Prevalence and correlates of rheumatic heart disease in American Indians (the Strong Heart Study).
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Biomedical subjects
Publications and source records attributed to Mary J Roman.
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The aims of the Strong Heart Family Study are to clarify the genetic determinants of cardiovascular disease (CVD) risk in American Indians and to map and identify genes for CVD susceptibility. The authors describe the design of the Strong Heart Family Study (conducted between 1998 and 1999) and evaluate the heritabilities of CVD risk factors in American Indians from this study. In the first phase of the study, approximately 950 individuals, aged 18 years or more, in 32 extended families, were examined. The examination consisted of a personal interview, physical examination, laboratory tests, and an ultrasound examination of the carotid arteries. The phenotypes measured during the physical examination included anthropometry, lipoproteins, blood pressure, glycemic status, and clotting factors. Heritabilities for CVD risk factor phenotypes were estimated using a variance component approach and the program SOLAR. After accounting for the effects of covariates, the authors detected significant heritabilities for many CVD risk factor phenotypes (e.g., high density lipoprotein cholesterol (heritability = 0.50) and diastolic blood pressure (heritability = 0.34)). These results suggest that heredity explains a substantial proportion of the variability of CVD risk factors and that these heritabilities are large enough to warrant a search for major risk factor genes.
BACKGROUND: It has been reported that aortic regurgitation, mitral valve regurgitation, or both are associated with lower body mass index, an index of body adiposity. However, the relations of valvular regurgitation to body composition and myocardial bioenergetic expenditure have not been previously investigated in a population-based sample. METHODS: We selected 1496 patients with hypertension who did not have diabetes mellitus to participate in the Hypertension Genetic Epidemiology Network (HyperGEN) study. We excluded participants with severe aortic or mitral stenosis or with known coronary heart disease. Bioimpedance was used to assess body composition. Echocardiography was used to assess left ventricular (LV) structure and function and to calculate myocardial workload (expressed as energy expenditure) from end-systolic stress, ejection time, and stroke volume. The study sample was divided into groups without mitral or aortic regurgitation (control subjects, n = 1175), with mild valvular regurgitation (1+, n = 246), and with at least moderate (>or=2+) mitral or aortic regurgitation (n = 75). RESULTS: The mean patient age was higher with more severe valvular insufficiency. Sex distribution and blood pressure were similar among the 3 groups. Body mass index and fat mass were significantly lower with more severe valvular regurgitation, whereas fat-free mass was only slightly lower in the group with >or=2+ regurgitation compared with control subjects. Skinfold thicknesses (brachial and subscapular) were lower with more severe valvular regurgitation, whereas self-reported physical activity per week was similar among the 3 groups. LV mass and circumferential end-systolic stress were higher with more severe valvular regurgitation. Noninvasively estimated myocardial energy expenditure was slightly higher in participants with 1+ valvular regurgitation and was significantly higher with >or=2+ regurgitation. Ejection fraction was mildly lower with >or=2+ aortic insufficiency, mitral insufficiency, or both. Midwall shortening and stress-corrected midwall shortening did not differ among groups. CONCLUSIONS: In a population-based sample of adults with hypertension and without diabetes mellitus, known coronary heart disease, or significant valvular stenosis, mitral and aortic regurgitation were associated with higher LV mass and total myocardial biomechanical workload but with lower body fat mass and slightly lower body fat-free mass, which suggests that global myocardial bioenergetic expenditure is elevated by concomitant valvular regurgitation beyond the effect of pressure overload caused by hypertension.
