Faculty Bibliography

We report a case of post-transplant lymphoproliferative disease presenting as a disseminated polymorphous B-cell lymphoma involving the cardiac allograft 3 months following transplantation in a recipient who did not receive anti-lymphocyte induction immunosuppression. In situ hybridization for the lytic Epstein-Barr virus marker NOT I was positive within a lymphocytic infiltrate on endomyocardial biopsy. Our case is the third of early post-transplant lymphoproliferative disease (within 6 months of transplantation) involving the heart allograft in the absence of anti-lymphocyte induction immunosuppression. Post-transplant lymphoproliferative disease of the heart allograft should be considered in the presence of an atypical cardiac lymphocytic infiltrate, with possible differentiation from allograft rejection using in situ hybridization for Epstein-Barr virus.

Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3. The hearts explanted from five victims of motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage cardiomyopathy. There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C delta but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.