Richard R. Fabsitz

Relationship of High and Low Ankle Brachial Index to All-Cause and Cardiovascular Disease Mortality The Strong Heart Study

Background—The associations of low (<0.90) and high (>1.40) ankle brachial index (ABI) with risk of all-cause and cardiovascular disease (CVD) mortality have not been examined in a population-based setting. Methods and Results—We examined all-cause and CVD mortality in relation to low and high ABI in 4393 American Indians in the Strong Heart Study. Participants had bilateral ABI measurements at baseline and were followed up for 8.3±2.2 years (36 589 person-years). Cox regression was used to quantify mortality rates among participants with high and low ABI relative to those with normal ABI (0.90 ≤ABI ≤1.40). Death from all causes occurred in 1022 participants (23.3%; 27.9 deaths per 1000 person-years), and of these, 272 (26.6%; 7.4 deaths per 1000 person-years) were attributable to CVD. Low ABI was present in 216 participants (4.9%), and high ABI occurred in 404 (9.2%). Diabetes, albuminuria, and hypertension occurred with greater frequency among persons with low (60.2%, 44.4%, and 50.1%) and high (67.8%, 49.9%, and 45.1%) ABI compared with those with normal ABI (44.4%, 26.9%, and 36.5%), respectively (P <0.0001). Adjusted risk estimates for all-cause mortality were 1.69 (1.34 to 2.14) for low and 1.77 (1.48 to 2.13) for high ABI, and estimates for CVD mortality were 2.52 (1.74 to 3.64) for low and 2.09 (1.49 to 2.94) for high ABI. Conclusions—The association between high ABI and mortality was similar to that of low ABI and mortality, highlighting a U-shaped association between this noninvasive measure of peripheral arterial disease and mortality risk. Our data suggest that the upper limit of normal ABI should not exceed 1.40.

Impact of Diabetes on Cardiac Structure and Function The Strong Heart Study

BACKGROUND Whether diabetes mellitus (DM) adversely affects left ventricular (LV) structure and function independently of increases in body mass index (BMI) and blood pressure is controversial. METHODS AND RESULTS Echocardiography was used in the Strong Heart Study, a study of cardiovascular disease in American Indians, to compare LV measurements between 1810 participants with DM and 944 with normal glucose tolerance. Participants with DM were older (mean age, 60 versus 59 years), had higher BMI (32.4 versus 28.9 kg/m(2)) and systolic blood pressure (133 versus 124 mm Hg), and were more likely to be female, to be on antihypertensive treatment, and to live in Arizona (all P<0.001). In analyses adjusted for covariates, women and men with DM had higher LV mass and wall thicknesses and lower LV fractional shortening, midwall shortening, and stress-corrected midwall shortening (all P<0.002). Pulse pressure/stroke volume, a measure of arterial stiffness, was higher in participants with DM (P<0.001 independent of confounders). CONCLUSIONS Non-insulin-dependent DM has independent adverse cardiac effects, including increased LV mass and wall thicknesses, reduced LV systolic chamber and myocardial function, and increased arterial stiffness. These findings identify adverse cardiovascular effects of DM, independent of associated increases in BMI and arterial pressure, that may contribute to cardiovascular events in diabetic individuals.

Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins.

SummaryConcordance for Type 2 (non-insulin-dependent) diabetes was determined in 250 monozygotic and 264 dizygotic white male twin pairs who participated in the National Heart, Lung, and Blood Institute Twin Study. These twins were born between 1917 and 1927 and were identified from military records without regard to disease status. We examined surviving members of the cohort twice — at mean ages of 47 and 57 years — and obtained 1-h post-load glucose tests and medication histories. Diagnostic criteria for Type 2 diabetes included a glucose value≥13.9 mmol/l or current use of antidiabetic medication; possible Type 1 (insulin-dependent) diabetic twins were excluded. A strong genetic predisposition to Type 2 diabetes was suggested by 3 lines of evidence from the second examination: (1) 58% of monozygotic co-twins of diabetic twins were themselves diabetic compared with an expected prevalence of 10%; (2) only 1 of 15 originally disease-discordant, monozygotic twin pairs remained discordant for diabetes; and (3) 65% of non-diabetic monozygotic co-twins of diabetic twins had elevated glucose values. Because concordance for diabetes was less than 100% for twins aged 52–65 years and because twins varied in age at onset of disease, non-genetic factors may also influence diabetes development. Among the 19 monozygotic twins pairs discordant for diabetes, diabetic twins did not differ from their non-diabetic co-twins in obesity, diet, alcohol consumption, or education. However, compared with unrelated nondiabetic twins of the same ages, non-diabetic co-twins of diabetic twins gained more weight as adults (p<0.02) and had higher glucose levels (p<0.03).

Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a “cosmopolitan” tagging approach to capture the genetic diversity across ∼2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

Mitral Ratio of Peak Early to Late Diastolic Filling Velocity as a Predictor of Mortality in Middle-Aged and Elderly Adults: The Strong Heart Study

Background—With aging, left ventricular filling tends to decrease in early diastole, reducing the mitral ratio of peak early to late diastolic filling velocity (E/A). However, the prognostic significance of low or high E/A in older adults remains to be elucidated in population-based samples. Methods and Results—Doppler echocardiograms were analyzed in 3008 American Indian participants in the second Strong Heart Study examination who had no more than mild mitral or aortic regurgitation. Participants were followed for a mean of 3 years after Doppler echocardiography to assess risks of all-cause and cardiac death associated with E/A <0.6 or >1.5; 2429 (81%) participants had normal E/A ratio, 490 (16%) had E/A <0.6, and 89 (3%) had E/A >1.5. All-cause mortality was higher with E/A <0.6 or E/A >1.5 (12% and 13% versus 6%), as was cardiac mortality (4.5% and 6.5% versus 1.6%; both P <0.001). Adjusting for age, sex, body mass index, systolic blood pressure, HDL and LDL cholesterol, smoking, hypertension, diabetes, coronary heart disease, left ventricular hypertrophy, and low ejection fraction (<40%), the relative risk of all-cause death with E/A >1.5 was 1.73 (95% CI, 0.99 to 3.03;P =0.05); the relative risk of cardiac death was 2.8 (95% CI, 1.19 to 6.75;P <0.05). E/A <0.6 was not independently associated with increased all-cause or cardiac mortality (P =0.19 and 0.31, respectively) after adjusting for covariates. Conclusions—In a population-based sample of middle-aged and elderly adults, mitral E/A >1.5 at baseline Doppler echocardiography is associated with 2-fold increased all-cause and 3-fold increased cardiac mortality independent of covariates; mitral E/A <0.6 was also associated with 2-fold increased all-cause and cardiac mortality but not independent of covariates.

Assessment of QT Interval and QT Dispersion for Prediction of All-Cause and Cardiovascular Mortality in American Indians The Strong Heart Study

BACKGROUND Both a prolonged QT interval and increased QT interval dispersion (QTD) have been proposed as surface ECG markers of vulnerability to ventricular arrhythmias and potential predictors of mortality. METHODS AND RESULTS The predictive values of QT prolongation and QTD were assessed in 1839 participants in the Strong Heart Study, a prospective study of cardiovascular disease in American Indians. ECGs were acquired at 250 Hz; QT intervals were measured by computer in all 12 leads and corrected for heart rate (QTc) by use of Bazetts formula. QTD was calculated as the difference between the maximum and minimum QTc. After a mean follow-up of 3.7+/-0.9 years, there were 188 deaths from all causes, including 55 cardiovascular deaths. In univariate Cox analyses, prolonged QTc and increased QTD were significant predictors of all-cause mortality (chi(2)=53.0, P<0.0001; chi(2)=11.3, P=0.0008) and cardiovascular mortality (chi(2)=14.7, P=0.0001; chi(2)=26.5, P<0.0001). In multivariate Cox regression analyses controlling for risk factors, QTc remained a strong predictor of all-cause mortality (chi(2)=16.5, P<0.0001) and a weaker predictor of cardiovascular mortality (chi(2)=5.8, P=0.016); QTD remained a significant predictor of cardiovascular mortality only (chi(2)=12.5, P=0.0004). CONCLUSIONS These findings support the value of computerized measurements of QTc and QTD in noninvasive risk stratification and suggest that these surface ECG variables may reflect different underlying abnormalities of ventricular repolarization.

