Cardiac transplantation is the most effective treatment for end-stage heart failure (HF) that is refractory to other therapies, not only increasing survival but improving patients’ quality of life.1–3 However, there has been a marked decrease in the number of donors, which is the main limitation to transplantation. This has led to a widening of the selection criteria in recent years to include older donors and those who have died of neurological causes, frequently with other diseases and/or cardiovascular risk factors.3,4

At the same time, progress in medical treatment of advanced HF has led to improvements in patients’ clinical condition, delaying their entry to the transplantation waiting list. New inotropic and vasodilator agents, cardioverter-defibrillators and resynchronization devices, temporary mechanical circulatory support systems, and the widening of indications for conventional surgery, as well as the establishment of HF intensive care units, have helped to control recurrent HF crises, all of which improve survival but have little effect on patients’ quality of life.5–8 Transplantation thus remains the last resort for patients who do not respond to these new therapies and technologies, and referral rates have not fallen.1,4,6

The cardiac transplantation program at our center began in November 2003. Overall results of the first five years of activity, in terms of morbidity, mortality, survival and quality of life, have been published in a detailed report in the Journal.9 In the present study, we aim to extend this analysis to 10 years and to assess the experience gained.

Cardiac transplantation is established as an effective treatment for end-stage HF that is refractory to other therapies. However, it is associated with a series of serious complications, some potentially fatal, which means it is essentially a palliative measure in the medium to long term. Ten-year survival is currently 50–60% and mean survival for those who survive the early post-transplant period is 12–13 years.1,3

The heart transplantation program of the University Hospital of Coimbra began in November 2003. Data on the first five years of activity were presented and analyzed in a report published in the Journal,9 which also presented a summary of the history and other aspects of cardiac transplantation in Portugal, including its place in the European context, and so this will not be addressed further here.

In the present study we analyze the results obtained in 258 patients transplanted in the first 10 years of the program. There were thus an average of 25 transplants per year, which fulfills the program's overall objective and makes it the largest accumulated experience of any Portuguese center. This high volume of activity is bound to have an impact on post-transplantation outcomes, particularly in cases of greater urgency and/or higher risk; the relationship between volume and quality in transplantation is well established.10–12 Furthermore, the experience acquired has allowed a widening of indications, the exploration of alternative techniques and the use of marginal donors, expanding the frontiers of organ acceptance and use.

There has been a progressive increase in both the mean age of recipients and the number of patients hospitalized for decompensated HF at the time of transplantation, requiring intensive drug therapy and in some cases mechanical circulatory and ventilatory support. The result is a growing number of recipients in poor clinical condition, which increases not only the urgency of the transplantation but also the risk of failure. This is further exacerbated by the scale of priorities for cardiac transplantation used in Portugal, initially implemented by the Portuguese Transplantation Organization, which was replaced by the Authority for Blood and Transplantation Services and then the Portuguese Blood and Transplantation Institute (Table 7), which is based on the candidate's clinical status on entering the waiting list, and thus means that more critical patients move ahead of those whose clinical condition allows them to wait for longer. However, this scale – and others like it in other countries – neither defines nor quantifies patients’ risk profile. The immediate results of transplantation are known to be highly sensitive to the quality of the donor organ and the candidate's clinical state.13,14 These are the main factors responsible for some unsatisfactory outcomes in the immediate post-transplant phase.15,16

Patients with lower priority, on the other hand, benefit from their home environment and family support, as well as greater mobility, which improve their psychological and physical state and lead to a marked reduction in the incidence and severity of post-transplantation nosocomial infection. These factors undoubtedly reduce these patients’ risk.17 However, Lietz and Miller5 and Mokadam et al.18 have shown that 32–48% of UNOS status 2 candidates, equivalent to the Portuguese degree VI–VII, suffered clinical deterioration while on the waiting list (UNOS, the United Network of Organ Sharing, is a private organization that manages the US organ transplant system). At the time of transplantation, patients in this group may therefore be in poor clinical condition, with intermittent instability, recurrent decompensation, or chronic persistent symptoms frequently associated with high morbidity.2

Another high-risk group is diabetic patients. As would be expected among transplant candidates, over a quarter (27.9%) were diabetic at the time of transplantation, while 29 (11.27%) developed new-onset diabetes in the first year. The relationship between immunosuppression, especially with corticosteroids and tacrolimus, and worsening or development of new-onset diabetes is well known, and diabetes is one of the main risk factors for arteriosclerosis involving the coronary arteries as well as the systemic circulation.19 In a previously published work, we found no significant differences in morbidity or mortality between diabetic and non-diabetic transplantees up to five years after the procedure,20 but this appears to change in the longer term.21

Diabetes is also an important factor in the genesis and propagation of infections, which are now the leading cause of late morbidity and mortality following transplantation, rather than acute rejection, which nowadays is rarely fatal. In our series, 43 patients (16.7%) developed serious infections in the first year, mostly pneumonia, requiring hospitalization and intravenous antibiotic therapy. Infection was the main cause of late mortality, followed by vascular and neoplastic complications. This is likely due to excessive immunosuppressive therapy; some centers report excellent results with considerably less aggressive immunosuppression protocols than standard regimens.22 The protocol initially used in our center has recently been modified, but it is too soon to assess the effect of this change on the main complications of transplantation.

