Posttransplant cardiovascular (CV) complications are the leading cause of non–graft-related death for orthotopic liver transplantation (OLT) patients.1 Although the high incidence of posttransplant CV events is regarded as multifactorial, the increased prevalence of metabolic syndrome, which is attributed to immunosuppressant therapy and end-stage liver disease, likely plays a role. End-stage liver disease leads to metabolic disturbances that alter lipid, glucose, and blood pressure levels considerably; for instance, hepatitis C virus (HCV) has been associated with an elevated risk of diabetes.2 With a national shortage of donors, the selection of candidates who are likely to benefit the most and live the longest after receiving a liver transplant is a priority. As liver transplant techniques advance and older and higher risk patients undergo transplantation, CV events are likely to increase. Therefore, our aim was to determine the overall cumulative risk of CV events after OLT and identify the predictors of CV events after liver transplantation.
As survival after orthotopic liver transplantation (OLT) improves, cardiovascular (CV) disease has emerged as the leading cause of non–graft-related deaths. The aims of our study were to determine the cumulative risk of CV events after OLT and to analyze predictive risk factors for those experiencing a CV event after OLT. We identified all adult patients who underwent OLT at our institution for end-stage liver disease between October 1996 and July 2008. The cumulative risk of CV events after OLT was analyzed with the Kaplan-Meier method. Multivariate logistic regression analysis was used to identify factors independently associated with CV events after OLT. In all, 775 patients were included in our study cohort (mean age of 53.3 years, female proportion = 44%, Caucasian proportion = 84%, median follow-up = 40 months). The most common indications for OLT were hepatitis C virus (33.2%), alcohol (14.5%), and cryptogenic cirrhosis (12.7%). Eighty-three patients suffered 1 or more CV events after OLT. Posttransplant metabolic syndrome was more prevalent in patients with CV events versus patients with no CV events (61.4% versus 34.1%, P < 0.001). According to a multivariate analysis, independent predictors of CV events were an older age at transplantation [odds ratio (OR) = 1.2, addition of 95% confidence interval (CI) = 1.1-1.3, P = 0.006], male sex (OR = 2.0, 95% CI = 1.2-3.3, P = 0.01), posttransplant diabetes (OR = 2.0, 95% CI = 1.3-3.3, P = 0.003), posttransplant hypertension (OR = 1.8, 95% CI = 1.1-3.0, P = 0.02), and mycophenolate mofetil (OR = 2.0, 95% CI = 1.3-3.2, P = 0.003). Among post-OLT patients, the cumulative risk at 5 years of 13.5%, respectively. In conclusion, cardiac complications after liver transplantation are common (Approximately 10% of patients experience 1 or move cv events). Patients with posttransplant hypertension and diabetes, which are modifiable risk factors, are approximately twice as likely to experience a CV event. Liver Transpl 18:370–375, 2012. © 2012 AASLD.
PATIENTS AND METHODS
The study was approved by the instituitional review board. Patients deemed to have a high risk of vascular complications were excluded from transplantation and thus were not included in this study. At our institution, we consider transplantation to be contraindicated for patients with the following conditions: (1) decreased left ventricular systolic function (<45%), (2) decreased right ventricular function and/or significant right ventricular dilation, (3) uncontrolled pulmonary hypertension, (4) significant structural valvular abnormalities (aortic stenosis, mitral stenosis, aortic regurgitation, or tricuspid regurgitation), (5) uncorrectable coronary artery disease (CAD) with induced ischemia on stress testing, (6) significant carotid disease (particularly if the patient is symptomatic), and (7) diffuse atherosclerosis disease involving multiple organs. Patients' medical records were reviewed from the time of their pretransplant evaluation through their routine posttransplant follow-up for CV complications. The baseline variables included the following: the patient's age, sex, ethnicity, indication for transplantation, date of transplantation, and immunosuppressive therapy; cardiac diseases; a history of diabetes (clinical notes, the use of insulin or an oral hypoglycemic, a hemoglobin A1c level >6.5%, or a fasting blood glucose level >126 mg/dL on 2 separate occasions); and hypertension (clinical notes and the use of antihypertensive medications), dyslipidemia, and obesity [body mass index (BMI >30 kg/m2)] 1 year after transplantation. Information on prescribed medications was also collected with a focus on antirejection drugs and lipid-lowering agents. All major CV events after OLT, including acute coronary syndrome (defined as an ST elevation myocardial infarct, a non-ST elevation myocardial infarct, or unstable angina), congestive heart failure, ischemic stroke, peripheral artery disease, and arrhythmias, were compiled. Each patient is represented only once in the cohort; 1 patient had stable angina and congestive heart failure, and 3 patients had both congestive heart failure and arrhythmia. The documentation of recorded CV events was based on the first documented event in the medical records. Pretransplant cardiac testing included electrocardiography and echocardiography in all patients. Echocardiography was used to assess the left ventricular ejection fraction with an estimation of the right ventricular systolic pressure (RVSP), and the rate pressure product (the heart rate times the systolic blood pressure) was determined with peak dobutamine stress echocardiography testing. Dobutamine stress echocardiography was performed for all patients with risk factors for cardiac disease and for all patients who were 50 years old or older (Table 1). Any stress-induced ischemia on the stress test warranted a referral to cardiology and left heart catheterization. When dobutamine stress echocardiography findings were nondiagnostic because of an inability to achieve >85% of the maximum predicted heart rate, patients were referred to cardiology for further workup to rule out significant CAD.
