Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration. METHODS: Using prospective data on American Indians from the Strong Heart Family Study, we identified 373 individuals defined as progressors (diabetes incident cases), 566 individuals with transitory impaired fasting glucose (IFG) and 1,011 controls (normal fasting glycaemia at all visits). We estimated the heritability (h(2)) of the traits and the evidence for association with 16 known variants identified in type 2 diabetes genome-wide association studies. RESULTS: We noted high h(2) for diabetes progression (h(2) = 0.65 ± 0.16, p = 2.7 × 10(-6)) but little contribution of genetic factors to transitory IFG (h(2) = 0.09 ± 0.10, p = 0.19) for models adjusted for multiple risk factors. At least three variants (in WFS1, TSPAN8 and THADA) were nominally associated with diabetes progression in age- and sex-adjusted analyses with estimates showing the same direction of effects as reported in the discovery European ancestry studies. CONCLUSIONS/INTERPRETATION: Our findings do not exclude these loci for diabetes susceptibility in American Indians and suggest phenotypic heterogeneity of the IFG trait, which may have implications for genetic studies when diagnosis is based on a single time-point measure.

Dietary patterns and their association with cardiovascular risk factors in a population undergoing lifestyle changes: The Strong Heart Study.

BACKGROUND AND AIMS: Rates of cardiovascular disease (CVD) are disproportionately high in American Indians (AI), and changes in lifestyle may be responsible. It is not known whether diverse dietary patterns exist in this population and whether the patterns are associated with CVD risk factors. This article describes the relationships between dietary patterns and CVD risk factors in this high-risk population. METHODS AND RESULTS: Nutrition data were collected via food frequency questionnaire from 3438 Strong Heart Study (SHS) participants, ≥ age 15 y. All participants were members of 94 extended families. The final sample consisted of 3172 men and women. Diet patterns were ascertained using factor analysis with the principal component factoring method. We derived four predominant dietary patterns: Western, traditional AI/Mexican, healthy, and unhealthy. Participants following the Western pattern had higher LDL cholesterol (LDL-C) (p < 0.001), slightly higher systolic blood pressure (BP) (p < 0.001), lower HDL cholesterol (HDL-C) (p < 0.001), and slightly lower homeostasis model assessment estimates of insulin resistance (HOMA-IR) in the lowest vs. highest deciles of adherence to this pattern (p < 0.001). The traditional diet was associated with higher HDL-C (p < 0.001), but higher body mass index (BMI) (p < 0.001) and HOMA-IR (p < 0.001). Followers of the healthy pattern had lower systolic BP, LDL-C, BMI, and HOMA-IR in increasing deciles (p < 0.001). The unhealthy pattern was associated with higher LDL-C. CONCLUSIONS: Dietary patterns reflect the changing lifestyle of AI and several of the patterns are associated with CVD risk factors. Evolving methods of food preparation have made the traditional pattern less healthy.

Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study.

BACKGROUND AND AIMS: It was reported that high coffee consumption was related to decreased diabetes risk. The aim of this study is to examine the association between coffee consumption and the incidence of type 2 diabetes in persons with normal glucose tolerance in a population with a high incidence and prevalence of diabetes. METHODS AND RESULTS: In a prospective cohort study, information about daily coffee consumption was collected at the baseline examination (1989-1992) in a population-based sample of American Indian men and women 45-74 years of age. Participants with normal glucose tolerance (N = 1141) at the baseline examination were followed for an average of 7.6 years. The incidence of diabetes was compared across the categories of daily coffee consumption. The hazard ratios of diabetes related to coffee consumption were calculated using Cox proportional hazards models, adjusted for potential confounders. Levels of coffee consumption were positively related to levels of current smoking and inversely related to body mass index, waist circumference, female gender, and hypertension. Compared to those who did not drink coffee, participants who drank 12 or more cups of coffee daily had 67% less risk of developing diabetes during the follow-up (hazard ratio: 0.33, 95% confidence interval: 0.13, 0.81). CONCLUSION: In this population, a high level of coffee consumption was associated with a reduced risk of deterioration of glucose metabolism over an average 7.6 years of follow-up. More work is needed to understand whether there is a plausible biological mechanism for this observation.

