Prediction of Perioperative Cardiovascular Events in Liver... : Transplantation (original) (raw)

INTRODUCTION

Major adverse cardiovascular events (MACE) represent a major cause of early morbidity and mortality following liver transplantation (LT).1-4 Despite rigorous preoperative assessment, the rates of early cardiovascular death following LT are 4-fold higher when compared with other types of high-risk noncardiac surgery.1,5 Moreover, analysis of early mortality following LT demonstrates a preponderance of noncoronary events.1,2,6 It has been proposed that cirrhotic cardiomyopathy, characterized by an impaired inotropic and chronotropic response to stress, may be a contributing factor.7 However, inclusion of cirrhotic cardiomyopathy in current risk stratification algorithms is challenging due to difficulty in both establishing this diagnosis and quantifying its severity.8 Furthermore, there is a paucity of data evaluating whether perioperative cardiac events following LT affects long-term survival.2,9

Hepatorenal syndrome (HRS) is a serious complication of cirrhosis that occurs in up to 30% of patients with end-stage liver disease.10 HRS occurs due to progressive systemic arterial vasodilation and a maladaptive neurohormonal response.11 Several concordant lines of evidence have also linked subclinical cardiac dysfunction and cirrhotic cardiomyopathy in its pathogenesis.12-16 Patients with HRS, therefore, represent a cohort with both profound circulatory and cardiac dysfunction. Whether HRS increases the risk of perioperative MACE following LT is unclear. The primary aim of this study was to assess whether occurrence of HRS before LT confers significant risk for the development of perioperative cardiovascular events in a contemporary cohort. A secondary aim was to evaluate the effect of perioperative cardiovascular events on posttransplant survival.

MATERIALS AND METHODS

Patient Population

Consecutive adult patients (≥age 18 y) that underwent cardiac assessment for LT between 2010 and 2017 at the state-wide liver transplant center in Melbourne, Australia, were included in this retrospective cohort study. Over 1200 LT have been undertaken at our institution to date, and, currently, over 100 LT are performed annually.17 Only patients who had undergone preoperative cardiovascular evaluation, which included a cardiologist review and dobutamine stress echocardiogram (DSE) were included. At our center, a DSE was performed in all LT candidates over 50 years or those aged ≥45 years with diabetes mellitus, unless patients had a prior history of cardiac disease or symptoms suggestive of coronary or structural heart disease. Patients undergoing multiple organ transplantation or retransplantation were excluded. The project received approval from the Human Research Ethics Committee at Austin Health (LNR/18/Austin/177).

Patient demographics, medical history, medication use, cause, and severity of liver disease (based on the biological model for end-stage liver disease [MELD] score and Child-Pugh score) were obtained from the prospectively collected institutional liver transplant database. Clinical details were supplemented by case history review as required. Diagnosis of cirrhosis was made on histology or on clinical, laboratory, and radiologic findings. Transplantation for nonalcoholic steatohepatitis was defined as a primary or secondary listing diagnosis of nonalcoholic steatohepatitis or cryptogenic cirrhosis with at least 1 risk factor for the metabolic syndrome (pretransplant obesity, diabetes, hypertension, and dyslipidemia). The presence of ascites was determined clinically and confirmed by abdominal ultrasound examination.

Pulmonary hypertension was defined as right ventricular systolic pressure ≥35 mm Hg on echocardiography or a mean pulmonary artery pressure ≥25 mm Hg on right heart catheterization. Assessment of functional status in this study focused on the impact of disease on the ability to carry out activities of daily living (ie, personal care) and work-related activities. We used a modified version of the Eastern Cooperative Oncology Group performance status as suggested by prior studies in the LT population.18 Poor functional status was defined as those patients only capable of limited self-care, confined mostly to chair or bed or patients completely reliant on nursing/medical care as assessed by the transplant multidisciplinary team. Blood samples were taken for measurement of liver function, urea, serum electrolytes, and creatinine before transplantation. No major changes in institutional surgical, anesthetic techniques, or preoperative assessment were instituted during this study period.

