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1.  Midlife Fitness and the Development of Chronic Conditions in Later Life 
Archives of internal medicine  2012;172(17):1333-1340.
Background
The association between cardiorespiratory fitness (fitness) and mortality is well described. However, the association between midlife fitness and the development of nonfatal chronic conditions in older age has not been studied.
Methods
To examine the association between midlife fitness and chronic disease outcomes in later life, participant data from the Cooper Center Longitudinal Study were linked with Medicare claims. We studied 18 670 healthy participants (21.1% women; median age, 49 years) who survived to receive Medicare coverage from January 1, 1999, to December 31, 2009. Fitness estimated by Balke treadmill time was analyzed as a continuous variable (in metabolic equivalents [METs]) and according to age- and sex-specific quintiles. Eight common chronic conditions were defined using validated algorithms, and associations between midlife fitness and the number of conditions were assessed using a modified Cox proportional hazards model that stratified the at-risk population by the number of conditions while adjusting for age, body mass index, blood pressure, cholesterol and glucose levels, alcohol use, and smoking.
Results
After 120 780 person-years of Medicare exposure with a median follow-up of 26 years, the highest quintile of fitness (quintile 5) was associated with a lower incidence of chronic conditions compared with the lowest quintile (quintile 1) in men (15.6 [95% CI, 15.0–16.2] vs 28.2 [27.4–29.0] per 100 person-years) and women (11.4 [10.5–12.3] vs 20.1 [18.7 vs 21.6] per 100 person-years). After multivariate adjustment, higher fitness (in METs) was associated with a lower risk of developing chronic conditions in men (hazard ratio, 0.95 [95% CI, 0.94–0.96] per MET) and women (0.94 [0.91–0.96] per MET). Among decedents (2406 [12.9%]), higher fitness was associated with lower risk of developing chronic conditions relative to survival (compression hazard ratio, 0.90 [95% CI, 0.88–0.92] per MET), suggesting morbidity compression.
Conclusions
In this cohort of healthy middle-aged adults, fitness was significantly associated with a lower risk of developing chronic disease outcomes during 26 years of follow-up. These findings suggest that higher midlife fitness may be associated with the compression of morbidity in older age.
doi:10.1001/archinternmed.2012.3400
PMCID: PMC3926651  PMID: 22928178
2.  Cardiorespiratory Fitness and Classification of Risk of Cardiovascular Disease Mortality 
Circulation  2011;123(13):1377-1383.
Background
Cardiorespiratory fitness (fitness) is associated with cardiovascular disease (CVD) mortality. However, the extent to which fitness improves risk classification when added to traditional risk factors is unclear.
Methods and Results
Fitness was measured by the Balke protocol in 66 371 subjects without prior CVD enrolled in the Cooper Center Longitudinal Study between 1970 and 2006; follow-up was extended through 2006. Cox proportional hazards models were used to estimate the risk of CVD mortality with a traditional risk factor model (age, sex, systolic blood pressure, diabetes mellitus, total cholesterol, and smoking) with and without the addition of fitness. The net reclassification improvement and integrated discrimination improvement were calculated at 10 and 25 years. Ten-year risk estimates for CVD mortality were categorized as <1%, 1% to <5%, and ≥5%, and 25-year risk estimates were categorized as <8%, 8% to 30%, and ≥30%. During a median follow-up period of 16 years, there were 1621 CVD deaths. The addition of fitness to the traditional risk factor model resulted in reclassification of 10.7% of the men, with significant net reclassification improvement at both 10 years (net reclassification improvement=0.121) and 25 years (net reclassification improvement=0.041) (P<0.001 for both). The integrated discrimination improvement was 0.010 at 10 years (P<0.001), and the relative integrated discrimination improvement was 29%. Similar findings were observed for women at 25 years.
Conclusions
A single measurement of fitness significantly improves classification of both short-term (10-year) and long-term (25-year) risk for CVD mortality when added to traditional risk factors.
doi:10.1161/CIRCULATIONAHA.110.003236
PMCID: PMC3926656  PMID: 21422392
cardiovascular disease; classification; exercise capacity; mortality; risk
3.  Association of Cardiorespiratory Fitness With Total, Cardiovascular, and Noncardiovascular Mortality Across 3 Decades of Follow-Up in Men and Women 
Background
The inverse, dose-dependent association between cardiorespiratory fitness and mortality is well-established; however, the pattern of the association between low fitness and mortality across short- (0 to 10 years), intermediate- (10 to 20 years), and long-term (>20 years) follow-up has not been studied.
Methods and Results
We included 46 575 men and 16 151 women (mean age 44 years) from the Cooper Center Longitudinal Study. Participants were categorized as either “low fit” or “not low fit,” based on age- and sex- adjusted treadmill times, and were followed for mortality, determined from the National Death Index. Multivariable-adjusted Cox proportional hazards models were constructed to compare the association between fitness and traditional risk factors, with mortality outcomes across short-, intermediate-, and long-term follow-up. After a median follow-up of 16 years, there were 1295 cardiovascular disease and 2840 noncardiovascular disease deaths. Low fitness was associated with all-cause mortality across all periods in men [0 to 10 years: hazard ratios (HR), 1.99 (95% confidence interval [CI], 1.66 to 2.40); 10 to 20 years: HR, 1.61 (95% CI, 1.41 to 1.84); and >20 years: HR, 1.42 (95% CI, 1.27 to 1.60)] and in women [0 to 10 years: HR, 1.98 (95% CI, 1.27 to 3.10); 10 to 20 years: HR, 1.90 (95% CI, 1.40 to 2.56); and >20 years: HR, 1.54 (95% CI, 1.15 to 2.07)]. Similar results were seen for both cardiovascular disease and noncardiovascular disease mortality. Although these associations were also consistent across most subgroups, low fitness appeared to be most strongly associated with mortality in the short term among individuals at highest short-term risk (ie, older age, abnormal exercise test).
