Clinical Data The studies evaluated the effects of vepoloxamer on ventricular function and calcium cycling proteins in dogs with severe heart failure. Animals were randomized to receive vepoloxamer or placebo (saline) and each received two infusions of vepoloxamer or saline control administered three weeks apart. Tissue samples obtained three weeks after the second infusion were assessed for Ca2+-ATPase activity, phosphorylated (p) phospholamban at serine-16 (p-PLB-s16), p-ryanodine receptors at serine-2808 (p-RYR-s2808) and p-sodium-calcium-exchanger 1 (p-NCX-1) measured using specific antibodies and Western blotting. LV tissue from seven normal animals was utilized for comparison. LV function was assessed by full hemodynamics, plasma n-terminal-pro brain natriuretic peptide (NT-proBNP) and plasma- troponin-I (Tn-I) at baseline and at 1, 2 and 3 weeks following each infusion.With regard to calcium cycling proteins, saline infusions had no effect on any of the examined functional measures.  However, as previously reported, treatment with vepoloxamer partially normalized activity and protein levels. The results suggest that by limiting unregulated calcium entry into the cell, vepoloxamer decreased calcium overload in failing cardiomyocytes and improved calcium cycling proteins, leading to improved LV function. With regard to ventricular function, vepoloxamer increased LV ejection fraction and progressively reduced NT-proBNP and Tn-I. These benefits were sustained for up to 3 weeks after the second infusion of vepoloxamer. The results suggest that therapy with repeat intravenous 2-hour infusions of vepoloxamer, pulsed at 3-week intervals, limits calcium overload, normalizes sarcoplasmic reticulum (SR) calcium cycling, improves LV systolic function, lowers NT-proBNP and reduces Tn-I, a measure of ongoing cardiomyocyte death.