Abstract
Background
Myocardial fibrosis is a well-described histopathological feature in heart transplant recipients. Whether myocardial fibrosis in heart transplant recipients is independently associated with clinical outcomes is unclear. We sought to determine whether myocardial fibrosis on late gadolinium enhancement cardiovascular magnetic resonance imaging (LGE CMR) in heart transplant recipients was independently associated with all-cause death or major adverse cardiac outcomes in the long term.
Methods
Using a cohort of consecutive heart transplant recipients that had CMR, we determined the prevalence and the patterns of myocardial fibrosis and analyzed associations between myocardial fibrosis and a composite endpoint of all-cause death or major adverse cardiac events (MACE): retransplantation, non-fatal myocardial infarction, coronary revascularization, and heart failure hospitalization.
Results
One hundred and fifty-two heart transplant recipients (age, 54±15 years; 29% women; 5.0±5.4 years after heart transplantation) were included. Myocardial fibrosis was present in 18% (37% infarct pattern, 41% non-infarct pattern, and 22% both). Its prevalence was positively associated with cardiac allograft vasculopathy (CAV) grade. With a median follow-up of 2.6 years, myocardial fibrosis was independently associated with all-cause death or MACE (hazard ratio [HR], 2.88; 95% confidence interval [CI] 1.59–5.23; p<0.001) after adjustment for CAV, history of rejection, time since transplantation, left ventricular ejection fraction (LVEF), and indexed right ventricular end-diastolic volume (RVEDVI). Every 1% increase in myocardial fibrosis was independently associated with a 6% higher hazard for all-cause death or MACE (HR, 1.06; 95% CI, 1.03–1.09; p<0.001). The addition of myocardial fibrosis variables to models with CAV, history of rejection, time since transplantation, LVEF, and RVEDVI resulted in significant improvements in model fit, suggesting incremental prognostic value.
Conclusions
In heart transplant recipients, myocardial fibrosis is seen on LGE CMR in 18%. Both the presence and the extent of myocardial fibrosis are independently associated with the long-term risk of all-cause death or MACE.
Keywords: myocardial fibrosis, cardiac magnetic resonance imaging, heart transplantation, prognosis, Fibrosis, Magnetic Resonance Imaging (MRI), Transplantation
INTRODUCTION
Heart transplantation improves survival, functional status, and quality of life for patients with advanced heart failure1. The outcome of heart transplantation has significantly improved owing largely to advances in immunosuppressive therapy and the management of long-term complications. Cardiac allograft vasculopathy (CAV) and allograft failure are among the leading causes of long-term morbidity, death, and retransplantation in heart transplant recipients2.
Myocardial fibrosis is a well-described histopathological feature in heart transplant recipients. It has been described in serial endomyocardial biopsies of cardiac allografts,3, 4 and it has been associated with restrictive physiology5, advanced CAV6, 7, and poor allograft survival6.
Cardiovascular magnetic resonance imaging (CMR) using the late gadolinium enhancement (LGE) technique is considered the in vivo reference standard for imaging focal myocardial fibrosis8. LGE CMR has been validated by histology in heart transplantation9. In prior studies, the prevalence of myocardial fibrosis on LGE CMR in heart transplant recipients has varied from 0%10, 11 to >50%12–14. Whether myocardial fibrosis on LGE CMR is independently associated with all-cause death or long-term adverse cardiac outcomes in heart transplant recipients is unclear. We, therefore, sought to determine the independent prognostic significance of the presence and the extent of myocardial fibrosis on LGE CMR in a large consecutive cohort of heart transplant recipients with long-term follow-up. We hypothesized that myocardial fibrosis on LGE CMR is associated with a higher risk of all-cause death or long-term cardiovascular events after heart transplantation.
METHODS
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.
Patients
The study sample consisted of consecutive adult heart transplant recipients who had CMR performed for surveillance between January 2004 and December 2017 at the University of Minnesota, Minneapolis, Minnesota, USA. The institutional heart transplant database was cross-matched with the University of Minnesota Cardiovascular Magnetic Resonance Registry15–17 to identify the study patients. For recipients with multiple CMRs, the earliest one was included. This retrospective cohort study was approved by University of Minnesota’s Institutional Review Board with a waiver of informed consent.
