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Abstract

Background

 Data regarding cardiovascular mortality (CVM) among patients undergoing liver transplantation (LT) is limited. We want to assess the current incidence of CVM in LT patients at our institution. We will also review preoperative cardiovascular assessment strategy and outcomes.

Methods

 Baseline characteristics and cardiovascular risk assessment from patients who underwent LT between 2008 and 2012 were collected. All cause mortality (ACM) and CVM (defined as death by either an acute coronary syndrome (ACS), arrhythmia or heart failure (HF)) were assessed at 1 year.

Results

203 patients (mean age 53 years, 67% men) underwent LT. All patients had an EKG and an echocardiogram. Most patients with 3 or more risk factors underwent a non-invasive test for coronary heart disease.  One year all cause mortality and cardiovascular mortality were 12.3% and 2.5%, respectively. Cardiovascular events were the second cause of mortality and accounted for 20% of all deaths. Three patients died from decompensated heart failure and two patients died from arrhythmia, while none died from ischemic heart disease. 

Conclusions

 Although cardiovascular events are the second cause of mortality at 1 year after liver transplantation, the cardiovascular mortality rate was low at our institution. Cardiac ischemic events seem to be prevented by a non-invasive pre liver transplant cardiac risk assessment strategy as recommended by the ACC/AHA guidelines. Other complications such as malignant arrhythmia and terminal heart failure constituted the main cardiovascular mortality causes. 

Background

Liver transplantation (LT) is a therapy of choice for end stage liver disease (ESLD).  There are specific cardiovascular alterations in ESLD such as decreased systemic vascular resistance, high cardiac output, bradycardia and impaired ventricular response to stress.  All these changes seem to be related to altered beta-receptor signalling [1] and altered hepatic metabolism.  In addition, liver transplantation is associated with important hemodynamic changes and increased fluid load once the donated organ is functional. At the moment of reperfusion, the sudden increase in pre-load can contribute to increased pulmonary artery and wedge pressure, hepatic congestion and hemodynamic instability.  All these disturbances may result in right and left ventricular failure, arrhythmia, acute coronary events and death [2-4].  

Mortality after liver transplantation has been reported to be as high as 50%, especially in patients with known coronary artery disease (CAD) [5-7]. Identifying patients at high risk of complications for liver transplant candidates would be of great importance.  Unfortunately, optimal preoperative strategy is still controversial.

In 2012, the ACC and the AHA published recommendations regarding preoperative cardiac assessment in patients undergoing LT².  CAD risk stratification is recommended in the presence of 3 or more traditional risk factors for coronary heart disease (diabetes, prior cardiovascular disease, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension and dyslipidemia).  However, the use of invasive or non-invasive testing for CAD assessment remains unclear. Some authors suggest using coronary angiography as routine preoperative cardiac stratification considering the limited sensitivity and poor predictive value of non-invasive imaging for myocardial ischemia in patients with ESLD.  Transthoracic echocardiography is suggested in all candidates to assess left and right ventricular function and pulmonary artery pressure.  There are no specific recommendations regarding pre-operative assessment of patients with established heart failure or arrhythmia.

The aims of this study are to present the liver transplant cardiac risk assessment strategy of our institution and to review the associated cardiac morbidity and mortality.  We will also try to determine how cardiovascular risk assessment in liver transplant may have impacted on cardiac complications and mortality after LT.

Methods

We retrospectively reviewed charts from 203 patients who underwent LT in our institution between January 2008 and January 2012. Baseline characteristics, pre-operative cardiac stratification strategies and postoperative complications were recorded.

Baseline characteristics included specific risk factors (diabetes, prior cardiovascular disease, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension and dyslipidemia) as suggested by the 2012 ACC/AHA guidelines [2].  Any patient with history of sick sinus syndrome, 2^nd degree heart block or more, atrial or ventricular arrhythmia was considered as having a history of arrhythmia. Patients were considered as having cardiac disease if they had an ejection fraction below 50%, a history of arrhythmia, a bundle branch block or CAD.

