Blood Viscosity and its Relationship to Iron Deficiency, Symptoms, and Exercise Capacity in Adults With Cyanotic Congenital Heart Disease Craig S. Broberg, MD,* Bridget E. Bax, PHD, Darlington O. Okonko, BSC, MRCP,† Michael W. Rampling, MD,¶ Stephanie Bayne, BS,‡ Carl Harries, BS,* Simon J. Davidson, BS,§ Anselm Uebing, MD,* Arif Anis Khan, MD,* Swee Thein, MD,# J. Simon R. Gibbs, MD,** John Burman, MD,‡ Michael A. Gatzoulis, MD, PHD* London, England OBJECTIVES This study sought to determine the relationship between blood viscosity and iron deficiency and their impact on symptoms and exercise function in adults with cyanotic congenital heart disease. BACKGROUND Iron deficiency is believed to raise whole blood viscosity in cyanotic congenital heart disease, although available data are inconsistent. METHODS Thirty-nine cyanotic adults were prospectively assessed for iron deficiency (transferrin saturation 5%), hyperviscosity symptoms, and exercise capacity. Same-day measurement of whole blood viscosity and hematocrit (Hct) adjusted viscosity (cells resuspended in autologous plasma to Hct of 45%) was performed at shear rates ranging from 0.277 s -1 to 128.5 s -1 . RESULTS Viscosity did not differ between patients with iron deficiency (n = 14) and those without (n = 25). Whole blood viscosity correlated with Hct (r = 0.63, p  0.001 at low shear and r = 0.84, p  0.001 at high shear) but not with red blood cell size or iron indices. Hyperviscosity symptoms were independent of iron indices but directly correlated with increased Hct-adjusted viscosity (r = 0.41, p = 0.01). Exercise capacity did not differ in iron-deficient patients. However, peak oxygen consumption was higher in those with Hct  65% (12.6  3.4 ml/kg/m 2 vs. 9.8  2.6 ml/kg/m 2 , mean  SD, p = 0.036) despite higher whole blood viscosity in these same individuals (p  0.01 for all shear rates). CONCLUSIONS Iron deficiency is common in cyanotic adults but does not alter viscosity. Hyperviscosity symptoms are associated with a higher Hct-adjusted viscosity independent of cell size or iron stores. Higher Hct is associated with better exercise capacity. Further work to understand the origin of hyperviscosity symptoms is warranted. (J Am Coll Cardiol 2006;48:356 – 65) © 2006 by the American College of Cardiology Foundation Increased whole blood viscosity in adults with cyanotic con- genital heart disease is an unavoidable result of secondary erythropoiesis. Little is known about the role of nonerythro- cytotic factors in the genesis of hyperviscosity. Improved understanding of the determinants of blood viscosity in cyanotic congenital heart disease is of substantial clinical importance. Data showing that iron deficiency and microcytosis in- crease whole blood viscosity are inconsistent. This relation- ship, based on red blood cell (RBC) studies from the 1970s and 1980s (1,2), has been shown in animals (3), polycythe- mic adults (4), iron-deficient children (5), and cyanotic children (6), although never in cyanotic adults. In contrast, more recent research showed viscosity to be independent of mean corpuscular volume (MCV) in mammals (7), polycy- themic adults (8 –10), and iron-deficient adults, in whom RBC filtration resistance was in fact lower (11). Such conflicting results may in part be explained by the hetero- geneity of subjects and methodology. Viscosity of whole blood varies according to shear rate (Fig. 1). Moreover, iron deficiency per se can also cause hyperviscosity-like symp- toms such as headache, paresthesias, irritability, and exercise intolerance (12), adding complexity to the clinical care of cyanotic patients. Iron deficiency is a spectrum that in its extreme will sufficiently limit production of hemoglobin (Hb). Lower Hb and hematocrit (Hct) result in lower viscosity and systemic oxygen transport (13,14). Because Hct is the strongest deter- minant of whole blood viscosity (5,15), it is logical to hypoth- esize that lower viscosity rather than higher viscosity would result from iron deficiency in cyanotic congenital heart disease. To test this hypothesis, we quantified whole blood viscosity, iron indices, hyperviscosity symptoms, and exercise capacity specifically in adults with cyanotic congenital heart disease. From the *Adult Congenital Heart Centre, †Department of Cardiac Medicine, ‡Department of Exercise Physiology, and the §Department of Haematology, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College School of Medicine; Child Health, Department of Clinical Developmental Sciences, St. George’s Hospital, University of London; ¶Division of Biomedical Sciences, Depart- ment of Physiology and Biophysics, Imperial College School of Medicine; #Depart- ment of Haematological Medicine, King’s College London Medical School, King’s College Hospital; and **Hammersmith Hospital, London, England. This study was funded by a grant from the Royal Brompton Hospital Clinical Research Committee. Salary support for Dr. Broberg was provided by the Waring Trust, as well as an unrestricted grant from Actelion, United Kingdom. Dr. Gatzoulis and the Royal Brompton Adult Congenital Heart Centre and Centre for Pulmonary Hypertension have received support from the British Heart Foundation. Portions of this data were presented orally at the American College of Cardiology Scientific Sessions, March 2005, in Orlando, Florida. Manuscript received December 8, 2005; revised manuscript received February 24, 2006, accepted March 16, 2006. Journal of the American College of Cardiology Vol. 48, No. 2, 2006 © 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2006.03.040