Moderate Alcohol Intake and Risk of Functional Decline: The Health, Aging, and Body Composition Study

OBJECTIVES: To investigate the prospective relationship between alcohol consumption and incident mobility limitation. DESIGN: Cohort study. SETTING: The Health Aging and Body Composition study, conducted in Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Three thousand sixty‐one adults aged 70 to 79 without mobility disability at baseline. MEASUREMENTS: Incidence of mobility limitation, defined as self‐report at two consecutive semiannual interviews of any difficulty walking one‐quarter of a mile or climbing stairs, and incidence of mobility disability, defined as severe difficulty or inability to perform these tasks at two consecutive reports. Alcohol intake, lifestyle‐related variables, diseases, and health status indicators were assessed at baseline. RESULTS: During a follow‐up time of 6.5 years, participants consuming moderate levels of alcohol had the lowest incidence of mobility limitation (total: 6.4 per 100 person‐years (person‐years); men: 6.4 per 100 person‐years; women: 7.3 per 100 person‐years) and mobility disability (total: 2.7 per 100 person‐years; men: 2.5 per 100 person‐years; women: 2.9 per 100 person‐years). Adjusting for demographic characteristics, moderate alcohol intake was associated with lower risk of mobility limitation (hazard ratio (HR)=0.70, 95% confidence interval (CI)=0.55–0.89) and mobility disability (HR=0.66, 95% CI=0.45–0.95) than never or occasional consumption. Additional adjustment for lifestyle‐related variables substantially reduced the strength of the associations (HR=0.85, 95% CI=0.66–1.08 and HR=0.81, 95% CI=0.56–1.18, respectively). Adjustment for diseases and health status indicators did not affect the strength of the associations, suggesting that lifestyle is most important in confounding this relationship. CONCLUSION: Lifestyle‐related characteristics mainly accounted for the association between moderate alcohol intake and lower risk of functional decline over time. These findings do not support a direct causal effect of alcohol intake on physical function.     

High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study

Aim: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. Methods: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) ＜120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months–at baseline) and (absolute difference/baseline)×100, respectively. Results: During a median follow-up period of 4.0 (IQR 3.2–4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91–1.08, HR 1.03, 95% CI 0.94–1.12, HR 1.05, 95% CI 0.98–1.12, and HR 1.08, 95% CI 0.94–1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. Conclusions: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.     

Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial

BackgroundData on PCSK9 inhibition in chronic kidney disease (CKD) is limited.ObjectivesThe purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function.MethodsThe FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or non–high-density lipoprotein cholesterol ≥100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate.ResultsThere were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with ≥stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio [HR]: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage ≥3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); p_int = 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (p_int = 0.75)—preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage ≥3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were −2.5% (95% CI: -4.7% to -0.4%) for stage ≥3 CKD compared with −1.7% (95% CI: -2.8% to 0.5%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage.ConclusionsLDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633)     

Chronic kidney disease and functional limitation in older people: health, aging and body composition study

OBJECTIVES: To assess whether chronic kidney disease (CKD) is independently associated with incident physical-function limitation. DESIGN: Prospective cohort study. SETTING: Two sites: Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Two thousand one hundred thirty-five men and women aged 70 to 79 without functional limitation at baseline from the Health, Aging and Body Composition Study. MEASUREMENTS: Functional limitation was defined as difficulty in walking one-quarter of a mile or climbing 10 steps on two consecutive reports 6 months apart (in the same function). Kidney function was measured using serum cystatin C. Estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula (<60 versus > or =60 mL/min per 1.73 m(2)), was a secondary predictor. Muscle strength, lean body mass according to dual energy x-ray absorptiometry, comorbidity, medication use, and inflammatory markers were evaluated as covariates. RESULTS: Persons in the highest (> or =1.13 mg/L) quartile of cystatin C experienced a significantly higher risk of developing functional limitation than those in the lowest (<0.86 mg/L) quartile (hazard ratio (HR)=1.70, 95% confidence interval (CI)=1.40-2.07). The association between the fourth cystatin C quartile and functional limitation remained after adjustment for demographics, lean body mass, comorbidity, muscle strength, and gait speed (HR=1.41, 95% CI=1.13-1.75), although the association was attenuated after adjustment for markers of inflammation (HR=1.15, 95% CI=0.90-1.46). Similar results were found for eGFR less than 60 mL/min per 1.73 m(2), although the association with functional limitation remained after adjustment for inflammatory markers (HR=1.30, 95% CI=1.08-1.56). CONCLUSION: CKD is associated with the development of functional impairment independent of comorbidity, body composition, and tests of strength and physical performance. The mechanism may be related to a heightened inflammatory state in CKD.     

