Cirrhotic Cardiomyopathy Research Articles

Investigating the Effect of Serotonin II and III Receptor Inhibitors on the Chronotropic Changes of the Heart to Isoproterenol in Rat Models of Biliary Cirrhosis

Cirrhotic patients have hyperdynamic circulation and at-rest tachycardia, and agents that activate the sympathetic pathway, such as physical practice and pharmacologic stimulations, compared with the normal population, cannot cause enough increase in heartbeat, a condition known as cirrhotic cardiomyopathy. Concerning the presentation of 5-HT2 & 5-HT3 receptors in rat hearts, we used Ketanserin as a 5-HT2 receptor inhibitor & Tropisetron as a 5-HT3 receptor inhibitor to evaluate chronic therapeutic effects of 5-HT2 & 5-HT3 antagonists on the cardiac chronotropic response of cirrhotic rats to adrenergics. Cirrhosis was induced by surgical ligation of the bile duct in Male Wistar rats, and another group remained sham. A week after bile duct ligation or sham surgery, the subjects were given an intraperitoneal injection of either saline or Tropisetron (2 mg/kg). In other BDL & Sharm groups, the subjects were given an intraperitoneal injection of either saline or Ketanserin (6 mg/kg) every other 3 days in the last 3 weeks. Four weeks after bile duct ligation or sham surgery, the atria were isolated and chronotropic responsiveness to Isoproterenol was assessed using a standard organ bath. Our data showed that chronic treatment with Tropisetron (5-HT3 antagonist) in cirrhotic rats could decrease the cardiac chronotropic response. Chronic treatment with Tropisetron can cause a significant decrease in cardiac chronotropic response to Isoproterenol in healthy and cirrhotic rats, even lower than that in cirrhotic rats (without any special treatment). Chronic treatment with Ketanserin cannot change their impaired chronotropic response to Isoproterenol.

Assessment of Cardiac Dysfunctions in Patients with Liver Cirrhosis Admitted in a Tertiary Care Centre

BACKGROUND
 The presence of cardiovascular dysfunction in liver cirrhosis has been studied over the past several years. Cardiovascular dysfunctions in cirrhosis increase the risk of coronary artery disease and mortality after TIPSS insertion and liver transplantation. Cirrhotic cardiomyopathy also plays an important role in the pathogenesis of hepatorenal syndrome. All these data highlight the need for rigorous cardiovascular risk assessment in patients with liver cirrhosis.
 METHODS
 After obtaining institutional approval, we analysed 96 consenting patients with liver cirrhosis satisfying inclusion criteria. Relevant history of the cases was sought through a structured questionnaire. Appropriate clinical examinations were done. Echocardiogram, ECG and biochemical parameters of the patients were examined and recorded. Data analysis was done using SPSS software.
 RESULTS
 51% of the patients had QTc > 0.44 seconds in ECG which was suggestive of electrophysiological abnormality. The systolic dysfunction was assessed by presence of left ventricular ejection fraction below 55%, which was detected in 4.2% of the patients. E/A ratio less than 1 and deceleration time more than 200 msec were taken as parameters suggestive of the presence of diastolic dysfunction. 34.4% had an E/A ratio < 1 and 42.7% of the patients had a deceleration time more than 200 msec. 53% were found to have cirrhotic cardiomyopathy. The prevalence of CCM was increasing with the severity of liver disease. 53.1% of the patients had left ventricular hypertrophy and there was significant association between the prevalence of LVH and severity of cirrhosis. 38.5% of the patients had coronary artery disease as per history and ECG findings. No significant association was obtained between the prevalence of CAD and severity of CLD. 4.2% patients had arrhythmia and there was a significant association with the severity of disease. Troponin I was elevated in 20.8% of the patients.
 CONCLUSIONS
 Liver cirrhosis is a risk factor for cardiovascular dysfunctions. Most of the patients with cardiac compromise were asymptomatic. 53% patients were diagnosed to have cirrhotic cardiomyopathy. The prevalence of cardiovascular dysfunctions was found to increase with the rising severity of cirrhosis as per CTP score. Diastolic dysfunction was more prevalent than systolic dysfunction. The prevalence of cardiovascular dysfunctions was lesser among patients with regular follow-up and treatment for cirrhosis liver. 38.5% of the patients had coronary artery disease. The prevalence of arrhythmias was 4.2%. Troponin levels were elevated in 20.8% patients.

