Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury.

ABSTRACT

Thymosin beta 4 (Tß4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action an acute phase, just after injury, when Tß4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when Tß4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of Tß4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of Tß4 treatment suitable for use in clinical studies, we tested Tß4 in a rat model of chronic myocardial ischemia using two dosing regimens short term dosing (Tß4 administered only during the first 3 days following injury), and long term dosing (Tß4 administered during the first 3 days following injury and also every third day until the end of the study). Tß4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved. Tß4 administered only during the first 3 days following injury tended to reduce infarct size, chamber volumes and improve hemodynamic performance. Plasma biomarkers of myocyte injury were significantly reduced by Tß4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic Tß4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of Tß4.