Heart transplantation in adults: Prognosis

INTRODUCTION — Cardiac transplantation remains the treatment of choice for many patients with end-stage heart failure with severely impaired functional capacity despite optimal medical therapy. Although barriers to long-term survival remain, survival among transplant recipients has improved over several decades as a result of careful recipient and donor selection, advances in immunosuppression, and the prevention and treatment of opportunistic infections. (See "Heart transplantation in adults: Indications and contraindications" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

Survival in adults after orthotopic heart transplantation, retransplantation, and combined organ transplantation will be reviewed here. Additional information regarding the indications for cardiac transplantation and treatment following transplantation is presented separately. (See "Heart transplantation in adults: Indications and contraindications" and "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy" and "Heart transplantation in adults: Diagnosis of allograft rejection" and "Heart transplantation in adults: Treatment of rejection".)

OUTCOME AFTER HEART TRANSPLANTATION — The most comprehensive information regarding patient survival after thoracic organ transplantation comes from data collected by the International Society for Heart and Lung Transplantation (ISHLT). This database includes data from over 140,000 cardiac transplants performed worldwide since 1982 by more than 480 transplant programs. Although center-specific data may vary, survival figures from data like the ISHLT registry are often quoted when providing patients with realistic expectations regarding survival after transplantation. For additional information, see the slides Adult Heart Transplantation Statistics.

Survival — For patients undergoing heart transplantation, one-year survival is approximately 90 percent in North America and approximately 80 percent in Europe and other regions of the world that report heart transplantation outcomes to the ISHLT [1]. Median survival is greater than 12 years [2].

Determinants of prognosis — A number of recipient and donor factors are associated with prognosis after heart transplantation.

Recipient factors — Among patients who underwent heart transplantation between January 2010 and June 2017, the need for end-organ support with extracorporeal membrane oxygenation and mechanical ventilation conferred the greatest risk of one-year mortality. Additional risk factors include the use of bridging ventricular assist devices, hospitalization at the time of transplant, and prior cardiac surgery (figure 1).

Patients who undergo transplantation for congenital heart disease, restrictive cardiomyopathy, valvular cardiomyopathy, ischemic cardiomyopathy, hypertrophic cardiomyopathy, and those undergoing retransplantation have lower one-year survival when compared with patients who undergo transplantation for nonischemic cardiomyopathy [1]. Patients with congenital heart disease, restrictive cardiomyopathy, and prior heart transplantation have the lowest survival (figure 1).

When adjusted for other factors, recipient characteristics that are commonly associated with increased one-year mortality include both younger and older recipient age, reduced estimated glomerular filtration rates, elevated total bilirubin levels, elevated pulmonary vascular resistance, and elevated panel of reactive antibodies at the time of transplant [1].

Finally, the severity of illness prior to transplantation is typically a predictor of adverse outcomes. The acuity of illness at the time of transplant is largely determined by patient factors and the ability of centers to successfully manage critically ill patients with therapies that include inotropes and temporary mechanical circulatory support devices until transplantation can occur. In one study that included patients listed for emergent heart transplantation in the Spanish National Heart Transplant Registry database, recipients meeting the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 criteria (critical cardiogenic shock) and profile 2 criteria (progressive clinical decline despite treatment with inotropes) had the highest risk of primary graft failure, dialysis requirement, and in-hospital mortality following heart transplantation [3].

Donor factors — The following donor factors are commonly associated with posttransplantation survival:

●Age – Increasing donor age is consistently associated with lower posttransplant survival, and most of the effect is seen within the first month posttransplantation. In a report from the ISHLT Registry, survival was highest in adult heart transplant recipients whose donors were younger than 35 years of age and lowest in recipients whose donors ≥50 years of age [1,4].

●LV dysfunction – The presence of left ventricular (LV) dysfunction, defined as an LV ejection fraction of <50 percent, particularly when combined with a graft ischemic time of ≥4 hours, has been associated with lower one-year posttransplant survival [4].

●Female donor to male recipient – Transplantation of a female heart into a male recipient, compared with a male heart into a male recipient, has also been associated with worse one-year survival [1].

●Donor-to-recipient size mismatch – Transplantation of a donor heart into a relatively larger recipient has been shown to negatively affect one-year survival. In an analysis of the United Network for Organ Sharing registry for transplants occurring between 2007 and 2016, recipients of a severely undersized heart, defined as a donor-recipient predicted heart mass ratio less than 0.86, had inferior one-year posttransplant survival compared with recipients of less undersized or oversized hearts [5]. Of note, the effect of donor-recipient size mismatch on posttransplant outcomes was not seen when donors were undersized for weight, height, body mass index, or body surface area, suggesting that predicted heart mass may be a better marker of size match.

