Excessive range of statin dose in Western Australian primary care.

BACKGROUND: Statins are very effective in reducing coronary disease and ischaemic stroke but guidelines although evolving have not been clear on statin dose. AIM: To audit and review community statin prescribing. METHODS: A retrospective audit of the type and dose of statin dispensed was undertaken at five pharmacies in and around Perth, the capital city of Western Australia. Patients were de-identified. RESULTS: Statins made up 6.5% of all prescriptions. Statin dose when adjusted for different potency effectively varied 64-fold between patients. Rosuvastatin and atorvastatin accounted for 79% of prescriptions, at a mean dose of 10 times the effective dose 50. CONCLUSION: The extraordinarily wide variation in statin dose is at odds with the more consistent doses of other drugs used in the management of arterial disease. Unnecessarily high statin dosing increases side-effects and may not improve clinical outcomes appreciably. Rational prescribing of statins based on the pharmacodynamic evidence, with lower doses in most patients, combined with close attention to reduction of smoking, blood pressure and weight, is likely to reduce arterial disease most efficiently and safely.

Low density lipoprotein composition and oxidizability in coronary disease--apparent favourable effect of beta blockers.

The oxidative modification of LDL in vivo may have an important role in atherogenesis. To determine whether LDL fatty acid, anti-oxidant composition and sensitivity to oxidation in vitro is different in subjects with established atherosclerosis we compared 20 men with angiogram proven coronary disease with 25 controls without clinical evidence of arterial disease. LDL-cholesterol, total triglycerides and LDL fatty acid composition did not differ significantly between the groups. LDL oxidation lag time and oxidation rate in coronary patients (132 min, 0.02 absorbance units/min) and controls (140, 0.017) were not significantly different. However coronary disease subjects taking beta-blockers had evidence for reduced LDL oxidizability (lag time 148 +/- 7 min; oxidation rate 0.017 +/- 0.002 abs units/min) compared with those not on beta-blockers (lag time 114 +/- 7 min, rate 0.025 +/- 0.003, P < 0.005). LDL beta-carotene was significantly lower in coronary patients (0.92 mumol/mmol LDL cholesterol; controls 1.58; P = 0.001). LDL alpha-tocopherol appeared lower in coronary patients (2.8 mumol/mmol LDL cholesterol; controls 3.3; P = 0.056) and was significantly lower in smokers (2.56; non-smokers 3.24; P = 0.04). LDL oxidation rate was negatively correlated with LDL alpha-tocopherol (r = -0.51, P = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

A controlled trial of the effects of pattern of alcohol intake on serum lipid levels in regular drinkers.

To determine whether the effects of drinking pattern (predominantly weekend versus daily drinking) have differential effects on serum lipids, 55 healthy male drinkers were recruited on the basis of a regular alcohol intake, 210-500 ml absolute alcohol/week (approximately 3-6 standard drinks/day), with more than 60% consumed as beer. Fourteen subjects were categorised as predominantly weekend drinkers, while 41 subjects regularly drank on a daily basis. After maintenance of their drinking pattern during a 4-week familiarisation, subjects were randomised to either consume low alcohol beer (0.9%, v/v) only, or to maintain their usual drinking habit consuming full-strength beer (5%, v/v) for the next 4 weeks. They then switched to full-strength or low alcohol beer, respectively, for a further 4 weeks. Their drinking pattern remained constant during the study. In both weekend and daily drinkers, a reduction in alcohol intake (i.e. from 387 ml/week to 88 ml/week for weekend drinkers and from 418 ml/week to 95 ml/week for daily drinkers, respectively, P < 0.001) resulted in a similar 0.12 mmol/l fall in HDL-C (P < 0.01) with a concomitant significant fall in both apolipoproteins A-I and A-II. In daily drinkers total cholesterol fell by 0.28 mmol/l (P < 0.001) and triglyceride by 0.22 mmol/l (P < 0.01) with a reduction in alcohol intake, but no change in LDL-C was seen. In contrast, weekend drinkers total cholesterol was unchanged while triglyceride decreased by 0.26 mmol/l (P < 0.05) and LDL-C increased by 0.25 mmol/l (P < 0.01). Lp(a) increased with a reduction in alcohol intake in both daily (9.1 U/l, P < 0.05) and weekend drinkers (27.6 U/l, P = 0.07). Previous reports of a more atherogenic lipid profile with episodic versus regular daily drinking were not confirmed in this study and potentially favourable effects of alcohol to increase HDL-C and decrease Lp(a) were shown to be independent of drinking pattern in these moderate to heavy drinkers.

