The Pre-Transplant Profile of Cardiovascular Risk Factors and Its Impact on Long-Term Mortality After Liver Transplantation

Background

The recent European Society of Cardiology (ESC) and European Society of Anesthesiology (ESA) guidelines on cardiovascular assessment and management before non-cardiac surgery list orthotopic liver transplantation (OLT) as a type of procedure with high risk of cardiovascular death and myocardial infarction within 30 days of surgery [1].

Cardiovascular disease (CVD) is an important aggravating factor for OLT outcomes. Patients with coronary artery disease (CAD) treated either medically or surgically before OLT were reported to have 3-year mortality of 50% and morbidity of 81% [2]. CVD was also found to be the third most common cause of death in the 5-year post-transplant period, accounting for 12–16% of deaths [3], and the calculated 10-year post-transplant CVD risk was estimated to be 7.9% in a Framingham study population [4]. The risk of CAD in OLT candidates has not been accurately defined. The routine screening tests for CAD should be further evaluated in this group of patients. Nevertheless, there are some limited data available regarding the optimal strategy of risk assessment during OLT candidate evaluation.

Material and Methods

ESDL SEVERITY:

The following data were retrospectively recorded: demographic characteristics, laboratory results, cardiovascular risk factors, ESLD etiology (alcoholic, viral, nonalcoholic steatohepatitis, cryptogenic, or other), severity of liver disease (the Child-Pugh classification and model for end stage liver disease (MELD score), ascites, gastroesophageal varices, and history of overt encephalopathy. The term “compensated disease” refers to Child-Pugh class A and “decompensated disease” includes Child-Pugh class B and C.

CARDIOVASCULAR RISK FACTORS:

The cardiologist obtained medication history for CAD and heart failure, previous myocardial revascularization procedures, renal failure, and previous stroke. The cardiovascular risk factors recorded were advanced age (men ≥55 years old and women ≥65 years old), diabetes mellitus, hypertension, hyperlipidemia, smoking habit, and family history positive for premature CAD.

ECHOCARDIOGRAPHIC EXAMINATION:

Transthoracic echocardiographic examinations were performed in all patients at the echocardiography laboratory by experienced cardiologists using a Philips iE33 ultrasound system. The echocardiographic variables recorded were chamber sizes, valvular dysfunction, diastolic dysfunction, intracardiac and intrapulmonary shunting, contractility abnormalities, and ejection fraction (EF). Left ventricular EF was determined by Simpson’s method, with reduced EF diagnosed below 50%. Additionally, echocardiography studies with agitated saline contrast (“bubble”) were performed in 96 patients (53.3%).

EXERCISE TESTING:

According to the algorithm used in our hospital at that time, we performed exercise testing in routine cardiac assessment for OLT. Every exercise test was performed on a treadmill using Bruce protocol or modified Bruce protocol. What made an exercise test positive was the presence of a typical horizontal or down-sloping ST-segment depression at least 0.1 mV in at least one lead.

CAG:

The consulting cardiologist could order CAG based on a previous history of cardiovascular events, CVD, at least 2 cardiovascular factors, or abnormal exercise test results. Coronary angiographies were performed via a radial approach and at the time of qualification for liver transplantation.

FOLLOW-UP:

This study was a single-center study, with a register-based follow-up design. We used the Polish Civil Personal Registration Numbers, which are unique to each Polish citizen, to link the information from the national registry of deaths at the Ministry of the Interior and Administration to the clinical data obtained in this study.

The single endpoint of the study was all-cause mortality. Observations were censored at the date of last available follow-up (July 18, 2014).

STATISTICAL METHODS:

The patients were categorized into 2 groups according to post-OLT survival. Continuous variables were summarized as means ± standard deviation, whereas frequencies and percentages were used for categorical variables. Unpaired t-tests were used for comparison of continuous normally distributed variables. Differences between dead and alive patients at the end of follow-up were analyzed by the independent-samples t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data.

Multivariate analyses (by stepwise multivariate model building) were assessed with a Cox proportional hazards model. Hazard ratios were presented with 95% confidence intervals. The corresponding Kaplan-Meier curves for stroke occurrences were also plotted, and then compared using log-rank test. Statistical significance for all analyses was determined at P<0.05. All analyses were undertaken by using STATISTICA version 12 software.