Genetic influence on smoking--a study of male twins.

BACKGROUND The results of twin and family studies suggest that heredity has a small influence on smoking behavior. METHODS We conducted a genetic analysis of several aspects of smoking behavior among subjects in the National Academy of Sciences-National Research Council Twin Registry. The registry includes male twins who were born in the United States between 1917 and 1927 and who were members of the armed services during World War II. Information on smoking history was available for 4775 pairs of twins, who were first surveyed in 1967 through 1969, when they were 40 to 50 years old, and then re-surveyed in 1983 through 1985, when they were 56 to 66. Eighty percent of the subjects in this cohort had smoked at some time in their lives, 60 percent were smokers in 1967 through 1969, and 39 percent were smoking in 1983 through 1985. Similarities between twins in smoking habits at base line and at the second follow-up 16 years later were examined. The comparison of concordance for smoking between monozygotic and dizygotic twins was used to assess the relative contribution of familial and genetic factors. RESULTS In 1967-1969 survey the ratio of observed to expected concordance for smoking was higher among the monozygotic twins than among the dizygotic twins for those who had never smoked (overall rate ratio, 1.38; 95 percent confidence interval, 1.25 to 1.54), for former smokers (overall rate ratio, 1.59; 95 percent confidence interval, 1.35 to 1.85), for current cigarette smokers (overall rate ratio, 1.18; 95 percent confidence interval, 1.11 to 1.26), and for current cigar or pipe smokers (overall rate ratio, 1.60; 95 percent confidence interval, 1.22 to 2.06). The data also suggest genetic influences on quitting smoking. Monozygotic twins were more likely than dizygotic twins to be concordant for quitting smoking (overall rate ratio, 1.24; 95 percent confidence interval, 1.06 to 1.45). CONCLUSIONS In this cohort of adult male twins, there were moderate genetic influences on lifetime smoking practices.

The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart Study.

OBJECTIVES We sought to determine the effect of diabetes mellitus (DM) on left ventricular (LV) filling pattern in normotensive (NT) and hypertensive (HTN) individuals. BACKGROUND Diastolic abnormalities have been extensively described in HTN but are less well characterized in DM, which frequently coexists with HTN. METHODS We analyzed the transmitral inflow velocity profile at the mitral annulus in four groups from the Strong Heart Study: NT-non-DM (n = 730), HTN-non-DM (n = 394), NT-DM (n = 616) and HTN-DM (n = 671). The DM subjects were further divided into those with normal filling pattern (n = 107) and those with abnormal relaxation (AbnREL) (n = 447). RESULTS The peak E velocity was lowest in HTN-DM, intermediate in NT-DM and HT-non-DM and highest in the NT-non-DM group (p < 0.001), with a reverse trend seen for peak A velocity (p < 0.001). In multivariate analysis, E/A ratio was lowest in HTN-DM and highest in NT-non-DM, with no difference between NT-DM and HTN-non DM (p < 0.001). Likewise, mean atrial filling fraction and deceleration time were highest in HTN-DM, followed by HTN-non-DM or NT-DM and lowest in NT-non-DM (both p < 0.05). Among DM subjects, those with AbnREL had higher fasting glucose (p = 0.03) and hemoglobin A1C (p = 0.04). CONCLUSIONS Diabetes mellitus, especially with worse glycemic control, is independently associated with abnormal LV relaxation. The severity of abnormal LV relaxation is similar to the well-known impaired relaxation associated with HTN. The combination of DM and HTN has more severe abnormal LV relaxation than groups with either condition alone. In addition, AbnREL in DM is associated with worse glycemic control.

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.

Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.