Predictors of long-term mortality in the elderly: the Dubbo Study.

BACKGROUND: This study examines the predictors of long-term all-causes mortality (ACM) in Australian senior citizens. METHODS: We have analysed ACM in a cohort of 2805 citizens, 1233 men and 1572 women aged ≥60 years, first examined in 1988 and followed for 20 years. Hazard ratios and 95% confidence intervals for ACM were obtained from Cox models employing conventional predictors. RESULTS: Over 20 years 66% of men (815/1233) and 53% of women (833/1572) died. Constant proportional hazard over the 20 years was demonstrated for all predictors, indicating similar relative hazard of ACM during long-term or short-term follow up. There was significant prediction of ACM by current smoking (hazard ratio 1.96, 95% confidence interval 1.57-2.43 in men; 1.67, 1.32-2.10 in women), high blood pressure (1.37, 1.03-1.81; 1.41, 1.07-1.86), diabetes (1.46, 1.17-1.82; 1.83, 1.43-2.34), impaired peak expiratory flow (1.39, 1.15-1.69; 1.80, 1.47-2.21), coronary heart disease at study entry in men (1.33, 1.13-1.57), physical disability (1.38, 1.13-1.68; 1.45, 1.17-1.79) and alcohol intake (0.82, 0.69-0.97; 0.77, 0.66-0.89 respectively). ACM was not significantly predicted by standard lipid parameters. Over the 20-year period smoking was associated with reduced survival of 41 months in men and 25 months in women, hypertension with reduced survival of 20 and 17 months, and diabetes with reduced survival of 24 and 30 months respectively. CONCLUSIONS: The findings confirm the contribution of cigarette smoking, hypertension and diabetes to ACM in senior citizens, conditions that are potentially amenable to intervention.

Cholesterol and other lipids predict coronary heart disease and ischaemic stroke in the elderly, but only in those below 70 years.

The prediction of coronary heart disease (CHD) and stroke by total and low density lipoprotein (LDL) cholesterol in older persons remains problematical. This study tests the hypothesis that cholesterol and other risk factors may be differentially predictive of CHD and ischaemic stroke in older persons when they are segregated into different age groups. CHD and ischaemic stroke outcomes were recorded during 129 months follow-up in a cohort of 2805 men and women of 60 years and older. There were 899 CHD events (32/100) and 326 stroke events (12/100). Using Cox proportional hazards, outcomes were modelled for the total cohort and for age groups 60-69, 70-79, and 80+ years. Total cholesterol, LDL cholesterol, serum apo-B, total cholesterol/high density lipoprotein (HDL) cholesterol and apo-B/apo-A1 were significant predictors of CHD in the total cohort, but significant only in the sub-group of 60-69 years. The respective hazard ratios (CI 95%) were 1.21 (1.09-1.35), 1.21 (1.09-1.35), 1.25 (1.13-1.39), 1.25 (1.14-1.37) and 1.21 (1.10-1.38). Similar findings were applicable with respect to ischaemic stroke in the age group of 60-69 years. Total cholesterol predicted CHD in men above a threshold value of 7.06 mmol/l and in women above 7.8 mmol/l, but with stroke the prediction was incremental. Other risk factors such as HDL cholesterol, triglycerides, lipoprotein(a), diabetes, hypertension and smoking predicted CHD, although only HDL and hypertension similarly predicted ischaemic stroke. The findings support a case for cholesterol testing in older subjects up to 70 years, in whom there is ancillary evidence of CHD and stroke prevention through treatment designed to reduce LDL cholesterol.

Molecular classification of estrogens.

Estrogens are involved in a multiplicity of programmed events in target tissues e.g.: uterus, breast, and pituitary gland, and hormone-responsive tumors occur at these target sites. We have addressed the possibility that all of the estrogens do not produce the same conformation of estrogen receptor alpha (ER). A novel assay in vitro was used to activate the transforming growth factor alpha (TGF-alpha) gene in situ in MDA-MB-231 cells stably transfected with cDNA for D351 ER or D351G ER. Three estrogen types were used: estradiol, diethylstilbestrol, and a triphenylethylene (TPE) derivative of tamoxifen without the antiestrogenic side chain. Computer molecular modeling was used to interpret data. A flat estrogen such as estradiol or diethylstilbestrol can induce TGF-alpha through a correctly positioned activating function 2 (AF2) and bind SRC-1. The TPE did not activate AF2 but activated the TGF-alpha gene through AF2b. This was demonstrated because D351 but not D351G ER activated the TGF-alpha gene with the TPE. We propose two classes of estrogens with different ER complexes that may incorporate different coactivators to function. Phytoestrogens and environmental xenoestrogens will fall into different classes based on structure and may exhibit selective actions and carcinogenic potential based on different ER conformations.

