Cardiovascular disease (CVD) is the leading cause of death in the world and USA today. In particular, myocardial infarction (MI), commonly known as heart attack caused by blockage of coronary, is the number one killer of CVD patients. Existing treatments do not address the fundamental problem of cardiomyocyte (CM) loss and pumping function weakened after MI. Therefore, developing new effective first-aid therapeutic strategies to treat MI is highly desired.
In our recent studies, we found that valproic acid (VPA), an FDA approved HDAC inhibitor for epilepsy and bipolar disorders, reduced ~50% of the infarct size, preserved the pumping function and prevented CM death by up-regulating Foxm1 mediated CM protection pathway after MI in rats. Our objective of this project is to translate our previous findings from bench closer to clinical trial. We will, therefore, set out to 1) investigate the dose response and the treatment time points of VPA in MI rat model, 2) determine Foxm1 mediated downstream protective mechanism of VPA on human embryonic stem cells derived CMs in an in vitro MI mimicking model, directly reflecting the protective effects and mechanism of VPA on human CMs, and 3) analyze clinical data from the Michigan Medicine health system to determine whether VPA is associated with protection from MI. Clinical translation will be accomplished by comparing acute phase cardiac function and long-term clinical outcomes in patients with treated and not treated with VPA at the time of an MI.
This proposal has evolved from our combined expertise in cardiovascular biology, clinical cardiac surgery, clinical pharmacology, and clinical informatics. We expect that this project may promote repurposing VPA for an expedited clinical trial for MI patients.