Claudia U. Chae

Blood Pressure and Inflammation in Apparently Healthy Men

Inflammation plays an important role in the development of atherosclerosis, but the specific stimuli governing cytokine release in atherogenesis are unknown. We examined the hypothesis that hypertension may increase the risk of atherosclerosis via proinflammatory effects. In a cross-sectional study involving 508 apparently healthy men, we studied the association between blood pressure and baseline plasma concentrations of 2 inflammatory markers, intercellular adhesion molecule-1 (sICAM-1) and interleukin-6 (IL-6). Increase in systolic blood pressure (SBP) (P =0.003), pulse pressure (PP) (P =0.019), and mean arterial pressure (P =0.014) was significantly associated with levels of sICAM-1. All of these measures of blood pressure, as well as diastolic blood pressure (DBP), were significantly associated with levels of IL-6 (all, P ≤ 0.001). In multiple linear regression models controlled for age and other cardiac risk factors, SBP (7.6 ng/mL per 10 mm Hg, P =0.016) and PP (8.13 ng/mL per 10 mm Hg, P =0.038) were significantly associated with sICAM-1 levels, whereas SBP (0.11 pg/mL per 10 mm Hg, P <0.001), DBP (0.11 pg/mL per 10 mm Hg, P =0.008), PP (0.10 pg/mL per 10 mm Hg, P =0.009), and mean arterial pressure (0.15 pg/mL per 10 mm Hg, P <0.001) had similar strong relationships with log-transformed IL-6 levels. Therefore, in apparently healthy men, we observed significant graded relationships between blood pressure and levels of sICAM-1 as well as IL-6. These data suggest that increased blood pressure may be a stimulus for inflammation and that this is a possible mechanism underlying the well-established role of hypertension as a risk factor for atherosclerotic disease.

Coronary Computed Tomography Angiography for Early Triage of Patients With Acute Chest Pain The ROMICAT (Rule Out Myocardial Infarction using Computer Assisted Tomography) Trial

OBJECTIVES This study was designed to determine the usefulness of coronary computed tomography angiography (CTA) in patients with acute chest pain. BACKGROUND Triage of chest pain patients in the emergency department remains challenging. METHODS We used an observational cohort study in chest pain patients with normal initial troponin and nonischemic electrocardiogram. A 64-slice coronary CTA was performed before admission to detect coronary plaque and stenosis (>50% luminal narrowing). Results were not disclosed. End points were acute coronary syndrome (ACS) during index hospitalization and major adverse cardiac events during 6-month follow-up. RESULTS Among 368 patients (mean age 53 +/- 12 years, 61% men), 31 had ACS (8%). By coronary CTA, 50% of these patients were free of coronary artery disease (CAD), 31% had nonobstructive disease, and 19% had inconclusive or positive computed tomography for significant stenosis. Sensitivity and negative predictive value for ACS were 100% (n = 183 of 368; 95% confidence interval [CI]: 98% to 100%) and 100% (95% CI: 89% to 100%), respectively, with the absence of CAD and 77% (95% CI: 59% to 90%) and 98% (n = 300 of 368, 95% CI: 95% to 99%), respectively, with significant stenosis by coronary CTA. Specificity of presence of plaque and stenosis for ACS were 54% (95% CI: 49% to 60%) and 87% (95% CI: 83% to 90%), respectively. Only 1 ACS occurred in the absence of calcified plaque. Both the extent of coronary plaque and presence of stenosis predicted ACS independently and incrementally to Thrombolysis In Myocardial Infarction risk score (area under curve: 0.88, 0.82, vs. 0.63, respectively; all p < 0.0001). CONCLUSIONS Fifty percent of patients with acute chest pain and low to intermediate likelihood of ACS were free of CAD by computed tomography and had no ACS. Given the large number of such patients, early coronary CTA may significantly improve patient management in the emergency department.