DATA INTEGRITY:

The authors had full access to the data sets and vouch for data integrity. All authors have read and approved this form of the manuscript. The study was approved by the Ethics Committee at the Medical University of Warsaw.

Results

BASELINE CHARACTERISTICS:

Patient baseline characteristics and clinical aspects of ESLD are shown in Table 1. The most common indications for liver transplantation were viral cirrhosis (45%), alcoholic cirrhosis (18.1%), and autoimmune cirrhosis (20.6%). The average age was 49 years; 61.9% of the patients were male.

HISTORY OF CARDIOVASCULAR DISORDERS:

The prevalence of pre-transplant cardiovascular risk factors in patients with ESLD in our study population are shown in Table 2.

History of cardiovascular disorders or cardiovascular risk factors were present in 37 patients (23.1%). The cardiovascular risk factors most common in our group of patients with ESLD were hypertension (41 patients; 25.6%), diabetes (42; 26.3%), and hepatopulmonary syndrome (37; 23.1%). Forty-one patients had a history of hypertension, but no patient had elevated blood pressure at the time of cardiac consultation. No patient had previous myocardial infarction, but 4 patients (2.5%) had had a revascularization procedure (3 percutaneous coronary angioplasties and 1 coronary artery bypass grafting). Eight patients (5%) had a known history of CAD.

ECHOCARDIOGRAPHY:

Systolic dysfunction with a reduced EF (below 50%) was found only in 1 patient in the whole population of transplantation patients with ESLD. In a subgroup of 96 patients (53.3%) whom had agitated saline contrast (“bubble”) studies performed, intrapulmonary shunts were reported in 37 patients (38.5%) and intracardiac shunts in 2 patients.

EXERCISE TEST:

Only 6 patients (3.8%) had positive exercise tests with electrocardiographic abnormalities. Those patients had a consult by a cardiologist and then referred for CAG.

CAG:

CAG was done in 12 patients (7.5%), and 3 of whom it revealed at least 50% stenosis in some epicardial arteries. All CAG patients had single-vessel coronary disease, and none had indication for further coronary revascularization prior to liver transplantation.

FOLLOW-UP:

Overall, there were 18 post-liver-transplantation deaths (11.3%) in the study population, with no observed cases of sudden cardiac death during the hospital stay. The mean follow-up period was over 2 years (736.5±260.6 days). The mean time spent on the transplant waiting list was approximately 3 months (110.2±101.3 days). This contributed to the 21-month follow-up in patients with a successful liver transplantation (626.4±250.7 days). In a multivariate analysis of patient characteristics, the risk of death in long-term post-liver-transplantation follow-up was most strongly associated with 3 variables: history of CAD, angiographically confirmed coronary stenosis, and left ventricular EF below 50% (Table 3).

Figure 2 shows the cumulative incidence of death during an over 2-year follow-up period in patients with coronary artery lesions on CAG versus patients without CAD.

Kaplan-Meier curves of survival in patients with history of CAD versus patients without history of CAD are presented in Figure 3.

Discussion

STUDY LIMITATIONS:

There were several limitations of our study. First, it was a the single-center study conducted in a retrospective manner. We did not correlate long-term mortality with the potential occurrence of perioperative cardiovascular events. We could not identify the cause of death because the exact information on the death and the time of death was not available. Based on this data we have planned other prospective studies including biomarker analysis, cardiopulmonary exercise testing, and follow-up.

Conclusions

According to our knowledge, this is the first European study concerning a prognostic impact of the pre-transplant CVD risk factor profile on long-term mortality after OLT, which indicates that the risk of death in long-term follow-up of liver transplant recipients was most strongly associated with 3 cardiac variables: history of CAD, angiographically confirmed coronary stenosis, and reduced left ventricular EF. However, the number of death was quite low but still had the prognostic impact. There is one point-based prediction model (risk score) for major 1-year CVD complications after OLT recently published, but the Cardiovascular Risk in Orthotopic Liver Transplantation risk score was not yet validated in European population [25] at the time of our study.