BACKGROUND: Although echocardiography is commonly used to assess left ventricular (LV) systolic function, few data are available concerning the prognostic significance of LV ejection fraction (EF) calculated from linear echocardiographic measurements or 2-dimensional (2-D) wall motion scores in population-based samples. METHODS: Echocardiography was used in the second Strong Heart Study (SHS) examination to calculate LV EF in 2948 American Indians without prevalent coronary heart disease; 2923 had 2-D wall motion scores. RESULTS: Mildly and severely reduced LV EF occurred in 10% and 2% of participants, was associated with older age, male sex, higher systolic pressure, heart rate and markers of renal disease and inflammation. During 37 +/- 9 months follow-up, cardiovascular death occurred in 2%, 5% and 12% of participants with normal, mildly reduced and severely reduced EF; all cause mortality rates were 6%, 10% and 32% (both P <.001). In Cox proportional hazards analyses, adjusting for covariates, cardiovascular death was higher with mildly reduced EF (risk ratio [RR] 2.9, 95% CI 1.6-5.4, P =.0007) and especially with severely reduced EF (RR 6.9, 95% CI 3.0-15.9, P <.0001); all-cause mortality was increased with severe LV dysfunction (RR 4.8, 95% CI 2.8-8.1, P <.001) and marginally with mildly reduced EF (odds ratio 1.4, 95% CI 0.95-2.15, P =.08). Segmental LV dysfunction and mildly and severely reduced EF from 2-D wall motion scores were associated with 3.3-fold (95% CI 1.1-9.4, P =.02), 3.5-fold (95% CI 2.1-5.8) and 3.8-fold (95% CI 1.9-7.6) (all P <.001) increased rates of cardiovascular death. CONCLUSIONS: LV EF from linear echocardiographic measurements as well as segmental LV dysfunction and EF from 2-D wall motion scores strongly and independently predict cardiovascular mortality. Reduced EF by simple echocardiographic method has estimated population-attributable risks of about 35% for cardiovascular death and 12% for all-cause mortality in a population-based sample of middle-aged to elderly adults.
PURPOSE: Despite the prognostic importance of left ventricular (LV) mass (LVM) by M-mode echocardiography, concern exists about bias introduced by missing data. The American Society of Echocardiography has made recommendations for linear measurements of LV wall thickness and internal dimension used to calculate LVM, but it is unknown whether their substitution for suboptimal M-modes improves measurement yield and reduces bias. METHODS: LVM measurement yield and associations of missing data with risk factors were assessed in 3487 American Indian participants in Strong Heart Study (SHS) Phase II and compared to data from other large-scale studies. RESULTS: In SHS, LVM was measurable in 3188 (91%) participants compared to 4947/6148 (80%) Framingham participants studied by classic M-mode technique, with less decrease in measurement yield with age in SHS. In univariate SHS analyses, missing LVM was significantly associated with male gender, older age, greater height, body mass index, fat-free mass, waist/hip ratio, fibrinogen and, marginally, diabetes but not smoking, blood pressure, or lipids. In logistic regression analysis, missing LVM was independently associated with male gender, older age, greater body mass index and lower forced expiratory volume (FEV(1)) (with a low multiple R(2) [.04]), but not other risk factors. Doppler stroke volume, a measure of hemodynamic volume load, was measurable in 96% of SHS participants; missing values were weakly associated with older age, higher creatinine and lower FEV(1). During 48 +/- 11 months of follow-up, inability to measures LV mass or stroke volume was not associated with higher rates of cardiovascular events or death (p = 0.25 to 0.96). CONCLUSIONS: Improvements in echocardiographic methods have increased the yield of LVM in middle-aged and older adults and allow even more consistent assessment of cardiac volume load. Despite small persistent biases, due to associations of missing LVM and Doppler stroke volume data with male gender, greater obesity, lower FEV(1) and (for LVM only) older age, individuals with missing measurement are not at higher risk of cardiovascular events.
BACKGROUND: It is unclear whether fibrinogen predicts cardiovascular events independently of echocardiographic cardiovascular abnormalities and traditional risk factors. METHODS: We studied 2671 American Indians who participated in the second Strong Heart Study examination (1993-1995) and were observed for an average of 50 +/- 6 months. Participants with baseline overt coronary artery disease or a plasma creatinine level > or =3 mg/dL were excluded. Left ventricular hypertrophy, elevated arterial stiffness, and subnormal myocardial contractility were assessed by echocardiography. RESULTS: Prevalences of echocardiographic abnormalities and cardiovascular event rates were higher with higher fibrinogen levels. Incident cardiovascular events (n = 158) and deaths (n = 64) were more frequent in participants with elevated fibrinogen levels (>400 mg/dL) than in participants with lower fibrinogen levels, as was the prevalence of echocardiographic abnormalities (both P <.01). Incident cardiovascular fatal and nonfatal events and cardiovascular deaths were 4 and 8 times higher, respectively, in participants with both elevated fibrinogen levels and echocardiographic abnormalities than in participants with neither echocardiographic abnormalities nor elevated fibrinogen levels. However, participants with fibrinogen levels >400 mg/dL had a 2 times greater relative risk of cardiovascular events or mortality, independent of both risk factors and echocardiographic abnormalities. CONCLUSIONS: In a population-based sample of adults without clinical evidence of coronary artery disease at baseline, fibrinogen levels predicted cardiovascular events independent of traditional risk factors, left ventricular hypertrophy, elevated arterial stiffness, and subnormal myocardial systolic function.
