Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.

Background-Depressed myocardial blood flow (MBF) has been reported in dilated cardiomyopathy. The aim of this study was to investigate whether MBF impairment is an independent predictor of prognosis in patients with idiopathic left ventricular (LV) dysfunction. Methods and Results-Sixty-seven patients (52 male, mean age 52Ϯ12 years) with different degrees of idiopathic LV systolic dysfunction (average LV ejection fraction, 0.34Ϯ0.10; range, 0.07 to 0.49) were prospectively enrolled. Thirty-four subjects (51%) had no history of heart failure symptoms at enrollment (NYHA class I). All patients underwent clinical and functional evaluation and a PET study to measure absolute MBF at rest and after intravenous dipyridamole. During a mean follow-up of 45Ϯ37 months, 24 patients had major cardiac events, including cardiac death in 8 and development or progression of heart failure in 16 patients. Multivariate regression analysis (Cox proportional hazards model) revealed heart rate ( 2 11.06, PϽ0.001), LV end-diastolic dimension ( 2 11.73, PϽ0.001), and dipyridamole MBF ( 2 11.04, PϽ0.001) as independent predictors of subsequent cardiac events. Dipyridamole MBF Յ1.36 mL ⅐ min Ϫ1 ⅐ g Ϫ1 was associated with an increase in the relative risk of death, development, or progression of heart failure of 3.5 times over other more common clinical and functional variables. Conclusions-The present study demonstrates that severely depressed MBF is a predictor of poor prognosis in patients with idiopathic LV dysfunction independently of the degree of LV functional impairment and of the presence of overt heart failure.

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