Moderate alcohol intake is associated with survival in the elderly: the Dubbo Study.

OBJECTIVE: To examine the relationship between alcohol intake and survival in elderly people. DESIGN AND SETTING: A prospective study over 116 months of non-institutionalised subjects living in Dubbo, a rural town (population, 34,000) in New South Wales. PARTICIPANTS: 1235 men and 1570 women aged 60 years and over who were first examined in 1988-89. MAIN OUTCOME MEASURES: All-causes mortality; gross cost of alcohol per life-year gained. RESULTS: Death occurred in 450 men and 392 women. Intake of alcohol was generally moderate (i.e., less than 14 drinks/week). Any intake of alcohol was associated with reduced mortality in men up to 75 years and in women over 64 years. In a proportional hazards model, the hazard ratio for mortality in men taking any alcohol was 0.63 (95% CI, 0.47-0.84) and in women was 0.75 (95% CI, 0.60-0.94). Cardiovascular deaths in men were reduced from 20/100 (95% CI, 14-26) to 11/100 (95% CI, 9-13) and in women from 16/100 (95% CI, 13-19) to 8/100 (95% CI, 6-10). The reduction in mortality occurred in men and women taking only 1-7 drinks/week--hazard ratios, 0.68 (95% CI, 0.49-0.94) and 0.78 (95% CI, 0.61-0.99), respectively, with a similar protective effect from intake of beer or other forms of alcohol. After almost 10 years' follow-up, men taking any alcohol lived on average 7.6 months longer, and women on average 2.7 months longer, compared with non-drinkers. The gross cost for alcohol per life-year gained if consuming 1-7 drinks/week was $5700 in men, and $19,000 in women. CONCLUSIONS: Moderate alcohol intake in the elderly appears to be associated with significantly longer survival in men 60-74 years and in all elderly women.

Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women.

Plant estrogen or phytoestrogens (PE) are increasingly consumed for the purposes of menopause symptom relief and prevention of cardiovascular and other diseases. The objective of this study was to evaluate the effects of PE on plasma lipids and lipoproteins and on endothelial function. Twenty healthy, postmenopausal women, 50 to 70 years old, and with evidence of endothelial dysfunction, were treated with a soybean PE tablet of 80 mg/day of isoflavones. Endothelial function was assessed noninvasively using brachial ultrasound. A double-blind, placebo-controlled, randomized crossover design was employed. After 3 weeks stabilization on a standard fat-reduced diet, subjects received PE or placebo for 8 weeks in random order, separated by a washout period of 8 weeks. Compared with placebo, there were no significant effects of PE on blood pressure and plasma lipid or lipoprotein concentrations. Flow-mediated endothelium-dependent dilation (FMD) in response to reactive hyperemia was not significantly changed by PE ingestion (3. 3 +/- 0.7% on placebo vs 4.1 +/- 0.7% on PE, p >0.4). Variation in FMD was not correlated with change in plasma isoflavone concentration (r = -0.09, p >0.7). Glyceryl trinitrate endothelium-independent dilation was not significantly changed with PE (15.9 +/- 1.3% vs 13.7 +/- 1.2%, p >0.1). These results fail to show a significant impact of medium-term supplementation with 80 mg/day of isoflavones on lipid and lipoprotein levels or on endothelial function in healthy, postmenopausal women.

Healthy ageing is associated with reduced and delayed disability.

