2017 Volume 81 Issue 6 Pages 806-814
Background: New-onset diabetes mellitus (DM) can occur as a serious complication after heart transplantation, but the comparative data on its clinical impact on survival and on transplant-related adverse events are limited.
Methods and Results: We reviewed a total of consecutive 391 patients aged ≥17 years undergoing isolated orthotopic heart transplantation at the present institution from 1992 to 2013. The entire cohort was divided into 3 groups: (1) no diabetes (n=257); (2) pre-existing DM (n=46); and (3) new-onset DM (n=88). Early and long-term clinical outcomes were compared across the 3 groups. Early death occurred in 8 patients (2.0%). Of the 345 non-diabetic patients before transplantation, 88 (25.5%) developed new-onset DM postoperatively. During follow-up, 83 (21.2%) died. On time-varying Cox analysis, new-onset DM was associated with increased risk for overall death (HR, 2.11; 95% CI: 1.26–3.55) and tended to have a greater risk for severe chronic kidney disease (HR, 1.77; 95% CI: 0.94–3.44). Compared with the no-diabetes group, the new-onset DM group had a worse survival rate (P=0.035), but a similar survival rate to that of the pre-existing DM group (P=0.364).
Conclusions: New-onset DM has a negative effect on long-term survival and kidney function after heart transplantation. Further studies are warranted to evaluate the relevance of early diagnosis and timely control of new-onset DM to improve long-term survival.
Heart transplantation has gained acceptance worldwide as a useful therapeutic option for the treatment of end-stage heart failure.1 Along with growing knowledge of immunosuppression therapy and evolving surgical techniques, the long-term survival rate has noticeably improved over the last several decades.1 Accordingly, the clinical application of heart transplantation has extended to high-risk recipients with comorbidities such as diabetes mellitus (DM).2,3 Concurrently, a growing number of cases of heart failure have been attributed to DM for the last several decades, and the proportion of diabetic candidates enrolled for heart transplantation is increasing.1,4
Aside from pre-existing DM, DM may also occur as a complication after heart transplantation, and this new-onset DM may further predispose the recipients to greater risk for overall mortality or other transplant-related adverse events.5 There are only a few studies, however, that provide comparative long-term data on clinical outcomes of heart transplant with new-onset DM; in addition, previous studies have yielded mixed results regarding such long-term clinical outcomes in these diabetic recipients diagnosed pre- and postoperatively.2,3,6–8
The aim of this study was therefore to assess the long-term survival and transplant-related adverse events in 3 recipient groups: (1) non-diabetic recipients; (2) those with pre-existing DM; and (3) those with new-onset DM to evaluate the clinical impact of new-onset DM after heart transplantation.
Between November 1992 and December 2013, a total of 391 consecutive patients aged ≥17 years underwent isolated orthotopic heart transplantation at the present institution, and the recipient demographic and clinical data were prospectively registered in the cardiac surgery database. Of these, 46 patients were diagnosed with DM preoperatively (pre-existing DM group), whereas 88 were newly diagnosed with DM after heart transplantation (new-onset DM group). These 2 diabetic groups were compared with the remaining non-diabetic patients (no-diabetes group, n=257).
The diagnosis of new-onset DM was made according to the criteria suggested by the American Diabetes Association:9 fasting blood glucose >126 mg/dL, and oral hypoglycemic agents and/or insulin therapy initiated postoperatively. Oral glucose tolerance test or glycated hemoglobin level were obtained as necessary to confirm the diagnosis of new-onset DM.8 Recipients were excluded if they had episodes of transient hyperglycemia (1) during immediate postoperative period (within 7 days); (2) during high-dose steroid therapy due to acute rejection; or (3) due to other causative factors such as i.v. nutritional support or sepsis.
Clinical data were retrieved from the institutional cardiac surgery database, and supplemented by reviewing individual patient medical records. This study was approved by the institutional ethics committee/review board with the requirement for informed consent waived due to the retrospective nature of the study.
Organ Procurement and Surgical TechniqueAll allograft hearts were harvested from brain-dead, heart-beating donors. Heart procurement and preservation were performed with cold histidine-tryptophan-ketoglutarate solution (Custodiol HTK; Essential Pharmaceuticals, Newtown, PA, USA), injected through the aortic root and topical cooling with slushed ice.
The surgical techniques for anastomosis have been described in a previous study.10 In brief, before 1999, heart transplantation was performed via the standard biatrial technique (n=53), whereas all recipients have undergone heart transplantation using the bicaval technique (n=338) thereafter.