Benzodiazepine use and physical disability in community-dwelling older adults

OBJECTIVES: To determine whether benzodiazepine use is associated with incident disability in mobility and activities of daily living (ADLs) in older individuals. DESIGN: A prospective cohort study. SETTING: Four sites of the Established Populations for Epidemiologic Studies of the Elderly. PARTICIPANTS: This study included 9,093 subjects (aged > or =65) who were not disabled in mobility or ADLs at baseline. MEASUREMENTS: Mobility disability was defined as inability to walk half a mile or climb one flight of stairs. ADL disability was defined as inability to perform one or more basic ADLs (bathing, eating, dressing, transferring from a bed to a chair, using the toilet, or walking across a small room). Trained interviewers assessed outcomes annually. RESULTS: At baseline, 5.5% of subjects reported benzodiazepine use. In multivariable models, benzodiazepine users were 1.23 times as likely as nonusers (95% confidence interval (CI) = 1.09-1.39) to develop mobility disability and 1.28 times as likely (95% CI = 1.09-1.52) to develop ADL disability. Risk for incident mobility was increased with short- (hazard ratio (HR) = 1.27, 95% CI = 1.08-1.50) and long-acting benzodiazepines (HR = 1.20, 95% CI = 1.03-1.39) and no use. Risk for ADL disability was greater with short- (HR = 1.58, 95% CI = 1.25-2.01) but not long-acting (HR = 1.11, 95% CI = 0.89-1.39) agents than for no use. CONCLUSION: Older adults taking benzodiazepines have a greater risk for incident mobility and ADL disability. Use of short-acting agents does not appear to confer any safety benefits over long-acting agents.     

Heterogeneity in rate of decline in grip, hip, and knee strength and the risk of all-cause mortality: the Women's Health and Aging Study II

OBJECTIVES: To assess the relationship between rate of change in muscle strength and all‐cause mortality. DESIGN: Prospective observational study of the causes and course of physical disability. SETTING: Twelve contiguous ZIP code areas in Baltimore, Maryland. PARTICIPANTS: Three hundred seven community‐dwelling women aged 70 to 79 at study baseline. MEASUREMENTS: The outcome was all‐cause mortality (1994–2009); predictors included up to seven repeated measurements of handgrip, knee extension, and hip flexion strength, with a median follow‐up time of 10 years. Demographic factors, body mass index, smoking status, number of chronic diseases, depressive symptoms, physical activity, interleukin‐6, and albumin were assessed at baseline and included as confounders. The associations between declining muscle strength and mortality were assessed using a joint longitudinal and survival model. RESULTS: Grip and hip strength declined an average of 1.10 and 1.31 kg/year between age 70 and 75 and 0.50 and 0.39 kg/year thereafter, respectively; knee strength declined at a constant rate of 0.57 kg/year. Faster rates of decline in grip and hip strength, but not knee strength, independently predicted mortality after accounting for baseline levels and potential confounders (hazard ratio (HR)=1.33, 95% confidence interval (95% CI)=1.06–1.67, HR=1.14, 95% CI=0.91–1.41, and 2.62, 95% CI=1.43–4.78 for every 0.5 standard deviation increase in rate of decline in grip, knee, and hip strength, respectively). CONCLUSION: Monitoring the rate of decline in grip and hip flexion strength in addition to absolute levels may greatly improve the identification of women most at risk of dying.     

