Background

The coronary artery calcium (CAC) score predicts coronary heart disease (CHD) events, but methods for interpreting the score in combination with conventional CHD risk factors have not been established.

Methods and results

We analyzed CAC scores and CHD risk factor measurements from 6757 black, Chinese, Hispanic, and white men and women aged 45 to 84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC was associated with age, sex, race/ethnicity, and all conventional CHD risk factors. Multivariable models using these factors predicted the presence of CAC (C statistic=0.789) and degree of elevation (16% of variation explained) and can be used to update a "pretest" CHD risk estimate, such as the 10-year Framingham Risk Score, that is based on an individual's conventional risk factors. In scenarios in which a high CAC score is expected, a moderately elevated CAC score of 50 is reassuring (eg, reducing risk from 10% to 6% in a healthy older white man), but when a low/zero CAC score is expected, even with identical pretest CHD risk, the same CAC score of 50 may be alarmingly high (eg, increasing risk from 10% to 20% in a middle-aged black woman with multiple risk factors). Both the magnitude and direction of the shift in risk varied markedly with pretest CHD risk and with the pattern of risk factors.

Conclusions

Knowledge of what CAC score to expect for an individual patient, based on their conventional risk factors, may help clinicians decide when to order a CAC test and how to interpret the results.

Coronary artery calcium (CAC) is a highly specific feature of coronary atherosclerosis. On the basis of single-center and multicenter clinical and population-based studies with short-term and long-term outcomes data (up to 15-year follow-up), CAC scoring has emerged as a widely available, consistent, and reproducible means of assessing risk for major cardiovascular outcomes, especially useful in asymptomatic people for planning primary prevention interventions such as statins and aspirin. CAC testing in asymptomatic populations is cost effective across a broad range of baseline risk. This review summarizes evidence concerning CAC, including its pathobiology, modalities for detection, predictive role, use in prediction scoring algorithms, CAC progression, evidence that CAC changes the clinical approach to the patient and patient behavior, novel applications of CAC, future directions in scoring CAC scans, and new CAC guidelines.

We evaluated 25 repolarization-related ECG variables for the risk of coronary heart disease (CHD) death in 52 994 postmenopausal women from the Women's Health Initiative study. Hazard ratios from Cox regression were computed for subgroups of women with and without cardiovascular disease (CVD). During the average follow-up of 16.9 years, 941 CHD deaths occurred. Based on electrophysiological considerations, 2 sets of ECG variables with low correlations were considered as candidates for independent predictors of CHD death: Set 1, Ѳ(Tp|Tref), the spatial angle between T peak (Tp) and normal T reference (Tref) vectors; Ѳ(Tinit|Tterm), the angle between the initial and terminal T vectors; STJ depression in V6 and rate-adjusted QTp interval (QTpa); and Set 2, TaVR and TV1 amplitudes, heart rate, and QRS duration. Strong independent predictors with over 2-fold increased risk for CHD death in women with and without CVD were Ѳ(Tp|Tref) >42° from Set 1 and TaVR amplitude >-100 μV from Set 2. The risk for these CHD death predictors remained significant after multivariable adjustment for demographic/clinical factors. Other significant predictors for CHD death in fully adjusted risk models were Ѳ(Tinit|Tterm) >30°, TV1 >175 μV, and QRS duration >100 ms. Ѳ(Tp|Tref) angle and TaVR amplitude are associated with CHD mortality in postmenopausal women. The use of these measures to identify high-risk women for further diagnostic evaluation or more intense preventive intervention warrants further study. http://www.clinicaltrials.gov. Unique identifier: NCT00000611.

