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

Thymosin beta 4 (T beta 4) 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 T beta 4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when T beta 4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of T beta 4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of T beta 4 treatment suitable for use in clinical studies, we tested T beta 4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (T beta 4 administered only during the first 3 days following injury), and long term dosing (T beta 4 administered during the first 3 days following injury and also every third day until the end of the study). T beta 4 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. T beta 4 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 T beta 4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic T beta 4 treatment significantly increased blood vessel density in pen-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 T beta 4.