Lipoprotein(a) and the risk of recurrent coronary heart disease: the Dubbo Study.

OBJECTIVE: Elevated Lipoprotein(a) [Lp(a)] has not been firmly established as a risk factor for recurrent coronary heart disease (CHD). The present analysis explored this relationship in senior citizens. METHODS: This was a longitudinal study in 607 subjects, all with prevalent CHD, mean age 71 years, followed for 16 years. Baseline examinations of lipids and other CHD risk factors were conducted in 1988-89 in Dubbo, Australia. The independent contribution of Lp(a) to a further CHD event was examined in proportional hazards regression models. RESULTS: There were 399 incident CHD cases. Median Lp(a) in CHD cases was 130 mg/L (Interquartile range 60-315) and in non-cases 105 mg/L (45-250) (p < .07, U-Test). 26% of CHD cases and 19% of non-cases had Lp(a) 300 + mg/L; 18% of CHD cases and 8% of non-cases had Lp(a) 500 + mg/L. Lp(a) in Quintile 5 of its distribution (355 + mg/L), using Lp(a) Quintile 1 (<50mg/L) as reference, significantly predicted recurrent CHD with Hazard Ratio 1.53 (95% CI 1.11-2.11, p = .01). Prediction was independent of other risk factors. Lp(a) 500 + mg/L versus lower, significantly predicted recurrent CHD with Hazard Ratio 1.59 (1.16-2.17, p < .01). Prediction was similarly significant for Lp(a) 300 + mg/L versus lower, with Hazard Ratio 1.37 (1.09-1.73, p < .01). CONCLUSION: Elevated Lp(a) is an independent and significant predictor of recurrent CHD in senior citizens. Upper reference Lp(a) levels of 500 mg/L (≈125nmol/L) or 300 mg/L (≈75nmol/L) both appear to be appropriate. The clinical benefit of therapy to reduce elevated Lp(a) remains to be confirmed.

Lipoprotein(a) [Lp(a)], a type of "bad cholesterol", has been shown to be an important cause of coronary artery disease (CAD). In the long-term Dubbo Study of senior citizens in Australia, Professor Simons' team have previously shown that citizens with Lp(a) readings greater than 276 mg/L had a 46% greater chance of a first CAD problem (e.g. a heart attack) compared with those having much lower readings. This new study asked whether Lp(a) might also increase the chance of a second or repeat episode of CAD in citizens who had already manifested CAD. In 607 senior citizens with previous CAD followed for 16 years, those with Lp(a) readings greater than 355 mg/L had a 53% greater chance of manifesting another CAD problem compared with those having much lower readings. The team concluded that Lp(a) remains an important cause of repeat CAD in senior citizens. The benefit of emerging treatments to lower Lp(a) remains to be confirmed in ongoing research.

Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells.

Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudobipolar division. Here, we set out to prevent clustering of extra centrosomes. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP-dependent peri-centriolar material recruitment, and concurrently microtubule nucleation. Screening for compounds that perturb CPAP-tubulin interaction led to the identification of CCB02, which selectively binds at the CPAP binding site of tubulin. Genetic and chemical perturbation of CPAP-tubulin interaction activates extra centrosomes to nucleate enhanced numbers of microtubules prior to mitosis. This causes cells to undergo centrosome de-clustering, prolonged multipolar mitosis, and cell death. 3D-organotypic invasion assays reveal that CCB02 has broad anti-invasive activity in various cancer models, including tyrosine kinase inhibitor (TKI)-resistant EGFR-mutant non-small-cell lung cancers. Thus, we have identified a vulnerability of cancer cells to activation of extra centrosomes, which may serve as a global approach to target various tumors, including drug-resistant cancers exhibiting high incidence of centrosome amplification.

LDL-cholesterol Predicts a First CHD Event in Senior Citizens, Especially So in Those With Elevated Lipoprotein(a): Dubbo Study of the Elderly.

