European Journal of Cardiovascular Medicine

Chronic liver disease (CLD) represents a major global health burden, affecting millions of individuals worldwide^[1]. While hepatic complications such as portal hypertension and hepatic encephalopathy are well-recognized, the cardiovascular sequelae of cirrhosis remain underappreciated in clinical practice. Approximately 50% of patients undergoing liver transplantation develop cardiac dysfunction, and cardiac complications account for 7-21% of post-transplantation mortality^[2,3].

The association between cirrhosis and cardiac dysfunction was first described by William Osler in 1892, who noted hemodynamic abnormalities in cirrhotic patients^[4]. However, it was not until 1989 that Dr. S.S. Lee formally introduced the term "cirrhotic cardiomyopathy" (CCM) to describe the distinct cardiac dysfunction associated with cirrhosis^[5]. Unlike overt cardiomyopathies, CCM is characterized by subclinical abnormalities that manifest only under physiological stress, making early detection challenging in the clinical setting.

Cirrhotic cardiomyopathy encompasses both structural and functional cardiac abnormalities: (1) baseline hyperdynamic circulation with blunted ventricular response to stress; (2) systolic and diastolic dysfunction; (3) electrophysiological abnormalities, particularly QT prolongation; and (4) absence of overt heart failure at rest^[6]. The pathophysiology is multifactorial and involves β-adrenergic receptor dysfunction, nitric oxide overproduction, inflammatory cytokine dysregulation, and altered calcium handling^[7].

Electrocardiography and echocardiography are readily available, non-invasive diagnostic modalities that have emerged as essential tools for detecting early cardiac abnormalities in CLD^[8]. Recent studies have demonstrated the prognostic significance of ECG and echocardiographic findings in predicting cardiac complications during stressful situations such as liver transplantation, transjugular intrahepatic portosystemic shunt (TIPS) placement, and sepsis^[9,10].

While previous studies have described the prevalence of individual cardiac abnormalities in cirrhotic patients, comprehensive regional data from the North-Eastern Indian population remain limited. This region has the highest prevalence of CLD in India, primarily driven by high alcohol consumption rates and viral hepatitis^[11]. The present study was designed to characterize the spectrum of cardiac abnormalities in CLD patients from this endemic region and correlate these findings with disease severity markers.

