Diastolic dysfunction coincides with early mild transplant rejection: In situ measurements in a heterotopic rat heart transplant model

Background: Diastolic dysfunction seen in early clinical transplant rejecti on has been difficult to demonstrate in experimental rodent models because of the inability to make sensitive in situ measurements of systolic and dia stolic functions, We have developed a heterotopic heart transplant model wi th Fisher 344 and ACI rats (without immunosuppression), where in situ measu rements of diastolic and systolic functions were made sequentially (daily) by use of an implanted left ventricular balloon. Methods: Syngeneic and allogeneic heterotopic heart transplants were perfor med. In situ function was determined by varying balloon volume to measure t he developed pressure, the rates of pressure rise (+dp/dt) and pressure fal l (-dp/dt), diastolic pressure-volume relationship, and the time constant o f diastolic relaxation (2). These results were compared with function measu rements in transplanted hearts that were excised and perfused in a Langendo rff mode (ex vivo) during the same posttransplantation period. Results: Histologic examination revealed that at day 3 after transplantatio n, allografts showed mild lymphocytic infiltration indicative of mild or ea rly rejection, and by day 5, there was severe rejection with myocyte necros is. By day 3, the slope of the diastolic pressure volume relationship (ie, left ventricular stiffness) was significantly higher in allografts as compa red with isografts (436 +/- 96 vs 177 +/- 26 mm Hg/mL, p < .05). Similarly, tau was significantly longer in allografts by day 3 after transplantation. Developed pressure and +dp/dt became significantly lower in allografts beg inning on day 6. Function measurements made in the isolated perfused ex viv o hearts yielded the same results at day 3 after transplantation as the in situ group of hearts. Conclusion: Using a chronically implanted left ventricular balloon, we have developed a heterotopic heart transplant model where sensitive measurement s of systolic and diastolic functions can be made. With this preparation, t he early changes in the diastolic dysfunction seen clinically can be reprod ucibly detected. Thus this model may be useful to study mechanisms and inte rventions during early transplant rejection.