External detection of early microvascular dysfunction after no-flow ischemia followed by reperfusion in isolated rabbit hearts

To define relationships better between the duration of severe ischemia and microvascular functional integrity with an approach potentially applicable to studies in vivo, the effects of 30 and 60 minutes of global, no-flow ischemia on the coronary vasculature of isolated, perfused rabbit hearts were determined. Residue-detection data, analyzed with a two-compartment model, were used to estimate indices of microvascular function, including the mean-transit time (t̄(BSA)) of radiolabeled bovine serum albumin (¹²⁵I-BSA), vascular into extravascular space clearance, and vascular and extravascular space volumes. It was shown that the Central Volume Principle of tracer kinetics does not hold when transport of label between vascular and extravascular spaces takes place convectively by solvent drag, and a more general expression for t̄(BSA) was derived and applied. Left ventricular end-diastolic pressure and left ventricular developed pressure were monitored with an isovolumic balloon. Aortic perfusion pressure, left ventricular end-diastolic pressure, left ventricular developed pressure and vascular space volume remained constant, while mean transit time, vascular into extravascular space clearance and extravascular space volumes increased gradually during 3-hour control perfusions. Perfusion pressure, mean transit time and extravascular space clearance increased significantly with reperfusion after 30 minutes of ischemia even though left ventricular end-diastolic and left ventricular-developed pressures returned to control levels. Vascular space volumes increased minimally, whereas extravascular space volumes increased 5-fold during reperfusion. These changes in ¹²⁵I-BSA washout and permeation across endothelium with reperfusion after no-flow ischemia indicate that compromised vascular integrity is an early manifestation of ischemia with functional consequences that persist even after ischemia sufficiently brief to permit restoration of left ventricular performance.