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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 13  |  Issue : 2  |  Page : 91-95

Cirrhotic cardiomyopathy- Survival at 3 months after liver transplantation


Institute of Gastrointestinal Sciences, Gleneagles Global Health City, Chennai, Tamil Nadu, India

Date of Submission29-Sep-2018
Date of Acceptance10-Jan-2019
Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Mayank Jain
Institute of Gastrointestinal Sciences, Gleneagles Global Health City, Chennai - 600 100, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_60_18

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  Abstract 


Background: Cirrhotic cardiomyopathy (CCM) occurs in 39.4%–48.3% of patients with chronic liver disease with or without decompensation. A significant number of patients are likely to be listed for liver transplantation (LT). The early outcome of LT in these patients is not known. Aims and Objectives: The aim is to study the prognostic implication of CCM on survival at 3 months post-LT. Materials and Methods: This prospective study was conducted from July 2016 to July 2017. Patients, who were diagnosed as cirrhosis of the liver based on clinical, biochemical, imaging, and endoscopic findings, were included in the study. After informed consent, details of demography, comorbidity, and cirrhosis-related complication were noted. Cardiac evaluation included electrocardiography, two-dimensional echocardiography, dobutamine stress test, and coronary angiography whenever indicated. CCM was diagnosed based on the standard criteria. Patients who underwent LT were followed up in the posttransplant period up to 3 months. Statistics: Mann–Whitney U-test, Chi-square test, and Kaplan–Meier survival plot were used for statistical analysis. P < 0.05 was considered statistically significant. Results: Five hundred and eighty-six adult patients with cirrhosis of the liver underwent cardiac evaluation. One hundred and ninety-eight (33.8%) patients were diagnosed with CCM. Forty-one patients underwent LT. Following LT, there was an improvement in diastolic dysfunction in a third of patients (12 patients; 29.3%) but with no survival benefit at 3 months (P = 0.23). Higher baseline model for end-stage liver disease and left ventricular diastolic dysfunction were more common among nonsurvivors. Conclusion: CCM does not influence the short-term survival in patients undergoing LT.

Keywords: Cardiomyopathy, cirrhosis, liver, outcome, transplantation


How to cite this article:
Bokarvadia R, Jain M, Varghese J, Venkataraman J. Cirrhotic cardiomyopathy- Survival at 3 months after liver transplantation. Indian J Transplant 2019;13:91-5

How to cite this URL:
Bokarvadia R, Jain M, Varghese J, Venkataraman J. Cirrhotic cardiomyopathy- Survival at 3 months after liver transplantation. Indian J Transplant [serial online] 2019 [cited 2019 Sep 15];13:91-5. Available from: http://www.ijtonline.in/text.asp?2019/13/2/91/261845




  Introduction Top


Cirrhotic cardiomyopathy (CCM) describes a state of impaired cardiac reserve function in patients with liver cirrhosis characterized by a systolic incompetence to stress, diastolic dysfunction, and electrophysiological abnormalities.[1] It is often clinically latent but gets unmasked after a physical or pharmacological stress. Management of CCM at the time of liver transplantation (LT) involves averting fluctuations in preload and after load. The outcome of Indian patients undergoing LT for liver cirrhosis and CCM is not known. The present prospective study was done to ascertain the outcome of these patients at 3 months after the LT.


  Materials and Methods Top


The study was done between July 2016 and June 2017. The study protocol was approved by the Ethics Committee of our institution (HR/2016/MS/014). Written informed consent was obtained from all patients.

Patients, who were diagnosed as liver cirrhosis based on clinical, biochemical, imaging, and endoscopic documentation of varices and who had a LT, were included in the study.

Exclusion criteria

Patients who were not willing to participate in the study and aged <18 years, patients with a known case of coronary artery disease, rheumatic heart disease, cardiac cirrhosis, pregnancy associated with a hyperdynamic circulatory state, anemia, thyrotoxicosis, and pulmonary arteriovenous shunts, and patients with follow-up <3 months posttransplant were excluded from the study.

Diagnostic criteria for cirrhotic cardiomyopathy

We used the following criteria for the diagnosis of CCM[2]

  1. Diagnostic


    1. Systolic dysfunction:


      • Resting ejection fraction <55%
      • Blunted increase, i.e., <10% increase in left ventricular ejection fraction (LVEF) after exercise, volume challenge, or pharmacological stimuli.


    2. Diastolic dysfunction:


      • The ratio of early to late (atrial) phases of ventricular filling (E/A) ratio <1.0 (age corrected).


