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Obesity is a typical metabolic disorder resulting from the imbalance between energy intake and expenditure. American Indians suffer disproportionately high rates of obesity and diabetes. The goal of this study is to identify metabolic profiles of obesity in 431 normoglycemic American Indians participating in the Strong Heart Family Study. Using an untargeted liquid chromatography-mass spectrometry, we detected 1,364 distinct m/z features matched to known compounds in the current metabolomics databases. We conducted multivariate analysis to identify metabolic profiles for obesity, adjusting for standard obesity indicators. After adjusting for covariates and multiple testing, five metabolites were associated with body mass index and seven were associated with waist circumference. Of them, three were associated with both. Majority of the obesity-related metabolites belongs to lipids, e.g., fatty amides, sphingolipids, prenol lipids, and steroid derivatives. Other identified metabolites are amino acids or peptides. Of the nine identified metabolites, five metabolites (oleoylethanolamide, mannosyl-diinositol-phosphorylceramide, pristanic acid, glutamate, and kynurenine) have been previously implicated in obesity or its related pathways. Future studies are warranted to replicate these findings in larger populations or other ethnic groups.

Purpose: The metabolic abnormalities that accompany diabetes mellitus are associated with an increased risk of many cancers. These associations, however, have not been well studied in American Indian populations, which experience a high prevalence of diabetes. The Strong Heart Study is a population-based, prospective cohort study with extensive characterization of diabetes status., Methods: Among a total cohort of 4,419 participants who were followed for up to 20 years, 430 cancer deaths were identified., Results: After adjusting for sex, age, education, smoking status, drinking status, and body mass index, participants with diabetes at baseline showed an increased risk of gastric (HR 4.09; 95% CI 1.42-11.79), hepatocellular (HR 2.94; 95% CI 1.17-7.40), and prostate cancer mortality (HR 3.10; 95% CI 1.22-7.94). Further adjustment for arsenic exposure showed a significantly increased risk of all-cause cancer mortality with diabetes (HR 1.27; 95% CI 1.03-1.58). Insulin resistance among participants without diabetes at baseline was associated with hepatocellular cancer mortality (HR 4.70; 95% CI 1.55-14.26)., Conclusions: Diabetes mellitus, and/or insulin resistance among those without diabetes, is a risk factor for gastric, hepatocellular, and prostate cancer in these American Indian communities, although relatively small sample size suggests cautious interpretation. Additional research is needed to evaluate the role of diabetes and obesity on cancer incidence in American Indian communities as well as the importance of diabetes prevention and control in reducing the burden of cancer incidence and mortality in the study population.

Objective: The purposes of this study were to investigate whether reduced lung function is associated with metabolic syndrome (MS) and diabetes (DM) in American Indians (AIs) and to determine whether lower pulmonary function presents before the development of DM or MS., Research Design and Methods: The Strong Heart Study (SHS) is a multicenter, prospective study of cardiovascular disease (CVD) and its risk factors among AI adults. The present analysis used lung function assessment by standard spirometry at the SHS second examination (1993-1995) in 2,396 adults free of overt lung disease or CVD, with or without DM or MS. Among MS-free/DM-free participants, the development of MS/DM at the SHS third examination (1996-1999) was investigated., Results: Significantly lower pulmonary function was observed for AIs with MS or DM. Impaired pulmonary function was associated with MS and DM after adjustment for age, sex, abdominal obesity, current smoking status, physical activity index, hypertension, and SHS field center. Both forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were negatively associated with insulin resistance or DM severity and with serum markers of inflammation (P < 0.05). FVC and FEV1-to-FVC ratio both predicted DM in unadjusted analyses but not when adjusted for covariates, including waist circumference. In the adjusted model, abdominal obesity predicted both MS and DM., Conclusions: Reduced lung function is independently associated with MS and with DM, and impaired lung function presents before the development of MS or DM; these associations may result from the effects of obesity and inflammation.

