Abstract 1885: Decreasing Hemoglobin Oxygen Affinity With Inositol Tripyrophosphate (itpp) Increases Maximal Exercise Capacity In Mice With Severe Heart Failure
Background: A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles, which in turn is a function of cardiac output and the amount of oxygen released from hemoglobin. Inositol tripyrophosphate (ITPP) is a membrane-permeant molecule that decreases the affinity of hemoglobin for oxygen via an allosteric effect, as reflected by an increase in the pressure of oxygen at which hemoglobin is 50% saturated (p50). We hypothesized that increased oxygen release by ITPP would increase maximal exercise capacity in mice with severe heart failure.
Methods: ITPP in a low dose (0.03mg) or high dose (0.06mg) or placebo solution was administered to mice by intraperitoneal injection. Wild-type (WT; n=16) and transgenic mice with dilated cardiomyopathy due to cardiac-specific Gαq overexpression (Gq; n=13) were studied. The hemoglobin oxygen affinity (p50) was determined from dissociation curves. Maximal exercise capacity (running distance in meters) was measured in a blinded manner on a rodent treadmill with air puff motivation.
Results: The mean p50 value in the placebo group was 37±2 mmHg. ITPP increased p50 by 18% (44±1 mmHg) at low dose and by 31% (51±2 mmHg) at high dose. Maximal exercise capacity at baseline was 389±8 meters in WT mice and was reduced to 255±24 meters in Gq mice. In WT mice ITPP increased exercise capacity by 22±8% and 57±13% in low- and high-dose groups, respectively (p=0.002). In Gq mice ITPP increased exercise capacity by 43±12% and 63±7% in low- and high-dose groups, respectively (p=0.005).
Conclusion: ITPP causes a dose-related decrease in hemoglobin-oxygen affinity that is associated with a parallel, dose-related increase in maximal exercise capacity in both normal mice and mice with reduced exercise capacity due to severe dilated cardiomyopathy. ITPP may be an attractive therapy for symptomatic benefit in patients with reduced exercise capacity due to heart failure.