Discussion
Survival after heart transplantation in Norway has increased over 40 years, from 11 years in the first decade to almost 15 years in the third decade. Median survival for the entire period was 13.4 years. The number of heart transplants per year has also risen, from a median of 24 in the period 6 November 1983 to 31 December 2005, to 32 between 1 January 2006 and 31 December 2023. Various types of cancer, together with chronic/progressive graft failure (including myocardial infarction/coronary artery disease, sudden death with known development of sclerosis and fibrosis in the graft) are the main causes of death.
Among the 346 centres that report annually to the International Society of Heart and Lung Transplantation (ISHLT) registry, most perform 10–19 heart transplants per year. Rikshospitalet is among the top 10 % performing 30 or more heart transplants annually (4). Having a single national centre with a high level of activity may have contributed to the favourable survival rates following heart transplantation in Norway, compared with international registries. The most recent ISHLT registry report shows a median survival of 11.3 years for adults in the period 1992–2017 (4), compared with 13.4 years among recipients in Norway. Outcomes have improved over time despite an increase in donor age, likely due to advances in immunosuppression, surgical techniques, anaesthesia and general transplant medicine. The fact that median survival continues to increase despite rising donor age and broader acceptance of donors with comorbidities ('marginal donors') suggests, however, that donor-related factors are less impactful than recipient-related factors.
Since our 2007 report, cancer has ranked alongside chronic/progressive graft failure as one of the most common causes of death following heart transplantation (2). This is consistent with international findings. As recipient age has not increased significantly, the increased cancer incidence may be attributed to better transplant care, leading to fewer cases of organ rejection and longer survival, with prolonged exposure to immunosuppressive therapy. Cardiomyopathy has now overtaken ischaemic heart disease as the most common underlying diagnosis. A lower age-adjusted incidence of coronary artery disease in the population – with fewer major infarctions, likely due to quicker and more effective interventions followed by improved pharmacotherapy – may have contributed to this shift. The geographical distribution remains relatively even, as in 2007 (2), while the proportion of female recipients has increased from 19 % to 24 %. Internationally, the ISHLT registry data shows 25 % female recipients.
Among European centres, the median donor age increased from 31 years in the period 1998–2000 to 45 years in the period 2010–18. Over the same period, the increase in donor age in North America was more modest, rising from 28 to 31 years. This trend can be partly explained by the ageing population and the limited supply of organs, leading to the acceptance of older donors. In the United States, the wave of opioid-related deaths may help explain why the increase has been significantly less pronounced (5). While all organ donations in this study were performed in accordance with Norwegian criteria for brain death, controlled donation after circulatory death (cDCD) has been introduced internationally as a supplementary method. Use of this approach offers the potential to increase the total number of transplants by 15–20 % (6). Randomised studies in heart transplantation show that six-month survival and complication rates with organs donated via this newer method are no worse than with conventional donation (7). Similar outcomes have been reported from centres with five years of experience (8). If we are to expand our activity and improve access to donor organs through circulatory death donation, the procedure must also be accepted for heart transplantation, and know-how and resources must be extended to all 28 donor hospitals in Norway.
Effective immunosuppression, including the discovery and introduction of calcineurin inhibitors, has been crucial for favourable outcomes after heart transplantation. However, these drugs have serious adverse effects that contribute to morbidity and can prevent further improvements in long-term survival. We have shown that renal function one year postoperatively is an independent predictor of survival and the development of graft sclerosis (9). Careful monitoring and dosing of tacrolimus/cyclosporine according to serum levels is essential to avoid nephrotoxic damage in patients, many of whom have renal impairment secondary to heart failure. In collaboration with other Nordic countries, we have introduced everolimus as an alternative treatment in patients with calcineurin inhibitor–induced renal failure (10). This treatment helps prevent progressive kidney damage, reduces early signs of graft sclerosis and lowers the incidence of cytomegalovirus infection. However, it is still not clear whether avoiding calcineurin inhibitors also decreases the risk of various types of cancer.
An evaluation of outcomes after heart transplantation should include more than just years of survival, and assessments of physical and mental quality of life have been central to our postoperative follow-up. Health-related quality of life improves significantly after surgery to levels comparable with the general population (11). Among a sample of 115 patients, improvement was still evident after 10–12 years of follow-up (11). However, in a survey of 147 patients more than five years post-transplant, depression (mainly mild to moderate) was found in 25 %, irrespective of lifestyle factors and somatic risk factors. At an average follow-up of six years, symptoms of depression were an independent predictor of death, highlighting a need for treatment (12). Compared with healthy controls, oxygen uptake one year after surgery was 60–80 % of the expected level (13). In a randomised study we conducted, supervised high-intensity interval training produced significantly greater and clinically relevant improvements in physical performance and muscle strength after nine months, compared with standard exercise (13). As self-reported physical health and maximal oxygen uptake are both strong predictors of survival among heart transplant recipients (14), patients are encouraged to remain physically active.
Retransplanted patients have experienced graft failure due to chronic rejection. Chronic rejection is an obliterative process that begins in the myocardial microvasculature and leads to diastolic dysfunction, followed by progressive systolic dysfunction. This low-grade form of rejection often manifests as vasculopathy, with angiographically visible deposits in the coronary arteries of the transplanted heart. It is the most common cause of late graft failure. Statins have been shown to reduce the incidence of graft sclerosis. In collaboration with our Scandinavian colleagues, we recently conducted a study in which we found that evolocumab, a PCSK9 inhibitor (proprotein convertase subtilisin/kexin type 9 inhibitor), despite significantly lowering circulating cholesterol levels, did not further reduce the extent of intimal thickening (15). These findings suggest that dyslipidaemia may be secondary to low-grade rejection and inflammation as the primary drivers of graft sclerosis.
Our results for retransplantation are in line with data from the ISHLT registry, where survival after second-time transplantation (data not shown) is almost the same as for first-time recipients (16). Outcomes are poorer in cases of early retransplantation due to primary graft failure or acute rejection, possibly due to acute immunological activation. Retransplantation is an ethical dilemma: some patients live longer thanks to a second donor organ, while others might die on the waiting list, never having had the opportunity for a first transplant. Internationally, several smaller centres therefore do not offer retransplantation.
A key strength of this study is the complete dataset covering all heart transplant recipients, with long follow-up and no loss to follow-up. Limitations include the retrospective nature of the analysis and a degree of uncertainty surrounding the causes of death.
The steadily improving survival rates following allograft heart transplantation (human-to-human grafts where the donor and recipient are genetically different) suggests that this procedure will remain an important treatment option for end-stage heart failure. The greatest challenges to further improvement lie in the chronic shortage of donor organs. There is a need to expand the supply of donors and ensure optimal utilisation of donated organs, improve and extend preservation of donor hearts after retrieval, develop safer pump technology to improve outcomes by serving as a temporary bridge to transplantation, and reduce long-term complications such as graft failure and cancer. Future alternatives may include artificial hearts and xenotransplantation (animal to human transplantation). The timeframe for when these might become viable alternatives to allotransplantation remains to be seen.