Baseline Measures
Demographic data, medical history, co-morbidities, and outcome data were collected blinded to CMR data. CAV was classified according to the International Society for Heart and Lung Transplantation (ISHLT)’s recommended nomenclature18. A history of rejection was defined as a history of ISHLT grade 2R or 3R cellular rejection or antibody-mediated rejection.
CMR Protocol
CMR was performed on clinical 1.5T Siemens scanners (Avanto or Aera) using phased-array receiver coils according to standard recommendations. A typical protocol was as follows: First, localizers were acquired to identify the cardiac position. Next, cine CMR images were acquired in short-axis (every 10 mm to cover the entire left ventricle (LV) from the mitral valve plane through the apex) and three long-axis views (two-, three-, and four-chamber) using a steady-state free-precession sequence. Standard LGE CMR imaging was performed 10–15 minutes after administration of gadolinium contrast (0.15 mmol/kg), using a two-dimensional segmented inversion-recovery gradient-echo sequence in identical views as cine CMR imaging. If LGE was seen at the time of the scan, it was confirmed by obtaining images in an orthogonal view. Typical inversion delay times were 280 to 360 ms. The same CMR protocol was used during the entire study period.
CMR Analyses
CMRs were re-interpreted and analyzed for the purposes of this study blinded to all other patient data by the consensus of two investigators using Precession software (Heart Imaging Technologies, Durham, NC). LV and right ventricular (RV) ejection fractions (LVEF and RVEF) were determined by quantitative analysis according to standard recommendations19.
For LGE analysis, the investigators first identified the presence or absence of focal myocardial fibrosis based on visual assessment. Myocardial fibrosis was noted only if LGE was seen in two orthogonal planes. Myocardial fibrosis distribution patterns were then classified as infarct pattern if there was subendocardial or transmural involvement, non-infarct pattern if there was no subendocardial involvement, or both. For those with myocardial fibrosis, the extent was quantified using the full width at half-maximum method and expressed as a percentage of the LV myocardial mass19, 20.
Clinical Follow-up and Outcomes
Follow-up data were collected through a review of electronic medical records blinded to CMR data. The pre-specified primary endpoint was a composite of all-cause death or major adverse cardiac events (MACE) after the CMR: retransplantation, non-fatal myocardial infarction, coronary revascularization, and heart failure hospitalization. When a recipient experienced more than one event, the first event was chosen for outcome analyses. Myocardial infarction was defined according to the Fourth Universal Definition of Myocardial Infarction21. Mortality status and death dates were cross-checked with data from the Minnesota Department of Health’s Office of Vital Records.
Statistical Analysis
Normally distributed continuous variables were expressed as mean ± standard deviation (SD), and non-normally distributed continuous variables were presented as medians with interquartile range (IQR). Categorical variables were expressed as counts with percentages. Comparison between groups was performed with a 2-sample Student t test for continuous, normal variables, and Mann-Whitney rank sum test for continuous, non-normal data. Pearson chi-square tests were used to compare discrete data between groups; in those cases where the expected cell count was <5, Fisher exact test was used. Kaplan–Meier analyses and unadjusted and adjusted Cox proportional hazards regression analyses were used to evaluate the relationships between clinical variables and all-cause death or MACE. The assumption of proportional hazards was assessed by plotting the scaled Schoenfeld residuals for each independent variable against time; these correlations were found to be nonsignificant for all variables included in the multivariable models. To evaluate the incremental prognostic value of myocardial fibrosis, the final models were compared with models in which myocardial fibrosis variables were not included, using the likelihood ratio test. All tests were 2-tailed. A p value of <0.05 was used to denote statistical significance. Analyses were performed using R, version 3.4 (R Foundation for Statistical Computing).
RESULTS
Overall Patient Characteristics
One hundred and fifty-two consecutive heart transplant recipients were included in the study. Patient characteristics at the time of the index CMR are reported in Table 1. The mean time from cardiac transplant to CMR was 5.0 years and the median was 3.1 years. Comorbidities were common (62% hypertension, 35% diabetes mellitus, and 42% chronic kidney disease [glomerular filtration rate <60 mL/min per 1.73 m2]). Thirty two percent had CAV, and 32% had a history of either ISHLT grade 2R or 3R cellular, or antibody-mediated rejection. Immunosuppression regimens varied but mycophenolate mofetil and tacrolimus were commonly used. Aspirin and statins were frequently used.