Skeletal muscle quantity and quality decrease with older age, which is partly attributed to ectopic fat infiltration and has negative metabolic consequences. To inform efforts to preserve skeletal muscle with aging, a better understanding of biologic correlates of quantity and quality of muscle and intermuscular adipose tissue (IMAT) is needed. We used targeted lipidomics of lipoprotein subfractions among 947 Multi-Ethnic Study of Atherosclerosis participants to provide a detailed metabolic characterization of area and density of abdominal muscle and IMAT. Serum lipoprotein subfractions were measured at the first visit using 1H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm²) and density (Hounsfield units) were estimated at visit 2 or 3 using computed tomography of the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, rectus abdominis) muscles. We identified lipoprotein subfractions associated with body composition using linear regression adjusting for demographics, lifestyle, and multiple comparisons. Among 105 lipoprotein subfractions, 24 were associated with total muscle area (absolute standardized regression coefficient range: 0.07-0.10, p-values ≤ 0.002), whereas none were associated with total muscle density. When examining muscle subgroups, 25 lipoprotein subfractions were associated with stabilization muscle area, with associations strongest among the obliques. For total IMAT area, there were 27 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.09-0.13, p-values ≤ 0.002). Specifically, 27 lipoprotein subfractions were associated with stabilization IMAT area, with associations strongest among the oblique and rectus abdominis muscles. For total IMAT density, there were 39 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.10-0.19, p-values ≤ 0.003). Specifically, 28 and 33 lipoprotein subfractions were associated with IMAT density of locomotion and stabilization (statistically driven by obliques) muscles, respectively. Higher VLDL (cholesterol, unesterified cholesterol, phospholipids, triglycerides, and apolipoprotein B) and lower HDL (cholesterol and unesterified cholesterol) were associated with higher muscle area, higher IMAT area, and lower IMAT density. Several associations between lipoprotein subfractions and abdominal muscle area and IMAT area and density were strongest among the stabilization muscles, particularly the obliques, illustrating the importance of examining muscle groups separately. Future work is needed to determine whether the observed associations indicate a lipoprotein profile contributing to worse skeletal muscle with fat infiltration.

Context

Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than randomized trials.

Objective

To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes.

Design, setting, and participants

Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers. The volunteer sample was 22,579 community-dwelling women aged 50 to 79 years without prior cholecystectomy.

Intervention

Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E + P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14,203).

Main outcome measures

Participants reported hospitalizations for gallbladder diseases and gallbladder-related procedures, with events ascertained through medical record review. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) using intention-to-treat and time-to-event methods.

Results

The CEE and the E + P groups were similar to their respective placebo groups at baseline. The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E + P trials, respectively. The annual incidence rate for any gallbladder event was 78 events per 10,000 person-years for the CEE group (vs 47/10,000 person-years for placebo) and 55 per 10,000 person-years for E + P (vs 35/10,000 person-years for placebo). Both trials showed greater risk of any gallbladder disease or surgery with estrogen (CEE: HR, 1.67; 95% CI, 1.35-2.06; E + P: HR, 1.59; 95% CI, 1.28-1.97). Both trials indicated a higher risk for cholecystitis (CEE: HR, 1.80; 95% CI, 1.42-2.28; E + P: HR, 1.54; 95% CI 1.22-1.94); and for cholelithiasis (CEE: HR, 1.86; 95% CI, 1.48-2.35; E + P: HR, 1.68; 95% CI, 1.34-2.11) for estrogen users. Also, women undergoing estrogen therapy were more likely to receive cholecystectomy (CEE: HR, 1.93; 95% CI, 1.52-2.44; E + P: HR, 1.67; 95% CI, 1.32-2.11), but not other biliary tract surgery (CEE: HR, 1.18; 95% CI, 0.68-2.04; E + P: HR, 1.49; 95% CI, 0.78-2.84).

Conclusions

These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy. The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy.

Background

The association between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) events is not well described in individuals with very high levels of HDL-C (>80 mg/dL).

Methods and results

Using pooled data from 6 community-based cohorts we examined CHD and total mortality risks across a broad range of HDL-C, including values in excess of 80 mg/dL. We used Cox proportional hazards models with penalized splines to assess multivariable, adjusted, sex-stratified associations of HDL-C with the hazard for CHD events and total mortality, using HDL-C 45 mg/dL and 55 mg/dL as the referent in men and women, respectively. Analyses included 11 515 men and 12 925 women yielding 307 245 person-years of follow-up. In men, the association between HDL-C and CHD events was inverse and linear across most HDL-C values; however at HDL-C values >90 mg/dL there was a plateau effect in the pattern of association. In women, the association between HDL-C and CHD events was inverse and linear across lower values of HDL-C, however at HDL-C values >75 mg/dL there were no further reductions in the hazard ratio point estimates for CHD. In unadjusted models there were increased total mortality risks in men with very high HDL-C, however mortality risks observed in participants with very high HDL-C were attenuated after adjustment for traditional risk factors.

Conclusions

We did not observe further reductions in CHD risk with HDL-C values higher than 90 mg/dL in men and 75 mg/dL in women.

Background

The coronary artery calcium (CAC) score predicts future coronary heart disease (CHD) events and could be used to guide primary prevention interventions, but CAC measurement has costs and exposes patients to low-dose radiation.