Immunosuppression ProtocolBefore June 1999, the initial induction therapy consisted of cyclosporine 5 mg/kg and azathioprine 4 mg/kg (era 1, November 1992–May 1999).10 Since July 1999, interleukin-2 monoclonal antibody (Basiliximab) was introduced in the induction therapy protocol, and mycophenolate mofetil (CellCept; Roche Laboratories, Nutley, NJ, USA) has mainly replaced azathioprine in both induction and maintenance therapy protocols. The maintenance therapy protocol generally consists of the triple-drug combination of calcineurin inhibitors (cylcosporine or tacrolimus), anti-proliferative agents (azathioprine or mycophenolate mofetil), and corticosteroid. Cyclosporine was generally discontinued at serum creatinine >1.5 mg/dL. Cyclosporine was the main calcineurin inhibitor until January 2007 (era 2, June 1999–December 2006), when tacrolimus replaced cyclosporine and became the main calcineurin inhibitor used at the present institution (era 3, January 2007–December 2013). Corticosteroid (i.v. methylprednisolone 500 mg) was first introduced intraoperatively immediately before release of the aortic cross-clamp.10 Postoperatively, i.v. methylprednisolone was given at the initial dose of 1 mg/kg/day. After the recipients were extubated and started on oral medications, i.v. methylprednisolone was switched to oral prednisolone, which was gradually tapered down over 1 month to 0.20–0.25 mg/kg/day; the recipients who developed hyperglycemia after transplantation were treated with s.c. insulin injection during this period with a goal of serum hemoglobin A1c <7.0. After tapering the dose of corticosteroid, the recipients were treated with oral hypoglycemic agents when blood glucose level was normalized.
Outcomes of Interest, Definitions and Follow-upThe primary outcome of interest was all-cause death, which was chosen over cardiac death as the primary outcome because it is a more robust and unbiased index.11 The secondary outcomes of interest were transplant-related adverse events including cerebrovascular accident (CVA), cardiac allograft vasculopathy (CAV), moderate-severe rejection, severe chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. The other outcomes of interest were the composite of the primary and secondary outcomes including CAV-free survival, severe CKD-free survival, and moderate-severe rejection-free survival.
The diagnosis of CAV was made on retrospective review of all coronary angiography (CAG) performed in every patient 1 year after transplantation and every 2 years thereafter by protocol. CAV was deemed to be present if postoperative CAG showed one of the following abnormalities: (1) discrete lesions >50% of the primary vessels; or (2) diffuse or concentric narrowing of any vessels.12
The diagnosis of cellular rejection was made on endomyocardial biopsy, and the results were classified according to the International Society for Heart and Lung Transplantation (ISHLT) grading system;13 moderate-severe rejection was defined as biopsy result consistent with >2R. Endomyocardial biopsy was performed in every patient: weekly for the first month after transplantation, monthly for the next 3 months, and every 6–12 months thereafter by protocol.
CKD was considered to be severe for estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 or requirement for dialysis for 3 consecutive months after transplantation according to the classification of the National Kidney Foundation.14 CMV infection was defined as positive CMV antigenemia assay regardless of the presenting symptoms.15 CMV antigenemia assay was performed in every patient weekly for the first month after transplantation, then at every outpatient clinic visit after discharge during the next 11 months.
Follow-up was performed at the outpatient clinic, and the follow-up interval was determined according to need for adjustment of immunosuppressive regimen and hemodynamic status on a case-by-case basis.
Statistical AnalysisCategorical variables are expressed as percentages or frequencies, and continuous variables are presented as mean±SD or median (inter-quartile range [IQR]). Difference in baseline characteristics between the groups was compared using Student’s t-test or analysis of variance (ANOVA) for continuous variables, and chi-squared test for categorical variables.
