17 November 2017: Original Paper
Heart Transplantation and Risk of Cardiac Vasculopathy Development: What Factors Are Important?
Małgorzata Sobieszczańska-Małek ABCDEF 1*, Jerzy Korewicki ADF 1, Krzysztof Komuda BDF 1, Małgorzata Karczmarz BDF 1, Sylwia Szymańska BDE 2, Alicja Cicha-Mikołajczyk CD 3, Paweł Bekta BD 4, Adam Parulski BD 5, Maciej Pronicki BD 2, Wiesława Grajkowska BD 6, Grzegorz Małek BCE 7, Przemysław Leszek CE 8, Maria Kaczorowska BF 9, Mariusz Kuśmierczyk AD 5, Tomasz Zieliński ACDEG 8
DOI: 10.12659/AOT.905267
Ann Transplant 2017; 22:682-688
Abstract
BACKGROUND: The aim of this study was to find the main risk factors for development of cardiac allograft vasculopathy (CAV), especially factors identified before the surgical procedure and factors related to the recipient profile and the medical history of the donor.
MATERIAL AND METHODS: There were 147 patients who had heart transplantation (HT) included in this study: mean age was 45.8±15.3 years. All study patients had coronary angiography after HT. Analyzed risk factors were: non-immunologic recipient risk factors (age of transplantation, smoking, hypertension, lipids, diabetes, obesity and weight gain after HT), immunologic recipient risk factors (acute cellular rejection (ACR), acute humoral rejection (AMR), cytomegalovirus (CMV) episodes), and donor-related risk factors (age, sex, catecholamine usage, ischemic time, compatibility of sex and blood groups, cause of death, cardiac arrest).
RESULTS: CAV was recognized in 48 patients (CAV group); mean age 53.6±13.6 years. There were 99 patients without CAV (nonCAV group); mean age 48.3±15.5 years. A univariate Cox analysis of the development of coronary disease showed statistical significance (p<0.05) for baseline high-density lipid (HDL), ACR, AMR, CMV, and donor age. Multivariate Cox regression model confirmed that only baseline HDL, episodes of ACR, donor age, and CMV infection are significant for the frequency of CAV after HT.
CONCLUSIONS: Older donor age is highly associated with CAV development. Older donor age and low level of HDL in heart recipients with the strongest influence of immunologic risk factors (ACR, CMV infection) were linked with development of CAV.
Keywords: Coronary Artery Disease, Heart Transplantation, Risk Factors
Background
Cardiac transplantation is a lifesaving therapy for patients with end-stage heart disease. Remarkable progress has been made in terms of controlling acute rejection of the transplanted heart. Nevertheless, three years after the transplantation, cardiac allograft vasculopathy (CAV), malignancy, and renal failure become common causes of death [1]. For this reason, the task of decreasing the burden of CAV in transplanted hearts has become one of the main goals of care in the transplantology arena. Prophylactic strategies have demonstrated significant improvements in long-term prognosis. These include control of classical risk factors for vascular disease (e.g., hyperlipidemia, obesity, hypertension, smoking, and diabetes) as well as controlling immunological risk factors: treatment of acute rejection and cytomegalovirus (CMV) infection, and type of immunosuppression therapy. Donor-related risk factors constitute a separate group of risk factors and encompass donor age, cause of brain death, and ischemia time.
The aim of this study was to find the main risk factors for development of CAV, especially factors identified before the surgical procedure and related to the recipient profile and the medical history of the donor. This study was conducted in one medical center in Poland.
Material and Methods
STATISTICAL ANALYSIS:
Continuous variables were presented as median and quartiles, categorical variables were presented as n (%). Wilcoxon rank sum test, chi-square test or Fisher’s exact test were used for analysis of patient characteristics as appropriate. Cox proportional hazard models were used to evaluate the risk factors of the development of coronary artery disease after orthotopic HT. The following factors were thought to affect the hazard of CAV: recipient age and sex, baseline values of recipient cholesterol LDL, HDL, TG, BMI, level of catecholamine, and ischemic time during transplantation, compatibility of sex and blood groups between donor and recipient, donor age, sex, and cause of death, sudden cardiac arrest, status of hypertension, diabetes and smoking, immunological factors such as ACR, AMR, and CMV.
The univariable Cox proportional hazards models were developed for each covariate and the final multivariable regression model, which was based on HDL, ACR, CMV, and donor age.
All analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA) and a
The proportional hazard assumption was checked using Schoenfeld’s residuals, martingale residuals, and cumulative martingale residuals in PROC PHREG. The
Results
Among 147 patients included into the study, CAV was identified in 48 patients (39 men), mean age 53.6±13.6 years (the CAV group). Patients without CAV (the nonCAV group) included 99 patients (80 men), mean age 48.3±15.5 years. Patients in the CAV group were older than patients in the nonCAV group,
There was no significant difference between patient survival and developing CAV (log-rank test chi-squared=0.0021
Coronary disease risk factors were compared for the CAV group and the nonCAV group.
Donor-related parameters were measured. In the CAV group, donors were significantly older (38 years versus 30 years,
Non-immunologic recipient risk factors were measured. No significant differences were found between the CAV group and the nonCAV group in the following: frequency of arterial hypertension, new onset of diabetes, smoking, and weight gain. There were also no statistically significant differences in LDL, HDL, and TG levels between the two groups.
Immunologic recipient risk factors were measured. ACR, AMR, and CMV infection were analyzed. Comparing the CAV group versus the nonCAV group, we found a significantly higher proportion of ACR (39.6% versus 18.2%,
A univariate analysis of the influence of separate factors on the development of coronary disease was conducted. It showed statistical significance (
A multivariate regression model for all risk factors was applied. We discovered that only baseline HDL concentration, episodes of ACR, age of donor, and CMV infection were significant for the frequency of CAV after HT (Table 2). The estimated survivor function curves of freedom from CAV according to the presence or absence of immunological factors (ACR, CMV) or their combination, for average HDL-level (1.43 mmol/L) and donor age (32.2 years) are presented in Figure 3. The combination of the presence of ACR episodes and CMV infection was linked with the worst chance of freedom of CAV for heart transplant patients. Each of those factors deteriorates prognosis separately, but CMV infection had the most negative influence.
Discussion
LIMITATIONS:
This study was retrospective in terms of AMR incidence analysis (C4d) and for this reason most patients did not receive AMR treatment. Other host immune factors, including HLA mismatch and the presence of anti-HLA class I or class II antibodies, were not analyzed. We could not define the impact of immunosuppression on vasculopathy.
In the years 2001–2008 cyclosporine A was the basic immunosuppression treatment. Since 2009, TAC has been used. Additionally, mTOR inhibitors (everolimus/sirolimus) were used starting in 2005. Patients with CAV or cancer were given mTOR instead of MMF. This change in therapy made assessment of CAV in relation to used drugs difficult.
According to this study, older donor age plays an important role in the risk of CAV, especially in connection with immunologic factors such as ACR and CMV infections. It has become very clear that this specific group of patients should be under close scrutiny for CAV after HT.
Conclusions
In conclusion, 1) older donor age is highly associated with CAV development, and 2) older donor age and low level of HDL in heart recipients with the strongest influence of immunologic risk factors (ACR, CMV infection) are linked with development of CAV.
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