Methods and results

We estimated the cost-effectiveness of measuring CAC and prescribing statin therapy based on the resulting score under a range of assumptions using an established model enhanced with CAC distribution and risk estimates from the Multi-Ethnic Study of Atherosclerosis. Ten years of statin treatment for 10,000 55-year-old women with high cholesterol (10-year CHD risk, 7.5%) was projected to prevent 32 myocardial infarctions, cause 70 cases of statin-induced myopathy, and add 1108 years to total life expectancy. Measuring CAC and targeting statin treatment to the 2500 women with CAC>0 would provide 45% of the benefit (+501 life-years), but CAC measurement would cost $2.25 million and cause 9 radiation-induced cancers. Treat all was preferable to CAC screening in this scenario and across a broad range of other scenarios (CHD risk, 2.5%-15%) when statin assumptions were favorable ($0.13 per pill and no quality of life penalty). When statin assumptions were less favorable ($1.00 per pill and disutility=0.00384), CAC screening with statin treatment for persons with CAC>0 was cost-effective (<$50 000 per quality-adjusted life-year) in this scenario, in 55-year-old men with CHD risk 7.5%, and in other intermediate risk scenarios (CHD risk, 5%-10%). Our results were critically sensitive to statin cost and disutility and relatively robust to other assumptions. Alternate CAC treatment thresholds (>100 or >300) were generally not cost-effective.

Conclusions

CAC testing in intermediate risk patients can be cost-effective but only if statins are costly or significantly affect quality of life.

Background

Known risk factors for intracerebral hemorrhage (ICH) include age, hypertension, smoking, alcohol intake, and anticoagulant use. Some previous reports have indicated that hemostatic factors measured many years before the onset of ICH might predict the later occurrence of ICH. The objective of this analysis was to test whether selected hemostatic factors measured years before the onset of ICH could identify patients at higher risk for future ICH.

Methods

We performed a nested case-control study within the Women's Health Initiative (WHI) cohort. Postmenopausal women aged 50-79 years (mean 68) at baseline (1993-1998) were enrolled at 40 Clinical Centers in the United States and followed for adjudicated ICH for a mean of 11.4 years. ICH cases (N = 75) and controls (N = 75) were matched on age, ethnicity, blood pressure, anticoagulant use, and treated hypertension. Stored blood samples from the baseline WHI examination were tested for von Willebrand factor (vWF), a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13 (ADAMTS13), tissue plasminogen activator (t-PA), and urokinase plasminogen activator (u-PA). Platelet count, white blood cell count, and hemoglobin concentration were also measured.

Results

Mean baseline levels of vWF (1.03 and .95 U/mL), ADAMTS13 (1.0 and 1.1 µg/mL), vWF : ADAMTS13 ratio (.99 and .92), t-PA (14.75 and 14.80 IU/mL), and u-PA (.09 and .10 IU/mL) were not significantly different by case-control status. Significant differences were also not identified for platelet count, hemoglobin, white blood count, or reported alcohol use.

Conclusion

None of the 4 baseline hemostatic factors nor the platelet count was predictive of future ICH risk in this long-term study of older postmenopausal women.

Background

Inflammatory biomarkers have shown consistent associations with disability and frailty in older adults. Statin medications may reduce the incidence the frailty because of their anti-inflammatory effects. This study examines associations between current use, duration, and potency of statin medications and incident frailty in initially nonfrail women 65 years old or older.

Methods

The authors conducted a prospective analysis of data from the Women's Health Initiative Observational Study (WHI-OS) conducted at 40 clinical centers in the United States. Eligible women were nonfrail and 65-79 years old at baseline (n = 25,378). Current statin use at baseline was ascertained through direct inspection of medicine containers during clinic visits. Frailty was ascertained through self-reported indicators and physical measurements at baseline and 3-year clinic contacts. Components of frailty included self-reported low physical function, exhaustion, low physical activity, and unintended weight loss. Multinomial logistic regression models were used to adjust for covariates predicting incident frailty.

Results

Among the 25,378 eligible women, 3453 (13.6%) developed frailty by the 3-year follow-up contact. Current statin use had no association with incident frailty (multivariate-adjusted odds ratio [OR] = 1.00; 95% confidence interval [CI], 0.85-1.16). Duration and potency of statin use were also not significantly associated with incident frailty. Among low potency statin users, longer duration of use was associated with reduced risk of frailty (p for trend =.02). A similar pattern of results was observed when frailty was studied in the absence of intervening, incident cardiovascular events.

Conclusions

Overall, incidence of frailty was similar in current statin users and nonusers.