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test.

Chylomicron remnant metabolism was studied using a stable isotope breath test in 25 patients with familial hypercholesterolaemia (FH) (10 homozygotes, 15 heterozygotes), and in 15 normolipidaemic controls. A lipid emulsion mimicking the composition of chylomicron remnants and labelled with cholesteryl (13)C-oleate was injected intravenously; (13)CO(2) was measured subsequently in breath using isotope-ratio mass spectrometry. The fractional catabolic rate (pools/h) of the emulsion, derived from a compartmental model, did not differ significantly among the groups: homozygous FH mean 0.20 (S.E.M. 0.05), heterozygous FH 0.12 (0.02), controls 0.16 (0.03). We suggest that the catabolism of chylomicron remnants from plasma is not impaired in FH and that the hepatic uptake of these particles is not dependent on functional LDL receptors.

Influence of pattern of alcohol intake on blood pressure in regular drinkers: a controlled trial.

OBJECTIVE: To evaluate the effects of patterns of drinking (weekend versus daily drinking) on the pressor responses to alcohol in 55 male drinkers using clinic and 24 h ambulatory blood pressure monitoring. DESIGN: A randomized, controlled cross-over trial. METHODS: Recruitment required a regular alcohol intake of 210-500 ml absolute alcohol/week, with > 60% consumed as beer. Fourteen subjects were categorized as predominantly weekend drinkers, whereas the remaining 41 subjects regularly drank on a daily basis. After 4 weeks of familiarization, all subjects were randomly allocated to drinking low-alcohol beer (0.9% vol:vol) only or to maintain their usual drinking habits with provision of full-strength beer (5% vol:vol) for 4 weeks. They then switched back to their usual drinking habits or low-alcohol beer, respectively, for a further 4 weeks while maintaining their usual drinking pattern. RESULTS: Baseline ambulatory systolic blood pressure in weekend but not in daily drinkers was 2.4 mmHg higher on Monday than it was on Thursday (P = 0.02). This Monday-Thursday difference was lost during intervention. When subjects switched from the high-alcohol to the low-alcohol period the falls in ambulatory systolic blood pressure in weekend (3.1 mmHg, P < 0.001) and daily drinkers (2.2 mmHg, P < 0.001) were similar. Most of the fall was evident during week 1 of the low-alcohol period for weekend drinkers but not until week 4 for daily drinkers. CONCLUSION: The pressor response to alcohol consumption is similar in magnitude in weekend and daily drinkers, present throughout a 24 h period and has a rapid onset/offset in weekend drinkers but is more sustained in daily drinkers.

Ovarian venous blood flow in non-pregnant and pregnant rats.

A modified venous outflow technique was used to measure ovarian blood flow in the rat. The rate of flow through the right ovary was 0-198+/-0-009 (S.E.M.), 0-476+/-0-076 and 0-958+/-0-162 ml/min in six Day 0 (dioestrous), five Day 16 and six Day 22 pregnant rats respectively. The intravenous administration of 50 i.u. human chorionic gonadotrophin increased ovarian blood flow by 26+/-4, 57+/-19 and 46+/-9% respectively, from 2 to 8 min after the injection. The present ovarian venous outflow results are substantially higher than those previously reported in the rat but agree with values determined with radioactive microspheres.

Progesterone secretion and ovarian blood flow in the pregnant rat.

A venous outflow technique was used to monitor the rates of ovarian blood flow and progesterone secretion simultaneously during periods of 2-3 h in nine rats pregnant for 16 days and anaesthetized with sodium pentobarbitone. The rate of ovarian blood flow was 0 x 460 +/- 0 x 135 (S.D.) ml/min and that of progesterone secretioin was 27 x 2 +/- 7 x 0 microgram/h per ovary. Within rats, progesterone secretion was unrelated to the rate of ovarian blood flow (common correlation coefficient, r = 0 x 136; degrees of freedom = 61; P, not significant) but the latter was inversely related to the arterio-venous difference in the concentratioin of progesterone (r = --0 x 731; P < 0 x 01).

Influence of pattern of drinking on cardiovascular disease and cardiovascular risk factors--a review.

