Increased plasma beta-thromboglobulin in patients with coronary artery vein graft occlusion: response to low dose aspirin.

The therapeutic effect of aspirin on vein graft patency was studied in patients undergoing coronary artery bypass graft surgery. The study design enabled the prospective evaluation of the relation of platelet activation, as measured by plasma beta-thromboglobulin concentration, to subsequent coronary vein graft occlusion. Serial beta-thromboglobulin levels were measured in 105 patients randomized to receive aspirin (324 mg/day) or placebo beginning within 1 h after surgery. Graft patency was assessed angiographically at 1 week and 1 year after surgery. Of 49 patients receiving placebo, 17 (34.7%) had one or more graft occlusions, 6 early, 10 late and 1 with both early and late occlusion. Of 56 patients receiving aspirin, 7 (12.5%) had one or more occlusions, 3 early and 4 late (p less than 0.01). Preoperatively, the beta-thromboglobulin level in surgical patients (29 +/- 13.5 ng/ml) was significantly higher than that of 51 control subjects (22.6 +/- 11.1 ng/ml) (p less than 0.004). Plasma beta-thromboglobulin levels remained comparatively constant at 3 and 12 months after surgery in the 43 patients who had both samples available (p less than 0.001, r = 0.65). The reduction in beta-thromboglobulin concentration from the preoperative level to 12 months postoperatively was greater in the aspirin-treated group (p less than 0.001). Multivariate logistic regression analysis demonstrated a significant association between preoperative beta-thromboglobulin concentration and graft occlusion (p less than 0.02), and aspirin treatment was effective in preventing occlusion when adjusted for the preoperative beta-thromboglobulin level (p less than 0.005). Plasma beta-thromboglobulin concentrations are elevated in patients with coronary artery disease, suggesting ongoing platelet activation.(ABSTRACT TRUNCATED AT 250 WORDS)

On the effects of dietary n-3 fatty acids (Maxepa) on plasma lipids and lipoproteins in patients with hyperlipidaemia.

An encapsulated preparation of fish oil (Maxepa) was administered to hyperlipidaemic patients in order to establish the responsiveness of the common lipid phenotypes to dietary supplementation with n-3 fatty acids. 13 patients took 6 g/day of fish oil and 12 patients took 16 g/day in a randomized, double-blind crossover study, whereby each subject took fish oil for 3 months and matching placebo for 3 months. The study was conducted against a background diet restricted in saturated fat and cholesterol. In Types IIa and IIb hyperlipoproteinaemia there was no substantial fall in plasma cholesterol concentration. Plasma triglyceride concentrations were reduced significantly in Types IIb and IV (28% and 41% respective reductions). In a separate study using 16 g/day of fish oil in patients with Type V hyperlipoproteinaemia, plasma triglycerides were reduced by 58% and plasma cholesterol concentration by 34%. The change in plasma triglyceride concentration was significantly correlated with the basal triglyceride level (r = -0.94), and was dose-related (33% fall on 6 g/day and 58% fall on 16 g/day). The fall in plasma triglyceride concentration was accompanied by a significant reduction in the concentration of very low-density lipoprotein cholesterol (-42%), a significant rise in low density lipoprotein cholesterol (+7%), and a significant rise in high-density lipoprotein cholesterol concentration (+6%), there being no significant change in the ratio of low density to high density lipoprotein cholesterol. There were changes in the fatty acid composition of plasma and platelet lipids which reflected dietary supplementation with n-3 fatty acids, notably an increase in the proportion of eicosapentaenoic and docosahexaenoic acids which occurred in a dose-dependent fashion. Despite these changes there was no significant variation in the bleeding time, platelet count or blood viscosity during the treatment.

Timing of cardiac transplantation in idiopathic dilated cardiomyopathy.

Seventy-nine patients with idiopathic dilated cardiomyopathy were assessed and followed up to evaluate 9 variables that might predict duration of survival after assessment for cardiac transplantation. Patients with ischemic heart disease, alcoholic and peripartum cardiomyopathy were excluded. There were 38 deaths (48%) during the 18-month (mean) follow-up. Patients underwent determination of left ventricular ejection fraction by radionuclide scan, echocardiography, cardiac catheterization and myocardial biopsy. Only left ventricular ejection fraction determined by radionuclide study correlated significantly with time to death in nonsurvivors (r = 0.38, p less than 0.05). Multivariant analysis and Cox multivariate regression analysis revealed that the single consistent determinant of prognosis was radionuclide-determined ejection fraction. It was an excellent predictor of survival to 3 months (p less than 0.0001) and a reasonable predictor of survival to 6 months (p less than 0.05). There was no variable that efficiently predicted survival for any period greater than 6 months. In 15 of 70 patients (21% of the entire group), clinical status and radionuclide ejection fraction improved after assessment but only one of these had an ejection fraction less than or equal to 0.10. No patient with a radionuclide ejection fraction greater than or equal to 0.20 died within 6 months of assessment. For those with ejection fraction between 0.11 and 0.19, survival after cardiac transplantation exceeded that of the natural history of their disease; this suggests that transplantation should be undertaken within 6 to 12 months of assessment. Left ventricular ejection fraction less than or equal to 0.10 predicts an extremely poor prognosis (6-month survival was 17%) and such patients should be transplanted with minimal delay.

