Heart failure reduced and preserved ejection fraction. In the failing hearts, there is excessive generation of toxic reactive aldehydes. These toxic aldehydes covalently bind with proteins, leading to the formation of aldehyde-modified protein adducts. These modified protein adducts are immunogenic and activate both the innate and adaptive immune responses. However, whether these adducts trigger maladaptive inflammation in the failing heart and whether diminishing their immunogenicity could influence heart failure reduced and preserved ejection fraction outcomes remains unexplored.

Exercise intolerance during Heart failure.  Exercise intolerance is the cardinal manifestation of heart failure, and a key factor associated with poor prognosis in heart failure patients. While extensive evidence demonstrates a shift in glucose utilization in the skeletal muscle during heart failure, the role of altered metabolism in contributing to exercise intolerance during heart failure is not fully understood.

Role of histidyl dipeptides in peripheral arterial disease. Histidyl dipeptides such as carnosine and anserine, are present in both heart and skeletal muscle and are synthesized via the enzyme carnosine synthase (CARNS, encoded by Carns). These dipeptides are unique, since their levels can be enhanced through supplementation and exercise. Moreover, histidyl dipeptides exhibit multifunctional properties, including buffer intracellular pH, scavenge reactive aldehydes, and quenching reactive oxygen species. 

While studying the physiological role of these dipeptides, we found these dipeptides could improve angiogenesis in the ischemic skeletal muscle and facilitate the removal of toxic aldehydes in humans. Since these dipeptides can be enhanced in the skeletal muscle and heart through exercise and supplementation and are non-toxic, we are conducting a Phase II clinical trial to evaluate whether supplementation with these dipeptides can improve lower extremity function in patients with peripheral arterial disease.