Cardiac dysfunction in patients with cirrhosis and acute decompensation.

The prevalence of cirrhotic cardiomyopathy (CCM) has been reported as high as 60%-70% in patients with liver cirrhosis and is associated with various negative outcomes. There has been a growing understanding of CCM over recent years. Indeed, the development of imaging techniques has enabled new diagnostic criteria to be proposed by the Cirrhotic Cardiomyopathy Consortium. However, important unanswered questions remain over pathophysiological mechanisms, optimal diagnostic modalities and potential treatment options. While there has been an increasing volume of literature evaluating CCM, there is a lack of clarity on its implications in acute decompensation, acute-on-chronic liver failure and following interventions such as transjugular intrahepatic portosystemic shunt insertion and liver transplantation. This review aims to summarise the literature in these challenging domains and suggest where future research should focus. We conclude that systemic inflammation and structural myocardial changes are likely to be crucial in the pathophysiology of the disease, but the relative contribution of different components remains elusive. Furthermore, future studies need to use standardised diagnostic criteria for CCM as well as incorporate newer imaging techniques assessing both myocardial structure and function. Finally, while specific treatments are currently lacking, therapeutics targeting systemic inflammation, microbial dysbiosis and bacterial translocation are promising targets and warrant further research.

Therapies for Cirrhotic Cardiomyopathy: Current Perspectives and Future Possibilities.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment.

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

BACKGROUND: 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). METHODS: 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%. RESULTS: 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. CONCLUSION: 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.

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.

Do You Have To Evaluate The Heart Of The Cirrhotic Patients?

Objectives: To identify patients with occult cardiac dysfunction and itsrelationship with the severity of liver impairment. Method: This is a Judgment (Purposive) Sampling, cross-sectionalstudy that was conducted at Kafrelsheikh University Hospital, Egypt, from November 2019 to December 2020, and comprised adult patients of either gender with liver cirrhosis. After detailed history, a clinical examination, pathological assessment and cardiac evaluation based on electrocardiogram and echocardiography, the patients were divided into three groups. Patients who had dyspnoea or cyanosis were in group A, those who did not have dyspnoea or cyanosis but had electrocardiogram and echocardiography abnormalities were in group B, and patients who did not have dyspnoea, cyanosis or electrocardiogram and echocardiography abnormalities were in group C. The severity of the liver disease was evaluated using Child-Pugh and Model of End Liver Disease scores. Data was analysed using SPSS 20. RESULTS: Of the 300 patients, 153(51%) were males and 147(49%) were females. The overall mean age was 55.1±5.1 years(range: 20-60 years). There were 58(19.33%) patientsin group A, 108(36%) in group B and 134(44.66%) in group C. Group A patientsshowed higher Child-Pugh and Model of End Liver Disease scoresthan the other groups(p<0.05). Child-Pugh score >6 and Model of End Liver Disease score >37 yielded the best accuracy for detecting cardiac abnormalities in group B (p<0.05). CONCLUSIONS: There were significant cardiac changes in cirrhotic patients.

Management of cardiac diseases in liver transplant recipients: Comprehensive review and multidisciplinary practice-based recommendations.

Cardiac diseases are one of the most common causes of morbidity and mortality following liver transplantation (LT). Prior studies have shown that cardiac diseases affect close to one-third of liver transplant recipients (LTRs) long term and that their incidence has been on the rise. This rise is expected to continue as more patients with advanced age and/or non-alcoholic steatohepatitis undergo LT. In view of the increasing disease burden, a multidisciplinary initiative was developed to critically review the existing literature (between January 1, 1990 and March 17, 2021) surrounding epidemiology, risk assessment, and risk mitigation of coronary heart disease, arrhythmia, heart failure, and valvular heart disease and formulate practice-based recommendations accordingly. In this review, the expert panel emphasizes the importance of optimizing management of metabolic syndrome and its components in LTRs and highlights the cardioprotective potential for the newer diabetes medications (e.g., sodium glucose transporter-2 inhibitors) in this high-risk population. Tailoring the multidisciplinary management of cardiac diseases in LTRs to the cardiometabolic risk profile of the individual patient is critical. The review also outlines numerous knowledge gaps to pave the road for future research in this sphere with the ultimate goal of improving clinical outcomes.