OBJECTIVE: To evaluate the relationship between arterial stiffness estimated by the pulse pressure/stroke index ratio (PP/SVi) and prognostically relevant abnormalities of left ventricular geometry and function. METHODS: Baseline data from the echocardiographic substudy of the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study were used. Patients involved in the present study had stage II-III hypertension and electrocardiographic left ventricular hypertrophy; those with a history of coronary heart disease or segmental wall motion abnormalities were excluded. Plasma glucose, total and high-density lipoprotein (HDL) cholesterol and creatinine concentrations and urinary albumin/creatinine were assessed by standard methods. RESULTS: The study sample (n = 667) was subdivided into tertiles of PP/SVi. With greater PP/SVi, age, proportion of women and prevalence of type 2 diabetes, systolic and mean blood pressures were greater, whereas body mass index, body height and diastolic blood pressure were lower. Total and HDL cholesterol, creatinine and albuminuria did not differ among the three groups. After adjustment for age, sex and body size, greater PP/SVi was related to concentric left ventricular geometry, but showed a weak negative relationship to left ventricular mass and aortic root diameter; the prevalence of aortic fibrocalcification and left atrial diameter did not differ among tertiles of PP/SVi. PP/SVi was related to greater left ventricular end-systolic stress; stress-corrected left ventricular chamber function was greater with greater PP/SVi, whereas myocardial contractility did not differ significantly among the three groups. Greater PP/SVi was related to greater mitral E-wave/A-wave ratio and shorter isovolumic relaxation time independently of age, sex, left ventricular geometry, systolic function and other confounders. CONCLUSION: Increased estimated arterial stiffness is associated with concentric left ventricular geometry and with diastolic left ventricular abnormalities suggestive of increased diastolic left ventricular stiffness.
OBJECTIVE: To evaluate in adults with type 2 diabetes the extent to which the relation of left ventricular hypertrophy (LVH) to markers of systemic inflammation (fibrinogen and high-sensitivity C-reactive protein [hsCRP]) are affected by microangiopathy. RESEARCH DESIGN AND METHODS: We selected adults with type 2 diabetes using American Diabetes Association criteria from a population-based cohort, excluding those with medical history or electrocardiographic evidence of coronary heart disease or dialysis-dependent renal failure. LVH was assessed by echocardiogram. RESULTS: Of the 1299 eligible participants, 384 (29.6%) had LVH, which was associated with higher BMI, hsCRP, fibrinogen, and albuminuria in univariate analyses. After controlling for significant confounders, fibrinogen and albuminuria were higher in the presence of LVH (both P < 0.01), whereas hsCRP was not (P = 0.2), mostly because of the confounding effect of BMI. Adjustment for albuminuria abolished the relation of LVH to higher fibrinogen (P = 0.2). However, fibrinogen was significantly higher in participants with LVH among those without pathologic levels of albuminuria (<30 mg/g creatinuria), but not independent of BMI. Although hsCRP and fibrinogen were moderately correlated, fibrinogen, but not CRP, showed a significant relation with albuminuria. CONCLUSIONS: In adults with type 2 diabetes, echocardiographic LVH is associated with susceptibility to atherothrombosis and increased albuminuria, which is a marker of microangiopathy and endothelial dysfunction that appears in turn to be a relevant pathogenetic link between LVH and inflammation. However, in the absence of significant microalbuminuria, elevated BMI is a relevant pathogenetic factor in the relation of LVH to increased levels of markers of inflammation, potentially preceding development of significant albuminuria. In the presence of microangiopathy, we found that the atherothrombotic risk profile associated with LVH was independent of BMI and possibly reflected the association of LVH with a higher degree of endothelial dysfunction.
