Heart transplantation (HT) for myocarditis has been controversial because of earlier reports of a poor prognosis after the procedure. We sought to determine whether lymphocytic myocarditis (LM) at the time of HT affects cardiac allograft rejection and survival after HT compared with other patients without LM in the current era of HT. We retrospectively reviewed 759 consecutive patients who underwent de novo HT at Columbia University Medical Center between 2000 and 2010 and compared prognosis after HT of the patients with pathologically proven LM in their explanted hearts with that of age- and gender-matched patients with idiopathic dilated cardiomyopathy (IDC group; n = 96) and with ischemic cardiomyopathy (IC group; n = 64). Thirty-two patients (4.2%) had LM in the explanted hearts pathologically. Among the 3 groups, no statistically significant difference was observed in the number of biopsy-diagnosed acute cellular rejection (ACR; International Society for Heart & Lung Transportation grade ≥2R) events during the first year after HT. In contrast, the frequency of biopsy-diagnosed ACR in subsequent years was greater in the LM group (n = 8, 3.8%) than in IC group (n = 3, 0.5%, p = 0.006), although no different from that of patients with IDC. The frequency of antibody-mediated rejection and posttransplant survival did not differ among the 3 groups. In conclusion, patients with pre-HT LM have an increased frequency of late ACR after HT compared with patients with IC. Nevertheless, survival of LM patients after HT is comparable to that of patients transplanted for IDC or IC.
Heart transplantation (HT) for myocarditis has been controversial because of higher risk of acute cellular rejection (ACR) and death after HT than in other patients without myocarditis as well as recurrence of myocarditis in the allograft. Regarding lymphocytic myocarditis (LM), the most common type of myocarditis, its recurrence in the allograft has been reported. Early reports showed that patients with LM had higher rate of ACR than other patients. In addition, the mortality was shown to be high compared with an age-matched control group without myocarditis. However, some studies have shown that LM at the time of HT is not a risk factor for a poor survival following HT. Therefore, we retrospectively studied whether pathologically proven LM at the time of HT is a risk factor for a poor outcome after HT in the current era compared with idiopathic dilated cardiomyopathy (IDC) and ischemic cardiomyopathy (IC), 2 major indications for HT.
Methods
The data collection protocol was approved by the institutional review board of Columbia University. The protocol complied with the Health Insurance Portability and Accountability Act and all ethical guidelines outlined by the 1975 Declaration of Helsinki.
We retrospectively reviewed 759 of patients (582 men, 177 women) who underwent de novo heart-only transplantation at Columbia University Medical Center between 2000 and 2010. Patients whose biopsy data after transplant were not available were excluded from the analysis. The patients included in the present study were as follows: those diagnosed with LM by histological evaluation of the explanted heart (LM group), those with IDC (IDC group), and those with IC (IC group). The diagnosis of IDC and IC was made clinically. Patients whose diagnosis was hypersensitivity myocarditis, giant cell myocarditis, sarcoidosis, or amyloidosis by histological evaluation in the explanted hearts were excluded from the study. Because of the older age and the predominance of male gender in the IC group compared with the other groups, pretransplant clinical characteristics and posttransplant prognosis in the LM group (n = 32) were compared with age- and gender-matched IDC patients (n = 96) and IC patients (n = 64).
Routinely sampled regions included 3 sites (base, middle, and apex) from both the left and right ventricles and the interventricular septum. At least 9 hematoxylin and eosin–stained sections of myocardium from each heart were analyzed. The diagnosis of LM was made according to the Dallas criteria and divided into 2 categories: active LM ( Figure 1 ), indicating lymphocytic infiltrate with evidence of myocyte damage and borderline LM ( Figure 1 ), indicating limited lymphocytic infiltrate (>14 lymphocytes/mm 3 ) without myocyte damage.
