EXPERIMENTAL AND CLINICAL TRANSPLANTATION

After the first successful cardiac transplant by Christiaan Barnard in 1967, heart transplant remains the gold standard therapy to improve survival and quality of life in patients with end-stage heart failure. The major limitation of cardiac transplant is the availability of donor hearts all over the world. Because the number of grafts is insufficient to cover increasing demands for transplant, it is necessary to expand the alternative sources of cardiac grafts for transplant. For cardiac transplant recipients, the conventional and legal route for donor procurement is donation after brain death (DBD). In the recent decade, heart transplant with donation after circulatory death (DCD) (also called non-heart beating donation) has become a very promising option to increase graft availability.¹ The short-term and mid-term results for recipient survival and rejection episodes are comparable to the results of conventional DBD.

The incidence of organ DCD is increasing; however, the use of hearts has lagged behind the use of other solid organs. New ex vivo perfusion devices and solutions may increase the recovery rates of heart DCDs. Donation after circulatory death is a simple, less expensive, familiar, cardiac function-preserved method. In addition to these advantages, there are also some significant limitations (such as shorter storage times, requirement of staff training, some social and ethical points of reanimating a heart in a person pronounced dead). It is necessary to redefine the criteria and/or parameters of organ DCD.² The incidence of organ DCD is increasing; however, the use of the heart has lagged behind other solid organs. New ex vivo perfusion devices and solutions may increase heart DCD recovery rates. Some biomarkers (especially B-type or brain natriuretic peptide [BNP]) can be used to indicate donor heart status and early posttransplant performance in recipients after cardiac transplant.

In DCD heart transplant recipients, some mitochondria-related parameters (mitochondrial damageassociated molecular patterns [mtDAMPs], including ATP, cytochrome c, mitochondrial DNA, and succinate) are released at different stages after cardiac DCD, and these are accepted as promising stress-induced biomarkers. These mtDAMPs are released after onset of ischemia and increase with reperfusion. Serial mtDAMP measurements (especially cytochrome c and succinate) may indicate graft quality and may provide information on graft suitability for transplant. However, further prospective clinical trials are needed to confirm the clinical validity of these biomarkers. With wide adoption of heart DCD transplant, there can be a substantial expansion in the donor pool size in the near future.

Approximately 55 years ago, Dr. Christiaan Barnard performed the first human to human heart transplant in Cape Town, South Africa. After this first successful operation, heart transplant has become the gold standard therapy to improve survival and quality of life in patients with end-stage heart failure.³ The donor for the first heart transplant was a female patient who sustained lifethreatening injuries, including brain damage, from a motor vehicle accident. Her survival was deemed not possible by the medical team. The recipient was a male with advanced ischemic cardiomyopathy. According to the International Society of Heart and Lung Transplantation data, there have been more than 140 000 heart transplants, reported from 390 international transplantation centers. Despite more than 250 000 patients listed as candidates for heart transplant annually, the number of heart transplant surgeries has increased only 4.2% annually.⁴

The first heart transplant had no legal definition of the organ donor. In 1968, the United States passed a uniform determination of death act, which allowed organ donation from people with irreversible complete and permanent brain damage (designated as DBD donors).⁵ Brain death is the development of catastrophic intracranial pressure elevation, leading to loss of brainstem function due to ischemia, infarction, hemorrhage, or herniation.⁴ Brain death is a clinical diagnosis characterized by the total and irreversible loss of function of the whole brain, including the cerebral cortex and the brainstem. The diagnosis requires demonstration of the absence of both cortical and brainstem activity. Brain death also causes some hemodynamic and neurohumoral disturbances in the body. Systemic hypertension, tachycardia, increased systemic vascular resistance, and progressive hypotension cause massive organ hypoperfusion. In addition, plasma catecholamine levels increase; thyroid hormones, vasopressin, cortisone, and insulin levels decrease; and substitution therapies must be started to control the pathway from brain injury to hemodynamic instability and damage to vital organs. The apnea-hypercapnia test, cerebral angiography, electroencephalography, transcranial Doppler ultrasonography, and cerebral scintigraphy may be necessary for confirmation of DBD.

This legalized option of organ donation has resulted in thousands of lives saved for organ recipients; however, because of the unmet recipient transplant needs, other potential organ donors were sought, including DCD donors. In accordance with the current definitions of DCDs and DBDs, those early cardiac transplants can be labeled as transplants from DCD donors, but that distinction or designation was then nonexistent.