Genome-wide linkage scan for plasma high density lipoprotein cholesterol, apolipoprotein A-1 and triglyceride variation among American Indian populations: the Strong Heart Family Study.

BACKGROUND: Recent studies have identified chromosomal regions linked to variation in high density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apo A-1) and triglyceride (TG), although results have been inconsistent and previous studies of American Indian populations are limited. OBJECTIVE: In an attempt to localise quantitative trait loci (QTLs) influencing HDL-C, apo A-1 and TG, we conducted genome-wide linkage scans of subjects of the Strong Heart Family Study. METHODS: We implemented analyses in 3484 men and women aged 18 years or older, at three study centres. RESULTS: With adjustment for age, sex and centre, we detected a QTL influencing both HDL-C (logarithm of odds (LOD) = 4.4, genome-wide p = 0.001) and apo A-1 (LOD = 3.2, genome-wide p = 0.020) nearest marker D6S289 at 6p23 in the Arizona sample. Another QTL influencing apo A-1 was found nearest marker D9S287 at 9q22.2 (LOD = 3.0, genome-wide p = 0.033) in the North and South Dakotas. We detected a QTL influencing TG nearest marker D15S153 at 15q22.31 (LOD = 4.5 in the overall sample and LOD = 3.8 in the Dakotas sample, genome-wide p = 0.0044) and when additionally adjusted for waist, current smoking, current alcohol, current oestrogen, lipid treatment, impaired fasting glucose, and diabetes, nearest marker D10S217 at 10q26.2 (LOD = 3.7, genome-wide p = 0.0058) in the Arizona population. CONCLUSIONS: The replication of QTLs in regions of the genome that harbour well known candidate genes suggest that chromosomes 6p, 9q and 15q warrant further investigation with fine mapping for causative polymorphisms in American Indians.

Sex-specific interaction between APOE genotype and carbohydrate intake affects plasma HDL-C levels: the Strong Heart Family Study.

Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are identified as a risk factor for cardiovascular disease (CVD). Sexual dimorphism, however, is widely reported in both HDL-C and CVD, with the underlying explanations of these sexual differences not fully understood. HDL-C is a complex trait influenced by both genes and dietary factors. Here we examine evidence for a sex-specific effect of APOE and the macronutrient carbohydrate on HDL-C, triglycerides (TG) and apoprotein A-1 (ApoA-1) in a sample of 326 male and 423 female participants of the Strong Heart Family Study (SHFS). Using general estimating equations in SAS to account for kinship correlations, stratifying by sex, and adjusting for age, body mass index (BMI) and SHS center, we examine the relationship between APOE genotype and carbohydrate intake on circulating levels of HDL-C, TG, and ApoA-1 through a series of carbohydrate-by-sex interactions and stratified analyses. APOE-by-carbohydrate intake shows significant sex-specific effects. All males had similar decreases in HDL-C levels associated with increased carbohydrate intake. However, only those females with APOE-4 alleles showed significantly lower HDL-C levels as their percent of carbohydrate intake increased, while no association was noted between carbohydrate intake and HDL-C in those females without an APOE-4 allele. These findings demonstrate the importance of understanding sex differences in gene-by-nutrient interaction when examining the complex architecture of HDL-C variation.

Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study.

Previous studies have demonstrated that low density lipoprotein cholesterol (LDL-C) concentration is influenced by both genes and environment. Although rare genetic variants associated with Mendelian causes of increased LDL-C are known, only one common genetic variant has been identified, the apolipoprotein E gene (APOE). In an attempt to localize quantitative trait loci (QTLs) influencing LDL-C, we conducted a genome-wide linkage scan of LDL-C in participants of the Strong Heart Family Study (SHFS). Nine hundred eighty men and women, age 18 years or older, in 32 extended families at three centers (in Arizona, Oklahoma, and North and South Dakota) were phenotyped for LDL-C concentration and other risk factors. Using a variance component approach and the program SOLAR, and after accounting for the effects of covariates, we detected a QTL influencing LDL-C on chromosome 19, nearest marker D19S888 at 19q13.41 [logarithm of odds (LOD) = 4.3] in the sample from the Dakotas. This region on chromosome 19 includes many possible candidate genes, including the APOE/C1/C4/C2 gene cluster. In follow-up association analyses, no significant evidence for an association was detected with the APOE*2 and APOE*4 alleles (P = 0.76 and P = 0.53, respectively). Suggestive evidence of linkage to LDL-C was detected on chromosomes 3q, 4q, 7p, 9q, 10p, 14q, and 17q. These linkage signals overlap positive findings for lipid-related traits and harbor plausible candidate genes for LDL-C.

