Charles Foster

Introduction. Congestive heart failure (CHF) is a common cardiopulmonary condition that is characterized by decreased cardiac output, particularly with reduced ejection fraction. CHF is one of the most prevalent causes of respiratory failure in the adult U.S. population.¹ Diagnosis of CHF often cannot be made by physical exam alone, as its symptoms are often non-specific and patients with less severe CHF may have no clinical presentation at all.² Furthermore, current diagnostic modalities are often not specific for CHF. At best, this leads to operator-dependent outcomes in CHF patients. At worst, less severe CHF patients may be left untreated for long periods of time until severity increases.³ This is why it is so crucial to develop ways not only to quickly and accurately diagnose patients with CHF, but also identify patients with existing predisposition to CHF to monitor for early signs of the disease. Methods. The metabolism of iron is well established in playing a key role in the development of cardiomyopathy and CHF.⁴ Ferritin is a key metabolite in storing excess iron, but its exact mechanism of function in cardiac myocytes remains unknown.⁵ In this study attempting to explore the role of Ferritin H, a subtype of Ferritin normally present in cardiac myocytes, knockout mice were produced lacking Ferritin H allele expression specifically in cardiomyocytes. This knockout allele was confirmed via PCR analysis of genomic DNA. These knockout mice were then compared to normal mice expressing these alleles. RNA sequencing and collection of oxylipids, amino acids, and cardiac enzymes were performed for analysis.⁶ Results. Knockout mice lacking Ferritin H exhibited decreased levels of cardiac iron as well as increased oxidative stress. Interestingly, this study also found that supplementing these mice with high doses of iron also caused cardiac dysfunction and myopathy. Molecular analysis of cardiac tissue after supplemental iron dosing revealed evidence of ferroptosis, such as severely decreased levels of glutathione and increased lipid peroxidation. Additionally, analysis found that mice deficient in Ferritin H downregulated the expression of Slc7a11, a potent regulator of ferroptosis in cardiac tissue. Slc7a11 was also shown to increase glutathione levels and prevent cardiac ferroptosis. Therefore, Ferritin H deficiency-mediated downregulation of this gene was a potent originator of cardiomyocyte dysfunction.⁶ Conclusions. Ferritin H may be a key regulator of cardiomyocyte function in cardiomyopathy and CHF. Patients suspected of predisposition to CHF should have their levels of ferritin evaluated in order to diagnose and/or manage this condition.

1. Figueroa, M., & Peters, J. Congestive heart failure: Diagnosis, pathophysiology, therapy, and implications for respiratory care. Respiratory Care. 2006; 5(4); 403-412.
2. Watson, R., Gibbs, C., & Lip, G. ABC of heart failure: Clinical features and complications. British Medical Journal. 2000; 320; 236-239.
3. Jahmunah, V., Lih Oh, S., Wei, J., et al. Computer-aided diagnosis of congestive heart failure using ECG signals – A review. European Journal of Medical Physics. 2019; 62; 95-104.
4. Hentze, M.W., Muckenthaler, M.U., Galy, B., & Camaschella, C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010; 142; 24-38.
5. Ganz, T. Systemic iron homeostasis. Physiol Rev. 2013; 93; 1721-1741.
6. Fang, X., Cai, Z., Wang, H., & Han, D., et al. Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis. Circulation Research. 2020; 127; 486-501.