Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications

Nature Reviews Cardiology volume 18, pages 117–135 (2021)Cite this article

Subjects

Abstract

The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression. The development of cardiovascular diseases in patients with chronic liver failure is associated with increased morbidity and mortality, and cardiovascular complications can in turn affect liver function and liver disease progression. Furthermore, numerous infectious, inflammatory, metabolic and genetic diseases, as well as alcohol abuse can also influence both hepatic and cardiovascular outcomes. In this Review, we highlight how chronic liver diseases and associated cardiovascular effects can influence different organ pathologies. Furthermore, we explore the potential roles of inflammation, oxidative stress, vasoactive mediator imbalance, dysregulated endocannabinoid and autonomic nervous systems and endothelial dysfunction in mediating the complex interplay between the liver and the systemic vasculature that results in the development of the extrahepatic complications of chronic liver disease. The roles of ageing, sex, the gut microbiome and organ transplantation in this complex interplay are also discussed.

Key points

  • Chronic liver diseases (CLD) trigger the development of severe extrahepatic complications, including cirrhotic cardiomyopathy, hepatorenal syndrome, ascites, hepatopulmonary syndrome, portopulmonary hypertension, gastrointestinal bleeding and hepatic encephalopathy, which are associated with further increased risk of death.

  • The extrahepatic complications of CLD are often overlooked or diagnosed late into the disease process owing to the lack of specific diagnostic markers, which results in delayed treatment.

  • No definitive therapies are available for the treatment of these extrahepatic complications of CLD with the exception of liver transplantation, but the presence of these complications might preclude eligibility for liver transplantation.

  • Novel disease-modifying treatment strategies targeted at counteracting one or more of the pathophysiological mechanisms involved in the development of CLD and its extrahepatic complications are needed and their investigation is warranted.

  • Potential future research areas for the extrahepatic complications of CLD include the effects of ageing, sex and the gut microbiome on disease progression and the development of novel biomarkers for early diagnosis.

  • The identification of shared pathophysiological pathways underlying these extrahepatic complications will facilitate the development of more specific drug therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Evolution of chronic liver disease and its extrahepatic complications.
Fig. 2: Extrahepatic complications associated with chronic liver disease.
Fig. 3: Liver inflammation and fibrosis promote microvascular and macrovascular dysfunction and extrahepatic complications.

Similar content being viewed by others

References

  1. Schuppan, D. & Afdhal, N. H. Liver cirrhosis. Lancet 371, 838–851 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Moon, A. M., Singal, A. G. & Tapper, E. B. Contemporary epidemiology of chronic liver disease and cirrhosis. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2019.07.060 (2019).

    Article  PubMed  Google Scholar 

  3. Do, A., Kuszewski, E. J., Langberg, K. A. & Mehal, W. Z. Incorporating weight loss medications into hepatology practice for nonalcoholic steatohepatitis. Hepatology 70, 1443–1456 (2019).

    PubMed  PubMed Central  Google Scholar 

  4. Pimpin, L. et al. Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies. J. Hepatol. 69, 718–735 (2018).

    PubMed  Google Scholar 

  5. Tapper, E. B. & Parikh, N. D. Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study. BMJ 362, k2817 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Wong, R. J. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 148, 547–555 (2015).

    PubMed  Google Scholar 

  7. Ko, J. S. New perspectives in pediatric nonalcoholic fatty liver disease: epidemiology, genetics, diagnosis, and natural history. Pediatr. Gastroenterol. Hepatol. Nutr. 22, 501–510 (2019).

    PubMed  PubMed Central  Google Scholar 

  8. World Health Organization. World health statistics 2018: monitoring health for the SDGs, sustainable development goals (WHO, 2018).

  9. Gracia-Sancho, J., Marrone, G. & Fernandez-Iglesias, A. Hepatic microcirculation and mechanisms of portal hypertension. Nat. Rev. Gastroenterol. Hepatol. 16, 221–234 (2019).

    PubMed  Google Scholar 

  10. Moller, S. & Bendtsen, F. Complications of cirrhosis. A 50 years flashback. Scand. J. Gastroenterol. 50, 763–780 (2015).

    CAS  PubMed  Google Scholar 

  11. Bernardi, M., Moreau, R., Angeli, P., Schnabl, B. & Arroyo, V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J. Hepatol. 63, 1272–1284 (2015).

    CAS  PubMed  Google Scholar 

  12. Matyas, C. et al. Interplay of liver-heart inflammatory axis and cannabinoid 2 receptor signalling in an experimental model of hepatic cardiomyopathy. Hepatology 71, 1391–1284 (2020).

    CAS  PubMed  Google Scholar 

  13. Trojnar, E. et al. Cannabinoid-2 receptor activation ameliorates hepatorenal syndrome. Free Radic. Biol. Med. 152, 540–550 (2020).

    CAS  PubMed  Google Scholar 

  14. Wijdicks, E. F. Hepatic encephalopathy. N. Engl. J. Med. 375, 1660–1670 (2016).

    CAS  PubMed  Google Scholar 

  15. Wiese, S., Hove, J. D. & Moller, S. Cardiac imaging in patients with chronic liver disease. Clin. Physiol. Funct. Imaging 37, 347–356 (2017).

    PubMed  Google Scholar 

  16. Kowalski, H. J. & Abelmann, W. H. The cardiac output at rest in Laennec’s cirrhosis. J. Clin. Invest. 32, 1025–1033 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Izzy, M. et al. Redefining cirrhotic cardiomyopathy for the modern era. Hepatology 71, 334–345 (2020).