Relation of insulin resistance to markers of preclinical cardiovascular disease: the Strong Heart Study.

BACKGROUND AND AIMS: To investigate whether insulin-resistance influences echocardiographic markers of preclinical disease, independent of significant confounders. METHODS AND RESULTS: We examined 1,471 (59 +/- 8 years) non-diabetic individuals (WHO criteria) with available echocardiograms from the Strong Heart Study cohort. Among them, 530 subjects had arterial hypertension (62% on medications), 152 had impaired glucose tolerance (GT) and 460 were normotensive, non-obese with normal GT. Insulin resistance was estimated by the Homeostasis Model Assessment (HOMA). LV mass, systolic function measured at the endocardium and the midwall (also correcting for circumferential wall stress) and arterial compliance (stroke volume/pulse pressure as a percent of predicted from body weight, age and heart rate [delta %SV/PP]) were measured by echocardiography, as prognostically validated markers of preclinical disease. HOMA-index was related positively to body mass index (BMI), waist/hip ratio (WHR), blood pressure, left ventricular (LV) mass, and negatively to arterial compliance (all p < 0.005) in the whole population, as well as in separate normotensive or hypertensive groups. In multiple regression models, relation of HOMA-index with the markers of risk was adjusted for age, sex, WHR, body mass index, presence of hypertension and number of antihypertensive medications. In this analysis, neither LV mass nor indices of systolic function were independently related to HOMA-index. In contrast, HOMA-index maintained a significant negative association with delta %SV/PP, independent of demographics, hypertension, treatment and body fat distribution. Also, HOMA-index maintained an independent relation with LV mass, when WHR and BMI were not included in the regression model. CONCLUSIONS: After accounting for relevant biological covariates, including body mass and fat distribution, insulin-resistance measured by HOMA is not an independent correlate of LV mass and function, but negatively influences arterial compliance.

Evidence for joint action of genes on diabetes status and CVD risk factors in American Indians: the strong heart family study.

OBJECTIVES: Previous research among American Indians of the strong heart family study (SHFS) has demonstrated significant heritabilities for CVD risk factors and implicated diabetes as an important predictor of several of the phenotypes. Moreover, we recently demonstrated that genetic effects on CVD risk factors differed in diabetic and nondiabetic individuals. In this paper, we investigated whether a significant genetic influence on diabetes status could be identified, and whether there is evidence for joint action of genes on diabetes status and related CVD risk factors. METHODS AND RESULTS: Approximately 950 men and women, age 18 or older, in 32 extended families, were examined between 1997 and 1999. We estimated the effects of genes and environmental covariates on diabetes status using a threshold model and a maximum likelihood variance component approach. Diabetes status exhibited a residual heritability of 22% (h2=0.22). We also estimated the genetic and environmental correlations between diabetes susceptibility and eight risk factors for CVD. All eight CVD risk factors displayed significant genetic correlations with diabetes status (BMI (rhoG=0.55), fibrinogen (rhoG=0.40), HDL-C (rhoG=-0.37), ln triglycerides (rhoG=0.65), FAT (rhoG=0.38 ), PAI-1 (rhoG=0.67), SBP (rhoG=0.57), and WHR (rhoG=0.58)). Three of eight traits (HDL-C (rhoE=-0.32), ln triglycerides (rhoE=0.33), and fibrinogen (rhoE=0.20)) displayed significant environmental correlations with diabetes status. CONCLUSIONS: These findings suggest that in the context of a high prevalence of diabetes, still unidentified diabetes genes may play an important role in influencing variation in CVD risk factors.