OBJECTIVE: We investigated cardiac and vascular remodeling in an unselected older population with either diastolic hypertension (HTN) or isolated systolic hypertension (ISH). BACKGROUND: Isolated systolic hypertension accounts for a substantial proportion of hypertension in individuals older than 65 years and is strongly associated with an increased risk of cardiac and cerebrovascular events. The exact mechanisms underlying the increased risk associated with ISH and elevated pulse pressure (PP), in comparison with HTN, have not been extensively investigated. METHODS: Community-dwelling residents age >/=65 years in a small town in Italy (Dicomano) were enrolled. Untreated subjects considered in this study included 173 normotensive subjects (blood pressure [BP] <140/90 mm Hg), 95 subjects with HTN (diastolic BP >/=90 mm Hg), and 43 subjects with ISH (BP >/=160/<90 mm Hg). All subjects underwent extensive clinical examination, echocardiography, carotid ultrasonography, and carotid applanation tonometry. RESULTS: Subjects with ISH had higher left ventricular (LV) mass, which was independently related to PP but not to systolic or mean pressures. Both carotid wall cross-sectional area and vascular stiffness were greater in ISH patients than in HTN and normal subjects and were independently related to PP but not to systolic BP. In addition, ISH was associated with a higher prevalence of carotid plaque and more extensive carotid atherosclerosis. CONCLUSIONS: In our community-based elderly population, individuals with ISH had higher prevalences of LV hypertrophy and carotid atherosclerosis than subjects with HTN despite lower mean BP. These findings provide potential pathophysiologic mechanisms underlying the associations of ISH and PP with increased risk of cardiovascular morbidity and mortality.
OBJECTIVE: Alterations in carotid artery structure and function may represent phenotypic measures of vascular disease that contain information beyond that which can be inferred from conventional cardiovascular disease risk assessment. However, apart from their associations with cardiovascular disease risk factors and outcome, the genetic basis of variations in carotid artery structure and function is largely unknown. The purpose of this study was to examine the genetic and environmental contributions to carotid artery structure and function in 3 large groups of American Indians. METHODS AND RESULTS: Approximately 950 men and women, aged > or =18 years, in 32 extended families were examined between 1997 and 1999. By use of a variance component approach and the program Sequential Oligogenic Linkage Analysis Routines, heritabilities for carotid artery structure and function phenotypes were estimated. After accounting for the effects of covariates (sex, age, diabetes, impaired glucose tolerance, smoking, cholesterol, body surface area, and hypertension), we detected significant heritabilities (given as h2 values) for common carotid artery diastolic diameter (h2<0.44), intimal-medial wall thickness (h2<0.21), vascular mass (h2<0.27), arterial stiffness (h2<0.23), and the augmentation index (h2<0.18). CONCLUSIONS: These results suggest that the additive effects of genes explain a moderate proportion of the variability of carotid artery structure and function.
PURPOSE: Previous studies of the association between the use of appetite suppressants and valvular heart disease have not accounted for the effects of valvular structure and aortic root diameter, which are associated with obesity. We assessed whether the use of the appetite suppressants fenfluramine/dexfenfluramine, either alone or with phentermine, was associated with aortic regurgitation while adjusting for these variables. SUBJECTS AND METHODS: The sample included 2524 adult participants in the population-based Hypertension Genetic Epidemiology Network study. Information regarding current drug use was assessed during a clinical examination. Medication use was continued at the time of echocardiographic study. Expert readers blinded to current therapy read echocardiograms centrally at Cornell Medical Center. Analyses of the associations between use of fenfluramine/dexfenfluramine (alone or with phentermine) and aortic regurgitation adjusted for potential confounders, including aortic root dilatation and valve fibrocalcification. RESULTS: Nineteen participants, all of whom had hypertension, were being treated with fenfluramine or dexfenfluramine (5 on these agents alone, 14 also with phentermine). Aortic regurgitation was present in 32% (n = 6) of those taking fenfluramine or dexfenfluramine versus 6% (162/2505) of remaining subjects (P = 0.001). In multivariate-adjusted analyses, treatment with fenfluramine or dexfenfluramine was associated with aortic regurgitation (odds ratio [OR] = 4.9; 95% confidence interval [CI]: 1.7 to 14) and aortic fibrocalcification (OR = 5.2; 95% CI: 1.9 to 15). CONCLUSION: In a population-based sample, use of fenfluramine or dexfenfluramine, alone or in combination with phentermine, was associated with aortic regurgitation independent of aortic dilatation or fibrocalcification.