Conclusions
Similar to traditional risk factors, fitness is associated with mortality across short-, intermediate-, and long-term follow-up.
doi:10.1161/CIRCOUTCOMES.111.963181
PMCID: PMC3631586  PMID: 22474246
fitness; epidemiology; risk factors; survival analysis
4.  Association Between Family History and Coronary Heart Disease Death Across Long-Term Follow-Up in Men 
Circulation  2012;125(25):3092-3098.
Background
Family history of coronary heart disease (CHD) has been well studied as an independent risk factor for CHD events in the short term (<10 years). However, data are sparse on the association between family history and risk for CHD across long-term follow-up.
Methods and Results
We included 49 255 men from the Cooper Center Longitudinal Study. Premature family history of CHD was defined as the presence of angina, myocardial infarction, angioplasty, or bypass surgery in a relative <50 years of age. Cause-specific mortality was obtained from the National Death Index. The association between premature family history and cardiovascular disease (CVD) or CHD death was compared across 3 unique follow-up periods (0–10, >10–20, and >20 years). Lifetime risk was estimated by use of a modified survival analytic technique adjusted for competing risk with non-CVD death as the competing event. After 811 708 person-years of follow-up, there were 919 CHD deaths and 1456 CVD deaths. After adjustment for traditional risk factors, premature family history was associated with CHD mortality >10 to 20 years (1.59; 95% confidence interval, 1.14–2.22) and >20 years (1.43; 95% confidence interval, 1.05–1.95) with wider confidence intervals at 0 to 10 years (1.32; 95% confidence interval, 0.76–2.31). Similar findings were observed for CVD mortality. Compared with men without a family history of coronary artery disease, premature family history was associated with an ≈50% higher lifetime risk for both CHD and CVD mortality (13.7% versus 8.9% and 21% versus 14.1%, respectively).
Conclusion
Premature family history was associated with a persistent increase in both CHD and CVD mortality risk across long-term follow-up, resulting in significantly higher lifetime risk estimates.
doi:10.1161/CIRCULATIONAHA.111.065490
PMCID: PMC3631594  PMID: 22623718
cardiovascular diseases; coronary disease; heredity; risk factors
5.  LIFETIME RISKS FOR CARDIOVASCULAR DISEASE MORTALITY BY CARDIORESPIRATORY FITNESS LEVELS MEASURED AT AGE 45-, 55-, AND 65-YEARS IN MEN: THE COOPER CENTER LONGITUDINAL STUDY 
Objectives
To determine the association between fitness and lifetime risk for cardiovascular disease (CVD).
Background
Higher levels of traditional risk factors are associated with marked differences in lifetime risks for CVD. However, data are sparse regarding the association between fitness and the lifetime risk for CVD.
Methods
We followed 11,049 men who underwent clinical examination at the Cooper Clinic in Dallas, TX before 1990 until the occurrence of CVD death, non-CVD death, or attainment of age 90 (281,469 person-years of follow-up, median follow-up 25.3 years, 1,106 CVD deaths). Fitness was measured by Balke protocol and categorized according to treadmill time into low-, intermediate-, and high- fitness with further stratification by CVD risk factor burden. Lifetime risk for CVD death determined by the National Death Index was estimated for fitness levels measured at ages 45-, 55-, and 65-years with non-CVD death as the competing event.
Results
Differences in fitness levels (low- fitness versus high- fitness) were associated with marked differences in the lifetime risks for CVD death at each index age (age 45: 13.7% versus 3.4%; age 55: 34.2% versus 15.3%; age 65: 35.6% versus 17.1%). These associations were strongest among individuals with CVD risk factors.
Conclusions
A single measurement of low fitness in mid-life was associated with higher lifetime risk for CVD death, particularly among individuals with a high burden of CVD risk factors.
doi:10.1016/j.jacc.2010.10.056
PMCID: PMC3608397  PMID: 21474041
cardiovascular disease; epidemiology; exercise testing; lifetime risk
6.  Dietary Fish Intake and Incident Atrial Fibrillation (from the Women's Health Initiative) 
The American journal of cardiology  2010;105(6):844-848.
Experimental and clinical trial data suggest an association between fish oil intake and atrial fibrillation (AF). However, prior observational studies have reported conflicting results regarding this association. Thus, we sought to compare the association between dietary fish intake and incident AF in a large sample of older, postmenopausal women. We included 44,720 participants from the Women's Health Initiative clinical trials not enrolled in the dietary modification intervention arm and without AF at baseline. The dietary intake of non-fried fish and omega-3 fatty acid intake were estimated from a Food Frequency Questionnaire at study entry. Incident AF was determined by follow-up ECG at year 3 and year 6. Baseline characteristics and rates of incident AF were compared across quartiles (Q) of fish intake. Adjusted logistic regression models were used to evaluate the association between dietary non-fried fish intake and incident AF. There were 378 incident cases of AF in follow-up. In age-adjusted models, there was no association between dietary non-fried fish intake and incident AF [odds ratios (95% confidence intervals) 1.17 (0.88–1.57) for Q 4 vs. Q 1 of dietary fish intake). Similar findings were observed in multivariable models and in subgroup analyses. In a large cohort of healthy women, we found no evidence of an association between fish or omega-3 fatty acid intake and incident AF.
doi:10.1016/j.amjcard.2009.11.039
PMCID: PMC2838232  PMID: 20211329
atrial fibrillation; diet; omega-3 fatty acids
7.  Relation of Regional Fat Distribution to Left Ventricular Structure and Function 
Background
The relation of body fat distribution to left ventricular (LV) structure and function is poorly defined.