OBJECTIVE: The analysis was designed to explore the combined effects of LDL-cholesterol and lipoprotein(a) (Lp(a)) in predicting incident coronary heart disease (CHD) in senior citizens without prior CHD. METHODS: This is a prospective cohort study in Dubbo NSW which has followed 2805 men and women 60 years and older for 16 years since 1988-1989. Subjects with prior CHD (n=607) were excluded from this analysis. Incident CHD events were identified by hospital record linkage. The contributions of LDL and Lp(a) to CHD events and their combined effects were evaluated in proportional hazards regression models. RESULTS: There were 689 CHD events over 16 years in a cohort of 2198 men and women without prior CHD. LDL-cholesterol (corrected for cholesterol content of Lp(a)) and Lp(a) modelled in quartile categories each independently predicted CHD, but exclusively in Quartile 4 (Q4) for each parameter. Using the combination of LDL Q1 and Lp(a) Q1 as a reference group, LDL Q4 (>4.90mmol/L) most clearly predicted CHD in combination with Lp(a) Q4 (>276mg/L), hazard ratio 1.95 (95%CI 1.31-2.90). CONCLUSION: The present findings may have important practical implications in clinical management. If Lp(a) is assessed in senior citizens without prior CHD and found to be genuinely low, elevated LDL-cholesterol may not require active intervention.

Seasonality of cardiovascular risk factors: an analysis including over 230†000 participants in 15 countries.

OBJECTIVE: To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies. METHODS: Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed. RESULTS: In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m(2) for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol. CONCLUSIONS: CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.

Childbearing history and late-life mortality: the Dubbo study of Australian elderly.

OBJECTIVE: to examine the association of parity with mortality in later life. DESIGN: a longitudinal, community-based study. SETTING: semi-rural town of Dubbo, NSW, Australia. SUBJECTS: a total of 1,571 women and 1,233 men 60 years and older first examined in 1988-89. OUTCOME MEASURES: all-cause and cause-specific mortality rates analysed over 16-year follow-up. Hazard ratios obtained from proportional hazards models employing conventional predictors, potential confounders and measure of parity. RESULTS: increasing parity in women was weakly associated with overweight, diabetes and hypertension. All-cause mortality fell progressively with increasing parity in women (hazard ratio and 95% confidence intervals): childless, 1.00; 1 child, 1.03 (0.75-1.43); 2 children, 0.83 (0.61-1.11); 3 children, 0.80 (0.60-1.08); 4 children, 0.91 (0.66-1.25); 5 children, 0.70 (0.49-1.01); 6+ children, 0.60 (0.43-0.85) (trend for parity P<0.002). This result was similar whether or not hypertension, diabetes and overweight were included in multivariate models adjusting for social variables and other confounders. The reduction in all-cause mortality was accompanied by a parallel reduction in deaths from cancer and respiratory conditions, while coronary heart disease mortality increased 60-111% in all parous women. CONCLUSION: there was increased all-cause mortality in later life in childless women, accompanied by reduced mortality as parity increased. Underlying mechanisms are unclear but findings may have public health importance.

Is prediction of cardiovascular disease and all-cause mortality genuinely driven by the metabolic syndrome, and independently from its component variables? The Dubbo study.

BACKGROUND: The Metabolic Syndrome (MetS) predicts an increased risk of cardiovascular disease and all-cause mortality. Is this prediction genuinely driven by the syndrome and independently from its component variables? METHODS: A longitudinal cohort study in Dubbo, Australia of 2805 men and women ≥60 years followed for 16 years from 1988. Cox proportional hazards models were calculated for coronary heart disease (CHD), ischaemic stroke and all-cause mortality with MetS as an independent variable. Separate models included the MetS variable, with or without the presence of one of its five component variables. RESULTS: MetS was present in 33% of subjects. Obesity was present in 43% of those with MetS, high blood pressure in 99%, elevated triglycerides in 83%, low HDL-C in 75% and glycaemia in 48%. With respect to CHD and all-cause mortality, prediction by MetS was similar in the presence or absence of individual component factors (e.g. hazard ratio (95% CI) for CHD by MetS when low HDL-C present 1.60(1.39-1.84) and 1.67(1.37-2.04) when low HDL-C absent). With stroke, prediction by MetS was lost in the absence of elevated triglycerides or glycaemia factors (e.g. hazard ratio for stroke by MetS when glycaemia present 1.59(1.24-2.05) and 1.08(0.82-1.42) when glycaemia absent). CONCLUSIONS: The findings suggest that prediction of CHD and all-cause mortality is genuinely driven by the MetS and independently of its component variables. Prediction of ischaemic stroke is more complex, with some components providing prediction independently from the MetS.