Dobutamine Stress Echocardiography

All echocardiographic data were independently reviewed by 2 cardiologists as per our institutional protocol. Echocardiographic images were acquired using a commercially available system (Siemens SC2000, Erlangen, Germany) and performed according to the American Society of Echocardiography guidelines.19 Right ventricular systolic pressure was estimated using the modified Bernoulli equation, and pulmonary vascular resistance was estimated using the Abbas formula.20,21 DSE was classified as positive in those with ≥1 mm horizontal or down-sloping ST-segment depression in 2 contiguous leads, new or worsening stress-induced wall motion abnormality, ventricular cavity dilation, or reduced global ventricular systolic function when compared with baseline. Decision to refer a patient for coronary angiography and revascularization was made at a multidisciplinary clinical meeting with the transplant physicians, anesthesiologists, and cardiologists. The major cardiac contraindications for LT at our center closely reflect the current guidelines from the American Society of Transplantation.22 This includes unrevascularized multivessel coronary artery disease (CAD), cardiomyopathy with a left ventricular ejection fraction ≤40%, severe pulmonary hypertension not responsive to therapy and severe valvular heart disease. Right heart catheterization was performed at our center, when there was echocardiographic evidence of elevated pulmonary artery systolic pressures ≥40 mm Hg or evidence of right ventricular systolic dysfunction. Portopulmonary hypertension was diagnosed as per guideline criteria that included a mean pulmonary artery systolic pressure ≥25 mm Hg, pulmonary vascular resistance ≥3 Wood’s units and a pulmonary capillary wedge pressure <15 mm Hg.23 As the focus of this study was to evaluate perioperative cardiac events following LT, data relating to patients that did not proceed to transplantation are not presented. Prior CAD was defined as obstructive (≥50%) coronary atherosclerosis either on pretransplant evaluation or a history of coronary revascularization including coronary stents or coronary artery bypass surgery.

Diagnosis of Hepatorenal Syndrome

All patients underwent regular follow-up with assessment of clinical status and blood biochemistry. HRS diagnosis was based on the 2019 revised diagnostic criteria proposed by International Club of Ascites and included both diagnoses of HRS-acute kidney injury and HRS-nonacute kidney injury, when other causes of acute kidney injury were excluded and when patients were nonresponsive to volume expansion and diuretic withdrawal.24 HRS-acute kidney injury diagnosis was primarily defined as an absolute increase in serum creatinine ≥0.3 mg/dL within 48 hours or a ≥50% increase in baseline creatinine. HRS-nonacute kidney injury was defined as a reduction in estimated glomerular filtration rate <60 mL/min for <3 months in the absence of other structural causes and <50% rise in baseline creatinine. As patients were closely monitored as inpatients or outpatients during transplant workup, serial serum creatinine readings were available to calculate change from baseline within 48 hours. If this was not available, a stable serum creatinine within the previous 3 months was used. HRS cases were identified by retrospective chart review of notes by 2 physician researchers and each case review and discussion with a transplant hepatologist for consensus. The time period for assessing the presence of HRS was from the time of commencing pretransplant workup up to the date of LT.

Study Outcomes

The primary endpoint was the occurrence of MACE occurring within 30 days. A 30-day time period was chosen for quantifying early outcomes in accordance with current reporting of perioperative outcomes in noncardiac surgery.25 MACE was defined as cardiovascular death, myocardial infarction (MI), coronary revascularization, heart failure, new atrial fibrillation (AF), cardiac arrest, or pulmonary embolism. Cardiovascular death was defined as sudden death or death secondary to MI, arrhythmia, or heart failure. MI was defined as a rise in troponin-t level above the 99th percentile with symptoms or ECG changes. Congestive heart failure in this study population was adjudicated based on clinical, radiologic, and echocardiographic findings. New AF in this study was defined as those without a preexisting history of AF and patients in sinus rhythm on the ECG before LT. When multiple MACE occurred in the same patient, only 1 event was included for analysis.

Outcomes were obtained from a prospectively maintained institutional liver transplant database and supplemented by retrospective electronic medical record review including operative and anesthetic records by 2 physician researchers (B.C. and J.K.).

Cases were subsequently reviewed by a cardiologist (A.N.K.) for confirmation of events and to establish cause of death. The secondary outcomes were to assess whether perioperative MACE affected posttransplant survival. After LT, all patients undergo routine follow-up on a 3–6 monthly basis at our center.

