Heejung Bang

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.

Early Versus Standard Antiretroviral Therapy for HIV Infected Adults in Haiti

BACKGROUND For adults with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain. METHODS We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support. RESULTS Between 2005 and 2008, a total of 816 participants--408 per group--were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01). CONCLUSIONS Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources. (ClinicalTrials.gov number, NCT00120510.)

Vitamin Intervention for Stroke Prevention Trial: An Efficacy Analysis

Background and Purpose— The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B12 in the low-dose arm, treatment with parenteral B12 in patients with low B12 levels in both study arms, a dose of B12 too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We conducted an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated. The criteria for this subgroup were defined before any data analysis. Methods— For this analysis, we excluded patients with low and very high B12 levels at baseline (<250 and >637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment (glomerular filtration rate <46.18; the 10th percentile). Results— This subgroup represents 2155 patients (37% female), with a mean age of 66±10.7 years. For the combined end point of ischemic stroke, coronary disease, or death, there was a 21% reduction in the risk of events in the high-dose group compared with the low-dose group (unadjusted P=0.049; adjusted for age, sex, blood pressure, smoking, and B12 level P=0.056). In Kaplan–Meier survival analysis comparing 4 groups, patients with a baseline B12 level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12 less than the median assigned to low-dose vitamin had the worst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke and coronary events). Conclusions— In the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine may be needed for some patients.

Implications of a New Definition of Vitamin D Deficiency in a Multiracial US Adolescent Population: The National Health and Nutrition Examination Survey III

OBJECTIVE. In children, vitamin D deficiency can interfere with bone mineralization, leading to rickets. In adults, it is linked to cardiovascular disease, insulin resistance, and hypertension. Accurate estimates of the prevalence of vitamin D deficiency are complicated by the lack of consensus as to optimal vitamin D status. Currently, individuals with serum 25-hydroxyvitamin D levels of <11 ng/mL are classified as vitamin D deficient. Experts collectively have proposed that minimum levels be at least 20 ng/mL. Our objectives were to (1) determine the national prevalence of vitamin D deficiency in adolescents by using both the current and recommended cutoffs and (2) examine the implications of the new recommendation after adjustment for various factors. METHODS. Data were obtained from National Health and Nutrition Examination Survey III, a cross-sectional survey administered to a nationally representative sample of noninstitutionalized civilians aged 2 months and older. Analyses were restricted to 2955 participants aged 12 to 19 with serum 25-hydroxyvitamin D levels. Relationships between serum 25-hydroxyvitamin D levels and sociodemographic variables were evaluated by using logistic regression. RESULTS. Changing the definition of vitamin D deficiency from <11 to <20 ng/mL increased the prevalence from 2% to 14%. After adjustment for all covariates, non-Hispanic black adolescents had 20 times the risk of serum 25-hydroxyvitamin D <20 ng/mL compared with non-Hispanic white adolescents. The risk of deficiency was more than double for females compared with males. An inverse relationship between weight and serum 25-hydroxyvitamin D levels was found. Overweight adolescents had increased risk of deficiency compared with normal-weight adolescents. CONCLUSIONS. There was a disproportionate burden of vitamin D deficiency in the non-Hispanic black adolescent population. Routine supplementation and monitoring of serum levels should be considered. Females and overweight adolescents are at increased risk. The consequences of chronic vitamin D deficiency in adolescents should be prospectively investigated.

Age-specific probability of live birth with oocyte cryopreservation: an individual patient data meta-analysis

OBJECTIVE To estimate age-specific probabilities of live birth with oocyte cryopreservation in nondonor (ND) egg cycles. DESIGN Individual patient data meta-analysis. SETTING Assisted reproduction centers. PATIENT(S) Infertile patients undergoing ND mature oocyte cryopreservation. INTERVENTION(S) PubMed was searched for clinical studies on oocyte cryopreservation from January 1996 through July 2011. Randomized and nonrandomized studies that used ND frozen-thawed mature oocytes with pregnancy outcomes were included. Authors of eligible studies were contacted to obtain individual patient data. MAIN OUTCOME MEASURE(S) Live birth probabilities based on age, cryopreservation method, and the number of oocytes thawed, injected, or embryos transferred. RESULT(S) Original data from 10 studies including 2,265 cycles from 1,805 patients were obtained. Live birth success rates declined with age regardless of the freezing technique. Despite this age-induced compromise, live births continued to occur as late as ages 42 and 44 years with slowly frozen and vitrified oocytes, respectively. Estimated probabilities of live birth for vitrified oocytes were higher than those for slowly frozen. CONCLUSION(S) The live birth probabilities we calculated would enable more accurate counseling and informed decisions for infertile women considering oocyte cryopreservation. Given the success probabilities, we suggest that policy makers should consider oocyte freezing as an integral part of prevention and treatment of infertility.