A comparison of risk factors for coronary heart disease and ischaemic stroke: the Dubbo study of Australian elderly.

BACKGROUND: Conventional risk factors for coronary heart disease (CHD) and ischaemic stroke (IS) have been well documented. This study examines whether there is a unique pattern of risk factors for each disease. METHODS: This is a prospective cohort study in Dubbo NSW which has followed 2805 men and women 60 years and older for 16 years since 1988-1989. CHD and IS events were identified by hospital record linkage. The independent contributions of risk factors to these events were evaluated in proportional hazards regression models. RESULTS: CHD events (without stroke) occurred in 853 subjects (30.4/100). IS events (without CHD) occurred in 185 subjects (6.6/100). Some risk factors produced broadly similar prediction of CHD and IS events (male sex, current smoking, diabetes, LDL cholesterol, reduced peak expiratory flow, physical disability). Other factors potentially produced unique prediction of CHD (CHD at baseline, family history of CHD, HDL cholesterol, ApoB/ApoA1 ratio) or IS (stroke at baseline), or stronger prediction of IS compared with CHD (age, hypertension, atrial fibrillation). CONCLUSIONS: CHD and IS may each have some unique predictors, but treatable risk factors have been demonstrated for both cardiovascular outcomes.

Usefulness of fasting plasma glucose to predict mortality or coronary heart disease in persons > or = 60 years of age without diabetes mellitus or in those with undiagnosed diabetes mellitus (from The Dubbo Study).

The role of fasting plasma glucose (FPG) levels below diabetes "thresholds" in predicting mortality or coronary heart disease (CHD) is unclear. This study examines whether FPG predicts mortality or CHD in subjects without diabetes (historical or undiagnosed) or in those with undiagnosed diabetes (or lesser degrees of glucose intolerance). We have analyzed all-causes mortality and CHD incidence from a 16-year follow-up in a cohort of Australian senior citizens, 60 years and older, first examined in 1988-89. Diabetes was defined on historical grounds or by use of medication; undiagnosed diabetics were those without history but with FPG >124 mg/dl. Hazard ratio and 95% confidence intervals of the specified outcomes were obtained from Cox models, with FPG being entered as a continuous variable. Mortality and CHD incidence rates in subjects with previous cardiovascular disease (CVD) and diabetes were substantially higher than in nondiabetics, but CHD rates were disproportionately higher in diabetic women. FPG did not significantly predict any outcome in men in the absence of diabetes. In women, FPG was a significant predictor of death (hazard ratio = 1.30, 95% confidence interval 1.09 to 1.56) and CHD (hazard ratio 1.24, confidence interval 1.02 to 1.51) in the cohort, which included previous CVD but excluded all diabetes. In women with undiagnosed diabetes, FPG predicted death independently of previous CVD presence but did not predict CHD. In conclusion, FPG in the range of 95 to 108 mg/dl in a nondiabetic woman is still of prognostic importance for survival or CHD if she has previous CVD, whereas FPG is of prognostic importance for survival if she has undiagnosed diabetes. No similar findings were made in men.

Private lives and public programs: an Australian longitudinal study of the elderly.

Major late life events, reported in the Dubbo longitudinal study of older Australians, are used to examine the interaction of private lives with public programs. First, the data indicate strong supportive effects of publicly funded income, health, and aged care programs in reducing family burdens from major life changes. In particular, financial crises were rarely mentioned, directly or indirectly, as major threats. Next, the central role of informal social support in these events is demonstrated, first, as in previous studies, family support was responsive to risky events and to aging itself. Also, in new findings, one-third of surviving elderly respondents coped with the burdens of family crises as a substantial proportion of the "major" life changes that occurred over 13 years of the study. Within the security and support provided by the Australian welfare system, and with strong social networks, families with older persons in the Dubbo study manage multiple, major life changes. With rapid population aging, the development of more, and more easily accessible, services for a growing population of older people is a priority. The critical challenge will be to harmoniously grow public financing, private funding, and informal caregiving to deal with the growing burden arising from an aging society.