Cardiovascular events after liver transplantation: MACE hurts.

The curative therapy for patients with end-stage liver disease is liver transplantation. However, liver transplantation challenges the cardiovascular system, and is associated with major adverse cardiovascular events (MACE). Immediately after implantation of the liver graft, changes in cardiac preload and afterload increase the cardiac workload. Longer-term postoperatively, a more sedentary lifestyle and enhanced appetite increase obesity and body mass index. Immunosuppressants may also affect the cardiovascular system. All these factors that liver recipients encounter impact the function of the cardiovascular system. Cardiac events are the third-leading cause of death in liver recipients. This review describes the pertinent factors that predispose to development of MACE after liver transplantation, and how to predict these cardiovascular events in the post-transplant period. We review the roles of metabolic syndrome, renal dysfunction, non-alcoholic fatty liver disease, diagnostic tests such as imaging and biomarkers, and parameters such as systolic and diastolic dysfunction, and QT interval prolongation in cardiovascular events. We summarize the current literature on scoring systems to predict cardiovascular events.

Impact of cardiac dysfunction on morbidity and mortality in liver transplant candidates.

The prognostic role of cardiac dysfunction in cirrhotic patients is increasingly recognized. We studied its impact on morbidity and mortality before and after liver transplantation (LT) including development of post-transplant cardiovascular disease (CVD). In this retrospective study, cirrhotic patients who underwent LT assessment from January 2010 to December 2020 were reviewed. Demographics, cardiac investigations and clinical courses were analyzed to identify the prevalence of cardiac dysfunction and its role in LT outcomes. Survival analysis was performed using Cox proportional hazard regression modelling, with LT as a time-varying covariate and as an interaction variable with cardiac dysfunction. Three hundred and eight patients (70% male) were studied. The median (interquartile range) age at LT assessment was 56 (12) years. Cardiac dysfunction was found in 178 (58%) patients (diastolic, 169; systolic, 26; both, 17) and was significantly associated with hepatorenal syndrome/acute kidney injury and peri- and post-transplant morbidity (adjusted odds ratio [aOR] 1.94, 95% CI 1.06-3.52, P < .001; aOR 2.01, 95% CI 1.06-3.82, P = .033; aOR 1.9, 95% CI 1.01-3.65, P = .023, respectively). Cardiac dysfunction was not associated with mortality before (adjusted hazard ratio [aHR] 1.01, 95% CI .99-1.01) or after LT (aHR .74, 95% CI .4-1.05. Post-transplant CVD (61% cardiac failure) occurred in 36 patients, and there was no significant association with cardiac dysfunction (P = .11). Cardiac dysfunction was common in LT candidates and was significantly associated with morbidity before and after LT. Studies on the role of advanced echocardiographic parameters to improve diagnosis of cardiac dysfunction and optimize LT outcomes are needed.

The prevalence of cirrhotic cardiomyopathy according to different diagnostic criteria.