Coronary Multidetector Computed Tomography in the Assessment of Patients With Acute Chest Pain

Background— Noninvasive assessment of coronary atherosclerotic plaque and significant stenosis by coronary multidetector computed tomography (MDCT) may improve early and accurate triage of patients presenting with acute chest pain to the emergency department. Methods and Results— We conducted a blinded, prospective study in patients presenting with acute chest pain to the emergency department between May and July 2005 who were admitted to the hospital to rule out acute coronary syndrome (ACS) with no ischemic ECG changes and negative initial biomarkers. Contrast-enhanced 64-slice MDCT coronary angiography was performed immediately before admission, and data sets were evaluated for the presence of coronary atherosclerotic plaque and significant coronary artery stenosis. All providers were blinded to MDCT results. An expert panel, blinded to the MDCT data, determined the presence or absence of ACS on the basis of all data accrued during the index hospitalization and 5-month follow-up. Among 103 consecutive patients (40% female; mean age, 54±12 years), 14 patients had ACS. Both the absence of significant coronary artery stenosis (73 of 103 patients) and nonsignificant coronary atherosclerotic plaque (41 of 103 patients) accurately predicted the absence of ACS (negative predictive values, 100%). Multivariate logistic regression analyses demonstrated that adding the extent of plaque significantly improved the initial models containing only traditional risk factors or clinical estimates of the probability of ACS (c statistic, 0.73 to 0.89 and 0.61 to 0.86, respectively). Conclusions— Noninvasive assessment of coronary artery disease by MDCT has good performance characteristics for ruling out ACS in subjects presenting with possible myocardial ischemia to the emergency department and may be useful for improving early triage.

Prospective Study of Sudden Cardiac Death Among Women in the United States

Background—There are few data regarding the determinants of sudden cardiac death (SCD) in women, primarily because of their markedly lower rate of SCD compared with men. Nonetheless, existing data, although sparse, suggest possible gender differences in risk factors for SCD. Methods and Results—In this prospective cohort of 121 701 women aged 30 to 55 years at baseline, SCD was defined as death within 1 hour of symptom onset. From 1976 to 1998, 244 SCDs were identified. Although the risk of SCD increased markedly with age, the percentage of cardiac deaths that were sudden decreased. Most (69%) women who suffered a SCD had no history of cardiac disease before their death. However, almost all of the women who died suddenly (94%) had reported at least 1 coronary heart disease risk factor. Smoking, hypertension, and diabetes conferred markedly elevated (2.5- to 4.0-fold) risk of SCD, similar to that conferred by a history of nonfatal myocardial infarction (relative risk, 4.1; 95% confidence interval, 2.9 to 6.7). Family history of myocardial infarction before age 60 years and obesity were associated with moderate (1.6-fold) elevations in risk. With regard to mechanism, 88% of SCDs were classified as arrhythmic. In 76% of these, the first rhythm documented was ventricular tachycardia or ventricular fibrillation. Conclusions—These prospective data suggest that, as in men, coronary heart disease risk factors predict risk of SCD in women and that SCD is usually an arrhythmic death. Therefore, prevention of atherosclerosis or ventricular arrhythmias may reduce the incidence of SCD in women.

Sex Hormone–Binding Globulin and the Free Androgen Index Are Related to Cardiovascular Risk Factors in Multiethnic Premenopausal and Perimenopausal Women Enrolled in the Study of Women Across the Nation (SWAN)

Background—Recent clinical trials have shifted attention away from estrogens and toward androgens and sex hormone–binding globulin (SHBG) as potential mediators of increasing cardiovascular (CV) risk in women at midlife. Methods and Results—The correlation between reproductive hormones and CV risk factors was evaluated in a multiethnic (white, black, Hispanic, Chinese, and Japanese) sample of 3297 premenopausal and perimenopausal women. Testosterone and estradiol (E2) were evaluated along with SHBG and the free androgen index (FAI), the amount of testosterone not bound by SHBG. Low SHBG and high FAI were strongly and consistently related to elevated CV risk factors (higher insulin, glucose, and hemostatic and inflammatory markers and adverse lipids) even after controlling for body mass index (P<0.001 for all). Low levels of E2 were associated with elevated CV risk factors to a lesser degree. These observations were consistent across the 5 ethnic groups. Compared with whites, blacks had higher levels of SHBG and lower levels of FAI, and Chinese had lower levels of SHBG and higher levels of FAI. Conclusions—Low SHBG and high FAI are strongly associated with CV risk factors in racially diverse women, and thus, androgens likely play a role in the CV risk profile of perimenopausal women.

