Anesth Pain Med Search

CLOSE


Anesth Pain Med > Volume 17(4); 2022 > Article
Kwon, Kim, Yang, and Hwang: Temporary postoperative myocardial injury and long-term survival in liver transplant patients with coronary artery disease

Abstract

Background

Coronary artery disease (CAD) is increasing worldwide due to the aging population and cardiometabolic syndrome. However, the extent of postoperative myocardial injury, the most common cause of death during the 30 days after noncardiac surgery, remains unclear with respect to liver transplant (LT) patients with CAD. We examined the link between post-LT high sensitivity cardiac troponin I (hs_cTnI) and long-term survival according to liver disease severity.

Methods

Consecutive patients who underwent LT (n = 3,220) from 2010 to 2020 were evaluated retrospectively. CAD was defined as a history of coronary artery bypass surgery or percutaneous intervention, or previous myocardial infarction. Peak hs_cTnI levels within 30 days post-transplant were compared in patients with and without CAD. The primary endpoint was defined as an all-cause mortality at 12 years following LT. Secondary endpoints include peak hs_cTnI level within post-transplant 30 days and 30-day mortality. Survival analysis was performed using the Kaplan-Meier method.

Results

CAD patients (n = 264, 8.2%) had higher peak hs_cTnI levels within 30 days post-LT than those without CAD (median [interquartile]: 0.068 [0.030-0.154] vs. 0.087 [0.037-0.203] ng/ml, respectively; P = 0.004); however, the mortality rate was comparable (14.7% vs. 14.8%, respectively, P = 0.999), at 12 years, and 1.9% vs. 1.1% (P = 0.522) at 30 days, respectively, at 30 days. Subgroup analysis with stratified liver disease severity identified a similar risk of long-term mortality.

Conclusions

Although the peak hs_cTnI level within 30 days was higher in revascularized or treated CAD patients after LT compared those without CAD, long-term mortality rates at 12 years and 30-day mortality rate were comparable.

INTRODUCTION

The prevalence of coronary artery disease (CAD) is rising worldwide due to an increase in coronary risk factors such as aging, obesity, diabetes, and cardiometabolic syndrome [1,2]. About 25% of liver transplantation (LT) candidates with traditional coronary risk factors may have a moderate degree of CAD (stenosis ≥ 50%), even though they are asymptomatic [2,3]. However, there is a consensus that CAD should not be regarded as an absolute contraindication to LT if patients are treated appropriately [3,4].
Cardiac death or postoperative myocardial injury is the leading cause of death within the first 30 days after noncardiac surgery [5-7]. Similarly, in the modern era of LT, cardiovascular events are the leading cause of early and late mortality [8]. However, the extent of myocardial injury or damage, as assessed by measurement of high sensitivity cardiac troponin I (hs_cTnI) after LT, in patients with CAD remains unclear.
In the current study, we first examined the extent of hs_cTnI increase within 30-day after LT in the patients with CAD. We then compared long-term mortality and 30-day mortality in the patients with and without CAD. In the subgroup analysis, we observed the long-term mortality across the stratification of liver disease severity, because high model for end-stage liver disease (MELD) score may affect the outcomes of CAD patients.

MATERIALS AND METHODS

Study population

A total of 4,432 consecutive, prospectively registered patients who underwent LT from January 2010 to February 2020 were enrolled. Of these, 1,212 were excluded for the following reasons: 227 were < 18 years old, 180 underwent retransplantation after rejection of the initial graft, 131 had acute fulminant liver failure, 130 had toxic hepatitis, and 544 had incomplete hs_cTnI data. Finally, 3,220 patients were included in the analysis (Fig. 1).