Predictors of Perioperative Cardiovascular Events

Potential risk factors for MACE after LT were specified a priori. These included demographic factors (age, gender), traditional cardiac risk factors (diabetes, hypertension, dyslipidemia, smoking, prior CAD), functional status, positive DSE, pulmonary hypertension, transplant-specific critical illness indicators (MELD score, history of HRS), medication use (aspirin, statin, beta blockers), and whether a significant postoperative complication occurred (bleeding requiring return to theater, infection or rejection). Validated perioperative risk scores including the revised cardiac risk index (RCRI) and cardiovascular risk index (CVRI) were also calculated. RCRI was estimated based on parameters including high-risk surgery (intrathoracic, intraperitoneal, or suprainguinal vascular surgery), ischemic heart disease, congestive heart failure, insulin therapy with diabetes mellitus, cerebrovascular disease, and renal dysfunction (preoperative serum creatinine >2.0 mg/dL).26 CVRI was estimated with a point each for age ≥75 years, history of heart disease, symptoms of angina or dyspnea, hemoglobin <12 mg/dL, vascular surgery, and emergency surgery.27

Statistical Analysis

Results are expressed as mean ± SD or median with interquartile range (IQR) for nonnormally distributed data. Comparisons between groups were performed with the chi-square test for categorical data and the Student _t_-test or Mann-Whitney U test as appropriate for continuous data. Stepwise logistic regression was used to identify independent predictors of perioperative MACE. Univariate predictors yielding P < 0.1 were entered in the multivariable model as covariates. It was determined a priori that age would be included in the final model. To avoid multicollinearity between univariable predictors, a correlation coefficient of <0.7 was set. Outcomes were presented as odds ratio (OR) with 95% confidence intervals (CIs). Discrimination of the final model was estimated using the area under the curve using the receiver operating curve with estimation of the c-statistic. The goodness of model fit was assessed by the Hosmer and Lemeshow statistic. Survival curves were generated using the Kaplan-Meier method and compared using the log-rank test. The assumption of proportional hazards was assessed graphically. A Cox-regression model was used to adjust for age in long-term survival. All reported P values are 2-tailed, with values <0.05 considered significant. Statistical analyses were performed using Stata 13/MP (Statacorp, College Station, TX).

RESULTS

Between 2010 and 2017, 560 patients underwent cardiovascular preoperative workup including a DSE. Among these, 319 patients underwent LT during the study period (Figure 1). Among the 241 patients that were not transplanted, 65 (27.0%) patients were subsequently listed and transplanted outside the time period of this study. Only 12 (4.9%) patients were excluded for primary cardiac reasons. Primary cause of LT was hepatitis B/C, and mean MELD score was 18 ± 7. Beta blockers were used for variceal prophylaxis in 20.7%. None of the patients were using beta blockers as therapy for angina or for treatment of systolic heart failure. The cardiovascular risk factor profile in this cohort was notable for a 43.9% prevalence of hypertension, 35.7% with diabetes, 31.3% with dyslipidemia, and 10% having preexisting CAD. Thirty-six (11.2%) patients had pulmonary hypertension including 4 with portopulmonary hypertension. Overall, 85 (26.6%) patients met the criteria for HRS at or before LT. Median duration from HRS diagnosis to transplantation was 2 (IQR, 0–5) months. Eight (2.5%) patients required dialysis in the perioperative period following transplantation.

FIGURE 1.:

Study flow chart. IQR, interquartile range.

A total of 46 (14.4%) patients underwent coronary angiography for a positive DSE (18 [5.6%]), clinical history, or according to the recommendation of the treating cardiologist (28 [8.7%]). Among these, 4 (1.3%) patients underwent percutaneous coronary intervention before transplantation.

Primary Outcomes: Major Adverse Cardiovascular Events

Overall, 90 MACE occurred in 74 (23.2%) patients. These were predominantly noncoronary events 77 (86.5% of MACE). Cause specific breakdown of events included 2 cardiovascular deaths, 19 cases of congestive cardiac failure, 11 cases of perioperative MI, 17 cases of resuscitated cardiac arrest or ventricular tachycardia, and 41 cases of new AF. Multiple MACE occurred in 15 (4.7%) patients and are summarized in Table S1, SDC, https://links.lww.com/TP/B941. Of the 2 cardiovascular deaths, first occurred in the context of refractory heart failure due to cirrhotic cardiomyopathy in a patient with normal pretransplant left ventricular systolic function and the second was due to a postoperative cardiac arrest. Among those with postoperative AF, only 4 (9.7%) patients were in persistent AF at discharge. One patient was discharged with a direct-acting oral anticoagulant.

