In 705 patients with non–ST-segment elevation acute coronary syndromes, Rousseau et al documented a strong inverse relation between baseline hemoglobin levels and recurrent ischemia on continuous ST-segment monitoring during the first 48 hours of hospitalization. The rate of ischemia increased more than threefold, from 12% for hemoglobin >16 g/dl to 39% for hemoglobin <12 g/dl (p for trend <0.001). To explain their findings in the presence of anemia compared to its absence, the investigators proposed several mechanisms, including reduced oxygen delivery, adrenergic activation, and enhanced bleeding tendency.

Hemoglobin is among the most abundant proteins in blood, and even modest changes in its levels may have important implications. Free hemoglobin found in hemolysis (as for example in sickle-cell disease) is a well-known scavenger of nitric oxide. Less well appreciated, however, is hemoglobin’s function within intact red blood cells as a physiologic carrier, donor, and potentiator of bioactive nitric oxide. At the molecular level, as blood is oxygenated in the pulmonary microcirculation, the relaxed conformation of hemoglobin triggers the transfer of nitric oxide from the heme iron to a cysteine at position 93 of the β chains. In the systemic microcirculation, as blood is deoxygenated, allosteric changes in hemoglobin cause release of nitric oxide into the bloodstream. Deoxyhemoglobin can also reduce nitrites to nitric oxide, further contributing to the physiologic vasodilation of the systemic microcirculation. Unloaded deoxyhemoglobin then reloads constitutive nitric oxide through iron binding, thus renewing the nitric oxide cycle. Hypoxic pulmonary vasoconstriction is in apparent contrast with systemic hypoxic vasodilation but is unrelated to hemoglobin; rather, it is determined by direct effects of alveolar hypoxia on pulmonary vascular smooth muscle cells.

Nitric oxide, in addition to vasodilation, mediates platelet inhibition, insulin sensitivity, progenitor cell output, cellular survival, and reduced inflammatory reactions. Thus, even mild anemia may significantly limit vascular patency and repair by blunting nitric oxide’s bioavailability. We propose that low hemoglobin levels may contribute to recurrent ischemia and to worse cardiovascular outcomes in patients with acute coronary syndromes by reducing bioactive nitric oxide within the coronary microcirculation.