| Iron mediated cardiomyopathy remains the leading cause of mortality in beta-thalassemia patients. Cardiac iron accumulates in the first and second decade of life and it is difficult to remove. Thus, treatment options to prevent cardiac iron uptake are much needed.;Recently, vitamin D deficiency has been associated with increased cardiac iron overload in beta-thalassemia patients. In these patients, PTH and 1-25-(OH)2-D are elevated. Both PTH and 1-25-OH-D levels upregulate L-type voltage gated calcium channels (LVGCC), in vitro. LVGCCs have also been proposed to be the dominant mechanism for iron influx into cardiomyocytes in mice. Therefore, we hypothesized that vitamin D deficiency increases cardiac iron uptake via LVGCC up-regulation by PTH and 1-25(OH)2-D.;We created vitamin D deficiency in a murine hemochromatosis model in order to understand possible contributing mechanisms. Verapamil decreased cardiac iron consistent with LVGCC involvement. Furthermore, we observed a strong correlation between cardiac and calcium iron stores (R2=0.63). However, large perturbations of the vitamin D axis failed to modulate either cardiac iron or cardiac calcium, contrary to our initial hypothesis. Since verapamil also unexpectedly lowered hepatic iron, we sought an alternate means of LVGCC manipulation. LVGCCs are also modulated by the autonomic nervous system via L-type current changes. Therefore, positive and negative inotropic interventions should impact cardiac iron levels. As predicted, beta-blockade lowered cardiac calcium (55%, p=0.021) and iron content (55%, p=0.011). Surprisingly isoproterenol reduced cardiac iron content the most (58%, p<0.001) without lowering calcium content, must likely through recruitment of T-type calcium transporters. While isoproterenol has many undesirable side effects, beta- blockers may be a safe, affordable treatment option to protect thalassemia major patients. |
