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1.  Subclinical, hemodynamic, and echocardiographic abnormalities of high pulse pressure in hypertensive and non-hypertensive adults 
Background: High pulse pressure (PP) is associated with cardiovascular events, but subclinical abnormalities in cardiac structure and function in relation to high pulse pressure are not well described. Methods and Results: 2225 hypertensive and 1380 non-hypertensive participants with adequate echocardiographic left ventricular measurements were evaluated. Non-hypertensives in the highest PP tertile (compared to the lower tertiles) were older (44 years vs. 40 years, p<0.009), had higher systolic pressure [(SBP) 136 mmHg vs. 108 mmHg] and lower diastolic pressure [(DBP) 54 vs. 71 mmHg (p=.0001)], greater BMI (27 vs. 25 kg/m2, p<.001) and more diabetes (4% vs. 2.25%, p<.001). In the hypertensive group, subjects in the highest PP tertile were older (52 vs 42 years), had higher SBP (157 vs. 116 mmHg) but lower DBP (65 vs. 83 mmHg). In the non-hypertensive group, higher PP (>60 mmHG) was associated with a higher frequency of echocardiographic structural and functional abnormalities, specifically, greater posterior and relative wall thickness, longer isovolumic relaxation time, and concentric left ventricular (LV) hypertrophy. Conclusion: In a population-based sample of hypertensive and non-hypertensive participants, higher PP was associated with subclinical abnormalities of cardiac structure and function, which exist even in the absence of hypertension and/or the use of antihypertensive treatment.
PMCID: PMC3499939  PMID: 23173105
Left ventricular hypertrophy; pulse pressure; hypertension; arterial stiffness; echocardiography
2.  Fish Intake and the Risk of Incident Heart Failure: The Women’s Health Initiative 
Circulation. Heart Failure  2011;4(4):404-413.
Whether fish or the fatty acids they contain are independently associated with risk for incident heart failure (HF) among postmenopausal women is unclear.
Methods and Results
The baseline Women’s Health Initiative Observational Study (WHI-OS) cohort consisted of 93,676 women aged 50–79 of diverse ethnicity and background of which 84,493 were eligible for analyses. Intakes of baked/broiled fish, fried fish and omega-3 fatty acid (eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), α-linolenic acid (ALA)), and trans fatty acid (TFA) were determined from the WHI food frequency questionnaire. Baked/broiled fish consumption was divided into 5 frequency categories: <1/mo (referent), 1–3/mo, 1–2/wk, 3–4/wk, ≥5/wk. Fried fish intake was grouped into 3 frequency categories: <1/mo (referent), 2) 1–3/mo, and 3) ≥1/wk. Associations between fish or fatty acid intake and incident HF were determined using Cox models adjusting for HF risk factors and dietary factors. Baked/broiled fish consumption (≥5 servings/wk at baseline) was associated with a hazard ratio (HR) of 0.70 (95% CI: 0.51, 0.95) for incident HF. In contrast, fried fish consumption (≥1 serving/wk at baseline) was associated with a HR of 1.48 (95% CI: 1.19, 1.84) for incident HF. No significant associations were found between EPA+DHA, ALA, or TFA intake and incident HF.
Increased baked/broiled fish intake may lower HF risk, while increased fried fish intake may increase HF risk in postmenopausal women.
PMCID: PMC3310223  PMID: 21610249
heart failure; epidemiology; nutrition; women
3.  High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering drugs and diet network (GOLDN): an interventional study 
Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA.
Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number.
We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.
PMCID: PMC3206850  PMID: 22008512
postprandial lipemia; lipoprotein particles; NMR; high-fat meal
4.  Aspirin Use, Dose, and Clinical Outcomes in Postmenopausal Women with Stable Cardiovascular Disease: The Women’s Health Initiative Observational Study 
Despite compelling evidence that aspirin reduces fatal and non-fatal vascular events among the overall population in various settings, women have frequently been underrepresented and their data underreported. We sought to evaluate the relationship between aspirin use, dose (81 or 325mg) and clinical outcomes among postmenopausal women with stable cardiovascular disease.
Women with cardiovascular disease (n=8928) enrolled in the Women’s Health Initiative Observational Study were used for this analysis. The primary outcome was the incidence of all-cause mortality and cardiovascular events (myocardial infarction, stroke and cardiovascular death).
Among 8928 women with stable cardiovascular disease, 4101 (46%) reported taking aspirin, of whom 30% were on 81 and 70% were on 325mg. At 6.5 years of follow-up, no significant association was noted for aspirin use and all-cause mortality or cardiovascular events. However, after multivariate adjustment, aspirin use was associated with a significantly lower all-cause (adjusted HR 0.86, [0.75-0.99], P=0.04) and cardiovascular related mortality (adjusted HR 0.75, [0.60-0.95], P=0.01) compared with no aspirin. Aspirin use was associated with a lower risk of cardiovascular events (adjusted HR 0.90, [0.78-1.04], P=0.14) which did not meet statistical significance. Compared with 325mg, use of 81mg was not significantly different for all-cause mortality, cardiovascular events or any individual endpoint.