OBJECTIVE: to identify subgroups within the population with reduced or delayed disability during healthy ageing. DESIGN: a longitudinal, community-based study. SETTING: Dubbo, New South Wales, Australia. PARTICIPANTS: 2805 men and women 60 years and older, first examined in 1988-89. OUTCOME MEASURES: activities of daily living assessed serially every 2 years over 8 years (scored in the range 0-6, least to most impaired); scores related to subsequent hospital admissions and to demographic, clinical and psychosocial characteristics at baseline. RESULTS: 1973 men and women provided complete follow-up data. Mean disability score at entry was low at 0.18 and increased to 0.69 by the final survey. Those having three or more hospital admissions (40% of the sample) had minimum disability (disability score approximately 0.3) around 5 years earlier than those with fewer admissions. Those with dementia or other mental illness had the most severe disability (mean disability scores of 3.15 and 2.13 respectively), but their numbers were very small. Those with a stroke or respiratory illness were more numerous and they had major physical disability (mean disability scores of 1.44 and 1.32 respectively). In a regression model, the statistically significant baseline predictors of disability at the final survey were age, body mass index, use of anti-hypertensive medication, history of stroke, depression score, peak expiratory flow and physical disability. CONCLUSIONS: the findings confirm reduced or delayed disability in older citizens requiring little or no hospitalization. Age, impaired peak expiratory flow and physical disability at study entry were most strongly predictive of disability, while stroke and respiratory illness were relatively common causes of severe disability.

Fasting plasma glucose in non-diabetic elderly women predicts increased all-causes mortality and coronary heart disease risk.

AIM: To confirm the hypothesis that upper normal plasma glucose levels in non-diabetic subjects are independently predictive of mortality and cardiovascular disease (CVD). METHODS: The study reports on 113 months' follow-up in a prospective study of CVD in the Australian elderly, The Dubbo Study. The cohort, first examined in 1988-89, consisted of 2805 men and women 60 years and older. Of the cohort, 2419 (86%) were defined as non-diabetic. The prediction of outcomes by quartile of fasting plasma glucose was examined in a Cox proportional hazards model, after linkage to hospital and death records. RESULTS: All-causes mortality increased progressively across quartile of fasting plasma glucose in both sexes, reaching statistical significance only in women. Coronary heart disease (CHD) incidence increased similarly, the increases being proportionately greater in women. Ischaemic stroke did not show a consistent gradient with fasting plasma glucose. After adjustment for age and other risk factors, all-causes mortality, CHD and ischaemic stroke incidence were not significantly related to plasma glucose in men. In women, all-causes mortality and CHD incidence showed a significant gradient with glucose quartile. Hazard Ratio (95% confidence intervals) for death in glucose Quartile IV (5.3-6.0 mmol/L) was 1.49 (1.03-2.14) and for CHD incidence was 1.52 (1.08-2.15). Subjects in the upper quartiles of fasting plasma glucose showed a clustering of overweight, hypertension, elevated serum triglycerides, reduced high density lipoprotein cholesterol and excess of small dense low density lipoprotein, suggestive of the Insulin Resistance Syndrome. CONCLUSION: Fasting plasma glucose levels in the upper normal range in non-diabetic elderly subjects appear to be associated with increased all-causes mortality and CHD, especially in women.

Choosing the most appropriate therapy for lipid disorders.

BACKGROUND: There is general acceptance of the need to treat hyperlipidaemia to reduce the risk of coronary artery disease. However, the level at which it is appropriate to introduce drug therapy varies with the cardiovascular risk of the patient. As the range of medications available increases, choosing the appropriate therapy for a patient becomes more difficult. OBJECTIVE: To provide the practitioner with a clear view of lipid treatment goals and how to select the most appropriate treatment. DISCUSSION: Diet is the cornerstone of treatment, with a discretionary use of drugs when hyperlipidaemia persists, particularly in those patients with unacceptably high cardiovascular risk. For a predominant cholesterol problem statin drugs are first choice, whereas fibrate drugs are most appropriate for hypertriglyceridaemia. For mixed hyperlipidaemia statin, fibrate or combinations may be required. Treatment is effective and safe but compliance with long term therapy remains a problem.

Vitamin E ingestion does not improve arterial endothelial dysfunction in older adults.

