The relationship of granzyme A and perforin expression to cardiac allograft rejection and dysfunction.

The mechanisms underlying contractile dysfunction following heart transplantation are poorly defined. To investigate the role of cytotoxic T cells (CTL) in cardiac transplant rejection, and during episodic contractile dysfunction, we performed a prospective study analyzing the expression of granzyme A and perforin, two functional markers of activated CTL. Sixteen consecutive patients were analyzed during the first year posttransplantation. All patients received induction therapy with OKT-3 and received standard three-drug immunosuppression therapy. Rejection status was monitored using routine surveillance endomyocardial biopsy and graded according to the ISHLT scale. Granzyme A and perforin mRNA were detected by reverse transcription PCR at the time of each routine biopsy. A total of 64/123 biopsies were positive for granzyme expression, while 38/123 samples were positive for perforin expression. LV function was monitored using M-mode derived fractional shortening and Doppler assessment of diastolic function (isovolumic relaxation time [IVRT] and pressure half-time [P1/2]). As expected, the presence of granzyme A message was associated with rejection score (ANOVA, P = 0.001). In addition, granzyme A expression was correlated with a decrease in diastolic function (chi 2 = 6.4, P < 0.02), but was not associated with systolic function. The presence of perforin message was not correlated with functional changes or with rejection grade, but was associated with granzyme expression (chi 2 = 9.11, P = 0.0025). These studies suggest that the presence of granzyme A message may be an important predictor of graft function.