Predictors of MACE

Baseline characteristics are presented in Table 1. On univariate analysis, patients that experienced MACE were older, had a higher CVRI score, were more likely to have pulmonary hypertension, functional impairment, and be on beta blockers at the time of transplant. A significantly higher proportion of patients with HRS experienced perioperative MACE (41.9% versus 22.0%, P = 0.001). A positive dobutamine stress echo demonstrated a trend toward increased MACE (P = 0.08). Conventional cardiac risk factors including hypertension, diabetes, smoking, dyslipidemia, and the RCRI were not significant on univariate analysis. Cause and severity of liver disease also did not confer significant risk for MACE.

TABLE 1. - Baseline characteristics

| | Overall (n = 319) | No MACE (n = 245) | MACE (n = 74) | P | | | --------------------------------------------------------- | ----------------- | ------------- | ------------- | ----- | | Age | 56.3 ± 7 | 55.9 ± 7 | 57.7 ± 6 | 0.04 | | Age ≥60 y | 111 (34.8) | 79 (32.2) | 32 (43.2) | 0.08 | | Male gender | 236 (74.0) | 179 (73.1) | 57 (77.0) | 0.49 | | Body mass index (kg/m2) | 27.8 ± 6 | 28.0 ± 5 | 27.4 ± 6 | 0.38 | | Cardiovascular risk factors at transplant | | | | | | Hypertension | 140 (43.9) | 111 (45.3) | 29 (39.2) | 0.33 | | Smoker (current or exsmoker) | 179 (56.1) | 138 (56.3) | 41 (55.4) | 0.95 | | Diabetes mellitus | 114 (35.7) | 87 (35.6) | 27 (36.5) | 0.89 | | History of CAD | 32 (10.0) | 21 (8.6) | 11 (14.9) | 0.09 | | Prior MI | 11 (3.4) | 7 (2.9) | 4 (5.4) | 0.3 | | Peripheral vascular disease | 5 (1.6) | 4 (1.6) | 1 (1.3) | 0.86 | | Dyslipidemia | 100 (31.3) | 76 (31.0) | 24 (32.4) | 0.82 | | Prior stroke | 9 (2.9) | 6 (2.5) | 3 (4.0) | 0.46 | | Pulmonary hypertension | 36 (11.3) | 19 (7.7) | 17 (22.9) | 0.001 | | RCRI score | 1.3 ± 0.5 | 1.3 ± 0.5 | 1.5 ± 0.6 | 0.3 | | CVRI score | 0.78 ± 0.7 | 0.74 ± 0.7 | 1.0 ± 0.7 | 0.05 | | Recipient functional status | | | | | | Partially or fully dependent | 56 (17.5) | 37 (15.1) | 19 (25.7) | 0.02 | | Cause of liver disease | | | | | | Hepatitis B/C | 129 (40.4) | 106 (43.3) | 23 (31.1) | 0.06 | | Alcohol | 39 (12.2) | 27 (11.0) | 12 (16.2) | 0.23 | | NASH | 48 (15.0) | 36 (14.7) | 12 (16.2) | 0.74 | | HCC | 28 (8.8) | 20 (8.2) | 8 (10.8) | 0.48 | | Other | 75 (23.5) | 56 (22.9) | 19 (25.7) | 0.62 | | Serum biochemistry at transplant | | | | | | Sodium (mmol/L) | 134 ± 15 | 134 ± 16 | 135 ± 6 | 0.9 | | Creatinine (µmol/L) | 84 (68–109) | 83 (68–110) | 85 (72–108) | 0.58 | | Albumin (g/L) | 30 ± 6 | 30 ± 6 | 29 ± 6 | 0.44 | | Severity and complications of liver disease at transplant | | | | | | MELD score | 17.7 ± 7.5 | 17.4 ± 7.5 | 18.5 ± 7.7 | 0.27 | | Child-Pugh score | 9.6 ± 2.7 | 9.4 ± 2.7 | 10.0 ± 2.6 | 0.22 | | Ascites | 195 (61.1) | 146 (59.6) | 49 (66.2) | 0.31 | | Encephalopathy (≥grade 1) | 138 (46.0) | 102 (43.6) | 36 (54.5) | 0.11 | | Hepatorenal syndrome | 85 (26.6) | 54 (22.0) | 31 (41.9) | 0.001 | | Postoperative complication | 40 (12.5) | 31 (12.6) | 9 (12.2) | 0.91 | | Cold ischemia time (min) | 368 (307–440) | 380 (310–404) | 363 (308–430) | 0.75 | | Warm ischemia time (min) | 44 (38–51) | 42 (38–50) | 44 (39–50) | 0.52 | | Medications at transplant | | | | | | Aspirin | 64 (20.1) | 45 (18.4) | 19 (25.7) | 0.17 | | Beta-blocker | 66 (20.7) | 42 (17.2) | 24 (32.4) | 0.005 | | Statin | 86 (27.0) | 65 (26.6) | 21 (28.4) | 0.77 | | Echocardiographic findings | | | | | | Positive stress test | 18 (5.6) | 11 (4.5) | 7 (9.5) | 0.08 | | Baseline cardiac output (L/min) | 7.1 ± 2 | 7.1 ± 2 | 7.3 ± 2 | 0.58 | | RVSP (mm Hg) | 26 ± 8 | 26 ± 7 | 29 ± 9 | 0.003 | | PVR (woods units) | 1.5 ± 0.4 | 1.5 ± 0.3 | 1.6 ± 0.5 | 0.23 | | Left atrial area (cm2) | 25.1 ± 6 | 24.5 ± 5 | 26.6 ± 8 | 0.11 | | E/A ratio | 1.1 ± 0.4 | 1.1 ± 0.3 | 1.2 ± 0.3 | 0.12 |