To analyze the time interval between heart transplantation and the development of new-onset DM, time-varying Cox proportional hazards models were used: new-onset DM was regarded as a time-dependent variable in the evaluation of impact on mortality and other transplant-related events. Multivariate Cox analysis was performed to evaluate the simultaneous influence of other baseline variables (Table 1). Variables with P≤0.2 on univariate Cox analysis were incorporated into the multivariate Cox models. Multivariate Cox analysis used a backward elimination technique. In addition, Kaplan-Meier analysis were performed to delineate actuarial survival as well as CAV-free, severe CKD-free, and rejection-free survival. Log-rank tests were used to assess inter-group differences in survival. Also, landmark survival analysis was performed to separately analyze the early and late mortality outcomes across the 3 groups.16
| No DM (n=257) |
Pre-existing DM (n=46) |
New-onset DM (n=88) |
P value | |||
|---|---|---|---|---|---|---|
| Overall | No DM vs. new-onset DM |
Pre-existing DM vs. new-onset DM |
||||
| Age (years) | 42.0±13.5 | 56.7±8.6 | 49.3±9.8 | <0.001 | <0.001 | <0.001 |
| Male | 177 (68.9) | 33 (71.7) | 73 (83.0) | 0.028 | 0.016 | 0.196 |
| BMI (kg/m2) | 21.8±3.2 | 22.5±3.8 | 22.5±3.3 | 0.060 | 0.219 | >0.99 |
| Pre-transplant diagnosis | 0.112 | 0.102 | 0.610 | |||
| DCM | 175 (68.1) | 25 (54.3) | 51 (58.0) | |||
| ICM | 30 (11.7) | 12 (26.1) | 18 (20.5) | |||
| VCM | 21 (8.2) | 2 (4.3) | 5 (5.7) | |||
| CM, other causes | 18 (7.0) | 5 (10.9) | 6 (6.8) | |||
| Tumor | 5 (1.9) | 0 (0.0) | 0 (0.0) | |||
| Re-transplant | 1 (0.4) | 0 (0.0) | 1 (1.1) | |||
| Congenital | 1 (0.4) | 1 (2.2) | 1 (1.1) | |||
| Others | 6 (2.3) | 1 (2.2) | 6 (6.8) | |||
| Male recipient/female donor | 23 (8.9) | 5 (10.9) | 7 (8.0) | 0.854 | 0.947 | 0.808 |
| Comorbidities | ||||||
| Hypertension | 19 (7.4) | 14 (30.4) | 14 (15.9) | <0.001 | 0.033 | 0.082 |
| CKD | 8 (3.1) | 4 (8.7) | 1 (1.1) | 0.065 | 0.538 | 0.087 |
| COPD | 3 (1.2) | 1 (2.2) | 2 (2.3) | 0.715 | 0.816 | >0.99 |
| Peripheral vascular disease | 1 (0.4) | 2 (4.3) | 1 (1.1) | 0.048 | >0.99 | 0.563 |
| Systolic PAP (>50 mmHg) | 63 (24.5) | 23 (50.0) | 38 (43.2) | <0.001 | 0.001 | 0.569 |
| History of CVA | 17 (6.6) | 1 (2.2) | 6 (6.8) | 0.490 | >0.99 | 0.460 |
| Previous cardiac surgery | 34 (13.2) | 7 (15.2) | 17 (19.3) | 0.381 | 0.224 | 0.726 |
| Serum hemoglobin A1c (%) | – | 8.0±1.4 | – | |||
| Serum creatinine (mg/dL) | 1.0±0.4 | 1.2±0.5 | 1.1±0.5 | 0.071 | 0.245 | 0.191 |
| eGFR <30 mL/min/1.73 m2 | 3 (1.2) | 3 (6.5) | 1 (1.1) | 0.015 | 0.021 | 0.052 |
| Serum total bilirubin (mg/dL) | 1.8±2.4 | 1.3±0.7 | 1.9±1.3 | 0.985 | 0.701 | 0.002 |
| Era by immunosuppressant protocol |
0.016 | 0.123 | 0.043 | |||
| Era 1 | 47 (18.3) | 5 (10.9) | 8 (9.1) | |||
| Era 2 | 60 (23.3) | 4 (8.7) | 24 (27.3) | |||
| Era 3 | 150 (58.4) | 37 (80.4) | 56 (63.6) | |||
| Echocardiographic data | ||||||
| Peak TR pressure gradient (mmHg) |
34.9±15.2 | 44.2±15.0 | 40.3±16.3 | 0.001 | 0.005 | 0.175 |
| Tricuspid regurgitation grade | 0.952 | 0.850 | 0.833 | |||
| 0 | 41 (16.0) | 8 (17.4) | 16 (18.2) | |||
| 1 | 63 (24.5) | 10 (21.7) | 17 (19.3) | |||
| 2 | 45 (17.5) | 8 (17.4) | 18 (20.5) | |||
| 3 | 41 (16.0) | 10 (21.7) | 13 (14.8) | |||
| 4 | 67 (26.1) | 10 (21.7) | 24 (27.3) | |||
| Operation type | 0.264 | 0.182 | 0.982 | |||
| Standard technique | 40 (15.6) | 5 (10.9) | 8 (9.1) | |||
| Bicaval technique | 217 (84.4) | 41 (89.1) | 80 (90.9) | |||
| Hospitalized at time of transplant | 150 (58.4) | 22 (47.8) | 45 (51.1) | 0.268 | 0.291 | 0.856 |
| Mechanical ventilation | 11 (4.3) | 1 (2.2) | 8 (9.1) | 0.132 | 0.151 | 0.248 |
| Preoperative inotropic and MCS | ||||||
| Inotropes | 137 (53.3) | 25 (54.3) | 47 (53.4) | >0.99 | >0.99 | >0.99 |
| MCS | 9 (3.5) | 1 (2.2) | 6 (6.8) | 0.313 | 0.311 | 0.460 |
| Allograft total ischemic time (min) | 148.8±62.0 | 143.5±54.6 | 158.2±60.7 | 0.287 | 0.222 | 0.173 |
| Donors | ||||||
| Age (years) | 31.5±10.2 | 35.8±10.9 | 33.1±10.8 | 0.100 | 0.217 | 0.174 |
| Male gender | 201 (78.2) | 35 (76.1) | 75 (85.2) | 0.306 | 0.206 | 0.283 |
Data given as n (%) or mean±SD. BMI, body mass index; CKD, chronic kidney disease; CM, cardiomyopathy; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DCM, dilated cardiomyopathy; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ICM, ischemic cardiomyopathy; MCS, mechanical circulatory support; PAP, pulmonary artery pressure; TR, tricuspid regurgitation; VCM, valvular cardiomyopathy.