Oxidative Mechanisms and Cardiovascular Abnormalities of Cirrhosis and Portal Hypertension

In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.

Evaluation of terlipressin-related patient outcomes in hepatorenal syndrome-acute kidney injury using point-of-care echocardiography.

Treatment of hepatorenal syndrome-acute kidney injury (HRS-AKI), with terlipressin and albumin, provides survival benefits, but may be associated with cardiopulmonary complications. We analyzed the predictors of terlipressin response and mortality using point-of-care echocardiography (POC-Echo) and cardiac and renal biomarkers. Between December 2021 and January 2023, patients with HRS-AKI were assessed with POC-Echo and lung ultrasound within 6 hours of admission, at the time of starting terlipressin (48 h), and at 72 hours. Volume expansion was done with 20% albumin, followed by terlipressin infusion. Clinical data, POC-Echo data, and serum biomarkers were prospectively collected. Cirrhotic cardiomyopathy (CCM) was defined per 2020 criteria. One hundred and forty patients were enrolled (84% men, 59% alcohol-associated disease, mean MELD-Na 25±SD 5.6). A median daily dose of infused terlipressin was 4.3 (interquartile range: 3.9-4.6) mg/day; mean duration 6.4 ± SD 1.9 days; the complete response was in 62% and partial response in 11%. Overall mortality was 14% and 16% at 30 and 90 days, respectively. Cutoffs for prediction of terlipressin nonresponse were cardiac variables [ratio of early mitral inflow velocity and mitral annular early diastolic tissue doppler velocity > 12.5 (indicating increased left filling pressures, C-statistic: 0.774), tissue doppler mitral velocity < 7 cm/s (indicating impaired relaxation; C-statistic: 0.791), > 20.5% reduction in cardiac index at 72 hours (C-statistic: 0.885); p < 0.001] and pretreatment biomarkers (CysC > 2.2 mg/l, C-statistic: 0.640 and N-terminal proBNP > 350 pg/mL, C-statistic: 0.655; p <0.050). About 6% of all patients with HRS-AKI and 26% of patients with CCM had pulmonary edema. The presence of CCM (adjusted HR 1.9; CI: 1.8-4.5, p = 0.009) and terlipressin nonresponse (adjusted HR 5.2; CI: 2.2-12.2, p <0.001) were predictors of mortality independent of age, sex, obesity, DM-2, etiology, and baseline creatinine. CCM and reduction in cardiac index, reliably predict terlipressin nonresponse. CCM is independently associated with poor survival in HRS-AKI.

Electrocardiographic and Echocardiographic Abnormalities, and Cirrhotic Cardiomyopathy in Patients Hospitalized at the Campus University Hospital (Lomé)

Electrocardiographic and Echocardiographic Abnormalities, and Cirrhotic Cardiomyopathy in Patients Hospitalized at the Campus University Hospital (Lomé)

Frequency of cirrhotic cardiomyopathy in decompensated liver cirrhosis patients.

