Gerardo Heiss

Genome-wide association study of blood pressure and hypertension

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10−7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10−8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

Association of Hormone-Replacement Therapy with Various Cardiovascular Risk Factors in Postmenopausal Women

Background Most epidemiologic studies of cardiovascular disease in postmenopausal women suggest that estrogen-replacement therapy has a protective effect. The effects of the use of estrogen combined with progestin are less well studied. Methods To examine the associations of hormone-replacement therapy with concentrations of plasma lipids and hemostatic factors, fasting serum concentrations of glucose and insulin, and blood pressure, we studied 4958 postmenopausal women participating in a population-based investigation. Using cross-sectional data, we classified the women into four groups according to their use of hormone-replacement therapy: current users of estrogen alone, current users of estrogen with progestin, nonusers who had formerly used these hormones, and nonusers who had never used them. Results Current users had higher mean levels of high-density lipoprotein cholesterol, its subfractions high-density lipoprotein2 and high-density lipoprotein3, and apolipoprotein A-I than nonusers, and lower me...

Arterial Wall Thickness Is Associated With Prevalent Cardiovascular Disease in Middle-Aged Adults: The Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND AND PURPOSE This study was done to assess the relationship between prevalent cardiovascular disease and arterial wall thickness in middle-aged US adults. METHODS The association of preexisting coronary heart disease, cerebrovascular disease, and peripheral vascular disease with carotid and popliteal intimal-medial thickness (IMT) (measured by B-mode ultrasound) was assessed in 13,870 black and white men and women, aged 45 to 64, during the Atherosclerosis Risk in Communities (ARIC) Study baseline examination (1987 through 1989). Prevalent disease was determined according to both participant self-report and measurements at the baseline examination (including electrocardiogram, fasting blood glucose, and medication use). RESULTS Across four race and gender strata, mean carotid far wall IMT was consistently greater in participants with prevalent clinical cardiovascular disease than in disease-free subjects. Similarly, the prevalence of cardiovascular disease was consistently greater in participants with progressively thicker IMT. The greatest differences in carotid IMT associated with prevalent disease were observed for reported symptomatic peripheral vascular disease (0.09 to 0.22 mm greater IMT in the four race-gender groups). CONCLUSIONS These data document the substantially greater arterial wall thickness observed in middle-aged adults with prevalent cardiovascular disease. Both carotid and popliteal arterial IMT were related to clinically manifest cardiovascular disease affecting distant vascular beds, such as the cerebral, peripheral, and coronary artery vascular beds.

Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study

BACKGROUND Type 2 diabetes mellitus and atherosclerotic cardiovascular disease have common antecedents. Since markers of inflammation predict coronary heart disease and are raised in patients with type 2 diabetes, we investigated whether they predict whether people will develop type 2 diabetes. METHODS 12,330 men and women, aged 45-64 years, were followed up for a mean of 7 years. We analysed the association between different markers of acute inflammation and subsequent diagnosis of diabetes. In a subgroup of 610 individuals selected originally for an unrelated atherosclerosis case-control study, we also investigated diabetes associations with total sialic acid and orosomucoid, haptoglobin, and alpha1-antitrypsin. FINDINGS 1335 individuals had a new diagnosis of diabetes. Adjusted odds ratios for developing diabetes for quartile extremes were 1.9 (95% CI 1.6-2.3) for raised white-cell count, 1.3 (1.0-1.5) for low serum albumin, and 1.2 (1.0-1.5) for raised fibrinogen. In the subgroup analysis, individuals with concentrations of orosomucoid and sialic acid of more than the median had odds ratios of 7.9 (2.6-23.7) and 3.7 (1.4-9.8), respectively. Adjustment for body-mass index and waist-to-hip ratio lessened the associations; those for white-cell count (1.5 [1.3-1.8]), orosomucoid (7.1 [2.1-23.7]), and sialic acid (2.8 [1.0-8.1]) remained significant. INTERPRETATION Markers of inflammation are associated with the development of diabetes in middle-aged adults. Although autoimmunity may partly explain these associations, they probably reflect the pathogenesis of type 2 diabetes.

Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994.