All reported P values are 2-sided, and the conventional P<0.05 was considered as statistically significant. R version 3.1.3 (http://www.r-project.org/), was used for statistical analysis.
Table 1 summarizes the baseline patient characteristics. The non-diabetic recipients were younger than those in the pre-existing and new-onset DM group. There were significant inter-group differences in the baseline characteristics including age (P<0.001), gender (P=0.028), and other morbidities including hypertension (HTN; P<0.001), high systolic pulmonary artery pressure (PAP, P<0.001) and severity of tricuspid regurgitation according to pressure gradient (P=0.001).
The anastomosis technique (P=0.264) according to surgical era was similar across the 3 groups. The total ischemic time for all recipients was 150.3±60.9 min, and there was no significant difference in the total ischemic time across the 3 groups (148.8±62.0 vs. 143.5±54.6 vs. 158.2±60.7 min; P=0.287).
New-Onset DMOf 345 non-diabetic patients before heart transplantation, 88 (25.5%) were diagnosed with new-onset DM. During follow-up, the cumulative incidence of new-onset DM was 17.1%, 21.2% and 22.7% at 2 months, 6 months and 1 year after transplantation, respectively with a median time to onset of 28 days (IQR, 19–108 days; Figure 1).
Cumulative incidence of new-onset diabetes mellitus (DM) in non-diabetic patients before heart transplantation.
Early death occurred in 8 patients (3.1%) in the no-diabetes group, while there was no early death in the pre-existing or new-onset DM group. Apart from early death, there were no significant differences in the rate of early major morbidities including mechanical circulatory support (P=0.909), early CVA (P=0.177), acute kidney injury requiring new dialysis (P=0.351), postoperative bleeding requiring re-exploration (P=0.278), or moderate-severe left ventricular primary graft dysfunction (PGD-LV; P=0.877; Table 2). The length of hospital (P=0.392) and intensive care unit stay (P=0.255) did not significantly vary across the 3 groups.
| No DM (n=257) |
Pre-existing DM (n=46) |
New-onset DM (n=88) |
P-value† | |||
|---|---|---|---|---|---|---|
| Overall | No DM vs. new-onset DM |
Pre-existing DM vs. new-onset DM |
||||
| Early outcomes | ||||||
| Early (<30 days) death | 8 (3.1) | 0 (0.0) | 0 (0.0) | 0.119 | 0.206 | – |
| Major early complications | ||||||
| Mechanical circulatory support | 7 (2.7) | 1 (2.2) | 3 (3.4) | 0.909 | >0.99 | >0.99 |
| CVA (<30 days) | 1 (0.4) | 0 (0.0) | 2 (2.3) | 0.177 | 0.328 | 0.780 |
| Requirement for new dialysis | 19 (7.4) | 2 (4.3) | 3 (3.4) | 0.351 | 0.286 | >0.99 |
| Bleeding requiring re-exploration | 26 (10.1) | 4 (8.7) | 4 (4.5) | 0.278 | 0.167 | 0.563 |
| Moderate-severe PGD-LV | 25 (9.7) | 4 (8.7) | 7 (8.0) | 0.877 | 0.778 | >0.99 |
| Hospital stay (days) | ||||||
| ICU stay | 8.0±7.8 | 6.3±2.1 | 7.3±4.2 | 0.255 | 0.274 | 0.073 |
| Postoperative hospital stay | 31.6±12.3 | 33.0±8.6 | 32.8±12.4 | 0.392 | 0.463 | 0.878 |
| Late outcomes | ||||||
| All-cause death/re-transplantation | 41/2 (16.7) | 12/0 (26.1) | 23/0 (26.1) | 0.011 | 0.035 | 0.364 |
| Cardiac death/re-transplantation | 25/2 (10.5) | 7/0 (15.2) | 14/0 (15.9) | 0.334 | 0.185 | >0.99 |
| Non-cardiac death | 16/0 (6.2) | 5/0 (10.9) | 9/0 (10.2) | 0.327 | 0.235 | >0.99 |
| Transplant-related adverse events | ||||||
| CVA | 11 (4.3) | 4 (8.7) | 4 (4.5) | 0.114 | 0.586 | 0.244 |
| CAV | 36 (14.0) | 5 (10.9) | 15 (17.0) | 0.559 | 0.310 | 0.651 |
| Moderate-severe rejection | 38 (14.8) | 4 (8.7) | 11 (12.5) | 0.705 | 0.615 | 0.818 |
| Severe CKD | 24 (9.3) | 7 (15.2) | 14 (15.9) | 0.027 | 0.027 | 0.850 |
| CMV infection | 121 (47.1) | 26 (56.5) | 57 (64.8) | 0.012 | 0.003 | 0.185 |
