Study Cardiac Dysfunction as an Early Predictor of Esophageal Varices in Patients with Liver Cirrhosis

index, E-wave deceleration time, atrial flow velocities, E/E′ ratio, and E/A ratio were significantly increased among cirrhotic patients compared to controls. However, only the LA volume was substantially


INTRODUCTION
Esophageal varices (EV), which are dangerously prone to bleeding and have a high mortality rate due to portal hypertension, are serious issue in patients with liver cirrhosis.Sixty to eighty percent of newly diagnosed cirrhotic patients have EV, and 5% to 15% of those who have large EV experience their first variceal bleeding within a year [1].As a result, Esophagogastroduodenoscopy (EGD) is necessary to detect EV in patients with cirrhosis at the time of diagnosis.

According
to recommendations, cirrhotic patients should have routine endoscopic surveillance and as a longterm follow-up in order to detect the development of EV and initiate prophylactic measures to reduce EV bleeding when it is substantial.However, EGD has a number of drawbacks, the most significant of which are that it is an invasive technique, always uncomfortable for the patient, and the cost is relatively high [2].
Numerous studies have tried to determine whether the existence esophageal varices may be detected by non-invasive measures, eliminating the requirement for screening endoscopy in all cirrhotic patients [3].However, there is no universal consensus on the optimum variable for predicting EV risk [4].In the absence of any other known causes of cardiac illness, cirrhotic patients frequently develop cirrhotic cardiomyopathy, a kind of chronic heart disease characterized by altered diastolic relaxation and/or impaired contractile response to stress [5].Diastolic dysfunction has been associated with larger left ventricular (LV) walls, subendocardial edoema, fibrosis, and altered collagen structure, which finally leads to aberrant relaxation in cirrhotic individuals [6].
Systolic dysfunction is primarily caused by decreased sympathetic sensitivity; it reduces contractility in response to volume challenge, pharmacological stress, and exercise, dampening the rise in cardiac output.Besides, issues with QTc prolongation and weak electromechanical coupling have been discovered [7].In terms of the pathogenesis, it has been proposed that the hyperdynamic circulation initially counteracts the significant splanchnic arterial vasodilatation seen in liver cirrhosis; eventually, as liver cirrhosis and portal hypertension (PHT) progress, the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are activated, leading to greater splanchnic vasodilatation as well as a decrease in the effective arterial blood volume [8,9].
A suggested likely causal mechanism is the increased synthesis of endogenous cardiac depressant mediators, such as nitric oxide, endogenous cannabinoids carbon monoxide, and inflammatory cytokines [10].Cirrhosis-related cardiovascular alterations affect prognosis of such patients.Therefore, the assessment of subclinical cardiac involvement could aid in the early identification of cirrhotic individuals who are more likely to decompensate and develop problems, allowing for better follow-up care [11].
Our goal was to investigate the relationship between cardiac dysfunction and endoscopic indicators of portal hypertension in cirrhotic patients.To link the occurrence of portal hypertension to cardiac involvement, the current investigation uses peak S-wave systolic velocities and to evaluate cardiac dysfunction, left atrial enlargement is employed as an echocardiographic indicator for both diastolic and systolic dysfunctions.

METHODS
The current cross-sectional study, was conducted by the Menoufia University Faculty of Medicine's Tropical Medicine and Cardiology departments.60 participants were included in the study; 40 cirrhotic patients with oesophageal varices as well as 20 non-cirrhotic individuals with no evidence of portal hypertension in endoscopy of matched age and sex as a control group.Between January 2021 and January 2022, participants were chosen from the Tropical Medicine Department's inpatient and outpatient clinic.Depending on upper endoscopic finding, patients were classified into one of following groups; Group I: included 27 cirrhotic patients with low grade esophageal varices, Group II: included 13 cirrhotic patients with high grade esophageal varices, and Group III: included 20 non-cirrhotic with no evidence of portal hypertension.

