Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Circulating microRNAs and sudden cardiac arrest outcomes.

AIM: MicroRNAs (miRNAs) have regulatory functions in organs critical in resuscitation from sudden cardiac arrest due to ventricular fibrillation (VF-SCA); therefore, circulating miRNAs may be markers of VF-SCA outcome. METHODS: We measured candidate miRNAs (N=45) in plasma using qRT-PCR among participants of a population-based VF-SCA study. Participants were randomly selected cases who died in the field (DF, n=15), died in hospital (DH, n=15), or survived to discharge (DC, n=15), and, age-, sex-, and race-matched controls (n=15). MiRNA levels were compared using ANOVA, t-tests, and fold-changes. RESULTS: Mean age of groups ranged from 66.9 to 69.7. Most participants were male (53-67%) and white (67%). Comparing cases to controls, plasma levels of 17 miRNAs expressed in heart, brain, liver, and other tissues (including miR-29c, -34a, -122, -145, -200a, -210, -499-5p, and -663b) were higher and three non-specific miRNAs lower (miR-221, -330-3p, and -9-5p). Among DH or DC compared with DF cases, levels of two miRNAs (liver-specific miR-122 and non-specific miR-205) were higher and two heart-specific miRNAs (miR-208b and -499-5p) lower. Among DC vs. DF cases, levels of three miRNAs (miR-122, and non-specific miR-200a and -205) were higher and four heart-specific miRNAs (miR-133a, -133b, -208b, and -499-5p) lower. Among DC vs. DH cases, levels of two non-specific miRNAs (miR-135a and -9-3p) were lower. CONCLUSIONS: Circulating miRNAs expressed in heart, brain, and other tissues differ between VF-SCA cases and controls and are related to resuscitation outcomes. Measurement of miRNAs may clarify mechanisms underlying resuscitation, improve prognostication, and guide development of therapies. Results require replication.

Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies.

OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids. DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800). RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed. CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women.

OBJECTIVES: Clinical trials have demonstrated that oral conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) increases venous thrombotic risk but this safety issue has not been investigated for other oral estrogens. Based on observational study findings that esterified estrogen (EE) was not associated with venous thrombotic risk whereas CEE was, we hypothesized that CEE users would be more resistant to activated protein C (APC), a prothrombotic phenotype, than EE users. METHODS: We conducted an observational, cross-sectional study of postmenopausal women 30-89 years old who were controls in a case-control study of venous thrombosis. Use of CEE, EE, and MPA at the time of phlebotomy was determined using computerized pharmacy records. APC resistance was measured in plasma by the endogenous thrombin potential normalized APC sensitivity ratio. Adjusted mean APC resistance values were compared across estrogen type and CEE:EE ratios are presented. RESULTS: There were 119 CEE and 92 EE users at the time of phlebotomy. Compared with EE users, CEE users had APC resistance measures that were 52% higher (1.52; 95% confidence intervals: 1.07-2.17) in adjusted analyses. Restricting to modal dose users (0.625 mg) and stratifying by MPA use did not materially change associations. CONCLUSIONS: CEE use was associated with higher levels of APC resistance when compared with EE use in postmenopausal women. These findings might provide an explanation for the higher risk of venous thromboembolism previously observed with CEE compared with EE use and, if replicated, may have safety implications for women when choosing an estrogen for symptom relief.

Clinical depression and risk of out-of-hospital cardiac arrest.

