New Clues Could Help Transplanted Hearts Last Longer
by Amanda Chase, PhD
June 10, 2026
Decades of cardiovascular research have transformed the care of patients with advanced heart disease. Heart transplantation, first performed by Dr. Shumway at Stanford in 1968, remains one of the only long-term lifesaving options for patients with end-stage heart failure. The first heart transplanted by Dr. Shumway lasted only two weeks. Short-term outcomes have improved significantly through advances in surgical technique, immunosuppression, and clinical care. Yet long-term outcomes remain a major challenge. One of the most serious barriers is cardiac allograft vasculopathy, or CAV, a form of chronic rejection that is the leading cause of mortality after heart transplant and affects nearly 50% of recipients within 10 years. CAV develops when the inner layer of the donor coronary arteries progressively thickens, narrowing the vessels that supply blood to the transplanted heart. Over time, this can limit oxygen delivery, lead to allograft failure, cause heart failure symptoms or arrhythmias, and ultimately create the need for repeat transplantation (if the patient is a candidate), an especially difficult outcome given the scarcity of donor hearts and the added risks of retransplantation.
Our understanding of CAV at the cellular and molecular level is limited. Given its apparent similarity to atherosclerotic disease, the disease is currently treated with statins (which lower cholesterol) and mTOR inhibitors (similar to those drugs that coat coronary stents), with limited success. A more detail molecular understanding of this disease was critically needed to extend the life of these transplanted hearts and extend Dr. Shumway’s legacy. In a new manuscript in Nature Cardiovascular Research, “Single Cell and Spatial Transcriptomics Identify Immune-Stromal Interactions in Cardiac Allograft Vasculopathy,” a cross-center collaborative effort co-led by groups at Stanford, Washington University St. Louis, and Univerisity of Colorado, investigated the cellular and molecular drivers of CAV. The study reflects a multi-institutional collaboration with critical contributions from Stanford Cardiovascular Institute researchers and Stanford School of Medicine collaborators, including Paul Cheng, MD, PhD, and colleagues in cardiovascular medicine and cardiothoracic surgery.
A particularly unusual and powerful aspect of this study was the team’s ability to directly analyze coronary arteries from explanted human hearts from Stanford, comparing arteries from patients with CAV to arteries from patients with coronary artery disease and to non-diseased control arteries. This allowed the researchers to ask not only what changes occur in CAV, but which changes are specific to transplant vasculopathy rather than shared across vascular disease more broadly. Using single-cell RNA sequencing, they measured gene activity in individual cells. Using spatial transcriptomics, they mapped those molecular signals back onto the architecture of the artery. Together, these approaches allowed the team to define a transcriptional signature of CAV, a disease-specific pattern of active genes and cell states that acts like a molecular fingerprint. Instead of only showing that the artery is thickened, this approach reveals which cells are present, where they are located, how they may communicate, and which inflammatory programs may be driving the damage.
The analysis revealed that CAV is driven by close interactions between immune cells and stromal cells within the neointima, the abnormal new inner layer of the vessel wall that narrows the artery. The researchers found that modulated vascular smooth muscle cells and macrophage subsets were dominant within this diseased region. Smooth muscle cells appeared to shift away from their normal vessel-supporting role into a more inflammatory, proliferative, and remodeling state, while macrophages expressed genes linked to type 1 interferon signaling. Importantly, this interferon-driven program was more prominent in CAV than in coronary artery disease or control arteries, suggesting that CAV is not simply coronary artery disease occurring in a transplanted heart, but a distinct immune-vascular disease process. Spatial mapping showed macrophages and modulated smooth muscle cells in proximity in the neointima, supporting the idea that these cells interact to sustain inflammation and progressive vessel narrowing.
Cardiac allography vasculopathy narrows the arteries of transplanted hearts.
Created with LLM
Importantly, the study moved beyond identifying a molecular signature by testing this pathway in a mouse model of CAV. Blocking JAK signaling with ruxolitinib, an inhibitor that reduces interferon-related inflammatory pathways, decreased the incidence and severity of CAV and prolonged allograft survival. These findings point to interferon signaling, specifically, macrophage-smooth muscle cell communication, as a potential therapeutic target. For transplant patients, the promise is not only a better understanding of why CAV develops, but also a path toward therapies designed to protect the transplanted heart for longer. By combining rare human tissue, advanced genomic technologies, and experimental validation, this work provides an important foundation for strategies that may improve long-term allograft survival and reduce the need for repeat transplantation in a setting where every donor heart is precious.
This is a great example of cross-center collaboration between three different groups to help solve a critical clinical need. Additional Stanford University collaborators who enabled this multidisciplinary effort include Daniel Li, Wenduo Gu, and Karim Sallam with the Division of Cardiovascular Medicine, and Albert Pedroza, Alex Dalal, Jack Boyd, and Joseph Woo in the Department of Cardiothoracic Surgery.
Paul Cheng, MD, PhD