Abstract 9422: T-Type Calcium Channel Inhibitor Attenuates Cardiac Dysfunction, Improves Cardiac Sympathovagal Imbalance and Decreases Mortality in Iron-Overloaded Mice

Abstract

Excess plasma iron can lead to iron deposition in many organs including the heart. In thalassemia, excess cardiac iron deposition can cause cardiac dysfunction and depressed heart rate variability (HRV). Recently, T-type calcium channel (TTCC) has been shown as a possible gateway for iron entry in thalassemic cardiomyocytes. However, the role of TTCC in “in vivo” with iron overload has never been investigated. We tested the hypothesis that TTCC blocker can improve impaired cardiac function and attenuate the depressed HRV, leading to decreased mortality in iron-overloaded mice. Methods: C57/BL6 adult mice were fed with either normal diet (control group) or diet supplemented with dicyclopentadienyl iron (FE group) for 90 days to induce iron overload condition. Then, mice in each group were divided into subgroups being treated with L-type calcium channel (LTCC) blocker, verapamil and nifedipine; TTCC blocker, efonidipine; or iron chelator deferoxamine (DFO) for 30 days. Pressure-volume (P-V) conductance catheter system was used for cardiac function assessment. HRV was determined at baseline and at the end of treatment in all mice. Results: Iron-overloaded mice demonstrated impaired cardiac function as shown by decreased stroke volume (SV), cardiac output (CO), ejection fraction (EF), impaired HRV as indicated by increased LF/HF ratio, with high mortality rate (Figure). Efonidipine effectively improved cardiac function impairment, whereas LTCC blockers and DFO did not. Efonidipine and DFO also significantly improved HRV parameter, whereas LTCC blockers could improve it at a lower extent. Both efonidipine and DFO markedly decreased mortality, while LTCC blocker did not, in these mice with iron overload. Conclusion: Impaired cardiac function and depressed HRV caused by iron overload were improved by efonidipine, but not by verapamil and nifedipine, suggesting that TTCC but not LTCC, plays an important role for iron uptake in the heart of iron-overloaded mice.