Background: Body fat mass distribution and deposition are determined by multiple environmental and genetic factors. Obesity is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes. We previously identified evidence for genotype-by-diabetes interaction on obesity traits in Strong Heart Family Study (SHFS) participants. To localize these genetic effects, we conducted genome-wide linkage scans of obesity traits in individuals with and without type 2 diabetes, and in the combined sample while modeling interaction with diabetes using maximum likelihood methods (SOLAR 2.1.4)., Methods: SHFS recruited American Indians from Arizona, North and South Dakota, and Oklahoma. Anthropometric measures and diabetes status were obtained during a clinic visit. Marker allele frequencies were derived using maximum likelihood methods estimated from all individuals and multipoint identity by descent sharing was estimated using Loki. We used variance component linkage analysis to localize quantitative trait loci (QTLs) influencing obesity traits. We tested for evidence of additive and QTL-specific genotype-by-diabetes interactions using the regions identified in the diabetes-stratified analyses., Results: Among 245 diabetic and 704 non-diabetic American Indian individuals, we detected significant additive gene-by-diabetes interaction for weight and BMI (P < 0.02). In analysis accounting for QTL-specific interaction (P < 0.001), we detected a QTL for weight on chromosome 1 at 242 cM (LOD = 3.7). This chromosome region harbors the adiponectin receptor 1 gene, which has been previously associated with obesity., Conclusion: These results suggest distinct genetic effects on body mass in individuals with diabetes compared to those without diabetes, and a possible role for one or more genes on chromosome 1 in the pathogenesis of obesity.

Objective: Obesity is a growing and important public health problem in Western countries and worldwide. There is ample evidence that both environmental and genetic factors influence the risk of developing obesity. Although a number of genes influencing obesity and obesity-related measures have been localized, it is clear that others remain to be identified. The rate of obesity is particularly high in American Indian populations. This study reports the results of a genome-wide scan for loci influencing BMI and weight in 963 individuals in 58 families from three American Indian populations in Arizona, Oklahoma, and North and South Dakota participating in the Strong Heart Family Study., Research Methods and Procedures: Short tandem repeat markers were genotyped, resulting in a marker map with an average spacing of 10 centimorgans. Standard multipoint variance component linkage methods were used., Results: Significant evidence of linkage was observed in the overall sample, including all three study sites, for a locus on chromosome 4q35 [logarithm of the odds (LOD)=5.17 for weight, 5.08 for BMI]. Analyses of the three study sites individually showed that the greatest linkage support for the chromosome 4 locus came from Arizona (LOD=2.6 for BMI), but that LOD scores for weight were >1 in all three samples. Suggestive linkage signals (LOD>2) were also observed on chromosomes 5, 7, 8, and 10., Discussion: The chromosome 4 locus detected in this scan is in a region lacking any obvious positional candidate genes with known functions related to obesity. This locus may represent a novel obesity gene.

Introduction: The myocardial performance index (MPI) introduced by Tei, a Doppler-derived echocardiographic measure that reflects both left ventricular (LV) systolic and diastolic function, has been shown to have prognostic value in several clinical settings, including myocardial infarction and congestive heart failure. There are scant data on the correlates and prognostic value of MPI in a population without overt cardiovascular (CV) disease., Methods: We investigated clinical and physiologic correlates of MPI, as assessed from echocardiographic Doppler recordings in 1,862 American Indian participants free of coronary or valvular disease or LV systolic dysfunction in the population-based strong heart study (SHS). We then assessed the prognostic value of MPI for incident CV events, including nonfatal stroke, coronary heart disease, congestive heart failure, and CV death., Results: The study population was 59 +/- 8 years old (66% women); 48% had diabetes, 44% hypertension, and 54% were obese. In univariable analyses, MPI (mean = 0.24 +/- 0.17) showed significant negative associations with creatinine clearance, C-reactive protein (CRP), LV ejection fraction (EF), mitral valve E- and A-wave velocities, cardiac index (CI), stroke index (SI) and stroke index/pulse pressure (SI/PP), and significant positive associations with serum creatinine and total peripheral resistance index (TPRI) (all P < 0.05). There were no significant associations of MPI with hypertension or diabetes status, systolic or diastolic blood pressure, body mass index, hemoglobin A1C or LV mass. After adjusting for age, sex, diabetes, and hypertension, MPI remained weakly but significantly correlated with CRP, EF, CI, SI, SI/PP, mitral E- and A-wave velocities, and TPRI. MPI did not predict fatal and nonfatal CV events (risk ratio 1.06 per unit MPI, 95% C.I. 0.56-2.04; P = 0.85) at a mean follow-up of 7.1 +/- 2.2 years., Conclusions: In a population-based sample of adults with high prevalence of diabetes, hypertension, and obesity but without overt CV disease, MPI has weak associations with clinical and physiologic determinants of cardiac function. Moreover, MPI does not provide prognostic information for CV events in this population. Though conceptually attractive as a global measure of cardiac function, MPI has limited utility in a high-risk population without clinical CV disease.