Methods and Results
2710 participants without heart failure or LV dysfunction in the Dallas Heart Study underwent dual energy x-ray absorptiometry and magnetic resonance imaging assessment of fat distribution, LV morphology, and hemodynamics. Cross-sectional associations of fat distribution with LV structure and function were examined after adjustment for age, sex, race, comorbidities, and lean mass. Mean age was 44 years with 55% women; 48% African-Americans; and 44% obese. After multivariable adjustment, visceral fat (VAT) was associated with concentric remodeling characterized by lower LV end-diastolic volume (β= -0.21), higher concentricity (β= 0.20) and wall thickness (β=0.09, p<0.0001 for all). In contrast, lower body subcutaneous fat (LBF) was associated with higher LV end-diastolic volume (β= 0.48), reduced concentricity (β= -0.50) and wall thickness (β= -0.28, p<0.0001 for all). VAT was also associated with lower cardiac output (β= -0.10, p<0.05) and higher systemic vascular resistance (β= 0.08, p<0.05) whereas LBF associated with higher cardiac output (β= 0.20, p<0.0001) and lower systemic vascular resistance (β= -0.18, p<0.0001). Abdominal subcutaneous fat (SAT) showed weaker associations with concentric remodeling and was not associated with hemodynamics. Among the subset of obese participants, VAT, but not SAT, was significantly associated with concentric remodeling.
Conclusions
VAT, a marker of central adiposity, was independently associated with concentric LV remodeling and adverse hemodynamics. In contrast, LBF was associated with eccentric remodeling. The impact of body fat distribution on heart failure risk requires prospective study.
doi:10.1161/CIRCIMAGING.113.000532
PMCID: PMC3931513  PMID: 23929898
obesity; body fat distribution; visceral fat; left ventricular hypertrophy; concentric remodeling
8.  Higher Natriuretic Peptide Levels Associate with a Favorable Adipose Tissue Distribution Profile 
Journal of the American College of Cardiology  2013;62(8):10.1016/j.jacc.2013.03.038.
Objectives
To investigate the association between natriuretic peptides and body fat distribution in a multiethnic cohort.
Background
Natriuretic peptides stimulate lipolysis, reduce weight gain, and promote adipocyte browning in animal models but data are lacking in humans.
Methods
2619 participants without heart failure in the Dallas Heart Study underwent measurements of 1) B-type natriuretic peptide (BNP) and NT-proBNP and 2) body fat distribution by dual energy x-ray absorptiometry and magnetic resonance imaging. Cross-sectional associations of natriuretic peptides with adiposity phenotypes were examined after adjustment for age, sex, race, comorbidities, and body mass index.
Results
Median BNP and NT-proBNP levels in the study cohort (mean age 44 years, 56% women, 48% African-Americans, 32% obese) were 3.0 and 28.1 pg/mL, respectively. Natriuretic peptide levels above the median were associated with a more favorable body fat profile and less insulin resistance including lower visceral fat, liver fat, and HOMA-IR; and more lower body fat and higher adiponectin (p<0.05 for each). In multivariable analyses, NT-proBNP remained inversely associated with visceral (β= −0.08, p<0.0001) and liver fat (β= −0.14, p<0.0001) and positively associated with lower body fat (β= 0.07, p<0.0001) independent of age, sex, race, and obesity-status; findings were similar with BNP. Adjustment for body composition, HOMA-IR, circulating androgens, and adipocytokines did not attenuate the associations.
Conclusions
Higher natriuretic peptide levels were independently associated with a favorable adiposity profile, characterized by decreased visceral and liver fat and increased lower body fat, suggesting a link between the heart and adipose tissue distribution mediated through natriuretic peptides.
doi:10.1016/j.jacc.2013.03.038
PMCID: PMC3857334  PMID: 23602771
natriuretic peptides; body fat distribution; visceral fat; insulin resistance
9.  Lifetime Risk for Heart Failure Among White and Black Americans: Cardiovascular Lifetime Risk Pooling Project 
Objective
To estimate lifetime risk for HF by sex and race.
Background
Prior estimates of lifetime risk for developing heart failure (HF) range from 20% to 33% in predominantly white cohorts. Short-term risks for HF appear higher for blacks than whites, but only limited comparisons of lifetime risk for HF have been made.
Methods
Using public-release and internal datasets from NHLBI-sponsored cohorts, we estimated lifetime risks for developing HF to age 95, with death free of HF as the competing event, among participants in Chicago Heart Association Detection Project in Industry (CHA), Atherosclerosis Risk in Communities (ARIC), and Cardiovascular Health Study (CHS) cohorts.
