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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.
Abstract| Volume 35, ISSUE 4, SUPPLEMENT , S141, April 2016

Vepoloxamer (Purified Sodium-Free Poloxamer-188) Improves LV Systolic Function in Dogs with Advanced Heart Failure and Protects Failing Cardiomyocytes from Calcium Overload

      Purpose

      Ca2+ overload occurs in cardiomyocytes (CMs) of the failing heart and contributes to loss of CMs and to progressive LV dysfunction. Vepoloxamer (VEPO), purified sodium-free poloxamer-188, is a rheologic agent that improves microvascular blood flow and potentially repairs damaged cell membranes. We examined the effects of multiple acute i.v. infusions of VEPO on LV function in dogs with heart failure (HF) (LV ejection fraction, EF~30%) and tested the hypothesis that the membrane reparative properties of VEPO attenuates Ca2+overload in CMs by preventing unregulated Ca2+ entry into the cells.

      Methods

      14 dogs were randomized to 2, 2 hr infusions of VEPO (450 mg/kg, n=7) or v/v saline (control, n=7) given 3 weeks (W) apart. LV EF and plasma nt-pro BNP were measured at baseline, at end of infusion and at 1, 2 and 3W after each infusion. The change (Δ) between baseline and each study time point (treatment effect) was calculated. Separately, freshly isolated CMs from 6 HF control dogs were incubated for 2 hrs with VEPO (4.5 mg/ml) or saline and then treated with 10 µM Fura-2 AM for 1 hr and resuspended in 1.0 mM extracellular Ca2+ for 2 hrs to flourometrically assess intracellular Ca2+ concentration.

      Results

      VEPO increased EF by 6.0±0.7%* at 2hrs; 7.0±0.7%*% at 1W; 4.5±0.5%* at 2W; 1.0±0.6% at 3W; 6.0±1.3%* at 4W; 6.0±1.4%* at 5W; 5.9±1.3%* at 6W (*=p<0.05 vs. control) and reduced BNP by 910±92* pg/ml at 2hrs; 328±103* pg/ml at 2W; 333±60* pg/ml at 4W;235±48* pg/ml at 6W (*=p<0.05 vs. control). Treatment of isolated CMs with VEPO reduced intracellular Ca2+ compared to saline (2.32±0.05 vs. 3.14±0.32 relative flourometric units, p<0.05) thus inhibiting unregulated Ca2+ entry into CMs.

      Conclusion

      VEPO relieves Ca2+overload in failing CMs. Multiple short i.v. infusions of VEPO, pulsed at 3W intervals, elicit progressive improvement in LV systolic function. The results support development of VEPO for pulsed treatment in patients with advanced HF and those on waiting lists for heart transplantation or LVADs requiring i.v. therapy.