hemostatic variables and the renin-angiotensin system activity were measured. RESULTS: The fibrinolytic capacity showed marked circadian variation at the end of the placebo phase (p = 0.002), plasminogen activator inhibitor-1 (PAI-1) activity peaking at 06.00 AM when tissue plasminogen activator (tPA) activity was at its nadir. Sympathovagal balance showed a sharp increase at approximately the same time but plasma renin activity did not rise until later in the day. Inspection of the 24-h profiles suggested that bisoprolol reduced sympathovagal balance and the morning peak of PAI-1 activity and antigen, with a small increase in tPA activity, although these changes were not significant. Quinapril produced a substantial rise in renin (p = 0.01) but did not significantly affect either PAI-1 or tPA. Sympathovagal balance was unaffected by quinapril. CONCLUSIONS: In patients with stable coronary artery disease, angiotensin-converting enzyme inhibition with quinapril does not affect either sympathovagal balance or the endogenous fibrinolytic system. Our data suggest that the sympathoadrenal system may modify fibrinolytic activity, judged by the response to beta-adrenoreceptor blockade with bisoprolol.

The effect of dietary lipids and antioxidants on the activity of epoxide hydratase in the rat liver and intestine.

The effect of varying the fatty acid composition of the lipid components of the diet on the activity of epoxide hydratase in the rat liver and intestinal mucosa has been studied. Feeding a 10% cod liver oil diet (containing 18% C20:5 and 11% C22:6) resulted in a 3-fold increase in epoxide hydratase activity in the liver and a 1.6-fold increase in the intestine compared to rats fed a fat-free diet. The activity of epoxide hydratase in rats fed a cod liver oil diet was significantly greater than that for the group fed a lard diet (containing mainly saturated and mono-unsaturated fatty acids) containing the same quantity of vitamin E. Thus, the enhancing effect of the cod liver oil diet was due to the polyunsaturated fatty acids in this oil. Dietary corn oil (58% C18:2) also stimulated epoxide hydratase activity in the liver but not in the intestine. Vitamin E levels of up to 500 mg/kg diet were ineffective at inducing epoxide hydratase activity in both the liver and intestine. Significant changes in the fatty acid composition of hepatic and intestinal microsomes took place when rats were fed diets of different fatty acid composition. These changes were such that the proportions of polyunsaturated fatty acids in the microsomal fractions reflected the amounts of these fatty acids in the dietary fat. Hepatic epoxide hydratase activity was found to be positively correlated to the proportion of polyunsaturated fatty acids in the microsomal fractions of the liver.

Autonomic dysfunction is related to impaired pancreatic beta cell function in patients with coronary artery disease.

OBJECTIVE: To assess the role of beta cell failure in the development of autonomic dysfunction in patients with coronary artery disease. DESIGN: Autonomic function was measured by standard clinical methods and by heart rate variability in 24 type II diabetic and 24 non-diabetic subjects with coronary artery disease. Quantitative estimates of pancreatic beta cell function (%beta) and insulin resistance were made from basal plasma glucose and insulin concentrations using a computer solved model. Fasting proinsulin levels provided an independent measure of beta cell function. RESULTS: The circadian rhythm of sympathovagal balance (ratio of low to high frequency spectral components of heart rate variability) was significantly attenuated in patients with below median (%beta

Attenuation or absence of circadian and seasonal rhythms of acute myocardial infarction.

OBJECTIVES: To examine the circadian, seasonal, and weekly rhythms of acute myocardial infarction, and to identify subgroups in whom the rhythms are attenuated or absent to provide further information about the mechanisms of the rhythms and the processes responsible for triggering plaque events. DESIGN AND SETTING: Prospective, observational study in a general hospital. PATIENTS AND METHODS: 1225 consecutive patients admitted to a coronary care unit with acute myocardial infarction were studied. Admission rates were calculated according to the hour of the day (circadian rhythm), day of the week (weekly rhythm), and month of year (seasonal rhythm). The data were analysed for variations within the whole group and within subgroups. RESULTS: A weekly rhythm of acute myocardial infarction could not be demonstrated but there was a trend towards higher admission rates at the beginning of the week. However, the time of onset of symptoms showed significant circadian variation for the group as a whole, peaking in the morning (P = 0.006), against an otherwise fairly constant background rate. Subgroup analysis showed complete absence of the circadian rhythm in patients who were diabetic, South Asian, or taking beta blockers or aspirin on admission. Significant seasonal variation in admission rates was also demonstrated for the group as a whole with a winter peak and a summer trough (P = 0.009). Again, no seasonal rhythm could be demonstrated in patients who were diabetic, South Asian, or taking beta blockers or aspirin on admission. CONCLUSIONS: The absence of circadian and seasonal rhythms of acute myocardial infarction in almost identical subgroups suggests that common mechanisms are involved in driving these rhythms. The autonomic nervous system is a likely candidate because the rhythms were absent in patients taking beta blockers as well as in patients in whom derangement of autonomic function commonly occurs.

Angiotensin-converting enzyme inhibitors and coronary artery disease.