Patients undergoing mechanical circulatory support as a bridge to transplant — Approximately 55 percent of patients undergoing heart transplantation are now bridged to transplant with a mechanical circulatory support (MCS) device [2]. The majority (50 percent) of patients undergoing MCS prior to transplant receive an LV assist device (LVAD), while the use of right ventricular assist devices, biventricular assist devices, and the total artificial heart remains relatively small (approximately 5 percent). Although LVAD use historically conferred a worse post-transplant prognosis, patients bridged to transplant with an LVAD between 2009 and June 2016 had comparable post-transplant survival to those supported to transplant with inotropes. The improved outcomes among patients supported with LVADs likely reflect the current practice of delaying transplantation after an LVAD implant to allow functional rehabilitation and recovery of end-organ function. By contrast, patients requiring extracorporeal membrane oxygenation (ECMO) support have considerably worse survival than those bridged to transplant with other forms of MCS [2]. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device".)

Causes of death — There are four major causes of death after cardiac transplantation:

●Graft failure – Primary graft failure accounts for the majority of mortality within the first 30 days after transplantation. It may be immediately apparent in the operating room or present within the first 24 hours after allograft implant. The syndrome is thought to be caused by a heterogeneous group of etiologies, including donor-related factors (preexisting donor myocardial dysfunction or catecholamine-induced myocardial injury), preservation injury, and transplant-related factors (air embolism, cardioplegia, or delayed reperfusion injury), and recipient related factors such as unrecognized pulmonary arterial hypertension. Graft failure occurring after the first week posttransplantation typically results from either acute rejection or cardiac allograft vasculopathy (CAV).

●Opportunistic infections – Infections are the leading single cause of death between six months to one year posttransplant. The types of infection in these patients are diverse, including common, community-acquired bacterial and viral diseases and uncommon opportunistic infections of clinical significance only in immunocompromised hosts [6,7]. The risk of infection in the heart transplant patient is determined by a semiquantitative relationship between two factors: the epidemiologic exposures of the individual and the "net state of immunosuppression," which is a measure of all of the factors that contribute to the individual's susceptibility (or resistance) to infection. (See "Infection in the solid organ transplant recipient".)

●Acute allograft rejection – Cellular and antibody-mediated rejection represent an important cause of death within the first three years after transplantation, accounting for approximately 10 percent of deaths during this period. Thereafter, the incidence of death related to allograft rejection declines. (See "Heart transplantation in adults: Diagnosis of allograft rejection".)

●Cardiac allograft vasculopathy – The incidence of CAV increases steadily after transplantation, and it is among the top three causes of death beyond the first year posttransplantation. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy" and "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

●Lymphoma and other malignancies – Malignancy is the most frequent cause of death beginning at five years post-cardiac transplantation. Analyses of multiple databases have shown that malignancies (both lymphoma and solid tumors) are more common in heart compared with renal transplant recipients, probably due to the overall need for more intense immunosuppression. (See "Treatment and prevention of post-transplant lymphoproliferative disorders" and "Malignancy after solid organ transplantation".)

Repeat cardiac transplantation — Given the factors limiting long-term graft survival, heart transplant recipients in a small and highly selected subset (approximately 3 percent of transplant recipients) are considered candidates for retransplantation. The incidence of retransplantation has remained constant worldwide at 2 to 4 percent of adult heart transplants performed since 1982. Overall, the outcomes after retransplantation are inferior to primary heart transplantation with 1- and 10-year survivals of 70 and 38 percent, respectively [8].

The prognosis after retransplantation is related to two important variables: the etiology of the graft failure leading to retransplantation and the interval between the first and second heart transplant. Patients retransplanted for CAV have the most favorable prognosis, whereas those retransplanted for primary graft failure have the worst prognosis, which is driven primarily by a very high mortality rate in the first year after re-transplant [8]. In a report of 514 patients, one-year mortality after retransplantation was also related to the time between the first and second transplant. Patients with an intertransplant interval of less than two years had inferior survival compared with those with longer intervals between transplants (60 versus 75 percent) (figure 2) [9].

HEART-LUNG TRANSPLANTATION — Heart-lung transplantation should be reserved for patients who cannot be treated by heart or lung transplantation alone. Suitable candidates include patients with severe, irreversible disease of the lung parenchyma or vasculature who also have severely compromised left or right ventricular function or other cardiac diseases that would preclude a successful outcome with lung transplantation alone. The two major causes among the small number of procedures that are performed are Eisenmenger syndrome associated with congenital heart disease and idiopathic pulmonary arterial hypertension with severe right ventricular failure. The outcomes in these patients are discussed separately. (See "Heart-lung transplantation in adults".)

HEART-KIDNEY TRANSPLANTATION — Simultaneous heart-kidney transplantation using allografts from the same donor is performed by some centers for patients with advanced heart failure and severely impaired renal function [10]. The number of heart-kidney transplants is steadily rising, with approximately 150 combined transplants per year (approximately 6 percent of all solid organ transplants) reported worldwide between 2015 and 2016 [2]. Single- and multicenter observational studies have demonstrated comparable short- and long-term survival with simultaneous heart-kidney transplantation compared with isolated heart transplantation. Additionally, patients who received combined heart-kidney transplants experienced fewer episodes of cardiac allograft rejection and lower rates of cardiac allograft vasculopathy [10,11].

