Pharmacologic modulation of the immune interaction between cytotoxic lymphocytes and ventricular myocytes.

Numerous studies have demonstrated that immune effector mechanisms cause serious heart diseases, among which are heart transplant rejection, myocarditis, and the resulting dilated cardiomyopathy, as well as Chagas' disease. Whereas different effectors of the immune system can affect cardiac function, this review primarily focuses on the immune damage caused by cytotoxic T lymphocytes. The immune attack staged by cytotoxic T lymphocytes is carried out by one of two distinct modes of lymphocytotoxicity: (a) secretion of lytic granules containing the pore-forming protein perforin and a family of serine proteases (i.e., granzymes) and (b) interaction between the lymphocyte Fas ligand and the target cell Fas receptor. Ventricular myocytes challenged by the immune system sustain diverse intracellular changes, among which the rise in intracellular calcium ([Ca2+]i) constitutes an important contributor to myocyte dysfunction. Hence, this [Ca2+]i rise, which does not necessarily result in apoptosis, can affect cardiac function directly and indirectly. Importantly, the final outcomes of these perturbations vary markedly and depend on intracellular circumstances such as the magnitude of the absolute rise in [Ca2+]i and its temporal and spatial determinants, the metabolic status of the myocyte, as well as a fine balance between pro-apoptotic and anti-apoptotic factors. In view of the central role of [Ca2+]i rise in immune-mediated myocyte dysfunction and possibly cell death, this review addresses three topics related to the immune assault on the heart: (a) [Ca2+]i rise in affected myocytes; (b) the source for the [Ca2+]i rise; and (c) pharmacologic modification of the immune-mediated [Ca2+]i rise.