Results
There were 39,578 participants (33,652 [85%] white; 5,926 [15%] black) followed for 716,976 person-years; 5,983 participants developed HF. At age 45 years, lifetime risks for HF through age 95 years in CHA and CHS were 30-42% in white men, 20-29% in black men, 32-39% in white women, and 24-46% in black women. Results for ARIC demonstrated similar lifetime risks for HF in blacks and whites through age 75 years (limit of follow-up). Lifetime risk for HF was higher with higher BP and BMI at all ages in both blacks and whites and did not diminish substantially with advancing index age.
Conclusions
These are among the first data to compare lifetime risks for HF between blacks and whites. Lifetime risks for HF are high and appear similar for black and white women, yet are somewhat lower for black compared with white men due to competing risks.
doi:10.1016/j.jacc.2013.01.022
PMCID: PMC3618527  PMID: 23500287
lifetime risk; heart failure; epidemiology
10.  Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults 
Obesity (Silver Spring, Md.)  2013;21(9):E439-E447.
Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n=942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n=1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p<0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque (p<0.001 for each). VAT independently associated with C-reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA-IR were significant in univariable analyses but attenuated after multivariable adjustment. In conclusion, VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk.
doi:10.1002/oby.20135
PMCID: PMC3751977  PMID: 23687099
Obesity; Lipoproteins; Inflammation; Atherosclerosis; Diabetes
11.  The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia 
Annals of internal medicine  2013;158(3):162-168.
Background
Primary prevention of Alzheimer disease and other types of dementia (all-cause dementia) is an important public health goal. Evidence to date is insufficient to recommend any lifestyle change to prevent or delay the onset of dementia.
Objective
To assess the association between objectively measured midlife cardiorespiratory fitness (“fitness”) levels and development of all-cause dementia in advanced age.
Design
Prospective, observational cohort study.
Setting
Preventive medicine clinic.
Patients
19 458 community-dwelling, nonelderly adults who had a baseline fitness examination.
Measurements
Fitness levels, assessed using the modified Balke treadmill protocol between 1971 and 2009, and incident all-cause dementia using Medicare Parts A and B claims data from 1999 to 2009.
Results
1659 cases of incident all-cause dementia occurred during 125 700 person-years of Medicare follow-up (median follow-up, 25 years [interquartile range, 19 to 30 years]). After multivariable adjustment, participants in the highest quintile of fitness level had lower hazard of all-cause dementia than those in the lowest quintile (hazard ratio, 0.64 [95% CI, 0.54 to 0.77]). Higher fitness levels were associated with lower hazard of all-cause dementia with previous stroke (hazard ratio, 0.74 [CI, 0.53 to 1.04]) or without previous stroke (hazard ratio, 0.74 [CI, 0.61 to 0.90]).
Limitations
Dementia diagnoses were based on Medicare claims, and participants generally were non-Hispanic white, healthy, and well-educated and had access to preventive health care. This study evaluated fitness levels, so a specific exercise prescription cannot be generated from results and the findings may not be causal.
Conclusion
Higher midlife fitness levels seem to be associated with lower hazards of developing all-cause dementia later in life. The magnitude and direction of the association were similar with or without previous stroke, suggesting that higher fitness levels earlier in life may lower risk for dementia later in life, independent of cerebrovascular disease.
doi:10.7326/0003-4819-158-3-201302050-00005
PMCID: PMC3926646  PMID: 23381040
12.  Association of Growth Differentiation Factor-15 with Coronary Atherosclerosis and Mortality in a Young, Multiethnic Population: Observations from the Dallas Heart Study 
Clinical chemistry  2011;58(1):172-182.
Background
Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined.
Methods
We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30–65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200–1799; and ≥1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC >10 Agatston units), increased CAC (CAC ≥100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths).
Results
Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P < 0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15 ≥1800 ng/L was associated with CAC >10 (odds ratio 2.1; 95% CI 1.2–3.7; P = 0.01), CAC ≥100 (odds ratio 2.6; 95% CI 1.4–4.9; P = 0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1–5.9, P < 0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1–5.8, P = 0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P = 0.025), the integrated discrimination index (0.028; P < 0.0001) and the category-less net reclassification index (0.42; P = 0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and cardiac troponin T.
Conclusions
GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.
doi:10.1373/clinchem.2011.171926
PMCID: PMC3926660  PMID: 22065155
13.  Left atrial structure and function and clinical outcomes in the general population 
European Heart Journal  2012;34(4):278-285.
Aims
Left atrial (LA) structural and functional abnormalities may be subclinical phenotypes, which identify individuals at increased risk of adverse outcomes.
Methods and results
Maximum LA volume (LAmax) and LA emptying fraction (LAEF) were measured via cardiac magnetic resonance imaging in 1802 participants in the Dallas Heart Study. The associations of LAEF and LAmax indexed to body surface area (LAmax/BSA) with traditional risk factors, natriuretic peptide levels, and left ventricular (LV) structure [end-diastolic volume (EDV) and concentricity0.67 (mass/EDV0.67)] and function (ejection fraction) were assessed using linear regression analysis. The incremental prognostic value of LAmax/BSA and LAEF beyond traditional risk factors, LV ejection fraction, and LV mass was assessed using the Cox proportional-hazards model. Both increasing LAmax/BSA and decreasing LAEF were associated with hypertension and natriuretic peptide levels (P < 0.05 for all). In multivariable analysis, LAmax/BSA was most strongly associated with LV end-diastolic volume/BSA, while LAEF was strongly associated with LV ejection fraction and concentricity0.67. During a median follow-up period of 8.1 years, there were 81 total deaths. Decreasing LAEF [hazard ratio (HR) per 1 standard deviation (SD) (8.0%): 1.56 (1.32–1.87)] but not increasing LAmax/BSA [HR per 1 SD (8.6 mL/m2): 1.14 (0.97–1.34)] was independently associated with mortality. Furthermore, the addition of LAEF to a model adjusting Framingham risk score, diabetes, race, LV mass, and ejection fraction improved the c-statistic (c-statistics: 0.78 vs. 0.77; P < 0.05, respectively), whereas the addition of LAmax/BSA did not (c-statistics: 0.76, P = 0.20).