Study Design and Setting This was a prospective, observational, single-center study conducted at the Department of Medicine, Gauhati Medical College and Hospital, Guwahati, Assam, India, between January 2023 and October 2024. The study was approved by the Institutional Ethics Committee (approval number: 190/2007/Pt-II/OCT.2023/41 dated 13/10/2023), and written informed consent was obtained from all participants. Study Population Inclusion criteria were: (1) diagnosed CLD with or without cirrhosis; (2) age ≥18 years; (3) willingness to undergo complete cardiovascular evaluation. Exclusion criteria were: (1) primary cardiac disease (cardiomyopathy, congenital heart disease, myocarditis); (2) acute liver failure; (3) pregnancy; (4) recent myocardial infarction or acute coronary syndrome; (5) hemodynamic instability precluding safe evaluation. Data Collection A detailed clinical history including age, sex, occupation, presenting symptoms, and risk factors was documented. Physical examination included vital signs, assessment of stigmata of liver disease (palmar erythema, spider angiomas, ascites, splenomegaly), and cardiovascular examination. Laboratory investigations included complete hemogram, liver function tests, renal function tests, coagulation profile, and NT-proBNP measurement. Disease severity was assessed using two scoring systems: Child-Pugh classification: Score range 5-15; Class A (5-6), B (7-9), C (10-15) MELD score: Calculated using the formula: "MELD"=3.78×ln⁡["bilirubin"]+11.2×ln⁡["INR"]+9.57×ln⁡["creatinine"]+6.43 Cardiovascular Investigations Electrocardiography: Standard 12-lead ECGs were recorded at 25 mm/s with 1 mV/cm standardization. ECG parameters analyzed included heart rate, rhythm, QT interval (corrected for heart rate using Bazett's formula: "QTc"="QT"/√("RR interval" )), QRS duration, PR interval, and identification of conduction abnormalities. ECG abnormalities were classified as: sinus tachycardia, prolonged QTc (>450 ms in males, >460 ms in females), first-degree AV block, bundle branch blocks (LBBB/RBBB), complete heart block, and low-voltage QRS (QRS amplitude <0.5 mV in limb leads and <1.0 mV in precordial leads). Echocardiography: 2D transthoracic echocardiography with Doppler analysis was performed by experienced sonographers using standard equipment. Left ventricular dimensions, wall thickness, ejection fraction, and wall motion were assessed. Diastolic function was evaluated using mitral inflow patterns (E/A ratio, DT), tissue Doppler imaging (E'), and left atrial volume. Diastolic dysfunction was graded as: Grade I (impaired relaxation with normal filling pressures), Grade II (pseudonormal pattern with elevated filling pressures), Grade III (restrictive pattern with elevated filling pressures). Systolic dysfunction was defined as LVEF <50%. Pulmonary artery systolic pressure was estimated from tricuspid regurgitation jet velocity. Pulmonary hypertension was defined as estimated RVSP >35 mmHg. Stress Echocardiography: Selected hemodynamically stable patients with baseline normal LVEF performed a 6-minute walk test (6MWT) with pre- and post-exercise echocardiography. Abnormal stress response was defined as LVEF increase <5% or development of new wall motion abnormalities. NT-proBNP Measurement: Serum NT-proBNP was measured using high-sensitivity immunoassay (cutoff: ≥125 pg/mL indicating cardiac stress). Statistical Analysis Data were analyzed using IBM SPSS Statistics version 26.0. Descriptive statistics were calculated for demographic and clinical variables, expressed as mean ± SD for continuous variables and percentages for categorical variables. Associations between categorical variables were assessed using chi-square test or Fisher's exact test. Correlation between continuous variables and disease severity scores was analyzed using Spearman's rank correlation coefficient. Differences across multiple groups were evaluated using Kruskal-Wallis test. p values <0.05 were considered statistically significant.

Demographic and Clinical Characteristics                                             

Seventy-three CLD patients were enrolled (mean age 42.7 ± 8.2 years; 78% male; male-to-female ratio 3.56:1). The demographic and etiological characteristics are summarized in Table 1. Alcohol-related liver disease was the predominant etiology (78.8%), followed by metabolic-associated steatotic liver disease (12.3%) and viral hepatitis (6.8%). The majority of patients were classified as Child-Pugh B (50.7%), with 38.4% in Class C and 11.0% in Class A. MELD score distribution was: MELD ≤10 in 37.0%, MELD 10-20 in 41.1%, and MELD 20-30 in 21.9%.

NT-proBNP Findings

Elevated NT-proBNP (≥125 pg/mL) was observed in 56.2% of total study population (41 of 73). NT-proBNP positivity progressively increased with disease severity: 50.0% in Child-Pugh A, 56.8% in Child-Pugh B, and 57.2% in Child-Pugh C. Similarly, NT-proBNP positivity correlated with MELD score: 59.3% in MELD ≤10, 50.0% in MELD 10-20, and 56.3% in MELD 20-30 ( = NS).

Electrocardiographic Findings

ECG abnormalities were observed in 68.5% of the study population. Sinus tachycardia (21.9%) and prolonged QTc (21.9%) were the most common findings. Conduction abnormalities (first-degree AV block, LBBB, RBBB, complete heart block) occurred in 8.2% of the  patients, while low-voltage QRS complexes were noted in 9.6% (Table 2).

ECG findings correlated with disease severity (Table 3). Sinus tachycardia was most prevalent in Child-Pugh B (62.5%) and least in Class A (12.5%). Prolonged QTc showed progressive increase: 0% in Class A, 43.8% in Class B, and 56.3% in Class C. Low-voltage QRS complexes were predominantly seen in Class C (57.1%), followed by Class B (28.6%), and Class A (14.3%) ( = 0.001, significant).

When stratified by MELD score, sinus tachycardia was most common in MELD ≤10 (62.5%), while prolonged QTc showed higher prevalence in MELD 20-30 (37.5%). Conduction abnormalities and low-voltage QRS complexes were more frequently observed in higher MELD categories.

