Reply to: Correspondence on “Cardiomyopathy in cirrhosis: From pathophysiology to clinical care”

HL: nil to disclose. JAN: nil to disclose. GL: Research grants from: Pfizer, Biotronik, IONIS, Anumana. Consulting for: Boston Scientific, IONIS. Equity: Empallo, HeartScreen Health. SSL: consulting or speaking for: Abbvie, Gilead, Grifols, Intercept, Jazz Pharmaceuticals, Lupin, Oncoustics. Please refer to the accompanying ICMJE disclosure forms for further details. no financial support for this work. We are delighted that our recent review (1Liu H. Naser J.A. Lin G. Lee S.S. Cardiomyopathy in cirrhosis: From pathophysiology to clinical care.JHEP Rep. 2024; 6100911Google Scholar) has stimulated two very thoughtful and thought-provoking responses (2Cailes B. Farouque O. Majumda A. et al.Reevaluating cirrhotic cardiomyopathy diagnostics.JHEP Rep. 2024; Google Scholar, 3Lo Russo G. Carugo S. Ridola L. et al.Cirrhotic Cardiomyopath and beyond: Underscoring The Interaction Between The Liver And The Heart.JHEP Reports. 2024; (in press)Google Scholar). Cailes and colleagues raise two points. First they propose that a dobutamine challenge stress test with a cutoff value of >25% increment in cardiac output, be added to the diagnostic criteria for cirrhotic cardiomyopathy (CCM), which currently includes only resting echocardiographic systolic and diastolic parameters. They base this suggestion on their previous study showing that failing to achieve this increment is associated with a four-fold higher risk of developing hepatorenal syndrome (4Koshy A.N. Farouque O. Cailes B. et al.Impaired Cardiac Reserve on Dobutamine Stress Echocardiography Predicts the Development of Hepatorenal Syndrome.Am J Gastroenterol. 2020; 115: 388-397Google Scholar). Their second point questions whether prolonged electrocardiographic QTc interval should be considered as a diagnostic criterion – they think not. It should be emphasized that neither the 2005 World Congress of Gastroenterology (WCG) Montreal nor the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria (5Izzy M. VanWagner L.B. Lin G. et al.Redefining Cirrhotic Cardiomyopathy for the Modern Era.Hepatology. 2020; 71: 334-345Google Scholar) were intended to be the definitive final criteria for the diagnosis of CCM. Instead the intent was that they be interim criteria serving as a basis for discussion and eventual refinement according to further studies. In particular clinical outcome studies of endpoints such as hepatorenal syndrome and mortality, including the aforementioned HRS study, will be crucial in revising and refining the criteria. We agree entirely that a cardiovascular stress test of some type is important in making the diagnosis of CCM – this was the subject of intense discussion at the CCC consensus-developing meeting in 2018, but ultimately was not added to the published 2019 criteria because there was no clearly-accepted and validated stress test then (Lee SS, Lin G: unpublished observations). So while Cailes and coworkers’ suggestion to use the dobutamine challenge test is certainly worth considering, we believe that at present it is premature to add this to the 2019 CCC criteria until further validation studies on this are performed. The same can be said for their contention that prolonged QTc should not be added to the diagnostic criteria, which is something that we had suggested as a topic for discussion. Although Cailes et al. and other groups have reported no relationship between prolonged QTc and post-transplant mortality, this point is still controversial as other centres have found such a correlation with both pre- and post-transplant mortality (6Lee W. Vandenberk B. Raj S.R. Lee S.S. Prolonged QT Interval in Cirrhosis: Twisting Time?.Gut Liver. 2022; 16: 849-860Google Scholar). Whether prolonged QTc is a part of a spectrum of other electrophysiologic abnormalities that contribute to the pathogenesis of arrhythmias such as atrial fibrillation (7Vandenberk B. Altieri M.H. Liu H. et al.Review article: diagnosis, pathophysiology and management of atrial fibrillation in cirrhosis and portal hypertension.Aliment Pharmacol Ther. 2023; 57: 290-303Google Scholar) remains unsettled. However, we agree that there is no direct correlation between QTc and cardiac contractility. Therefore, any notion of adding prolonged QTc to the diagnostic criteria is also premature and requires further investigation. Regarding the comments of Lo Russo and colleagues (3Lo Russo G. Carugo S. Ridola L. et al.Cirrhotic Cardiomyopath and beyond: Underscoring The Interaction Between The Liver And The Heart.JHEP Reports. 2024; (in press)Google Scholar), they highlight the complex connections and inter-relationships between liver and heart diseases, and we generally agree with their comments. However we disagree with one specific comment: “CCM can be considered end-stage cardiomyopathy with multiple causes, including coronary artery disease (CAD)”. The definition of cirrhotic cardiomyopathy specifically excludes known primary cardiac conditions such as CAD. Moreover, CCM rarely manifests with the clinical features of end-stage cardiomyopathy with overt failure, it almost always presents as heart failure with preserved ejection fraction (HFpEF). Otherwise, these investigators’ points are well taken, especially the need to study the role of cardiac dysfunction as a contributing pathogenic factor or important sequela to acute-on-chronic liver failure. In summary, we appreciate the interesting comments and important work in the field that both groups are doing. These letters underscore the need to do further research on cirrhotic cardiomyopathy and the broader topic of liver-heart connections (8Taniguchi T, Lee SS, (Eds) Cardio-Hepatology: Connections between Hepatic and Cardiovascular Diseases. Elsevier Academic Press, London UK, 2023.Google Scholar). Reevaluating cirrhotic cardiomyopathy diagnosticsJHEP ReportsPreviewN/A. Full-Text PDF Open AccessCirrhotic Cardiomyopathy And Beyond: Underscoring The Interaction Between The Liver And The HeartJHEP ReportsPreviewThe review by Liu et al elegantly summarizes the pathophysiology and clinical burden of cirrhotic cardiomyopathy (CCM).(1) Full-Text PDF Open AccessCardiomyopathy in cirrhosis: From pathophysiology to clinical careJHEP ReportsVol. 6Issue 1PreviewCirrhotic cardiomyopathy (CCM) is defined as systolic or diastolic dysfunction in the absence of prior heart disease or another identifiable cause in patients with cirrhosis, in whom it is an important determinant of outcome. Its underlying pathogenic/pathophysiological mechanisms are rooted in two distinct pathways: 1) factors associated with portal hypertension, hyperdynamic circulation, gut bacterial/endotoxin translocation and the resultant inflammatory phenotype; 2) hepatocellular insufficiency with altered synthesis or metabolism of substances such as proteins, lipids, carbohydrates, bile acids and hormones. Full-Text PDF Open Access

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