Conclusion
In the general population, both LAmax/BSA and LAEF are important subclinical phenotypes but LAEF is superior and incremental to LAmax/BSA.
doi:10.1093/eurheartj/ehs188
PMCID: PMC3549524  PMID: 22782941
Left atrial volume index; Left atrial systolic function; Population
14.  Biomarkers of Chronic Cardiac Injury and Hemodynamic Stress Identify a Malignant Phenotype of Left Ventricular Hypertrophy in the General Population 
Objectives
To determine if biomarkers of subclinical myocardial injury and hemodynamic stress identify asymptomatic individuals with left ventricular hypertrophy (LVH) at higher risk for heart failure (HF) and death.
Background
The interaction between LVH, low but detectable cardiac troponin T (cTnT), and elevated NT-proBNP on cardiovascular (CV) outcomes in the general population is unknown.
Methods
Participants in the Dallas Heart Study without clinical HF, LV dysfunction, or chronic kidney disease underwent measurement of LV mass by MRI, cTnT by highly sensitive assay, and NT-proBNP (n=2413). Subjects were stratified by LVH and by detectable cTnT (≥3 pg/mL) and increased NT-proBNP (>75th age- and sex-specific percentile).
Results
9% of participants were LVH+, 25% cTnT+, and 24% NT-proBNP+. Those LVH+ and cTnT+ and/or NT-proBNP+ (n=144) were older, more likely to be male, with greater risk factor burden and more severe LVH compared with those LVH+ biomarker- (p<0.01 for each). The cumulative incidence of HF or CV death over 8 years among LVH+ cTnT+ was 21% vs. 1% (LVH- cTnT-), 4% (LVH- cTnT+), and 6% (LVH+ cTnT-), p<0.0001. The interactions between LVH and cTnT (pinteraction=0.0005) and LVH and NT-proBNP (pinteraction=0.014) were highly significant. Individuals LVH+ and either cTnT+ or NT-proBNP+ remained at >4-fold higher risk for HF or CV death after multivariable adjustment for CV risk factors, renal function, and LV mass compared with those LVH- biomarker-.
Conclusions
Minimal elevations in biomarkers of subclinical cardiac injury and hemodynamic stress modify the association of LVH with adverse outcomes, identifying a malignant sub-phenotype of LVH with high risk for progression to HF and CV death.
doi:10.1016/j.jacc.2012.10.012
PMCID: PMC3547631  PMID: 23219305
heart failure; left ventricular hypertrophy; troponin; natriuretic peptides
15.  Addition of Highly Sensitive Troponin T and N-Terminal Pro-BNP to Electrocardiography for Detection of Left Ventricular Hypertrophy: Results from the Dallas Heart Study 
Hypertension  2012;61(1):105-111.
Left ventricular hypertrophy (LVH) is an independent, modifiable risk factor for cardiovascular disease. However, current screening strategies are limited. In 2478 participants without clinical disease from the Dallas Heart Study, we evaluated a multi-marker screening strategy that complements electrocardiographic (ECG) criteria for LVH with two biomarkers, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and highly sensitive cardiac troponin T (cTnT). An integer LVH risk score from 0 to 3 was determined as the sum of: (1) LVH by Sokolow-Lyon ECG, (2) NT-proBNP in the highest sex-specific quartile, and (3) detectable cTnT. Cardiac MRI-determined LVH served as the primary outcome.
The probability of LVH increased from 2% with an LVH risk score of 0 to 50% with a score of 3 (p < 0.001). S-L ECG afforded low sensitivity (26%, 95% CI 17–32%) and high specificity (96%, 95% CI 95–97%), while a risk score ≥2 offered higher sensitivity (44%, 95% CI 34–51%) with good specificity (90%, 95% CI 89–93%), a score threshold of 1 offered reasonable sensitivity (76%, 95% CI 67–83%) with lower specificity (55%, 95% CI 53–61%) and high negative predictive value (98%, 95% CI 97–98%). AUC improved from 0.760 (95% CI 0.716–0.804) for ECG alone to 0.798 (95% CI 0.754–0.842) for the LVH risk score (p = 0.0012) consistent with modest improvement in overall discrimination. Better screening for LVH may be achieved by combining simple tests, which collectively provide additional information compared to ECG alone. Further studies are needed to evaluate the impact and cost-effectiveness of a multi-marker screening strategy.
doi:10.1161/HYPERTENSIONAHA.112.195289
PMCID: PMC3521858  PMID: 23150502
left ventricular hypertrophy screening; diagnostic performance; amino-terminal B-type natriuretic peptide; highly sensitive troponin T; electrocardiographic Sokolow-Lyon criteria
16.  Remaining Lifetime Risk for Cancer Death at Selected Ages by Sex and Smoking status: The Lifetime Risk Pooling Project 
Cancer causes & control : CCC  2012;23(10):1729-1737.
Background
Understanding how sex and tobacco exposure may modify lifetime risks for cancer mortality is important for effective communication of risk in targeted public health messages.
