The first human heart transplant was performed over 40 years ago and since that time, heart transplantation has become a well-established therapeutic option for patients with end-stage heart disease. While post-transplant survival rates have continued to increase over the last 20 years, most advances have been made in short-term survival—the first 6 months after transplantation. Long-term survival rates have not significantly improved in the past 10 years, with cardiac allograft vasculopathy (CAV) being a major cause of late organ rejection. CAV is an aggressive form of atherosclerosis that progresses quickly, obstructing arteries and causing the heart to fail.
Dr. Valantine has studied the causes of heart-transplant rejection since the beginning of her clinical medicine career. Her research has led to fundamental discoveries about why heart transplants fail, including the pathogenesis of CAV. She has made significant contributions to areas such as the use of echocardiography for evaluating transplant rejection, the role of insulin sensitivity on cardiac allograft adverse outcomes, clinical testing of next-generation immunosuppressive agents to improve patient outcomes, and most recently, non-invasive methods to monitor transplant rejection.
Dr. Valantine first pioneered methods to use gene-expression profiling of peripheral blood leukocytes to detect signs of organ rejection and then shifted her focus to using cell-free DNA as a detection biomarker. This work began when she and Stanford colleague Dr. Stephen Quake reasoned that an organ transplant is akin to a genome transplant: Detection of increasing amounts of donor-derived circulating cell-free DNA in a transplant recipient’s blood—taking a “liquid biopsy”—would indicate damage of the transplanted organ and ultimately organ failure.
A retrospective, proof-of-principle study (and a follow-up prospective study) showed that a significant increase in circulating cell-free donor-derived DNA can be detected up to five months before acute rejection can be diagnosed an invasive biopsy. Dr. Valantine is now assessing the broader clinical utility of this method in graft-rejection surveillance.
She has established a prospective, multi-center extramural-intramural research consortium—the Genome Research Alliance for Transplantation (GRAfT)—that leverages the intellectual capacity of extramural clinical centers with cutting-edge genomic approaches available intramurally. The consortium includes five local transplant centers in the Washington, DC metropolitan area, all of which have pre-transplant and post-transplant clinics.
Future projects will explore the utility of cell-free donor DNA detection for identifying infection and level of immunosuppression. Currently, these two outcomes are difficult to distinguish in a clinical setting but require distinct treatment paradigms. Measurement of circulating cell-free donor-derived DNA may also open a new window to investigating early immunologic markers associated with antibody-mediated rejection and acute cellular rejection.