Table 1.
Patient Characteristics of All Recipients, and Stratified by the Presence or Absence of Myocardial Fibrosis
| All Recipients (n = 152) | Myocardial Fibrosis (n = 27) | No Myocardial Fibrosis (n = 125) | p Value | |
|---|---|---|---|---|
| Demographics | ||||
| Age, years (SD) | 54.2 (15.2) | 49.7 (15.4) | 55.2 (15.0) | 0.09 |
| Women, n (%) | 44 (28.9) | 7 (25.9) | 37 (29.6) | 0.70 |
| Time since transplantation, years (SD) | 5.0 (5.4) | 5.6 (6.2) | 4.9 (5.2) | 0.54 |
| Ischemic time, min (SD) | 224.0 (61.5) | 219.6 (67.2) | 224.9 (60.5) | 0.70 |
| Transplant indication | ||||
| Ischemic cardiomyopathy, n (%) | 53 (34.9) | 7 (25.9) | 46 (36.8) | 0.28 |
| Comorbidities | ||||
| Body mass index, kg/m2 (IQR) | 26.6 (23.5, 30.2) | 25.4 (21.9, 30.9) | 26.8 (23.7, 29.8) | 0.38 |
| Hypertension, n (%) | 95 (62.5) | 15 (55.6) | 80 (64.0) | 0.41 |
| Diabetes mellitus, n (%) | 54 (35.5) | 9 (33.3) | 45 (36.0) | 0.79 |
| Chronic kidney disease (eGFR <60 mL/min per 1.73 m2), n (%) | 64 (42.1) | 9 (33.3) | 55 (44.0) | 0.31 |
| CAV, n (%) | 48 (31.6) | 16 (59.3) | 32 (25.6) | <0.001 |
| History of rejection, n (%) | 48 (31.6) | 11 (40.7) | 37 (29.6) | 0.26 |
| Immunosuppressant medications | ||||
| Tacrolimus, n (%) | 114 (75.0) | 19 (70.4) | 95 (76.0) | 0.54 |
| Sirolimus/everolimus, n (%) | 28 (18.4) | 6 (22.2) | 22 (17.6) | 0.58 |
| Cyclosporine, n (%) | 26 (17.1) | 4 (14.8) | 22 (17.6) | 0.73 |
| Mycophenolate mofetil, n (%) | 123 (80.9) | 22 (81.5) | 101 (80.8) | 0.94 |
| Azathioprine, n (%) | 9 (5.9) | 2 (7.4) | 7 (5.6) | 0.72 |
| Prednisone, n (%) | 44 (28.9) | 4 (14.8) | 40 (32.0) | 0.08 |
| Other cardiac medications | ||||
| Aspirin, n (%) | 132 (86.8) | 23 (85.2) | 109 (87.2) | 0.78 |
| Statin, n (%) | 129 (84.9) | 24 (88.9) | 105 (84.0) | 0.52 |
| ACE-Inhibitor/ARB, n (%) | 69 (45.4) | 15 (55.6) | 54 (43.2) | 0.25 |
| Beta blocker, n (%) | 26 (17.1) | 10 (37.0) | 16 (12.8) | 0.002 |
| Calcium channel blocker, n (%) | 46 (30.3) | 8 (29.6) | 38 (30.4) | 0.94 |
| CMR findings | ||||
| LVEDVI, ml/m2 (IQR) | 53.8 (44.4, 61.8) | 56.3 (48.2, 65.3) | 53.1 (43.7, 61.6) | 0.14 |
| LVESVI, ml/m2 (IQR) | 22.3 (17.7, 27.8) | 26.7 (22.4, 35.0) | 21.2 (17.1, 26.5) | <0.001 |
| LVEF, % (IQR) | 56.4 (50.1, 62.2) | 51.2 (41.2, 56.2) | 57.6 (52.9, 63.2) | <0.001 |
| RVEDVI, ml/m2 (IQR) | 50.6 (44.3, 59.8) | 51.7 (44.1, 57.4) | 49.7 (44.4, 60.1) | 0.97 |
| RVESVI, ml/m2 (IQR) | 23.0 (18.2, 28.4) | 24.3 (17.6, 27.4) | 22.5 (18.3, 28.7) | 0.86 |
| RVEF, % (IQR) | 55.6 (47.0, 60.5) | 53.2 (47.8, 60.7) | 55.8 (46.7, 60.5) | 0.76 |
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; CAV = cardiac allograft vasculopathy; CMR = cardiovascular magnetic resonance; EDVI = end-diastolic volume index; EF = ejection fraction; ESVI = end-systolic volume index; ISHLT = International Society for Heart and Lung Transplantation; IQR = interquartile range; LV = left ventricle; RV = right ventricle; SD = standard deviation