Data collection

Baseline demographic characteristics, laboratory, and perioperative variables related to LT were collected using fully computerized database extraction software (ABLE, Asan Biomedical Research Environment). The study design and a waiver of informed consent from participants were approved by the Institutional Review Board (no 2022-0511).
The MELD score, a known index of liver disease severity, was calculated using variables measured during hospitalization for LT. When variables were measured repeatedly, they were updated at the time of LT.
As a part of our institution’s routine post-LT cardiac workup since 2008, all LT recipients were assessed with transthoracic echocardiography, coronary computed tomography (CT) angiography, B-type natriuretic peptide and hs_cTnI levels. All recipients, irrespective of signs and symptoms of heart failure/myocardial injury, have their hs_cTnI concentration measured immediately after LT (i.e., on postoperative day [POD] 1); this was repeated at least once on POD2 or POD3 [9,10]. Additionally, when patients suffered signs and symptoms of an adverse cardiovascular event, including myocardial ischemia, within 30 days after LT, hs_cTnI levels were measured and followed-up. In the current study, the peak hs_cTnI level within 30 days after LT was used for analysis. Hs_cTnI was assessed using the ADVIA Centaur XP TnI-Ultra (Siemens Healthcare Diagnostics, USA; the 99th percentile upper reference limit [URL] = 0.04 pg/L; lower limit = 0.006 ng/L).

1. Outcomes and follow-up

Mortality data were collected from the medical records database and the institution’s LT Registry, which is updated regularly by the Organ Transplantation Center. The primary endpoint was defined as an all-cause mortality at 12 years following LT and secondary endpoint include 30-day mortality and peak hs_cTnI level within post-transplant 30 days. Liver disease severity was assessed with the stratification of MELD score: MELD score< 16, MELD score 16-30 and MELD score > 30.

Statistics

Data were expressed as the mean and standard deviation, as the median and interquartile range (for continuous variables), or as numbers and percentages (for categorical variables). Intergroup comparisons were performed using a t-test or the Mann-Whitney U test (for continuous variables), or the χ2 test or Fisher’s exact test (for categorical variables), as appropriate. Kaplan-Meier survival curves were used to depict the risk of all-cause mortality during the entire follow-up period. To evaluate the relationship between clinical and biochemical parameters, liver disease severity, and mortality events, a Cox proportional multiple regression model was built, and adjusted hazard ratios (HR) were obtained for long-term mortality. Covariates included in long-term survival analysis were age, sex, body mass index, diabetes, hypertension, MELD score, intraoperative red blood cell transfusion, and postreperfusion syndrome and CAD. Statistical analyses were conducted using R (version 4.1.2, R Foundation for Statistical Computing, Austria) with a significance level of 0.05.

RESULTS

Of 3,220 LT recipients included in the study (Table 1), the median age was 54.0 (interquartile, 49, 59) years, and 2,411 (74.9%) were male. The MELD score was 14 (9, 22 (Table 1). The primary causes of liver disease were virus-related liver cirrhosis (65.8%), alcoholic liver disease (22.9%), and others (4.1%).

CAD patients

CAD patients (n = 264, 8.2%) were older, and had a higher prevalence of diabetes, hypertension, alcoholic cirrhosis, and a history of previous cardiovascular disease including stroke; however, the pretransplant MELD score for CAD and non-CAD patients was similar. Intraoperatively, patients with CAD required transfusion of more red blood cells (median [interquartile], 9.0 [4.0, 17.0] vs. 8.0 [3.0, 16.0] units, P = 0.013) and were more likely to suffer from postreperfusion syndrome (67.8% vs. 58.8%, P = 0.005). Following LT, patients with CAD had higher peak hs_cTnI levels within 30 days of LT than those without CAD (0.087 [0.037, 0.203] vs. 0.068 [0.030, 0.154] ng/ml, respectively; P = 0.004).