|1. Electrocardiography and echocardiography with RVSP estimation|
|• All patients undergoing an OLT evaluation|
|2. Dobutamine stress echo|
|• All patients who were 50 years or older|
|• Patients who were younger than 50 years and had 1 or more of the following risk factors:|
|• History of diabetes mellitus for more than 1 year|
|• Strong family history of CAD|
|• History of angina|
|• Electrocardiogram changes indicating a previous myocardial infarction|
|• Unexplained shortness of breath|
|3. Patients with known CAD (ie, previous myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft)|
|• Referral of all patients with established CAD to cardiology for further workup|
|4. Right heart catheterization|
|• Patients with an RVSP >45 mm Hg on transthoracic echo|
|• Patients with right ventricular dilation or dysfunction on transthoracic echo|
|5. Valvular disease of the heart|
|• Referral of patients with valvular stenosis or regurgitation graded at >2+ to cardiology to determine their need for surgical intervention and appropriate diagnostic testing|
|6. Patent foramen or any intracardiac shunt|
|• Evaluation of patients by congenital cardiology to determine their need for surgical intervention and appropriate diagnostic testing|
Clinical and mortality data were collected for a median follow-up of 40 months. The primary endpoint of this analysis was the occurrence of posttransplant CV events; this included the presence of acute coronary syndrome (defined as an ST elevation myocardial infarct, a non-ST elevation myocardial infarct, or unstable angina), ischemic stroke (thrombotic or cardioembolic), stable angina, congestive heart failure, arrhythmia, and peripheral artery disease. Ischemic stroke was classified with criteria adapted from the American Stroke Association.3 In symptomatic patients, the ankle brachial index was determined to evaluate them for peripheral artery disease, and a resting value <0.9 was deemed abnormal. Arrhythmias were recognized with outpatient Holter devices and inpatient telemetry. Most of these events were obtained from outpatient clinic notes, inpatient progress notes, and discharge summaries. Patients were not systematically screened for asymptomatic coronary heart disease after liver transplantation. Hence, it is possible that we may have missed certain subjects who developed asymptomatic CV disease after transplantation. In this respect, our cohort mirrors actual clinical practice at most transplant centers.
Definition of Metabolic Syndrome After Transplantation
Metabolic syndrome was defined according to the 2004 revised Adult Treatment Panel III (ATP III) guidelines from the National Cholesterol Education Program. Metabolic syndrome was determined to be present if patients had more than 3 of the following characteristics:
- 1Abdominal obesity [BMI >30 kg/m2 or waist girth = 102 (in men) or 88 cm (in women)].
- 2Triglyceride level ≥150 mg/dL.
- 3High-density lipoprotein (HDL) level <40 mg/dL in men and <50 mg/dL in women.
- 4Blood pressure >130/85 mm Hg.
- 5Fasting plasma glucose level >100 mg/dL.
For the purposes of our study, we also used clinical surrogates for diagnosing metabolic syndrome. Patients met the criteria if they were being treated for dyslipidemia, hyperglycemia, or systemic hypertension.
Patients were categorized into 2 groups according to the presence or absence of cardiac complications after OLT. Continuous variables were summarized with means, whereas frequencies and percentages were used for categorical variables. Univariate analyses and multivariate analyses (by stepwise multivariate model building) were assessed with a Cox proportional hazards model. A P value <0.05 was considered significant for all statistical methods. All statistical analyses were performed with SAS 9.2 (SAS Institute, Cary, NC) and R 2.4.1 (R Foundation for Statistical Computing, Vienna, Austria).
