Abstract P350: Interstitial Volume Regulation in the Heart: Mechanistic Insights from ex Vivo Fluid Dynamics in Pig Myocardia

Abstract

Developing and testing specific therapies for myocardial edema require understanding their mode and site of action. However, parsing determinants of interstitial volume/pressure relationships in vivo is difficult, particularly in the myocardium, where rhythmic contractions add to the confounding components of fluid-transfer driving pressures. Here, we describe a novel ex-vivo model system based on osmotic stress techniques and illustrate its application to analyses of local myocardial fluid dynamics that exclude systemic influences and systole/diastole compressive cycles. Freshly harvested ventricular explants were equilibrated in physiologic media at colloidosmotic pressures ranging from 3 to 219 mmHg, and fluid transfer in/out was measured gravimetrically as a function of time and pressure. The relationship between the change in explant volume and the imposed colloidosmotic pressure of the media was linear. The hydration potential , defined empirically as the pressure at which explant volume did not change, was calculated from the abscissa intercept at volume change = 0 , and the compliance from the slope of volume/pressure regression lines. Fluid-transfer rates and energies were derived from volume versus time trajectories measured at 4 and 37 °C. Hydration potential was 71.3 ± 10.6 and 23.0 ± 15.2 mmHg at 4 and 37°C (significant, P = 0.002), while compliance was 1.09 ± 0.3 and 1.22 ± 0.2 µl/g/ mmHg (not significant, P = 0.2, n = 5). Temperature-dependent differences between in/out flow rates were also significant, giving experimental activation energies of −5.9 ± 2.2 and 1.4 ± 0.7 kcal/mol for inflow and outflow, respectively. Results show that at physiologic temperatures, even without vascular hydrostatic pressure gradients and lymphatic drainage, the myocardial bias toward interstitial fluid efflux persists. These findings are consistent with local fluid-control mechanisms actuated by colloidosmotic and tensional forces rather than passive changes in flow resistance. This new approach allows quantitative evaluation of interstitial components of Starling’s forces and should help in mechanistic preclinical characterization of treatments to correct interstitial myocardial edema.