| Composite of death and transplant-related events |
177 (68.9) | 36 (78.2) | 75 (85.2) | 0.001 | 0.001 | 0.231 |
Data given as n (%) or mean±SD. †Chi-squared test for early outcome except hospital stay (days), and log-rank test for late outcome (Student’s t-test or ANOVA for hospital stay). CAV, cardiac allograft vasculopathy; CMV, cytomegalovirus; ICU, intensive care unit; LV, left ventricular; PGD, primary graft dysfunction. Other abbreviations as in Table 1.
Follow-up was complete in all recipients. During a median follow-up period of 5.4 years (IQR, 2.8–9.5 years), 78 patients (19.9%) died or underwent re-transplantation (n=2), and 270 (69.1%) had transplant-related adverse events. A difference in the overall survival rate was observed between the diabetic and the non-diabetic groups (no-diabetes vs. pre-existing DM vs. new-onset DM, 16.7% vs. 26.1% vs. 26.1%; P=0.011). Regarding transplant-related adverse-events, event-free rates were similar between the 3 groups except for severe CKD and CMV infection: CVA (P=0.114), CAV (P=0.559), moderate–severe rejection (P=0.705), severe CKD (P=0.027) and CMV infection (P=0.012).
On multivariate Cox proportional hazards analysis, male gender (P=0.039), pre-existing (P=0.006) and new-onset DM (P=0.005) and serum total bilirubin (P<0.001) were significant risk factors for all-cause mortality (Table 3). New-onset DM was associated with an increased risk for cardiac death (hazard ratio [HR] 2.35; 95% CI: 1.20–4.62; P=0.013). On Kaplan-Meier analysis there was a significant difference in the rate of overall survival (P=0.011), CAV-free survival (P=0.018), and severe CKD-free survival (P=0.002) favoring the non-diabetic patients over the either pre-existing or new-onset DM patients (Figure 2). In contrast, the 2 diabetic groups had no significant differences in the rate of overall survival (P=0.364), CAV-free survival (P=0.752), severe CKD-free survival (P=0.278) or moderate-severe rejection-free survival (P=0.621). On landmark survival analysis, differences in overall survival and CAV-free survival were mainly attributed to differences in the late post-transplant period (5-year landmark, P<0.001 for overall survival and P=0.001 for CAV-free survival), while there was no significant difference in the survival rate within the first 5 years across the 3 groups (P=0.709 for overall survival and P=0.496 for CAV-free survival; Figure 3A,B).
| Variable | Univariate | Multivariate | ||
|---|---|---|---|---|
| P value | HR | 95% CI | P value | |
| All-cause death | ||||
| Age | 0.185 | |||
| Male | 0.091 | 1.86 | 1.03–3.33 | 0.039 |
| Pre-existing DM | 0.038 | 2.46 | 1.30–4.68 | 0.006 |
| New-onset DM† | 0.001 | 2.11 | 1.26–3.55 | 0.005 |
| Male recipient/female donor | 0.192 | |||
| Serum total bilirubin | <0.001 | 1.19 | 1.11–1.27 | <0.001 |
| Peak TR pressure gradient | 0.060 | |||
| Allograft total ischemic time | 0.181 | |||
| Cardiac death | ||||
| Male gender | 0.062 | |||
| Male recipient/female donor | 0.158 | |||
| New-onset DM† | 0.014 | 2.35 | 1.20–4.62 | 0.013 |
| Hypertension | 0.079 | |||
| Serum total bilirubin | <0.001 | 1.16 | 1.07–1.26 | <0.001 |
| Previous cardiac surgery | 0.182 | |||
| Allograft total ischemic time | 0.038 | 1.01 | 1.00–1.01 | 0.020 |
| Non-cardiac death | ||||
| Age | 0.003 | 1.05 | 1.02–1.09 | 0.004 |
| Hypertension | 0.106 | |||
| Pre-existing DM | 0.073 | |||
| New-onset DM† | 0.060 | |||
| Serum total bilirubin | 0.001 | 1.18 | 1.06–1.31 | 0.002 |
| Peak TR pressure gradient | 0.109 | |||
†Time-varying Cox proportional hazards ratio analysis. Only variables with P≤0.20 on univariate analysis were included in the multivariate analysis. Abbreviations as in Table 1.