CMR Findings
The median LVEFs and RVEFs were normal (>55%) (Table 1). Myocardial fibrosis was detected in 27 (18%) recipients. Infarct pattern (subendocardial or transmural) myocardial fibrosis was seen in 10 (37%), non-infarct pattern (mid-myocardial or subepicardial) in 11 (41%), and both in 6 (22%) (Figure 1). The mean extent of the fibrosis was 12.2% and the median was 9.7%. The extent of myocardial fibrosis was significantly higher in heart transplant recipients with both infarct and non-infarct patterns (mean 23.8%), compared with those with either an infarct-only (mean 8.4%) or a non-infarct-only pattern (mean 9.2%), p=0.002.
Figure 1. LGE CMR images from example heart transplant recipients demonstrating the different patterns of myocardial fibrosis.
Panel A (upper left) shows images in orthogonal views from a recipient with infarct pattern myocardial fibrosis. The yellow arrows point to subendocardial LGE. Panel B (lower left) shows images in orthogonal views from a recipient with non-infarct pattern myocardial fibrosis. The yellow arrows point to mid-myocardial LGE. Panel C (right) shows images in orthogonal views from a recipient with myocardial fibrosis in both infarct and non-infarct patterns. The yellow arrows point to subendocardial, transmural, mid-myocardial, and subepicardial LGE.
Determinants of Myocardial Fibrosis
Clinical characteristics were similar between recipients with and without myocardial fibrosis, except for the prevalence of CAV and the use of beta-blockers, both of which were significantly higher in those with myocardial fibrosis. The prevalence of myocardial fibrosis increased as the severity of CAV increased, with a prevalence of 11% in CAV Grade 0, 22% in CAV Grade 1, 38% in CAV Grade 2 and 75% in CAV Grade 3 (p<0.001). While ischemic LGE increased in prevalence with increasing CAV grade, non-ischemic LGE decreased in prevalence with increasing CAV grade (Table 2). Not surprisingly, recipients with myocardial fibrosis had significantly higher indexed LV end systolic volumes and significantly lower LVEFs.
Table 2.
Patterns of Myocardial Fibrosis by Cardiac Allograft Vasculopathy Grade
| Ischemic (n = 10) | Non-ischemic (n = 11) | Both (n = 6) | |
|---|---|---|---|
| CAV0 (n = 11) | 3 (27%) | 7 (64%) | 1 (9%) |
| CAV1 (n = 7) | 4 (57%) | 2 (29%) | 1 (14%) |
| CAV2 (n = 3) | 3 (100%) | 0 (0%) | 0 (0%) |
| CAV3 (n = 6) | 0 (0%) | 2 (33%) | 4 (67%) |
CAV = cardiac allograft vasculopathy
Association of Myocardial Fibrosis With All-cause Death or MACE
Follow-up data were available for all recipients. Fifty-nine (38.8%) recipients experienced all-cause death or MACE over a median follow-up of 2.6 years (interquartile range, 1.3–5.2 years). A breakdown of the individual events stratified by the presence or absence of myocardial fibrosis is provided in Table 3.
Table 3.
