Anisocytosis is associated with myocardial fibrosis and exercise capacity in heart failure with preserved ejection fraction

Background: Red Blood Cell Distribution Width (RDW), a measure of variability in size of circulating red blood cells and is a marker of inflammation. Objectives: We sought to test the hypothesis that RDW reflects an inflammatory milieu permissive for cardiac fibrosis in those with Heart Failure and preserved ejection fraction (HFpEF). Methods: We analyzed the association between RDW and fibrosis in two separate cohorts. Cohort 1 (n = 200) was a retrospective analysis of blood biomarkers measured in the RELAX trial (Clinicaltrials.gov NCT00763867) and Cohort 2 (n = 160) included a single center cohort of patients with preserved ventricular function referred for cardiac magnetic resonance imaging (cMRI). Linear regression was used to adjust for potential confounders, and a mediation analysis used to explore relationships with exercise intolerance (peak VO2 max). Results: Within Cohort 1, anisocytosis (RDW > 14.5) was prevalent (49.5%) and was associated with greater baseline clinical comorbidities, a lower Peak VO2 and more frequent heart failure hospitalizations. The RDW was associated with biomarkers of inflammation and cardiac fibrosis. In Cohort 2, RDW was associated with cMRI myocardial fibrosis (extracellular volume; Spearman's rho=0.38, P<0.001) which was independent of age, sex, LV ejection fraction, and hematocrit (P = 0.026). Individuals with both anisocytosis and myocardial fibrosis identified a subgroup of at high risk for 2-year mortality (HR 16.28 [4.30–61.66], P<0.001). Conclusions: In two independent cohorts of patients with HFpEF, elevated RDW is associated reduced exercise capacity and greater fibrosis as measured by serum biomarkers and cMRI. Additional studies are needed to validate this novel relationship.