In all, 775 of 876 patients were 18 years or older at the time of transplantation and were included in the study. Table 2 shows the baseline demographic, clinical, and CV risk factors in the study population. The average age was 53.3 years, 33.9% of the patients were female, and 84.1% of the patients were Caucasian. The most common indications for liver transplantation were HCV (33.2%), alcoholic cirrhosis (14.5%), and cryptogenic cirrhosis (12.7%). High blood pressure was present in 350 subjects (45%), diabetes was present in 316 subjects (41%), and 275 subjects (39%) had a BMI >35 kg/m2. The ATP III diagnostic criteria for metabolic syndrome were fulfilled in 287 subjects. Eighty-three patients experienced 1 or more CV events with a median follow-up time of 40 months (25th percentile = 22 months, 75th percentile = 71 months), as shown in Table 3. More than half of these 83 patients developed either acute coronary syndrome (42%) or congestive heart failure (22%) after OLT. The median time from transplantation to the first CV event was 17.4 months. According to a comparison of posttransplant individuals with cardiac events and posttransplant individuals with no cardiac events, patients who experienced a cardiac event were more likely to have posttransplant metabolic syndrome (PTMS; 61% versus 37%, P < 0.001), posttransplant diabetes mellitus (64% versus 41%, P < 0.001), posttransplant hypertension (67% versus 45%, P < 0.001), posttransplant hypertriglyceridemia (49% versus 26%, P = 0.001), low posttransplant HDL levels (47% versus 31%, P = 0.04), and posttransplant obesity (49% versus 35%, P = 0.06). Table 4 summarizes the prevalence of PTMS and its 5 components after liver transplantation. In a multivariate analysis of patient characteristics, the risk of an adverse CV event in liver transplant patients was most strongly associated with 5 variables: (1) an older age at transplantation [odds ratio (OR) = 1.2, 95% confidence interval (CI) = 1.1-1.3, P = 0.006], (2) male sex (OR = 2.0, 95% CI = 1.2-3.3, P = 0.01), (3) posttransplant diabetes (OR = 2.0, 95% CI = 1.3-3.3, P = 0.003), (4) posttransplant hypertension (OR = 1.8, 95% CI = 1.1-3.0, P = 0.02), and (5) mycophenolate mofetil (MMF; OR = 2.0, 95% CI = 1.3-3.2, P = 0.003; Table 5).
|Factor||All Patients (n = 775)||CV Event (n = 83)||No CV Event (n = 692)||Hazard Ratio (95% CI)||P Value|
|Male sex||512 (66.1)||63 (75.9)||449 (64.9)||1.8 (1.09-3.0)||0.02|
|Caucasian||652 (84.1)||71 (85.5)||581 (84.0)||1.06 (0.58-2.0)||0.85|
|Age at OLT (years)||53.3 (46.5-59.2)||56.2 (51.1-62.2)||52.8 (46.2-59.1)||1.04 (1.02-1.07)||<0.001|
|HCV||257 (33.2)||30 (36.1)||227 (32.8)||1.3 (0.84-2.1)|
|Cryptogenic cirrhosis||98 (12.6)||14 (16.9)||84 (12.1)||1.1 (0.59-2.1)|
|Alcoholic cirrhosis||112 (14.5)||16 (19.3)||96 (13.9)||1.09 (0.59-2.0)|
|AIH||31 (4.0)||2 (2.4)||29 (4.2)||0.47 (0.11-2.0)|
|HBV||34 (4.4)||1 (1.2)||33 (4.8)||0.22 (0.03-1.6)|
|PSC||78 (10.1)||3 (3.6)||75 (10.8)||0.25 (0.08-0.81)|
|PBC||59 (7.6)||3 (3.6)||56 (8.1)||0.29 (0.09-0.96)|
|NASH||28 (3.6)||5 (6.0)||23 (3.3)||2.3 (0.88-6.0)|
|Other||78 (10.1)||9 (10.8)||69 (10.0)||0.90 (0.43-1.9)|
|HCV genotype 1||179 (69.6)||24 (80.0)||155 (68.3)||1.01 (0.38-2.6)||0.99|
|Hepatocellular carcinoma||163 (21.0)||22 (26.5)||141 (20.4)||1.8 (1.07-2.9)||0.03|
|Tacrolimus||643 (83.0)||65 (78.3)||578 (83.5)||0.63 (0.38-1.07)||0.09|
|Cyclosporine||73 (9.4)||9 (10.8)||64 (9.2)||1.2 (0.62-2.5)||0.56|
|MMF||258 (33.3)||37 (44.6)||221 (31.9)||2.3 (1.5-3.6)||<0.001|
|Sirolimus||104 (13.4)||17 (20.5)||87 (12.6)||1.7 (1.01-2.9)||0.05|
|1 year after OLT|
|BMI (kg/m2)||28.1 (24.9-32.1)||30.3 (26.5-33.9)||27.9 (24.7-32.0)||1.05 (1.01-1.08)||0.006|
|Diabetes mellitus||316 (41.0)||53 (64.0)||263 (38.0)||2.7 (1.7-4.3)||<0.001|
|Hypertension||350 (45.0)||56 (67.0)||294 (42.5)||2.9 (1.8-4.6)||<0.001|
|HDL (mg/dL)||42.0 (33.0-54.0)||38.0 (29.0-50.0)||43.0 (34.0-55.0)||0.98 (0.97-1.00)||0.04|