Objective
To determine lifetime risk estimates for cancer death associated with sex and smoking status in the United States.
Methods
A pooled cohort design using ten well-defined epidemiologic cohorts including middle-aged and older individuals was used to estimate the lifetime risk for cancer death at selected index ages, with death from non-cancer causes as the competing risk, by sex and smoking status.
Results
There were a total of 11,317 cancer-related deaths. At age 45 years, the lifetime risk of cancer death for male smokers is 27.7% (95% CI 24.0% to 31.4%) compared to 15.8% (95% CI 12.7% to 18.9%) for male non-smokers. At age 45 years, the lifetime risk of cancer death for female smokers is 21.7% (95% CI 18.8% to 24.6%) compared to 13.2% (95% CI 11.0% to 15.4%) for female non-smokers. Remaining lifetime risk for cancer death declined with age, and men have a greater risk for cancer death compared to women. Adjustment for competing risk of death, particularly representing cardiovascular mortality, yielded a greater change in lifetime risk estimates for men and smokers compared to women and non-smokers.
Conclusions
At the population level the lifetime risk for cancer death remains significantly higher for smokers compared to non-smokers, regardless of sex. These estimates may provide clinicians with useful information for counseling individual patients and highlight the need for continued public health efforts related to smoking cessation.
doi:10.1007/s10552-012-9959-0
PMCID: PMC3542389  PMID: 22825072
Tobacco; Smoking; Cancer; Lifetime Risk; Cancer mortality; Sex
17.  Impact of Blood Pressure and Blood Pressure Change during Middle Age on the Remaining Lifetime Risk for Cardiovascular Disease: The Cardiovascular Lifetime Risk Pooling Project 
Circulation  2011;125(1):37-44.
Background
Prior estimates of lifetime risk (LTR) for cardiovascular disease (CVD) examined the impact of blood pressure at the index age and did not account for changes in blood pressure over time. We examined how changes in blood pressure during middle-age affect LTR for CVD, coronary heart disease (CHD) and stroke.
Methods and Results
Data from 7 diverse US cohort studies were pooled. Remaining LTR for CVD, CHD and stroke were estimated for White and Black men and women with death free of CVD as a competing event. LTR for CVD by blood pressure (BP) strata and by changes in BP over an average of 14 years were estimated. Starting at age 55, we followed 61,585 men and women for 700,000 person-years. LTR for CVD was 52.5% (95% CI 51.3–53.7) for men and 39.9% (38.7–41.0) for women. LTR for CVD was higher for Blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining LTR for CVD, 22–41%, as compared to individuals who had or developed hypertension by the age of 55, 42–69%; suggesting a dose-response effect for the length of time at high BP levels
Conclusions
Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining LTR for CVD. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension in order to reduce the LTR for CVD.
doi:10.1161/CIRCULATIONAHA.110.002774
PMCID: PMC3310202  PMID: 22184621
cardiovascular disease; coronary heart disease; stroke; hypertension; risk factors
18.  Disparities in Counseling for Lifestyle Modification Among Obese Adults: Insights from the Dallas Heart Study 
Obesity (Silver Spring, Md.)  2011;20(4):849-855.
Clinician counseling is a catalyst for lifestyle modification in obesity. Unfortunately, clinicians do not appropriately counsel all obese patients about lifestyle modification. The extent of disparities in clinician counseling is not well understood. Obese participants (BMI ≥30 kg/m2, N = 2097) in the Dallas Heart Study (DHS), a probability-based sample of Dallas County residents ages 18–65, were surveyed regarding health-care utilization and lifestyle counseling over the year prior to DHS enrollment. Health-care utilization and counseling were compared between obese participants across three categories based on the presence of 0, 1, or 2+ of the following cardiovascular (CV) risk factors: hypertension, hypercholesterolemia, or diabetes. Logistic regression modeling was used to determine likelihood of counseling in those with 0 vs. 1+ CV risk factors, stratified by race, adjusting for age, sex, insurance status, and education. Among obese subjects who sought medical care, those with 0 CV risk factors, compared to those with 1 or 2+ CV risk factors, were less likely to report counseling about losing weight (41% vs. 67% vs. 87%, P trend <0.001), dietary changes (44% vs. 71% vs. 85%, P trend <0.001), and physical activity (46% vs. 71% vs. 86%, P trend <0.001). Blacks and Hispanics without CV risk factors had a lower odds of receiving counseling than whites without risk factors on weight loss (adjusted odds ratio (OR), 95% confidence interval (CI) for nonwhites 0.19, [0.13–0.28], whites 0.48, [0.26–0.87]); dietary changes (nonwhites 0.19, [0.13–0.27], whites 0.37, [0.21–0.64]); and physical activity (nonwhites 0.22, [0.16–0.32], whites 0.32, [0.18–0.57]). Lifestyle counseling rates by clinicians are suboptimal among obese patients without CV risk factors, especially blacks and Hispanics. Systematic education about and application of lifestyle interventions could capitalize on opportunities for primary CV risk prevention.
doi:10.1038/oby.2011.242
PMCID: PMC3514073  PMID: 21818156
19.  Race-Specific Associations of Myeloperoxidase with Atherosclerosis in a Population-Based Sample: The Dallas Heart Study 
Atherosclerosis  2011;219(2):833-838.
Objective
Myeloperoxidase (MPO) is a leukocyte-derived enzyme that appears to be directly involved in atherosclerosis development. We evaluated the association of circulating MPO with coronary and aortic atherosclerosis in a large, multiethnic population.
