A new study that explores gene expression during heart transplant rejection marks a step forward for precision medicine approaches to treat organ rejection.
A team of researchers at Vanderbilt Health and the Translational Genomics Research Institute ( TGen ) used image-based spatial transcriptomics to characterize acute rejection and response to immunomodulatory therapies following heart transplantation. Their study, reported Aug. 10 in Nature Cardiovascular Research , linked cell-specific gene expression patterns to the development of cardiac allograft vasculopathy (CAV), a form of chronic rejection that limits long-term survival.
"Our findings elucidate cellular dynamics during heart transplant rejection and provide a unique resource to guide future studies on acute rejection diagnosis, therapeutic response prediction, and risk stratification for CAV development," said Kaushik Amancherla , MD, MSCI, Assistant Professor of Medicine at Vanderbilt Health and co-first author of the study.
Solid organ transplant rejection occurs when the recipient's immune system attacks the transplanted organ. It is common — up to 40% of organ recipients experience rejection within one year of transplant — and can result in long-term transplanted organ failure and death. Diagnosis of acute rejection and its response to therapy relies on biopsy and analysis of tissue histology. Following heart transplantation, routine endomyocardial biopsies are performed for histologic rejection surveillance.
"We see substantial variability in histologic rejection grades, which impacts the precision of our immunosuppressive therapies, with a potential for over- or under-immunosupression with downstream clinical consequences," said Ravi Shah , MD, the Gottlieb C. Friesinger II Professor of Cardiovascular Medicine and Professor of Medicine at Vanderbilt Health, and co-corresponding senior author of the study. "We directly examined molecular phenotypes in tissue during rejection and antirejection therapy after heart transplantation to start to understand this heterogeneity. This was a true multidisciplinary effort, with collaborators across Vanderbilt Health and TGen, including our transplant medicine section."
The researchers used spatial transcriptomics, a technology that maps gene expression in a tissue with subcellular resolution, to analyze longitudinal endomyocardial biopsy samples from 49 adult and 13 pediatric heart transplant recipients. The biopsies were collected from the same patients during acute rejection and following a range of immunomodulatory therapies. The study's principal findings:
- Diverse cell types are involved in acute rejection and response to immunomodulation.
- There is substantial molecular heterogeneity, not apparent by histology alone, across rejection types and within the same rejection grades.
- Baseline rejection biopsies from patients who respond to immunomodulatory therapies have distinct transcriptomic profiles compared to biopsies from patients who do not respond.
- Cell-specific gene expression patterns are associated with CAV, and these genes are expressed in samples from patients with end-stage CAV that requires a repeat heart transplant.
"The molecular heterogeneity may help explain the spectrum of clinical presentations — from complete lack of symptoms to cardiogenic shock — for the same histologic grade of rejection, and why some individuals have resolution with minimal intervention while others require more intensive therapies," said Nicholas Banovich , PhD, Vice President of Scientific Development and Professor at TGen and co-corresponding senior author of the study. "We expect that data generated through approaches like ours will inform early biomarker and drug discovery to meaningfully prolong transplanted organ survival."
Endomyocardial biopsy samples were obtained from adult and pediatric heart transplant recipients at Vanderbilt Health undergoing routine surveillance or for-cause endomyocardial biopsies between December 2017 and January 2023. The Vanderbilt Transplant Center, No. 1 in the U.S. by volume for solid organ transplantation, set a world record for the number of heart transplants performed in 2024 and surpassed its own record in 2025.
Angela Oill, PhD, a computational scientist at TGen, is co-first author of the study. Additional Vanderbilt Health and Vanderbilt University School of Medicine co-authors are Xavier Bledsoe, PhD, Nelson Chow, Anna Smith, Melissa Farrow, PhD, Shilin Zhao, PhD, Quanhu Sheng, PhD, David Bearl, MD, Alexander Perez, MD, Robert Hoffman, MD, PhD, Jonathan Menachem, MD, Hasan Siddiqi, MD, MSCI, Douglas Brinkley, MD, Vineet Agrawal, MD, PhD, Jeffrey Schmeckpeper, MD, PhD, Aniket Rali, MD, Stacy Tsai, MD, Eric Farber-Eger, MS, Quinn Wells, MD, PharmD, Jane Freedman, MD, Jeffrey Spraggins, PhD, Kelly Schlendorf, MD, MHS, and Eric Gamazon, PhD.
TGen, located in Phoenix, is part of City of Hope . The research was supported by an International Society for Heart and Lung Transplantation Enduring Hearts Transplant Longevity Award, the American Heart Association, the Red Gates Foundation, and the National Institutes of Health ( grant K23HL166960 ).