Prevalence and correlates of mitral valve prolapse in a population-based sample of American Indians: the Strong Heart Study.

PURPOSE: Mitral valve prolapse is heritable and occurs frequently in the general population despite associations with mitral regurgitation and infective endocarditis, suggesting that selective advantages might be associated with mitral valve prolapse. SUBJECTS AND METHODS: Clinical examination and 2-dimensional and color Doppler echocardiography were performed in 3340 American Indian participants in the Strong Heart Study. RESULTS: Mitral valve prolapse (clear-cut billowing of one or both mitral leaflets across the mitral anular plane in 2-dimensional parasternal long-axis recordings or >2-mm late systolic posterior displacement of mitral leaflets by M mode) occurred in 37 (1.8%) of 2077 women and 20 (1.6%) of 1263 men (P = 0.88); 32 (3.5%) of 907 patients with normal glucose tolerance, 11 (2.3%) of 486 patients with impaired glucose tolerance, and 13 (0.7%) of 1735 patients with diabetes (P <0.0001). Participants with mitral valve prolapse had lower mean (+/- SD) body mass index (28 +/- 5 kg/m(2) vs. 31 +/- 6 kg/m(2), P = 0.001) and blood pressure (124/71 +/- 19/10 mm Hg vs. 130/75 +/- 21/10 mm Hg, P <0.05), as well as lower levels of fasting glucose, triglycerides, serum creatinine, and log urine albumin/creatinine ratio (all P <0.001), than did those without mitral valve prolapse, although all subjects were similar in age (60 +/- 8 years). Participants with mitral valve prolapse had lower ventricular septal (0.87 +/- 0.08 cm vs. 0.93 +/- 0.13 cm) and posterior wall thicknesses (0.82 +/- 0.08 cm vs. 0.87 +/- 0.10 cm), mass (38 +/- 7 g/m(2.7) vs. 42 +/- 11 g/m(2.7)), and relative wall thickness (0.33 +/- 0.04 vs. 0.35 +/- 0.05), and increased stress-corrected midwall shortening (all P <0.01). Mitral valve prolapse was associated with a higher prevalence of mild (16 of 57 [28%] vs. 614 of 3283 [19%]) and more severe mitral regurgitation (5 of 57 [9%] vs. 48 of 3283 [1%], P <0.0001). Regression analyses showed prolapse was associated with low ventricular relative wall thickness, high midwall function, and low urine albumin/creatinine ratio, independent of age, sex, body mass index, and diabetes. CONCLUSIONS: Mitral valve prolapse is fairly common and is strongly associated with mitral regurgitation in the general population. However, it is also associated with lower body weight, blood pressure, and prevalence of diabetes; a more favorable metabolic profile and ventricular geometry; and better myocardial and renal function.

Hypertension treatment patterns in American Indians: the strong heart study.

Pharmacologic treatment patterns for hypertensive American Indians from 13 communities in Arizona, Oklahoma, South Dakota, and North Dakota were assessed. Participants (2254 women and 1384 men, aged 48 to 79 years) completed a clinical examination between July 1993 and December 1995. The mean of two blood pressure (BP) measurements and detailed medication histories were obtained. The observed prevalence of hypertension was 46.7% (n=1698). In participants taking antihypertensive medications (n=1114), four principal drug classes were evaluated: diuretics, calcium channel blocking agents, beta-blocking agents, and angiotensin-converting enzyme (ACE) inhibitors. Among treated hypertensive participants, 71.4%, 24.6%, and 4.0% received one, two, and three medications, respectively. Among single drug regimens, ACE inhibitors (n=340) were used most often (49.4%), with calcium channel blocking agents and diuretics accounting for 24.2% and 19.9%, respectively. Although multiple drug class therapies varied, the combination of a diuretic and ACE inhibitor (n=120) accounted for 47.4% of dual therapy use. Hypertension control (SBP < 140 mm Hg, DBP < 90 mm Hg) rates were highest for those on dual therapies (65.4%), followed by participants on single (53.8%) and triple (43.6%) therapies. Among monotherapies, diuretics exhibited the best overall hypertension control rate in both diabetics (63.0%) and nondiabetics (68.0%), versus 47% to 61% for other remaining agents. The frequent use of ACE inhibitors, used singly or in combination, reflects the high prevalence of diabetes among American Indians. ACE inhibitors, combined with diuretics, were particularly useful in achieving BP control in this population.