  2. Supportive


    • Prolonged corrected QT (QTc) interval,
    • Enlarged left atrium.


Methodology

Baseline patient information included age, gender, nationality, weight, height, body mass index, details of alcohol, smoking, and use of tobacco. Clinical details included duration of cirrhosis, comorbidity, and cirrhosis-related complications (variceal bleed, ascites, spontaneous bacterial peritonitis, acute kidney injury, and hepatic encephalopathy).

Baseline laboratory parameters noted were hemogram, liver biochemistry, serum creatinine, screening for hepatitis B and C virus, Wilson's disease, hemochromatosis, and autoimmune liver disease. All patients had triple-phase computed enhanced tomography. Severity of liver disease was assessed by Child–Turcotte–Pugh (CTP score) and model for end-stage liver disease (MELD) score.

Cardiac evaluation

Medications such as β-blockers were discontinued for 48 h before cardiac evaluation. Assessment of cardiac status was measured by resting pulse rate, systolic–diastolic blood pressure, and an electrocardiography (ECG) with standard 12-lead ECG (GE MAC 1200). QT interval was measured in lead II limb.

Assessment of left ventricular systolic dysfunction

Transthoracic echocardiographic examination (two-dimensional echo; Model: General Electric Vivid E9)

Resting LVEF was calculated using Simpson's rule in apical four-chamber view. A value of <55% indicated left ventricular systolic dysfunction.

Dobutamine stress test

This test was done to unmask trivial CCM by administering dobutamine, a β1-receptor agonist. The drug was injected at an initial rate of 5 μg/kg/min and then gradually increased at 3-min interval to 10, 20, 30, and 40 μg/kg/min, to achieve, at least, 85% of maximum target heart rate predicted for that particular age. In case maximum heart rate was not achieved, atropine (0.25 mg given each minute to a maximum dose of 1 mg) was added to the 40 μg/kg/min dobutamine infusion. After the test, intravenous metoprolol (2.5 mg) was given every 5 min to a maximum dose of 10 mg until the basal heart rate was achieved. Reduced left ventricular contractile reserve was defined when the increase in LVEF was less than 10% of the basal value.

Assessment of left ventricular diastolic dysfunction

Pulse Doppler flowmetry

This assessed the pulse Doppler flow across the mitral valve. The denominators noted were peak early filling (E-wave) velocity and late diastolic atrial filling (A-wave) velocity. An E/A ratio was calculated [Table 1].
Table 1: Diagnostic criteria for the diagnosis and grading of left ventricular diastolic dysfunction

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Tissue Doppler imaging

This provided an average early diastolic myocardial velocity, i.e., e' at septal and lateral aspects of the mitral annulus and graded as mild (Grade I), moderate (Grade II), and severe (Grade III) left ventricular diastolic dysfunction [LVDD] [Table 1].[3]

Supportive measures

A left atrial size > 38 mm (is it the dimension of the left atrium or the wall thickness) was taken as a dilated. This was measured in apical four-chamber view.

QTc interval, i. e., QTc interval was calculated using Bazett's formula (QTc = QTmax in ms/[RR interval in ms]1/2 interval). An interval of >440 ms was considered as prolonged.

Coronary angiogram

This was considered as mandatory in patients above 60 years and those with known coronary artery disease and/or type 2 diabetes mellitus for 10 years and more.

For our study, a diagnosis of CCM was considered when a cirrhotic patient had definite criteria of either systolic or diastolic dysfunction with or without supportive criteria of QTc prolongation and dilated left atrium. Patients consuming significant alcohol or diabetics of long-standing duration were not excluded from the study. This was done to determine the effects of other associated causes of CCM. However, those with CAD were excluded from the analysis as these were likely to cause an ischemic cardiomyopathy.

Intraoperative data

Intraoperative data included need for two or more inotropic support, dysrhythmia, and pulmonary edema.

Postliver transplantation

Patients were under strict cardiac surveillance in the posttransplant intensive care unit. Cardiac monitoring was done by means of ECG and two-dimensional echo, and cardiac dysfunction was graded as improved, deteriorated, no change, or normalization at 1 and 3 months.

Statistical analysis

All parameters were expressed as absolute numbers and percentages. Age, CTP, and MELD scores were expressed as median and range. Comparison of two medians was by Mann–Whitney U-test and for proportions by Chi-square test through contingency tables. Survival was assessed with Kaplan–Meier survival plot. P < 0.05 was considered statistically significant.


