The severity of individual menopausal symptoms, cardiovascular disease, and all-cause mortality in the Women's Health Initiative Observational Cohort.

OBJECTIVE: The aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality. METHODS: In an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were multivariable adjusted, and individual associations were Bonferroni corrected to adjust for multiple comparisons. A machine learning approach (least absolute shrinkage and selection operator) was used to select the most parsimonious set of MS most predictive of CVD and all-cause mortality. RESULTS: The severity of night sweats, waking up several times at night, joint pain or stiffness, heart racing or skipping beats, dizziness, feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were each significantly associated with total CVD. The largest hazard ratio (HR) for total CVD was found for moderate or severe heart racing or skipping beats (HR, 1.55; 95% confidence interval [CI], 1.29-1.86). The individual severities of heart racing or skipping beats, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were associated with increased all-cause mortality. Moderate or severe dizziness had the largest HR (1.58; 95% CI, 1.24-2.01). Multiple symptom modeling via least absolute shrinkage and selection operator selected dizziness, heart racing, feeling tired, and joint pain as most predictive of CVD, whereas dizziness, tremors, and feeling tired were most predictive of all-cause mortality. CONCLUSION: Among postmenopausal women with no known CVD at baseline, the severity of specific individual MS was significantly associated with incident CVD and mortality. Consideration of severe MS may enhance sex-specific CVD risk predication in future cohorts, but caution should be applied as severe MS could also indicate other health conditions.

Heart fat and carotid artery atherosclerosis progression in recently menopausal women: impact of menopausal hormone therapy: The KEEPS trial.

OBJECTIVE: Heart fat deposition has been linked to atherosclerosis, and both accelerate after menopause. Hormone therapy (HT) may differentially slow heart fat deposition and progression of atherosclerosis, depending on the specific HT agent or its route of administration. Our objective was to evaluate the effects of different HT agents, oral and transdermal, on associations between heart fat accumulation and atherosclerosis progression, measured by carotid intima-media thickness (CIMT), in recently menopausal women from the Kronos Early Estrogen Prevention Study (KEEPS) trial. METHODS: KEEPS was a randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens (o-CEE) or 50 mcg/d transdermal 17ß-estradiol (t-E2), compared with placebo, on 48 months progression of CIMT. Epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT) volumes were quantified by computed tomography. RESULTS: In all, 467 women (mean age [SD] 52.7 [2.5]; 78.2% White; 30% on o-CEE, 30.8% t-E2, 39.2% placebo) with heart fat volumes and CIMT at baseline and 48 months were included. EAT and PAT changes were not associated with CIMT progression; however, the assigned treatment significantly modified the association between PAT (but not EAT) change and CIMT progression. In the o-CEE group, adjusted CIMT progression was 12.66 µm (95% confidence interval [CI] 1.80, 23.52) lower than in t-E2 group (P = 0.02), and 10.09 µm (95% CI 0.79, 19.39) lower than in placebo group (P = 0.03), as per 1-SD increase in PAT. CONCLUSION: Compared with t-E2, o-CEE appears to slow down the adverse effect of increasing PAT on progression of atherosclerosis. Whether this beneficial association is specific to CEE or to the oral route of CEE administration is unclear and should be assessed further.

Birth weight and carotid artery intima-media thickness.

OBJECTIVES: To determine the association between birth weight and carotid artery intima-media thickness (CIMT), a measure of atherogenesis, in a population of 11-year-old children. STUDY DESIGN: CIMT measured by high-resolution ultrasound, and birth registry data were available for 670 children of the Southern California Children's Health Study. Multivariate regression analyses were performed to investigate the association between birth weight and CIMT, with adjustment for child's health status and lifestyle, pregnancy information, and parental health. RESULTS: Mean CIMT was 0.57 mm (SD 0.04). We found a nonlinear association between birth weight and CIMT, with an increase in CIMT of 0.014 mm in the fifth (P value .01) compared with the third birth weight quintile. These associations were robust in subsample analyses in children considered normal-weight by gestational age or in term-born children. No significant association with CIMT was found for the lowest quintile. CONCLUSIONS: Greater birth weight was significantly associated with increased CIMT at age 11 years. No evidence for an impact of lower birth weight was found. The predictive value of childhood CIMT on future cardiovascular outcomes is largely unknown, but strong associations between childhood cardiovascular disease risk factors and adult vascular disease suggest that increased CIMT in childhood may be clinically important.