Clinical Events During Follow-Up in All Recipients, and Stratified by the Presence or Absence of Myocardial Fibrosis
| All Recipients (n=152) | Myocardial Fibrosis (n=27) | No Myocardial Fibrosis (n=125) | |
|---|---|---|---|
| All-cause death, n (%) | 36 (23.7) | 9 (33.3) | 27 (21.6) |
| Retransplantation, n (%) | 7 (4.6) | 4 (14.8) | 3 (2.4) |
| Nonfatal MI, n (%) | 1 (0.7) | 0 (0.0) | 1 (0.8) |
| Coronary revascularization, n (%) | 17 (11.2) | 7 (25.9) | 10 (8.0) |
| Heart failure hospitalization, n (%) | 28 (18.4) | 10 (37.0) | 18 (14.4) |
| All-cause death or MACE, n (%) | 59 (38.8) | 19 (70.4) | 40 (32.0) |
MACE indicates major adverse cardiac events; and MI, myocardial infarction.
Kaplan-Meier analyses stratified by the presence or absence of myocardial fibrosis showed a significantly higher estimated cumulative incidence of all-cause death or MACE in recipients with myocardial fibrosis compared with those without (log rank p<0.001; Figure 2).
Figure 2. Kaplan-Meier cumulative incidence curves for all-cause death or major adverse cardiac events (MACE) stratified by the presence or absence of myocardial fibrosis.
Cumulative incidence curves comparing all-cause death or MACE between heart transplant recipients with (red) and without myocardial fibrosis (blue). The log-rank was P<0.001. Each vertical tick on the curves displays a censored patient. See text for further details.
By univariable analyses (Table 4), predictors of all-cause death or MACE were prednisone use, lack of aspirin use, beta-blocker use, LVEF, myocardial fibrosis presence, and myocardial fibrosis extent. In multivariable models (Table 4) including CAV, history of rejection, time since transplantation, LVEF, RVEDVI, and either myocardial fibrosis presence or myocardial fibrosis extent, both myocardial fibrosis variables were independently associated with all-cause death or MACE. The presence of myocardial fibrosis was associated with a hazard ratio of 2.88, indicating that the risk of all-cause death or MACE nearly tripled in the presence of myocardial fibrosis. Myocardial fibrosis extent was associated with a hazard ratio of 1.06, indicating that the risk of all-cause death or MACE increased by 6% for every 1% increase in myocardial fibrosis. The addition of myocardial fibrosis presence or myocardial fibrosis extent to a Cox model that included CAV, history of rejection rejection, time since transplantation, LVEF and RVEDVI resulted in a significantly improved model fit as assessed with the likelihood ratio test (p<0.001 for both comparisons).
Table 4.
Cox Proportional Hazards Regression Modeling for All-cause Death or MACE
| Univariable Analyses | Multivariable Analyses – Model 1* | Multivariable Analyses – Model 2† | ||||
|---|---|---|---|---|---|---|
| Hazard Ratio (95% CI) | P value | Hazard Ratio (95% CI) | P value | Hazard Ratio (95% CI) | P value | |
| Age | 1.00 (0.98–1.01) | 0.68 | ||||
| Women | 0.80 (0.46–1.39) | 0.42 | ||||
| Ischemic cardiomyopathy | 0.85 (0.50–1.46) | 0.56 | ||||
| Body mass index | 0.98 (0.93–1.03) | 0.36 | ||||
| Hypertension | 1.19 (0.69–2.05) | 0.54 | ||||
| Diabetes mellitus | 1.50 (0.89–2.51) | 0.13 | ||||
| Chronic kidney disease (eGFR <60 mL/min per 1.73 m2) | 1.21 (0.72–2.02) | 0.47 | ||||
| CAV | 1.65 (0.96–2.83) | 0.07 | 1.21 (0.68–2.16) | 0.52 | 1.24 (0.70–2.23) | 0.46 |
| History of rejection | 1.06 (0.62–1.81) | 0.84 | 1.11 (0.64–1.92) | 0.71 | 0.96 (0.54–1.71) | 0.89 |
| Ischemic time | 1.00 (1.00–1.01) | 0.77 | ||||
| Time since transplantation | 1.03 (0.99–1.08) | 0.17 | 1.04 (0.99–1.09) | 0.15 | 1.02 (0.98–1.07) | 0.34 |
| Tacrolimus | 0.90 (0.52–1.55) | 0.69 | ||||