Delaying dementia and nursing home placement: the Dubbo study of elderly Australians over a 14-year follow-up.

In order to capture the "longevity dividend," modifiable risk factors for a diagnosis of dementia and nursing home placement were examined in a longitudinal study of an elderly cohort living in Dubbo, New South Wales, Australia. One thousand two-hundred thirty-three men and 1572 women 60 years and older living in the community were examined in 1988 and followed to 2002 for diagnosis of dementia and nursing home placement. There were 244 (8.7%) nursing home placements and 44% of these placements were primarily due to dementia, but dementia was a secondary diagnosis in another 20% of cases. In a proportional hazards model for dementia, any intake of alcohol predicted a 34% lower risk, and daily gardening a 36% lower risk. Daily walking predicted a 38% lower risk of dementia in men, but there was no significant prediction in women. The lowest tertile of peak expiratory flow predicted an 84% higher risk of dementia, the upper tertile of depression score predicted a 50% higher risk. The Cox proportional hazards model for nursing home placement, showed placement increased significantly with age, urinary incontinence, impaired peak expiratory flow, physical disability, and depression. The hazard of placement was significantly reduced by alcohol intake and female gender. Socioeconomic factors were not significant. Similar risk factors for dementia and nursing home placement indicate that the continuation of moderate alcohol intake, the maintenance of physical activity, especially daily gardening, and improvement of respiratory function, and the treatment of depression are recommended targets for interventions to delay or prevent major negative late-life experiences.

Does a diagnosis of the metabolic syndrome provide additional prediction of cardiovascular disease and total mortality in the elderly? The Dubbo Study.

OBJECTIVE: To assess whether a diagnosis of the metabolic syndrome (MetS) improves the prediction of cardiovascular disease or total mortality beyond that already provided by conventional risk factors. DESIGN AND SETTING: A longitudinal cohort study conducted in Dubbo, New South Wales. PARTICIPANTS: 2805 men and women aged 60 years and older living in the community, first assessed in 1988-1989 and followed for 16 years. MAIN OUTCOME MEASURES: Coronary heart disease (CHD) events, ischaemic stroke events, and total mortality. RESULTS: MetS was present in 31% of men and 34% of women. Crude CHD, ischaemic stroke, and total mortality rates were higher in the presence of MetS in men and women. In proportional hazards models that included conventional risk factors, but excluded variables used to define the presence of MetS, MetS was a significant predictor of CHD, stroke and total mortality. In men, the respective hazard ratios were 1.64 (95% CI, 1.37-1.96), 1.31 (95% CI, 0.97-1.77), and 1.53 (95% CI, 1.30-1.79). In women, the respective hazard ratios were 1.70 (95% CI, 1.43-2.02), 1.37 (95% CI, 1.04-1.82), and 1.35 (95% CI, 1.15-1.59). The use of MetS variables on an ordinal scale produced broadly similar conclusions. CONCLUSIONS: A diagnosis of MetS provides additional prediction of CHD events, stroke events, and total mortality beyond that provided by other conventional risk factors.

Lifestyle factors and risk of dementia: Dubbo Study of the elderly.

OBJECTIVE: To identify risk factors for dementia in an elderly Australian cohort. DESIGN AND SETTING: A longitudinal cohort study conducted in Dubbo, NSW. PARTICIPANTS: 2805 men and women aged 60 years and older living in the community and initially free of cognitive impairment, first assessed in 1988 and followed for 16 years. MAIN OUTCOME MEASURE: Admission to hospital or nursing home with any kind of dementia. RESULTS: There were 115 cases of dementia in 1233 men (9.3/100) and 170 cases in 1572 women (10.8/100). In a proportional hazards model for dementia, any intake of alcohol predicted a 34% lower risk, and daily gardening a 36% lower risk. Daily walking predicted a 38% lower risk of dementia in men, but there was no significant prediction in women. The lowest tertile of peak expiratory flow predicted an 84% higher risk of dementia, the upper tertile of depression score predicted a 50% higher risk. CONCLUSION: While excess alcohol intake is to be avoided, it appears safe and reasonable to recommend the continuation of moderate alcohol intake in those already imbibing, as well as the maintenance of physical activity, especially daily gardening, in the hope of reducing the incidence of dementia in future years.