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome

BackgroundLipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).ObjectivesA pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).MethodsOne to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.ResultsBaseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).ConclusionsBaseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)     

Low micronutrient levels as a predictor of incident disability in older women

BACKGROUND: The role of nutritional status in the disablement process is still unclear. The objective of this study was to assess whether low concentrations of nutrients predict the development and course of disability. METHODS: Longitudinal study including community-dwelling women 65 years or older enrolled in the Women's Health and Aging Study I. In total, 643 women were assessed prospectively at 6-month intervals from 1992 to 1995. RESULTS: Incidence rates of disability in activities of daily living (ADLs) during 3 years of follow-up. Incidence rates in the lowest quartile of each selected nutrient were compared with those in the upper quartiles. The hazard ratios were estimated from Cox models adjusted for potential confounders. Women in the lowest quartile of serum concentrations of vitamin B(6) (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.03-1.67), vitamin B(12) (HR, 1.40; 95% CI, 1.12-1.74), and selenium (HR, 1.38; 95% CI, 1.12-1.71) had significantly higher risk of disability in ADLs during 3 years of follow-up compared with women in the upper 3 quartiles. CONCLUSIONS: Low serum concentrations of vitamins B(6) and B(12) and selenium predict subsequent disability in ADLs in older women living in the community. Nutritional status is one of the key factors to be considered in the development of strategies aimed at preventing or delaying the disablement process.     

Antecedent blood pressure, body mass index, and the risk of incident heart failure in later life

Higher blood pressure and body mass index (BMI) are risk factors for heart failure. It is unknown whether the presence of these risk factors in midadulthood affect the future development of heart failure. In the community-based Framingham Heart Study, we examined the associations of antecedent blood pressure and BMI with heart failure incidence in later life. We studied 3362 participants (57% women; mean age: 62 years) who attended routine examinations between 1969 and 1994 and examined their systolic and diastolic blood pressure, pulse pressure, and BMI at current (baseline), recent (average of readings obtained 1 to 10 years before baseline), and remote (average of readings obtained 11 to 20 years before baseline) time periods. During 67 240 person-years of follow-up, 518 participants (280 women) developed heart failure. Current, recent, and remote systolic pressure; pulse pressure; and BMI were individually associated with incident heart failure (all P<0.001). Recent systolic pressure (hazards ratio [HR] per 1-SD increment: 1.31; 95% CI: 1.11 to 1.55), pulse pressure (HR per 1-SD increment: 1.33; 95% CI: 1.14 to 1.54), and BMI (HR per unit increase: 1.15; 95% CI: 1.08 to 1.23) were associated with heart failure risk even after adjusting for current measures. Similarly, remote systolic pressure (HR per 1 SD: 1.17; 95% CI: 1.04 to 1.31), pulse pressure (HR per 1 SD: 1.17; 95% CI: 1.06 to 1.31), and BMI (HR per unit: 1.09; 95% CI: 1.05 to 1.14) remained associated with incident heart failure after adjusting for current measurements. Higher blood pressure and BMI in midlife are harbingers of increased risk of heart failure in later life. Early risk factor modification may decrease heart failure burden.     