BACKGROUND AND AIMS: Recently published criteria by 2019 Cirrhotic Cardiomyopathy Consortium set a lower threshold for reduced ejection fraction to diagnose systolic dysfunction in cirrhotic patients, and stress testing was replaced by echocardiography strain imaging. The criteria to diagnose diastolic dysfunction are in general concordant with the 2016 ASE/EACVI guidelines and differ considerably from the 2005 Montreal recommendations. We aimed to assess the prevalence of cirrhotic cardiomyopathy according to different diagnostic criteria. METHODS: Cirrhotic patients without another structural heart disease, arterial hypertension, portal vein thrombosis, HCC outside Milan criteria and presence of TIPS were enrolled. Speckle-tracking echocardiography was performed by EACVI certified investigators. RESULTS: A total of 122 patients with cirrhosis fulfilled the inclusion criteria. Overall prevalence of cirrhotic cardiomyopathy was similar for 2005 Montreal and 2019 CCC: 67.2% vs 55.7% (P = .09); and significantly higher compared to 2009 ASE/EACVI criteria: 67.2% vs 35.2% (P < .0001) and 55.7% vs 35.2% (P = .002) respectively. Significantly more patients had diastolic dysfunction according to the 2005 Montreal compared to the 2009 ASE/EACVI and 2019 CCC criteria: 64.8% vs 32.8% (P < .0001) and 64.8% vs 7.4% (P < .0001). Systolic dysfunction was more frequently diagnosed according to 2019 CCC criteria compared to 2005 Montreal (53.3% vs 16.4%,P < .0001) or ASE/EACVI criteria (53.3% vs 4.9%,P < .0001). CONCLUSION: Cirrhotic cardiomyopathy was present in around 60% of cirrhotic patients when applying the hepatological criteria. A considerably higher prevalence of systolic dysfunction according to the 2019 CCC criteria was observed. Long-term follow-up studies are needed to establish the validity of these criteria to predict clinically relevant outcomes.

Prolonged QTc interval predicts long-term mortality in cirrhosis: a propensity score matching analysis.

BACKGROUND: Prolonged corrected QT (QTc) interval is a hallmark of cirrhotic cardiomyopathy (CCM) and has been ascertained to predict mortality in cirrhosis. However, some critical issues remain to be addressed including unanimous cut-off, calculation approach and applicable population. METHODS: A total of 274 patients with cirrhosis were included. The prolonged QTc interval over 440 ms according to adjusted Fridericia's formula was used to stratify enrolled subjects. Independent predictors of 3-year mortality were identified with Cox regression model. The Kaplan-Meier method was implemented to obtain survival curves. To reduce impact of selection bias and possible confounders, a propensity score matching (PSM) analysis was used. RESULTS: QTc > 440 ms was an independent risk factor in the entire cohort and PSM subset (HR 2.532, 95% CI 1.431-4.480, p=.001; HR 2.802, 95% CI 1.171-6.701, p=.021, respectively). Subgroup analysis showed that QTc > 440 ms was an independent predictor in cirrhotics with age ≤60 years (HR = 1.02, p=.035) and in the presence of ascites (HR = 1.01, p=.008). CONCLUSIONS: The prolonged QTc interval might help to identify patients with high-risk of all-cause mortality.

Markedly prolonged QTc interval in end-stage liver disease and risk of 30-day cardiovascular event after liver transplant.

BACKGROUND AND AIM: The proportional increase of corrected QT interval (QTc) along end-stage liver disease (ESLD) severity may lead to inconsistent outcome reporting if based on conventional threshold of prolonged QTc. We investigated the comprehensive QTc distribution among ESLD patients and assessed the association between QTc > 500 ms, a criterion for diagnosing severe long-QT syndrome, and the 30-day major adverse cardiovascular event (MACE) after liver transplantation (LT) and identified the risk factors for developing QTc > 500 ms. METHODS: Data were collected prospectively from the Asan LT Registry between 2011 and 2018, and outcomes were retrospectively reviewed. Multivariable analysis and propensity score-weighted adjusted odds ratios (ORs) were calculated. Thirty-day MACEs were defined as the composite of cardiovascular mortality, arrhythmias, myocardial infarction, pulmonary thromboembolism, and/or stroke. RESULTS: Of 2579 patients, 194 (7.5%) had QTc > 500 ms (QTc500_Group), and 1105 (42.8%) had prolonged QTc (QTcP_Group), defined as QTc > 470 ms for women and >450 ms for men. The 30-day MACE occurred in 336 (13%) patients. QTc500_Group showed higher 30-day MACE than did those without (20.1% vs 12.5%, P = 0.003), with corresponding adjusted OR of 1.24 (95% CI: 1.06-1.46, P = 0.007). However, QTcP_Group showed comparable 30-day MACE (13.3% vs 12.8% without prolonged QTc, P = 0.764). Significant risk factors for QTc > 500 ms development were advanced liver disease, female sex, hypokalemia, hypocalcemia, high left ventricular end-diastolic volume, and tachycardia. CONCLUSION: Our results revealed that, among ESLD patients, a novel threshold of QTc > 500 ms was associated with post-LT 30-day MACE but not with conventional threshold, indicating that a longer QTc threshold should be considered for this unique patient population.