Methods and Results
Plasma levels of MPO were measured in 3294 subjects participating in the Dallas Heart Study, a probability-based population sample. Coronary artery calcification (CAC) was measured by EBCT, and abdominal aorta plaque prevalence (AP) and burden (APB), as well as abdominal aorta wall thickness (AWT) were determined by MRI. Associations between MPO and atherosclerosis phenotypes were assessed in multivariable analyses adjusting for traditional atherosclerosis risk factors. MPO levels in the 4th compared with 1st quartile independently associated with prevalent AP (OR 1.41, 95% CI 1.08–1.84), APB (beta coefficient 0.23, p=0.02), and AWT (beta coefficient 0.04, p=0.03), but not with prevalent CAC (OR 0.84, 95% CI 0.61–1.17). MPO remained associated with aortic atherosclerosis phenotypes but not coronary calcification after adjustment for other inflammatory biomarkers. A significant interaction was observed between race/ethnicity, MPO and AP (pinteraction=0.038), such that MPO levels in the 4th vs 1st quartile associated with prevalent AP in African Americans, (OR 1.81, 95% CI 1.23–2.65) but not in White or Hispanic participants (OR 0.99, 95% CI 0.68–1.44).
Conclusion
Higher levels of MPO associated with aortic but not coronary atherosclerosis, with significant associations limited to African American participants. These findings suggest that MPO might be a novel risk factor contributing to racial disparities in peripheral vascular disease.
doi:10.1016/j.atherosclerosis.2011.08.029
PMCID: PMC3226883  PMID: 21917261
Myeloperoxidase; atherosclerosis; peripheral vascular disease; African American
20.  Interactions Between Smoking, Pulmonary Surfactant Protein B, and Atherosclerosis in the General Population: The Dallas Heart Study 
Objective
Pulmonary surfactant protein B (SP-B), an alveolar protein normally detectable at only very low concentrations in blood, circulates at higher levels among smokers and those with alveolar injury and inflammation. We hypothesized that SP-B may serve as a marker of the vascular effects of smoking, and would thus associate with subclinical measures of atherosclerosis.
Methods and Results
Plasma levels of SP-B were measured in 3,294 subjects, ages 30-65, enrolled in the Dallas Heart Study, a probability-based population sample of Dallas County adults. Coronary artery calcium (CAC) was measured by computed tomography and abdominal aortic plaque (AP) by magnetic resonance imaging. The cohort comprised 29% current and 17% former smokers. The overall prevalence of CAC was 22% and AP 39%. Median SP-B levels were 5-fold higher among current vs. never smokers (P<0.0001) and significantly correlated with estimated pack-years smoked (Spearman rho=0.35, P<0.0001). Increasing levels of SP-B also associated with other traditional cardiac risk factors and higher levels of inflammatory biomarkers. In univariable analyses, increasing SP-B quartiles associated with higher prevalence of both CAC and AP (Ptrend <0.0001 for each). In multivariable analyses adjusting for traditional cardiovascular risk factors, SP-B remained associated with AP (OR 1.87 for the 4th vs. 1st quartile, 95% CI 1.39 to 2.51; P<0.0001) but not CAC. An interaction was observed between SP-B, smoking status, and AP (Pinteraction=0.01), such that SP-B associated with AP in current smokers (adjusted OR 2.15 for the 4th vs. 1st quartile, 95% CI 1.26 to 3.67; P=0.005), but not in former or never smokers.
Conclusions
Circulating levels of SP-B increase with greater smoking burden and independently associate with abdominal aortic plaque among current smokers. Our findings support further investigation of the role of SP-B as a marker of the vascular effects of smoking.
doi:10.1161/ATVBAHA.111.228692
PMCID: PMC3177606  PMID: 21817103
21.  Cardiorespiratory Fitness and Long-Term Survival in “Low-Risk” Adults 
Background
We sought to establish whether cardiorespiratory fitness had important implications for long-term cardiovascular risk among individuals classified as low risk by the Framingham Risk Score (10-year coronary heart disease risk <10%). Prognostic factors of long-term cardiovascular risk are needed for low-risk subjects who make up the largest percentage of the US population.
Methods and Results
The study population was composed of men and women, 30 to 50 years of age, who had a baseline medical exam at the Cooper Clinic, Dallas, TX, between 1970 and 1983. Eligible individuals were defined as at low risk for coronary heart disease by Framingham Risk Score at the time of study entry and had no history of diabetes (n=11 190). Cardiorespiratory fitness was determined by maximum graded exercise treadmill tests. Over an average 27±2-year period, 15% of low-fit (quintile 1) compared to 6% of high-fit (quintile 5) individuals died (P<0.001). A 1–metabolic equivalent level increase in baseline fitness was associated with an 11% reduction in all-cause deaths and an 18% reduction in deaths due to cardiovascular disease (CVD) after adjustment for age, sex, body mass index, systolic blood pressure, total cholesterol, blood glucose levels, smoking, and early family history of coronary disease. There was an incremental decrease in CVD risk with increasing fitness quintile, such that the high fit had the lowest adjusted 30-year CVD mortality rate (hazard ratio 0.29, 95% CI: 0.16–0.51) compared to the low fit.