  Results Top


Five hundred and eighty-six patients with liver cirrhosis underwent cardiac evaluation. One hundred and ninety-eight (33.78%) patients had CCM, 41 (20.7%) of whom had a LT and were followed up for 3 months. The remaining were either lost to follow-up (62) or expired (56) within a month or were patients who had a LTx at a satellite center within the state of Tamil Nadu (39) and followed up thereafter in the same center; perioperative data were not accessible for these 39 patients.

Baseline characteristics (41 patients)

Majority of the participants were men (73.2%) with a median age of 47 years; more than three-fourth had LDLT and had a high MELD score. Two patients had systolic and 10 had diastolic dysfunction. About 87.8% had prolonged QTC interval. None of the patients had a positive dobutamine stress test [Table 2].
Table 2: Baseline characteristics of study cohort

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In the intraoperative period, of the 41 patients, 33 patients (80.5%) had hypotension and required inotropes, 11 patients (26.8%) had pulmonary edema, and 4 (1%) had dysrhythmia (tachyarrhythmia in 3 and bradyarrhythmia in 1).

Posttransplant [Table 3] and [Figure 1], at the end of 3 months, approximately a third of patients (12; 29.3%) showed an improvement in diastolic function with no change in 21 (51.2%) and deterioration in 8 (19.5%). QTc showed no significant improvement in 35 (85.4%) patients. No discernible changes were seen either in the size of the left atrium (39 patients; 95.1%) or in the systolic function (38 patients; 92.7%).
Table 3: Comparison of pre- and posttransplant cardiac parameters

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Figure 1: Changes in cardiac indices posttransplant

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Impact of cirrhotic cardiomyopathy on posttransplant survival

There were 6 (14.7%) deaths during follow-up at 3 months and 7 (7.3%) among the 96 patients without CCM. Statistically, there was no difference in the survival between the two groups (P = 0.234) [Figure 2]. However, nonsurvivors in Post LT CCM had a significantly higher MELD score (24 vs. 20, P 0.00014) and LVDD (100% vs. 11.2%, P = 0.00001) compared to survivors. None of the other demographic, etiological, and comorbid diseases and cardiac parameters affected survival [Table 4].
Figure 2: Kaplan–Meier survival by group at 90 days (Chi-square statistic: 1.414853; P = 0.234252)

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Table 4: Comparison between nonsurvivors and survivors

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  Discussion Top


One-third of our patients with liver cirrhosis had CCM. The short-term mortality following LT was 14.7%, with no differences in survival between those and without CCM. However, nonsurvivors had a higher baseline MELD score and higher prevalence of LVDD before surgery compared to survivors. Although a significant number of patients did not show any reversal of changes in cardiac parameters at 3-month follow-up, diastolic dysfunction improvement was seen in nearly a third.

The prevalence of CCM in our cohort was similar to that reported in the literature.[4],[5],[6] Post-LT, reversion of CCM was not impressive. In our series, we found that there was a significant improvement in diastolic dysfunction at the end of 3 months.

Physiologically, following a LT, there is a significant increase in blood pressure and peripheral vascular resistance with restoration of normal liver function and portal pressure. However, in patients with CCM, in the 1st week following a LT, there is further deterioration in cardiac function secondary to hypertensive side effects of the calcineurin inhibitors causing an increase in cardiac after load. With restoration of portal flow, there is a volume overload to the heart resulting in further decompensation.[7] LV diastolic function continues to worsen until hemodynamic stability is established which may take place until 6 to 12 months post-LT during which there is recovery of functional, structural, and electrophysiological abnormalities, normalization of the systolic response to stress, improvement in diastolic dysfunction, and regression of ventricular wall thickness.[8] Improvement of QT prolongation occurs in approximately 50% of patients.[9],[10],[11]

Large observational differences on the outcome of LT on CCM have been reported in different series. These may be related to differences in ethnicity, nutritional status, etiology of cirrhosis, and severity of disease. Ibrahim et al.,[12] in a 4-year follow-up study from Cleveland Clinic, reported that post-LT, there was a significant increase in LV mass index and a high prevalence of diastolic dysfunction with a significant reduction in QTc. Torregrosa et al.[13] reported a significant improvement in cardiac measurements at 6 and 12 months in 15 patients who underwent LT for CCM.