Are Changes in Cardiovascular Disease Risk Factors in Midlife Women due to Chronological Aging or to the Menopausal Transition

OBJECTIVES This prospective study examined whether changes in traditional and novel coronary heart disease (CHD) risk factors are greater within a year of the final menstrual period (FMP), relative to changes that occur before or after that interval, in a multiethnic cohort. BACKGROUND Understanding the influence of menopause on CHD risk remains elusive and has been evaluated primarily in Caucasian samples. METHODS SWAN (Study of Womens Health Across the Nation) is a prospective study of the menopausal transition in 3,302 minority (African American, Hispanic, Japanese, or Chinese) and Caucasian women. After 10 annual examinations, 1,054 women had achieved an FMP not due to surgery and without hormone therapy use before FMP. Measured CHD risk factors included lipids and lipoproteins, glucose, insulin, blood pressure, fibrinogen, and C-reactive protein. We assessed which of 2 models provided a better fit with the observed risk factor changes over time in relation to the FMP: a linear model, consistent with chronological aging, or a piecewise linear model, consistent with ovarian aging. RESULTS Only total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B demonstrated substantial increases within the 1-year interval before and after the FMP, consistent with menopause-induced changes. This pattern was similar across ethnic groups. The other risk factors were consistent with a linear model, indicative of chronological aging. CONCLUSIONS Women experience a unique increase in lipids at the time of the FMP. Monitoring lipids in perimenopausal women should enhance primary prevention of CHD.

Nonsteroidal Antiinflammatory Drugs, Acetaminophen, and the Risk of Cardiovascular Events

Background— Although randomized trials of cyclooxygenase-2 (COX-2) inhibitors have shown increased cardiovascular risk, studies of nonselective, nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen have been inconsistent. Methods and Results— We examined the influence of NSAIDs and acetaminophen on the risk of major cardiovascular events (nonfatal myocardial infarction, fatal coronary heart disease, nonfatal and fatal stroke) in a prospective cohort of 70 971 women, aged 44 to 69 years at baseline, free of known cardiovascular disease or cancer, who provided medication data biennially since 1990. During 12 years of follow-up, we confirmed 2041 major cardiovascular events. Women who reported occasional (1 to 21 d/mo) use of NSAIDs or acetaminophen did not experience a significant increase in the risk of cardiovascular events. However, after adjustment for cardiovascular risk factors, women who frequently (≥22 d/mo) used NSAIDs had a relative risk (RR) for a cardiovascular event of 1.44 (95% CI, 1.27 to 1.65) compared with nonusers, whereas those who frequently consumed acetaminophen had a RR of 1.35 (95% CI, 1.14 to 1.59). The elevated risk associated with frequent NSAID use was particularly evident among current smokers (RR=1.82; 95% CI, 1.38 to 2.42) and was absent among never smokers (Pinteraction=0.02). Moreover, we observed significant dose-response relations: Compared with nonusers, the RRs for a cardiovascular event among women who used ≥15 tablets per week were 1.86 (95% CI, 1.27 to 2.73) for NSAIDs and 1.68 (95% CI, 1.10 to 2.58) for acetaminophen. Conclusions— Use of NSAIDs or acetaminophen at high frequency or dose is associated with a significantly increased risk for major cardiovascular events, although more moderate use did not confer substantial risk.

Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation

CONTEXT The risks associated with new-onset atrial fibrillation (AF) among middle-aged women and populations with a low comorbidity burden are poorly defined. OBJECTIVES To examine the association between incident AF and mortality in initially healthy women and to evaluate the influence of associated cardiovascular comorbidities on risk. DESIGN, SETTING, AND PARTICIPANTS Between 1993 and March 16, 2010, 34,722 women participating in the Womens Health Study underwent prospective follow-up. Participants were 95% white, older than 45 years (median, 53 [interquartile range {IQR}, 49-59] years), and free of AF and cardiovascular disease at baseline. Cox proportional hazards models with time-varying covariates were used to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF. MAIN OUTCOME MEASURES Primary outcomes included all-cause, cardiovascular, and noncardiovascular mortality. Secondary outcomes included stroke, congestive heart failure, and myocardial infarction. RESULTS During a median follow-up of 15.4 (IQR, 14.7-15.8) years, 1011 women developed AF. Incidence rates per 1000 person-years among women with and without AF were 10.8 (95% confidence interval [CI], 8.1-13.5) and 3.1 (95% CI, 2.9-3.2) for all-cause mortality, 4.3 (95% CI, 2.6-6.0) and 0.57 (95% CI, 0.5-0.6) for cardiovascular mortality, and 6.5 (95% CI, 4.4-8.6) and 2.5 (95% CI, 2.4-2.6) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 (95% CI, 1.64-2.77), 4.18 (95% CI, 2.69-6.51), and 1.66 (95% CI, 1.19-2.30), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (all-cause: HR, 1.70 [95% CI, 1.30-2.22]; cardiovascular: HR, 2.57 [95% CI, 1.63-4.07]; and noncardiovascular: HR, 1.42 [95% CI, 1.02-1.98]). Among women with paroxysmal AF (n = 656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94; 95% CI, 1.55-5.59). CONCLUSION Among a group of healthy women, new-onset AF was independently associated with all-cause, cardiovascular, and noncardiovascular mortality, with some of the risk potentially explained by nonfatal cardiovascular events.