30 day and long-term mortality

All-cause mortality (14.7% vs. 14.8%, P = 0.999, Fig. 2) at 12 years and at 30 days (1.9% vs. 1.1%, P = 0.522) was similar for patients with and without CAD.
When patients are grouped with peak hs_cTnI > 0.04 ng/ml and hs_cTnI ≤ 0.04 ng/ml level within 30 days of LT, patients with CAD did not show differences in mortality compared with those without CAD (Fig. 3).
In multivariable Cox proportional HR analysis, CAD did not remain as an important determinant for long-term survival, as expected in the univariate analysis (Fig. 4).
Subgroup analysis after stratification according to liver disease severity (MELD score < 16, 16-30, or > 30) revealed a comparable risk of long-term mortality (log-rank P = 0.41, P = 0.89, and P = 0.52, respectively) (Fig. 5).

DISCUSSION

In the current study, the peak hs_cTnI level within 30 days after LT was higher in those with CAD; however, we found long-term mortality rates at 12 years were comparable with those of patients without CAD, irrespective of liver disease severity.
We evaluated postoperative peak hs_cTnI levels within 30 days in a large cohort of LT patients, especially those with CAD. Only a few studies have analyzed hs_cTnI levels in the field of LT surgery, despite the importance of post-LT myocardial injury [11].
Myocardial injury after noncardiac surgery (MINS) is defined as myocardial injury/damage caused by ischemia occurring during or within 30 days after surgery [7]. Among patients undergoing cardiac and noncardiac surgery, peak postoperative troponin levels during the first 3 days post-surgery are significantly associated with 30-day mortality, and a number of studies show that elevated cardiac troponin is an independent predictor of major adverse cardiac events [11,12]. Therefore, perioperative troponin screening is highly recommended because it can identify patients with MINS who are at higher risk for major cardiovascular events after noncardiac surgery. Another study shows that after living-donor LT surgery, myocardial injury detected by elevated hs-cTnI levels immediately after surgery is independently associated with adverse outcomes during hospital stay [11].
LT can be an extremely stressful event for patients with end-stage liver disease because they often suffer from refractory hypotension, tachyarrhythmia, massive bleeding with extreme anemia, inferior vena cava clamping, prolonged vasoplegia with high dose vasopressors, and acute overload of ventricular preload during surgery [9,13,14]. Additionally, afterload increase during the immediate postoperative period transforms silent cardiovascular disease into early heart failure status [15-17]. Therefore, it might not be surprising that CAD patients had higher postoperative hs_cTnI levels. However, the difference was not sufficiently high to discriminate long-term mortality in the current study, suggesting that adequately treated CAD patients may tolerate the stressful event well, as did patients without CAD, resulting in comparable long-term outcomes.
By contrast, a previous retrospective study [10] of 2,118 consecutive LT patients who underwent CAD screening using coronary CT angiography identified unknown obstructive CAD (> 50% narrowing, 9.2% prevalence) in 21.7% of patients with three or more known CAD risk factors listed by the American Heart Association (i.e., diabetes mellitus, hypertension, prior cardiovascular disease, left ventricular hypertrophy, age > 60 years, smoking, and dyslipidemia) [18]. Of these, two‐vessel or three‐vessel obstructive CAD had a 4.9‐fold higher post‐LT type 2 myocardial infarction risk than normal coronary vessels [10]. This finding emphasizes the importance of pretransplant identification of unknown CAD, and administration of appropriate treatments such as revascularization.
However, another study evaluated cardiovascular events after LT; patients were stratified according to the presence and severity of CAD, as measured by coronary angiography. The authors found no evidence of a relationship between the presence and severity of CAD and composite cardiovascular events and concluded that the risk of cardiovascular events during the immediate post‐transplant period is not associated with the presence or severity of CAD [19].
Similarly in the Satapathy et al.’s study [4], it was emphasized that listing for LT after appropriate revascularization in the preoperative period in patients with high risk for potential or known CAD would lead to similar post-LT survival compared with those without obstructive CAD irrespective of underlying severity, or extent disease, if appropriately revascularized. In the current study, our definition of patients with CAD was already revascularized or treated patients from old myocardial infraction. Therefore, our results showing comparable long-term outcomes in patients with and without CAD are in line with previous studies [4,20]. Specifically, our comparable long-term results were across the stratification of liver disease severity of MELD score, which importantly affect the critical determinants of post-LT survival.
In multivariable Cox proportional HR analysis, CAD did not remain significant, however, age, body mass index (BMI), MELD score, and intraoperative red blood cell transfusion remained significant. Of these, although above variables remained are generally expectable for important risk factors of long-term mortality, decreased BMI is interesting. Presumably, it is thought that low BMI might be associated with sarcopenia, which is known risk factors of poor LT outcomes [21]. However, further controlled study will be needed.
The current study has several limitations. Although the study cohort was collected prospectively, the retrospective review of mortality from medical records has limitations. Second, despite the large LT population, our patients are all from a single institution. Therefore, a prospective multicenter study will be needed in the future.
In conclusion, patients with CAD showed transient myocardial injury with slightly higher peak hs_cTnI within 30 days after LT compared with those without CAD, however, long-term mortality rates at 12 years and 30-day mortality rate were comparable.

