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Elevated Red Cell Distribution Width Identifies Elevated Cardiovascular Disease Risk in Patients With HIV Infection

Al-Kindi, Sadeer G. MD; Kim, Chang H. MD; Morris, Stephen R. MD; Freeman, Michael L. PhD; Funderburg, Nicholas T. PhD; Rodriguez, Benigno MD; McComsey, Grace A. MD; Dalton, Jarrod E. PhD; Simon, Daniel I. MD; Lederman, Michael M. MD; Longenecker, Chris T. MD; Zidar, David A. MD, PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 01, 2017 - Volume 74 - Issue 3 - p 298–302
doi: 10.1097/QAI.0000000000001231
Clinical Science
Free

Abstract: Red cell distribution width (RDW) is linked to cardiovascular risk in the general population, an association that might be driven by inflammation. Whether this relationship holds for patients with HIV infection has not been previously studied. Using a large clinical registry, we show that elevated RDW (>14.5%) is independently associated with increased risk of coronary artery disease {odds ratio [OR] 1.39 [95% confidence interval (CI): 1.25 to 1.55]}, peripheral vascular disease [OR 1.41 (95% CI: 1.29 to 1.53)], myocardial infarction [1.43 (95% CI: 1.25 to 1.63)], heart failure [OR 2.23 (95% CI: 1.99 to 2.49)], and atrial fibrillation [OR 1.96 (95% CI: 1.64 to 2.33)]. In conclusion, in the context of the inflammatory milieu that accompanies HIV infection, RDW remains a powerful marker of cardiovascular disease.

*Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH;

Division of Infectious Diseases and HIV Medicine, Department of Medicine, Center for AIDS Research, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH;

Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, Ohio State University, Columbus, OH;

§School of Medicine, Case Western Reserve University, Cleveland, OH; and

Section of Health Outcomes Research and Clinical Epidemiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.

Correspondence to: David A. Zidar, MD, PhD, Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, 11100 Euclid Avenue, Mailstop LKS 5038, Cleveland, OH 44106 (e-mail: David.Zidar@UHhospitals.org).

Supported by the Clinical and Translational Science Collaborative of Cleveland, KL2TR000440 to D.A.Z., from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research; and by K23 HL123341 to C.T.L.

The authors have no conflicts of interest to disclose.

C.T.L. and D.A.Z. have contributed equally.

The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Received June 26, 2016

Accepted September 21, 2016

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INTRODUCTION

Red cell distribution width (RDW) is a measure of the variability of red blood cell (RBC) size, also known as anisocytosis. Over the past decade, RDW has also been associated with incident myocardial infarction (MI)1,2 and heart failure (HF)3 in the general population. RDW has also emerged as one of the strongest predictors of poor survival in patients with established HF4–6 and coronary artery disease (CAD).7–10 Anisocytosis is typically a result of impaired iron metabolism11 and tends to correlate with low hemoglobin, reduced mean corpuscular volume, high iron-binding capacity, and elevated erythropoietin levels despite normal ferritin levels. RDW has also been proposed as marker of immune activation, correlating with levels of tumor necrosis factor–α12 and interleukin (IL)-6.11 The processes of inflammation and dysregulated hematopoiesis may be linked because IL-6 is crucial for the production of hepcidin in the liver, and thus may indirectly regulate iron metabolism.

Antiretroviral therapy (ART) has improved life expectancy in patients living with HIV, but the burden cardiovascular disease (CVD) in this population is increasingly recognized.13 Patients with HIV have a high prevalence of silent and clinically apparent CVDs.14–16 We and others have shown that CVD in patients with HIV seems to be associated with inflammation, including IL-617–21 elevations, but as intraindividual variability in IL-6 levels is high, the identification of “at risk” patients remains problematic. The RDW is routinely reported as part of automated blood count from clinical laboratories, and therefore could be an attractive pragmatic biomarker of immune activation and cardiovascular risk. We therefore sought to test whether RDW is associated with CVD prevalence specifically in patients with HIV.

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METHODS

Data Source

Explorys (Explorys, Inc., Cleveland, OH) is a commercial cloud-based database that aggregates data from electronic health records of participating hospital systems. It currently encompasses 23 integrated health systems consisting of 360 hospitals, 315,000 providers, and approximately 50 million unique patients. It collects data through a health care gateway server behind the firewall of participating institutions. The data are collected from billing inquiries, electronic health records, and laboratory systems. These data aggregates are then deidentified and standardized into Unified Medical Language Systems (UMLS) ontologies to facilitate searching and indexing.22 Diagnoses are mapped into systematized nomenclature of medicine–clinical terms (SNOMED-CT) hierarchy, prescriptions mapped to RxNorm, and laboratory test observations mapped to logistical observation identifier names and codes (LOINC). Data collection started in 1999 and is updated every 24–48 hours. The platform is compliant with the Health Insurance Portability and Accountability Act (HIPAA) and Health Information Technology for Economic and Clinical Health (HITECH) Act standards; hence, its use is exempted from institutional review board review under a prespecified policy. The database rounds number of patients to the nearest 10 for an added data protection. This platform has been used for research purposes and has been validated in fields of oncology,23 orthopedics,24 gastroenterology,25 gynecology26 among others.

