Introduction

Liver transplantation is a life-saving therapy in patients with end-stage liver disease. Multiple risk factors have been identified, and despite advances in immunosuppressive therapy and surgical techniques to improve post-liver transplant outcomes, graft rejection occurs between 23% and 64%^1,2. It is imperative to understand the predictive factors related to adverse graft outcomes. Thus, identifying cardiovascular conditions without intervention before transplantation defines short- and long-term morbidity and mortality outcomes with the graft^3,4. Post-transplant hemodynamic stress after reperfusion of the graft characterized by increased preload may result in multiple cardiovascular complications. The pre-transplant study protocol includes screening for traditional cardiovascular risk factors, coronary disease, and Doppler echocardiography analysis in the search for right or left ventricular dysfunction, portopulmonary hypertension, hepatopulmonary syndrome, and cirrhotic cardiomyopathy^5,6.

Cirrhotic cardiomyopathy is an entity with no diagnostic criteria yet established. However, the best-accepted definition is that of the Cirrhotic Cardiomyopathy Consortium (2019), made up of variables such as systolic/diastolic alterations, supported by the assessment of global longitudinal shortening (GLS) and electrocardiographic changes such as QT prolongation^7,8. This syndrome, which is usually not recognized in the initial phase, but rather in its decompensation, has gained importance in recent years as a predictor of outcomes such as heart failure, kidney injury, and even graft loss in the short and long term^3,9-11. Data on cardiovascular complications and deaths from heart failure are found in up to 70% after transplantation¹².

The discrepancy in some data, the insufficient evaluation of systolic/diastolic function parameters, incomplete data on the degree of diastolic dysfunction, imprecise determination of cardiac dysfunction in the final stage of cirrhosis with a physiological basis of a hyperdynamic state with high cardiac output, and non-adherence to echocardiographic assessment protocols limit the presentation of data in the literature^9,11,13.

Due to the importance of hemodynamic assessment by echocardiography in its correlation with post-transplant outcomes such as heart failure, graft dysfunction, and mortality, for which no specific data can be found in the literature in our setting, we describe the experience of a leading Colombian hospital in liver transplantation.

Materials and methods

Results

Within the established date, the study found 550 patients with liver transplantation, of which 397 had complete data and met the inclusion and exclusion criteria.

CART predictive model

This method built a predictive model with mortality during the study, graft dysfunction, and acute kidney injury variables. The mortality during the study model found a mortality of 15%, in which patients with BMI < 19 had a 56% probability of dying. Meanwhile, with a BMI > 19 (98% of patients with fatal outcomes), patients who do not require dialysis have a 95% chance of survival. However, patients with a BMI > 19 and < 24 and requiring dialysis have a 55% chance of dying (Figure 1).

Figure 1 Distribution of transplant patients with mortality during the study, classified by risk groups in the regression tree (CART). This method builds a predictive model of three risk profiles with BMI < 19 and < 24, with or without dialysis requirement. Source: The authors. 

Concerning graft dysfunction, they were 8% of all patients. Patients with BMI < 19 had a 56% chance of graft dysfunction, and those with BMI > 19 and < 24 requiring dialysis had a 55% chance of death (Figure 2).

Figure 2 Distribution of transplant patients with graft dysfunction, classified by risk groups in the regression tree (CART). This method builds a predictive model of three risk profiles with BMI < 19 and < 24, with or without dialysis requirement. Source: The authors. 

Discussion

Globally, in 2017, approximately 1.5 million people had liver cirrhosis, whose main etiologies were NASH (60%), HBV (29%), HCV (9%), and alcoholic cirrhosis (2%); it produced 1.2 million deaths and was 3.5% of all causes of death¹⁶. In data from local studies, it gains importance as an etiology of alcoholic cirrhosis, as shown in our study¹⁷. There are multiple risk factors in the pre-transplant study, and even its poor selection is related to a cost burden for the healthcare system¹⁸. Pretransplant detection of cardiac dysfunction is a predictor of adverse events after liver transplantation, based on analysis of systolic or diastolic abnormalities^9,11,19. Cardiac dysfunction leads to early mortality from cardiovascular causes (40%), followed by other causes of mortality, such as infections (27.2%) and graft rejection (12%)²⁰. Even data have shown liver transplantation as a treatment for cardiovascular disorders, as reported by a study in which a decrease in biventricular dilatation and improvement in global strain post-transplantation were observed²¹.

Regarding the findings in our study, no relationship was identified between LVEF and mortality during follow-up. The data are similar to the literature, in which no relationship was found with the mortality or post-transplant cardiac arrest outcomes⁹. However, in another study, a low LVEF is related to mortality²²; even in the hyperdynamic state, it correlates with high LVEF, whose minimal variations are related to cardiovascular outcomes^10,22. Therefore, in assessing a patient with a hyperdynamic state associated with decreased peripheral vascular resistance, not only the evaluation of the systolic component becomes vital for diagnosing cirrhotic cardiomyopathy. An integration of variables such as those stipulated in the last CCC classification, with findings of LVEF < 50% and decrease in GLS > 18%, is also relevant, with careful assessment of the diastolic component considering the multiple variables that can affect preload based on electromechanical abnormalities such as QT prolongation⁸.