Kaplan-Meier curves delineating (A) overall survival, (B) cardiac allograft vasculopathy (CAV)-free survival, (C) severe chronic kidney disease (CKD)-free survival, and (D) moderate-severe rejection-free survival vs. the no diabetes mellitus (DM), pre-existing and new-onset DM groups.
Kaplan-Meier curve for (A) cumulative all-cause mortality, (B) composite of cumulative all-cause mortality and cardiac allograft vasculopathy (CAV), and (C) composite of cumulative all-cause mortality and severe chronic kidney disease (CKD) at 5 years on landmark survival analysis.
On multivariate logistic regression analysis, several independent risk factors for new-onset DM were identified: advanced age (≥50 years; P=0.001), male gender (P=0.009), and high systolic PAP (>50 mmHg; P=0.004). HTN (OR, 2.14; 95% CI: 1.02–4.46; P=0.043) and ischemic cardiomyopathy (ICM; OR, 1.81; 95% CI: 0.95–3.45; P=0.070) were identified as significant risk factors for new-onset DM on univariate analysis, but were not included in the final stage of multivariate analysis (Table 4).
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P value | OR | 95% CI | P value | |
| Age ≥50 for recipient | 2.38 | 1.45–3.90 | 0.001 | 2.32 | 1.39–3.86 | 0.001 |
| Male recipient | 2.20 | 1.19–4.07 | 0.012 | 2.33 | 1.23–4.39 | 0.009 |
| Male donor | 0.158 | |||||
| ICM vs. non-ICM | 1.95 | 1.02–3.70 | 0.042 | |||
| Operation type | 0.135 | |||||
| Immunosuppressant protocol | ||||||
| Era 1 vs. era 2 | 0.059 | |||||
| Era 1 vs. era 3 | 0.057 | |||||
| Creatinine | 0.175 | |||||
| Hypertension | 2.37 | 1.13–4.96 | 0.022 | |||
| Systolic PAP >50 mmHg | 2.34 | 1.41–3.89 | 0.001 | 2.16 | 1.28–3.66 | 0.004 |
| Previous cardiac surgery | 0.167 | |||||
| Preoperative MCS | 0.196 | |||||
Only variables with P≤0.20 on univariate analysis were included in multivariate analysis. Abbreviations as in Table 1.
Table 5 lists the results of risk analysis of pre-existing- and new-onset DM affecting all-cause death and transplant-related adverse events. On univariate time-varying Cox analysis, pre-existing DM was associated with increased risk of all-cause death (P=0.038), CVA (P=0.039) and severe CKD (P=0.025), whereas new-onset DM significantly influenced the increased risk of all-cause death (P=0.001) and tended to be associated with increased risk for severe CKD (P=0.078). On multivariate analysis, both pre-existing (HR, 2.46; 95% CI: 1.27–4.77; P=0.006) and new-onset DM (HR, 2.11; 95% CI: 1.26–3.55; P=0.005) were associated with increased risks of all-cause death.