| Sirolimus/everolimus | 1.06 (0.56–2.00) | 0.86 | ||||
| Cyclosporine | 1.11 (0.61–2.03) | 0.72 | ||||
| Mycophenolate mofetil | 0.68 (0.38–1.21) | 0.19 | ||||
| Azathioprine | 1.00 (0.36–2.76) | 1.00 | ||||
| Prednisone | 1.78 (1.05–3.02) | 0.033 | ||||
| Aspirin | 0.39 (0.21–0.73) | 0.003 | ||||
| Statin | 0.96 (0.50– 1.86) | 0.91 | ||||
| ACE-Inhibitor/ARB | 0.93 (0.56–1.56) | 0.79 | ||||
| Beta blocker | 1.79 (1.01–3.19) | 0.046 | ||||
| Calcium channel blocker | 0.70 (0.39–1.25) | 0.23 | ||||
| LVEDVI | 0.99 (0.97–1.01) | 0.51 | ||||
| LVESVI | 1.01 (0.99–1.04) | 0.30 | ||||
| LVEF | 0.97 (0.95–1.00) | 0.025 | 0.98 (0.95–1.00) | 0.10 | 0.98 (0.95–1.01) | 0.14 |
| RVEDVI | 0.98 (0.96–1.00) | 0.07 | 0.98 (0.96–1.00) | 0.050 | 0.98 (0.96–1.00) | 0.051 |
| RVESVI | 0.94 (0.97–1.01) | 0.10 | ||||
| RVEF | 1.01 (0.99–1.04) | 0.41 | ||||
| Myocardial fibrosis presence | 3.16 (1.82–5.49) | <0.001 | 2.88 (1.59–5.23) | <0.001 | Not included | |
| Myocardial fibrosis extent | 1.07 (1.04–1.10) | <0.001 | Not included | 1.06 (1.03–1.09) | <0.001 | |
Model 1 included CAV, history of rejection, time since transplantation, LVEF, RVEDVI and myocardial fibrosis presence.
Model 2 included CAV, history of rejection, time since transplantation, LVEF, RVEDVI and myocardial fibrosis extent.
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; CAV = cardiac allograft vasculopathy; CI = confidence interval; EDVI = end-diastolic volume index; EF = ejection fraction; ESVI = end-systolic volume index; ISHLT = International Society for Heart and Lung Transplantation; LV = left ventricle; RV = right ventricle
DISCUSSION
In this large cohort study of 152 heart transplant recipients, myocardial fibrosis was present in 18%. Its prevalence was positively associated with the CAV grade. Myocardial fibrosis was associated with a higher incidence of all-cause death or MACE over a median follow-up of 2.6 years. Moreover, the presence and the extent of myocardial fibrosis were both independently associated with all-cause death or MACE after adjustment for CAV, history of rejection, time since transplantation, LVEF, and RVEDVI. Addition of myocardial fibrosis to a model with CAV, history of rejection, time since transplantation, LVEF, and RVEDVI resulted in a significant improvement in model fit, suggesting incremental prognostic value.
Comparison with Prior Studies
The prevalence of myocardial fibrosis after heart transplantation in prior studies ranged from around 60% for University Hospital, Heidelberg, Germany12, 22, 23 and around 50% for University of Alberta Hospital, Edmonton, Canada13, 24 to 0% for University of Toronto, Toronto, Canada25–27. Interestingly a fourth study from University Hospital, Heidelberg, Germany described a much lower 31% prevalence28. In all studies describing a high prevalence of LGE, the infarct pattern was infrequent (12–27% of recipients with LGE).
Four studies investigated the prognostic relevance of myocardial fibrosis and showed mixed results13, 14, 24, 28. Hofmann et al.28 did not find an independent prognostic value for myocardial fibrosis. Butler et al.24 found an association between the presence of myocardial fibrosis and adverse cardiac outcomes on univariable analyses but they had too few events for multivariable analysis. A second study by Butler et al.13 found an independent association between the presence of myocardial fibrosis and adverse cardiac outcomes. Pedrotti et al.14 did not find an independent prognostic value for the presence of myocardial fibrosis but found the extent of myocardial fibrosis to be significantly associated with adverse cardiovascular outcomes.