During liver transplant eligibility evaluation, patients had preoperative lipid profile, EKG, transthoracic echocardiography (TTE) and chest radiograph (CXR). The following cardiac assessment tests (dobutamine stress echocardiography, myocardial perfusion SPECT study coronary angiography or right heart catheterisation) were done based on physician’s assessment without any restrictions. Post-operative mortality, cardiac mortality (defined as mortality by either an acute coronary syndrome, an arrhythmic event or heart failure) and cardiac complications (heart failure, arrhythmia or ischemic cardiac events) were reviewed at 30 days and 1 year after LT.

Statistics

Description of population characteristics was summarized using categorical, parametric, or non parametric descriptors. We evaluated the link between the prevalent number of risk factors (<3 RF or ≥3 RF) and the use of complementary cardiac assessment tests using T Student test. We also evaluated the relationship between the aforementioned cardiac risk factors with cardiac morbidity and mortality using T Student test as well. We calculated the specificity and sensitivity of preoperative non-invasive tests to predict fatal ischemic events. All statistical analysis was performed using Stattools.

Results

Baseline patient’s characteristics

203 patients underwent liver transplantation. No patients were excluded from the study. 67% of patients were males and the mean age was 53. Sixteen percent (16%) of patient had known cardiac disease. 9% of patients had a history of arrhythmia, 7% had diagnosed CAD and 4% had an EF under 50%. None of the patients had pulmonary hypertension. All patient characteristics are summarized in Table 1.

	Entire population (n=203)
Age (years)	53
Sex	67 % males
60 years or older	27.5%
HTA	37%
Diabetes	29%
Ventricular hypertrophy	12%
Smokers	21%
DLP	26%
Known CAD	7%
Family history of CAD	5%
NASH	16%
Ischemia on EKG	12 %
Preop arrhythmia	9%
Mean QTc	446ms
Mean EF (%)	64
EF < 50%	3.5%
Preop cardiac disease	16%
Renal failure Creat >120	23%
Mean RNI	2.0
Mean Creatinine	98
Mean PLT count	101

Table 1. Population characteristics

Pre-operative cardiac assessment

As shown in Table 2, 143 (70.5%) patients had less than 3 risk factors and 60 (29.5%) patients had 3 or more risk factors. As per current recommendations, EKG, TTE and Chest X-Ray were performed in almost all patients.

	<3 Risk Factors (70.5%)	³3 Risk Factors (30.5%)	P value
Sample size	143	60
Stress EKG	6	8
SPECT	23	26
Stress TTE	7	4
Total non invasive	36	38	0.001
Coronary angiography	4	6	0.017

Table 2. Initial Stratification strategy in patients undergoing liver transplant

As shown in Figure 1, only 26% of patients with 2 RF or less underwent cardiac stratification. 36 patients of them had non-invasive investigations and only one patient had a positive test. In contrast, the majority (65%) of patients with 3 or more risk factors were investigated (p=0.001). 38 patients had non-invasive investigation and only 5 patients had a positive test. Only two of those patients had proven atherosclerotic disease on angiography and both underwent coronary revascularisation. None of the patients with zero risk factors had a positive non-invasive exam.

Coronary angiography was performed in 3% of patients with less than 3 risk factors and in 10% of patient with 3 risk factors or more (p=0.02). Two positive coronary angiograms (considered as a new lesion of 70% in a main branch or 50% in the left main) were reported in our study and both were in the patients with 3 or more RF. Furthermore, only 2 patients underwent coronary revascularization and both had a positive nuclear stress test.

EKG abnormality (2^nd degree heart block, bundle branch block, atrial or ventricular arrhythmia or ischemia) was present in 51% of patients with 2 risk factors or less and in 49% of patients with respectively 2 risk factors or less and 3 or more risk factors. 

Post-operative events

Post-operative cardiac complications were recorded in 16% of all patients. 2% of patients had acute coronary events, 10% had arrhythmic events and 8% suffered heart failure. 50% of these complications occurred in patients with 3 more specific risk factors.