Sample size estimation:
Based on previous studies (Dadhich et al., 2014) who reported that ratio of early diastolic annular velocity to peak early diastolic annular wave velocity (E/eʹ) was the most significant marker for diastolic dysfunction.E/eʹ ratio was 12.55±1.73

Electrocardiographic evaluation (ECG):
Each patient had a 12-lead ECG, and the QTc interval was calculated for each one using Bazett's formula: QTc = QTmax/RR interval [14].The thorough echocardiographic examination known as echocardiography includes measurements of the (left atrium) L A volume, left ventricular mass index (LVMI), and S′-wave velocity on TDI (Tissue Doppler Imaging).Peak early (E wave), atrial (A wave), E/A ratio, E/È ratio, and E-wave deceleration time were all identified and recorded.The 4-chamber apical view was used for tissue Doppler imaging (TDI), and tissue velocity was estimated.The lateral and septal mitral annuli were used to measure the myocardial peak systolic velocity (S′), which is a measure of systolic function.
FIB-4: Degree of fibrosis was assessed by calculating Fib-4 according to the equation: FIB 4 = (Age x AST) / (Platelet count x √ALT).The FIB-4 scoring system makes use of the patient's age, platelet count, AST, and ALT levels, all tests that the primary care doctor can order.According to the scoring system, a score of 1.45 indicates severe liver fibrosis with numerous aetiologies with a negative predictive value of more than 90% [15].

Statistical Analysis: Statistical Package for the Social Sciences (SPSS) version 23 was used on
an IBM compatible personal computer to gather, tabulate, and statistically analyse the data (Armnok, NY: IBM Corp.)The first quartile is subtracted from the third quartile in descriptive statistics; these quartiles are easily seen on a box plot of the data.A data set is divided into quartiles to get the IQR, which is a measure of variability.It is a robust measure of scale that is commonly used and is a trimmed estimator, defined as the 25% trimmed range.The quantitative data was presented as numbers and percentages (%).(N).Analytical statistics: A P value of 0.05 was used to deem the chi-square test (2), Student t test (t), Mann-Whitney test (U), ANOVA test statistically significant (F) and ROC curve analysis.P value≤ considered a significant level.

RESULTS
The demographic comparison between the two patient groups is displayed in Table 1: age, sex, and history smoking, history of hypertension, the heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) did not substantially differ across the study groups(p>0.05),although diabetes was significantly more prevalent in the cirrhotic group than in the non-cirrhotic group.
The cirrhotic group's platelet count, WBC (white blood cells), and serum albumin levels were lower than those of the non-cirrhotic group's (P <0.001, 0.018, and <0.001 respectively).However, the cirrhotic group's AST, total and direct bilirubin, INR, prothrombin time, and fasting blood glucose levels were considerably higher.Haemoglobin concentration, ALT, blood urea, and serum creatinine levels did not differ significantly across the examined groups (p>0.05).Total and direct bilirubin, INR, and prothrombin time were all substantially higher in the group of patients with high esophageal varices than in the group of patients with low esophageal varices.Additionally, there was a statistically non-significant difference between patients with high grade and low grade esophageal varices when comparing platelet count, serum albumin, fasting blood glucose, and FIB-4 score although we nevertheless observed a trend toward lower platelet and albumin with higher fasting glucose and FIB-4 values in those with high grades as shown in Table 2.
Regarding electrocardiographic evaluation among the studied groups, table 3 demonstrated that the QTc interval was significantly increased in all cirrhotic patients compared to control group (p <0.001) with no statistically significant difference between those with high and low grades esophageal varices (p = 0.109), however still a trend in high esophageal varices grade group to show a higher value.
Concerning the echocardiographic examination; the results of this investigation demonstrated that the LA volume, LV mass index, E-wave deceleration time, atrial (A wave) flow velocities, Ratio E/E′ and ratio E/A were significantly increased among cirrhotic patents compared to control group.However, in comparing between high and low esophageal varices grades, only the LA volume was significantly higher and Ratio E/E′ was significantly lower patients with high grade esophageal varices than those with low esophageal varices grades.Furthermore, there were no discernible variations in TDI, peak early (E wave), A velocity, or E velocity across the studied groups (p>0.05)(Table 3).