Commonly associated with chronic rejection is GVD, the etiology and natural history of which are little understood. GVD appears late, generally after five years, and results in progressive severe graft dysfunction, leading to total loss and death unless the patient is retransplanted, which rarely occurs.23 Unusually, most cases of GVD in our series were diagnosed within three years of transplantation. When diagnosed early, the evolution of GVD can be significantly slowed by changing the immunosuppression protocol, particularly by introducing the mTOR inhibitors sirolimus and everolimus.

In an attempt to increase the number of donors, age limits have been progressively raised. The use of older donors does not appear to be as important as might be expected; in another study based on our experience, we showed similar survival in recipients of hearts from older donors, even in young patients. Donor age, at least up to sixty years, thus appears not to be a limiting factor.24–27 It is, however, recommended to minimize ischemia time in such hearts,28 and we therefore prefer donors referred by institutions closer to our center.

Another way to increase the supply of donors is to use hearts with minor structural abnormalities that can be corrected. Twelve patients in our series received hearts with mild to moderate mitral disease, all of which were known before harvesting except in one case that was corrected before transplantation, while two patients underwent tricuspid annuloplasty. In addition, two patients underwent surgical revascularization of the anterior descending artery, one with the mammary artery used in a previous surgical revascularization. Some of these cases have been described in previous publications.29,30 All these patients are currently well, with no complications related to these procedures, except for one who died of stroke a few weeks after transplantation.

There was a female donor–male recipient gender mismatch in 17% of our cases. Such mismatches are often associated with worse outcomes,31 but in our series there were no significant differences in complications or mortality in cases of gender mismatch, and so it is not taken to be a reason for donor rejection so long as other selection criteria, such as morphological matching (weight and BMI) are met.

Survival was 87% at one year, 78% at five years and 65% at 10 years, which compares favorably with the results of other series, including the ISHLT registry of more than 100 000 cases,1 although the latter began much earlier. It is perhaps too early to draw conclusions, since the decline in survival curves appears to become steeper after the first 10 years due to late complications such as GVD and cancer, as well as progressive deterioration in renal function.

Worsening renal function caused by drug toxicity is common in cardiac transplant patients.32,33 Preoperative creatinine levels fell in the first month following transplantation, but then rose progressively up to the end of the first year, exceeding initial values. In most cases they remained relatively stable during the first five years, but thereafter many patients suffered significant renal deterioration in renal function. Three patients have undergone renal transplantation and two others are under renal replacement therapy while awaiting transplantation.

The number of patients awaiting cardiac transplantation is growing, unlike the supply of donors. The situation is exacerbated by the increase in the number of candidates with worsening clinical status (degrees of priority II–V). This has led on one hand to a widening of the frontiers of organ donation and on the other to more careful and pragmatic candidate selection.

Transplantees generally derive great benefit from cardiac transplantation in terms of both quality of life and increased longevity. However, a considerable number suffer severe complications, some of them fatal, and so continuous monitoring and care are essential. This places a major burden on transplant teams, and requires a specific organizational structure. For this reason, and because outcomes are heavily dependent on level of experience, cardiac (and indeed other forms of) transplantation should be limited to centers with a reasonable level of activity, and should on no account be dispersed.

Demand in this area in Portugal is currently met to a reasonable extent, but the number of centers is probably excessive for the population served. We thus recommend a reappraisal of the situation, in order to ensure the quality of care for patients with end-stage heart failure that is refractory to conventional, conservative therapies. The current competition for donors does not serve the goal of appropriate distribution between patients on the waiting list in different transplantation centers.

The fall in donor numbers in recent years may change the relatively favorable situation which we have enjoyed in the 10 years since our transplantation program began. However, actions to raise awareness and reorganization of the ways that donors are identified and registered are already having an effect. In 2013, which may come to be seen as a turning-point in all areas of transplantation, 30 patients were transplanted in our center alone, a figure that had previously only been attained in 2005. Nevertheless, we still have a long way to go before reaching our maximum potential.

The authors have no conflicts of interest to declare.