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BACKGROUND The current cornerstone treatment of myocardial infarction (MI) is restoration of coronary blood flow by means of thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion of ischemic myocardium can actually provoke tissue damage, defined as "ischemia-reperfusion (I/R) injury." TVP1022 [the S-isomer of rasagiline (Azilect), FDA-approved anti-Parkinson's drug] was found to exert cardioprotective activities against various cardiac insults, such as chronic heart failure and I/R, in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against I/R injury and post-MI remodeling in a pig model. METHODS For inducing MI, we used an I/R model of midleft anterior descending artery occlusion for 90 minutes followed by follow-up for 8 weeks in 18 farm pigs (9 pigs in each group, MI + TVP1022 or MI + Vehicle). Echocardiographic measurements were performed and cardiac scar size was calculated using histopathological methods. For fibrosis evaluation, we measured the interstitial collagen volume fraction in the remote noninfarcted tissue. RESULTS TVP1022 administration significantly decreased cardiac scar size, attenuated left ventricular dilation, and improved cardiac function assessed by segmental circumferential strain analysis. Furthermore, TVP1022 significantly reduced myocardial fibrosis 8 weeks post-MI. CONCLUSIONS Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R pig model.

We recently reported that propargylamine derivatives such as rasagiline (Azilect) and its S-isomer TVP1022 are neuroprotective. The aim of this study was to test the hypothesis that the neuroprotective agents TVP1022 and propargylamine (the active moiety of propargylamine derivatives) are also cardioprotective. We specifically investigated the protective efficacy of TVP1022 and propargylamine in neonatal rat ventricular myocytes (NRVM) against apoptosis induced by the anthracycline chemotherapeutic agent doxorubicin and by serum starvation. We demonstrated that pretreatment of NRVM cultures with TVP1022 or propargylamine attenuated doxorubicin-induced and serum starvation-induced apoptosis, inhibited the increase in cleaved caspase 3 levels, and reversed the decline in Bcl-2/Bax ratio. These cytoprotective effects were shown to reside in the propargylamine moiety. Finally, we showed that TVP1022 neither caused proliferation of the human cancer cell lines HeLa and MDA-231 nor interfered with the anti-cancer efficacy of doxorubicin. These results suggest that TVP1022 should be considered as a novel cardioprotective agent against ischemic insults and against anthracycline cardiotoxicity and can be coadministered with doxorubicin in the treatment of human malignancies.

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 ([Ca 2+ ] i ) constitutes an important contributor to myocyte dysfunction. Hence, this [Ca 2+ ] 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 [Ca 2+ ] 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 [Ca 2+ ] 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) [Ca 2+ ] i rise in affected myocytes; (b) the source for the [Ca 2+ ] i rise; and (c) pharmacologic modification of the immune-mediated [Ca 2+ ] i rise.

Barbiturates, which are widely used in clinical anesthesia, exert a negative inotropic effect on the myocardium. To investigate the mechanism for the negative inotropism, we studied the effect of sodium pentobarbital (SP) on the action potential and the slow inward current recorded from guinea pig ventricular myocytes. We found that SP at 0.6, 1.0, and 1.6 microM decreased action potential duration at 50% repolarization by 17 +/- 6, 25 +/- 11, and 29 +/- 8%, respectively (p less than 0.05, n = 4). At the concentration range of 0.6-1.6 microM, resting potential and action potential amplitude were unaffected. Voltage-clamp studies in ventricular myocytes demonstrated that SP at 0.6, 1.0, and 1.6 microM reduced the peak slow inward current by 30 +/- 4, 36 +/- 14, and 67 +/- 5%, respectively (p less than 0.005, n = 4). In conclusion, SP, a frequently used anesthetic, decreases the slow inward current in guinea pig ventricular myocytes at clinically relevant concentrations.