|Triglycerides (mg/dL)||136.0 (97.0-207.0)||165.0 (131.0-260.0)||132.0 (93.5-198.0)||1.00 (1.00-1.00)||0.001|
|Metabolic syndrome||287 (37)||51 (61)||236 (34.1)||3.5 (2.1-5.8)||<0.001|
|CV Event After OLT||n (%)|
|Acute coronary syndrome||35 (42)|
|Stable angina||4 (5)|
|Congestive heart failure||18 (22)|
|Peripheral artery disease||8 (10)|
|Factor||All Patients (n = 775)||CV Event (n = 83)||No CV Event (n = 692)||P Value|
|Low HDL level (mg/dL)||237 (31)||39 (47)||198 (29)||0.04|
|Triglyceride level ≥150 mg/dL||202 (26)||41 (49)||161 (23)||0.001|
|BMI >30 kg/m2||275 (35)||41 (49)||234 (34)||0.06|
|Diabetes mellitus||316 (41)||53 (64)||263 (38)||<0.001|
|Hypertension||350 (45)||56 (67)||294 (42)||<0.001|
|Metabolic syndrome||287 (37)||51 (61)||236 (34)||<0.001|
|Factor||OR (95% CI)||P Value|
|Older age at OLT (years)||1.2 (1.1-1.3)||0.006|
|Male sex||2.0 (1.2-3.3)||0.01|
|Posttransplant diabetes||2.0 (1.3-3.3)||0.003|
|Posttransplant hypertension||1.8 (1.1-3.0)||0.02|
The 1- and 3-year overall cumulative risks of CV events were 4.5% and 10.1%, respectively, in patients after liver transplantation (Fig. 1). In comparison with all other etiologies, patients undergoing transplantation for nonalcoholic steatohepatitis (NASH) had a significantly higher risk of a CV event 1 and 3 years after transplantation (15.3% and 19.3%, P = 0.05), whereas patients undergoing transplantation for primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) had a significantly lower risk of a CV event 1 and 3 years after transplantation (0% and 4.5%, P = 0.02; Fig. 2). During the reported long-term follow-up, CV related deaths = 83/775 = 10.7% and represented the third most common cause of mortality in our study population after infections and liver failure after transplantation.
In the present study examining risk factors for cardiac complications in OLT patients, we found that components of metabolic syndrome predicted an increased risk of major CV events. Patients with posttransplant hypertension and posttransplant diabetes were approximately twice as likely to have a CV event after transplantation. Because both variables are modifiable, it is vital that hepatologists and primary care physicians become more engaged in managing metabolic complications after transplantation. Future studies are needed to determine whether or not the liver transplant community is doing an adequate job of managing metabolic complications.
Our results agree with and expand on those of several previous studies describing similar rates of metabolic derangements and CV events during the long-term follow-up of liver transplant recipients. With the availability of liver transplantation as an effective therapy for end-stage liver disease and with greater than 90% survival at 1 year and greater than 70% survival at 5 years, the occurrence of metabolic syndrome after liver transplantation is being increasingly recognized.4 As observed in other studies,5-8 patients are at increased risk for metabolic syndrome with an overall prevalence of 43% to 58% after liver transplantation; this is higher than the reported prevalence of metabolic syndrome in the US adult population (24%).9 Clearly, metabolic syndrome and its components are prevalent after OLT but are not well controlled. As expected, this translates into a higher long-term rate of cardiac events, which have been noted to be the leading cause of late death after OLT.10, 11 Laryea et al.5 reported that patients with PTMS had significantly more CV events than those without PTMS (30% versus 8%, P = 0.003). This is consistent with our results, which showed that patients with PTMS had a significantly increased risk of CV events versus patients without PTMS (18% versus 7%, P < 0.001). Our results show that these complications are common; acute coronary syndrome was the most common among our patients and accounted for 42% of all cardiac complications.
