Showing papers by "Howard N. Hodis published in 2005"

Carotid artery intima–media thickness and HIV infection: traditional risk factors overshadow impact of protease inhibitor exposure

Abstract: Context The impact of HIV infection and exposure to antiretroviral therapy on the development of subclinical atherosclerosis is incompletely understood.

A Genome-Wide Scan for Carotid Artery Intima-Media Thickness The Mexican-American Coronary Artery Disease Family Study

Abstract: Background and Purpose— Carotid artery intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with coronary artery disease (CAD), and stroke. CIMT is also an important predictor of clinical cardiovascular events. To systematically identify the genetic determinants of CIMT, we performed a genome-wide scan using data from 91 2-generation Mexican American families ascertained via a parent with CAD diagnosed. Methods— CIMT was measured in 274 adult offspring (mean age, 34.6 years) using high-resolution B-mode ultrasound; 413 subjects, including adult offspring and their parents, were genotyped using Marshfield screen set 12 (380 microsatellite markers at ≈10-cM interval). Heritability was estimated using the variance component approach implemented in SOLAR. Linkage analyses were performed using both the sib-pair regression approach and the variance component approach. Results— The estimated heritability was 0.68, 0.45, and 0.40 for unadjusted, gender- and age-adjusted, and mult...

Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes.

Abstract: We tested the effects of treatment with a thiazolidinedione drug on rates of progression of carotid intima-media thickness (CIMT) and some putative determinants of CIMT in young women at high risk for type 2 diabetes. A total of 266 nondiabetic, Hispanic women with recent gestational diabetes were randomized to placebo or troglitazone. CIMT measurements were made at baseline, annually, and at study end, together with measurements of obesity, serum lipids, and glucose and insulin levels during oral glucose tolerance tests. Insulin sensitivity (minimal model analysis) was measured at baseline and 3 months later. Data were analyzed to compare CIMT progression rates between treatment groups and investigate potential determinants of differences in CIMT progression. One hundred ninety-two women had a CIMT measurement at baseline and at least one follow-up visit. The mean rate of CIMT change was 31% lower in women assigned to troglitazone (P = 0.048). This intergroup difference was not explained by baseline or o...

Determinants of the effect of estrogen on the progression of subclinical atherosclerosis: Estrogen in the Prevention of Atherosclerosis Trial.

Abstract: OBJECTIVE To determine the extent to which the estrogen-induced changes in lipids and markers of carbohydrate metabolism explain the beneficial effect of estrogen therapy on the progression of carotid artery intima-media thickness (IMT) in postmenopausal women. DESIGN A randomized, double-blind, placebo-controlled, single-center trial enrolling 222 postmenopausal women 45 years and older without cardiovascular disease and with low-density lipoprotein (LDL) cholesterol levels of 3.37 mmol/L or greater (> or = 130 mg/dL). Intervention was unopposed micronized 17beta-estradiol versus placebo. Measurements were made using high-resolution B-mode ultrasonography to measure carotid artery IMT at baseline and every 6 months on-trial. RESULTS Progression of carotid IMT was inversely related to on-trial high-density lipoprotein (HDL) cholesterol (P = 0.04) and was directly related to on-trial LDL-cholesterol (P = 0.005). Compared with placebo, women randomized to estradiol showed a higher mean on-trial HDL-cholesterol level and a lower mean on-trial LDL-cholesterol level. In contrast, fasting glucose, insulin, and hemoglobin A1C were lowered and insulin sensitivity increased with estradiol therapy, but the changes were not related to carotid IMT progression. On-trial HDL-cholesterol and LDL-cholesterol were significant independent determinants of carotid IMT progression, jointly explaining 30% of the treatment effect of unopposed estrogen on the progression of carotid IMT. CONCLUSION Unopposed 17beta-estradiol reduced carotid IMT progression in postmenopausal women in part by increasing HDL-cholesterol and decreasing LDL-cholesterol. Although women randomized to estradiol showed improvement in all the markers of carbohydrate metabolism, these factors did not play a significant role in carotid IMT progression.