Notes

FUNDING

This research was supported partly by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which is funded by the Ministry of Health & Welfare of the Republic of Korea (grant number: HI18C2383).

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

DATA AVAILABILITY STATEMENT

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

AUTHOR CONTRIBUTIONS

Conceptualization: J Yang, Gyu-Sam Hwang. Data curation: Jae Hwan Kim, Ji-Woong Yang. Formal analysis: Gyu-Sam Hwang. Methodology: Jae Hwan Kim. Visualization: Hye-Mee Kwon, Ji-Woong Yang. Writing - original draft: Hye-Mee Kwon. Writing - review & editing: Gyu-Sam Hwang. Investigation: Ji-Woong Yang. Software: Hye-Mee Kwon. Supervision: Gyu-Sam Hwang.

Fig. 1.
Flow diagram of current study.
apm-22167f1.jpg
Fig. 2.
Kaplan-Meier plot showing cumulative overall survival rate between patients with and without coronary artery disease (CAD).
apm-22167f2.jpg
Fig. 3.
Impact of coronary artery disease (CAD) prevalence on cumulative overall survival rate between patients with low (≤ 0.04 ng/ml) and high (> 0.04 ng/ml) troponin I (TnI).
apm-22167f3.jpg
Fig. 4.
Uni- and multivariable cox regression analysis with long-term mortality rates at 12 years. BMI: body mass index, MELD: model for end-stage liver disease, RBC: red blood cell, PRS: post-reperfusion syndrome, CAD: coronary artery disease, CI: confidence interval.
apm-22167f4.jpg
Fig. 5.
Kaplan-Meier plot of cumulative overall survival rate between patients with and without coronary artery disease (CAD), in subset of patients with MELD score of < 16, 16-30, or > 30. MELD: model for end-stage liver disease.
apm-22167f5.jpg
Table 1.
Demographics and Perioperative Variables According to CAD
Variable CAD (-) (n = 2,956) CAD (+) (n = 264) Total (n = 3,220) P value
Demographics
 Age (yr) 54 (48, 59) 57 (53, 62) 54 (49, 59) < 0.001
 Male 2,178 (73.7) 233 (88.3) 2,411 (74.9) < 0.001
 Body mass index (kg/m2) 24.2 (21.9, 26.5) 24.7 (22.4, 27.0) 24.2 (22.0, 26.6) 0.059
 MELD score 14 (9, 23) 13 (9, 20) 14 (9, 22) 0.221
 Cardiovascular disease 379 (12.8) 264 (100.0) 643 (20.0) < 0.001
 Diabetes mellitus 680 (23.0) 113 (42.8) 793 (24.6) < 0.001
 Hypertension 511 (17.3) 79 (29.9) 590 (18.3) < 0.001
 Varix bleeding 51 (1.7) 3 (1.1) 54 (1.7) 0.643
 Intractable ascites 863 (29.2) 88 (33.3) 951 (29.5) 0.180
 Pre-LT RRT 229 (7.7) 23 (8.7) 252 (7.8) 0.660
 Pre-LT vasopressor use 128 (4.3) 10 (3.8) 138 (4.3) 0.796
 Pre-LT ventilator use 172 (5.8) 8 (3.0) 180 (5.6) 0.080
Etiology of liver cirrhosis
 Viral cirrhosis 1,966 (66.5) 153 (58.0) 2,119 (65.8) 0.006
 Alcoholic cirrhosis 657 (22.2) 80 (30.3) 737 (22.9) 0.004
 Biliary cirrhosis 120 (4.1) 2 (0.8) 122 (3.8) 0.012
 Other disease 10 (0.3) 1 (0.4) 11 (0.3) 1.000
Laboratory findings
 Total bilirubin 2.0 (1.0, 6.5) 1.8 (0.9, 4.2) 2.0 (1.0, 6.3) 0.040
 Prothrombin time, INR 1.42 (1.20, 1.81) 1.38 (1.17, 1.71) 1.41 (1.20, 1.79) 0.147
 Creatinine (mg/dl) 0.79 (0.64, 1.00) 0.80 (0.67, 1.06) 0.80 (0.64, 1.01) 0.114
 Serum sodium (mEq/L) 139 (135, 141) 138 (135, 141) 139 (135, 141) 0.240
Intraoperative variables
 pRBC transfusion 8 (3, 16) 9 (4, 17) 8 (3, 16) 0.013
 Postreperfusion syndrome 1,737 (58.8) 179 (67.8) 1,916 (59.5) 0.005
Outcome after LT
 30-day mortality 56 (1.9) 3 (1.1) 59 (1.8) 0.522
 Overall mortality 434 (14.7) 39 (14.8) 473 (14.7) 1.000