Post-HT endomyocardial biopsies were performed weekly for 1 month, every 2 weeks for 2 months, monthly for 3 months, every 2 months for 6 months and for a clinical suspicion of rejection. In the second year, the patients had biopsies typically at months 15, 18, and 24. Thereafter biopsies were performed either every 6 months or annually depending on the rejection history. Biopsy grading of ACR was performed according to the 2004 International Society for Heart and Lung Transplantation (ISHLT) classification. For endomyocardial biopsies evaluated before the IHSLT-2004 criteria, reclassification was performed. Pathologic diagnosis of AMR was made based on the diffuse, strong staining for C4d in capillaries by paraffin immunohistochemistry. Biopsy samples obtained before the HT including left ventricular core specimens taken at the time of left ventricular assist device (LVAD) implantation, and right ventricle endomyocardial biopsies specimens were also investigated. Cardiac angiography was performed 1 year after HT and repeated annually. Cardiac allograft vasculopathy (CAV) was defined as an angiographic stenosis ≥30%.
Data are presented as mean ± SD and frequency (percentage). Kruskal-Wallis test was used to assess the differences among the groups. The 2-tailed Mann-Whitney U test with Bonferroni correction was performed after the Kruskal-Wallis test for multiple comparisons. Categorical variables are compared using chi-square test or Fisher exact tests as appropriate. Values of p <0.05 were considered significant, except that p <0.017 was considered significant in the multiple comparisons. Survival after transplant was compared using Kaplan-Meier methods with log-rank test. All data were analyzed using SPSS for windows version 13.0.
Results
Of the 759 transplanted patients, 32 patients (19 male, 13 female) showed histological LM in the explanted heart (4.2%). Analysis of demographic characteristics of the groups is shown in Table 1 . In the LM group, >60% of patients were clinically diagnosed with IDC before HT. Left ventricular core biopsy at the time of LVAD placement and/or endomyocardial biopsies were performed before HT in 9 patients (28%), and 7 of them were suspected or diagnosed as LM histologically. LM was diagnosed clinically in 6 patients (19%) before HT. A statistically significant difference was observed in the rate of pretransplant LVAD implantation among the groups, but multiple comparisons did not achieve statistical significance between any of these groups. Mean follow-up times were longer in the IC group compared with the other 2 groups.
| Variable | LM (n = 32) | IDC (n = 96) | IC (n = 64) | p Value |
|---|---|---|---|---|
| Age (yrs), mean ± SD | 46.1 ± 14.3 | 49.2 ± 13.1 | 51.1 ± 11.1 | 0.195 |
| Male | 19 (59%) | 57 (59%) | 38 (59%) | 1.000 |
| White | 17 (53%) | 43 (45%) | 36 (56%) | 0.682 |
| African-American | 6 (19%) | 30 (31%) | 13 (20%) | |
| Hispanic | 3 (9%) | 9 (9%) | 5 (8%) | |
| Others | 6 (19%) | 14 (15%) | 10 (16%) | |
| Body mass index (kg/m 2 ) | 25.4 ± 5.4 | 26.8 ± 4.7 | 25.5 ± 4.3 | 0.148 |
| LVAD | 13 (41%) | 36 (38%) | 13 (20%) | 0.041 |
| Diabetes mellitus | 8 (25%) | 23 (24%) | 19 (30%) | 0.713 |
| Hypertension | 11 (34%) | 32 (33%) | 25 (39%) | 0.752 |
| Smoker | 11 (34%) | 29 (30%) | 26 (41%) | 0.397 |
| Clinical diagnosis | ||||
| Idiopathic dilated cardiomyopathy | 20 (63%) | |||
| Myocarditis | 6 (19%) | |||
| Postpartum cardiomyopathy | 3 (9%) | |||
| Ischemic cardiomyopathy | 2 (6%) | |||
| Hypertrophic cardiomyopathy | 1 (3%) | |||