BACKGROUND: The association of depression with coronary heart disease-related mortality has been widely recognized. This finding may partly reflect an association between depression and sudden death, in part because the imbalance between sympathetic and parasympathetic tone is altered in depressed subjects. We, thus, investigated whether the presence and severity of clinical depression was associated with a higher risk of sudden cardiac death. METHODS: We used data from a population-based case-control study of risk factors for incident out-of-hospital cardiac arrest (CA) conducted among enrollees of a health maintenance organization in western Washington State. Cases (n = 2228) were aged 40 to 79 years and experienced CA between January 1, 1980, and December 31, 1994. Controls (n = 4164) were a stratified random sample of enrollees defined by calendar year, age, sex, and prior heart disease. Clinical depression was defined as physician diagnosis of depression or use of antidepressant treatment within the year before the event. Referral to mental health clinics or hospitalization for depression defined severe depression. RESULTS: Clinically depressed patients had a higher odds ratio (OR) of CA (1.88; 95% confidence interval [CI], 1.59-2.23), which persisted after adjustment for confounders (OR, 1.43; 95% CI, 1.18-1.73). The association was observed in both sexes, in various age groups, and in subjects with prior physician-diagnosed heart disease (OR, 1.27; 95% CI, 1.01-1.60) and without prior physician-diagnosed heart disease (OR, 1.71; 95% CI, 1.22-2.41) (P = .13 for the interaction). Compared with nondepressed subjects, the risk of CA was increased in less severely depressed subjects (OR, 1.30; 95% CI, 1.04-1.63) and further increased in severely depressed subjects (OR, 1.77; 95% CI, 1.28-2.45) (P<.001 for trend). CONCLUSION: Clinical depression may be associated with a higher risk of CA independently of established coronary heart disease risk factors.

Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups.

OBJECTIVE: To perform a health maintenance organization-based case-control study to evaluate the association of total and high density lipoprotein (HDL) cholesterol with the risk of stroke subtypes and in patient subgroups. METHODS: Cases had a confirmed incident ischemic stroke (n = 1,242) or hemorrhagic stroke (n = 313). Controls (n = 6,455) were identified in a companion myocardial infarction study. Risk of stroke was modeled using logistic regression. RESULTS: The highest total cholesterol quintile was associated with an increased risk of ischemic stroke compared to the lowest quintile (OR = 1.6, 95% CI 1.3 to 2.0) with the strongest subtype associations for atherosclerotic stroke (OR = 3.2) and lacunar stroke (OR = 2.4). The highest HDL cholesterol quintile was associated with a decreased risk of ischemic stroke compared to the lowest quintile (OR = 0.8, CI 0.6 to 1.0). Subgroup analyses suggested that the total cholesterol association was more important for patients < 66 years of age and those with HDL < 50 mg/dL; the HDL association was more important for patients without diabetes or atrial fibrillation. The second through fourth total cholesterol quintiles were associated with a decreased risk of hemorrhagic stroke compared to the lowest quintile (OR = 0.7, CI 0.5 to 1.0). CONCLUSIONS: Higher total and lower HDL cholesterol levels were associated with increased risk of ischemic stroke, especially certain stroke subtypes and patient subgroups. The lowest levels of total cholesterol were associated with an increased risk of all hemorrhagic strokes.

Body mass index and the risk of recurrent coronary events following acute myocardial infarction.

Although excess adiposity appears to increase the risk of coronary heart disease in the general population, its importance in patients with established coronary disease is less defined. We evaluated a population-based inception cohort of survivors to hospital discharge following first acute myocardial infarction (AMI) (n = 2,541) to assess the association between body mass index (BMI) and the risk of recurrent coronary events and to explore the mechanisms for this relation. Using Cox proportional-hazards regression, we assessed the risk of recurrent coronary events associated with levels of adiposity as defined by BMI and then investigated potential mechanisms through which adiposity conferred risk by examining how adjustment for diabetes mellitus, systemic hypertension, and dyslipidemia affected the association. Forty-one percent of the cohort were overweight (BMI 25 to 29.9), and 27.8% were obese (BMI > or =30). After adjustment for other risk factors, the risk of recurrent coronary events (n = 418) increased as BMI increased, especially among those who were obese. Using a BMI of 16 to 24.9 as the reference group, for mildly overweight patients (BMI 25 to 27.4), the relative risk (RR) was 0.93 (95% confidence interval [CI] 0.70 to 1.24); it was 1.16 for more severe overweight patients (BMI 27.5 to 29.9; 95% CI 0.87 to 1.55). For patients with class I obesity (BMI 30 to 34.9), the RR was 1.49 (95% CI 1.12 to 1.98), and for class II to III obesity (BMI > or =35), the RR was 1.80 (95% CI 1.30 to 2.48). We estimated that clinical measurements of diabetes, hypertension, and dyslipidemia explained approximately 43% of this risk. Thus, excess adiposity as measured by BMI was associated with an increased risk of recurrent coronary events following AMI, particularly among those who were obese.

Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women.

CONTEXT: Estrogens are known to be prothrombotic, and findings from the Heart and Estrogen/progestin Replacement Study suggest that in women with clinically recognized heart disease, hormone replacement therapy (HRT) may be associated with early harm and late benefit in terms of coronary events. OBJECTIVE: To assess whether, as hypothesized, prothrombotic mutations modify the association between HRT use and incidence of first myocardial infarction (MI). DESIGN AND SETTING: Population-based, case-control study conducted in a Seattle-based health maintenance organization. PARTICIPANTS: Cases were 232 postmenopausal women aged 30 to 79 years who had their first nonfatal MI between 1995 and 1998. Controls were a stratified random sample of 723 postmenopausal women without MI who were frequency-matched to cases by age, calendar year, and hypertension status. MAIN OUTCOME MEASURE: Risk of first nonfatal MI based on current use of HRT and the presence or absence of coagulation factor V Leiden and prothrombin 20210 G-->A variants among cases and controls, stratified by hypertension. RESULTS: One hundred eight MI cases and 387 controls had hypertension and 124 MI cases and 336 controls did not. Among hypertensive women, the prothrombin variant was a risk factor for MI (odds ratio [OR], 4.32; 95% confidence interval [CI], 1.52-12.1) and, in this stratum, there was also a significant interaction between use of HRT and presence of the prothrombin variant on risk of MI. Compared with nonusers of HRT with wild-type genotype, women who were current users and who had the prothrombin variant (n = 8) had a nearly 11-fold increase in risk of a nonfatal MI (OR, 10.9; 95% CI, 2.15-55.2). The interaction with the prothrombin variant was more pronounced in analyses assuming 100% compliance than in those assuming 80% compliance with HRT. The interaction was absent among nonhypertensive women and was less pronounced if hypertensive and nonhypertensive women were combined into 1 group. No interaction was found for factor V Leiden in either hypertensive or nonhypertensive women. Among hypertensive women, the estimates were affected only in trivial ways by adjustment, and the interaction with the prothrombin variant was specific to HRT. CONCLUSIONS: Our results suggest that among postmenopausal hypertensive women, the association between HRT use and MI risk differed between those with and without the prothrombin 20210 G-->A variant. If these findings are confirmed in other studies, screening for the prothrombin variant may permit a better assessment of the risks and benefits associated with HRT in postmenopausal women.

Antihypertensive drug therapies and the risk of ischemic stroke.