BACKGROUND AND METHODS To clarify the determinants of contemporary trends in mortality from coronary heart disease (CHD), we conducted surveillance of hospital admissions for myocardial infarction and of in-hospital and out-of-hospital deaths due to CHD among 35-to-74-year-old residents of four communities of varying size in the United States (a total of 352,481 persons in 1994). Between 1987 and 1994, we estimate that there were 11,869 hospitalizations for myocardial infarction (on the basis of 8572 hospitalizations sampled) and 3407 fatal coronary events (3023 sampled). RESULTS The largest average annual decrease in mortality due to CHD occurred among white men (change in mortality, -4.7 percent; 95 percent confidence interval, -2.2 to -7.1 percent), followed by white women (-4.5 percent; 95 percent confidence interval, -0.7 to -8.2 percent), black women (-4.1 percent; 95 percent confidence interval, -10.3 to +2.5 percent), and black men (-2.5 percent; 95 percent confidence interval, -6.9 to +2.2 percent). Overall, in-hospital mortality from CHD fell by 5.1 percent per year, whereas out-of-hospital mortality declined by 3.6 percent per year. There was no evidence of a decline in the incidence of hospitalization for a first myocardial infarction among either men or women; in fact, such hospital admissions increased by 7.4 percent per year (95 percent confidence interval for the change, +0.5 to +14.8 percent) among black women and 2.9 percent per year (95 percent confidence interval, -3.6 to +9.9 percent) among black men. Rates of recurrent myocardial infarction decreased, and survival after myocardial infarction improved. CONCLUSIONS From 1987 to 1994, we observed a stable or slightly increasing incidence of hospitalization for myocardial infarction. Nevertheless, there were significant annual decreases in mortality from CHD. The decline in mortality in the four communities we studied may be due largely to improvements in the treatment and secondary prevention of myocardial infarction.

Lipoprotein-Associated Phospholipase A2, High-Sensitivity C-Reactive Protein, and Risk for Incident Coronary Heart Disease in Middle-Aged Men and Women in the Atherosclerosis Risk in Communities (ARIC) Study

Background—Measuring C-reactive protein (CRP) has been recommended to identify patients at high risk for coronary heart disease (CHD) with low LDL cholesterol (LDL-C). Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a proinflammatory enzyme associated primarily with LDL. Methods and Results—In a prospective, case cohort study in 12 819 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities study, the relation between Lp-PLA2, CRP, traditional risk factors, and risk for CHD events over a period of ≈6 years was examined in a proportional hazards model, stratified by LDL-C. Lp-PLA2 and CRP levels were higher in the 608 cases than the 740 noncases. Both Lp-PLA2 and CRP were associated with incident CHD after adjustment for age, sex, and race with a hazard ratio of 1.78 for the highest tertile of Lp-PLA2 and 2.53 for the highest category of CRP versus the lowest categories. Lp-PLA2 correlated positively with LDL-C (r =0.36) and negatively with HDL-C (r =−0.33) but not with CRP (r =−0.05). In a model adjusted for traditional risk factors including LDL-C, the association of Lp-PLA2 with CHD was attenuated and not statistically significant. For individuals with LDL-C below the median (130 mg/dL), Lp-PLA2 and CRP were both significantly and independently associated with CHD in fully adjusted models. For individuals with LDL-C <130 mg/dL, those with both Lp-PLA2 and CRP levels in the highest tertile were at the greatest risk for a CHD event. Conclusions—Lp-PLA2 and CRP may be complementary in identifying individuals at high CHD risk who have low LDL-C.

Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC Investigators.

Background and Purpose B-mode ultrasound is a widely used technique for the clinical and epidemiological assessment of carotid atherosclerosis. This article provides a description of the distribution of carotid atherosclerosis in the general population. Methods Intimal-medial arterial wall thickness was measured by B-mode real-time ultrasound as an index of atherosclerotic involvement in the extracranial carotid arteries as part of the population-based Atherosclerosis Risk in Communities (ARIC) study. The distribution was described by race-sex strata, in which 759 to 4952 individuals were imaged depending on strata and location in the carotid system. Results Median wall thickness ranged between 0.5 and 1 mm at all ages; fewer than 5% of ARIC participants had values exceeding 2 mm. Individuals tended to have a larger wall thickness in the carotid bifurcation than in the common carotid artery. Internal carotid artery values were more variable, with higher proportions of both large and small wall thicknesses than in the common carotid. The proportion of individuals with a large wall thickness was greatest at the bifurcation and smallest at the common carotid artery. Men had uniformly larger wall thickness than women. Cross-sectional analysis suggests that age-related increases in wall thickness average approximately 0.015 mm/y in women and 0.018 mm/y in men in the carotid bifurcation, 0.010 mm/y for women and 0.014 mm/y for men in the internal carotid artery, and 0.010 mm/y in both sexes in the common carotid artery. Conclusions Estimates provided for wall thickness percentiles can serve as “nomograms” by age, race, and sex.

Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. A case-control study.

To evaluate the consistency, strength, and independence of the relation of carotid atherosclerosis to coronary atherosclerosis, we quantified coronary artery disease risk factors and extent of carotid atherosclerosis (B-mode score) in 343 coronary artery disease patients and 167 disease-free control patients. In univariable analyses, there was a strong association between coronary status and extent of carotid artery disease in men and women older than and younger than 50 years (p less than 0.001 for men and women greater than 50 years, p less than 0.001 for women less than or equal to 50 years, p = 0.045 for men less than or equal to 50). The relation remained strong after control for age in men and women older than 50 years and in women younger than 50 (p less than 0.001 for men and women greater than 50 years, p = 0.003 for women less than or equal to 50) but did not persist after control for age in men younger than 50. Logistic models that included coronary disease risk factors, with or without B-mode score, as independent variables and presence or absence of coronary disease as the outcome variable indicated that the extent of carotid atherosclerosis was a strong, statistically significant independent variable in models for men and women older than 50 years of age. Next, we examined the usefulness of B-mode score as an aid in screening for coronary artery disease in men and women older than 50 years. Classification rules, both including and excluding B-mode score, were developed based on logistic regression and, for comparison, recursive partitioning (decision trees). The performance of these rules and the bias of their performance statistics were estimated. The improved classification of the study sample when B-mode score was incorporated in the rule was statistically significant only for men (p = 0.015). However, the addition of B-mode score was found to 1) increase the median discrimination score for both sex groups based on the logistic model, and 2) yield better sensitivities and specificities for rules based on recursive partitioning. Thus B-mode score is strongly, consistently, and independently associated with coronary artery disease in patients older than 50 and is at least as useful as well-known risk factors for identifying patients with coronary artery disease.

Calcium/Vitamin D Supplementation and Cardiovascular Events

Background— Individuals with vascular or valvular calcification are at increased risk for coronary events, but the relationship between calcium consumption and cardiovascular events is uncertain. We evaluated the risk of coronary and cerebrovascular events in the Women’s Health Initiative randomized trial of calcium plus vitamin D supplementation. Methods and Results— We randomized 36 282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo. Cardiovascular disease was a prespecified secondary efficacy outcome. During 7 years of follow-up, myocardial infarction or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). In subgroup analyses, women with higher total calcium intake (diet plus supplements) at baseline were not at higher risk for coronary events (P=0.91 for interaction) or stroke (P=0.14 for interaction) if assigned to active calcium/vitamin D. Conclusions— Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period.

Lipoprotein-cholesterol distributions in selected North American populations: the lipid research clinics program prevalence study.

SUMMARYTotal plasma lipid and lipoprotein-cholesterol distributions of 4756 white men and women ages 20–59 years are presented. Measurements were obtained during the visit-2 survey of the Lipid Research Clinics Program Prevalence Study and correspond to a 15% random sample of 35,748 white adults screened during the LRC visit-1 survey. Standardized examinations were carried out by 10 North American clinics using a common protocol, on diverse target populations chosen to include a range of sociodemographic characteristics. Age-specific means, medians and selected percentiles are given by sex, with stratification on exogenous sex hormone use in women.Plasma lipid and lipoprotein concentrations in men and women vary with age. Differences in lipid and lipoprotein levels between the study populations are also present and manifest themselves as parallel trends of age-related changes in the 10 populations examined.Higher total cholesterol values in men compared with women appear between the ages 20–50 years and higher LDL cholesterol between the ages 20–55 years. VLDL cholesterol levels are similar in both sexes at ages 20 and 59 years but higher in men than in women in all intermediate age groups. HDL cholesterol is higher in women than in men throughout the age range considered.Women taking sex hormone preparations have higher total cholesterol than women not on hormones between ages 20–50 years, and higher LDL cholesterol between ages 20–40 years. From the third age decade onward, HDL cholesterol levels are progressively higher in women taking hormones than in women not taking sex hormones. Compared with women not taking exogenous sex hormones, women taking hormones have higher total plasma triglyceride values at all ages from 20–59 years. VLDL cholesterol values are higher in women on hormones compared with nonusers of hormones younger than 55 years.