Additionally, the incidence of new CV events after OLT in our study (10.7%) was similar to the incidence reported in a recent study from the United Kingdom during the long-term follow-up of liver transplant recipients (11.6% with a median follow-up of 54 months).12 This significant finding shows a dramatically increased risk of CV events among liver transplant recipients versus the general adult population. These results suggest the need for a stratification model to identify those at high risk of developing cardiac complications after liver transplantation by detailed cardiac investigations and for aggressive care of modifiable factors such as metabolic derangements after transplantation. According to the Framingham study, metabolic syndrome alone can predict up to 25% of all cases of new-onset CV disease.13 PTMS may be related to the metabolic side effects of immunosuppressive agents or underlying liver disease.14 In our study, we found that patients undergoing transplantation for NASH had a significantly higher risk of experiencing a CV event 3 years after transplantation (19.3%, P = 0.05) in comparison with patients undergoing transplantation for PBC or PSC, who had a significantly lower risk of a CV event at 3 years (4.5%, P = 0.02; Fig. 2). Among patients with hepatocellular carcinoma, there was a significant association with the development of posttransplant cardiac events according to a univariate analysis (hazard ratio = 1.8, 95% CI = 1.07-2.9, P = 0.03). This may be due to the fact that hepatocellular carcinoma was diagnosed in patients affected by longstanding cirrhosis, and these patients were older; this association was no longer significant after we adjusted for age in the final analyses. These results may suggest the need for an individualized approach to cardiac assessment and risk stratification after transplantation that includes the consideration of not only traditional CV risk factors but also the etiology of liver disease. Patients with metabolic syndrome after liver transplantation have higher risks of experiencing a major vascular event, and immunosuppression can also affect PTMS. In addition to increasing oxidative stress and lipid peroxidation, calcineurin inhibitors in general cause hyperlipidemia, hypertension, and renal insufficiency. In our patient population, immunosuppressive therapy was primarily tacrolimus-based; the remaining patients received either a cyclosporine-based regimen or a sirolimus-based regimen. MMF was used as an adjuvant medication when side effects precluded a full therapeutic dose of calcineurin inhibitors. In our study, MMF was significantly associated with the risk of posttransplant CV events. We believe that this association is indirect and is related to an underlying renal insufficiency in those patients requiring MMF because of side effects of calcineurin inhibitors; it is well established that concomitant renal dysfunction in the setting of end-stage liver disease is associated with increased CV risk.15 This study has several potential limitations. This is a single-center, retrospective study. Because of the retrospective nature of the study, an assessment bias was a possibility. We minimized this by following a protocol for posttransplant patients, who were asked for information about CV events at every follow-up visit. We had complete information about risk factors for CV disease and relied on patients' self-reports and physicians' assessments to ascertain CV events that took place outside our health system. We did not screen all patients for CV disease with stress tests before transplantation, but we followed a standardized institutional protocol for pretransplant cardiac evaluations. Hence, it is possible that we may have missed certain subjects who had asymptomatic CV disease at the time of transplantation. In this respect, our cohort mirrors actual clinical practice at most transplant centers.
We conclude that cardiac complications are common within 3 years of liver transplantation. There is a strong relationship between patients with posttransplant hypertension and posttransplant diabetes and the risk of CV events after OLT, and this is consistent with the nontransplant population. The CV risk appears to vary with the liver disease etiology and is lowest for patients with cholestatic liver disease and is higher for patients with NASH. Because of the increasing incidence of cardiac complications after liver transplantation, it is important that all potential liver transplant recipients undergo rigorous cardiac risk stratification before transplantation to allow focused CV intervention and organ allocation that will maximize the benefits to the patients and facilitate the appropriate use of donor organs, which are increasingly scarce. Furthermore, future research in the area of posttransplant metabolic complications is required to investigate whether the clinical relevance is the same as that for the general population. Finally, identifying barriers to care in the treatment of metabolic complications is crucial so that the transplant community can intervene with the goal of improving long-term patient survival. Devising prospective studies to answer these questions may lead to real changes in the natural history of patients with liver transplantation.