Current Research and Scholarly Interests
Prior to my expanded administrative role, my lab focused on understanding the mechanism mediating acute and chronic allograft failure, in particular on the role of microvascular injury in acute allograft failure and the mechanisms of mediating transplant coronary artery disease.
1. Role of microvascular injury in acute allograft failure. We observed decreased cardiac allograft function in patients to be significantly associated with loss of microvascular cell surface markers, consistent with altered biology of the vascular endothelium or injury, and with up-regulation of cytokines such as IL-6, IL-10, TGF-b, and TNF-a. Decreased cardiac allograft function, in particular diastolic dysfunction, was highly predictive of allograft vascular disease and poor outcome in long-term patients. To further characterize cellular and molecular mechanisms we developed quantitative methods to monitor allograft function and correlate it with cytokine expression in a rat heterotopic transplant model. We developed echocardiographic markers of systolic and diastolic function and found decreasing systolic and diastolic function highly correlated with up-regulation of IL-6 expression.
2. Mechanisms mediating allograft dysfunction. We observed the major risk factors for transplant atherosclerosis in patients to be metabolic (hyperglycemia, hypertriglyceridemia, and low HDL). To further study cellular and molecular mechanisms mediating this process, we recapitulated metabolic abnormalities in the rat heart transplant model and confirmed rapid development of transplant atherosclerosis.
My current focus is on clinical and translational research, expanding on my earlier laboratory-based research on the mechanisms of allograft failure and vasculopathy. I study the role of sub-clinical cytomegalovirus infection in the development of cardiac allograft vasculopathy (CAV), and the effect of antiviral agents in preventing CAV, work that has been supported by a program project grant from NIH. Translating my earlier work on gene expression profiling, I conduct clinical trials on the application of this technology for non-invasive diagnosis of transplant rejection. This work, recently published in the New England Journal of Medicine, showed that peripheral blood leukocyte gene expression can be used safely for monitoring rejection in heart transplant recipients, with a substantial decrease in the number of endomyocardial biopsies performed. On going studies in this area will include application of the technology to diagnose CAV; monitor level of immunosuppression in a patient to guide therapy; and individualization of immunosuppression. My current research, in collaboration with bio-X faculty, uses the new technologies of whole genome scans, to detect the appearance of donor DNA in the recipient’s blood as a novel, non-invasive marker of allograft damage due to acute rejection. Ongoing studies include confirmation studies of the utility, and then external validation in a randomized controlled trial.