Endothelial dysfunction is thought to be an important early event in atherogenesis, related in part to reduced bioavailability of nitric oxide in the arterial wall. Endothelial function may be impaired in the presence of oxidised low density lipoprotein. The use of vitamin E as an anti-oxidant might enhance the bioavailability of nitric oxide in this situation. The effect of vitamin E 1000 IU/day on arterial endothelial physiology was studied in 20 asymptomatic older subjects, aged 45-70 years, who showed evidence of age-related endothelial dysfunction. Endothelial function was assessed non-invasively using brachial ultrasound and the primary outcome measure was flow-mediated endothelium-dependent dilatation (FMD) in response to reactive hyperaemia. A double-blind, placebo-controlled, randomised crossover design was employed. After 3 weeks of stabilisation on a standard fat-reduced diet, subjects received vitamin E or placebo for 10 weeks in random order, separated by a washout period of 8 weeks. There were no significant changes in blood pressure, plasma lipid or lipoprotein concentrations. Plasma alpha-tocopherol increased from 50+/-3 (mean+/-S.E.M.) to 91+/-6 micromol/l (P < 0.001) with vitamin E ingestion. Total plasma F2alpha-isoprostanes, a measure of free radical-induced lipid peroxidation, were not altered by vitamin E ingestion (0.86+/-0.26 versus 0.82+/-0.25 nmol/l, P > 0.6). FMD was not significantly different between the placebo and vitamin E periods (2.7+/-0.6% versus 2.4+/-0.4%). Variation in FMD was not correlated with change in plasma alpha-tocopherol (r = - 0.03, P > 0.8). The study was powered to detect a minimum change in FMD of 2%. Glyceryl trinitrate endothelium-independent dilatation was not significantly changed with vitamin E (13.7+/-1.3% versus 13.6+/-1.4%,). These results exclude a major impact of medium-term supplementation with vitamin E on arterial endothelial function when age-related dysfunction is already present.

Risk factors for ischemic stroke: Dubbo Study of the elderly.

BACKGROUND AND PURPOSE: One in 10 deaths in Australia is due to stroke. The predictors of ischemic stroke have not been well defined, although hypertension, atrial fibrillation, and previous stroke have been consistently reported. We report on 98 months' follow-up in a prospective study of cardiovascular disease in the Australian elderly, the Dubbo Study. METHODS: The cohort, first examined in 1988, was composed of 2805 men and women 60 years and older. The prediction of ischemic stroke by potential risk factors was examined in a Cox proportional hazards model, after linkage to hospital and death records. RESULTS: Three hundred six men and women manifested an ischemic stroke event (ICD-9-CM 433 to 437), and 95 subjects suffered a fatal stroke event. In the multivariate model, the significant independent predictors of stroke were advancing age, female sex (48% lower risk), being married (30% lower risk), prior history of stroke (227% higher risk), use of antihypertensive drugs (37% higher risk), belonging to the highest category of blood pressure reading (67% higher risk), presence of atrial fibrillation (58% higher risk), HDL cholesterol (36% lower risk for each 1-mmol/L increment), impaired peak expiratory flow (77% higher risk for tertile I than for tertile III), physical disability (59% higher risk), and depression score (41% higher risk for tertile III than for tertile I). CONCLUSIONS: These findings suggest that morbidity and mortality associated with ischemic stroke can be predicted by various clinical indicators, some of which may be amenable to intervention. The matters of impaired peak expiratory flow, depression score, and ischemic stroke require further study.

Comparison of atorvastatin alone versus simvastatin +/- cholestyramine in the management of severe primary hypercholesterolaemia (the six cities study).

BACKGROUND: Atorvastatin is a new member of the class of drugs which inhibit the enzyme Hydroxy-Methylglutaryl Co-A reductase, the rate limiting step in cholesterol biosynthesis. AIM: To compare the effects of atorvastatin alone versus simvastatin +/- low dose resin (i.e. versus standard care) on low density lipoprotein (LDL) cholesterol in severe primary hypercholesterolaemia. METHODS: An open, multi-centre, randomised study in patients previously stabilised on a cholesterol-lowering diet and simvastatin 40 mg daily, having LDL cholesterol > or = 5.0 mmol/L and triglycerides < 4.0 mmol/L. After five weeks washout, 92 were randomised to receive atorvastatin 10 mg and 44 to receive simvastatin 10 mg. The dose was doubled every six weeks if LDL cholesterol remained > or = 3.5 mmol/L. In accordance with manufacturers' recommendations, maximum dosage was atorvastatin 80 mg daily or simvastatin 40 mg daily (+cholestyramine 4 g daily in 84% of cases). Treatment was continued over 30 weeks. Lipids, lipoproteins, haematological and biochemical safety parameters were measured at regular intervals. Adverse events were monitored. RESULTS: Baseline LDL cholesterol was approximately 9 +/- 2 mmol/L (SD). After 30 weeks treatment serum cholesterol reduction was 42 +/- 10% on atorvastatin versus 32 +/- 13% on simvastatin +/- resin (p < 0.001), LDL cholesterol reduction 49 +/- 12% versus 38 +/- 14% (p < 0.001), and triglyceride reduction 33 +/- 20% versus 25 +/- 22% (p < 0.02). High density lipoprotein cholesterol increased by 7-10% on both treatments. The proportion of subjects achieving goal LDL cholesterol < 3.5 mmol/L was two to three times greater in those on atorvastatin compared with those on simvastatin +/- resin at each titration point. Six patients on simvastatin and one on atorvastatin were withdrawn. The drugs were generally well tolerated and the pattern of adverse events was similar with either treatment. CONCLUSIONS: Atorvastatin up to 80 mg daily appears to be an effective new treatment for the management of primary hypercholesterolaemia. It shows greater efficacy than simvastatin up to 40 mg daily +/- resin and has a similar safety profile.