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Cohort Selection and Definitions

We selected all patients who are at least 18 years of age with a diagnosis of “Human Immunodeficiency Virus Infection” who had at least one measurement of RDW after documentation of HIV infection. High RDW (>14.5%) and low/normal RDW (≤14.5%) were defined in accordance with previously used cutoffs.27,28 CVDs were identified by their umbrella terms: “disorder of coronary artery,” “peripheral vascular disease,” “heart failure,” “myocardial infarction” and “atrial fibrillation.” We calculated the prevalence of CVDs separately in patients (18–65 years old) with or without HIV using their most recent RDW. This analysis was also replicated in patients without anemia (hemoglobin >12 g/dL) to test the effect of RDW in nonanemic patients, and in whites to evade the possible interaction between RDW and sickle-cell trait that is prevalent in African Americans.

We also selected a cohort with HIV without CVD and then followed for incident CVDs (MI or HF) stratified by the first RDW after documentation of HIV infection. This analysis was adjusted for traditional cardiovascular risk factors: age, sex, hypertension, diabetes, and dyslipidemia.

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Statistical Analysis

The data are presented as numbers and percentages. Pearson χ2 test was used to test for differences. Logistic regression models were used to identify the adjusted odds ratio (OR) of cardiovascular events. Social Package for Social Studies (SPSS) version 19.0 was used for all analyses, with significance level set at P < 0.05.

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RESULTS

Of the 30,590,990 adults (18–65 years) in the database at the time of the inquiry, 79,590 (0.26%) had HIV infection and 46,720 had at least one documented RDW. Of those who were HIV infected, 16,570 patients (35% of the total HIV population) had an elevated RDW. Patients with HIV and a high RDW had several important clinical and demographic differences compared with those with a low or normal RDW (Table 1). Patients with high RDW were slightly older, more likely to be women (39% vs 26%, P < 0.001), African American (62% vs 42%, P < 0.001), and to have diabetes (22% vs 13%, P < 0.001), hypertension (48% vs 36%, P < 0.001), and to be actively smoking (45% vs 40%, P < 0.001), compared with individuals with low or normal RDW. HIV-infected patients with elevated RDW were also less likely to be treated with ART, compared with HIV-infected patients with a low/normal RDW (50% vs 53%, P < 0.001). Differences in subclasses of ART use are displayed in Table 1.

TABLE 1

TABLE 1

In the HIV-negative population, an elevated RDW was associated with a higher prevalence of CVDs, compared with those with a low/normal RDW (Fig. 1). For instance, among the uninfected, patients with a high RDW had higher prevalence of CAD (8% vs 3%, P < 0.001) and HF (7% vs 1%, P < 0.001), compared with those having a normal or low RDW. HIV was associated with a higher prevalence of CVD compared with HIV-uninfected subjects, regardless of RDW status. For example, among patients with high RDW, CAD (12% vs 8%, P < 0.001) and HF (14% vs 7%, P < 0.001) were more prevalent in HIV positive than uninfected controls. Patients with HIV were more likely to have an elevated RDW compared with the HIV uninfected (35% vs 17%, P < 0.001).

FIGURE 1

FIGURE 1

Patients with HIV infection and an elevated RDW had a higher prevalence of CVD compared with HIV-positive subjects with a low/normal RDW. For instance, HIV-positive patients with high RDW had higher prevalence of CAD (12% vs 6%, P < 0.001), previous MI (8% vs 4%, P < 0.001), and peripheral vascular disease (PVD) (19% vs 10%, P < 0.001). Patients with HIV and an elevated RDW also had a higher prevalence of HF compared with low/normal RDW HIV-positive patients (14% vs 4%, P < 0.001). Atrial fibrillation (AF) also tended to be more common in patients with elevated RDW among patients living with HIV (5% vs 2%, P < 0.001).

To determine whether anemia or hemoglobinopathies might be confounding the association between RDW and CVD, 2 sensitivity analyses were performed. In HIV-positive patients without anemia, the relationships between RDW and CVD remained unchanged: CAD (high RDW 10% vs low/normal 6%, P < 0.001), PVD (high RDW 16% vs low/normal 10%, P < 0.001), HF (high RDW 9% vs low/normal 3%, P < 0.001), MI (high RDW 7% vs low/normal 4%, P < 0.001), and AF (high RDW 4% vs low/normal 2%, P < 0.001). Similar findings persisted in the white subgroup: CAD (high RDW 11% vs low/normal 7%, P < 0.001), PVD (high RDW 18% vs low/normal 10%, P < 0.001), HF (high RDW 11% vs low/normal 3%, P < 0.001), MI (high RDW 9% vs low/normal 4%, P < 0.001), and AF (high RDW 5% vs low/normal 2%, P < 0.001).