BACKGROUND: The relative effectiveness of various antihypertensive drugs with regard to the reduction of stroke incidence remains uncertain. OBJECTIVE: To assess the association between first ischemic stroke and use of antihypertensive drugs. METHODS: A population-based case-control study was performed among enrollees of the Group Health Cooperative of Puget Sound. Case patients included pharmacologically treated hypertensive patients who sustained a first ischemic stroke (fatal or nonfatal; n = 380) between July 1, 1989, and December 31, 1996. Control subjects were a random sample of treated hypertensive enrollees without a history of a stroke (n = 2790). Medical record review and a telephone interview of consenting survivors were used to collect information on risk factors for stroke. Computerized pharmacy records were used to assess antihypertensive drug use. RESULTS: Among 1237 single-drug users with no history of cardiovascular disease, the adjusted risk of ischemic stroke was higher among users of a beta-blocker (risk ratio [RR], 2.03; 95% confidence interval [CI], 1.05-3.94), calcium channel blocker (RR, 2.30; 95% CI, 1.16-4.56), or angiotensin-converting enzyme inhibitor (RR, 2.79; 95% CI, 1.47-5. 27) than among users of a thiazide diuretic alone. Among 673 single-drug users with a history of cardiovascular disease, the RRs were 1.22 (95% CI, 0.63-2.35), 1.18 (95% CI, 0.59-2.33), and 1.45 (95% CI, 0.70-3.02) among users of a beta-blocker, calcium channel blocker, and angiotensin-converting enzyme inhibitor, respectively, compared with users of a thiazide diuretic alone. CONCLUSIONS: In this study of pharmacologically treated hypertensive patients, antihypertensive drug regimens that did not include a thiazide diuretic were associated with an increased risk of ischemic stroke compared with regimens that did include a thiazide. These results support the use of thiazide diuretics as first-line antihypertensive agents.

Influenza vaccination and the risk of primary cardiac arrest.

Influenza epidemics are associated with an excess of mortality not only from respiratory diseases but also from other causes, and cardiovascular mortality increases abruptly during influenza epidemics, with little evidence of a lag period. In a population-based case-control study, the authors examined whether influenza vaccination was associated with a reduced risk of out-of-hospital primary cardiac arrest (PCA), a major contributor to cardiovascular mortality in the community. Cases of PCA (n = 342) without prior heart disease or life-threatening comorbidity that occurred in King County, Washington, were identified from paramedic incident reports from October 1988 to July 1994. Demographically similar controls (n = 549) were identified from the community by using random digit dialing. Spouses of subjects were interviewed to assess treatment with influenza vaccine during the previous year and other risk factors. After adjustment for demographic, clinical, and behavioral risk factors, influenza vaccination was associated with a reduced risk of PCA (odds ratio = 0.51, 95 percent confidence interval: 0.33, 0.79). The authors suggest that while the association of influenza vaccination with a reduced risk of PCA is consistent with cohort studies of influenza vaccination and total mortality, further studies are needed to determine whether the observed association reflects protection or selection.

The risk of myocardial infarction associated with inhaled beta-adrenoceptor agonists.

Beta-adrenoceptor agonists (beta-agonists), in widespread clinical use for obstructive lung disease, have been associated with an increased risk of cardiovascular mortality. The objective of this study was to assess the association between incident myocardial infarction and the use of inhaled beta-agonists. We performed a case-control study within the Group Health Cooperative of Puget Sound (GHC). Between 1989 and 1994, we identified 1,444 cases with an incident myocardial infarction and 4,094 control subjects frequency-matched on age, sex, hypertension, and index date. The computerized pharmacy database of the health maintenance organization (HMO) was used to assess the use of beta-agonists by metered dose inhaler (MDI). Cardiovascular risk factor information was obtained from medical record review. In comparison to subjects who did not fill a beta-agonist prescription, subjects who had filled one beta-agonist MDI prescription in the 3 mo prior to their index date had an elevated estimated risk of myocardial infarction (adjusted odds ratio [OR]: 1.67 [95% CI, 1.07 to 2.60]). The elevated risk was limited to those subjects who had a history of cardiovascular disease (adjusted OR: 3.22 [95% CI, 1.63 to 6.35]) and among those with cardiovascular disease, to new users of beta-agonists (adjusted OR: 7.32 [95% CI, 2.34 to 22.8]). There was no dose-response relationship between beta-agonists use and risk of myocardial infarction. In this study, new use of beta-agonists was associated with an increased risk of myocardial infarction, although we cannot determine if the association is causal. Our study suggests that clinicians should exercise caution when giving an initial beta-adrenoceptor agonist prescription to patients with cardiovascular disease.