Objective: To determine the frequency of cirrhotic cardiomyopathy in decompensated liver cirrhosis patients. Study Design: Descriptive, Cross-sectional. Setting: Department of Medicine, Bahawal Victoria Hospital, Bahawalpur. Period: February 2022 to August 2022. Material &amp; Methods: Patients of either gender having age between 25-65 years with decompensated liver cirrhosis (duration &gt;6 months) were analyzed. Demographic and clinical characteristics of each patient were recorded at the time of the inclusion. Then, echocardiography was done in each patient by consultant cardiologist and presence or absence of cirrhotic cardiomyopathy was noted. Results: In a total of 92 patients, 54 (58.7%) were male and 38 (41.3%) were female with male to female ratio as 1.4:1. The mean age was 42.92±8.72 years while 57 (61.96%) patients were aged between 25 to 45 years. The mean duration of disease was 8.52±2.48 months. The mean body mass index was 27.46±2.97 kg/m2. Diabetes was noted in 28 (30.4%) patients while 35 (38.0%) had hypertension. Frequency of cirrhotic cardiomyopathy in patients with decompensated liver cirrhosis was found in 38 (41.3%). Conclusion: This study concluded that the frequency of cirrhotic cardiomyopathy in decompensated liver cirrhosis patients is quite high.

Comparison of the 2005 Montreal Criteria and the 2019 Cirrhotic Cardiomyopathy Consortium Criteria for the Diagnosis of Cirrhotic Cardiomyopathy

The comparison between the diagnostic criteria for cirrhotic cardiomyopathy (CCM) first proposed in 2005 (2005 Montreal criteria), and those redefined in the 2019 Cirrhotic Cardiomyopathy Consortium (2019 CCC criteria) has generated significant controversy. Importantly, the predictive value of these criteria in cirrhotic patients (CPs) remains unclear to this date. Thus, the present study aims to compare the 2 sets of criteria and investigate their predictive value in CPs. Between April 2021 and April 2023, a total of 104 CPs with an average age of 46.4 ± 8.9years, who had no history of other cardiac diseases or malignancies were enrolled in this prospective single-center observational cohort study, conducted at the Third Affiliated Hospital of Sun Yat-Sen University. Various echocardiographic indicators were measured and assessed for their prognostic value and association with clinical outcomes. The prevalence of CCM was found to be comparable when evaluated using both the 2019 CCC and 2005 Montreal criteria (54.8% vs 44.2%, p=0.161). However, the diagnosis of systolic dysfunction was significantly different between the 2 criteria (52.9% vs 1.0%, p <0.001). Among patients with systolic dysfunction, 27.9% had reduced left ventricular global longitudinal strain, while 25% had increased left ventricular global longitudinal strain. Moreover, fewer patients were diagnosed with diastolic dysfunction (DD) using the 2019 CCC criteria (4.8% vs 44.2%, p <0.001). Multivariate Cox analysis revealed that CPs who had encephalopathy, a high model for end-stage liver disease score, and DD diagnosed using the 2019 CCC criteria exhibited a poorer prognosis. In conclusion, although the prevalence of CCM according to both criteria is similar, the consistency is poor, indicating that they are not the same group of patients. Importantly, CPs with DD diagnosed according to the 2019 CCC criteria might be associated with increased adverse events.

Utility of transesophageal echocardiography during orthotopic liver transplantation: A narrative review.

Orthotopic liver transplantation (OLT) is the standard of care for patients suffering from end stage liver disease (ESLD). This is a high-risk procedure with the potential for hemorrhage, large shifts in preload and afterload, and release of vasoactive mediators that can have profound effects on hemodynamic equilibrium. In addition, patients with ESLD can have preexisting coronary artery disease, cirrhotic cardiomyopathy, porto-pulomary hypertension and imbalanced coagulation. As cardiovascular involvement is invariable and patient are at an appreciable risk of intraoperative cardiac arrest, Trans esophageal echocardiography (TEE) is increasingly becoming a routinely utilized monitor during OLT in patients without contraindications to its use. A comprehensive TEE assessment performed by trained operators provides a wealth of information on baseline cardiac function, while a focused study specific for the ESLD patients can help in prompt diagnosis and treatment of critical events. Future studies utilizing TEE will eventually optimize examination safety, quality, permit patient risk stratification, provide intraoperative guidance, and allow for evaluation of graft vasculature.