Objectives: The goal here was to examine left ventricular (LV) geometry and function in a large, unselected group of adolescents with different degrees of abnormal body build, and verify whether possibly higher LV mass is compensatory for increased cardiac workload., Background: There is little information on how much the excess of body weight impacts LV geometry and function in populations of adolescents., Methods: Anthropometric, laboratory, and Doppler echocardiographic parameters of cardiac geometry and function were obtained in 460 adolescent participants (age 14 to 20 years, 245 female participants, 27 hypertensive, 10 with diabetes) from the Strong Heart Study. Body build was classified based on 85th and 95th percentiles of body mass index (BMI)-for-age charts., Results: Range of BMI was 16.3 to 56.5 kg/m2 (28.8 +/- 8.3 kg/m2); 114 participants (24.9%) fell within the 85th percentile of BMI distribution (normal weight [NW]), 113 (24.6%) fell between 85th and 95th percentile (overweight [OW]), and 223 (48.5%) fell above the 95th percentile (obese [OB]). Obese participants were older than OW and NW subjects (p < 0.01), without differences in heart rate. Both OW and OB had greater LV diameter and mass than NW (all p < 0.05). Left ventricular hypertrophy was more prevalent in the OB (33.5%) and OW (12.4%), as compared with NW participants (3.5%; p < 0.001), largely compensating increased cardiac workload. However, OB subjects had four-fold higher probability of carrying an LV mass exceeding values compensatory for their cardiac workload (p < 0.001), a feature associated with lower ejection fraction, myocardial contractility, and greater force developed by left atrium to complete LV filling (all p < 0.05)., Conclusions: While in OW adolescents increased levels of LV mass are appropriate to compensate their higher hemodynamic load, in OB increase in LV mass exceeds this need and is associated with mildly reduced LV myocardial performance and increased left atrial force to contribute to LV filling.

To localize quantitative trait loci for insulin metabolism and obesity, genome scans/linkage analyses were performed on >900 members of 32 extended families participating in phase 3 of the Strong Heart Study, an investigation of the genetic and environmental determinants of cardiovascular disease in American-Indian populations from Arizona, Oklahoma, and North and South Dakota. Linkage analyses of fasting insulin and two obesity-related phenotypes, BMI and percent fat mass, were performed independently in each of the three populations. For log fasting insulin, we found a genome-wide maximum, robust logarithm of odds (LOD) score of 3.42 at 51 cM on chromosome 2p in the Dakotas. Bivariate linkage analyses of log fasting insulin with both BMI and fat mass indicate a situation of incomplete pleiotropy, as well as several significant bivariate LOD scores in the Dakotas.

Previous analyses of American Indians of the Strong Heart Study have demonstrated that various insulin-resistance variables cluster, although knowledge about the genetic determination of these clusters is unknown. In an effort to explore the influences on the aggregation of insulin-resistance phenotypes, we used principal component factor analysis to examine the clustering of these phenotypes in participants of the Strong Heart Family Study and evaluated the genetic and environmental contributions of such factors. Nine traits were chosen for principal component factor analysis: BMI, diastolic blood pressure, fasting glucose, high-density lipoprotein-cholesterol, natural log-transformed insulin, natural log-transformed triglycerides, percentage of body fat, systolic blood pressure, and waist-to-hip ratio. Analyses revealed three clusters: glucose/insulin/obesity, blood pressure, and dyslipidemia factors. Using a variance component approach and accounting for the effects of age, sex, center, and medication, we detected significant heritabilities (h2) for the three factors: h2 = 0.67, h2 = 0.33, and h2 = 0.61, respectively. In multivariate analysis, no significant genetic correlations among factors were found. These results suggest that heredity explains a substantial proportion of the variability of the factors that underlie the insulin resistance syndrome in American Indians and that these factors are genetically independent.

