Letter by Sullivan et al Regarding Article, “Lower Mortality from Coronary Heart Disease and Stroke at Higher Altitudes in Switzerland”
To the Editor:
Faeh et al1 report an inverse association of altitude with mortality from coronary heart disease and stroke. The mechanism for this effect is unknown but appears “unlikely to be due to differences in classic risk factors.”1 The authors did not address a role for increased hypoxia-inducible factors (HIF) at high altitude and their impact on iron, hepcidin, and hemoglobin with consequences for atherogenesis and cardiovascular mortality. These HIF-induced alterations at high altitude are of relevance in the debate on the mechanism of the sex difference in cardiovascular disease.
High altitude is associated with both decreased cardiovascular mortality1 and increased hemoglobin level. Some investigators have proposed that menstruating women are protected from cardiovascular disease in comparison with men because of their slightly lower hemoglobin levels.2 This has been questioned because a hemoglobin sex difference persists after menopause despite increasing cardiovascular disease in older women.2 The high-altitude findings of Faeh et al1 represent an additional argument against hemoglobin level as the basis for the sex difference. With increasing altitude, women approach or exceed low-altitude male hemoglobin levels but enjoy a decrease, rather than an increase, in cardiovascular disease.
However, the alternative hypothesis that lower stored iron level in menstruating women is a cardiovascular protective factor2 is compatible with the high-altitude effect. Altitude raises hemoglobin level but lowers the amount of iron in storage in men and women by a mechanism distinct from the loss of iron from bleeding. Increased HIF can cause a marked decrease in storage iron at high altitude as measured by serum ferritin.3 The HIF induces erythropoietin, downregulates hepcidin, and induces ferroportin. In human volunteers exposed to high-altitude hypoxia for a few days, ferroportin messenger ribonucleic acid synthesis increases more than 6-fold.3 Hepcidin has also been proposed as a risk factor for atherosclerosis,4 and there is recent evidence supporting this possibility.5 Diminished hepcidin production together with increased ferroportin synthesis strongly favors release of iron from reticuloendothelial storage sites and thus supports a shift of endogenous iron from storage to new red blood cell hemoglobin. High altitude could protect against cardiovascular disease by lowering hepcidin and storage iron. Future studies to confirm the findings of Faeh et al1 should include assessment of long-term HIF-associated alterations in hepcidin and storage iron in relation to hemoglobin level and cardiovascular mortality in men and women living at high altitude.
Faeh D, Gutzwiller F, Bopp M. Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation. 2009; 120: 495–501.
Robach P, Cairo G, Gelfi C, Bernuzzi F, Pilegaard H, Vigano A, Santambrogio P, Cerretelli P, Calbet JAL, Moutereau S, Lundby C. Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle. Blood. 2007; 109: 4724–4731.
Sullivan J. Macrophage iron, hepcidin, and atherosclerotic plaque stability. Exp Biol Med. 2007; 232: 1014–1020.
Valenti L, Swinkels DW, Burdick L, Tjalsma H, Bertelli C, Fatta C, Bignamini D, Dongiovanni P, Rametta R, Motta BM, Fargion S, Fracanzani AL. Serum ferritin and hepcidin levels predict vascular damage in patients with nonalcoholic fatty liver disease. Am J Hematol. 2009; 84: E236–E375.