How non-alcoholic fatty liver disease and cirrhosis affect the heart.

Liver diseases affect the heart and the vascular system. Cardiovascular complications appear to be a leading cause of death in patients with non-alcoholic fatty liver disease (NAFLD) and cirrhosis. The predominant histological changes in the liver range from steatosis to fibrosis to cirrhosis, which can each affect the cardiovascular system differently. Patients with cirrhotic cardiomyopathy (CCM) and NAFLD are at increased risk of impaired systolic and diastolic dysfunction and for suffering major cardiovascular events. However, the pathophysiological mechanisms behind these risks differ depending on the nature of the liver disease. Accurate assessment of symptoms by contemporary diagnostic modalities is essential for identifying patients at risk, for evaluating candidates for treatment, and prior to any invasive procedures. This review explores current perspectives within this field.

Cirrhotic cardiomyopathy influences clinical outcomes and enhances performance of conventional risk prediction models in acute-on-chronic liver failure with severe sepsis.

Point-of-care echocardiography (POC-Echo) is an essential intensive care hemodynamic monitoring tool. To assess POC-Echo parameters [i.e., cardiac index (CI), systemic vascular resistance index (SVRI) and cirrhotic cardiomyopathy (CCM) markers] and serum biomarkers in predicting circulatory failure (need for vasopressors) and mortality in patients with acute-on-chronic liver failure (ACLF) having sepsis-induced hypotension. We performed serial POC-Echo within 6 hours (h)of presentation and subsequently at 24, 48 and 72 h in patients with ACLF and sepsis-induced hypotension admitted to our liver intensive care unit. Clinical data, POC-Echo data and serum biomarkers were collected prospectively. We enrolled 120 patients [59% men, aged 49 ± 12 years, 56% alcohol-related disease and median MELDNa of 30 (27-32)], of whom 68 (56.6%) had circulatory failure, with overall mortality of 60%. CCM was present in 52.5%. The predictors of circulatory failure were CI (aHR -1.5; p = 0.021), N-terminal brain natriuretic peptide (aHR -1.1; p = 0.007) and CCM markers; e' septal mitral velocity (aHR -0.5; p = 0.039) and E/e' ratio (aHR -1.2; p = 0.045). Reduction in CI by 20% and SVRI by 15% at 72 h predicted mortality with a sensitivity of 84% and 72%, and specificity 76% and 65%, respectively (p < 0.001). The MELD-CCM model and CLIF-CCM model were computed as MELDNa + 1.815 × E/e' (septal) + 0.402 × e' (septal) and CLIF-C ACLF + 1.815 × E/e' (septal) + 0.402 × e' (septal), respectively, based on multivariable logistic regression. Both scores outperformed MELDNa (z-score = -2.073, p = 0.038) and CLIF-C ACLF score (z score = -2.683, p-value = 0.007), respectively, in predicting 90-day mortality. POC-Echo measurements such as CCM markers (E/e' and e' velocity) and change in CI reliably predict circulatory failure and mortality in ACLF with severe sepsis. CCM markers significantly enhanced the CLIF-C ACLF and MELDNa predictive performance.

Study of the left ventricle in cirrhosis and correlation with the Model for End-stage Liver Disease score