Postoperative complication included bleeding requiring return to theater, infection, or rejection.

CAD, coronary artery disease; CVRI, cardiovascular risk index; HCC, hepatocellular carcinoma; MACE, major adverse cardiovascular event; MELD, model for end-stage liver disease; MI, myocardial infarction; NASH, nonalcoholic steatohepatitis; PVR, pulmonary vascular resistance; RCRI, revised cardiac risk index; RVSP, right ventricular systolic pressure.

Univariate predictors assessed for prediction of MACE are shown in Table 2. Age, preexisting CAD, CVRI, pulmonary hypertension, poor functional status, HRS, beta-blocker use, and a positive DSE were included in the final model. On multivariate logistic regression, poor functional status (OR, 3.38; 95% CI, 1.41-8.13), pulmonary hypertension (OR, 3.26; 95% CI, 1.17-5.56), beta-blocker use (OR, 2.56; 95% CI, 1.10-6.48), and HRS (OR, 2.44; 95% CI, 1.13-5.78) were independent predictors of MACE (Figure 2). The multivariate model demonstrated good discrimination (C statistic 0.76) with excellent calibration (Hosmer-Lemeshow, P = 0.23) (Figure 3). Additional sensitivity analyses of dichotomizing RCRI and CVRI risk indices to only high scores (RCRI or CVRI ≥3) did not improve model fit.

TABLE 2. - Univariate and multivariate predictors of major adverse cardiovascular events at 30 d following liver transplantation

Bold values indicate multivariate _p_-value <0.05. CAD, coronary artery disease; CI, confidence interval; CVRI, cardiovascular risk index; DSE, dobutamine stress echocardiography; OR, odds ratio.

FIGURE 2.:

Predictors of major adverse cardiovascular events at 30 d following liver transplantation. Figure reports the final adjusted odds ratios and 95% confidence intervals for all the listed variables included in the multivariable analysis.

FIGURE 3.:

Receiver operating characteristic curve illustrating overall model prediction for major adverse cardiovascular events.