Restrictive pulmonary dysfunction at spirometry and mortality in the elderly

OBJECTIVES: To evaluate the association between pulmonary restriction and mortality in the elderly, taking into account potential confounders not considered in the past (disability, cognitive dysfunction, diabetes, and visceral obesity). DESIGN: Longitudinal study. SETTING: Community-based. PARTICIPANTS: Twelve hundred sixty-five patients (51.9% men) aged 65-97 years old from the Salute Respiratoria nell'Anziano (SaRA) Italian multicentric study. MEASUREMENTS: Participants were divided in 4 groups: normal spirometry (NS): FEV1/FVC>/=70%, FVC>/=80% of predicted; restrictive ventilatory pattern (RVP): FEV1/FVC>/=70%, FVC<80%; obstructive ventilatory pattern (OVP): FEV1/FVC<70%, FVC>/=80%, and mixed ventilatory pattern (MVP): FEV1/FVC<70%, FVC<80%. We calculated the association between restriction and mortality corrected for potential confounders using a multivariable Cox regression model. RESULTS: We found a prevalence of RVP, OVP and MVP of 10.9%, 25.4%, and 17.3%, respectively. Compared to people with normal spirometric pattern, disability (19.6% vs. 10.1%), poor physical performance (35.4% vs. 22.3%), cognitive impairment (21.0% vs. 11.5%), increased waist circumference (62.1% and 26.8%), and kyphoscoliosis (56.8 and 13.5%) were more prevalent in the RVP group. After correction for potential confounders, RVP was associated with increased mortality (HR: 1.89; 95% CI: 1.15-3.11), as well as OVP (HR: 2.33; 95% CI: 1.58-3.11) and MVP (HR: 2.60; 95% CI: 1.74-3.93). Other factors associated with mortality were disability (HR: 1.92; 95% CI: 1.35-2.72), poor physical performance (HR: 1.37; 95% CI: 1.01-1.85), cognitive impairment (HR: 1.55; 95% CI: 1.06-2.27), depression (HR: 1.57; 95% CI: 1.16-2.13) and diagnosis of stroke (HR: 1.90; 95% CI: 1.18-3.05). CONCLUSIONS: RVP is associated with higher mortality in the elderly and, thus, deserves the same attention paid to an obstructive pattern. However, mechanisms mediating this association need to be clarified.     

Relationship between classic risk factors, plasma antioxidants and indicators of oxidant stress in angina pectoris (AP) in Tehran

Cardiovascular disease (CVD) in general seems to be the leading cause of death in the Eastern Mediterranean Region (EMR) including Iran. This may be due to classic risk factors such as high triglyceride (TG), high total cholesterol (TC), and low levels of high density lipoprotein cholesterol (HDL-C). The impact of antioxidants as potentially protective risk factors against early coronary heart disease (CHD) is unknown in Iran. Therefore, relationships between angina and plasma antioxidants and indicators of lipid peroxidation were investigated in a case-control study. In this study, 82 cases of previously undiagnosed angina pectoris (AP), identified by a modified WHO Rose chest pain questionnaire and verified by electrocardiography during treadmill exercise testing, were compared with 146 controls selected from the same population of over 4000 male civil servants aged 40–60 years. Subjects with AP declared significantly less physical activity and had higher serum TG [means (S.E.M.) 2.32 (0.18) versus 1.61 (0.07) mmol/l] but lower HDL-C [1.01 (0.04) versus 1.18 (0.03) mmol/l] than age-matched controls. Levels of total serum cholesterol, low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] were not significantly different between the two groups, while the ratio of LDL-C/HDL-C was significantly higher [4.51 (0.23) versus 3.54 (0.11)] for subjects with AP than for the controls. There was no significant difference in plasma levels of -tocopherol, vitamin C, - and β-carotene. However, retinol [1.90 (0.06) versus 2.09 (0.05)] and β-cryptoxanthin [0.398 (0.04) versus 0.467 (0.03)] were significantly lower in AP. Furthermore, angina cases exhibited a higher index of lipid peroxidation than controls (e.g. malondialdehyde, MDA; 0.376 (0.010) versus 0.337 (0.009) μmol/l). On multiple logistic regression analysis, retinol with odds ratio (OR) of 0.644 [95% confidence interval (CI; 0.425–0.978)], β-cryptoxanthin, with an OR of 0.675 (CI; 0.487–0.940), oxidation indices, MDA with OR of 1.612 (95% CI; 1.119–2.322) and LDL-C/HDL-C ratio with OR of 2.006 (95% CI; 1.416–2.849) showed the most significant independent associations with AP in this group of Iranians. In conclusion, the state of lipid peroxidation as well as the status of special antioxidants may be co-determinants of AP in Iran, in parallel with the influence of classical risk factors for cardiovascular disease.     