| Allograft ischemic time (min) | 205 ± 62 | 198 ± 56 | 188 ± 60 | 0.547 |
| CMV serology mismatch positive donor to negative recipient | 6 (19%) | 14 (15%) | 13 (20%) | 0.621 |
| Time between HT and the latest biopsy (yr) | 3.2 ± 2.1 | 3.5 ± 2.7 | 4.5 ± 3.1 | 0.102 |
| Time between HT and the latest cardiac angiography (yr) | 3.5 ± 2.5 | 3.8 ± 2.7 ∗ | 5.1 ± 3.0 | 0.021 |
| Follow-up times (yr) | 3.7 ± 2.5 ∗ | 4.1 ± 2.9 ∗ | 5.6 ± 3.6 | 0.013 |
Table 2 shows the numbers and percentage of biopsies with rejection and Quilty lesions. In the first year after HT, the number of biopsies with ACR was not significantly different among the groups. In contrast, a statistically significant difference was observed in the frequency of ACR in subsequent years among the groups (p = 0.005). Multiple comparisons showed that the LM and IDC groups had a greater frequency of ACR compared with the IC group (LM vs IDC, p = 0.350; LM vs IC, p = 0.002; IDC vs IC, p = 0.006). Comparing the frequency of ACR between the first year and subsequent years post-HT, ACR in subsequent years was less frequent than that of first year only in IC group (Year 1 vs Year ≥2 = 19 [2.3%] vs 3 [0.5%], p = 0.009). In contrast, LM group showed an increasing tendency for ACR in subsequent years, although it was not statistically significant (Year 1 vs Year ≥2 = 6 [1.5%] vs 8 [3.8%], p = 0.070). Regarding AMR and Quilty lesion, no statistically significant difference was observed among the groups throughout the study period.
| LM | IDC | IC | p Value | |
|---|---|---|---|---|
| n = 400 (Yr 1) | n = 1,225 (Yr 1) | n = 810 (Yr 1) | ||
| n = 213 (Yr ≥2) | n = 670 (Yr ≥2) | n = 556 (Yr ≥2) | ||
| ACR | ||||
| Yr 1 | 6 (1.5%) | 31 (2.5%) | 19 (2.3%) | 0.488 |
| Yr ≥2 | 8 (3.8%) | 17 (2.5%) | 3 (0.5%) †,‡ | 0.005 |
| AMR | ||||
| Yr 1 | 3 (0.8%) | 6 (0.5%) | 3 (0.4%) | 0.627 |
| Yr ≥2 | 0 (0.0%) | 5 (0.7%) | 1 (0.2%) | 0.264 |
| Quilty | ||||
| Yr 1 | 65 (16.3%) | 144 (11.8%) | 108 (13.3%) | 0.064 |
| Yr ≥2 | 81 (38.0%) | 208 (31.0%) | 161 (29.0%) | 0.052 |
∗ “R” denotes revised grade to avoid confusion with 1990 scheme.
We also analyzed the frequency of rejection based on the number of patients with a positive biopsy for rejection. In the first year, 5 LM patients had ≥1 biopsies with grade ≥2R ACR, and 2 of those 5 also had positive biopsies for ACR after the first year. Three of 32 LM patients had rejection only after the first year. The number of patients who experienced ACR was not statistically different among the groups (Year 1: p = 0.684, Year ≥2: p = 0.095). Similarly, no significant difference was observed in the prevalence of AMR and Quilty lesion among the groups. The number of patients who experienced ACR decreased significantly in subsequent years compared with the first year only in the IC group (Year 1 vs Year ≥2 = 13 [20.6%] vs 2 [4.0%], p = 0.01), but this was not true in the LM group (Year 1 vs Year ≥2 = 5 [16.1%] vs 5 [18.5%], p = 0.541) or in the IDC group (Year 1 vs Year ≥2 = 22 [23.4%] vs 11 [14.9%], p = 0.167).
To assess whether pathologic distinction affects the frequency of rejection, we then divided the LM patients into 2 groups: active LM (n = 24, Figure 1 ) and BLM (n = 8, Figure 1 ). No statistically significant association was found between the 2 groups in the number of biopsies with ACR and AMR throughout the study period ( Table 3 ). We also analyzed the frequency of rejection based on the number of patients with ≥1 episode of ACR or AMR, but again, we did not find significant difference among the groups (data not shown).