Urogenital Schistosomiasis in Women of Reproductive Age in Tanzania's Lake Victoria Region

We conducted a community-based study of 457 women aged 18-50 years living in eight rural villages in northwest Tanzania. The prevalence of female urogenital schistosomiasis (FUS) was 5% overall but ranged from 0% to 11%. FUS was associated with human immunodeficiency virus (HIV) infection (odds ratio [OR] = 4.0, 95% confidence interval [CI] = 1.2-13.5) and younger age (OR = 5.5 and 95% CI = 1.2-26.3 for ages < 25 years and OR = 8.2 and 95% CI = 1.7-38.4 for ages 25-29 years compared with age > 35 years). Overall HIV prevalence was 5.9% but was 17% among women with FUS. We observed significant geographical clustering of schistosomiasis: northern villages near Lake Victoria had more Schistosoma mansoni infections (P < 0.0001), and southern villages farther from the lake had more S. haematobium (P = 0.002). Our data support the postulate that FUS may be a risk factor for HIV infection and may contribute to the extremely high rates of HIV among young women in sub-Saharan Africa.

A Simple Algorithm to Predict Incident Kidney Disease

BACKGROUND Despite the growing burden of chronic kidney disease (CKD), there are no algorithms (to our knowledge) to quantify the effect of concurrent risk factors on the development of incident disease. METHODS A combined cohort (N = 14 155) of 2 community-based studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, was formed among men and women 45 years or older with an estimated glomerular filtration rate (GFR) exceeding 60 mL/min/1.73 m(2) at baseline. The primary outcome was the development of a GFR less than 60 mL/min/1.73 m(2) during a follow-up period of up to 9 years. Three prediction algorithms derived from the development data set were evaluated in the validation data set. RESULTS The 3 prediction algorithms were continuous and categorical best-fitting models with 10 predictors and a simplified categorical model with 8 predictors. All showed discrimination with area under the receiver operating characteristic curve in a range of 0.69 to 0.70. In the simplified model, age, anemia, female sex, hypertension, diabetes mellitus, peripheral vascular disease, and history of congestive heart failure or cardiovascular disease were associated with the development of a GFR less than 60 mL/min/1.73 m(2). A numeric score of at least 3 using the simplified algorithm captured approximately 70% of incident cases (sensitivity) and accurately predicted a 17% risk of developing CKD (positive predictive value). CONCLUSIONS An algorithm containing commonly understood variables helps to stratify middle-aged and older individuals at high risk for future CKD. The model can be used to guide population-level prevention efforts and to initiate discussions between practitioners and patients about risk for kidney disease.

Lipoprotein-Associated Phospholipase A2 and High-Sensitivity C-Reactive Protein Improve the Stratification of Ischemic Stroke Risk in the Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— Inflammation plays a critical role in the development of vascular disease, and increased levels of the inflammatory biomarkers, lipoprotein-associated phospholipase A2 (Lp-PLA2), and high-sensitivity C-reactive protein (hs-CRP) have been shown to be associated with an increased risk for ischemic stroke. Methods— In a prospective case–cohort (n=949) study in 12 762 apparently healthy, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, we first examined whether Lp-PLA2 and hs-CRP levels improved the area under the receiver operator characteristic curve (AUC) for 5-year ischemic stroke risk. We then examined how Lp-PLA2 and hs-CRP levels altered classification of individuals into low-, intermediate-, or high-risk categories compared with traditional risk factors. Results— In a model using traditional risk factors alone, the AUC adjusted for optimism was 0.732, whereas adding hs-CRP improved the AUC to 0.743, and adding Lp-PLA2 significantly improved the AUC to 0.752. Addition of hs-CRP and Lp-PLA2 together in the model improved the AUC to 0.761, and the addition of the interaction between Lp-PLA2 and hs-CRP further significantly improved the AUC to 0.774. With the use of traditional risk factors to assess 5-year risk for ischemic stroke, 86% of participants were categorized as low risk (<2%); 11%, intermediate risk (2% to 5%); and 3%, high risk (>5%). The addition of hs-CRP, Lp-PLA2, and their interaction to the model reclassified 4%, 39%, and 34% of the low-, intermediate- and high-risk categories, respectively. Conclusion— Lp-PLA2 and hs-CRP may be useful in individuals classified as intermediate risk for ischemic stroke by traditional risk factors.