There is an established inverse relationship between the regular light consumption of alcohol (5-10 g/day) and the incidence of coronary artery disease (CAD). This association has several biologically plausible mechanisms with dose-dependent effects of alcohol to increase HDL cholesterol, lower plasma fibrinogen and inhibit platelet aggregation. However, such a protective effect against atheroma cannot be considered in isolation from known adverse effects on blood pressure and triglycerides or possible detrimental effects of episodic or binge drinking on several other cardiovascular end-points and risk factors. In subjects with pre-existing CAD, an alcoholic binge can increase both silent myocardial ischaemia and angina. During withdrawal following binge drinking, marked fluctuations in blood pressure together with heightened platelet activation and adverse changes in the balance of fibrinolytic factors, may offer an explanation for the reported association between episodic heavy drinking and ischaemic stroke. This has been seen particularly in young males and extends further to an increase in both subarachnoid haemorrhage and intracerebral haemorrhage after binge drinking. Intervention studies in man have shown acute increases in blood pressure in men who drink predominantly at weekends, compared to longer-term pressor effects in regular daily drinkers. We have been unable, however, to reproduce the finding of unfavourable effects of binge drinking on the lipid profile that have been reported in animal studies and man. Binge drinking may also induce cerebrovascular spasm or cause both ventricular and supraventricular arrhythmias, especially atrial fibrillation. Alcohol-induced arrhythmia has been postulated as the basis for alcohol-related sudden coronary death in those subjects with pre-existing CAD. Hence, further exploration of any protective association of alcohol against CAD needs to carefully consider the implications of pattern of drinking for the relationship. The modulating influences of co-timing of drinking with meals, cigarette smoking or illicit drug use also need to be evaluated. Without such vital information, public health advice on alcohol and CAD will be limited in its scope and potentially flawed in its impact.

Urine albumin excretion in healthy subjects.

The relationship between cardiovascular risk factors and urine albumin excretion were studied in 474 healthy office workers. Albumin concentration was measured fresh in first morning midstream urines. Lifestyle details, oscillometric BP and lipids were assessed. Subjects with urine albumin concentration above the median (5.30 mg/l) were compared with those with albumin concentration below the median. Subjects with above median urinary albumin concentration had higher systolic blood pressure (mean 115.2 vs. 113.1 mm Hg for above median, respectively, P = 0.06), were more likely to be male (56.8 vs. 45.0%, respectively, P = 0.01) and to have lower levels of high density lipoprotein (HDL)-cholesterol (mean 1.34 vs. 1.41 mmol/l, P = 0.006). Multivariate analysis following adjustment for urine creatinine concentration to allow for urine volume confirmed the relationship with systolic blood pressure (P = 0.01) and sex (P = 0.02), and in addition revealed a relationship with alcohol intake approaching significance (mean intake 70.8 and 76.0 g/week, respectively, P = 0.06). The univariate finding of increased albuminuria with lower HDL-cholesterol appeared to be attributable to the associated relationships with male sex and lower alcohol intake. The relationships between albumin excretion and BP, male sex and alcohol intake may reflect the effects of asymptomatic developing arterial disease. The relationship with BP may also be a consequence of effects on glomerular hydrostatic or interstitial renal pressure on albumin filtration or resorption. Very low level urine albumin excretion in healthy subjects is associated with factors which predict arterial disease. Urine albumin excretion may prove to be a useful early marker of cardiovascular disease in population studies.

The effects of alcohol on coagulation and fibrinolytic factors: a controlled trial.

Light-to-moderate alcohol intake is associated with a reduced incidence of ischaemic cardiovascular events, whilst heavy alcohol intake can predispose individuals to stroke. Alcohol-induced changes in coagulation and fibrinolysis may be relevant and are the subject of this controlled trial of varying alcohol intake in 55 predominantly beer-drinking men. Following 4 weeks stabilization maintaining usual drinking habits, participants were randomized to either continue usual alcohol intake or to restrict alcohol by changing to low alcohol beer for 4 weeks. In a final 4 week period, they crossed over to low or usual alcohol intake, respectively. Comparing combined low and usual alcohol periods, an increase in mean weekly alcohol intake from 92 to 410 ml (mean daily intake from 13 to 58 ml) was associated with a decrease in plasma fibrinogen (by 11%, P < 0.001) and platelet count (3%, P < 0.05), but increases in factor VII (7%, P = 0.001), tissue plasminogen activator (tPA; 16%, P = 0.01) and plasminogen activator inhibitor-1 (PAI-1; 21%, P < 0.001). The ratio, tPA/PAI-1, fell from 0.50 to 0.44 (P = 0.02) confirming the relatively greater increase in PAI-1 with alcohol consumption. Two lipid-associated natural anticoagulants, tissue factor pathway inhibitor and beta 2-glycoprotein-I, did not change. The substantial reduction in plasma fibrinogen with alcohol intake may well contribute to the apparent protection alcohol confers against ischaemic coronary and cerebral events. The increase in factor VII and relatively greater increase in PAI-1 than tPA with alcohol intake may attenuate this benefit and indeed may sufficiently predispose individuals to thrombosis to contribute to the increased incidence of ischaemic stroke seen in heavier drinkers. The balance of anticoagulant and procoagulant and fibrinolytic effects in any individual may vary depending on quantity and type of alcoholic beverage ingested, as well as on genetic and other variables, all of which merit further study.