Values are presented as median (1Q, 3Q) or number (%). CAD: coronary artery disease, MELD: model for end-stage liver disease, LT: liver transplantation, RRT: renal replacement therapy, pRBC: packed red blood cells, INR: international normalized ratio.

REFERENCES

1. Xia VW, Taniguchi M, Steadman RH. The changing face of patients presenting for liver transplantation. Curr Opin Organ Transplant 2008; 13: 280-4.
crossref pmid
2. VanWagner LB, Harinstein ME, Runo JR, Darling C, Serper M, Hall S, et al. Multidisciplinary approach to cardiac and pulmonary vascular disease risk assessment in liver transplantation: an evaluation of the evidence and consensus recommendations. Am J Transplant 2018; 18: 30-42.
crossref pmid pmc pdf
3. Skaro AI, Gallon LG, Lyuksemburg V, Jay CL, Zhao L, Ladner DP, et al. The impact of coronary artery disease on outcomes after liver transplantation. J Cardiovasc Med (Hagerstown) 2016; 17: 875-85.
crossref pmid
4. Satapathy SK, Vanatta JM, Helmick RA, Flowers A, Kedia SK, Jiang Y, et al. Outcome of liver transplant recipients with revascularized coronary artery disease: a comparative analysis with and without cardiovascular risk factors. Transplantation 2017; 101: 793-803.
pmid pmc
5. Mauermann E, Puelacher C, Lurati Buse G. Myocardial injury after noncardiac surgery: an underappreciated problem and current challenges. Curr Opin Anaesthesiol 2016; 29: 403-12.
pmid
6. Writing Committee for the VISION Study Investigators, Devereaux PJ, Biccard BM, Sigamani A, Xavier D, Chan MTV, et al. Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA 2017; 317: 1642-51.
pmid
7. Costa MCDBG, Furtado MV, Borges FK, Ziegelmann PK, Suzumura ÉA, Berwanger O, et al. Perioperative troponin screening identifies patients at higher risk for major cardiovascular events in noncardiac surgery. Curr Probl Cardiol 2021; 46: 100429.
crossref pmid
8. VanWagner LB, Lapin B, Levitsky J, Wilkins JT, Abecassis MM, Skaro AI, et al. High early cardiovascular mortality after liver transplantation. Liver Transpl 2014; 20: 1306-16.
crossref pmid pmc pdf
9. Kwon HM, Moon YJ, Kim KS, Shin WJ, Huh IY, Jun IG, et al. Prognostic value of B-type natriuretic peptide in liver transplant patients: implication in posttransplant mortality. Hepatology 2021; 74: 336-50.
crossref pmid pdf
10. Moon YJ, Kwon HM, Jung KW, Jeong HW, Park YS, Jun IG, et al. Risk stratification of myocardial injury after liver transplantation in patients with computed tomographic coronary angiography-diagnosed coronary artery disease. Am J Transplant 2019; 19: 2053-66.