There are some distinctions between DBD and DCD heart donors⁶: (1) DCD donors do not have complete loss of brain function, (2) because of the futile nature of illness, withdrawal of life support is required to pronounce death in the person, (3) warm ischemia of varying duration based on cardiorespiratory reserve of the donor to all organs (including heart) is inevitable, and (4) the amount of permanent damage to donor organs and their potential for recovery of function are unknown.

Quader and associates summarized the process and timelines for DBD and DCD donor heart procurement.⁶ Warm ischemic time and cold ischemic time are 2 important parameters involved in heart DCD and ex situ perfusion.

Expansion of the donor pool requires some new definitions of extension in the criteria of donors, including clarity on new organ perfusion systems, prolongation of cold ischemic time, donor procurement from documented coronary heart disease, left ventricular dysfunction, and increased donor age.⁷ New antiviral agents and the presence of preformed HLA antibodies may also help to extend the criteria in donor selection.

Quader and associates⁶ summarized some small trials related to heart transplants with DCDs. In up to 1 year of follow-up, mortality rates varied from 0% to 8%.

To expand the pool of heart donors, Suarez-Pierre and associates reported that it was possible to increase the donor pool by approximately 21% with heart DCDs.⁸ In heart DCD transplant, some donor-related factors may cause rapid and severe cardiac damage and poor posttransplant prognosis (such as increased levels of circulating catecholamines, severity of hemodynamic instability, prolongation of warm ischemia). Although coronary blood flows and serial serum lactate levels can be used to evaluate the donor heart, their sensitivity is unsatisfactory. Therefore, there is an urgent need to identify new biomarkers for graft evaluation.^9,10

Some biomarkers, including high-sensitive troponin T, soluble suppression of tumorigenicity, and BNP, can provide important diagnostic and prognostic information on the donor heart after transplant. It becomes possible to evaluate donor heart status and early posttransplant performance and mortality in recipients after cardiac transplant.¹¹

Cellular stress and ischemia may cause ischemia/ reperfusion damage in the cell, including the mitochondria. In heart DCD transplant recipients, measurement of mtDAMPs released after the onset of ischemia, which increase with reperfusion, may indicate graft quality and provide information on graft suitability for transplant. Circulating mtDAMPs were recorded in some preclinical and clinical trials. Longnus and associates summarized the results of these trials.^9,12-15

In both DBDs and DCDs, mtDAMPs are elevated compared with levels shown in living donors. These elevations were significantly correlated with proinflammatory cytokines. Early graft dysfunction after liver transplant was associated with higher levels of circulating mtDAMPs. In kidney transplant recipients, donor mtDNA independently indicated early graft dysfunction. In cardiac transplant, mtDAMPs can be used to indicate early reperfusion injury. Although there are no clinical data on mtDAMP release during ex situ heart perfusion of DCD hearts, published data are available on circulating mtDAMPs measured in patients with acute myocardial infarction and cardiac arrest, which represented ex situ heart perfusion conditions.¹⁶ Commercial kits for the detection of circulating cytochrome c and succinate are also available.⁹

At the beginning of the warm ischemic period, systemic release of mtDAMPs occurs first and then cardiac mtDAMPs are released, thus showing the possibility of mtDAMP as a biomarker of graft viability. In addition, mtDAMPs are also called biomarkers of DCD heart quality. Circulating levels of cytochrome c and mtDNA positively correlate with markers of myocardial ischemic injury assessed after reperfusion. In addition to serial mtDAMP measurements (especially cytochrome c and succinate) indicating graft quality, mtDNA may also predict patient survival after circulatory arrest. Donor BNP may provide information about early posttransplant performance and early mortality.¹¹

In conclusion, for cardiac transplant, the conventional and legal route for organ procurement is DBD. The major limitation of cardiac transplant is availability of donor hearts. It is necessary to expand the alternative sources of cardiac grafts for transplant. Donation after circulatory death is a simple, less expensive, familiar, cardiac functionpreserved alternative method. It is necessary to redefine the criteria and parameters for organ DCD. Further prospective clinical trials are needed to confirm the clinical validity of potential biomarkers. A wide adoption of heart DCD transplant can result in an expanded donor pool.

Volume: 20 Issue: 8 August 2022 - Supplement - 4

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