Background: The relationship between diabetes and increased cardiovascular disease (CVD) risk is well established. Previous data from the Strong Heart Family Study (SHFS) have demonstrated significant heritabilities for CVD risk factors and implicated diabetes as an important predictor of several of the phenotypes in three large groups of American Indians in Arizona (AZ), Oklahoma (OK), and the Dakotas (DK). However, the genetic architecture of this relationship is not well understood. The purpose of the present paper is to determine whether the genetic effects on CVD risk factors in the SHFS are different in diabetic and nondiabetic individuals., Methods: Approximately 950 men and women, 18 years or older, in 32 extended families, were examined between 1997 and 1999. Interaction between genotype and diabetes status was estimated for nine CVD risk factors [body fat mass (FAT), body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), log-transformed fibrinogen, log-transformed triglycerides, log-transformed urinary albumin : creatinine ratio (LACR), plasminogen activator inhibitor 1 (PAI-1), systolic blood pressure (SBP), and waist-to-hip ratio (WHR)], using a maximum likelihood variance decomposition technique., Results: We found evidence that genetic factors influencing BMI, FAT, log-transformed triglycerides, HDL-C, and WHR are differentially expressed in individuals with diabetes compared to those without diabetes., Conclusion: Thus, in the environmental and genetic milieu of diabetes, there may be distinct genetic determinants of various CVD risk factors., (Copyright 2002 John Wiley & Sons, Ltd.)

OBJECTIVE--Prevalence of insulin resistance is high in the American Indian population, likely as a result of the high prevalence of obesity. This condition may be influential for clinical outcomes such as cardiovascular disease (CVD) and decreased kidney function. RESEARCH DESIGN AND METHODS--Normal glucose tolerant (NGT) participants free of hypertension and CVD at the baseline examination (1989-1992) (N = 964) of the Strong Heart Study were selected to explore the cross-sectional association between insulin resistance quantified by homeostasis model assessment (HOMA-IR) and demographic, behavioral, and cardiometabolic variables. The longitudinal association between baseline HOMA-IR and the development of CVD was also explored. The longitudinal association between baseline HOMA-IR and the development of high urinary albumin-to-creatinine ratio was explored among nondiabetic participants (N = 1,401). RESULTS--Cross-sectionally, HOMA-IR was associated with sex, residence location, smoking, and high-risk cardiometabolic profile. Prospectively, insulin resistance is associated with the development of CVD and decreased kidney function in this population. CONCLUSIONS--Insulin resistance may have an important role in the pathogenesis of CVD and chronic kidney disease. Since obesity contributes to the development of insulin resistance, intervention focusing on modifiable factors such as physical activity and weight control may reduce the development of these diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- This study analyzed which definition of the metabolic syndrome is more predictive of cardiovascular events in both diabetic and nondiabetic members of a populationbased sample. RESEARCH DESIGN AND METHODS -- A 10-year, longitudinal follow-up of the Strong Heart Study cohort has been evaluated. The analysis included 3,945 participants (2,384 female) with complete data (1,700 with diabetes and 1,468 with arterial hypertension) for evaluation of metabolic syndrome. Those with prevalent cardiovascular disease were excluded (n = 287, of whom 127 were female). Prevalence of metabolic syndrome was assessed based on the World Health Organization (WHO), the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III, and International Diabetes Federation (IDF) definitions. The main outcome was 10-year incidence of combined fatal and nonfatal cardiovascular events, including stroke, coronary heart disease, and congestive heart failure. RESULTS -- Fatal and nonfatal cardiovascular events occurred in 1,120 participants. After adjusting for age, sex, and diabetes, metabolic syndrome by all definitions was significantly associated with higher incidence of cardiovascular events (all P < 0.0001). In nondiabetic individuals, incident cardiovascular event rates were about 30-40% higher in those with metabolic syndrome, without a significant difference among definitions (0.03 < P < 0.001), and remained significant in WHO and NCEP ATP III definitions even after further adjustment for obesity, hypertension, and low HDL cholesterol. In the diabetic group, metabolic syndrome risk for cardiovascular events was greatest using the WHO definition (P < 0.002 vs. other models). CONCLUSIONS -- In individuals without diabetes, metabolic syndrome is associated with incident cardiovascular disease, especially with WHO and NCEP ATP III definitions. Metabolic syndrome also predicts higher cardiovascular event rates in diabetic participants, a prediction that is greatest using the WHO definition. [ABSTRACT FROM AUTHOR]