The renin-angiotensin system and angiotensin converting enzyme (ACE) are increasingly being implicated in the pathogenesis of coronary artery disease and its sequelae. Genetic studies of ACE gene polymorphism hint at an association between the ACE genotype and atherosclerosis. Animal studies have demonstrated the potential beneficial effects of ACE inhibition at a variety of sites, including improvement of endothelial function, inhibition of platelet aggregation, reduction of atherosclerosis, and inhibition of myointimal proliferation. Although these have not all been validated in human studies, the reduction of ischemic events in studies of ACE inhibition in left ventricular dysfunction cannot be explained solely by improved hemodynamics, and it is possible that actions on the endothelium, the atherosclerotic process, and platelets are at least in part responsible. The results of studies in humans looking more directly at the influence of ACE inhibitors on atherosclerosis and ischemic heart disease are awaited.

One-stop chest pain clinic can identify high cardiac risk.

The aim of this study was to record prognosis for patients with stable chest pain referred for outpatient cardiac assessment. All 660 patients in the study had a normal resting ECG and no history of myocardial infarction, unstable angina or coronary revascularisation. Main outcome measures were all-cause mortality, non-fatal ischaemic events and coronary revascularisation. Cardiac chest pain was diagnosed in 182 patients (28%). It was more frequent in patients with recent onset of symptoms (< 6 months), patients over 50, white patients, and patients with hypertension or diabetes. The mean follow-up was 622 +/- 338 days. Among survivors, 37% continued to suffer from symptoms (cardiac group: 59 (35.1%); non-cardiac group: 177 (38.4%)). When all hard events were considered, event-free survival (95% confidence interval) for the cardiac group was 90.9% (86.7-95.2%) at six months, 88.9% (84.2-93.6%) at one year, and 83.6% (77.5-89.7%) at two years. Corresponding figures for the non-cardiac group at the same time points were better (p < 0.0001): 98.5% (97.4-99.6%), 97.5% (96.1-99.0%) and 96.6% (94.7-98.5%), respectively. In conclusion, the use of clinical criteria in a cardiac outpatient clinic, backed up by simple non-invasive investigations, can reliably identify a population at high risk of subsequent cardiac events.

Frequency and prognostic implications of conduction defects in acute myocardial infarction since the introduction of thrombolytic therapy.

OBJECTIVE: To document the frequency of conduction defects and their influence on prognosis in a large series of patients with acute myocardial infarction who underwent coronary care during a period when thrombolytic therapy was in common usage. BACKGROUND: Conduction defects have been associated with an adverse prognosis following acute myocardial infarction, but there are few data on the incidence and outcome of conduction defects since the introduction of thrombolytic therapy. PATIENTS AND METHODS: The study group comprised 1225 consecutive patients with acute myocardial infarction treated in the coronary care unit from 1 January 1988 to 31 December 1994. Conduction defects were recorded prospectively and were classified as follows: complete atrioventricular node block associated with narrow complex escape rhythms; left or right bundle branch block; bifascicular block; complete heart block involving both bundle branches. RESULTS: Electrocardiographic data were available in 1220 patients. Complete atrioventricular node block occurred in 65 (5.3%), left and right bundle branch block in 29 (2.4%) and 44 (3.6%) bifascicular block in 36 (2.9%) and complete heart block involving both bundle branches in 20 (1.6%). The more advanced degrees of block in the bundle branches occurred more commonly in patients with diabetes, previous infarction. Q-wave infarction, anterior infarction and left ventricular failure. Survival analysis showed an increased short- and long-term cardiac mortality in patients with conduction defects, prognosis worsening as the severity of the conduction defect increased. CONCLUSION: Conduction defects complicated acute myocardial infarction in 16% of cases and had a graded impact on the short- and long-term prognosis, patients with advanced bundle branch involvement faring worst. The data showed a small decline in the rate of severe conduction defects compared with previous studies, possibly reflecting the beneficial effects of thrombolytic therapy on infarct size.

Prognostic implications of ventricular fibrillation in acute myocardial infarction: new strategies required for further mortality reduction.

OBJECTIVE: To determine the changing risk of ventricular fibrillation, the prognostic implications, and the potential long term prognostic benefit of earlier hospital admission, after acute myocardial infarction. DESIGN: Prospective observational study. SETTING: A district general hospital in east London. PATIENTS: 1225 consecutive patients admitted to a coronary care unit with acute myocardial infarction. MAIN OUTCOME MEASURES: Time of onset of pain and ventricular fibrillation, and long term survival of patients admitted with acute myocardial infarction. RESULTS: The rate of ventricular fibrillation in these hospital inpatients was high in the first hour from onset of pain (118 events/1000 persons/h; 95% confidence interval (CI) 50.7 to 231) and fell rapidly to an almost constant low level by six hours; 27.4% of patients with early ventricular fibrillation died in hospital, compared with 11.6% of those without (p < 0.0001), but mortality in patients who survived to hospital discharge was not altered by early ventricular fibrillation (five year survival: 75.0% (95% CI 60.0% to 84.8%) with ventricular fibrillation v 73.3% (95% CI 69.6% to 76.6%) without ventricular fibrillation). CONCLUSIONS: Patients successfully resuscitated from early ventricular fibrillation have the same prognosis as those without ventricular fibrillation after acute myocardial infarction. Faster access to facilities for resuscitation must be achieved if major improvements in the persistently high case fatality of patients after acute myocardial infarction are to be made.