Prognostic guides in patients with idiopathic or ischemic dilated cardiomyopathy assessed for cardiac transplantation.

In an attempt to identify which parameters predict survival in advanced dilated cardiomyopathy, 232 patients presenting for assessment for cardiac transplantation were investigated and followed for 10 +/- 12 months (range 2 weeks to 5 years). Etiology of dilated cardiomyopathy included ischemic heart disease (33%), idiopathic (42%) and miscellaneous (25%). In each patient, 26 parameters were recorded. Whole group survival was 68% at 1 year, 56% at 2 years, 41% at 3 years and 25% at 4 years. On Cox multivariate regression analysis, 3 parameters predicted survival: New York Heart Association symptom class (p less than 0.0001), pulmonary capillary wedge pressure (p less than 0.008) and plasma atrial natriuretic factor level (p less than 0.002). On paired testing of actuarial survival curves, plasma noradrenaline also held predictive value (p less than 0.002), as did left ventricular ejection fraction less than or equal to 20% on radionuclide ventriculography (p = 0.007) and presence of greater than or equal to 4 beats of ventricular tachycardia on Holter monitoring (p = 0.007). Treatment with amiodarone did not appear to influence survival. Conventional determinants of prognosis in cardiomyopathy (symptom class, wedge pressure, nonsustained ventricular tachycardia and ejection fraction) do not alone always adequately differentiate survival in this group of high risk patients. More attention to plasma noradrenaline and to atrial natriuretic factor levels may give important additional information in the context of assessment of patients for transplantation.

Risk of infective endocarditis in mitral valve prolapse with and without precordial systolic murmurs.

The risk of infective endocarditis (IE) associated with a systolic murmur in patients with mitral valve prolapse (MVP) was investigated in a case-control study. The case group comprised all patients with MVP (n = 19) from a series of 136 consecutive adult admissions for IE. Three matched control subjects were chosen for each case from a series of 144 MVP patients without IE. Seventeen of the 19 cases (89%) had documented evidence of systolic murmurs existing before the IE episode; systolic murmurs were documented in 25 of the 57 control subjects (47%). The data indicate a significant increase in the risk of IE in MVP patients with a systolic murmur (p less than 0.01). The absolute probability of IE developing in a patient with MVP and a murmur was estimated to be approximately 1 in 1,400 per year; this was 35 times greater than the probability in a patient with MVP without a murmur. The results suggest that by restricting prophylaxis to MVP patients with a systolic murmur, cover would be provided for almost 90% of those with MVP in whom IE would be likely to develop.

Reproducibility of radionuclide left ventricular ejection fraction in patients awaiting cardiac transplantation.

Radionuclide-derived left ventricular ejection fraction (LVEF) is used to assess LV systolic function, to follow trends in the natural history of dilated cardiomyopathy, and to prioritize patients waiting for cardiac transplantation. Reproducibility of LVEF at extremely low levels has not, however, been reported. To assess the reproducibility of radionuclide LVEF at levels below 0.30 EF U, 17 highly symptomatic patients (NYHA Class III/IV) with dilated cardiomyopathy were studied on two occasions, 72 hours apart. Sequential scans were analyzed by two independent observers. Mean LVEF was 0.18 +/- 0.06 U (scan 1) and 0.17 +/- 0.06 U (scan 2). Interoperator reproducibility (SD) was 0.03 U (R = 0.76), interscan reproducibility (SD) was 0.03 U (R = 0.62), and overall reproducibility (SD) was 0.04 U (R = 0.50). The interobserver variation of 0.03 (actually 0.027) was just over one half that seen in normal volunteers (variation 0.05, n = 29) studied previously in this department. A change of greater than or equal to 0.08 U (2SD) in either direction is highly likely to represent a real change in LV function in those with LVEF less than or equal to 0.30 units, compared with the change of at least 0.10 units required in those with normal LV function. Lower interobserver and interscan reproducibility should be taken into account when interpreting sequential scans in patients with severe LV dysfunction.