Background: Left ventricular hypertrophy (LVH) is identified by left ventricular mass (LVM) normalized by body surface area (BSA) or height (in meters) also raised to allometric powers. The presence of LVH detected by these indices predicts increased cardiovascular (CV) events. Whether different indexations of LVH differ in their ability to predict excess risk is unknown. Methods: A total of 2400 subjects, (1589 women and 811 men), 59 ± 8 years of age and without prevalent CV disease, valve disease or wall motion abnormalities and high prevalence of obesity were followed for an average of 86 months. Reference values (mean ± 1.96 SD) for LVM/BSA, LVM/BSA1.5, LVM/m, LVM/m2.7, and LVM/m2.13 were obtained in 251 normal participants and population-attributable risk percent (PAR%) for fatal and nonfatal CV events were calculated from prevalence of LVH and hazard ratios (HR). Results: In the entire population or in hypertensive participants, prevalence of LVH was higher for LVM/m2.7 (20% and 28%) and LVM/m2.13 (18% and 25%) than for BSA (7% and 11%). Age and sex-adjusted PAR% for LVM/m2.7 or LVM/m2.13 were on average 1.8-fold greater than for LVM/BSA in the entire population, and 1.6-fold greater in hypertensive participants, differences that were statistically significant. Conclusions: The presence of LVH identified by LVM normalized for height to allometric powers is associated with a higher proportion of incident CV events than is LVH detected by normalization for BSA and is convenient for identification of individuals at high risk and in need of preventive intervention in populations with high prevalence of obesity. Allometric power methods allow detection of prognostically adverse, obesity-related LVH, which is unidentified using BSA. [Copyright &y& Elsevier]

Background: Myocardial energetic efficiency (MEE), is a strong predictor of CV events in hypertensive patient and is reduced in patients with diabetes and metabolic syndrome. We hypothesized that severity of insulin resistance (by HOMA-IR) negatively influences MEE in participants from the Strong Heart Study (SHS). Methods: We selected non-diabetic participants (n = 3128, 47 ± 17 years, 1807 women, 1447 obese, 870 hypertensive) free of cardiovascular (CV) disease, by merging two cohorts (Strong Heart Study and Strong Heart Family Study, age range 18–93). MEE was estimated as stroke work (SW = systolic blood pressure [SBP] × stroke volume [SV])/"double product" of SBP × heart rate (HR), as an estimate of O2 consumption, which can be simplified as SV/HR ratio and expressed in ml/sec. Due to the strong correlation, MEE was normalized by left ventricular (LV) mass (MEEi). Results: Linear trend analyses showed that with increasing quartiles of HOMA-IR patients were older, more likely to be women, obese and hypertensive, with a trend toward a worse lipid profile (all p for trend < 0.001), progressive increase in LV mass index, stroke index and cardiac index and decline of wall mechanics (all p < 0.0001). In multivariable regression, after adjusting for confounders, and including a kinship coefficient to correct for relatedness, MEEi was negatively associated with HOMA-IR, independently of significant associations with age, sex, blood pressure, lipid profile and central obesity (all p < 0.0001). Conclusions: Severity of insulin resistance has significant and independent negative impact on myocardial mechano-energetic efficiency in nondiabetic individual from a population study of American Indians. Trial registration number NCT00005134, Name of registry: Strong Heart Study, URL of registry: https://clinicaltrials.gov/ct2/show/NCT00005134, Date of registration: May 25, 2000, Date of enrolment of the first participant to the trial: September 1988 [ABSTRACT FROM AUTHOR]

