Red Blood Cell Distribution Width as a Predictor of Pulmonary Valve Replacement in Patients with Repaired Tetralogy of Fallot

Research Article

Austin Biomark Diagn. 2015;2(2): 1018.

Red Blood Cell Distribution Width as a Predictor of Pulmonary Valve Replacement in Patients with Repaired Tetralogy of Fallot

Weinreich MA¹ and Ephrem G²*

¹Department of Medicine, Hofstra North Shore-LIJ School of Medicine, USA

²Department of Cardiovascular Disease, Oakland University-William Beaumont School of Medicine, USA

*Corresponding author: Ephrem G, Department of Cardiovascular Disease, Oakland University-William Beaumont School of Medicine, 3601 West 13 Mile Road, Royal Oak, MI 48073, USA

Received: July 13, 2015; Accepted: August 17, 2015; Published: August 25, 2015


Background: The timing of pulmonary valve replacement (PVR) in patients with repaired Tetralogy of Fallot (rToF) is an important factor in adult congenital heart disease care. High red blood cell distribution width (RDW) is an independent predictor for recourse to cardiac surgery. This study assesses the relation between RDW and cardiac magnetic resonance imaging (cMRI) in predicting recourse to PVR.

Methods: The study is a retrospective observational cohort analysis. Data were gathered by review of electronic medical records. The relation between a high RDW and PVR was assessed, with a focus on comparing the area under the receiver operating characteristics (AUC) with those of the cMRI-based right ventricle (RV) measurements: RV end diastolic volume index (RVEDVI) >150 ml/m2, RV end systolic volume Index (RVESVI) >85 ml/m2, and RV ejection fraction (RVEF) <45%.

Results: In 44 rToF patients (26 PVR), the cMRI-RV measurements did not show any statistically significant association with PVR (RVEDVI OR 1.04, p=0.979; RVESVI OR 1.62, p=0.765; RVEF OR 0.64, p=0.573 respectively). An RDW=15% was associated with PVR (OR 2.05) but did not reach statistical significance (p=0.559). The AUCs showed similar findings. There was no statistically significant difference between the C-statistics (p=0.868).

Conclusion: In a sample population of adult rToF patients, there was no statistically significant difference between a high RDW and cMRI-based RV measurements in predicting PVR. An inexpensive and readily available marker, RDW warrants further investigation in large multicenter datasets to fully determine its role as an additional predictive biomarker for PVR in adult ToF patients.

Keywords: Tetralogy of fallot; Red cell distribution width; Pulmonary valve replacement


PVR: Pulmonary Valve Replacement; ToF: Tetralogy of Fallot; rToF: Repaired ToF; RDW: Red Cell Distribution Width; cMRI: Cardiac Magnetic Resonance Imaging; RV: Right Ventricle; AUC: Area Under the Receiver Operative Characteristics; RVEDVI: RV End Diastolic Volume Index; RVESVI: RV End Systolic Volume Index; RVEF: RV Ejection Fraction; OR: Odds Ratio; MI: Myocardial Infarction


Tetralogy of Fallot (ToF) is the most common congenital cyanotic heart disease. The syndrome is characterized by the compilation of ventricular septal defect, right ventricular hypertrophy, an overriding aorta, and pulmonary artery obstruction. The pathology is noted in roughly 1 in 3,600 live births and almost always requires surgical intervention [1]. Techniques of repair have evolved with time, but the mainstay of treatment remains patching of the ventricular septal defect and opening the pulmonary artery outflow tract. With cutting edge improvements in therapy, 85% of children with ToF are likely to reach adulthood and 90% have a 40-year survival rate. Despite these successes, many patients experience sequelae later in life, namely congestive heart failure, arrhythmias, or sudden cardiac death [1,2]. The etiology of these symptoms is believed to be secondary to chronic pulmonary valve insufficiency. Many patients require eventual pulmonary valve replacement (PVR) to alleviate the associated comorbidities. While PVR is imperative for this goal, the timing of intervention remains controversial.

Currently, the gold standard to determine the timing for PVR remains based on assessment of right ventricular status as measured by cardiac magnetic resonance imaging (cMRI). Imaging is recommended every 2-3 years to monitor both right ventricular (RV) volume and systolic function. The American College of Cardiology/American Heart Association 2008 Guidelines for the Management of Adults with Congenital Heart Disease provides Class IIa recommendations for PVR in rToF adults with severe pulmonary regurgitation with either moderate to severe RV dysfunction, moderate to severe RV enlargement, symptomatic arrhythmias, or moderate to severe tricuspid regurgitation [3]. However serial cMRIs are both costly and time consuming. They are also contraindicated in patients with implanted cardiac defibrillators. Thus, other predictive modalities are being explored.