Reference values for echocardiographic measurements in urban and rural populations of differing ethnicity: the Strong Heart Study.

Discrepancies in reported reference values for left ventricular (LV) dimensions and mass may be due to imaging errors with early echocardiographic methods or effects of subject characteristics and inclusion criteria. To determine whether contemporary echocardiographic methods provide stable normal limits for left ventricular measurements in different populations, M-mode/2-dimensional echocardiography was applied in 176 American Indian participants in the Strong Heart Study and 237 New York City residents who were clinically normal. No consistent difference in any measure of LV size or function existed between populations. Upper normal limits (98th percentile) for LV mass were 96 g/m(2) in women and 116 g/m(2) in men and 3.27 cm/m for LV chamber diameter normalized for height. Thus contemporary M-mode/2D echocardiography provides reference ranges for LV measurements that approximate necropsy measurements and have acceptable stability in apparently normal white, African-American/Caribbean, and American Indian populations.

Computerized ST depression analysis improves prediction of all-cause and cardiovascular mortality: the strong heart study.

BACKGROUND: Nonspecific ST depression assessed by standard visual Minnesota coding (MC) has been demonstrated to predict risk. Although computer analysis has been applied to digital ECGs for MC, the prognostic value of computerized MC and computerized ST depression analyses have not been examined in relation to standard visual MC. METHODS: The predictive value of nonspecific ST depression as determined by visual and computerized MC codes 4.2 or 4.3 was compared with computer-measured ST depression >or= 50 microV in 2,127 American Indian participants in the first Strong Heart Study examination. Computerized MC and ST depression were determined using separate computerized-ECG analysis programs and visual MC was performed by an experienced ECG core laboratory. RESULTS: The prevalence of MC 4.2 or 4.3 by computer was higher than by visual analysis (6.4 vs 4.4%, P < 0.001). After mean follow-up of 3.7 +/- 0.9 years, there were 73 cardiovascular deaths and 227 deaths from all causes. In univariate Cox analyses, visual MC (relative risk [RR] 4.8, 95% confidence interval [CI] 2.6-9.1), computerized MC (RR 6.0, 95% CI 3.5-10.3), and computer-measured ST depression (RR 7.6, 95% CI 4.5-12.9) were all significant predictors of cardiovascular death. In separate multivariate Cox regression analyses that included age, sex, diabetes, HDL and LDL cholesterol, body mass index, systolic and diastolic blood pressure, microalbuminuria, smoking, and the presence of coronary heart disease, computerized MC (RR 3.0, 95% CI 1.6-5.6) and computer-measured ST depression (RR 3.1, 95% CI 1.7-5.7), but not visual MC, remained significant predictors of cardiovascular mortality. When both computerized MC and computer-measured ST depression were entered into the multivariate Cox regression, each variable provided independent risk stratification (RR 2.1, 95% CI 1.0-4.4, and RR 2.1, 95% CI 1.0-4.4, respectively). Similarly, computerized MC and computer-measured ST depression, but not visual MC, were independent predictors of all-cause mortality after controlling for standard risk factors. CONCLUSIONS: Computer analysis of the ECG, using computerized MC and computer-measured ST depression, provides independent and additive risk stratification for cardiovascular and all-cause mortality, and improves risk stratification compared with visual MC. These findings support the use of routine computer analysis of ST depression on the rest ECG for assessment of risk and suggest that computerized MC can replace visual MC for this purpose.

Relationship of impaired glucose tolerance to left ventricular structure and function: The Strong Heart Study.