Echocardiographic Findings

Of 73 patients with CLD, 45.2% had completely normal 2D TTE findings. Cardiac dysfunction was detected in 54.8% of patients: Grade I diastolic dysfunction in 26.0%, Grade II in 24.7%, Grade III in 4.1%, combined diastolic and systolic dysfunction in 4.1%, and pulmonary hypertension in 1.4%.

Diastolic dysfunction showed a strong correlation with disease severity (Table 4). Grade I dysfunction was most prevalent in Child-Pugh B (57.9%), while Grade II and Grade III dysfunctions were predominantly seen in Class C (55.6% and 66.7%, respectively). Combined systolic and diastolic dysfunction and pulmonary hypertension occurred exclusively in Child-Pugh C patients (100%). This correlation was statistically significant ( = 0.001).

Similarly, when stratified by MELD score, Grade I diastolic dysfunction was most common in MELD ≤10 (68.4%), while higher grades of dysfunction and pulmonary hypertension showed progressive increase with advancing MELD scores, reaching 100% in MELD 20-30 for pulmonary hypertension ( = 0.002, significant).

Stress Echocardiography Findings

Among the 73 study patients, 13 hemodynamically stable patients with preserved baseline LVEF underwent 6-minute walk test with pre- and post-exercise echocardiography. Results showed that 100% of Child-Pugh C patients (2 of 2) demonstrated blunted contractile reserve with LVEF increase <5% (Table 5). In contrast, 100% of Child-Pugh A patients (4 of 4) showed normal stress response with LVEF increase ≥5%. Child-Pugh B patients showed a mixed pattern: 71.4% (5 of 7) demonstrated normal response while 28.6% (2 of 7) showed blunted response. Overall, 30.8% of tested patients (4 of 13) demonstrated impaired cardiac response to stress.

Table 1: Demographic and Clinical Characteristics of Study Population

Table 2: Electrocardiographic Abnormalities in Study Population

Table 3: Correlation of ECG Findings with Child-Pugh Class

NS, not statistically significant

Table 4: Echocardiographic Findings Stratified by Child-Pugh Class

Table 5: Stress Echocardiography Findings (6-Minute Walk Test)

*Normal response: LVEF increase ≥5%
†Blunted response: LVEF increase <5% or new wall motion abnormalities

This hospital-based observational study comprehensively characterized the spectrum of cardiac abnormalities in a cohort of 73 CLD patients from a region of high disease prevalence. Our findings underscore the pervasiveness of subclinical cardiac dysfunction across the spectrum of liver disease severity and highlight the utility of non-invasive cardiac assessment in cirrhotic patients.

Demographic and Etiological Profile

The male predominance (78%) and mean age of 42.7 years in our cohort align with findings from comparable studies in the North-Eastern Indian population[12,13]. The predominance of alcohol-related liver disease (78.8%) reflects the high prevalence of alcohol consumption in this region, consistent with previous epidemiological surveys[13]. This differs from some Western studies and Asian centers where viral hepatitis represents a more significant proportion of CLD cases.

Electrocardiographic Abnormalities

The prevalence of QT prolongation (21.9%) in our study is lower than reported by Shah et al. (43.3%) and Gollamudi et al. (44%), though comparable to Sharma and Kavya (34%)[14,15,16]. This variability likely reflects differences in patient populations, disease severity, and measurement techniques. Nevertheless, QT prolongation represents an important risk factor for ventricular arrhythmias and sudden cardiac death in cirrhotic patients, particularly during acute decompensation[17].

The correlation between sinus tachycardia and disease severity (most prevalent in Class B) suggests autonomic dysfunction and hyperdynamic circulation even in moderate liver disease. Progressive increase in conduction abnormalities and low-voltage QRS complexes with worsening liver function indicates progressive myocardial infiltration, fibrosis, or pericardial effusion.