DISCUSSION
According to the evidence that is currently available, liver cirrhosis is commonly ignored until complications such as ascites, spontaneous bacterial peritonitis (SBP), variceal haemorrhage, or hepatic encephalopathy manifest themselves [17].Nearly half of all cirrhotic patients had EV at the time of diagnosis.Varices expand from tiny to large at a rate of 5-12% per year, and once they have formed, they bleed at a rate of 5-12% per year [18].Numerous studies have shown that when liver cirrhosis is found, patients should be checked for the presence of EV.However, endoscopy is an invasive and unpleasant procedure that can have uncommon but serious side effects [4].
Patients with liver cirrhosis may experience cirrhotic cardiomyopathy, a kind of chronic heart dysfunction that is defined by altered diastolic relaxation and/or decreased contractile responsiveness to stress in the lack of any other previously recognised causes of cardiac disease.Latent cardiac failure is the term used to describe cirrhotic cardiomyopathy.But more research is needed to determine whether cardiac dysfunction exists even while the patient is at rest [19,20].Increased left ventricular (LV) wall thickness, subendocardial edoema, fibrosis, and altered collagen structure have all been linked to diastolic dysfunction in cirrhotic individuals, which eventually affects relaxation [21].
Cirrhosis-related cardiovascular alterations affect prognosis.Therefore, the assessment of subclinical cardiac involvement could aid in the early identification of cirrhotic individuals who are more likely to decompensate and experience complications, enabling more effective follow-up care [22].Therefore, the goal of this study was to evaluate the cardiac dysfunction in cirrhotic patients and relate endoscopic evidence of portal hypertension with cardiac involvement using echocardiographic indicators of diastolic dysfunction.Between Journey 2021 and Journey 2022, a clinical trial research study including 40 patients with a confirmed diagnosis of liver cirrhosis and a control group of 20 volunteers of a matched age and sex was conducted to clarify our findings.
Considering electrocardiographic evaluation among the studied groups, we demonstrate that the QTc interval was considerably longer in all cirrhotic patients when compared to the control group.We also noticed that QTc interval did not differ significantly between cirrhotic patients with high and low grades of esophageal varices, however still a trend in high esophageal varices grade group to show a higher value.
A measurement of ventricular repolarization is the length of the QT interval as estimated by 12lead electrocardiography.Ventricular repolarization abnormalities may be the basis for ventricular arrhythmia and sudden death; as a result, they are crucial for both ECG diagnosis and therapeutic decision-making [23].At first, Patients with alcoholic cirrhosis had longer QT intervals and rapid deaths; later, it was further clarified in cirrhosis of other etiologies, coupled with the severity of the illness, the emergence of portosystemic shunts, and poor survival [24].Nevertheless, well-compensated liver illness can also be observed as having a longer QTc interval [25].
The cause of the QT interval's extension is still a question.Modifications at the molecular level had been proposed.Other causes involve myocardial ischemia, altered electrolytes, and changes in the autonomic nervous system that may affect the heart rate and electromechanical coupling via a variety of mechanisms.Additionally, in advanced cirrhosis, abnormalities in gonadal hormone metabolism have been proposed to have a role in the development of QT prolongation [26].
On the echocardiographic evaluation, the findings of this study showed that cirrhotic patients had considerably higher LA volume, LV mass index, E-wave deceleration time, atrial (A wave) flow velocities, E/E′ ratio, and E/A ratio values than the control group.Yet, when comparing individuals with high grade esophageal varices to those with low grade esophageal varices, only the LA volume was considerably larger and Ratio E/E′ was significantly lower.Additionally, there were no notable variations in TDI, peak early (E wave), A velocity, or E velocity across the groups under study.
Our results are near to those of Marconi et al. study, which indicates that echocardiographic parameters including LA volume, LV mass index, and TDI S′-wave velocity may be beneficial in predicting the existence of esophageal varices [27].They verify that patients with compensated cirrhosis have left atriums (LA) that are significantly larger, as determined by either the volume index or the AP diameter, and that the only independent indicator of LA enlargement is liver stiffness (LS).Furthermore, Merli et al. previously documented LA enlargement in cirrhotic individuals, along with an increase in LV diameters but not volumes [28].
Being a stronger predictor of chronic diastolic dysfunction, the LA enlargement reflects the effects of elevated filling pressures over time, regardless of hemodynamic changes.In the course of cirrhotic cardiomyopathy, LA enlargement may be used as a diagnostic marker for diastolic dysfunction [27].additionally, Njideoforet al. found that CLD patients had a larger left atrial diameter, a higher LVMI that was related with diastolic dysfunction, and retained systolic performance at rest [29].
However, Kazankov et al. reported that the E/A ratio did not significantly differ between the cirrhotic and non-cirrhotic groups.Patients with cirrhosis who were primarily alcohol-related had increased left ventricular wall thickness, mass, and volumes [19].These results might be a part of the well-known condition (alcoholic cardiomyopathy) in that particular group of patients.In such circumstances, the toxicity of ethanol is connected to cardiac hypertrophy and contractile dysfunction [30].Besides, calculating tissue velocity and TDI in our investigation using the four-chamber apical view.
To evaluate its performance, the lateral mitral annulus' cardiac peak systolic velocity (S′) was recorded.Because all patients were selected with an EF of more than 55%, indicating that there was no systolic dysfunction in these people, there is no discernible difference in TDI across the tested groups.This finding is in line with the findings of Bodys Furthermore, we utilized the ROC curve to identify the applicability of electrocardiographic and echocardiographic finding to discriminate patients with high grade esophageal varices from those with low ones, we noticed that LA volume, Ratio E/È and QTc interval had the highest accuracy.Even though multiple studies have been undertaken, EGD is currently the screening approach for all cirrhotic patients because no other noninvasive procedures have demonstrated an acceptable predictive value for signs of portal hypertension.
In a study by Marconi et al., who examined the relationship between echocardiographic and EGD data, they revealed that the existence of esophageal varices tends to be closely related to the cardiovascular alterations associated with cirrhotic cardiomyopathy [27].In addition, a decrease in the peak S′-wave velocity on TDI, an increase in LV mass, and LA dilatation may be early indicators of portal hypertension and may be helpful for the early identification of patients who are at a higher risk of portal hypertension and its associated complications.Compared to liver elastography, echocardiography appears to perform better as a predictor of endoscopic findings of portal hypertension The present study has limitations, including its relatively small sample size and lack of a stress test (such as one involving physical exertion or a pharmacological), which would have revealed subclinical systolic dysfunction more clearly.Secondly, we currently lack prospective data that would allow us to assess the potential use of echocardiographic findings as prognostic indicators for patients with portal hypertension.