Total mortality at 30 days after liver transplantation was 5% and cardiac mortality represented 20% of all deaths. Total mortality at one year was 12.5% and cardiac mortality was 20% of all deaths. Sepsis was the leading cause of death in all patients. As shown in Table 3, cardiac mortality represented 1% of all deaths at 30 days and 2.5% of all deaths after 1 year. Arrhythmia was the main cause of early mortality and heart failure accounted for all cardiac deaths at 1 year (Table 4 and 5).

	Acute coronary syndrome	Heart Failure	Arrhythmia
Cardiac mortality at 30 days	0	0	2
Cardiac mortality at 1 year	0	3	2

Table 3. Causes of early and late cardiac mortality in patients undergoing liver transplant

	2 or less risk factors (n= 143)	3 or more risk factors (n= 60)
Mortality	13	9
Cardiac related mortality	0	3
Cardiac events (arrhythmic, HF, ACS)	18	18
ACS	0	2
Arrythmia	8	10
HF	10	6

Table 4. Cardiac complications and events according to number of risk factors

Table 5. Pre-existing condition in patients with early cardiovascular mortality

Discussion

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Coronary artery disease is common in patients with end stage of liver disease.  In a study by Tiukinhy-Lang et al. [8] than 25% of patients undergoing liver transplantation have at least one moderate to severe coronary obstruction [8]. A routine pre-operative cardiac assessment is necessary in this population and it is based on traditional cardiac risk factors (history of previous CAD, baseline functional class, EKG and LV function) [8]. Exercise stress test is rarely performed to these patients because of inability of liver transplant patients to perform exercise. Non-invasive testing to detect asymptomatic coronary artery disease is used in patients with the risk factors mentioned earlier [9]. Dobutamine stress echocardiography has been shown to have low sensitivity and low negative predictive value in this setting [10]. However, due to chronic systemic vasodilation in patients with liver cirrhosis, the specificity of such non-invasive testing has been shown to be limited [1]. There is only one retrospective study that showed an excellent negative predictive value of 99% for SPECT in patients with cirrhosis [9].

Most patients at our institution received non-invasive investigation when they had 3 or more risk factors. Most patients who had a negative non-invasive test did not undergo coronary angiography and did not die from cardiovascular cause. This stratification using non-invasive testing alone seems to be able to identify fatal ischemic events prior to liver transplantation. This study further corroborates the finding of high negative predictive value of SPECT as reported by Zoghbi GJ et al. [10].

In addition, we believe that using 3 risk factors, as a cut-off for additional investigation is reasonable in order to prevent most cardiac complications and deaths. Patients less than 3 risk factors are probably at low risk of cardiac ischemic events and will not need CAD risk assessment prior to liver transplantation.  In contrast, patients with more than 3 risk factors are at higher risk and require CAD risk assessment with the cardiac stratification strategy mentioned above.  We believe that this finding will help clinicians in decision making for pre-operative investigation prior liver transplant. Also, we find it important to emphasize that there is not necessary to use coronary angiography as a routine screening test for cardiac risk assessment prior liver transplant.

Complications and mortality

Total post-operative cardiac complications occurred in 16% of patients. This is lower then previously described in the literature. We also observed lower than described mortality rates [11]. We believe that this might be in part due to patient selection according to cardiac risk assessment and to improved perioperative management during LT. Cardiovascular mortality was exclusively related to heart failure and arrhythmia.  We recorded no fatal ischemic events in our study population. Using non-invasive cardiac assessment based on specific RF seemed to have accurately identify patients at high risk of fatal ischemic, thus in agreement with present ACC/AHA risk assessment guidelines position [6].

Cirrhotic cardiomyopathy

 In patients who died from cardiac cause (HF and arrhythmia) at 30 days, the mean amount of risk factors was 2.5. All patients had a known cardiac disease and all had a history of arrhythmia. Pre-LT known cardiac disease was a statistically significant risk factor for early and late mortality (p=0.03) as well as pre-LT arrhythmia (p<0.01).

