Separate mechanisms cause anemia in ischemic vs. nonischemic murine heart failure

Abstract

In ischemic congestive heart failure (CHF), anemia is associated with poor prognosis. Whether anemia develops in nonischemic CHF is uncertain. The hematopoietic inhibitors TNF-α and nitric oxide (NO) are activated in ischemic CHF. We examined whether mice with ischemic or nonischemic CHF develop anemia and whether TNF-α and NO are involved. We studied mice ( n = 7–9 per group) with CHF either due to myocardial infarction (MI) or to overexpression of the Ca2+-binding protein calsequestrin (CSQ) or to induced cardiac disruption of the sarcoplasmic reticulum Ca2+-ATPase 2 gene (SERCA2 KO). Hematopoiesis was analyzed by colony formation of CD34+bone marrow cells. Hemoglobin concentration was 14.0 ± 0.4 g/dl (mean ± SD) in controls, while it was decreased to 10.1 ± 0.4, 9.7 ± 0.4, and 9.6 ± 0.3 g/dl in MI, CSQ, and SERCA2 KO, respectively ( P < 0.05). Colony numbers per 100,000 CD34+cells in the three CHF groups were reduced to 33 ± 3 (MI), 34 ± 3 (CSQ), and 39 ± 3 (SERCA2 KO) compared with 68 ± 4 in controls ( P < 0.05). Plasma TNF-α nearly doubled in MI, and addition of anti-TNF-α antibody normalized colony formation. Inhibition of colony formation was completely abolished with blockade of endothelial NO synthase in CSQ and SERCA2 KO, but not in MI. In conclusion, the mechanism of anemia in CHF depends on the etiology of cardiac disease; whereas TNF-α impairs hematopoiesis in CHF following MI, NO inhibits blood cell formation in nonischemic murine CHF.