Aerobic exercise and lipids and lipoproteins in children and adolescents: a meta-analysis of randomized controlled trials

OBJECTIVE: Use the meta-analytic approach to examine the effects of aerobic exercise on total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) in children and adolescents. STUDY DESIGN: Randomized controlled trials which were limited to aerobic exercise >or=4 weeks in children and adolescents 5-19 years of age. RESULTS: Twelve outcomes representing 389 subjects were available for pooling. Using random-effects modeling, a trend for statistically significant decreases of 12% was found for TG (X +/-S.E.M., -11.0+/-6.1mg/dl; 95% CI, -22.8-0.8 mg/dl) with no statistically significant changes for TC, HDL-C, and LDL-C. Decreases in LDL-C were associated with increased training intensity (r=-0.89; 99% CI, -0.99 to -0.04) and older age (r=-0.90; 99% CI, -0.99 to -0.25) while increases in HDL-C were associated with lower initial HDL-C (r=-0.75; 99% CI, -0.94 to -0.80). Statistically significant decreases in TG were observed in overweight/obese subjects with a trend for increases in HDL-C (TG, X +/-S.E.M., -23.9+/-7.0mg/dl; 95% CI, -37.6 to -10.1mg/dl; HDL-C, X +/-S.E.M., 4.0+/-2.3mg/dl; 95% CI, -0.5-8.5mg/dl). CONCLUSIONS: Aerobic exercise decreases TG in overweight/obese children and adolescents.     

Musculoskeletal pain and incident disability in community‐dwelling older adults

Objective

To test the hypothesis that the number of areas of musculoskeletal pain reported is related to incident disability.

Methods

Subjects included 898 older persons from the Rush Memory and Aging Project without dementia, stroke, or Parkinson's disease at baseline. All participants underwent detailed baseline evaluation of self‐reported pain in the neck or back, hands, hips, knees, or feet, as well as annual self‐reported assessments of instrumental activities of daily living (IADLs), basic activities of daily living (ADLs), and mobility disability. Mobility disability was also assessed using a performance‐based measure.

Results

The average followup was 5.6 years. Using a series of proportional hazards models that controlled for age, sex, and education, the risk of IADL disability increased by ～10% for each additional painful area reported (hazard ratio [HR] 1.10, 95% confidence interval [95% CI] 1.01–1.20) and the risk of ADL disability increased by ～20% for each additional painful area (HR 1.20, 95% CI 1.11–1.31). The association with self‐report mobility disability did not reach significance (HR 1.09, 95% CI 0.99–1.20). However, the risk of mobility disability based on gait speed performance increased by ～13% for each additional painful area (HR 1.13, 95% CI 1.04–1.22). These associations did not vary by age, sex, or education and were unchanged after controlling for several potential confounding variables including body mass index, physical activity, cognition, depressive symptoms, vascular risk factors, and vascular diseases.

Conclusion

Among nondisabled community‐dwelling older adults, the risk of disability increases with the number of areas reported with musculoskeletal pain.     

Effects of pravastatin on coronary events in 2073 patients with low levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol: results from the LIPID study.