| Outcomes | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Pre-existing DM vs. no DM | ||||||
| All-cause death | 2.15 | 1.12–4.12 | 0.038 | 2.46 | 1.30–4.68 | 0.006 |
| Transplant-related adverse events | ||||||
| CVA | 3.47 | 1.06–11.28 | 0.039 | 1.42 | 0.35–5.71 | 0.625 |
| CAV | 1.15 | 0.44–2.96 | 0.780 | 0.59 | 0.19–1.85 | 0.361 |
| Moderate-severe rejection | 0.67 | 0.24–1.88 | 0.442 | 1.05 | 0.34–3.22 | 0.936 |
| Severe CKD | 2.69 | 1.13–6.42 | 0.025 | 1.18 | 0.40–3.43 | 0.767 |
| New-onset DM vs. no DM | ||||||
| All-cause death | 2.27 | 1.35–3.81 | 0.001 | 2.11 | 1.26–3.55 | 0.005 |
| Transplant-related adverse events | ||||||
| CVA | 0.88 | 0.19–4.06 | 0.870 | 0.83 | 0.17–1.27 | 0.820 |
| CAV | 1.77 | 0.96–3.26 | 0.067 | 1.36 | 0.70–2.66 | 0.367 |
| Moderate-severe rejection | 0.83 | 0.37–1.87 | 0.656 | 1.32 | 0.56–3.10 | 0.521 |
| Severe CKD | 1.77 | 0.94–3.34 | 0.078 | 1.60 | 0.75–3.42 | 0.228 |
Only variables with P≤0.20 on univariate analysis were included in multivariate analysis. Abbreviations as in Tables 1,2.
The key findings of this study are as follows: (1) non-diabetic patients had superior survival/event-free survival rates and freedom from severe CKD after heart transplantation compared with new-onset or pre-existing DM patients; (2) there was no significant difference in long-term overall or event-free survival rate between the new-onset DM and the pre-existing DM groups; and (3) advanced age (>50), male gender, and high systolic PAP were significant risk factors for new-onset DM.
Heart transplantation is the treatment of choice for end-stage heart failure, and overall clinical outcomes such as post-transplant survival rate have improved in recent years.1 Along with these clinical advancements, the spectrum of transplant candidates has been widened to include more morbidities: the proportion of patients with pre-existing DM enrolled for heart transplantation is increasing.1,17 Uncontrolled DM, however, may predispose the transplant candidates to preoperative end-organ damage such as CKD or CVA, and increased mortality and morbidity after heart transplantation.2 For these reasons, pre-existing complicated DM is still considered a relative contraindication for heart transplantation,18,19 but previous studies on the impact of pre-existing DM on overall mortality after heart transplantation showed mixed results: Klingenberg et al reported on a series of 243 patients receiving heart transplantation and noted better long-term survival in the non-diabetic recipients (P=0.004) compared with the recipients with pre-existing DM.7 In contrast, Russo et al reported that the survival rates after heart transplantation were similar between the uncomplicated diabetic and the non-diabetic patients.2
Meanwhile, new-onset DM has not attracted as much clinical attention as pre-existing DM, and there are few studies on its impact on clinical outcomes after heart transplantation.20 Klingenberg et al reported in the aforementioned study that the overall survival rate was similar between the non-diabetic (n=151) and new-onset DM patients (n=39; P=0.50),7 and Cho et al also reported that the mid-term survival rate was not significantly different (92.9±4.1% vs. 85.8±3.2%; P=0.22) between the non-diabetic (n=140) and new-onset DM patients (n=54).8 The present study involved a larger cohort of new-onset DM patients (n=88) during a longer follow-up period (median, 5.4 years; IQR, 2.8–9.5 years) and the new-onset DM as well as the pre-existing DM patients had worse survival outcomes compared with the non-diabetic patients. We speculate that new-onset DM may affect survival in a similar fashion to uncomplicated DM in the short term, but act in a complicated fashion as DM progresses, eventually resulting in worse survival in the long term;2,7 as shown on landmark survival analysis (Figure 3), the survival difference mainly stemmed from the late post-transplant period (5-year landmark, P<0.001). This appears to reflect the time interval in which DM progression worsens survival. We speculate that the use of landmark survival analysis is the unique strength of this study because many of the biases inherent in disease with variable onset such as new-onset DM could be adjusted for, using this analysis technique. The lower survival rate in the new-onset DM group may not be surprising given the higher age in the new-onset DM group compared with the no-diabetes group (49.3±9.8 vs. 42.0±13.5 years; P<0.001). After adjusting for other risk factors including age, however, new-onset DM was still significantly associated with the increased risk for all-cause death (HR 2.11; 95% CI: 1.26-3.55; P=0.005).