After multivariate adjustment, aspirin use was associated with significantly lower risk of all-cause mortality, specifically cardiovascular mortality, among postmenopausal women with stable cardiovascular disease. No significant difference was noted between 81 and 325mg of aspirin. Overall, aspirin use was low in this cohort of women with stable cardiovascular disease.
PMCID: PMC2801891  PMID: 20031819
Aspirin; Dose; Women; Cardiovascular Disease; Observational Study
5.  Identification of a pleiotropic locus on chromosome 7q for a composite left ventricular wall thickness factor and body mass index: the HyperGEN Study 
BMC Medical Genetics  2009;10:40.
Left ventricular (LV) mass and wall thickness are closely associated with measures of body size and blood pressure and also correlated with systolic and diastolic function, suggesting a contribution of common physiologic mechanisms, including pleiotropic genes, to their covariation.
Doppler echocardiography was performed in 434 African-American (1344 individuals) and 284 white families (1119 individuals). We conducted a genome-wide linkage scan for LV mass, LV structure and function, and composite factors derived from a factor analysis of LV structure and function in the HyperGEN Study population.
Factor analysis identified (i) a LV wall thickness factor correlated strongly with interventricular septal thickness (IVSTd) and posterior wall thickness (PWTd) and (ii) a LV diastolic filling factor strongly correlated with early and atrial phase peak transmitral filling velocities. The LV phenotypes and composite factor scores were analyzed in multipoint variance components linkage model implemented in SOLAR with 387 microsatellite markers. In whites, the two highest LODs were 3.42 for LV atrial phase peak filling velocity at 144 cM on chromosome 1 and 3.12 for the LV wall thickness factor at 160 cM on chromosome 7. The peak LODs of the component traits (IVSTd and PWTd) clustered at the same region as the composite factor. Adjusting the factor score for body mass index (BMI) substantially reduced the peak LOD at this region (LOD = 1.92). Bivariate linkage analysis of the composite factor with BMI improved LOD to 3.42 at 158 cM. Also in whites, suggestive linkage was observed on chromosomes 2 and 4 for LV mass, chromosomes 3, 5, 10, and 17 for LV atrial phase peak filling velocity, and chromosome 10 for LV diastolic filling factor. In African Americans, suggestive linkage was observed on chromosome 12 for LV mass, chromosome 21 for IVSTd, and chromosome 3 for LV internal diameter at end-diastole.
Our study suggests that a region on chromosome 7 contains pleiotropic genes contributing to the variations of both LV wall thickness and BMI in whites.
PMCID: PMC2692848  PMID: 19426520
6.  A Whole-genome Scan for Pulse Pressure/Stroke Volume Ratio in African Americans: The HyperGEN Study 
American journal of hypertension  2007;20(4):398-402.
Arterial stiffness is reported in numerous family studies to be heritable; linkage analysis has identified genomic regions that likely harbor genes contributing to its phenotypic expression. We sought to identify loci contributing to arterial stiffness in a large group of African American hypertensive families.
We performed a genome scan on 1251 African Americans in families participating in the HyperGEN (Hypertension Genetic Epidemiology Network) study. Children of the hypertensive proband generation were also included in the analysis. Arterial stiffness was estimated as pulse pressure (PP: systolic –diastolic blood pressure) divided by echocardiographically determined stroke volume (SV). PP/SV ratio was adjusted for several non-genetic sources of variation, including demographic and lifestyle factors; the residual phenotype was analyzed using multipoint variance components linkage implemented in SOLAR 2.0.3.
Arterial stiffness was 20% heritable in African Americans. Two regions were highly suggestive of linkage, one between markers D1S1665 and D1S1728 in the 215 cM region of chromosome 1 (LOD = 3.08), and another between D14S588 and D14S606 in the 85 cM region of chromosome 14 (LOD = 2.42). Two candidate genes (GPR-25, SMOC-1) are located in the linked regions. SMOC-1 is of physiological interest because it codes a secreted glycoprotein with five domains, each containing regions homologous to those on other proteins that mediate cell-matrix interactions. GPR-25 is homologous to receptors involved in blood pressure regulation.
At least two chromosomal regions in humans are likely to harbor genes contributing to interindividual variation in PP/SV ratio, an index of arterial stiffness, in African Americans.
PMCID: PMC1997287  PMID: 17386346
Blood Pressure; Pulse Pressure; Arterial Stiffness; Genetic Linkage
7.  Circulating Levels of Endothelial Adhesion Molecules and Risk of Diabetes in an Ethnically Diverse Cohort of Women 
Diabetes  2007;56(7):1898-1904.