Background: In normal conditions, energy to support cardiac work is provided almost exclusively by aerobic oxidation of substrate, 60-70% represented by fatty acid and 30-40% by glucose-pyruvate. In diseased condition the energy production shifts toward the more convenient glucose-pyruvate oxidation. The efficiency of LV performance is the ratio between the produced external work (SW) and the amount of O2 needed to produce the due energy (MVO2). We hypothesized that severity of insulin resistance influences myocardial mechano-energetic efficiency (MEE) for each g of LV mass. Methods: We selected non diabetic participants (n=3128), by merging 2 cohorts (Strong Heart Study and Strong Heart Family Study). MEE was estimated as the ratio between the stroke work (SW=systolic blood pressure [SBP]хstroke volume [SV]) and the "double product" of SBPхheart rate (HR), which can be simplified as SV/HR ratio and expressed in mL/sec. We have previously shown that MEE normalized by LV mass (MEEi) predicts increased incidence of composite cardiovascular (CV) independently of LV hypertrophy. The population sample was divided into quartiles of HOMA-IR. The trend among HOMA-IR quartiles was also adjusted for relevant confounders, using multivariable procedures. Results: The population was 47±17 years, and included 1807 women, 1447 obese, 870 hypertensive, 476 with impaired fasting glucose. A linear polynomial contrast demonstrated that with increasing HOMA-IR, patients were older more likely to be women, obese and hypertensive with a trend toward a worse lipid profile (all p for trend <0.001). Increasing in HOMA-IR was also associated with progressively increase in LV mass index, stroke index and cardiac index (all p<0.0001). In multivariable regression model, after adjusting for significant confounder, including a kinship coefficient to correct for relatedness, reduced MEEi was associated with increased HOMA-IR, independently of significant association with older age, female sex, higher SBP, higher triglycerides level and central obesity (all p < 0.0001). Conclusions: Severity of insulin resistance has significant and independent impact on myocardial mechano-energetic efficiency in non-diabetic individual from a population study of American Indians. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to evaluate the impact of metabolic syndrome (MetS) on cardiac phenotype in adolescents. Background: A high prevalence of MetS has been reported in adolescents. Methods: Four hundred forty-six nondiabetic American Indian adolescents (age 14 to 20 years, 238 girls) underwent clinical evaluation, laboratory testing, and Doppler echocardiography. Age- and gender-specific partition values were used to define obesity and hypertension. Metabolic syndrome was defined according to Adult Treatment Panel III criteria, modified for adolescents. Left ventricular (LV) hypertrophy and left atrial (LA) dilation were identified using age- and gender-specific partition values. Results: One hundred eleven participants met criteria for MetS. They had a similar age and gender distribution as non-MetS participants. Analysis of covariance, controlling for relevant confounders, demonstrated that participants with MetS had higher LV, LA, and aortic root diameters, higher LV relative wall thickness, and greater LV mass index. Accordingly, MetS participants showed higher prevalences of LV hypertrophy (43.2% vs. 11.7%) and LA dilation (63.1% vs. 21.9%, both p < 0.001) compared with non-MetS participants. In addition, MetS was associated with a reduction in midwall shortening, lower transmitral mitral early to atrial peak velocity ratio, and mildly prolonged mitral early deceleration time (all p < 0.05). In multiple regression analysis, independently of demographics, obesity, blood pressure, and single metabolic components of MetS, clustered MetS was associated with a 2.6-fold higher likelihood of LV hypertrophy and a 2.3-fold higher likelihood of LA dilation (both p ≤ 0.02). Conclusions: In a population sample of adolescents, MetS is associated with higher prevalences of LV hypertrophy and LA dilation and with reduced LV systolic and diastolic function, independently of individual MetS components. [Copyright &y& Elsevier]