BACKGROUND: We have identified increased left ventricular (LV) mass, wall thickness, relative wall thickness, and reduced systolic function in diabetic individuals after adjusting for blood pressure and body mass index. However, the cardiovascular correlates of impaired glucose tolerance (IGT), a precursor of diabetes, are unknown. METHODS: We compared LV measurements between 457 American Indian participants in the Strong Heart Study with IGT (34% men) by World Health Organization criteria and 888 participants (49% men) with normal glucose tolerance. RESULTS: Participants with IGT were older (60 vs 59 years, P < .01), more overweight (body mass index, 32 +/- 6 vs 29 +/- 5 g/m(2)), and had higher systolic blood pressure (129 +/- 20 vs 124 +/- 18 mm Hg, P < .001) and heart rate (67 +/- 10 vs 66 +/- 11 beats/min, P = .011). In univariate analyses, women but not men with IGT had higher LV mass (mean, 150 vs 138 g, P < .001) and cardiac index (2.6 vs 2.5 L/min/m(2), P < .05). LV wall thicknesses and relative wall thickness were greater in women and men with IGT. Regression analysis, adjusting for multiple covariates in the entire study population, identified independent associations of IGT with higher LV relative wall thicknesses, LV mass/height(2.7), and cardiac output/height(1.83). CONCLUSIONS: IGT is associated with increased LV wall thickness, mass, and cardiac output independent of effects of relevant covariates.

Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure and function in American Indians (the Strong Heart Study).

Although the association of systemic hypertension (SH) with diabetes mellitus (DM) is well established, the cardiac features and hemodynamic profile of patients with SH and DM diagnosed by American Diabetes Association criteria have not been elucidated. To address this issue, echocardiograms were analyzed in 1,025 American Indian participants of the Strong Heart Study with neither DM nor SH, 642 with DM alone, 614 with SH alone, and 874 with SH and DM. In analyses that adjusted for age, gender, body mass index, and heart rate, DM and SH were associated with increased left ventricular (LV) wall thicknesses, with the greatest impact of DM on LV relative wall thickness and of the combination of DM and SH on LV mass (both p <0.001). LV fractional shortening was reduced with SH and SH + DM, midwall shortening was reduced with DM, SH, and their combination, and was reduced in both diabetic groups compared with their nondiabetic counterparts (p <0.001). DM alone was associated with lower measures of LV pump performance (stroke volume, cardiac output, and their indexes) than SH alone. Pulse pressure/stroke index, an indirect measure of arterial stiffness, was elevated in participants with DM or SH alone and most in those with both conditions. There were progressive increases from the reference group to DM alone, SH alone, and DM + SH with regard to prevalences of LV hypertrophy (12% to 19%, 29% and 38%) and subnormal LV myocardial function (7% to 10%, 11% and 18%, both p <0.001). In conclusion, DM and SH each have adverse effects on LV geometry and function, and the combination of SH and DM results in the greatest degree of LV hypertrophy, myocardial dysfunction, and arterial stiffness.

A population-based assessment of left ventricular systolic dysfunction in middle-aged and older adults: the Strong Heart Study.

BACKGROUND: Although clinical congestive heart failure (CHF) is increasingly common, few data document the prevalence and correlates of underlying left ventricular (LV) systolic dysfunction (D) in population-based samples. METHODS: Echocardiography was used in the second Strong Heart Study (SHS) examination to identify mild and severe LVD (LV ejection fraction [EF] 40%-54% and <40%, respectively) in 3184 American Indians. RESULTS: Mild and severe LVD were more common in men than women (17.4% vs 7.2% and 4.7% vs 1.8%) and in diabetic than nondiabetic participants (12.7% vs 9.1% and 3.5% vs 1.6%). Stepwise increases were observed from participants with normal EF to those with mild and severe LVD in age (mean 60 vs 61 and 63 years, P <.001), prevalence of overt CHF (2% vs 6% and 28%) and definite coronary heart disease (3% vs 11% and 32%), systolic pressure (129 vs 135 and 136 mm Hg), serum creatinine level (0.98 vs 1.34 and 2.16 mg/dL), and log urinary albumin/creatinine level (3.2 vs 3.7 and 4.7); a negative relation was seen with body mass index (31.1 vs 31.0 and 28.4 kg/m(2)) (all P <.001). In multivariate analyses lower LVEFs were independently associated with clinical CHF and coronary heart disease, lower myocardial contractility, male sex, hypertension, overweight, arterial stiffening (higher pulse pressure/stroke volume) and renal dysfunction (higher serum creatinine level), higher LV mass, and lower relative wall thickness. CONCLUSIONS: LVD, present in approximately 14% of middle-aged to elderly adults, is independently associated with overt heart failure and coronary heart disease, male sex, hypertension, overweight, arterial stiffening, and renal target organ damage and, less consistently, with older age and diabetes.