Due to the complex assessment of cardiac dysfunction, there is no protocolized evaluation of this specific condition by echocardiography without following the latest recommendations for diagnosing cirrhotic cardiomyopathy. According to our study, there is no detail of the diastolic evaluation without the GLS and electromechanical component measurements. In the literature, systolic involvement is low, as shown in our study, where 100% of patients did not meet the criteria for systolic changes²². Some studies even reveal an incidence of only 2% of systolic involvement¹³.

Although the CCC’s latest classification of cirrhotic cardiomyopathy has an LVEF cut-off < 55%, data of LVEF < 60% in patients undergoing immunosuppression should have a closer follow-up, as it is a predictor of mortality and cardiovascular outcomes²³.

Among the findings of our study is that 17.8% presented with diastolic dysfunction, which does not agree with the literature since it shows a varied prevalence, possibly secondary to the non-standardization of echocardiographic variables. Reports in the literature have demonstrated that up to 66% of patients with end-stage liver disease have, according to the ASE classification, type 1 (53%) and type 2 (47%) diastolic dysfunction, with no type 3 patients²², as found in our study (no findings of type 3 patients). Another study shows a prevalence similar to ours with data of diastolic dysfunction of 19%: mild (48%), moderate (30%), and severe (22%), and the findings of pre-transplant diastolic dysfunction were related to the risk of graft rejection, graft failure, and mortality³. Nevertheless, in our study, the finding of diastolic dysfunction was related to the development of acute kidney injury (p = 0.0378).

Additional echocardiographic variables, such as left atrial volume index (LAVI) > 40 mL/m², were associated with the risk of mortality within one year post-transplant⁹. The rate of moderate to severe tricuspid regurgitation is related to mortality since mild findings are expected in the patient’s hyperdynamic state²⁴; our study’s data were not measured because they were found to be normal. Other findings are LVH, which occurs in 12% to 30% of patients with cirrhosis, an indication of possible diastolic dysfunction in the context of left ventricular remodeling in the patient’s hyperdynamic state; in our study, it was found in 30.9% of patients, with no relationship with mortality outcomes or graft dysfunction. These data differ from those in the literature, in which LVH was associated with mortality nine months after transplantation; it was more frequent in the elderly and patients with a history of arterial hypertension²⁵. Even its presence before transplantation has been observed as a predictor of post-transplant echocardiographic deterioration²⁶. However, the relationship between LVH and diastolic dysfunction was related to acute kidney injury, as shown by studies related to a low cardiac index in severe arterial vasodilation changes^22,27,28; some data even show a correlation between a high LVEF and the deteriorating renal function possibly secondary to this hyperdynamic state²⁹. Progressing to the requirement of renal replacement therapy was related in our study to graft dysfunction and mortality, as found in the literature, in which its relationship with mortality was noted, with an odds ratio (OR) of 14.18 (confidence interval [CI] 1.65-121.89; p < 0.05)¹¹.

Within our study, increased PASP was observed in 22% of the patients, which was related to mortality with p = 0.038; this finding may be related to increased left ventricular diastolic pressure and, therefore, be a marker of diastolic dysfunction. In one study, it was connected to the risk of cardiac events (hazard ratio [HR]: 1.79 [1.48-2.17]; p < 0.001)²⁹ and has even been directly associated in some studies with pulmonary artery pressure with catheterization, allowing for adequate screening with a detailed echocardiogram³⁰.

The transfusion requirement in the post-transplant period was related to graft dysfunction, and in the regression tree, to acute kidney injury in the initial stages and progression to dialysis. Previous studies have associated these findings with adverse post-transplant outcomes³¹. Another variable related to mortality and acute kidney injury was a post-transplant infection. These data are related to the literature concerning the immunosuppression state due to the pathology and the level of immunological activation to the infectious stimulus in a patient with a chronic inflammatory disease and hemodynamic dysregulation, causing mortality rates close to 50%³².

Within the CART, the critical data related to mortality and graft dysfunction are low BMI, with a cut-off < 19 in our study, even related to renal replacement therapy. These data indirectly indicate sarcopenia since they show that 30%-70% of individuals with cirrhosis suffer from this condition due to the patient’s degree of inflammation, chronic bacterial translocation, insulin resistance, hyperammonemia, and decreased testosterone. Previous data condition higher mortality (19 ± 6 months with sarcopenia vs. 34 ± 11 months without sarcopenia; p = 0.005)^33,34. Even data already related to post-transplant outcomes of skeletal muscle indices measured by tomography were linked to lower post-transplant survival³⁵.

Conclusions

Pre-transplant variables, from echocardiogram aids to previously associated conditions such as sarcopenia, considerations during liver transplantation, and the requirement or not of renal replacement therapy related to acute kidney injury are points of intervention and follow-up to reduce long-term complications and even impact the mortality of these patients.