Background: Recent research has increased amount of evidence for heart disease associated with cirrhosis, which has led to the definition of the entity cirrhotic cardiomyopathy. The present study was conducted with an objective to evaluate the clinical, biochemical, and echocardiographic evaluation of patients presenting with cirrhosis and to find its correlation between the severity of cirrhosis and cardiac dysfunction. Materials and Methods: The present study was a case–control study conducted from July 2021 to September 2022. All the cases were examined using two-dimensional echocardiography, electrocardiogram, and other laboratory parameters. The Model for End-stage Liver Disease (MELD) score was calculated for each of the cases. Results: Alcohol ingestion was the most common (76%) etiological factor associated with cirrhosis. There was a significant difference between the QTc interval among cases and controls and among the MELD score group. A significant difference was observed in the left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), interventricular septal thickness (IVST), left atrial diameter, cardiac output (CO), E (Peak velocity flow in early diastole)/A (peak velocity flow in late diastole), E (Peak velocity in early diastole)/e’(passive left ventricular filling during early diastole), and deceleration time among the cases and controls. Conclusion: Based on our results, we conclude that liver cirrhosis cases revealed increased cardiac dysfunction with an increase in the MELD severity, particularly involving left ventricular diastolic dysfunction. Cirrhotic patients presented with increased CO and decreased E/A ratio. With increasing MELD score, there was a significant increase in the LVESD, LVEDD, IVST, and CO and a decreased E/A ratio.

Left atrial strain and ventricular global longitudinal strain in cirrhotic patients using the new criteria of Cirrhotic Cardiomyopathy Consortium.

The new criteria of Cirrhotic Cardiomyopathy Consortium (CCC) propose the use of left ventricular global longitudinal strain (LV-GLS) for evaluation of systolic function in patients with cirrhosis. The aim of this study was to evaluate LV-GLS and left atrial (LA) strain in association with the severity of liver disease and to assess the characteristics of cirrhotic cardiomyopathy (CCM). One hundred and thirty-five cirrhotic patients were included. Standard echocardiography and speckle tracking echocardiography (2D-STE) were performed, and dual X-ray absorptiometry was used to quantify the total and regional fat mass. CCM was defined, based on the criteria of CCC, as having advanced diastolic dysfunction, left ventricular ejection fraction ≤50% and/or a GLS <18%. LV-GLS lower or higher than the absolute mean value (22.7%) was not associated with mortality (logrank, p = 0.96). LV-GLS was higher in patients with Model for end stage liver disease (MELD) score ≥15 compared to MELD score <15 (p = 0.004). MELD score was the only factor independently associated with systolic function (LV-GLS <22.7% vs. ≥22.7%) (Odds Ratio:1.141, p = 0.032). Patients with CCM (n = 11) had higher values of estimated volume of visceral adipose tissue compared with patients without CCM (median: 735 vs. 641 cm3 , p = 0.039). On multivariable Cox regression analysis, MELD score [Hazard Ratio (HR):1.26, p < 0.001] and LA reservoir strain (HR:0.96, p = 0.017) were the only factors independently associated with the outcome. In our study, absolute LV-GLS was higher in more severe liver disease, and LA reservoir strain was significantly associated with the outcome in patients with end-stage liver disease.

Postoperative alterations in ventriculoarterial coupling are an indicator of cardiovascular outcomes in liver transplant recipients.

Liver transplantation (LT) increases the heart and vessel workload in patients with cirrhotic cardiomyopathy. While the interaction of the left ventricle (LV) with the arterial system (ventriculoarterial coupling, VAC) is a key determinant of cardiovascular performance, little is known about changes in VAC after LT. Therefore, we evaluated the relationship between VAC after LT and cardiovascular outcomes. 344 consecutive patients underwent echocardiographic assessments before and within 30 days after LT. Non-invasive arterial elastance (Ea), LV end-systolic elastance (Ees), and LV end-diastolic elastance (Eed) were calculated. The postoperative outcomes included the development of major adverse cardiovascular events (MACE) and the length of stay in the intensive care unit and hospital. A total of 240 patients were included in the analyses. After LT, Ea increased by 16% (P < 0.001), and Ees and contractility index of systolic velocity (S') increased by 18% (P < 0.001) and 7% (P < 0.001), respectively. The Eed increased by 6% (P < 0.001). The VAC remained unchanged (0.56 to 0.56, P = 0.912). Of these patients, 29 had MACE, and those with MACE had significantly higher postoperative VAC. Additionally, a higher postoperative VAC was an independent risk factor for a longer postoperative hospital stay (P = 0.038). These data suggest that ventriculoarterial decoupling is associated with poor postoperative outcomes after LT.