Prevalence and correlates of mitral regurgitation in a population-based sample (the Strong Heart Study).

Evidence suggesting that mitral regurgitation (MR) may be induced by appetite suppressant medications heightens the importance of understanding the prevalence and correlates of MR, especially its relation to obesity, in population-based samples. MR was assessed by color Doppler echocardiography in 3,486 American Indian participants in the Strong Heart Study. Mild (1+) MR was present in 19.2%, moderate (2+) MR in 1.6%, moderately severe (3+) in 0.3%, and severe (4+) in 0.2% of participants. In univariate analyses, MR was unrelated to gender, diabetes, or lipid levels, but was more frequent in North/South Dakota (28.3%) than in Oklahoma (21.6%) or Arizona (14.3%) (p <0.001). MR was related to lower body mass index (BMI) (p <0.001), older age (p <0.001), higher systolic blood pressure (p = 0.003), higher serum creatinine (p <0.001), and higher urine albumin/creatinine ratio (p <0.001). In multivariate analyses, the presence and severity of MR were independently associated with higher serum creatinine, lower BMI, mitral stenosis, prior myocardial infarction, female gender, mitral valve prolapse and, variably, older age. In conclusion, MR, mostly mild, is detected by color Doppler echocardiography in >20% of middle-aged and older adults. MR is independently associated with female gender, lower BMI, older age, and renal dysfunction, as well as with prior myocardial infarction, mitral stenosis, and mitral valve prolapse. It is not related to dyslipidemia or diabetes.

Relations of stroke volume and cardiac output to body composition: the strong heart study.

BACKGROUND: Although cardiac output (CO) plays the vital role of delivering nutrients to body tissues, few data are available concerning the relations of stroke volume (SV) and CO to body composition in large population samples. METHODS AND RESULTS: Doppler and 2D echocardiography and bioelectric impedance in 2744 Strong Heart Study participants were used to calculate SV and CO and to relate them to fat-free body mass (FFM), adipose mass, and demographic variables. Both SV and CO were higher in men than women and in overweight than normal-weight individuals, but these differences were diminished or even reversed by normalization for FFM or body surface area. In both sexes, SV and CO were more strongly related to FFM than adipose mass, other body habitus measures, arterial pressure, diabetes, or age. In multivariate analyses using the average of Doppler and left ventricular SV to minimize measurement variability, FFM was the strongest correlate of SV and CO; other independent correlates were adipose mass, systolic pressure, diabetes, age, and use of digoxin and calcium channel and beta-blockers. CONCLUSIONS: In a population-based sample, SV and CO are more strongly related to FFM than other variables; increased FFM may be the primary determinant of increased SV and CO in obesity.

Imputation strategies for missing data in a school-based multi-centre study: the Pathways study.

Pathways is a multi-centre school-based trial sponsored by the National Heart, Lung, and Blood Institute testing the efficacy of an obesity prevention intervention in American Indian children. During the study's protocol development, we prepared an analysis plan that accounted for missing data. In this paper, we present a case study of the process we used to decide upon the final analysis plan. The primary endpoint of the Pathways study is a comparison of per cent body fat between treatment and usual care groups at the end of a three-year intervention. Other studies on children and Native Americans have had moderate to large amounts of missing data. As a result we were concerned that missing data in Pathways would affect the type I error rate and power of the test of our primary endpoint. We present results from our evaluation of three alternative procedures in this paper. The first is a multiple imputation procedure in which we replace missing values with resampled values from the observed data. The second is based on the Wilcoxon rank sum test; missing data in the intervention group receive the worst ranks. In the third, we use a multiple imputation procedure and replace missing values with predicted values from a regression equation with the coefficients estimated from observed follow-up data and baseline values. We found that the multiple imputation procedure that replaces missing values with predicted values had the best properties of the procedures we considered. The results from our simulation study showed that, for missing data patterns that are relevant to the Pathways study, this procedure has high power and maintains the type I error rate. Published in 2001 by John Wiley & Sons, Ltd.