AIMS: Fibrates or nicotinic acid are usually recommended for secondary prevention of coronary heart disease in patients with low plasma levels of both low-density lipoprotein cholesterol (LDL-C) < or =140 mg/dL (< or =3.6 mmol/L) and high-density lipoprotein cholesterol (HDL-C) < or =40 mg/dL (< or =1.03 mmol/L). The LIPID trial, a randomised, placebo-controlled trial in 9014 patients at 87 centres in Australia and New Zealand, provided an opportunity to investigate the effects of an HMG-CoA reductase inhibitor in patients with low LDL-C and low HDL-C. METHODS AND RESULTS: Participants in this post hoc substudy were 2073 patients aged 31-75 years with baseline LDL-C < or =140 mg/dL (< or =3.6 mmol/L), HDL-C < or =40 mg/dL (< or =1.03 mmol/L), and triglyceride < or =300 mg/dL (< or =3.4 mmol/L). The relative risk reduction with pravastatin treatment was 27% for major coronary events (95% CI 8-42%), 27% for coronary heart disease mortality (95% CI 0-47%), 21% for all-cause mortality (95% CI 0-38%), and 51% for stroke (95% CI 24-69%). The number needed to treat to prevent a major coronary event over 6 years was 22. CONCLUSIONS: Treatment with pravastatin in patients with both low LDL-C and low HDL-C significantly reduced major coronary events, stroke, and all-cause mortality. The level of HDL-C is crucial to the risk of recurrent CHD events and, consequently, the benefit of lowering LDL-C.     

Diabetes,plasma insulin,and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT)

BACKGROUND: Diabetes mellitus, impaired fasting glucose level, or insulin resistance are associated with increased risk of cardiovascular disease. OBJECTIVES: To determine the efficacy of gemfibrozil in subjects with varying levels of glucose tolerance or hyperinsulinemia and to examine the association between diabetes status and glucose and insulin levels and risk of cardiovascular outcomes. METHODS: Subgroup analyses from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized controlled trial that enrolled 2531 men with coronary heart disease (CHD), a high-density lipoprotein cholesterol level of 40 mg/dL or less (/=271 pmol/L) was associated with a 31% increased risk of events (P =.03). Gemfibrozil was effective in persons with diabetes (risk reduction for composite end point, 32%; P =.004). The reduction in CHD death was 41% (HR, 0.59; 95% CI, 0.39-0.91; P =.02). Among individuals without diabetes, gemfibrozil was most efficacious for those in the highest fasting plasma insulin level quartile (risk reduction, 35%; P =.04). CONCLUSION: In men with CHD and a low high-density lipoprotein cholesterol level, gemfibrozil use was associated with a reduction in major cardiovascular events in persons with diabetes and in nondiabetic subjects with a high fasting plasma insulin level.     

The relative strength of C-reactive protein and lipid levels as determinants of ischemic stroke compared with coronary heart disease in women.

OBJECTIVES: We sought to determine the relative strength of high-sensitivity C-reactive protein (hs-CRP) and lipid levels as markers for future ischemic stroke compared with coronary heart disease (CHD) in women. BACKGROUND: Although hs-CRP and lipid levels are established risk determinants for vascular disease, the relative strength of these biomarkers for ischemic stroke compared with CHD is uncertain. METHODS: Among 15,632 initially healthy women who were followed for a 10-year period, we compared hs-CRP, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoproteins A-I and B100, and lipid ratios as determinants of ischemic stroke compared with CHD. RESULTS: After adjustment for age, smoking status, blood pressure, diabetes, and obesity, the hazard ratios (HRs) and 95% confidence intervals (CIs) for the third versus the first tertile for future ischemic stroke compared with CHD were, respectively, 1.91 (95% CI 1.13 to 3.21) and 2.26 (95% CI 1.64 to 3.12) for TC, 1.29 (95% CI 0.83 to 2.02) and 2.09 (95% CI 1.53 to 2.85) for LDL-C, 0.57 (95% CI 0.36 to 0.92) and 0.38 (95% CI 0.27 to 0.52) for HDL-C, 1.72 (95% CI 1.03 to 2.86) and 2.93 (95% CI 2.04 to 4.21) for non-HDL-C, and 2.76 (95% CI 1.51 to 5.05) and 1.66 (95% CI 1.17 to 2.34) for hs-CRP. Of the lipid ratios, that of TC to HDL-C had the largest HR for both future ischemic stroke and CHD (HR 1.95 [95% CI 1.16 to 3.26] and 4.20 [95% CI 2.79 to 6.32], respectively). CONCLUSIONS: In this large prospective cohort of initially healthy women, lipid levels are significant risk determinants for ischemic stroke, but with a magnitude of effect smaller than that observed for CHD. High-sensitivity CRP associates more closely with ischemic stroke than with CHD. Concomitant evaluation of lipid levels and hs-CRP may improve risk assessment for stroke as well as CHD. (The Women's Health Study; http://www.clinicaltrials.gov/ct/show/NCT00000479/; NCT00000479).     

Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging in older men and women

OBJECTIVES: To compare two methods for classifying an individual as sarcopenic for predicting decline in physical function in the Health, Aging and Body Composition Study. DESIGN: Observational cohort study with 5 years of follow-up. SETTING: Communities in Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Men and women aged 70 to 79 (N=2,976, 52% women, 41% black). MEASUREMENTS: Appendicular lean mass (aLM) was measured using dual energy x-ray absorptiometry, and participants were classified as sarcopenic first using aLM divided by height squared and then using aLM adjusted for height and body fat mass (residuals). Incidence of persistent lower extremity limitation (PLL) was measured according to self-report, and change in objective lower extremity performance (LEP) measures were observed using the Short Physical Performance Battery. RESULTS: There was a greater risk of incident PLL in women who were sarcopenic using the residuals sarcopenia method than in women who were not sarcopenic (hazard ratio (HR)=1.34, 95% confidence interval (CI)=1.11-1.61) but not in men. Those defined as sarcopenic using the aLM/ht(2) method had lower incident PLL than nonsarcopenic men (HR=0.76, 95% CI=0.60-0.96) and women (HR=0.75, 95% CI=0.60-0.93), but these were no longer significant with adjustment for body fat mass. Using the residuals method, there were significantly poorer LEP scores in sarcopenic men and women at baseline and Year 6 and greater 5-year decline, whereas sarcopenic men defined using the aLM/ht(2) method had lower 5-year decline. Additional adjustment for fat mass attenuated this protective effect. CONCLUSION: These findings suggest that sarcopenia defined using the residuals method, a method that considers height and fat mass together, is better for predicting disability in an individual than the aLM/ht(2) method, because it considers fat as part of the definition.     

Impact of tricuspid regurgitation on long-term survival

OBJECTIVES: The goal of this study was to examine mortality associated with tricuspid regurgitation (TR) after controlling for left ventricular ejection fraction (LVEF), right ventricular (RV) dilation and dysfunction, and pulmonary artery systolic pressure (PASP). BACKGROUND: Tricuspid regurgitation is a frequent echocardiographic finding; however, the association with prognosis is unclear. METHODS: We retrospectively identified 5,223 patients (age 66.5 +/- 12.8 years; predominantly male) undergoing echocardiography at one of three Veterans Affairs Medical Center laboratories over a period of four years. Follow-up data were available for four years (mean 498 +/- 402 days). Kaplan-Meier and proportional hazards methods were used to compare differences in survival among TR grades. RESULTS: Mortality increased with increasing severity of TR. The one-year survival was 91.7% with no TR, 90.3% with mild TR, 78.9% with moderate TR, and 63.9% with severe TR. Moderate or greater TR was associated with increased mortality regardless of PASP (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.16 to 1.49 for PASP >40 mm Hg; HR 1.32, 95% CI 1.05 to 1.62 for PASP < or =40 mm Hg) and LVEF (HR 1.49, 95% CI 1.34 to 1.66 for EF <50%; HR 1.54, 95% CI 1.37 to 1.71 for EF > or =50%). When adjusted for age, LVEF, inferior vena cava size, and RV size and function, survival was worse for patients with moderate (HR 1.17, 95% CI 0.96 to 1.42) and severe TR (HR 1.31, 95% CI 1.05 to 1.66) than for those with no TR. CONCLUSIONS: We conclude that increasing TR severity is associated with worse survival in men regardless of LVEF or pulmonary artery pressure. Severe TR is associated with a poor prognosis, independent of age, biventricular systolic function, RV size, and dilation of the inferior vena cava.     