Role of Galectin in Cardiovascular Conditions including Cirrhotic Cardiomyopathy.

Abnormal cardiac function in the setting of cirrhosis and in the absence of a primary cardiac disease is known as cirrhotic cardiomyopathy. The pathogenesis of cirrhotic cardiomyopathy is multifactorial but broadly is comprised of two pathways. The first is due to cirrhosis and synthetic liver failure with abnormal structure and function of many substances, including proteins, lipids, hormones, and carbohydrates such as lectins. The second is due to portal hypertension which invariably accompanies cirrhosis. Portal hypertension leads to a leaky, congested gut with resultant endotoxemia and systemic inflammation. This inflammatory phenotype comprises oxidative stress, cellular apoptosis, and inflammatory cell infiltration. Galectins exert all these pro-inflammatory mechanisms across many different tissues and organs, including the heart. Effective therapies for improving cardiac function in patients with cirrhosis are not available. Conventional strategies for other noncirrhotic heart diseases, including vasodilators, are not feasible because of the significant baseline vasodilation in cirrhotic patients. Therefore, exploring new treatment modalities for cirrhotic cardiomyopathy is of great importance. Galectin-3 inhibitors such as modified citrus pectin, N-acetyllactosamine, TD139 and GB0139 exert anti-apoptotic, anti-oxidative and anti-inflammatory effects and thus have potential therapeutic interest. This review briefly summarizes the physiological and pathophysiological role of galectin and specifically examines its role in cardiac disease processes. We present a more detailed discussion of galectin in cardiovascular complications of cirrhosis, particularly cirrhotic cardiomyopathy. Finally, therapeutic studies of galectin-3 inhibitors in cirrhotic cardiomyopathy are reviewed.

Dysregulated Calcium Handling in Cirrhotic Cardiomyopathy.

Cirrhotic cardiomyopathy is a syndrome of blunted cardiac systolic and diastolic function in patients with cirrhosis. However, the mechanisms remain incompletely known. Since contractility and relaxation depend on cardiomyocyte calcium transients, any factors that impact cardiac contractile and relaxation functions act eventually through calcium transients. In addition, calcium transients play an important role in cardiac arrhythmias. The present review summarizes the calcium handling system and its role in cardiac function in cirrhotic cardiomyopathy and its mechanisms. The calcium handling system includes calcium channels on the sarcolemmal plasma membrane of cardiomyocytes, the intracellular calcium-regulatory apparatus, and pertinent proteins in the cytosol. L-type calcium channels, the main calcium channel in the plasma membrane of cardiomyocytes, are decreased in the cirrhotic heart, and the calcium current is decreased during the action potential both at baseline and under stimulation of beta-adrenergic receptors, which reduces the signal to calcium-induced calcium release. The study of sarcomere length fluctuations and calcium transients demonstrated that calcium leakage exists in cirrhotic cardiomyocytes, which decreases the amount of calcium storage in the sarcoplasmic reticulum (SR). The decreased storage of calcium in the SR underlies the reduced calcium released from the SR, which results in decreased cardiac contractility. Based on studies of heart failure with non-cirrhotic cardiomyopathy, it is believed that the calcium leakage is due to the destabilization of interdomain interactions (dispersion) of ryanodine receptors (RyRs). A similar dispersion of RyRs may also play an important role in reduced contractility. Multiple defects in calcium handling thus contribute to the pathogenesis of cirrhotic cardiomyopathy.

Pathophysiology and management of liver cirrhosis: from portal hypertension to acute-on-chronic liver failure.