Effect of 30-day MACE on Posttransplant Survival

Patients were followed up for a median of 3.6 years (IQR, 2–6 y). Data on perioperative MACE and survival were complete for all patients. During this period, 33 (10.3%) patients died and cardiovascular cause-specific mortality accounted for 7 (21.2%) deaths. A significantly higher proportion of patients with perioperative MACE died on long-term follow-up (14 [18.9%] versus 19 [7.8%]; P = 0.006) with Kaplan-Meier curves that illustrate early divergence of the curves that extended over the follow-up period (Figure 4). After adjustment for age, perioperative MACE demonstrated a trend toward higher long-term mortality (hazard ratio, 2.0; 95% CI, 0.98-4.10; P = 0.057).

FIGURE 4.:

Kaplan-Meier curve illustrating long-term survival stratified by occurrence of 30-d major adverse cardiovascular event following liver transplantation. CI, confidence interval; MACE, major adverse cardiovascular event.

DISCUSSION

This study aimed to assess key predictors of perioperative cardiac events following LT with a particular focus on whether HRS was associated with a significant risk. Adverse cardiac events were common in our cohort, occurring in approximately 1 in 4 patients. Patients with a history of HRS at or before transplantation, beta-blocker use, pulmonary hypertension, and a poor functional status were all independent predictors of perioperative MACE. Finally, perioperative MACE conferred a trend toward poor age-adjusted posttransplant survival in this population. Our findings highlight some novel risk predictors for adverse cardiovascular events and the importance of heightened long-term surveillance for patients that experience MACE following LT.

Assessment of cause-specific cardiac events in this study demonstrated that arrhythmia, heart failure, and cardiac arrest constituted over 85% of MACE. This may reflect the fact that all patients in this study underwent preoperative workup and treatment of CAD as deemed appropriate by the treating physicians.

However, an underlying substrate of cirrhotic cardiomyopathy that is unmasked during the hemodynamic stress of LT has also been suggested.1,7,8 Although underrecognized, cirrhotic cardiomyopathy is estimated to be present in 40%–50% of patients with end-stage liver disease.28 Strong evidence linking it to perioperative cardiac events is currently lacking and may be compounded by a lack of universally accepted diagnostic criteria.8,29 However, it is conceivable that a blunted ventricular response to stress and electrophysiological abnormalities can precipitate perioperative noncoronary events including heart failure and arrhythmia. Our findings importantly highlight gaps in contemporary guidelines of preoperative risk stratification in LT that focus primarily in ruling out CAD.

HRS is a manifestation of end-stage liver cirrhosis that occurs due to profound systemic vasodilation, maladaptive neurohormonal response, and heightened sympathetic activation.11 Several studies in the last decade have also implicated subclinical cardiac dysfunction or cirrhotic cardiomyopathy in the genesis of HRS.12,13,15 In our study, HRS was associated with a 2-fold higher risk for the occurrence of perioperative MACE. This remained significant after adjusting for relevant cardiovascular, functional, and stress echocardiography findings. Although a prior study reported higher unadjusted rates of perioperative MACE in patients with HRS, this was not assessed on multivariate analyses and the diagnostic criteria for HRS was not defined.30 As such, our findings are novel and highlight that HRS before transplantation warrants consideration as an adverse cardiac risk predictor. Similarly, the risk conferred by beta blocker use and pulmonary hypertension may also reflect the link between the cirrhotic cardiomyopathy substrate and MACE.8,31

Nonselective beta blockers are the cornerstone of medical treatment of portal hypertension and variceal prophylaxis.32,33 They reduce hepatic venous portal pressure gradient, cardiac output, and splanchnic vasoconstriction through the inhibition of catecholamine binding to β1 and β2 adrenoreceptors.33 Despite controversy surrounding the safety of beta blockade before noncardiac surgery, there is a paucity of data on its effects in patients undergoing LT.34 A prior study over 10 years previously reported a protective effect of beta blockers before LT, although this has not been shown subsequently.35 The independent association between beta blockers and MACE in this study is a finding of considerable interest given their ubiquitous use globally in patients with end-stage liver disease.36 The use of beta blockers may represent selection bias where they could have been used in patients with more advanced liver disease, refractory varices, and prior variceal bleeds. However, it is also recognized that cirrhotic cardiomyopathy characterized by beta-1 receptor downregulation in cardiac myocytes can also lead to a blunted inotropic and chronotropic reserve.29,37,38 Beta blockers can further diminish cardiac reserve during the extreme physiological stress of transplantation and may be a proposed mechanism for this finding.39 Similarly, the association between elevated pulmonary pressures and MACE may reflect the underlying diastolic dysfunction that characterizes cirrhotic cardiomyopathy.22,31

