Long‐term survival after heart transplantation for cardiac sarcoidosis

Cardiac sarcoidosis is an increasingly common indication for a heart transplant, but there is a paucity of knowledge with regard to long‐term outcomes following transplant.


| INTRODUCTION
Cardiac manifestations of sarcoidosis are the second-most common cause of death among patients with sarcoidosis in the Western hemisphere. [1][2][3][4][5] Between 25% and 50% of all sarcoidosis-related deaths are attributable to heart failure, and cardiac complications are estimated to occur in as many as 25%-27% of systemic sarcoidosis patients in postmortem analyses. 2,6,7 These complications range from silent myocardial granulomas to sudden cardiac death and can be grouped into conduction abnormalities, arrhythmias, and heart failure. 1 The incidence of cardiac sarcoidosis and sarcoidosis-related mortality are steadily increasing in the United States, with the greatest rise in mortality seen among black women-this demographic also has the highest incidence of systemic disease. [8][9][10][11] Standard medical treatment of sarcoidosis includes immuno-suppression, usually with corticosteroids, and permanent pacemakers or implantable cardioverter defibrillators (ICDs) in patients at risk for sudden cardiac death. 1 Transplant is an increasingly common treatment option in end-stage heart failure secondary to restrictive cardiomyopathy from cardiac sarcoidosis. Although these patients are at risk for sarcoid recurrence in the allograft, extracardiac manifestations of sarcoidosis, and right ventricular dysfunction from pulmonary sarcoidosis, studies have shown that these complications are rare and often manageable with the continuation of corticosteroids following transplantation. [12][13][14] Data characterizing survival following transplant for cardiac sarcoidosis have been mixed. Case reports and single-center studies have reported both worse and comparable outcomes compared to patients receiving transplant for all other indications, [15][16][17] while one cohort study of posttransplant hemodynamics reported no deaths among 12 patients followed for almost 74 months. 12  indications. 18 However, long-term outcomes for these patients have not been characterized. Additionally, the interplay between corticosteroids for immunosuppression in transplant and management of sarcoidosis are not well described.
We sought to use a national database to study survival outcomes among patients with cardiac sarcoidosis who receive heart transplant, with a specific focus on long-term survival.

| Study population
The Organ Procurement and Transplantation Network (OPTN) database was queried for adult (≥18 years) patients receiving a first-time heart transplant between January 1, 1999, and March 20, 2020. This period was selected to provide 20 years of follow-up data from the earliest transplants and to include only those patients receiving modern immunosuppression regimens. Patients were excluded from analysis if they had multiple organs transplanted, any previous transplant, heterotopic heart transplants, or no clinical follow-up. Variables were excluded from analysis if missing data was >20%, with exception of up to 25% for clinically relevant variables. Institutional review board approval was obtained for analysis of the UNOS database in a prognostic study of survival following heart transplant, with no requirement to obtain informed consent.
Patients were sorted into three groups based on the primary indication for transplant: restrictive cardiomyopathy due to cardiac sarcoidosis (RCM-Sarcoidosis), restrictive cardiomyopathy due to other causes (RCM-Other), and non-RCM. Linear regression was used to determine if the number of transplants for cardiac sarcoidosis increased over the study period. Logistic regression was used to determine if the proportion of transplant patients with cardiac sarcoidosis increased over the same period. Pearson's χ 2 and Fisher's exact test were used to measure differences in categorical demographic and baseline clinical characteristics across groups and between RCM-Sarcoidosis and non-RCM groups. Differences in continuous variables with normal distribution were assessed using analysis of variance while those with nonnormal distribution were assessed with the Kruskal-Wallis H test. Logistic regression was used to assess the incidence of secondary outcomes in each group, including coronary artery disease, stroke, pacemaker requirement, acute rejection, treatment for rejection, hospitalization for rejection, hospitalization for infection, graft failure, and retransplantation. The incidence of the most common causes of death in each group were compared using Fisher's exact test.

| Survival analysis
Twenty-eight variables were associated with 10-year survival in the univariate model, and all were subsequently included in the multivariable model (Table 3) (Figure 3).
In multivariable logistic regression, RCM-Sarcoidosis was not associated with any morbidity outcomes, including coronary artery disease, stroke, pacemaker requirement, acute rejection, treatment or hospitalization for rejection, hospitalization for infection, graft failure, or retransplantation (Table 5).  Furthermore, we found that transplant for cardiac sarcoidosis is more common among black and female patients, who also experience the highest incidence of the systemic disease. 10,11 There is a growing awareness of racial disparities in heart transplant outcomes, and our study further demonstrates an increased risk of 10-year mortality among black cardiac sarcoidosis patients. 20  This study has shown that survival following transplant for cardiac sarcoidosis is not only acceptable but also superior compared to that of patients undergoing transplant for all other indications. In addition, concerns of sarcoid recurrence, which is both rare and usually experienced without mortality, and of right heart dysfunction due to pulmonary disease, have been mitigated by recent literature. 12,17,22 In light of our study's findings and other recent data, cardiac sarcoidosis should be considered a viable indication for transplant in selected patients with the expectation of excellent long-term survival and morbidity.