Cirrhosis transcends various progressive stages from compensation to decompensation driven by the severity of portal hypertension. The downstream effect of increasing portal hypertension severity leads to various pathophysiological pathways, which result in the cardinal complications of cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. Additionally, the severity of portal hypertension is the central driver for further advanced complications of hyperdynamic circulation, hepatorenal syndrome, and cirrhotic cardiomyopathy. The management of these individual complications has specific nuances which have undergone significant developments. In contrast to the classical natural history of cirrhosis and its complications which follows an insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill course with high short-term mortality unless intervened at the early stages. The management of ACLF involves specific interventions, which have quickly evolved in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF.

SAT-538 - Application of updated diagnostic criteria for cirrhotic cardiomyopathy: evaluation of its clinical impact in liver transplantation candidates

SAT-538 - Application of updated diagnostic criteria for cirrhotic cardiomyopathy: evaluation of its clinical impact in liver transplantation candidates

Cirrhotic Cardiomyopathy Following Bile Duct Ligation in Rats-A Matter of Time?

Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second surgery 28 days later. Cardiac function was assessed by conductance catheter and echocardiography. Histology, gene expression, and serum parameters were analyzed. A chronotropic incompetence (Pd31 < 0.001) and impaired contractility at rest and a reduced contractile reserve (Pd31 = 0.03, Pdob-d31 < 0.001) were seen 31 days after BDL with increased creatine (Pd35, Pd42, and Pd56 < 0.05) and transaminases (Pd31 < 0.001). A total of 56 days after BDL, myocardial fibrosis was seen (Pd56 < 0.001) accompanied by macrophage infiltration (CD68: Pgroup < 0.001) and systemic inflammation (TNFα: Pgroup < 0.001, white blood cell count: Pgroup < 0.001). Myocardial expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was increased after 31 (Pd31 < 0.001) and decreased after 42 (Pd42 < 0.001) and 56 days (Pd56 < 0.001). Caspase-3 expression was increased 31 and 56 days after BDL (Pd31 = 0.005; Pd56 = 0.005). Structural changes in the myocardium were seen after 8 weeks. After the second surgery (second hit), transient myocardial insufficiency with secondary organ dysfunction was seen, characterized by reduced contractility and contractile reserve.

Elevated bile acids are associated with left ventricular structural changes in biliary atresia.

In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood. Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5. In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152µmol/L (C-statistics=0.68). Children with bile acid concentrations >152µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry. This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.

Value of red blood cell distribution width in prediction of diastolic dysfunction in cirrhotic cardiomyopathy.

Clinical diagnosis of cirrhotic cardiomyopathy (CCM) often encounters challenges of lack of timeliness and disease severity, with the commonly positive indicator usually associated with advanced heart failure. To explore suitable biomarkers for early CCM prediction. A total of 505 eligible patients were enrolled in this study and divided into four groups according to Child-Pugh classification: Group I, Class A without CCM (105 cases); Group II, Class A with CCM (175 cases); Group III, Class B with CCM (139 cases); and Group IV, Class C with CCM (86 cases). Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to determine whether red blood cell distribution width (RDW) was an independent risk factor for CCM risk. The relationships between RDW and Child-Pugh scores, Model for End-Stage Liver Disease (MELD) scores, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were analyzed by Pearson correlation analysis. A constant RDW increase was evident from Group I to Group IV (12.54 ± 0.85, 13.29 ± 1.19, 14.30 ± 1.96, and 16.25 ± 2.13, respectively). Pearson correlation analysis showed that RDW was positively correlated with Child-Pugh scores (r = 0.642, P < 0.001), MELD scores (r = 0.592, P < 0.001), and NT-proBNP (r = 0.715, P < 0.001). Furthermore, between Group I and Group II, RDW was the only significant index (odds ratio: 2.175, 95% confidence interval [CI]: 1.549-3.054, P < 0.001), and it reached statistical significance when examined by ROC curve analysis (area under the curve: 0.686, 95%CI: 0.624-0.748, P < 0.001). RDW can serve as an effective and accessible clinical indicator for the prediction of diastolic dysfunction in CCM, in which a numerical value of more than 13.05% may indicate an increasing CCM risk.