Poor functional status at transplantation was independently associated with MACE in our study, even after adjusting for age. Loss of muscle mass and function, or sarcopenia, is present in 40%–70% of patients with end-stage liver disease and confers risk for worse survival and complications following transplantation.40 Impaired functional status that often coexists with sarcopenia can be a poor prognostic marker that reflects accumulating physiological decline and may warrant closer consideration than just biological age.41 Our findings are consistent with results from a recent study that used employment status as a surrogate for functional status.30 Whether pretransplant rehabilitation and nutritional supplementation in these at-risk individuals improves perioperative cardiac outcomes warrant further study.42

A number of relevant neutral findings from this study also warrant further discussion. Covariates assessed including age, cardiovascular risk factors such as diabetes, nonalcoholic steatohepatitis, positive stress test, RCRI and CVRI scores, and body mass index did not independently predict MACE in our study.43-48 The lack of independent association for these risk predictors that have biologic plausibility in increasing cardiac events is unclear. Heterogeneity in clinical risk predictors and discrepant predictive values of cardiac imaging modalities for cardiac events following LT were highlighted in a recent systematic review and consensus document from the American Society of Transplantation.22 Whether routine assessment of posttransplant myocardial injury with biomarkers and evaluation for subclinical cardiac dysfunction in high-risk patients can facilitate targeted preventative therapies warrants investigation.49,50

The effect of 30-day MACE on long-term survival following transplantation is unclear primarily due to a paucity of studies reporting outcomes beyond 1 year. A trend toward higher age-adjusted mortality in patients over a 3-year period in this study is of interest particularly due to the increasing age, frailty, and risk factor profile of patients being considered for LT. Whether these individuals experiencing perioperative MACE may benefit from closer posttransplant surveillance warrants consideration.

Strengths of the present study include the systematic assessment of multiple demographic, cardiovascular, and critical illness risk predictors for predicting MACE. Further, all patients underwent rigorous cardiovascular testing, which included DSE as recommended by current guidelines. As such, the suggested link between HRS, beta-blocker use, pulmonary hypertension, and their proposed mechanistic links with cirrhotic cardiomyopathy and perioperative cardiac complications are novel findings that warrant further study. Furthermore, the mean MELD score of 17 in our cohort is lower than reported in other centers globally. While this may affect overall generalizability, it also strengthens our findings by the fact that our predictor variables conferred risk of cardiovascular events in a cohort with less pronounced physiological derangements.

However, we acknowledge certain limitations of this study. First, given the retrospective design of this study, assessment of clinical outcomes may be subject to reporting bias with the possibility of missed events or misclassification of adverse events. However, 2 independent reviewers and a cardiologist undertook individual case review to ensure appropriate assessment of MACE outcomes. Second, this study only included patients deemed to be of intermediate to high cardiovascular risk who all underwent preoperative stress testing. As such, there may be selection bias that could affect the generalizability of our findings. Third, given the retrospective nature of this study, functional status was primarily an assessment of physical dependence and did not include more sensitive markers of frailty. Forth, we lacked donor specific data which could also affect perioperative outcomes. Further, objective measures of functional status and frailty were not undertaken given the retrospective nature of this study. Given our preliminary findings, further research to better characterize this relationship is warranted. Fifth, outcomes were assessed at 30 days to reduce the risk of misclassification bias or missed events that may occur in a retrospective study. Although our study focused on perioperative outcomes following LT, it would be of interest to assess whether these variables predict the occurrence of cardiovascular events in the longer term. Finally, despite the strength of our findings linking HRS with MACE, it is also conceivable that patients with HRS may reflect a high-risk population with subclinical cardiovascular disease that may not be fully appreciated in the pretransplant setting.

CONCLUSION

In a contemporary cohort undergoing LT, manifestation of HRS, beta-blocker use, poor functional status, and pulmonary hypertension were independently associated with a risk of perioperative MACE. Occurrence of 30-day MACE was associated with a trend toward worse age-adjusted posttransplant medium-term survival. The pathophysiologic link between these risk factors to cirrhotic cardiomyopathy and their ability to predict perioperative cardiac events in liver transplant recipients merit further study.

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