Conclusions
Cardiorespiratory fitness is associated with a significant reduction in long-term CVD among individuals identified as low risk by Framingham Risk Score. These data suggest that preventive lifestyle interventions geared to optimize cardiorespiratory fitness, even among a “low-risk” subset, should be considered to improve CVD-free survival. (J Am Heart Assoc. 2012;1:e001354 doi: 10.1161/JAHA.112.001354.)
doi:10.1161/JAHA.112.001354
PMCID: PMC3487345  PMID: 23130161
cardiorespiratory fitness; risk, low; Framingham Risk Score; cardiovascular disease
22.  Lifetime Risks of Cardiovascular Disease 
The New England Journal of Medicine  2012;366(4):321-329.
BACKGROUND
The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults.
METHODS
We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.
RESULTS
We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts.
CONCLUSIONS
Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.)
doi:10.1056/NEJMoa1012848
PMCID: PMC3336876  PMID: 22276822
23.  DISTRIBUTION OF 10-YEAR AND LIFETIME PREDICTED RISKS FOR CARDIOVASCULAR DISEASE IN U.S. ADULTS: FINDINGS FROM THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY 2003 TO 2006 
Background
National guidelines for primary prevention suggest consideration of lifetime risk for cardiovascular disease in addition to 10-year risk, but it is currently unknown how many U.S. adults would be identified as having low short-term but high lifetime predicted risk if stepwise stratification were employed.
Methods and Results
We included 6,329 CVD-free and nonpregnant individuals aged 20 to 79 years, representing approximately 156 million U.S. adults, from the National Health and Nutrition Examination Survey 2003–2004 and 2005–2006. We assigned 10-year and lifetime predicted risks to stratify participants into three groups: low 10-year (<10%)/low lifetime (<39%) predicted risk, low 10-year (<10%)/high lifetime (≥39%) predicted risk, and high 10-year (≥10%) predicted risk or diagnosed diabetes. The majority of U.S. adults (56%, or 87 million individuals) are at low short-term but high lifetime predicted risk for cardiovascular disease. Twenty-six percent (41 million adults) are at low short-term and low lifetime predicted risk, and only 18% (28 million individuals) are at high short-term predicted risk. The addition of lifetime risk estimation to 10-year risk estimation identifies higher risk women and younger men in particular.
Conclusions
Whereas 82% of U.S. adults are at low short-term risk, two-thirds of this group, or 87 million people, are at high lifetime predicted risk for cardiovascular disease. These results provide support for use of a stepwise stratification system aimed at improving risk communication, and they provide a baseline for public health efforts aimed at increasing the proportion of Americans with low short-term and low lifetime risk for cardiovascular disease.
doi:10.1161/CIRCOUTCOMES.109.869727
PMCID: PMC3058791  PMID: 20123666
24.  MRI plaque imaging and its role in population-based studies 
BMC Medicine  2010;8:78.
Noninvasive direct vessel wall (plaque) imaging may provide a good opportunity to study unique aspects of atherosclerotic lesions in different populations. The article published by Esposito et al. provides new insights into our understanding of diabetic atherosclerotic vascular disease by using direct plaque imaging techniques. The findings from this article call for attention to more in vivo imaging to understand the nature of high-risk atherosclerosis, especially in prospective studies in diabetic patients.
See research article: http://www.biomedcentral.com/1471-2342/10/27/abstract
doi:10.1186/1741-7015-8-78
PMCID: PMC3002295  PMID: 21118507
25.  Differential Associations between Soluble Cellular Adhesion Molecules and Atherosclerosis in the Dallas Heart Study: a Distinct Role for Soluble Endothelial Cell-Selective Adhesion Molecule 
Objective
Endothelial cell-selective adhesion molecule (ESAM) is a junctional-type cellular adhesion molecule (CAM) that is uniquely expressed in vascular endothelium and activated platelets and mediates neutrophil and monocyte diapedesis across the endothelium. Given its role in endothelial pathobiology, we hypothesized that soluble ESAM (sESAM) would be independently associated with atherosclerosis and vascular stiffness.
Methods and Results
We measured sESAM, soluble intercellular adhesion molecule (sICAM)-1 and soluble vascular cell adhesion molecule (sVCAM)-1 in 3222 subjects participating in the Dallas Heart Study, a probability-based population sample. Coronary artery calcium (CAC) was measured by electron beam computed tomography, and abdominal aortic wall thickness (AWT), aortic plaque burden (APB), and aortic compliance (AC) by magnetic resonance imaging (MRI). Increasing levels of sESAM were associated with all major cardiovascular risk factors as well as with inflammatory markers such as monocyte chemoattractant protein-1, but only weakly correlated with sICAM-1 and sVCAM-1. In multivariate analyses, sESAM was independently associated with prevalent CAC (OR 1.2 per SD increase, 95% CI 1.1–1.3; p=0.005), AWT (p=0.035), and AC (p=0.006), but not APB (p=0.15). In contrast, no independent associations were observed between sICAM-1 or sVCAM-1 and any of the atherosclerosis phenotypes.
Conclusions
In this first reported clinical study of sESAM in humans, sESAM levels were independently associated with CAC, AWT, and AC, while sICAM-1 and sVCAM-1 were not. These findings support a unique role of this cellular adhesion molecule in atherosclerosis and suggest the need for further exploration of sESAM as a predictive biomarker and potential mediator of atherosclerosis.
doi:10.1161/ATVBAHA.109.190553
PMCID: PMC2771407  PMID: 19759376
Inflammation; Adhesion molecules; Atherosclerosis; Aortic compliance; Coronary calcium; Biomarkers

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