Beneficial effect on average lipid levels from energy restriction and fat loss in obese individuals with or without type 2 diabetes.

OBJECTIVE: The risk of cardiovascular disease in type 2 diabetes is greater than is accounted for by conventional risk factors. We investigated whether energy restriction or modest fat loss improved the lipid profile in obese subjects with and without type 2 diabetes. The relationship of site of adipose tissue loss to lipid changes was also examined. RESEARCH DESIGN AND METHODS: Lipid levels were measured in 18 subjects with normal glucose tolerance (NGT) (n = 9, BMI = 31.5 +/- 0.8 [SEM] kg/m2) or type 2 diabetes (n = 9, BMI = 31.8 +/- 0.7) before and on the 4th (d4) and 28th (d28) days of a hypocaloric formula diet. Body composition was assessed with dual energy X-ray absorptiometry on d0 and d28. RESULTS: Mean daily energy intake during the diet was 1,100 +/- 60 kcal (33% protein, 38% carbohydrate, and 29% fat). Mean weight loss was 6.2 +/- 0.4 kg. Initial lipid profiles were similar in subjects with or without diabetes, and diabetes did not affect the responses. Dietary intervention resulted in early (d4) and late (d28) changes. Energy restriction (d4) reduced VLDL cholesterol and total triglyceride (TG) concentrations and increased LDL particle size. LDL TG, and LDL apolipoprotein B (apoB) concentrations. Reduction in central abdominal fat (but not other body fat) was correlated with a less atherogenic lipid profile: delta abdominal fat versus delta LDL free cholesterol, r = 0.65, P = 0.006 and versus delta apoB, r = 0.64, P = 0.008. CONCLUSIONS: Even in obese subjects with an average lipid profile, modest weight loss reduces atherogenicity, independently of type 2 diabetes, and abdominal fat loss is specifically related to such improvements.

Effects of atorvastatin monotherapy and simvastatin plus cholestyramine on arterial endothelial function in patients with severe primary hypercholesterolaemia.

Endothelial dysfunction is an important early event in atherogenesis. Changes in arterial endothelial physiology were studied in patients with severe primary hypercholesterolaemia participating in an ongoing clinical trial evaluating atorvastatin and simvastatin. Endothelial function was assessed non-invasively using brachial ultrasound and the primary outcome measure was flow-mediated endothelium-dependent dilatation (FMD) in response to reactive hyperaemia. Patients were studied upon entry while still using simvastatin 40 mg daily and again after a 10-week washout (baseline). Over the next 30 weeks, 20 patients received atorvastatin titrated up to 80 mg daily and 12 patients received simvastatin titrated up to 40 mg daily (plus cholestyramine 4 g daily in 10/12), followed by a final ultrasound study. During simvastatin washout, total and low density lipoprotein (LDL) cholesterol rose by a median 23-29% and 30-34%, respectively. During atorvastatin therapy, total and LDL cholesterol fell by a median of 41 and 46%, respectively, triglycerides fell by 45%, and high density lipoprotein (HDL) cholesterol rose by 10%. During simvastatin plus cholestyramine therapy, the respective median changes were - 32, - 39, - 44 and + 11%. Patients at baseline showed evidence of impaired FMD and this improved significantly on either treatment, from a median + 2.2 to + 5.5% on atorvastatin and from + 1.8 to + 4.5% on simvastatin plus cholestyramine (P < 0.01 for both treatments). Typical response in healthy subjects would be from + 8 to + 9%. FMD at baseline was correlated with HDL cholesterol (r=0.49, P < 0.01). Change in FMD was inversely correlated with baseline FMD (r=-0.54, P < 0.001). Endothelial dysfunction in primary hypercholesterolaemia was improved by treatment with atorvastatin or simvastatin plus cholestyramine and this effect may result in the prevention of future coronary events.