Control of blood pressure and risk of stroke among pharmacologically treated hypertensive patients.

BACKGROUND AND PURPOSE: Despite improved control of blood pressure during the last decades in the United States, a considerable proportion of treated hypertensives have not achieved target blood pressure levels. We estimated the proportion of strokes occurring among treated hypertensive patients that may be attributable to uncontrolled blood pressure. METHODS: A population-based case-control study was conducted among treated hypertensive members of Group Health Cooperative of Puget Sound. Cases were treated hypertensive patients who sustained a first fatal or nonfatal, ischemic (n=460) or hemorrhagic (n=95) stroke during 1989-1996. Controls were a random sample of stroke-free, treated hypertensive Group Health Cooperative enrollees (n=2966), similar in age to the stroke cases. Multiple measurements of blood pressure and other cardiovascular risk factors were collected from medical records. Logistic regression was used to estimate the risk of ischemic stroke and hemorrhagic stroke associated with uncontrolled blood pressure, defined as diastolic blood pressure >90 mm Hg or systolic blood pressure >140 mm Hg. The fraction of strokes attributable to uncontrolled blood pressure among treated hypertensives was calculated. RESULTS: Blood pressure was uncontrolled in 78% of ischemic stroke cases, 85% of hemorrhagic stroke cases, and 65% of controls. After adjustment for potential confounders, uncontrolled blood pressure among treated hypertensive patients was moderately associated with ischemic stroke (risk ratio=1.5 [95% CI, 1.2 to 1. 9]) and strongly related to hemorrhagic stroke (risk ratio=3.0 [95% CI, 1.7 to 5.4]). We estimated that 27% (95% CI, 11% to 39%) of the ischemic strokes and 57% (95% CI, 26% to 75%) of the hemorrhagic strokes among treated hypertensive patients were attributable to uncontrolled blood pressure. Overall, 32% (95% CI, 14% to 45%) of all strokes were attributable to uncontrolled blood pressure. CONCLUSIONS: A considerable proportion of incident strokes among treated hypertensive patients may be prevented by achieving control of blood pressure.

Blood pressure level and incidence of myocardial infarction among patients treated for hypertension.

OBJECTIVES: This study examined the relationship between achieved blood pressure and risk of myocardial infarction among patients treated for hypertension. METHODS: Blood pressure and other cardiovascular risk factors were assessed among 718 myocardial infarction case patients and 2136 matched controls. RESULTS: Blood pressure level was directly related to risk of myocardial infarction. Patients with treated hypertension who had mild elevations in blood pressure accounted for a larger share of the excess myocardial infarction incidence than those who had higher blood pressure readings. CONCLUSIONS: Achieving normotensive levels in treated hypertensive patients with uncontrolled blood pressure might prevent more than 15% of myocardial infarctions in the treated hypertensive population.

Leisure-time physical activity and the risk of primary cardiac arrest.

BACKGROUND: Because the risks of sudden cardiac death and myocardial infarction are transiently increased during acute bouts of high-intensity activity, it is an important question from the public health perspective whether regular participation in moderate-intensity activity confers overall protection from sudden cardiac death. PARTICIPANTS AND METHODS: We used data from a population-based case-control study to assess the associations of regular high-intensity and moderate-intensity leisure-time physical activity with primary cardiac arrest. Cases were patients with primary cardiac arrest, aged 25 to 74 years, attended by paramedics between 1988 and 1994 in King County, Washington (n = 333). Controls were randomly identified from the same community (n = 503), matched for age and sex. All case patients and controls were free of prior clinical heart disease, major comorbidity, and self-reported poor health. Spouses of case patients and controls were interviewed to assess participation in 15 high-intensity and 6 moderate-intensity physical activities during the prior year. RESULTS: Compared with subjects who performed none of the activities, the odds ratio for primary cardiac arrest from matched analyses was 0.34 (95% confidence interval, 0.13-0.89) among subjects who performed only gardening activities for more than 60 minutes per week; 0.27 (95% confidence interval, 0.11-0.67) among subjects who walked for exercise for more than 60 minutes per week; and 0.34 (95% confidence interval, 0.16-0.75) among subjects who engaged in any high-intensity activities, after adjustment for age, smoking, education, diabetes, hypertension, and health status. CONCLUSIONS: The results suggest that regular participation in moderate-intensity activities, such as walking and gardening, are associated with a reduced risk of PCA and support current exercise recommendations.

Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study.

Coagulation factor levels predict arterial thrombosis in epidemiological studies, but studies of older persons are needed. We studied 3 plasma antigenic markers of fibrinolysis, viz, plasminogen activator inhibitor-1 (PAI-1), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) for the prediction of arterial thrombosis in healthy elderly persons over age 65. The study was a nested case-control study in the Cardiovascular Health Study cohort of 5201 men and women >/=65 years of age who were enrolled from 1989 to 1990. Cases were 146 participants without baseline clinical vascular disease who developed myocardial infarction, angina, or coronary death during a follow-up of 2.4 years. Controls remained free of cardiovascular events and were matched 1:1 to cases with respect to sex, duration of follow-up, and baseline subclinical vascular disease status. With increasing quartile of D-dimer and PAP levels but not of PAI-1, there was an independent increased risk of myocardial infarction or coronary death, but not of angina. The relative risk for D-dimer above versus below the median value (>/=120 microg/L) was 2.5 (95% confidence interval, 1.1 to 5.9) and for PAP above the median (>/=5.25 nmol/L), 3.1 (1.3 to 7.7). Risks were independent of C-reactive protein and fibrinogen concentrations. There were no differences in risk by sex or presence of baseline subclinical disease. D-dimer and PAP, but not PAI-1, predicted future myocardial infarction in men and women over age 65. Relationships were independent of other risk factors, including inflammation markers. Results indicate a major role for these markers in identifying a high risk of arterial disease in this age group.

Poisson regression with missing durations of exposure.

In this paper, we develop Poisson-type regression methods that require the durations of exposure be measured only on a possibly nonrandom subset of the cohort members. These methods can be used to make inferences about the incidence density during exposure as well as the ratio of incidence densities during exposure versus not during exposure. Numerical studies demonstrate that the proposed methods yield reliable results in practical settings. We describe an application to a population-based case-control study assessing the transient increase in the risk of primary cardiac arrest during leisure-time physical activity.

Assessment of trans-fatty acid intake with a food frequency questionnaire and validation with adipose tissue levels of trans-fatty acids.

Past studies of the association of trans-fatty acid intake with coronary heart disease have been hindered by the lack of a database on the trans-fatty acid content of various foods. The authors used new data from the US Department of Agriculture to estimate trans-fatty acid intake using a self-administered food frequency questionnaire (FFQ), and they assessed the validity of the FFQ by comparing the dietary estimates with trans-fatty acid concentrations in adipose tissue. The 1996 study included 27 women and 24 men aged 51-78 years. The mean consumption of total trans-fatty acids estimated from the FFQ was 2.24 g per day and 5% of total dietary fat. The mean concentration of total trans-fatty acids in buttock adipose tissue was 4.7% of total fatty acids. Pearson correlations between total dietary intake of trans-fatty acids and total trans-fatty acid levels in adipose tissue were 0.67 (95% confidence interval (CI) 0.36-0.84) among men and 0.58 (95% CI 0.26-0.79) among women. After adjustment for energy intake, age, and body mass index, the correlation coefficients were 0.76 (95% CI 0.51-0.89) among men and 0.52 (95% CI 0.17-0.75) among women. The FFQ validated in this study is an important new tool for assessing usual intake of trans-fatty acids.

Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.

OBJECTIVES: To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. SUBJECTS AND METHODS: A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. RESULTS: The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. CONCLUSIONS: Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.