Myocardial infarction--the problems and prognosis: Paper 1.

Deaths from coronary heart disease and myocardial infarct may occur in previously undiagnosed subjects (the so called pre-hospital phase), in hospital following admission to a coronary care unit, or following discharge. Mortality in the pre-hospital phase has been estimated at 35--40 per cent. Within Australia the mortality in the coronary care unit is 11--17 per cent. Following discharge, the mortality is about 20 per cent in the first 12 months and then occurs at about four to five per cent per year for the first five years.

Success of a new health administration strategy. The patient-focused institute with a tripartite management.

As the result of the restructuring and decentralisation of the administration of St Vincent's Hospital, Sydney, I was Clinical Chief of a pilot "institute" for three years operating within a "patient-focused model" in hospital management. By the end of the trial, we had improved performance despite reductions in hospital and unit budgets.

Clinical representation in the development of casemix: measures and applications in Australia.

The Australian Casemix Clinical Committee coordinated the clinical evaluation of inpatient casemix classifications leading to the development of Australian national diagnosis-related groups 1, 2 and 3. It has provided and will continue to provide advice on clinical matters associated with casemix activities to the Commonwealth and State health authorities, public and private hospital associations, insurers and the clinical professions. In future, all clinicians will be expected to understand casemix, diagnosis-related groups and cost weights, especially those relevant to their speciality.

Fifty years of medical specialisation: from foundation to fragmentation.

The past 50 years of medicine have been dominated by revolutions in biological sciences and clinical therapeutics. No less dramatic have been changes in our healthcare systems, with medical specialisation playing a leading role. The middle of the century saw the rapid development of the teaching hospital as the centre of professional education, collegiate identity, medical specialisation and clinical research. By contrast, the past 20 years have seen dramatic shifts in response to the demands of a more diverse community.

Changing concepts in management of infective endocarditis.

Sixty-four patients were treated for 73 episodes of infective endocarditis over the five-year period 1970 to 1974 at St Vincent's Hospital, Sydney. There were 13 deaths with a mortality rate of 18-1% compared with 38% (1950 to 1959). Included were 13 cases of infection on prosthetic valves with three deaths. Fifty-one per cent of patients were studied by cardiac catheterization. Early or emergency surgery was performed in 28% of cases and late surgery in 16%. The improved results were due to multiple factors, including early diagnosis, prompt investigation in a specialized unit, rational use of appropriate antibiotics, careful management of complications and early surgery.

Validity of echocardiographic determination of left ventricular systolic wall thickening.

Previous direct measurements of left ventricular systolic wall thickening (SWT) in animal studies have yielded values approximately one-half those found echocardiographically in humans, suggesting a possible overestimation of SWT by echocardiographic techniques. To test the validity of echocardiographic SWT measurements, the relationship between echocardiographically determined end-diastolic and end-systolic left ventricular short-axis myocardial cross-sectional areas (ED Myo CSA and ES Myo CSA, respectively) was assessed in 18 normal subjects. Since Myo CSA is a function of wall thickness and wall circumference, overestimation of SWT by echocardiography would be expected to produce an overestimation of ES Myo CSA relative to ED Myo CSA. SWT, as determined by both M mode (52%) and two-dimensional echocardiography (48%), was consistent with previously reported echocardiographic values, but exceeded that reported in animal studies. By least squares linear regression analysis, ES Myo CSA was 1.078 X ED Myo CSA - 0.385 cm2 (r = .947 SEE = 1.183 cm2) when assessed by one observer and was 1.042 X ED Myo CSA - 0.142 cm2 (r = .906, SEE = 1.831 cm2) when assessed independently by another. The close relationship observed between echocardiographically determined ES Myo CSA and ED Myo CSA was consistent with constant left ventricular myocardial mass throughout the cardiac cycle and thus did not suggest an overestimation of SWT by echocardiographic techniques.

Treatment of hypercholesterolaemia with oral lecithin.

An open clinical trial was performed to evaluate the plasma cholesterol-lowering potential of oral lecithin in large doses (20--30 g/day), with or without supplementary clofibrate. Three healthy subjects and seven patients with hypercholesterolaemia were studied over periods ranging from eight weeks to 11 months. In one-third of healthy subjects and in 3/7 patients, lecithin therapy led to a significant fall in plasma cholesterol concentration (10--18% fall). Combination of lecithin and clofibrate in two of the patients led to still lower plasma cholesterol levels (21 and 22% fall). Most of the change in plasma cholesterol concentration, when it occurred, was due to a reduction in beta lipoproteins. Evidence is presented that oral lecithin may reduce plasma cholesterol levels by acting as a source of linoleic acid.