The mixed results in these prior prognostic studies may be due to the relative paucity of events and short follow up times. In the largest study to date, with more adverse outcomes and longer follow up, we found an independent and incremental prognostic value for both the presence and the extent of myocardial fibrosis.
Etiology of Myocardial Fibrosis
The exact mechanisms underlying the occurrence of myocardial fibrosis in heart transplant recipients is not known. Possible explanations have included CAV29, cellular and antibody-mediated rejection30, cold ischemic injury pretransplantation31, and reperfusion injury32. Higher donor age resulting from attempts to expand the availability of donor hearts may also result in a higher prevalence of pre-existing myocardial fibrosis from unrecognized myocardial infarctions33. Indeed, higher donor age has been associated with a higher prevalence of CAV34, 35, early graft failure36, and long-term survival37.
Clinical Implications
Our finding of a close association between the prevalence of myocardial fibrosis and the severity of CAV suggests that CAV plays an important role in the pathogenesis of myocardial fibrosis. Thus, the assessment of myocardial fibrosis may have clinical implications for the management of CAV. Since treatment of CAV is most effective when started early in its course38–40, myocardial fibrosis could serve as a non-invasive biomarker for the early identification of CAV. This, in turn, could allow for changes in medical therapy and immunosuppression (such as the use of mammalian targets of rapamycin inhibitors sirolimus and everolimus) that could prevent progression of CAV, graft failure, and other adverse cardiovascular outcomes. Prospective studies are warranted to demonstrate that such a strategy is associated with improved long-term outcomes. Studies comparing the prognostic performances of myocardial fibrosis and other markers such as myocardial ischemia17 and myocardial flow reserve28, 41 are also needed.
Limitations
The retrospective nature of the study introduces the possibility of referral bias. Inherent to the long (14 years) study period is heterogeneity in the recipients and the care they received. While T1 mapping identifies diffuse myocardial fibrosis and could potentially add incremental prognostic value to LGE CMR, the technique was not clinically available during the entire study period. Chronic kidney disease is not an uncommon complication in heart transplant recipients and may preclude the use of LGE CMR in some recipients due to the perceived risk of nephrogenic systemic fibrosis.
Conclusions
In heart transplant recipients, myocardial fibrosis is identified on LGE CMR in 18%. Both the presence and the extent of myocardial fibrosis are independently associated with the long-term risk of all-cause death or MACE.
SHORT COMMENTARY.
There is a critical need for ways to non-invasively risk stratify heart transplant recipients - a cohort with a median survival of only 12.4 years. An important prognostic role for myocardial fibrosis has been demonstrated in many cardiac pathologies. Therefore, the prognostic value of myocardial fibrosis in heart transplant recipients warrants careful study. Prior small studies have shown myocardial fibrosis on late gadolinium enhancement cardiovascular magnetic resonance (LGE CMR) with the prevalence ranging from 0% to >50%. Similarly, small studies with relatively few events have investigated the prognostic significance of myocardial fibrosis in heart transplant recipients with mixed results. To provide clarity on this topic, we performed the largest study to date. We found that the prevalence of myocardial fibrosis was 18%. We found an independent and incremental prognostic value for both the presence and the extent of myocardial fibrosis. Our results carry important implications for the risk stratification and management of heart transplant recipients and provide the basis for future multicenter and prospective randomized studies on this important topic.
Acknowledgments
SOURCES OF FUNDING
Mehmet Akçakaya was supported by NIH grant R00HL111410. Chetan Shenoy was supported by NIH grant K23HL132011, University of Minnesota Clinical and Translational Science Institute KL2 Scholars Career Development Program Award (NIH grant KL2TR000113-05), and NIH grant UL1TR000114.
NON-STANDARD ABBREVIATIONS AND ACRONYMS
- CAV
cardiac allograft vasculopathy
- CI
confidence interval
- CMR
cardiovascular magnetic resonance imaging
- EDVI
end-diastolic volume index
- EF
ejection fraction
- HR
hazard ratio
- IQR
interquartile range
- ISHLT
International Society for Heart and Lung Transplantation
- LGE
late gadolinium enhancement
- LV
left ventricle
- MACE
major adverse cardiac events
- RV
right ventricle
- SD
standard deviation
Footnotes
DISCLOSURES
None
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