In order to improve quality of life and patient survival, we must be able to predict, which transplants are doomed to be lost and which recipients will face an untimely death. We aim to establish biomarkers for transplant dysfunction and the side effects of immunosuppressive drugs based on peripheral blood samples and transplant biopsies and employing both classical pathology and new precision medicine tools integrated with electronic health records and eHealth. Moreover, to address the unmet need for heart and lung transplants, we will develop treatment algorithms for the utilization of marginal donors and organs from non-heart beating donors for heart and lung transplantation.
Heart and lung transplantation are the primary life-saving treatment options for patients diagnosed with either end-stage heart or lung diseases, respectively. The first successful heart transplantation was performed at Groote Schuur Hospital, Cape Town, South Africa in 1967 and the first successful lung transplantation in Toronto General Hospital, Toronto, Canada in 1983. With advances in surgical techniques, intensive care, control of infection diseases, and the discovery of calcineurin inhibitors, heart and lung transplantations have become a plausible treatment for many end-stage heart and lung diseases. According to the International Society of Heart and Lung Transplantation, the average life expectancy is 11.9 years after heart transplantation and 7.3 years after lung transplantation.
Heart transplantation remains the optimal treatment for end-stage heart failure. However, the number of heart transplantations is limited by a critical shortage of donor hearts. Therefore, hearts from marginal donors are increasingly used. As a consequence, the transplant may be exposed to increased danger of primary graft dysfunction and early mortality. And despite progress in immunosuppression, acute rejection still constitutes a significant risk for early morbidity and mortality. Additionally, the life-long need of taking immunosuppressive medication exposes the patient to metabolic side-effects, infections, and malignancies. Last but not least, long-term survival is limited by chronic rejection leading to cardiac fibrosis and cardiac allograft vasculopathy (CAV).
The surveillance of acute rejection is based on histological analysis of endomyocardial biopsies (EMB), taken 8-12 times during the first year. EMB has a false negative rate of 10-20% related to sampling error, artefacts, and misread pathology. In addition, EMB only provides a very restricted perspective of the transplant and does not yield any information on the underlying cellular, vesicular, and molecular mechanisms.
Although annual surveillance with coronary angiography is considered the standard of care to detect CAV, it lacks the sensitivity of intravascular ultrasound for detection within the first year, which is an independent risk predictor of death at 5 years. Both, EMB and coronary angiography are invasive and potentially risky procedures, and they lack predictive value.
In our recent break-through prospective, randomized, single-center clinical trial (SIMVA) donor simvastatin treatment decreases plasma biomarker levels of myocardial injury and heart failure, and reduces the number of acute rejection episodes with hemodynamic compromise early after transplantation (Nykänen et al 2019). Next generation sequencing analysis of heart transplant biopsies showed that donor simvastatin treatment altered the expression of genes related to a variety of cell functions and responses, including leukocyte migration, inflammatory response, chemokine receptors and adhesion molecules, cellular response to oxidative stress, and platelet activation during reperfusion. Based on our SIMVA study, SIGNET study (Statins for improving organ outcome in transplantation), the largest randomised controlled trial in organ donation with 2600 organ donors to be recruited, commenced in UK in September 2021 (nhsbt.nhs.uk).
To date, there are no accurate and reliable biomarkers available to evaluate donor heart quality before transplantation, to optimize donor management, or to predict the development of PGD and acute and chronic rejection in the recipient. Evaluation of both the donor and the recipient is of critical importance to improve organ allocation and to develop specific treatments. Therefore, a detailed cellular, vesicular, and molecular understanding of the complex interactions between donor and recipient, i.e., between heart transplant and host immune system, is needed to improve the results of heart transplantation. This could reveal novel biomarkers to (1) improve organ allocation and recipient access to transplantation; (2) allow tailored individualized immunosuppression that would minimize both the risk of rejection as well as the side-effects of immunosuppressive drugs; and (3) distinguish novel therapeutic targets for modification of innate and adaptive immune responses and pathological fibroproliferation after heart transplantation.
The objectives of our research are to
(i) understand the complex cellular, vesicular, and molecular interactions between the donor and the recipient in PGD and acute and chronic rejection;
(ii) develop biomarkers for organ allocation, PGD, and acute and chronic rejection;
(iii) develop innovative donor and recipient therapies and possible new drug targets;
(iv) develop predictive computational models for integrated longitudinal high-quality clinical multi-omics, digital imaging of endomyocardial biopsies, and magnetic resonance imaging data;
(v) to create a single cell transcriptome atlas of “healthy” and transplanted hearts by combining data from preclinical and clinical heart samples in order to analyze the spatial and temporal cell-specific changes of gene expression that lead to allograft failure.