There are two other issues related to impaired renal function and heart transplantation:

●Underlying moderate chronic kidney disease, defined as a stable plasma creatinine concentration above 2 mg/dL (177 micromol/L) or a creatinine clearance below 40 mL/min, is a relative contraindication to isolated heart transplantation. Part of the concern in this setting is the superimposed nephrotoxicity of long-term calcineurin-inhibitor therapy. (See "Heart transplantation in adults: Indications and contraindications", section on 'Relative contraindications' and "Cyclosporine and tacrolimus nephrotoxicity".)

●Renal transplantation may be performed as a later procedure to treat end-stage kidney disease that has developed after heart transplantation (see "Kidney function and non-kidney solid organ transplantation", section on 'Cardiac transplantation'). Among recipients of a kidney transplant after heart transplantation, kidney allograft survival was comparable to that of patients undergoing simultaneous heart and kidney transplantation [12].

HEART-LIVER TRANSPLANTATION — Approximately 20 to 30 combined heart-liver transplants are performed world-wide each year by a small number of transplant centers [2]. Among combined heart-liver transplants performed in the United States between October 1987 and February 2007, the most common indications for concurrent liver transplantation include familial transthyretin amyloidosis (30 percent), hepatitis C-associated cirrhosis (13 percent), hemochromatosis (13 percent), and cardiac cirrhosis (11 percent). Patient survival at one year, three years, and five years was 85, 80, and 76 percent and comparable to outcomes observed for single-organ liver or heart transplantation. Additionally, lower rates of rejection in the cardiac allograft were observed despite reduced levels of immunosuppression compared with isolated heart transplantation [13].

MEDICAL CONDITIONS AFTER CARDIAC TRANSPLANTATION THAT MAY AFFECT OUTCOME — Hypertension, hyperlipidemia, diabetes mellitus, and renal dysfunction are all noted in a significant proportion of cardiac transplant recipients. Among recipients of a heart transplant between January 1994 and June 2016, diabetes was noted in 35 percent of patients at five years, severe renal dysfunction (serum creatinine greater than 2.5 mg/dL [221 micromol/L]) in 13 percent, long-term dialysis in 3 percent, kidney transplant in 1 percent, and angiographic evidence of cardiac allograft vasculopathy in 29 percent [2]. Although no longer reported in the registry, hypertension and hyperlipidemia are noted in over 90 percent and over 85 percent of heart transplant recipients, respectively [2]. (See "Heart transplantation: Hyperlipidemia after transplantation" and "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)

Due to the requirement for life-long immunosuppression, malignancies are also commonly noted in heart transplant recipients, and the incidence increases over time. Among patients receiving their heart transplants between January 1994 and June 2016, malignancies were reported in 16 percent of patients at five years and 28 percent at 10 years. The most common types of cancer detected at five years included cutaneous malignancies (10 percent), followed by solid organ tumors (6 percent), and lymphoproliferative malignancies (1 percent) [2].

QUALITY OF LIFE AFTER TRANSPLANTATION — Data from the International Society for Heart and Lung Transplantation (ISHLT) indicate that over 70 percent of patients are able to perform normal activities of daily living without minimal to no symptoms. However, despite generally excellent functional capacity following cardiac transplantation, only 27 and 38 percent of recipients between the ages of 25 and 60 return to work at one and five years posttransplantation, respectively. In the United States, the discrepancy between functional status and employment may be in part related to the link between employability and insurability [2].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Heart transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Survival – For patients undergoing heart transplantation, one-year survival is approximately 90 percent in North America and approximately 80 percent in Europe and other regions of the world that report heart transplant outcomes to the International Society for Heart and Lung Transplantation (ISHLT). Median survival is greater than 12 years. (See 'Survival' above.)

●Causes of death – The major causes of early death (within the first year) after heart transplantation include primary graft failure, infections, and rejection. After the first year, deaths due to cardiac allograft vasculopathy (CAV), nonspecific graft failure, and malignancies are more common. (See 'Causes of death' above.)

●Repeat cardiac transplantation – Retransplantation represents a viable option for a very small group (approximately 3 percent of transplant recipients) of highly selected individuals with graft failure. Outcomes are inferior to those noted in primary heart transplantation but acceptable. Patients who are retransplanted for primary graft failure and those with an intertransplant interval of less than two years have a worse prognosis. (See 'Repeat cardiac transplantation' above.)

●Multi-organ transplantation – Highly selected patients undergoing combined heart-kidney and heart-liver transplants have short- and long-term outcomes comparable to those observed in primary heart transplantation. (See 'Heart-kidney transplantation' above and 'Heart-liver transplantation' above.)

●Quality of life – The majority of heart transplant recipients report excellent quality of life and functional status. (See 'Quality of life after transplantation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Allen S Anderson, MD, FACC, who contributed to earlier versions of this topic review.