Figure 1 .
Figure 1.Flowchart of the study groups.

Figure 2A .
Figure 2A.ROC curve analysis for studied parameter for prediction of cardiac dysfunction in discriminating Cirrhotic and Non-Cirrhotic groups.

Figure 2B .
Figure 2B.ROC curve analysis for studied parameter for prediction of cardiac dysfunction in discriminating cirrhotic patients with high and low grades of esophageal varices.
frequent condition, cardiac dysfunction is the area of clinical examination that receives the least attention.Therefore, all cirrhotic individuals should have their heart function evaluated.Echocardiographic indicators of diastolic failure in liver cirrhosis include Ewave deceleration time, left atrial enlargement, E/E′, LV mass index, and E/A ratio.Cardiac changes are closely related to endoscopic finding of portal hypertension.Possible early warning signs of heart malfunction include QTc prolongation.A left atrium enlargement, a considerable increase in E/E′, LV mass index, E/A ratio, and E-wave deceleration time are all characteristics of cirrhotic individuals.

figure 2B and table 5).Table 1 : Esophageal varices grades in relation to sociodemographic, clinical data and vital signs among the studied groups.
ANOVA F test, X 2 : Chi-square test, *Significant, MAP: mean arterial pressure, DBP: Diastolic blood pressure, SBP: Systolic blood pressure, BMI: body mass index

Table 3 : Esophageal varices grades in relation to echocardiography and electrocardiographic evaluation among the studied groups.
E: E wave, A: A wave, TDI: Tissue Doppler imaging, LV: Left ventricle, LA: Left atrial

Table 5 : Validity (Accuracy, sensitivity, specificity) to identify the applicability of electrocardiographic and echocardiographic finding to discriminate patients with high grade esophageal varices from those with low ones. ROC curve between Cirrhotic High and Low
non-cirrhotic groups.The QTc interval, E-wave deceleration time and Ratio E/A had highest accuracy.This is in line with the findings of Somani et al. who found that the ratio of early-to-late diastolic filling (E/A) is the most often utilized metric and that cirrhotic individuals have lower E/A ratios than controls [32].The Montreal definition's diagnostic criteria now include an E/A ratio of 1.This agrees with De et al., who discovered that non-cirrhotic portal fibrosis also exhibits diastolic impairment.It suggests that the development of heart dysfunction is strongly influenced by portal hypertension [33].