Dietary α-Linolenic Acid Intake and Risk of Sudden Cardiac Death and Coronary Heart Disease

Background— &agr;-Linolenic acid, an intermediate-chain n-3 fatty acid found primarily in plants, may decrease the risk of fatal coronary heart disease (CHD) through a reduction in fatal ventricular arrhythmias and sudden cardiac death (SCD). Methods and Results— We prospectively examined the association between dietary intake of &agr;-linolenic acid assessed via updated food-frequency questionnaires and the risk of SCD, other fatal CHD, and nonfatal myocardial infarction (MI) among 76 763 women participating in the Nurses’ Health Study who were free from cancer and completed a dietary questionnaire at baseline in 1984. During 18 years of follow-up, we identified 206 SCDs, 641 other CHD deaths, and 1604 nonfatal MIs. After controlling for coronary risk factors and other fatty acids, including long-chain n-3 fatty acids, the intake of &agr;-linolenic acid was inversely associated with the risk of SCD (P for trend, 0.02) but not with the risk of other fatal CHD or nonfatal MI. Compared with women in the lowest quintile of &agr;-linolenic acid intake, those in the highest 2 quintiles had a 38% to 40% lower SCD risk. This inverse relation with SCD risk was linear and remained significant even among women with high intakes of long-chain n-3 fatty acids. Conclusions— These prospective data suggest that increasing dietary intake of &agr;-linolenic acid may reduce the risk of SCD but not other types of fatal CHD or nonfatal MI in women. The specificity of the association between &agr;-linolenic acid and SCD supports the hypothesis that these n-3 fatty acids may have antiarrhythmic properties.

Ethnic Differences in C-Reactive Protein Concentrations

BACKGROUND Limited data exist regarding the ethnic differences in C-reactive protein (CRP) concentrations, an inflammatory marker associated with risk of cardiovascular disease (CVD). We hypothesized that known CVD risk factors, including anthropometric characteristics, would explain much of the observed ethnic variation in CRP. METHODS We performed a cross-sectional analysis of 3154 women, without known CVD and not receiving hormone therapy, enrolled in the Study of Womens Health Across the Nation (SWAN), a multiethnic prospective study of pre- and perimenopausal women. RESULTS The study population was 47.4% white, 27.7% African-American, 8.5% Hispanic, 7.7% Chinese, and 8.6% Japanese; mean age was 46.2 years. African-American women had the highest median CRP concentrations (3.2 mg/L), followed by Hispanic (2.3 mg/L), white (1.5 mg/L), Chinese (0.7 mg/L), and Japanese (0.5 mg/L) women (all pairwise P < 0.001 compared with white women). Body mass index (BMI) markedly attenuated the association between ethnicity and CRP. After adjusting for age, socioeconomic status, BMI, and other risk factors, African-American ethnicity was associated with CRP concentrations >3 mg/L (odds ratio 1.37, 95% CI 1.07-1.75), whereas Chinese and Japanese ethnicities were inversely related (0.58, 0.35-0.95, and 0.43, 0.26-0.72, respectively). CONCLUSIONS Modifiable risk factors, particularly BMI, account for much but not all of the ethnic differences in CRP concentrations. Further study is needed of these ethnic differences and their implications for the use of CRP in CVD risk prediction.