Congestive heart failure despite normal left ventricular systolic function in a population-based sample: the Strong Heart Study.

In selected clinical series, > or = 50% of adults with congestive heart failure (CHF) do not have left ventricular (LV) systolic dysfunction. Little is known of the prevalence of this phenomenon in population samples. Therefore, clinical examination and echocardiography were used in the second examination of the Strong Heart Study (3,184 men and women, 47 to 81 years old) to identify 95 participants with CHF, 50 of whom had normal LV ejection fraction (EF) (> 54%), 19 of whom had mildly reduced EF (40% to 54%), and 26 of whom had EF < or = 40%. Compared with those with no CHF, participants with CHF and no, mild, or severe decrease in EF had higher creatinine levels (2.34 to 2.85 vs 1.01 mg/dl, p < 0.001) and higher prevalences of diabetes (60% to 70% vs 50%) and hypertension (75% to 96% vs 46%, p < 0.05). Compared with those with no CHF, participants with CHF and normal EF had prolonged deceleration time (233 vs 204 ms, p < 0.05) and a reduced E/A, whereas those with CHF and EF < or = 40% had short deceleration time (158 ms, p < 0.05) and high E/A (1.70, p < 0.001); patients with CHF and normal EF had higher LV mass (98 vs 84 g/m2, p < 0.001) and relative wall thickness (0.37 vs 0.35, p < 0.05) than those without CHF. Patients with CHF with normal EF were, compared with those without CHF or with CHF and EF < or = 40%, disproportionately women (mean 84% vs 63% and 42%, p < 0.001), older (mean 64 vs 60 years and 63 years, respectively, p < 0.01), had higher body mass index (mean 33.1 vs 31.0 and 27.7 kg/m2, p < 0.05), and higher systolic blood pressure (mean 137 vs 130 and 128 mm Hg, both p < 0.05). Thus, in a population-based sample, patients with CHF and normal LV EF were older and overweight, more often women, had renal dysfunction, impaired early diastolic LV relaxation, and concentric LV geometry, whereas patients with CHF and severe LV dysfunction were more often men, had lower body mass index, a restrictive pattern of LV filling, and eccentric LV hypertrophy.

Prevalence and correlates of aortic regurgitation in American Indians: the Strong Heart Study.

OBJECTIVES: We sought to determine the prevalence and correlates of aortic regurgitation (AR) in a population-based sample group. BACKGROUND: Concern over induction of AR by weight loss medication highlights the importance of assessing the prevalence and correlates of AR in unselected patient groups. METHODS: Aortic regurgitation was assessed by color flow Doppler echocardiography in 3,501 American Indian participants age 47 to 81 years during the second Strong Heart Study. RESULTS: Mild (1+) AR was present in 7.3%, 2+ AR in 2.4% and 3+ to 4+ AR in 0.3% of participants, more frequently in those > or =60 years old than in those <60 years old (14.4% vs. 5.8%, p<0.001); AR was unrelated to gender. Compared with participants without AR, those with mild AR had a lower body mass index (p<0.004) and higher systolic pressure (p<0.003). Participants with AR had larger aortic root diameters (3.6+/-0.4 vs. 3.4+/-0.4 cm, p<0.001), higher creatinine levels (1.3+/-1.3 vs. 1.0+/-1.0 mg/dl, p<0.001) and higher urine albumin/creatinine levels (3.6+/-2.3 vs. 3.3+/-2.0 log, p<0.001), as well as higher prevalences of aortic stenosis (AS) or mitral stenosis (MS) (p<0.001). Regression analysis showed that AR was independently related to older age and larger aortic roots (p<0.0001), AS and absence of diabetes (p = 0.002), MS (p = 0.003) and higher log urine albumin/creatinine (p = 0.005). CONCLUSIONS: Aortic regurgitation occurred in 10% of a sample group of middle-aged to older adults and was related to older age, larger aortic root diameter, aortic and mitral stenosis and albuminuria. There was no association of AR with being overweight and a negative association of AR with diabetes.