Effects of Intravenous Infusion of Vepoloxamer on Left Ventricular Function in Dogs with Advanced Heart Failure.

Abstract

PURPOSE: Vepoloxamer (VEPO), a rheologic agent, repairs damaged cell membranes, thus inhibiting unregulated Caentry into cardiomyocytes. This study examined the effects of i.v. infusion of VEPO on LV function in dogs with coronary microembolization-induced heart failure (HF) (LV ejection fraction, EF ~&#x2009;30%). METHODS: Thirty-five HF dogs were studied. Study 1: 21 of 35 dogs were randomized to 2-h infusion of VEPO at dose of 450&#xa0;mg/kg (n&#x2009;=&#x2009;7) or VEPO at 225&#xa0;mg/kg (n&#x2009;=&#x2009;7) or normal saline (control, n&#x2009;=&#x2009;7). Hemodynamics were measured at 2&#xa0;h, 24&#xa0;h, 1&#xa0;week, and 2&#xa0;weeks after infusion. Study 2: 14 HF dogs were randomized to 2-h infusions of VEPO (450&#xa0;mg/kg, n&#x2009;=&#x2009;7) or normal saline (control, n&#x2009;=&#x2009;7). Each dog received 2 infusions of VEPO or saline (pulsed therapy) 3&#xa0;weeks apart and hemodynamics measured at 24&#xa0;h, and 1, 2, and 3&#xa0;weeks after each infusion. In both studies, the change between pre-infusion measures and measures at other time points (treatment effect, &#x394;) was calculated. RESULTS: Study 1: compared to pre-infusion, high dose VEPO increased LVEF by 11&#x2009;&#xb1;&#x2009;2% at 2&#xa0;h, 8&#x2009;&#xb1;&#x2009;2% at 24&#xa0;h (p&#x2009;<&#x2009;0.05), 8&#x2009;&#xb1;&#x2009;2% at 1&#xa0;week (p&#x2009;<&#x2009;0.05), and 4&#x2009;&#xb1;&#x2009;2% at 2&#xa0;weeks. LV EF also increased with low-dose VEPO but not with saline. Study 2: VEPO but not saline significantly increased LVEF by 6.0&#x2009;&#xb1;&#x2009;0.7% at 2&#xa0;h (p&#xa0;<&#x2009;0.05); 7.0&#x2009;&#xb1;&#x2009;0.7%% at 1&#xa0;week (p&#xa0;<&#x2009;0.05); 1.0&#x2009;&#xb1;&#x2009;0.6% at 3&#xa0;weeks; 6.0&#x2009;&#xb1;&#x2009;1.3% at 4&#xa0;weeks (p&#xa0;<&#x2009;0.05); and 5.9&#x2009;&#xb1;&#x2009;1.3% at 6&#xa0;weeks (p&#xa0;<&#x2009;0.05). CONCLUSIONS: Intravenous VEPO improves LV function for at least 1&#xa0;week after infusion. The benefits can be extended with pulsed VEPO therapy. The results support development of VEPO for treating patients with acute on chronic HF.