Aortic root dilatation is a major pathophysiological mechanism for aortic regurgitation and predisposes the aortic root to dissection or rupture. However, only a small proportion of the variance of aortic root size can be explained by its known clinical and demographic correlates. The present study was undertaken to determine the heritability of echocardiographically derived aortic root diameter in the American Indian participants in the second Strong Heart Study examination. Echocardiograms were analyzed in 1373 SHS participants who had > or =1 family member in the cohort. Heritability calculations were performed by using variance component analysis as implemented in SOLAR, a computer analysis program. In a polygenic model, the variables entered and identified as covariates of larger aortic root diameter were older age, male sex, and center (P<0.001), which accounted for 35% of the overall variability of aortic root diameter. After simultaneous adjustment was made for these significant covariates, the proportion of phenotypic variance due to additive genetic contribution or residual heritability (h2) was 0.51 (SE=0.08, P<0.001). Additionally, simultaneous adjustment for height, weight, and systolic and diastolic BPs yielded slightly lower residual h2 of aortic root diameter (h2=0.44, SE=0.08, P<0.001), which accounted for 26% of the overall variance of aortic root size. Because center effects were identified as significant covariates in the analyses, h2 analyses were performed separately in Arizona, Oklahoma, and North/South Dakota centers, which confirmed that a significant proportion of the phenotypic variance of aortic root diameter is due to additive genetic contribution. Heredity explains a substantial proportion of the variability of aortic root size that is not accounted for by age, sex, body size, and blood pressure. Echocardiographic screening of family members with aortic root dilatation may identify other individuals predisposed to aortic dissection or rupture.
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.
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BACKGROUND: It has been hypothesized that the level of end-systolic wall stress (sigma(m)) is a feedback signal that regulates the level of hypertrophy. Thus, low levels of sigma(m) may signify inappropriate hypertrophy. METHODS: To characterize left ventricular (LV) structure and systolic function in hypertensive subjects with low levels of sigma(m), we studied 763 patients. LV function was studied by midwall stress-shortening analysis. Partition values for sigma(m) were derived from a separate group of normal subjects, and the study population was divided into low stress (group I, n = 136), high stress (group III, n = 157), and intermediate stress group II (n = 470). LV chamber and myocardial function were characterized by relating shortening at the endocardium and at the midwall, respectively, to stress. RESULTS: As expected, group III patients had the highest values for systolic blood pressure and LV cavity size but the lowest values for wall thickness and relative wall thickness. Surprisingly, however, there were no significant differences among stress groups with regard to age or body mass index. Contrary to the hypothesis that low levels of stress are indicative of excessive hypertrophy, there were no significant differences among the 3 groups with regard to LV mass or any form of LV mass index. Furthermore, despite lower mean values for afterload, group I patients had significantly lower values for midwall shortening, and this finding was indicative of reduced myocardial function; stress-shortening plots demonstrated that 28% of group I patients fell below 95% CI compared with 10% of group II and only 5% of group III patients. CONCLUSIONS: Hypertensive subjects with low values for sigma(m) have more concentric LV geometry (higher relative wall thickness) and, on average, reduced myocardial function.
We evaluated the association of insulin and echocardiographic left ventricular (LV) measurements in 1,388 (45% men) nondiabetic American Indian participants in the Strong Heart Study (SHS). Significant (all P < 0.05) relations were found in men and women between log(10) fasting insulin and LV mass (r = 0.24 and 0.26), left atrial diameter (r = 0.25 and 0.28), posterior wall thickness (r = 0.20 and 0.26), septal thickness (r = 0.19 and 0.24), LV diameter (r = 0.17 and 0.16), and cardiac output (r = 0.20 and 0.24) and in women relative wall thickness (r = 0.11) and peripheral resistance (r = -0.17). In regression analyses, adjusting for BMI, age, height, and systolic pressure, fasting insulin was independently correlated with cardiac output in men and relative wall thickness and septal thickness in women (all P < 0.05). The 97th percentiles of fasting insulin (25 microU/ml for men, and 23 microU/ml for women) in 163 apparently normal (BMI <26; blood pressure <140/90; and absence of diabetes, valvular disease, LV wall motion abnormality, or antihypertensive treatment) SHS participants were used to separate normal from elevated fasting insulin levels. Adjusting for age, BMI, and height, men with elevated insulin levels had larger LV diameters (5.41 vs. 5.16 cm; P = 0.05), higher cardiac output (5.5 vs. 4.9 l/min; P < 0.001), and lower peripheral resistance (1,487 vs. 1,666; P = 0.01), paralleling results of regression analyses. Positive relations between insulin and heart size in nondiabetic adults are largely due to associations with body size; after adjustments for covariates, fasting insulin levels are related to greater LV size and cardiac output in men and more concentric LV geometry in women.