Red blood cell distribution width (RDW) is a hematologic measurement of the variation in erythrocyte diameter. Elevated RDW has been reported as a marker of oxidative stress, dysregulated erythropoiesis, and anemia [4]. As patients with repaired ToF age, worsening pulmonary valve regurgitation causes remodeling of the right ventricle with resultant congestive heart failure and poor oxygenation. This hypoxemic state will drive hematopoiesis and contribute to elevations in the RDW. Recent reports have found RDW a valuable prognostic biomarker in patients with heart failure [5,6], pulmonary hypertension [7], myocardial infarction [8,9], coronary artery disease (CAD) [10,11], or in those undergoing angiography [12,13]. Other studies suggest its value in predicting readmission [14], recourse to cardiac surgery [15], and postoperative recovery after ToF repair [16]. The present study examines the relation between a high RDW and PVR, with a focus on comparing its area under the receiver operating characteristic (AUC) with those of the cMRI-based RV measurements. The hypothesis is that high RDW is a readily available and relatively inexpensive predictor for recourse to PVR in rToF patients.


Study population

The present retrospective, observational, cohort study was conducted at North Shore University Hospital and Long Island Jewish Medical Center, two tertiary care centers of the North Shore-Long Island Jewish Health System in New York. The patient population included all patients age 18 years or older with rToF who were seen at the adult congenital heart disease (ACHD) clinic between January 1, 2010 and August 31, 2014.

Data collection

Laboratory and imaging data was obtained via electronic chart review. Data regarding age, gender, body mass index, age at ToF repair, common laboratory studies (including RDW), and cMRI findings were recorded. Longitudinal follow-up ended on February 1, 2015, and the outcomes (PVR) were recorded from the electronic databases.


Three imaging parameters of right ventricular size and function were utilized and compared based on standardized cutoff values for optimal outcomes [17]: RV end diastolic volume index (RVEDVI) >150 ml/m2, RV end systolic volume index (RVESVI) >85 ml/m2, and RV ejection fraction (RVEF) <45%. The RDW level (along with complete blood count results) had to be obtained 6 months or more prior to PVR or end of follow up if no intervention was performed. The rationale was to avoid perioperative fluctuations or acute changes at the time of censoring. RDW =15% was classified as an elevated value based on previous literature [18,19] and on the calibration and the reported normal range of the health system’s laboratory. Of note, decision for valve replacement was made at the treating physician’s discretion, likely through a combination of cMRI results, clinical status, and presence of co-morbidities.


The study was approved by the North Shore-Long Island Jewish Health System Institutional Review Board. The requirement for obtaining an informed consent was waived. There were no conflicts of interest.

Statistical analysis/Calculation

Data were analyzed using Stata version 11.2 (StataCorp, College Station, TX). Categorical data were analyzed using Chi square or Fisher exact tests. Continuous variables whose distribution followed the normality assumptions were analyzed using the Student t test. Variables whose distribution did not approximate normality were analyzed using the nonparametric Wilcoxon rank sum tests. Multivariable logistic regression analyses were used to determine the independent relation of an elevated RDW as well as the cMRI-based RV measurements and PVR. A receiver operating characteristic (ROC) analysis was performed to assess the sensitivity of these prediction variables. The multivariate models were adjusted for all the variables that were of statistical significance in the bivariate analyses. Assessment for confounders and effect modifiers was performed and none were detected. Regression diagnostics and assessment of the fit of the models were conducted via the Hosmer-Lemeshow goodness of fit test, which showed that they fit well. All tests were 2-tailed, and P values <0.05 were considered statistically significant.


Among the 44 rToF patients who were seen at the institution’s ACHD clinic, 26 had PVR. The baseline characteristics of the study subjects are listed in Table 1. On average the patients were 30 years old, almost evenly split across the gender divide, and had their ToF repaired around 3 years of age. They were not anemic and had good left and right ventricular sizes and functions. The bivariate analyses by outcome (PVR) showed no statistically significant differences in characteristics except for hemoglobin and hematocrit which were lower in the PVR group, likely from post-operative complications. This significant finding was not coupled with a statistically significant difference in RDW levels (13.5% versus 13.3%, p=0.691). The cMRIRV measurements did not show any statistically significant differences between the 2 groups either (Table 1).