In vivo indices of myocardial performance in cardic gene therapy
Demonstrating the efficacy of Cardiac Gene Therapy (CGT) remains hindered by the inability to measure changes in in vivo cardiac function in small animals. Post-implantation of transfected biopsy-derived skeletal muscle cells into the left ventricle (LV) of rabbits, ectopic gene expression was evident indicating a need to assess regional myocardial performance in intact, closed-chested rabbits. Using micromanometry and sonomicrometry, LV transmural pressure and myocardial segment length (SL) in the anterior LV were measured in ten rabbits over a range of inotropic and loading states. Myocardial performance was quantified using dP/dt max, the Frank-Starling (FSR) relationship between regional stroke work and end-diastolic SL with slope (Mw) and intercept (Lo), and % Systolic Shortening (%SS) defined as maximum ejection SL difference versus end-diastolic SL with slope (Ms) and intercept (Ys). Data are mean± S.D., =p<0.05 vs. control. FSR %SS dP/dt max Mw Lo Ms Ys Control 5.7±.7 6.0 5.9±2 0.9±I 2400 170 Dobutimine 7.9±9 5.4±8 5.0±2 -9.0±15 3100±220 Nitropuitlde 6.2±4 5.6±5 10±3.6 -50±4- 1800±340 Phtnykphrint 7.4±9 5.2±5 6.9±2.4 -17±8 3000±190 These results demonstrate that inotropic state and loading conditions affect dP/dt max, whereas Mw reflects changes in regional cardiac function in a loadindependent fashion. This method of assessment of regional cardiac performance combined with myoblast transfer provides a good framework for evaluating cardiac gene therapy in the smaller animals.
Silvestrv, SC; Taylor, DA; Eric Lilly, R; Marathe, US; Davis, JW; Kraus, WE; Glower, DD
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