In our study, we found that among patients with CCM and those without CCM, higher baseline MELD score and LVDD were associated with higher mortality. Deaths were mainly due to either sepsis[5] or surgery-related complications.[1] In CCM, LVDD is the most cardiac dysfunction and usually precedes systolic dysfunction. The presence of LVDD does not correlate with the etiology of liver disease and factual information similar to ours.[14] With increasing MELD score, the severity of LVDD worsens.[14],[15] Our observations were similar to that reported by Josefsson et al., i.e., high MELD and LVDD before transplantation correlated with an increased mortality.[16]

Strength of the study

It includes large sample size; prospective design; exclusion of patients with coronary artery disease; use of dobutamine stress test and coronary angiography; influence of comorbid conditions such as hypertension, hypothyroid, and diabetes and alcohol; and assessment of post-LT outcome.

Limitations of the study

It includes inadequate intraoperative details; short posttransplantation follow-up; and no biomarkers such as brain natriuretic peptide which were used to confirm CCM or prognosticate these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rahman S, Mallett SV. Cirrhotic cardiomyopathy: Implications for the perioperative management of liver transplant patients. World J Hepatol 2015;7:507-20.  Back to cited text no. 1
    
2.
Møller S, Henriksen JH. Cardiovascular complications of cirrhosis. Gut 2008;57:268-78.  Back to cited text no. 2
    
3.
Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10:165-93.  Back to cited text no. 3
    
4.
Snowden CP, Hughes T, Rose J, Roberts DR. Pulmonary edema in patients after liver transplantation. Liver Transpl 2000;6:466-70.  Back to cited text no. 4
    
5.
Fouad TR, Abdel-Razek WM, Burak KW, Bain VG, Lee SS. Prediction of cardiac complications after liver transplantation. Transplantation 2009;87:763-70.  Back to cited text no. 5
    
6.
Donovan CL, Marcovitz PA, Punch JD, Bach DS, Brown KA, Lucey MR, et al. Two-dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation. Transplantation 1996;61:1180-8.  Back to cited text no. 6
    
7.
Therapondos G, Flapan AD, Dollinger MM, Garden OJ, Plevris JN, Hayes PC, et al. Cardiac function after orthotopic liver transplantation and the effects of immunosuppression: A prospective randomized trial comparing cyclosporin (Neoral) and tacrolimus. Liver Transpl 2002;8:690-700.  Back to cited text no. 7
    
8.
Møller S, Hove JD, Dixen U, Bendtsen F. New insights into cirrhotic cardiomyopathy. Int J Cardiol 2013;167:1101-8.  Back to cited text no. 8
    
9.
García González M, Hernandez-Madrid A, Lopez-Sanromán A, Candela A, Nuño J, Barcena R, et al. Reversal of QT interval electrocardiographic alterations in cirrhotic patients undergoing liver transplantation. Transplant Proc 1999;31:2366-7.  Back to cited text no. 9
    
10.
Mohamed R, Forsey PR, Davies MK, Neuberger JM. Effect of liver transplantation on QT interval prolongation and autonomic dysfunction in end-stage liver disease. Hepatology 1996;23:1128-34.  Back to cited text no. 10
    
11.
Bal JS, Thuluvath PJ. Prolongation of QTc interval: Relationship with etiology and severity of liver disease, mortality and liver transplantation. Liver Int 2003;23:243-8.  Back to cited text no. 11
    
12.
Ibrahim A, Schuster A, Sonny A, Cywinski JB, Jaber WA. Liver transplantation does not reverse cirrhotic cardiomyopathy. Circulation 2014;130:A15985.  Back to cited text no. 12
    
13.
Torregrosa M, Aguadé S, Dos L, Segura R, Gónzalez A, Evangelista A, et al. Cardiac alterations in cirrhosis: Reversibility after liver transplantation. J Hepatol 2005;42:68-74.  Back to cited text no. 13
    
14.
Karagiannakis DS, Vlachogiannakos J, Anastasiadis G, Vafiadis-Zouboulis I, Ladas SD. Diastolic cardiac dysfunction is a predictor of dismal prognosis in patients with liver cirrhosis. Hepatol Int 2014;8:588-94.  Back to cited text no. 14
    
15.
Ruíz-del-Árbol L, Achécar L, Serradilla R, Rodríguez-Gandía MÁ Rivero M, Garrido E, et al. Diastolic dysfunction is a predictor of poor outcomes in patients with cirrhosis, portal hypertension, and a normal creatinine. Hepatology 2013;58:1732-41.  Back to cited text no. 15
    
16.
Josefsson A, Fu M, Allayhari P, Björnsson E, Castedal M, Olausson M, et al. Impact of peri-transplant heart failure and left-ventricular diastolic dysfunction on outcomes following liver transplantation. Liver Int 2012;32:1262-9.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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