Usefulness of right ventricular fractional area change to predict death, heart failure, and stroke following myocardial infarction (from the VALIANT ECHO Study)

Severe right ventricular dysfunction independent of left ventricular ejection fraction increased the risk of heart failure (HF) and death after myocardial infarction (MI). The association between right ventricular function and other clinical outcomes after MI was less clear. Two-dimensional echocardiograms were obtained in 605 patients with left ventricular dysfunction and/or clinical/radiologic evidence of HF from the VALIANT echocardiographic substudy (mean 5.0 +/- 2.5 days after MI). Clinical outcomes included all-cause mortality, cardiovascular (CV) death, sudden death, HF, and stroke. Baseline right ventricular function was measured in 522 patients using right ventricular fractional area change (RVFAC) and was related to clinical outcomes. Mean RVFAC was 41.9 +/- 4.3% (range 19.2% to 53.1%). The incidence of clinical events increased with decreasing RVFAC. After adjusting for 11 covariates, including age, ejection fraction, and Killip's classification, decreased RVFAC was independently associated with increased risk of all-cause mortality (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.31 to 1.98), CV death (HR 1.62, 95% CI 1.30 to 2.01), sudden death (HR 1.79, 95% CI 1.26 to 2.54), HF (HR 1.48, 95% CI 1.17 to 1.86), and stroke (HR 2.95, 95% CI 1.76 to 4.95), but not recurrent MI. Each 5% decrease in baseline RVFAC was associated with a 1.53 (95% CI 1.24 to 1.88) increased risk of fatal and nonfatal CV outcomes. In conclusion, decreased right ventricular systolic function is a major risk factor for death, sudden death, HF, and stroke after MI.     

Low levels of high-density lipoprotein cholesterol are a marker of disability in the elderly

BACKGROUND: In the elderly, high-density lipoprotein cholesterol (HDL-C) seems to have further clinical meanings besides the inverse relationship with coronary heart disease (CHD); indeed, low values have been found in elderly subjects with functional disability, chronic illness, and in severe clinical conditions. OBJECTIVE: To verify the hypothesis that low HDL-C might be a 'marker' for disability, we evaluated the relationship between lipoprotein parameters and functional status, over a period of 2 years, in a large sample of institutionalized elderly. METHODS: 344 institutionalized subjects aged over 65 years were studied. They were divided into two groups according to basal disability level: 'low-mild': class A-E, and 'high': class F-G of the Katz index. 124 survivors, independent in at least two basic activities of daily living (BADL) at enrollment, were divided into two groups on the basis of 2 years' modifications in functional status: stable/improved or worsened (lost >/=2 BADL). RESULTS: Total cholesterol, LDL-C, HDL-C, and apo A-I levels were lower in the high disability group, while no differences in triglycerides and apo B levels emerged. Multiple logistic regression analysis showed that severe disability was associated with HDL-C (II vs. III tertile: OR 2.01; CI 95% 1.04-3.91; I vs. III tertile: OR 2.52; CI 95% 1.23-5. 15), total cholesterol (I vs. III tertile: OR 2.35; CI 95% 1.14-4. 81), blood glucose (OR 0.98), and body mass index (OR 0.91), independently from uric acid, number of pathologies, number of drugs, body cell mass, vitamin B(12) and folic acid plasma levels, waist/hip ratio, age, and gender. Subjects who lost >/=2 BADL in the 2-year follow-up consistently showed lower basal HDL-C levels compared to subjects with stable/improved functional status, and this difference was significant after adjustment for basal Katz class, age, gender, number of pathologies, blood glucose, body mass index, and waist/hip ratio. CONCLUSIONS: The results of this study suggest that in the elderly severe disability is strongly associated with low HDL-C levels. Longitudinal data support the hypothesis that low HDL-C might be considered as a marker for 'ongoing' disability in BADL.