Long-term Effects of Immunosuppressive Drugs on Human Hearts

By Amanda Chase, PhD
April 28, 2022

More than 6 million Americans are living with heart failure, and about 10% of those individuals have advanced heart failure. This end-stage of heart failure means that typical heart therapies and symptom management are no longer working. For patients with end-stage heart failure, heart transplantation remains the key therapy. There are over 5,500 heart transplants performed annually. A critical piece to successful transplantation is the use of immunosuppression strategies, along with developing methods to decrease long-term co-morbidities. As patient survival time after heart transplant increases, there is an increased need to understand how immunosuppression drugs could have unintended effects long-term, especially on transplanted heart function.

A team of Stanford Cardiovascular Institute researchers, led by first and corresponding author Karim Sallam, MD, and senior author Joseph C. Wu, MD., PhD, specifically looked at the long-term cardiovascular effects of two immunosuppression drugs: tacrolius and sirolimus. Their findings were recently published in Circulation.

The team used a unique combination of clinical observations and human induced pluripotent stem cells (iPSCs) assembled in a three-dimensional way to more closely resemble an organ (i.e., “human cardiac organoids”). They were able to look at changes in the left ventricular (LV) mass of patients between 6-30 months after transplantation, grouped by type of immunosuppression drug (tacrolimus or sirolimus). Interestingly, they found a reduction in LV mass over time in those treated with sirolimus but not tacrolimus. This is important because an increase in the LV mass is a feature that can contribute to graft dysfunction over time.

They then moved into the human cardiac organoid model to understand what contributed to the changes in LV mass, and to assess drug-specific responses to each immunosuppressive drug that could explain the differences observed in patients. They observed that tacrolimus caused changes in gene expression associated with increased fibrosis (scar tissue formation) compared to sirolimus in cardiac fibroblasts. Cardiac fibroblast cells are the heart cells responsible for forming the scaffold that supports the structure of the heart. Excess secretion and change in the composition of proteins that form the scaffold can result in scar formation and adverse remodeling that leads to heart dysfunction. The authors then confirmed that cardiac fibroblasts treated with tacrolimus secreted more scar tissue protein (collagen) compared to sirolimus. This evidence supports the premise that sirolimus may be associated with less risk of damage to the transplanted heart (graft dysfunction).

Overview of the progression from iPSCs to cardiac organoids to show that sirolimus use is associated with decreased fibrosis than tacrolimus.

The results of this study may offer supporting evidence to clinicians in selecting immunosuppressive drugs for transplant patients. It also provides a framework to understand fibrosis as an important mechanism of immunosuppressive drug-induced changes in transplanted hearts. Lastly, the study delivers a platform for future studies to find more targeted immunosuppression approaches that also promote favorable cardiac remodeling to avoid graft dysfunction.

Other Stanford Cardiovascular Institute affiliated authors include Dilip Thomas, Nicole Kopex, Amiee Beck, Albert J Rogers, Hao Zhang, Ian Chen, Mohamed Ameen, June-Wha Rhee, and Nazish Sayed. Other Stanford researchers include Sadhana Gaddam, Leila Beach, William Hiesinger, Jeffrey Teuteberg, and Kevin Wang.

Dr. Karim Sallam

Dr. Joseph Wu