Point-of-Care Echocardiography and Hemodynamic Monitoring in Cirrhosis and Acute-on-Chronic Liver Failure in the COVID-19 Era.

Point-of-Care (POC) transthoracic echocardiography (TTE) is transforming the management of patients with cirrhosis presenting with septic shock, acute kidney injury, hepatorenal syndrome and acute-on-chronic liver failure (ACLF) by correctly assessing the hemodynamic and volume status at the bedside using combined echocardiography and POC ultrasound (POCUS). When POC TTE is performed by the hepatologist or intensivist in the intensive care unit (ICU), and interpreted remotely by a cardiologist, it can rule out cardiovascular conditions that may be contributing to undifferentiated shock, such as diastolic dysfunction, myocardial infarction, myocarditis, regional wall motion abnormalities and pulmonary embolism. The COVID-19 pandemic has led to a delay in seeking medical treatment, reduced invasive interventions and deferment in referrals leading to "collateral damage" in critically ill patients with liver disease. Thus, the use of telemedicine in the ICU (Tele-ICU) has integrated cardiology, intensive care, and hepatology practices across the spectrum of ICU, operating room, and transplant healthcare. Telecardiology tools have improved bedside diagnosis when introduced as part of COVID-19 care by remote supervision and interpretation of POCUS and echocardiographic data. In this review, we present the contemporary approach of using POC echocardiography and offer a practical guide for primary care hepatologists and gastroenterologists for cardiac assessment in critically ill patients with cirrhosis and ACLF. Evidenced based use of Tele-ICU can prevent delay in cardiac diagnosis, optimize safe use of expert resources and ensure timely care in the setting of critically ill cirrhosis, ACLF and liver transplantation in the COVID-19 era.

Echocardiography in the Liver Transplant Patient.

PURPOSE OF REVIEW: The aim of this study is to review current echocardiographic modalities utilized in the assessment of the preoperative liver transplant candidate with an emphasis on newer techniques. We sought to assess if newer methods imparted additional diagnostic or prognostic accuracy compared to prior methods based on existing studies. RECENT FINDINGS: Standard dobutamine stress echocardiography offers important information regarding operative risk and post-operative survival in liver transplant candidates; however, technologies such as speckle-tracking echocardiography (STE) and evaluation of diastolic function have emerged as useful tools as well. 2D-STE and diastolic echocardiography offer additional parameters such as global longitudinal strain and measures of diastolic dysfunction that can better predict peri-operative and post-operative complications in liver transplant candidates. If able, practitioners should utilize these methods routinely in their assessment of liver transplant candidates.

Short-term hemodynamic effects of ß-blockers influence survival of patients with decompensated cirrhosis.

BACKGROUND & AIMS: Whether the effect of ß-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of ß-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis. METHODS: Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting ß-blockers and again after 1 to 3 months of treatment (short-term). RESULTS: Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under ß-blockers, decompensated patients had lower portal pressure decrease (10 ± 18% vs. 15 ± 12%; p <0.05) and had greater reductions in heart rate (p <0.001) and CO (17 ± 15% vs. 10 ± 21%; p <0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with ß-blockers than survivors (21 ± 14% vs. 15 ± 16%; p <0.05) and CO under ß-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66-0.83). Death risk was higher in decompensated patients with CO <5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25-0.77; p = 0.004). CONCLUSIONS: In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to ß-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of ß-blockers on CO might adversely influence survival in decompensated cirrhosis. LAY SUMMARY: ß-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of ß-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of ß-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of ß-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis.