Recent insights into dietary fats and cardiovascular disease.

1. Fat deposition in the arterial intima is fundamental to the atheroma process. Circulating lipoproteins are thought to be the source of much of the deposited fat. The interplay of dietary fat has not been fully clarified. 2. Observational studies have furnished evidence of relationships between the different dietary fats and clinical cardiovascular events. In these, total fat and in particular, saturated fat appear culprit. Mono-unsaturated (MUFA) and poly-unsaturated (PUFA) fats have less consistent relationships with cardiovascular disease, though all classes of fatty acid are found in atheroma. 3. Comparing the effects on lipoproteins of saturates, mono-unsaturates and polyunsaturates, they all increase high density lipoproteins (HDL) and reduce triglycerides when substituted isocalorically for carbohydrate. Saturates increase low density lipoproteins (LDL), while PUFA > MUFA reduce LDL. 4. Upon oxidative modification, lipoproteins are more liable to arterial deposition and, in vitro at least, LDL oxidizability is enhanced by enrichment with PUFA. 5. Trans-MUFA have some unique properties in that they somewhat resemble saturates and seem to predispose to coronary disease, quite possibly because of their adverse effects on LDL, HDL and Lp(a) levels. 6. omega-3 fatty acids seem unique among the dietary fats in that they inhibit thrombosis and platelet aggregation, and can lower blood pressure. 7. The net effect of these various potential influences of fatty acids on atherogenesis in vivo is unclear. It may well be that all fats, with the exception of the omega-3 class, are detrimental with response to atherogenesis. Modification of the diet, with particular attention to fat, has been demonstrated to reduce clinical coronary events in several studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum HDL cholesterol: should it be routinely measured?

HDL cholesterol is only one of many risk factors which can be used to predict coronary disease events, and the relationship between the benefits of lipid-lowering strategies and changes in HDL levels is, at present quite unclear.

Fibrates, dyslipoproteinaemia and cardiovascular disease.

Recent epidemiological data have reaffirmed that elevated plasma triglyceride and low HDL-cholesterol levels are important risk factors for atherosclerotic vascular disease. The rationale for the clinical use of fibric acid derivatives, which are designed to correct this metabolic nexus, is now on firmer ground. The mechanism of action of fibrates on lipoprotein metabolism has recently been elucidated at the molecular level and involves the activation of peroxisome proliferator-activated receptor-alpha 1 in the liver, with the net effect of improving the plasma transport rates of several lipoproteins. Other potential anti-atherothrombotic effects include the inhibition of coagulation and enhancement of fibrinolysis, as well as the inhibition of inflammatory mediators involved in atherogenesis. These consequences probably underpin the favourable effects of fibrates seen in recent angiographic and clinical trials. Two important clinical trials on the effect of gemfibrozil (Veterans Administration-HDL-Cholesterol Intervention Trial) and bezafibrate (Bezafibrate Infarction Prevention Study) have recently been completed in subjects with elevated triglyceride, low HDL and normal or near-normal LDL-cholesterol levels. The results testify to the efficacy of these agents in decreasing the incidence of cardiovascular events, particularly in patients with multiple risk factors and plasma triglyceride levels of over 2.2 mmol/l. The findings of these trials are compared with the statin-based Air Force/Texas Coronary Atherosclerosis Prevention Study, with a recommendation that future studies in appropriately selected patients should examine the synergistic effect of the fibrate/statin combination. The absolute risk reduction in the incidence of coronary events in the Veterans Administration-HDL-Cholesterol Intervention Trial compares favourably with the statin trials. The therapeutic aspects of the efficacy and safety of fibrates are reviewed. Besides primary mixed hyperlipidaemias, particular indications for the clinical use of fibrates include type 2 diabetes, the metabolic syndrome and renal insufficiency. The St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study has suggested that fibrates may decrease the incidence of coronary events in type 2 diabetes, but this hypothesis will be more extensively tested in the Diabetes Atherosclerosis Intervention Study, Fenofibrate in Event Lowering in Diabetes Study and Lipids in Diabetes Study projects. Although significant new knowledge has accrued over the past few years concerning the fundamental and clinical aspects of fibrates, the success of these agents in clinical practice depends on the availability of methods for assessing cardiovascular risk as well as on treatment guidelines, which as presently designed and recommended may be inaccurate and suboptimal.