An elevated RDW in patients with HIV without CVD was associated with the development of future disease, even after adjustment for age, sex, hypertension, diabetes, and dyslipidemia. Compared with low/normal RDW HIV-positive patients, those HIV-positive patients with an elevated RDW had increased odds of incident CAD {unadjusted OR 1.42 [95% confidence interval (CI): 1.29 to 1.56], P < 0.001; adjusted OR 1.39 (95% CI: 1.25 to 1.55), P < 0.001}, PVD [unadjusted OR 1.49 (95% CI: 1.38 to 1.61), P < 0.001; adjusted OR 1.41 (95% CI: 1.29 to 1.53), P < 0.001], MI [unadjusted OR 1.43 (95% CI: 1.26 to 1.62), P < 0.001; adjusted 1.43 (95% CI: 1.25 to 1.63), P < 0.001], HF [unadjusted OR 2.39 (95% CI: 2.16 to 2.65), P < 0.001; adjusted OR 2.23 (95% CI: 1.99 to 2.49), P < 0.001], and AF [unadjusted OR 2.04 (95% CI: 1.72 to 2.41), P < 0.001; adjusted OR 1.96 (95% CI: 1.64 to 2.33), P < 0.001].

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DISCUSSION

In this large electronic medical record cohort, we find that irrespective of HIV status, an elevated RDW is associated with a higher burden of atherosclerotic CVD, HF, and AF. Thus, despite differences in the inflammatory milieu and medication exposures between those with and without HIV, the mechanisms that link RDW and CVD seem to remain relevant. Given the availability of RDW during routine clinical practice and its strong relationship to CVD, these findings suggest that additional study of this parameter as a possible immune and cardiovascular biomarker in HIV is warranted.

Several studies have described the association between RDW and CVD in the general population. Felker et al29 were the first to demonstrate the association between RDW and HF outcomes in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program (n = 2679) and Duke Database (n = 2140). This association was independent of other laboratory and clinical predictors including age and was more powerful than functional class or ejection fraction. Other similar studies have confirmed this relationship.30 In a population-based analysis of 25,612 persons in Norway, there was a linear association between baseline RDW and risk of MI, with 13% increase in MI risk for every 1% increment in RDW,31 which persisted after exclusion of patients with anemia.31 Similarly, studies have associated RDW with the presence of CAD,32 PVD,33 and AF.34 We are unaware of any previous report describing the relationship between RDW and CVD in the context of HIV infection. Thus, our study suggests that the relationship between RDW and CVD holds in HIV infection. This is particularly interesting as both immunologic and erythropoietic perturbations are characteristic of HIV disease and its treatment.

There are a number of factors that may explain the RDW–CVD association. Increased RDW can be observed in states of ineffective RBC production, including vitamin deficiency, malnutrition states, and anemia of chronic disease.35 How such bone marrow dysfunction might promote CVD is uncertain. Several groups have ascribed the relationship between RDW and CVD to subclinical immune activation, which has been previously linked to CVD. For example, RDW has been associated with elevated levels of C-reactive protein, tumor necrosis factor–α,12 malondialdehyde,12 and IL-6,36 all of which have been associated with CVD. Inflammatory cytokines can worsen RBC survival, lead to erythropoietin resistance, and stimulate the production of hepcidin. Each of these mechanisms may impair RBC production and increase RDW.

A previous study by Gallegio et al37 did not find an association between RDW and the aggregate of traditional cardiovascular risk factors (Framingham Risk Score) in patients with HIV. In this study, an elevated RDW was associated with modest differences in some, but not all, cardiovascular risk factors. We therefore sought to examine whether the association between RDW and CVD was linked to traditional risk factors. After adjustment for age, sex, dyslipidemia, diabetes, and hypertension, an elevated RDW independently predicts cardiovascular events. Thus, RDW may have added value to improve cardiovascular risk assessment in addition to traditional risk factors in patients with HIV. Future studies are needed to explore the extent to which RDW correlates with immune activation, which has also been linked to CVD in HIV, and whether RDW might also be a marker of immunologic outcomes in HIV.

This large analysis is limited by its retrospective design, lack of patient-level data, and the potential variability of RDW measurements across different hospital systems. We were unable to explore in any detail the mechanisms of the observed associations. Because of these limitations, this study must be interpreted with caution as hypothesis generating. Nevertheless, the substantial risk differences and large sample size provide a broad observational overview of these relationships in a real-world population.

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CONCLUSIONS

In patients with HIV, an elevated RDW is associated with a higher risk of CVD. The connections between bone marrow function, immune activation, and thrombosis should be examined further. If validated prospectively, the RDW may be a convenient, pragmatic biomarker of risk in addition to that conferred by HIV and traditional risk factors alone.

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Keywords:

cardiovascular disease; coronary; peripheral; heart failure; RDW

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