Postmenopausal oral estrogen therapy and blood pressure in normotensive and hypertensive subjects: the Estrogen in the Prevention of Atherosclerosis Trial.

Abstract: OBJECTIVE To determine if 17beta-estradiol increases blood pressure in postmenopausal women. DESIGN A total of 222 healthy postmenopausal women were randomly assigned to either 1 mg micronized 17beta-estradiol daily or placebo for 2 years. Blood pressure measurements were obtained every other month and common carotid artery intima-media thickness measured every 6 months. Statistical analyses comparing longitudinal changes in systolic and diastolic blood pressure between treatment groups used a mixed general linear model including interaction terms to evaluate variations by age or estradiol level. RESULTS Both placebo and estradiol groups showed small declines in systolic and diastolic blood pressure during the trial among the normotensive subjects and subjects on antihypertensive medications. However, the decline did not differ significantly between the groups. Treatment effects on systolic blood pressure differed significantly by the age of the subject (interaction P value = 0.04) with younger women on estradiol showing on average a rise in systolic blood pressure, and older women a decline. The association between serum estradiol level and systolic blood pressure showed a similar modification with age (P = 0.03). Changes in systolic blood pressure in women on estradiol were positively correlated with intima-media thickness progression (P = 0.03). CONCLUSIONS Overall, 17beta-estradiol did not influence changes in blood pressure in normotensive or hypertensive women. The effect of 17beta-estradiol treatment on systolic blood pressure may be influenced by a woman's age. Estradiol may increase systolic blood pressure in younger postmenopausal women, while having the opposite effect in older postmenopausal women.

Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study

Abstract: Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast. We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17β-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17β-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/≥ 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD. The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%). Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone.

The association of smoking and subclinical atherosclerosis in Type 2 diabetes: modification by duration of diabetes

Abstract: Background Diabetes is a relatively common disease in the United States, and cardiovascular disease is the major cause of morbidity and mortality among persons with diabetes. While smoking is one of the most well-established risk factors for heart disease and atherosclerosis, the effect of smoking on atherosclerosis among diabetic patients has not been thoroughly investigated. The primary objective of this paper was to evaluate the impact of smoking on atherosclerosis among Type 2 diabetic patients and to evaluate whether smoking associations with atherosclerosis are modified by diabetes-related variables. Methods We used cross-sectional baseline data from a randomized controlled trial to evaluate the associations between smoking and common carotid artery intima-media thickness (IMT) in 299 subjects with Type 2 diabetes. There were 34 (11%) current cigarette smokers, 73 (24%) former cigarette smokers, and 192 (64%) subjects who had never smoked regularly. Results There was an increasing trend in mean carotid IMT with both longer duration and increased frequency of smoking (adjusted P for trend 0.04 and 0.02, respectively). The mean ± SE carotid IMT was non-significantly thicker (0.872 ± 0.01 mm) in diabetic patients who had ever smoked than never smokers (0.842 ± 0.01 mm) after controlling for age, gender and other potential confounders (P = 0.08). The negative effects of ever smoking (P = 0.01 for interaction), number of cigarettes smoked daily (P = 0.003 for interaction) and duration of smoking (P = 0.03 for interaction) on carotid IMT were accentuated with longer duration of diabetes. Conclusion Smoking is associated with subclinical atherosclerosis in diabetic persons and interacts with duration of diabetes to accentuate atherosclerosis. The association between carotid IMT and duration of diabetes increases with both the frequency and duration of smoking.