 Pre-operative cardiac assessment has not completely prevented death from non-ischemic cardiac complications (arrhythmia and HF). All patients who died from heart failure had a preoperative TTE that shown a normal left ventricular ejection fraction and a negative non-invasive investigation. This might suggest the presence of a subclinical cardiomyopathy. It is now proven that patients with end stage liver disease (ESLD) have an increased cardiac output state with lower resistance and a compromised ventricular response to stress: this condition is called cirrhotic cardiomyopathy [12,13]. Also early cardiac dysfunction can be missed by usual evaluation due to the decreased afterload associated with ESLD [2].

Pre-LT non-invasive CAD testing based on RF seems preventing mainly fatal ischemic events in our population. However, fatal arrhythmic and fatal HF events accounted for 1% at 30 days and 2.5% at 1 year despite pre-LT cardiovascular work-up. This could be linked with the presence of a cirrhotic cardiomyopathy that was not detected even by TTE. Newer imaging techniques like strain imaging on TTE and cardiac MRI might offer an alternative for detecting this condition and could maybe take a role in the future in pre-LT CV assessment [14].

Conclusion

Cardiovascular mortality is the second cause of death in LT patients and is mainly due to arrhythmia and heart failure. A negative non-invasive test result prior to liver transplantation can effectively predict that patients will not suffer ischemic events. We can also conclude that the use of 3 risk factors cut-off to assess patients with non-invasive test seems to be adequate to screen for coronary artery disease in patients who will undergo liver transplant. 

Limitations

Our study is a retrospective study. We studied only the patients who underwent liver transplantation and had no data about patients who were excluded from liver transplantation because of a positive stress test. This creates a selection bias. While a negative stress test is reassuring, we could not evaluate the impact of a positive stress test.   Further studies are needed.

Appendix A. Case records of patients who died from cardiovascular causes

We will review in this section all patients who died from cardiac causes.

Patient A underwent liver transplant for alcoholic cirrhosis. He had 3 risk factors for cardiovascular disease (hypertension, dyslipidemia and age over 60). Rest EKG showed 2^nd degree AV block (Mobitz I) and left ventricular wall hypertrophy.  TTE did not detect any abnormalities and ejection fraction was 58%. MIBI perfusion scan did not detect any significant ischemic changes. The patient died during the LT procedure. Death was caused by ventricular tachycardia and subsequent asystole. (3 risk factors)

Patient B was suffering from hepatitis C and alcoholic cirrhosis. He was an active smoker. Rest EKG showed prolonged QTc (500 ms). Pre-operative TTE did not detect any abnormalities and ejection fraction was 65%. MIBI perfusion scan did not detect any significant ischemic changes. While waiting for liver transplant, the patient developed aortic regurgitation due to bacterial endocarditis. An aortic valve replacement was performed and pre-operative coronary angiography did not detect any significant coronary occlusions. The patient underwent liver transplant 14 days later but died of asystole. (1 risk factor)

Patient C underwent liver transplant for hepatitis B cirrhosis. He was known for CAD and a history of smoking. His baseline EKG was normal and his TTE showed an EF of 50%. MIBI scan showed low risk ischemia. The patient developed heart failure and atrial fibrillation more than 30 days after having had liver transplant. (2 risk factors)

Patient D received a liver transplant for autoimmune hepatitis. He was known for hypertension, CREST syndrome and dyslipidemia. Baseline EKG showed left ventricular hypertrophy and his preoperative TTE was normal (EF = 62%). He died from decompensated heart failure and multi organ failure. (3 risk factors)

Patient E underwent liver transplant for alcoholic cirrhosis. He was 67 years old and he was known for hypertension, dyslipidemia and diabetes. Pre operative creatinine was 154 mmol/L. Baseline EKG showed a corrected QT interval of 475 msec and his preoperative TTE was normal. (EF = 70%). Liver transplantation was complicated by pulmonary embolism. He was readmitted 6 months later and died from decompensated heart failure and sepsis. (4 risk factors).

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