Elevated circulating levels of soluble adhesion molecules as markers of endothelial dysfunction have been related to insulin resistance and its associated metabolic abnormalities. However, their associations with type 2 diabetes remain inconclusive. We conducted a prospective nested case-control study to examine the associations between plasma levels of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) and diabetes risk among 82,069 initially healthy women aged 50 to 79 years from the Women’s Health Initiative Observational Study. During a median follow-up of 5.9 years, 1,584 incident diabetes case subjects were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. Baseline median levels of the biomarkers were each significantly higher among case subjects than among control subjects (E-selectin, 49 vs. 37 ng/ml; ICAM-1, 324 vs. 280 ng/ml; and VCAM-1, 765 vs. 696 ng/ml [all P values <0.001]). After adjustment for risk factors, the relative risks of diabetes among women in the highest quartile versus those in the lowest quartile were 3.46 for E-selectin (95% confidence interval 2.56–4.68; P for trend <0.0001), 2.34 for ICAM-1 (1.75–3.13; P for trend <0.0001), and 1.48 for VCAM-1 (1.07–2.04; P for trend = 0.009). E-selectin and ICAM-1 remain significant in each ethnic group. Higher levels of E-selectin and ICAM-1 were consistently associated with increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women, implicating an etiological role of endothelial dysfunction in the pathogenesis of type 2 diabetes.
PMCID: PMC1952236  PMID: 17389327
8.  Impact of Cyclooxygenase Inhibitors in the Women's Health Initiative Hormone Trials: Secondary Analysis of a Randomized Trial 
PLoS Clinical Trials  2006;1(5):e26.
We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials.
The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6.
The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States.
The trials enrolled 27,347 postmenopausal women, aged 50–79 y.
We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
Outcome Measures:
Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68–1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86–2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57–1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69–1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified.
Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results.
Editorial Commentary
Background: As part of a set of studies known as the Women's Health Initiative trials, investigators aimed to find out whether providing postmenopausal hormone therapy (estrogen in the case of women who had had a hysterectomy, and estrogen plus progestin for women who had not had a hysterectomy) reduced cardiovascular risk as compared to placebo. Earlier observational studies had suggested this might be the case. The trials found that postmenopausal hormone therapy did not reduce cardiovascular risk in the groups studied. However, there was a concern that medication use outside the trial with nonsteroidal anti-inflammatory drugs (NSAIDs), and specifically the type of NSAID known as COX-2 inhibitors, could have affected the findings. This concern arose because it is known that COX-2 inhibition lowers levels of prostacyclin, a molecule thought to be beneficial to cardiovascular health, whereas estrogen increases prostacyclin levels. Evidence from randomized trials and observational studies has also shown that patients treated with some COX-2 inhibitors are at increased risk of heart attacks and strokes; the cardiovascular safety of other NSAIDs is also the focus of great attention. Therefore, the authors of this paper aimed to do a statistical exploration of the data from the Women's Health Initiative hormone trials, to find out whether NSAID use by participants in the trials could have affected the trials' main findings.
What this trial shows: In this reanalysis of the original data from the trials, the investigators found that the effects of hormone therapy on cardiovascular outcomes were similar among users and non-users of NSAIDs, confirming that use of these drugs did not significantly affect the results from the Women's Health Initiative hormone trials.
Strengths and limitations: The original hormone trials were large, appropriately randomized studies that enrolled a diverse cohort of participants. Therefore, a large number of cardiovascular events occurred in the groups being compared, allowing this subsequent analysis to be done. One limitation is that use of COX-2 inhibitors in the trial was low; therefore, the investigators were not able to specifically test whether COX-2 inhibitor use (as opposed to NSAID use generally) might have affected their findings.
Contribution to the evidence: The investigators did not set out specifically to evaluate the cardiovascular safety of particular medications in this study. Rather, they wanted to see if these NSAIDs could have modified the effects of the hormone therapy. The secondary analysis done here shows that the main findings from the Women's Health Initiative hormone trials were not significantly affected by use of NSAIDs outside the trial.
PMCID: PMC1584256  PMID: 17016543
9.  Healthy Exercise 
Western Journal of Medicine  1984;141(6):864-871.
Persons at any age can substantially improve their fitness for work and play through appropriate exercise training. Considerable evidence indicates that physical activity is valuable for weight control, modifying lipids and improving carbohydrate tolerance. Less rigorous scientific data are available for associated long-term blood pressure and psychological changes with habitual exercise. Strenuous physical activity most likely reduces the incidence of coronary heart disease and the detrimental impact of certain chronic diseases on health. Adverse effects may result from a training program, but the major concern is the susceptibility to cardiovascular events during and immediately after exertion. To achieve optimal benefits with minimal risk, exercise must be carefully prescribed within the context of overall health and training objectives. Taken altogether, a distinct rationale exists for regular vigorous exercise as an integral part of a personal health maintenance program.
PMCID: PMC1011222  PMID: 6395501

Results 1-9 (9)