Association of the Diabetes Gene Calpain-10 With Subclinical Atherosclerosis: The Mexican-American Coronary Artery Disease Study

Abstract: The powerful relation between atherosclerosis and diabetes may have a common genetic basis. However, few genes predisposing to both have been identified. Calpain-10 (CAPN10) was the first gene for type 2 diabetes identified by positional cloning, wherein a combination of haplotypes conferred increased risk of diabetes. We sought to determine whether CAPN10 influences subclinical atherosclerosis. Among nondiabetic subjects from 85 Mexican-American families with a history of coronary artery disease, subclinical atherosclerosis was assessed by common carotid artery intima-media thickness (IMT), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and insulin secretion was estimated by the oral glucose tolerance test. These phenotypes were tested for association with CAPN10 haplotypes. Haplotype 1112 (of single nucleotide polymorphisms [SNPs] 44, 43, 56, and 63) was associated with increased IMT, while haplotype 1221 was associated with decreased IMT. The 112/121 haplotype combination (of SNPs 43, 56, and 63), originally found to confer increased risk for diabetes, was associated with the largest IMT in our study population. CAPN10 was also associated with both insulin sensitivity and insulin secretion. Covariate analysis suggested that CAPN10 affects IMT independently of these diabetes-related phenotypes. The fact that the diabetes gene CAPN10 also influences the risk for atherosclerosis shows that inherited factors may underlie the frequent co-occurrence of these two conditions.

Relation of progression of coronary artery atherosclerosis to risk of cardiovascular events (from the Monitored Atherosclerosis Regression Study).

Abstract: We investigated whether change in coronary artery atherosclerosis as measured by quantitative coronary angiography is related to cardiovascular event risk. Although many studies have demonstrated the effectiveness of statins in decreasing atherosclerotic progression and cardiovascular event risk, a relation between coronary atherosclerotic progression and event risk has not been documented in clinical trials that have evaluated statin therapy. The Monitored Atherosclerosis Regression Study (MARS) was a randomized, double-blind, placebo-controlled trial designed to test whether lovastatin would decrease coronary atherosclerotic progression as measured by quantitative coronary angiography. We followed 173 subjects in the MARS who had minimum luminal diameter and percent diameter stenosis measured at the beginning and end of a 2-year intervention. Postintervention follow-up events over a mean period of 9.4 years were reported by subjects and verified by medical records. Two-year percent stenosis and minimum luminal diameter changes were tested in relation to clinical event risk in multivariate Cox's regression models. Events ascertained were (1) coronary death and myocardial infarction, (2) coronary death, myocardial infarction, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty, and (3) any cardiovascular event. Increased percent stenosis was associated with significantly increased hazard ratios (HRs) in all event categories (category 1 HR 1.55 per SD percent stenosis, p <0.01; category 2 HR 1.58, p <0.01; category 3 HR 1.47, p = 0.01). Conversely, event risks were decreased for subjects who had increased minimum luminal diameter (category 1 HR 0.79, p = 0.04) and were not associated with category 2 (HR 0.79, p = 0.12) or category 3 (HR 0.81, p = 0.17). These results indicate that quantitative coronary angiographic changes are associated with cardiovascular events and support the long-term benefit of early intervention to decrease atherosclerosis.

Antioxidant Vitamin Supplementation and Cardiovascular Disease

Abstract: Key Points Free radical-related processes underlie many of the proinflammatory and vascular cell changes associated with atherogenesis. Although observational studies have been mixed, the most consistent inverse association between antioxidant vitamin intake and reduced cardiovascular disease (CVD) has been reported with vitamin E. Primary and secondary randomized controlled trials, including arterial imaging trials, have predominantly indicated a null effect of antioxidant vitamin supplementation on CVD events and progression of atherosclerosis. Troublesome data from randomized controlled trials (RCTs) of antioxidant vitamin supplementation have arisen in certain subgroups. Limited data indicate that low antioxidant levels may be a prerequisite for the cardioprotective effects of antioxidant vitamin supplementation to be expressed. Current data do not support the use of antioxidant vitamin supplementation for the prevention or treatment of CVD. The divergent information derived from observational trials and RCTs warrants further investigation. Consumption of fruits and vegetables high in antioxidant vitamins appears to be an important component of a healthy lifestyle.