Adherence to Guideline‐Recommended Therapy Is Associated With Decreased Major Adverse Cardiovascular Events and Major Adverse Limb Events Among Patients With Peripheral Arterial Disease

Background Current guidelines recommend that patients with peripheral arterial disease (PAD) cease smoking and be treated with aspirin, statin medications, and angiotensin‐converting enzyme (ACE) inhibitors. The combined effects of multiple guideline‐recommended therapies in patients with symptomatic PAD have not been well characterized. Methods and Results We analyzed a comprehensive database of all patients with claudication or critical limb ischemia (CLI) who underwent diagnostic or interventional lower‐extremity angiography between June 1, 2006 and May 1, 2013 at a multidisciplinary vascular center. Baseline demographics, clinical data, and long‐term outcomes were obtained. Inverse probability of treatment propensity weighting was used to determine the 3‐year risk of major adverse cardiovascular or cerebrovascular events (MACE; myocardial infarction, stroke, or death) and major adverse limb events (MALE; major amputation, thrombolysis, or surgical bypass). Among 739 patients with PAD, 325 (44%) had claudication and 414 (56%) had CLI. Guideline‐recommended therapies at baseline included use of aspirin in 651 (88%), statin medications in 496 (67%), ACE inhibitors in 445 (60%), and smoking abstention in 528 (71%) patients. A total of 237 (32%) patients met all four guideline‐recommended therapies. After adjustment for baseline covariates, patients adhering to all four guideline‐recommended therapies had decreased MACE (hazard ratio [HR], 0.64; 95% CI, 0.45 to 0.89; P=0.009), MALE (HR, 0.55; 95% CI, 0.37 to 0.83; P=0.005), and mortality (HR, 0.56; 95% CI, 0.38 to 0.82; P=0.003), compared to patients receiving less than four of the recommended therapies. Conclusions In patients with claudication or CLI, combination treatment with four guideline‐recommended therapies is associated with significant reductions in MACE, MALE, and mortality.

Association of C-Reactive Protein and Microalbuminuria (from the National Health and Nutrition Examination Surveys, 1999 to 2004)

Chronic kidney disease and cardiovascular disease share many risk factors. Injury to the vascular endothelium, measured by elevated levels of serum C-reactive protein (CRP), may play a role in kidney and cardiovascular disease. We therefore examined the association of CRP with microalbuminuria, a marker of early kidney injury. We conducted a cross-sectional analysis of a nationally representative, population-based survey. Weighted multiple logistic regression was used to study the association between CRP and microalbuminuria, adjusting for well-known risk factors. CRP was analyzed by a continuous variable and two categorized variables using quartiles and clinically recommended cutpoints. CRP concentration was positively associated with microalbuminuria. In the multivariate model, a one unit (in milligrams per liter) increase in CRP concentration was associated with a 2% increased odds of microalbuminuria (odds ratio 1.02, 95% confidence interval [CI] 1.01 to 1.02, p=0.0003). When CRP concentrations were stratified by clinically recommended cutpoints, compared with persons with CRP concentrations<1 mg/dl, persons with CRP concentrations between 1 and 3 mg/L and >3 mg/L were 1.15 times (95% CI 0.94 to 1.42) and 1.33 times (95% CI 1.08 to 1.65) more likely to have microalbuminuria, respectively. In subgroup analyses, the strength of association was comparable or stronger. In conclusion, elevated CRP levels were associated with microalbuminuria in a large, nationally representative data set. Vascular inflammation, as measured by CRP, may be a common contributor to early heart and kidney disease.