Echocardiographic Abnormalities and Cirrhotic Cardiomyopathy

Our finding of diastolic dysfunction in 54.8% of CLD patients is consistent with previous studies, which report prevalence ranges from 43% to 79% depending on the population studied[18,19]. Notably, Grade I diastolic dysfunction was detected even in Child-Pugh A patients, suggesting that cardiac involvement begins early in the disease process, well before clinical decompensation occurs.

The stepwise increase in diastolic dysfunction severity with progressive liver disease (Child-Pugh A→B→C) and the exclusive occurrence of combined systolic-diastolic dysfunction and pulmonary hypertension in Child-Pugh C patients support the hypothesis that myocardial involvement parallels hepatic dysfunction. This finding has important clinical implications for patient risk stratification, particularly for procedures requiring cardiovascular adaptation.

Biomarker Profile

The elevated NT-proBNP in 56.2% of patients with progressive increase across disease severity strata indicates subclinical myocardial stress. While NT-proBNP is not specific for cirrhotic cardiomyopathy (as it may also reflect volume overload or renal dysfunction), its consistent elevation across disease severity groups suggests myocardial involvement. Recent guidelines recommend NT-proBNP measurement as part of the cardiac evaluation protocol in cirrhotic patients scheduled for major interventions[20].

Stress Testing and Contractile Reserve

Our finding that 100% of Child-Pugh C patients demonstrated blunted contractile reserve during stress testing is particularly significant. This finding directly addresses a critical gap in clinical practice: many cirrhotic patients appear to have normal cardiac function at rest, potentially leading to false reassurance before liver transplantation or other major procedures. The fact that stress testing unmasked latent dysfunction in a significant proportion of patients (30.8% overall, 100% of Class C) emphasizes the importance of incorporating stress echocardiography into the preoperative evaluation protocol.

Clinical Implications and Outcomes

These findings have substantial implications for patient management. First, systematic cardiac evaluation should be performed in all cirrhotic patients, not just those scheduled for transplantation. Second, even patients with apparent hemodynamic stability at rest warrant stress testing to assess true cardiac reserve. Third, the progressive nature of cardiac abnormalities with advancing liver disease severity suggests that cardiac complications during major interventions may be preventable through appropriate preoperative optimization and intraoperative monitoring.

Patients with blunted stress response represent a high-risk group for decompensation during transplantation, TIPS placement, or sepsis. These patients may benefit from enhanced perioperative monitoring, judicious volume management, and potentially inotropic support[21,22].

Limitations

The present study has several limitations. First, this was a single-center, hospital-based observational study with a relatively small sample size (n=73), which may limit generalizability. Second, the high proportion of alcohol-related liver disease in our population may not be representative of other geographic regions. Third, stress testing was performed in only 13 patients due to clinical constraints, limiting the robustness of stress echocardiography findings. Fourth, longitudinal follow-up data regarding outcomes and mortality were not available. Fifth, we did not perform cardiac magnetic resonance imaging, which provides superior tissue characterization, or advanced strain imaging, which may have detected additional subclinical abnormalities.

This study demonstrates that cardiac dysfunction is highly prevalent in CLD patients across the entire spectrum of disease severity. Diastolic dysfunction was present even in compensated cirrhosis (Child-Pugh A), while combined systolic-diastolic dysfunction and pulmonary hypertension occurred exclusively in advanced disease. Electrocardiographic abnormalities, particularly QT prolongation and low-voltage QRS complexes, correlated with disease severity. Stress testing effectively unmasked impaired contractile reserve, particularly in advanced cirrhosis. These findings underscore the importance of: (1) systematic cardiac evaluation in all CLD patients, not just transplant candidates; (2) incorporation of stress testing in the preoperative assessment of cirrhotic patients; (3) development of standardized protocols for cardiac risk stratification; and (4) consideration of cardiac-protective interventions in high-risk patients. Future large-scale, prospective studies with longer follow-up are warranted to validate the prognostic significance of these cardiac markers and to develop evidence-based strategies for preventing cardiac complications in cirrhotic patients. Acknowledgments We acknowledge the technical support of the echocardiography laboratory staff and the clinical assistance provided by residents and nursing personnel. Special thanks to Dr. [names of collaborators] for valuable discussions during manuscript preparation.

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