The detrimental influence of DM on the progression of kidney disease is well established, and this may be further corroborated by the present study, in which the no-diabetes group had the superior severe CKD-free rate compared with the pre-existing (P=0.020) and new-onset DM group (P=0.027). On univariate risk analysis, pre-existing DM was associated with increased risk of severe CKD (HR, 2.69; 95% CI: 1.13–6.42; P=0.025), whereas new-onset DM strongly tended to affect the increased risk for severe CKD (HR, 1.77; 95% CI: 0.94–3.34; P=0.078). This indicates that the detrimental effects of new-onset DM may be less severe than those of pre-existing DM, presumably due to the shorter duration of DM. In contrast to severe CKD, the risk of developing CAV was significantly affected by neither pre-existing DM (P=0.780) nor new-onset DM (P=0.067) on univariate risk analysis, and there was no significant difference in the CAV-free rates across the 3 groups (P=0.559). As suggested by Kato et al, glucose intolerance may contribute to the development of CAV,21 but other risk factors rather than DM may play a more important role in the development of CAV, such as lipid abnormalities or an underlying immunologic mechanism.22 In the present institution, we routinely start the recipients on statin therapy irrespective of low-density lipoprotein cholesterol (LDL-C) level within 1 month after transplantation. We adjust the dose of statin to maintain LDL-C <100 mg/dL. In the present cohort, 286 recipients (73.1%) developed hyperlipidemia after heart transplant. On time-varying Cox modeling, however, post-transplant hyperlipidemia was not associated with an increased risk for the progression of CAV (HR, 1.62; 95% CI: 0.84–3.10; P=0.147).
Other comorbidities, such as HTN, may have influenced the development of CKD or CAV after heart transplantation. In this study, pre-transplant HTN was associated with an increased risk for CKD (HR, 2.27; 95% CI: 1.09–4.72; P=0.028). The causal relationship between high blood pressure (BP) and the development of CKD after heart transplantation, however, was difficult to investigate because all recipients with high BP after heart transplant were treated with anti-HTN medications to maintain systolic BP <140 mmHg. In contrast, pre-transplant HTN was not a risk factor for the development of CAV after heart transplantation (HR, 1.21; 95% CI: 0.55–2.68; P=0.636). In the management of high BP, we did not use renin-angiotensin system blockers (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker) because these agents have the potential to induce hyperkalemia or reduction in GFR, thereby causing life-threatening hyperkalemia or nephrotoxicity in recipients taking calcineurin inhibitors.
Given the detrimental impacts of new-onset DM on survival and renal function, we performed a risk analysis in an attempt to identify the modifiable risk factors for new-onset DM: male gender (P=0.009), advanced age (≥50 years; P=0.001) and high systolic PAP (>50 mmHg; P=0.004) emerged as significant predictors for new-onset DM on multivariate analysis. ICM was also associated with the development of new-onset DM on univariate analysis. These results are partly consistent with previous studies that identified old age and ICM as risk factors.8,23 In this study, we could not identify any modifiable risk factors, and the immunosuppressant choice did not affect the development of new-onset DM. Despite the reported higher incidence of new-onset DM in solid-organ transplant recipients receiving tacrolimus,24 in the present study there was no difference in the incidence of new-onset DM between the era 2 (cyclosporine) and era 3 (tacrolimus) groups (28.6% vs. 27.2%; P=0.885). Likewise, immunosuppression treatment with steroid is a well-known risk factor for the development of new-onset DM after transplantation. Particularly, high-dose steroid use and the duration of therapy were clearly associated with the increased risk of new-onset DM. Under our steroid-use protocol, 88 (25.5%) patients developed new-onset DM, which is comparable to the incidence of new-onset DM reported by ISHLT.1 Among 88 patients with new-onset DM, 63 (71.6%) and 77 (87.5%) developed new-onset DM within 3 months and 12 months after transplantation, respectively. During follow-up at the outpatient clinic, steroid could be tapered out in 323 patients (82.6%) at 1 year after heart transplantation.
Interestingly, we found that high systolic PAP was identified as a significant risk factor for new-onset DM. Of note, Hansmann et al noted in their animal model that insulin resistance may be a predisposing factor for pulmonary HTN.25 From this we inferred that high systolic PAP in the present study may have acted as a surrogate marker for insulin resistance. But, clearly, this inference warrants further study. Although the identified risk factors for new-onset DM were not potentially modifiable, recipients with these risk factors may require close monitoring and timely control of new-onset DM to minimize the potential complications.
Study LimitationsThis study was subject to the limitations inherent in retrospective analysis with single-center observational data. The present results could also have been affected by undetected confounders and detection bias. Also, the subjects belonged to a single Asian ethnic group except for 1 patient, who was Caucasian, therefore, these results may not be generalized to the non-Asian patients undergoing heart transplantation.
New-onset DM as well as pre-existing DM is associated with increased risk of overall death and may confer additional risk for impaired kidney function in heart-transplant recipients. The long-term survival in the new-onset DM group was not significantly different from that in the pre-existing DM group, and the survival difference between this and the no-diabetes group mainly stemmed from the late postoperative period. Further studies are warranted to investigate the relevance of early diagnosis and timely control of new-onset DM for improvement of long-term survival and reduction of transplant-related adverse events.
The authors declare no conflict of interest.