Impact of smoking, diabetes and hypertension on survival time in the elderly: the Dubbo Study.

OBJECTIVE: To study the impact of various risk factors on survival time in a cohort of elderly Australians. DESIGN, SETTING AND PARTICIPANTS: A longitudinal, prospective cohort study conducted in Dubbo, NSW. Participants were men and women aged 60 years or over living in the community, first assessed in 1988-1989 and followed for 15 years. MAIN OUTCOME MEASURES: Mortality rates; risk factors; survival times. RESULTS: There were 668 deaths in 1233 men (54%) and 625 deaths in 1572 women (40%). Coronary heart disease was the major cause of death, rates being higher in men than women until age group 80+ years; stroke death rates were similar in both sexes; cancer and respiratory death rates were higher in men than women across all ages. In a proportional hazards model, the independent predictors of mortality were cigarette smoking, diabetes, very high blood pressure (BP), impaired peak expiratory flow (PEF), physical disability, and zero intake of alcohol. Over 15 years, the average reductions in survival time associated with various risk factors, in men and women respectively, were smoking, 22 and 15 months; diabetes, 18 and 18 months; very high BP, 16 and 9 months; impaired PEF, 14 and 17 months; physical disability, 16 and 12 months; zero alcohol intake, 9 and 5 months. Combinations of selected risk factors were associated with a multiplier effect. CONCLUSION: The reduction in survival time in elderly citizens demonstrated in the presence of smoking, diabetes and hypertension highlights a potential benefit to healthy ageing to be gained from prevention and intervention.

Risk functions for prediction of cardiovascular disease in elderly Australians: the Dubbo Study.

OBJECTIVES: To evaluate a Framingham risk function for coronary heart disease in an elderly Australian cohort and to derive a risk function for cardiovascular disease (CVD) in elderly Australians. DESIGN AND SETTING: Analysis of data from a prospective cohort study (the Dubbo Study) in a semi-urban town (population, 34 000). PARTICIPANTS: 2805 men and women 60 years and older living in the community, first assessed in 1988, and a subcohort of 2102 free of CVD at study entry. MAIN OUTCOME MEASURES: Incidence of CVD (myocardial infarction, coronary death or stroke) over 5 and 10 years. RESULTS: A Framingham risk function assessing "hard" coronary heart disease (ie, myocardial infarction or coronary death) accurately predicted 10-year incidence in men and women aged 60-79 years who were free of prevalent CVD or diabetes at study entry. In a multiple logistic model, CVD incidence was significantly predicted by age, sex, taking antihypertensive medication, blood pressure, smoking, total cholesterol level and diabetes. For a given age and cholesterol level, CVD risk over 5 years was doubled in the presence of antihypertensive medication or diabetes, increased by 50% with cigarette smoking, and halved in women compared with men. CONCLUSIONS: We have derived a simple CVD risk function specifically for elderly Australians that employs risk factors readily accessible to all medical practitioners.

Vascular risk to late-life depression: evidence from a longitudinal community study.

OBJECTIVE: To determine prospectively relationships between minor cerebrovascular episodes and depressive symptoms in a community cohort of older persons. METHOD: In 1988-1989, baseline measurements of vascular risk factors and depressive symptoms were obtained in older community residents (mean age = 67). At 10-year follow-up, three subgroups of subjects still residing in the community were re-assessed: those who had suffered a transient ischaemic attack (TIA) (n = 16) in the intervening period; those with hypertension but no TIAs (n = 38); and, those with neither TIAs nor hypertension (n = 40). RESULTS: Of the 16 persons with depressive symptoms at 10-year follow-up, only three had reported depressive symptoms initially. Subjects who had experienced TIAs during the longitudinal phase had higher rates of depressive symptoms than the subjects from the other two groups (38%vs 13%, p < 0.05). CONCLUSIONS: This study supports the notion that cerebrovascular incidents predispose to late-onset depression in older persons residing in the community. Intrinsically, this provides epidemiological support for the validity of the concept of 'vascular depression'.