crossref pmid pdf
11. Park J, Lee SH, Han S, Kim KY, Kim GE, Park M, et al. Elevated high-sensitivity troponin I during living donor liver transplantation is associated with postoperative adverse outcomes. Transplantation 2018; 102: e236-44.
crossref pmid
12. Sessler DI, Devereaux PJ. Perioperative troponin screening. Anesth Analg 2016; 123: 359-60.
crossref pmid
13. Kwon HM, Moon YJ, Jung KW, Park YS, Kim KS, Jun IG, et al. Appraisal of cardiac ejection fraction with liver disease severity: implication in post-liver transplantation mortality. Hepatology 2020; 71: 1364-80.
crossref pmid pdf
14. Kwon HM, Hwang GS. Cardiovascular dysfunction and liver transplantation. Korean J Anesthesiol 2018; 71: 85-91.
crossref pmid pmc pdf
15. Zaky A, Bendjelid K. Appraising cardiac dysfunction in liver transplantation: an ongoing challenge. Liver Int 2015; 35: 12-29.
crossref pmid pdf
16. Raval Z, Harinstein ME, Skaro AI, Erdogan A, DeWolf AM, Shah SJ, et al. Cardiovascular risk assessment of the liver transplant candidate. J Am Coll Cardiol 2011; 58: 223-31.
crossref pmid
17. Izzy M, VanWagner LB, Lin G, Altieri M, Findlay JY, Oh JK, et al. Cirrhotic Cardiomyopathy Consortium. Redefining cirrhotic cardiomyopathy for the modern era. Hepatology 2020; 71: 334-45. Erratum in: Hepatology 2020; 72: 1161.

18. Lentine KL, Costa SP, Weir MR, Robb JF, Fleisher LA, Kasiske BL, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. Circulation 2012; 126: 617-63.
crossref pmid
19. Patel SS, Lin FP, Rodriguez VA, Bhati C, John BV, Pence T, et al. The relationship between coronary artery disease and cardiovascular events early after liver transplantation. Liver Int 2019; 39: 1363-71.
crossref pmid pmc pdf
20. Barman PM, VanWagner LB. Cardiac risk assessment in liver transplant candidates: current controversies and future directions. Hepatology 2021; 73: 2564-76.
crossref pmid pmc pdf
21. Tantai X, Liu Y, Yeo YH, Praktiknjo M, Mauro E, Hamaguchi Y, et al. Effect of sarcopenia on survival in patients with cirrhosis: a meta-analysis. J Hepatol 2022; 76: 588-99.
crossref pmid


ABOUT
ARTICLE & TOPICS
Article category

Browse all articles >

Topics

Browse all articles >

BROWSE ARTICLES
AUTHOR INFORMATION
Editorial Office
101-3503, Lotte Castle President, 109 Mapo-daero, Mapo-gu, Seoul 04146, Korea
Tel: +82-2-792-5128    Fax: +82-2-792-4089    E-mail: journal@anesthesia.or.kr                

Copyright © 2022 by Korean Society of Anesthesiologists.

Developed in M2PI

Close layer
prev next