Subclinical atherosclerosis in Latino youth: progression of carotid intima-media thickness and its relationship to cardiometabolic risk factors.

OBJECTIVE: To assess carotid artery intima-media thickness (CIMT) change over 2 years in overweight Latino adolescents and examine its relationship to cardiometabolic risk. STUDY DESIGN: Seventy-two healthy overweight male and female Latino adolescents (mean age, 14.5 ± 1.7 years; mean body mass index, 31.5 ± 6.9 kg/m(2)) were evaluated at baseline and 2 years later for CIMT by high-resolution B-mode ultrasound, the metabolic syndrome and its features, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging, glucose/insulin measures by fasting blood, and oral and intravenous glucose tolerance tests. RESULTS: Baseline CIMT did not differ from 2-year follow-up; however, 38 participants increased CIMT (0.017 ± 0.003 mm; +2.8%) and 34 decreased or remained the same (-0.019 ± 0.002 mm; -3.1%). ANCOVA analyses showed that participants with CIMT progression had higher baseline low-density lipoprotein (LDL)-cholesterol and total cholesterol (91.3 ± 3.4 and 150.3 ± 3.9 mg/dL) compared with those with CIMT non-progression (78.1 ± 3.6 and 135.6 ± 4.2 mg/dL, P < .05), independent of sex, baseline CIMT, age, and height. In multivariate regression, LDL-cholesterol was the sole predictor of CIMT progression, but the effect was small (odds of CIMT progression increased by 3% for each 1 mg/dL higher baseline LDL-cholesterol; 95% CI, 1.004 to 1.006, P = .03). CONCLUSIONS: These results indicate a high variability in the magnitude of CIMT change in growing overweight Latino youth and support the use of LDL-cholesterol to assess subclinical atherosclerosis risk in this population.

Association of the diabetes gene calpain-10 with subclinical atherosclerosis: the Mexican-American Coronary Artery Disease Study.

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.

A genome-wide scan for carotid artery intima-media thickness: the Mexican-American Coronary Artery Disease family study.

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 approximately 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 multivariate-adjusted CIMT, respectively. The strongest evidence of linkage was found on chromosome 2 at D2S2944 (logarithm of the odds [LOD]=3.08). Other suggestive linkages were also found on chromosome 6 at D6S1022 to D6S2410 (LOD=2.21) and chromosome 13 at D13S796 to D13S895 (LOD=1.34). CONCLUSIONS: These results show that there is a strong genetic effect on CIMT in these Mexican American CAD families. The linkage peak on chromosome 2 suggests that there is a gene (or genes) at this chromosome location influencing CIMT.

Early onset of subclinical atherosclerosis in young persons with type 1 diabetes.

OBJECTIVE: To evaluate the degree of atherosclerosis and its risk factors in adolescents and young adults with type 1 diabetes. STUDY DESIGN: We measured carotid artery intima-media thickness (IMT) in 142 subjects with type 1 diabetes (mean [SD] age = 16.0 [2.6] years) and 87 control subjects (18.8 [3.1] years). Fasting lipid and homocysteine levels, degree of glycemic control, blood pressure, and body mass index were measured in persons with diabetes. RESULTS: The mean carotid IMT was greater in persons with diabetes ( P = .002). Among subjects with type 1 diabetes, lipid levels were significantly higher in female subjects compared with male subjects. The mean carotid IMT was significantly higher in persons with a diabetic complication (including hypertension, retinopathy, or microalbuminuria). In male subjects but not female subjects, HDL cholesterol and the LDL/HDL ratio were correlated with carotid IMT. CONCLUSIONS: Adolescents with type 1 diabetes have increased atherosclerosis compared with control subjects. Risk factors for increased carotid IMT in these younger patients include diabetic complications and HDL cholesterol and the LDL/HDL ratio, which may be sex-specific.