Impact of cardiac function, refractory ascites and beta blockers on the outcome of patients with cirrhosis listed for liver transplantation.

BACKGROUND & AIMS: Whether non-selective beta blockers (NSBBs) are deleterious in patients with end-stage cirrhosis and refractory ascites has been widely debated. We hypothesized that only the subset of patients on the liver transplant waiting list who had impaired cardiac performance would be at increased risk of mortality if receiving NSBBs. METHODS: This study included 584 consecutive patients with cirrhosis evaluated for transplantation between 1999 and 2014. All patients had right heart catheterization with hemodynamic measurements at evaluation. Fifty percent received NSBBs. Refractory ascites was present in 33%. Cardiac performance was assessed by left ventricular stroke work index (LVSWI). Waiting list mortality without liver transplantation was explored using competing risk analysis. RESULTS: LVSWI was significantly lower in patients with refractory ascites. In multivariate analysis using competing risk, refractory ascites, NSBBs and LVSWI were associated with waiting list mortality in the whole population, with a statistically significant interaction between NSBBs and LVSWI. The most discriminant value of LVSWI was 64.1 g-m/m2. In the final model, refractory ascites (subdistribution hazard ratio 1.52; 95% CI1.01-2.28; p = 0.0083) and treatment by NSBBs with LVSWI <64.1 g-m/m2 (subdistribution hazard ratio 1.96; 95% CI 1.32-2.90; p = 0.0009) were significantly associated with waiting list mortality, taking into account serum sodium and the model for end-stage liver disease score. CONCLUSIONS: This study suggests that compromised cardiac performance is more common in patients with refractory ascites and that NSBBs are deleterious in cirrhotic patients with compromised cardiac performance. These results highlight the prognostic value of cardiac function in patients with end-stage cirrhosis. LAY SUMMARY: There are still controversies concerning the impact of non-selective beta blockers on outcomes in patients with decompensated cirrhosis, especially in those with refractory ascites. In this study of 584 cirrhotic patients evaluated for liver transplantation, who underwent right heart catheterization, we have shown that global cardiac performance measured by left ventricular stroke work index is lower in patients with refractory ascites. Administration of non-selective beta blockers in patients with compromised cardiac performance may increase waiting list mortality. These results highlight the prognostic value of global cardiac performance in patients with end-stage cirrhosis.

Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.

BACKGROUND & AIMS: The safety of non-selective ß-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. METHODS: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. RESULTS: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. CONCLUSION: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. ß-blockade should be used cautiously or even avoided in patients with RA. LAY SUMMARY: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, ß-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.

Protective role of cardiac-specific overexpression of caveolin-3 in cirrhotic cardiomyopathy.

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TGneg) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TGneg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TGneg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TGneg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TGneg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis.NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy.

Impaired myosin isoform shift and calcium transients contribute to cellular pathogenesis of rat cirrhotic cardiomyopathy.

BACKGROUND & AIMS: Cirrhotic cardiomyopathy is a recently recognized entity, but detailed cellular and molecular mechanisms remain unclarified. We aimed to elucidate the role of myosin heavy chain isoform shifts and their relation to calcium transients in the contractile kinetics of cirrhotic rats. METHODS: Cirrhosis was induced in male Lewis Brown-Norway rats by bile duct ligation (BDL). Myosin heavy chain (MHC) isoform distribution was evaluated by gel electrophoresis. Contractile force, Ca2+ transients and cell shortening were studied at varied frequency and extracellular [Ca2+ ]. T-tubular integrity was analysed by power spectrum analysis of images of myocytes stained with di-8-ANEPPS. RESULTS: Compared with sham controls, the phenotypes of cirrhotic rats were as follows: (a) alpha-myosin heavy chain shifted to beta-MHC isoform; (b) mild loss of T-tubular integrity in myocytes; (c) a reduced maximum and rate of rise of the Ca2+ transient (max F/Fo ); (d) a reduction in both the rate of rise and fall of contraction; (e) decreased maximal force-generating capacity; (f) loss of the inotropic effect of increased stimulus frequency; (g) unchanged sensitivity of force development to varied extracellular [Ca2+ ] and (h) increased spontaneous diastolic sarcomere length fluctuations. CONCLUSION: Cardiomyocytes and ventricular trabeculae in a cirrhotic rat model showed features of typical heart failure including systolic and diastolic prolongation, impaired force-frequency relation and decreased force-generating capacity. Impaired myosin isoform shift and calcium transients are important contributory mechanisms underlying the pathogenesis of the heart failure phenotype seen in cirrhosis.