Nifedipine in the treatment of life threatening Prinzmetal angina.

Nifedipine is a non-nitrate vasodilator which has proved effective, in oral form, in Europe, Japan, and the USA for treatment of Prinzmetal Angina. The drug has not been used before in Australia. We report a patient with Prinzmetal's variant angina, complicated by recurrent syncopal episodes due to ventricular arrhythmias. The attacks were resistant to standard therapy except sublingual nitroglycerin but ceased completely during treatment with nifedipine.

Coronary artery disease in young Australian women.

Over a 12-year period, from 1965 to 1977, 43 women under 46 years of age were documented with angiographic evidence of coronary atherosclerosis at St Vincent's Hospital, Sydney. Twenty-five of the women were able to be followed up at a mean interval of 31 months. This group of young women with coronary artery disease was compared with an age-matched control group of 660 "healthy" women drawn from the general population. Hyperlipidaemia was present in 72% of patients and in 13% of controls. Seventy-three percent of patients were regular cigarette smokers compared with 21% of controls. Only one patient out of 43 showed neither hyperlipikaemia, nor hypertension, nor smoked cigarettes, and multiple risk factors were commonly present. The level of high density or alpha-lipoprotein was significantly reduced in young women with coronary artery disease. These results highlight the presence of classical risk factors in these young women, as well as the importance of alpha-lipoproteins.

Diagnosis and management of acute myocarditis aided by serial myocardial biopsy.

Two cases in which right ventricular endomyocardial biopsy established a definitive pathologic diagnosis of acute myocarditis are presented. Both patients presented with severe left ventricular dysfunction, atrial flutter and an intraventricular conduction defect. Immunofluorescent and immunoperoxidase examination of the biopsy specimens suggested a humoral immune mechanism in one case and a cell-mediated immune mechanism in the other. Substantial improvement in cardiac function followed treatment with prednisolone and azathioprine in both cases. Significant regression of the myocardial inflammatory changes was documented by a further endomyocardial biopsy in each case following clinical improvement.

The effects of adrenergic blockade on lipoproteins using the rat as an experimental model.

Adrenergic blocking drugs are known to have adverse effects on lipids and lipoproteins in man, although the mechanisms underlying these effects are unclear. In order to see whether the rat might be a suitable model to explore this issue, adrenergic blockers having differing properties with respect to receptor interaction were administered to rats orally over seven days, followed by measurement of plasma lipids and lipoproteins. Total plasma cholesterol was not significantly influenced by any of the drugs used, while triglycerides were reduced by 20% and 31% respectively with pindolol and prazosin. With respect to changes in HDL cholesterol, it was found that: (a) HDL cholesterol was significantly reduced by 8% during combined beta 1, beta 2 blockade with propranolol; (b) HDL cholesterol was not significantly changed during selective beta 1 blockade using atenolol, or during combined beta 1, beta 2 blockade and partial beta 2 stimulation using pindolol; and (c) HDL cholesterol was significantly increased during combined beta 1 blockade and beta 2 stimulation using celiprolol by 12%, or during alpha 1 blockade with prazosin by 8%. It appears that beta 2 receptor exposure or stimulation may be one of the key points in the interaction between adrenergic blockade and lipoprotein metabolism.

Reduction in plasma cholesterol and increase in biliary cholesterol by a diet rich in n-3 fatty acids in the rat.

Cholesterol and lipoprotein metabolism were investigated in a group of rats fed a fish oil-supplemented diet, a rich source of n-3 fatty acids. For comparison purposes, other groups of rats were fed either safflower oil (n-6 fatty acids) or coconut oil (saturated fatty acids). Diets were isocaloric and contained identical amounts of cholesterol. Rats fed fish oils for 2 weeks showed a 35% lower plasma cholesterol level than rats fed safflower oil, who in turn showed a 14% lower plasma cholesterol level than those fed coconut oil. The fall in plasma cholesterol level with fish oils was associated with significant falls in low density and high density lipoprotein cholesterol levels, but with no significant change in the ratio of low density to high density lipoprotein cholesterol. The fatty acid compositions of plasma, hepatic, and biliary lipids showed relative enrichment with n-3 fatty acids, reflecting the composition of the diet. The fish oil diet increased the basal secretion rate of cholesterol into bile, but the bile acid secretion rate remained unchanged. It is suggested that n-3 fatty acids reduce the plasma cholesterol level in rats by increasing the transfer of cholesterol into bile.