Chlamydial endocarditis.

Echocardiographic diagnosis of a case of endocarditis, subsequently proven to be due to a chlamydial organism, is described. Early echocardiographic diagnosis guided initial medical management and directed urgent surgical intervention when the patient deteriorated. Reported cases of chlamydial endocarditis are reviewed.

Verapamil withdrawal as a possible cause of myocardial infarction in a hypertensive woman with a normal coronary angiogram.

Verapamil is an effective and relatively-safe antihypertensive drug. Serious adverse effects are uncommon and mainly have been related to the depression of cardiac contractility and conduction, especially when the drug is combined with beta-blocking agents. We report a case in which myocardial infarction coincided with the introduction of captopril and the withdrawal of verapamil in a previously asymptomatic woman with severe hypertension. Possible mechanisms that involve a verapamil-related increase in platelet and/or vascular alpha 2-adrenoreceptor affinity for catecholamines are discussed.

Non-diabetic microalbuminuria in clinical practice and its relationship to posture, exercise and blood pressure.

1. The effects of posture and exercise on the relationship between low-level urinary albumin excretion (microalbuminuria) and blood pressure was investigated in two groups of non-diabetic patients at increased cardiovascular risk: 21 otherwise healthy patients with untreated essential hypertension (blood pressure greater than 160/90 mmHg), and 14 age-matched patients with blood pressure at presentation within the normotensive range (less than 160/90 mmHg) attending a cardiovascular clinic for assessment of chest pain. 2. A significant linear relationship between logarithmically transformed 'spot' urinary albumin/creatinine ratio and simultaneous clinic blood pressure existed when data from both groups of patients were analysed (r = 0.58, P less than 0.05). The relationship between the scatter plot of blood pressure and the albumin/creatinine ratio appeared most marked when the mean blood pressure exceeded 120 mmHg. 3. In patients with essential hypertension, clinic systolic blood pressure was related to the albumin/creatinine ratio in simultaneous 'spot' urine samples (r = 0.69, P less than 0.05) and also to the albumin/creatinine ratio in early-morning urine samples (r = 0.51, P less than 0.05). However, the relationship between clinic blood pressure and simultaneous 'spot' urinary albumin/creatinine ratio in the patients with chest pain did not achieve significance when analysed independently. 4. Hourly averaged ambulatory intra-arterial blood pressure was recorded in four of the patients with essential hypertension during normal daytime activity, and a significant correlation with the simultaneous hourly daytime urinary albumin/creatinine ratio was found (r = 0.65, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of beta-blockers on the concentration and oxidizability of plasma lipids.

1. beta-blockers improve morbidity and mortality after myocardial infarction, probably by several mechanisms. We investigated potentially relevant effects of beta-blockers in vivo and in vitro on plasma lipid oxidizability. Forty-two healthy men were randomized to receive placebo (13), metoprolol (14) or propranolol (15). 2. At 4 weeks, the effects on heart rate, blood pressure and lipids appeared similar and subjects taking a beta-blocker were combined. Compared with placebo, those on a beta-blocker gained 0.5 kg in weight (P = 0.04), heart rate fell from 63 to 52 beats/min (P < 0.0001) and blood pressure fell from 116/74 to 113/69 mmHg (P < 0.005); high-density lipoprotein (HDL)-cholesterol fell from 1.26 to 1.11 mmol/l (P = 0.005), there being no change in the ratio of free to esterified cholesterol in HDL, and there was an apparent rise in serum triacylglycerols from 1.18 to 1.43 mmol/l (P = 0.15 when adjusted for weight gain). Low-density lipoprotein (LDL)-cholesterol and lipoprotein (a) did not change. In this study, the oxidizability of LDL was unaffected by beta-blocker therapy. beta-blockade was not associated with any change in LDL fatty acid profile, or beta-carotene or alpha-tocopherol content which might account for the reduced LDL oxidizability previously reported in patients treated with beta-blockers. Furthermore, neither atenolol nor propranolol, at concentrations up to 100 mumol/l, had any effect on in vitro oxidizability of LDL obtained from healthy volunteers. 3. In contrast to the favourable haemodynamic effects conferred by beta-blockers, the effects on weight and serum triacylglycerols and HDL-cholesterol appear to be adverse and we did not demonstrate any changes in lipid oxidizability which might be relevant to the protective effects of beta-blockers in patients with coronary disease.