Cirrhotic Cardiomyopathy.

PURPOSE OF REVIEW: Cirrhotic cardiomyopathy is a syndrome of depressed cardiac function in patients with cirrhosis. We aimed to review the historical background, pathophysiology and pathogenesis, diagnostic definitions, clinical relevance, and management of this syndrome. RECENT FINDINGS: An inflammatory phenotype underlies the pathogenesis: gut bacterial translocation with endotoxemia stimulates cytokines and cardiodepressant factors, such as nitric oxide and endocannabinoids. Cardiomyocyte plasma membrane biochemical and biophysical changes also play a pathogenic role. These factors lead to impaired beta-adrenergic function. Proposed new echocardiographic criteria for the diagnosis of cirrhotic cardiomyopathy include systolic global longitudinal strain and indices of diastolic dysfunction. Cardiac dysfunction participates in the pathogenesis of hepatorenal syndrome and increased morbidity/mortality of cirrhotic patients to hemorrhage, infection, and surgery, including liver transplantation. There is no specific treatment, although ß-adrenergic blockade and supportive management have been proposed, but it needs further study. Cirrhotic cardiomyopathy is a clinically relevant syndrome afflicting patients with established cirrhosis. Optimum management remains unclear, and further study is needed in this area.

Cardiac dysfunction in cirrhosis: a 2-yr longitudinal follow-up study using advanced cardiac imaging.

The temporal relationship between cirrhotic cardiomyopathy, progression of liver disease, and survival remains unknown. Our aim was to investigate the development of structural and functional cardiac changes over time with the progression of cirrhosis and outcome. Sixty-three cirrhotic outpatients (Child class: A = 9, B = 46, C = 8) and 14 healthy controls were included in this 2-yr longitudinal study. Advanced cardiac characteristics such as cardiac MRI with extracellular volume (ECV) quantification, speckle tracking echocardiography, and biomarkers were assessed at 0/6/12/18/24 mo. Patients were followed-up for a median of 30 mo with registration of acute decompensations (ADs), liver transplantations (LTs), and deaths. Patients who progressed, underwent LT or died had more pronounced cardiac dysfunction, structural myocardial changes, and left atrial enlargement. Conversely, limited cardiac deterioration was seen in patients who remained stable or improved in cirrhosis. During follow-up 25 patients developed AD, 4 underwent LT, and 20 died. Mean arterial pressure was the only cardiovascular parameter associated with death in a univariate analysis (P = 0.037), and the main predictors were model for end-stage liver disease and age. However, last-visit myocardial ECV was independently associated with the combined end point of LT/death (P = 0.001), and in patients with AD a low cardiac index was independently associated with death (P = 0.01). Cardiac function seems to deteriorate with the progression of cirrhosis and affects prognosis, especially in patients with AD. Conversely, patients with stable cirrhosis have limited progression in cardiac dysfunction over a 2-yr period with modest impact on survival. The results encourage careful cardiac monitoring in advanced cirrhosis.NEW & NOTEWORTHY For the first time, we have performed advanced cardiac imaging to investigate the development of cirrhotic cardiomyopathy over 2 years. We show that cardiac dysfunction deteriorates with progression of cirrhosis and may affect the prognosis in patients developing acute decompensation. Especially, structural myocardial abnormalities, left atrial enlargement, and a hypodynamic cardiac state seem of importance. Conversely, limited cardiac progression is seen in stable cirrhosis. These findings provide new insight into our understanding of cirrhotic cardiomyopathy.