    PubMed  Google Scholar 

  18. Moller, S., Danielsen, K. V., Wiese, S., Hove, J. D. & Bendtsen, F. An update on cirrhotic cardiomyopathy. Expert Rev. Gastroenterol. Hepatol. 13, 497–505 (2019).

    PubMed  Google Scholar 

  19. Wiese, S., Hove, J. D., Bendtsen, F. & Moller, S. Cirrhotic cardiomyopathy: pathogenesis and clinical relevance. Nat. Rev. Gastroenterol. Hepatol. 11, 177–186 (2014).

    CAS  PubMed  Google Scholar 

  20. Nazar, A. et al. Left ventricular function assessed by echocardiography in cirrhosis: relationship to systemic hemodynamics and renal dysfunction. J. Hepatol. 58, 51–57 (2013).

    PubMed  Google Scholar 

  21. Cazzaniga, M. et al. Diastolic dysfunction is associated with poor survival in patients with cirrhosis with transjugular intrahepatic portosystemic shunt. Gut 56, 869–875 (2007).

    PubMed  PubMed Central  Google Scholar 

  22. Eyvazian, V. A. et al. Incidence, predictors, and outcomes of new-onset left ventricular systolic dysfunction after orthotopic liver transplantation. J. Card. Fail. 25, 166–172 (2019).

    PubMed  Google Scholar 

  23. Shin, W. J. et al. Effect of ventriculo-arterial coupling on transplant outcomes in cirrhotics: analysis of pressure-volume curve relations. J. Hepatol. 66, 328–337 (2017).

    PubMed  Google Scholar 

  24. Ruiz-del-Arbol, L. et al. Diastolic dysfunction is a predictor of poor outcomes in patients with cirrhosis, portal hypertension, and a normal creatinine. Hepatology 58, 1732–1741 (2013).

    CAS  PubMed  Google Scholar 

  25. Premkumar, M. et al. Left ventricular diastolic dysfunction is associated with renal dysfunction, poor survival and low health related quality of life in cirrhosis. J. Clin. Exp. Hepatol. 9, 324–333 (2019).

    PubMed  Google Scholar 

  26. Wiese, S. et al. Myocardial extracellular volume quantified by magnetic resonance is increased in cirrhosis and related to poor outcome. Liver Int. 38, 1614–1623 (2018).

    CAS  PubMed  Google Scholar 

  27. Lee, S. K., Song, M. J., Kim, S. H. & Ahn, H. J. Cardiac diastolic dysfunction predicts poor prognosis in patients with decompensated liver cirrhosis. Clin. Mol. Hepatol. 24, 409–416 (2018).

    PubMed  PubMed Central  Google Scholar 

  28. Desai, M. S. et al. Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology 65, 189–201 (2017).

    CAS  PubMed  Google Scholar 

  29. Bortoluzzi, A. et al. Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms. Hepatology 57, 266–276 (2013).

    CAS  PubMed  Google Scholar 

  30. Jarkovska, D. et al. Expression of classical mediators in hearts of rats with hepatic dysfunction. Can. J. Physiol. Pharmacol. 95, 1351–1359 (2017).

    CAS  PubMed  Google Scholar 

  31. Henriksen, J. H. et al. Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease. Gut 52, 1511–1517 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Coss, E. et al. Predictors of cardiovascular events after liver transplantation: a role for pretransplant serum troponin levels. Liver Transpl. 17, 23–31 (2011).

    PubMed  Google Scholar 

  33. Watt, K. D. et al. Pretransplant serum troponin levels are highly predictive of patient and graft survival following liver transplantation. Liver Transpl. 16, 990–998 (2010).

    PubMed  Google Scholar 

  34. Wiese, S. et al. Cardiac and proinflammatory markers predict prognosis in cirrhosis. Liver Int. 34, e19–e30 (2014).

    CAS  PubMed  Google Scholar 

  35. Wiese, S. et al. Cardiac dysfunction in cirrhosis: a 2-yr longitudinal follow-up study using advanced cardiac imaging. Am. J. Physiol. Gastrointest. Liver Physiol. 317, G253–G263 (2019).

    CAS  PubMed  Google Scholar 

  36. Koshy, A. N. et al. Impaired cardiac reserve on dobutamine stress echocardiography predicts the development of hepatorenal syndrome. Am. J. Gastroenterol. 115, 388–397 (2020).

    PubMed  Google Scholar 

  37. Moller, S. & Bernardi, M. Interactions of the heart and the liver. Eur. Heart J. 34, 2804–2811 (2013).

    PubMed  Google Scholar 

  38. Henriksen, J. H., Fuglsang, S. & Bendtsen, F. Arterial pressure profile in patients with cirrhosis: Fourier analysis of arterial pulse in relation to pressure level, stroke volume, and severity of disease: on the reduction of afterload in the hyperdynamic syndrome. Scand. J. Gastroenterol. 47, 580–590 (2012).

    PubMed  Google Scholar 

  39. Robotham, J. L., Takata, M., Berman, M. & Harasawa, Y. Ejection fraction revisited. Anesthesiology 74, 172–183 (1991).

    CAS  PubMed  Google Scholar 

  40. Israelsen, M. et al. Dobutamine reverses the cardio-suppressive effects of terlipressin without improving renal function in cirrhosis and ascites: a randomised controlled trial. Am. J. Physiol. Gastrointest. Liver Physiol. 318, G313–G321 (2020).

    CAS  PubMed  Google Scholar 

  41. Lang, R. M. et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J. Am. Soc. Echocardiogr. 28, 1–39.e14 (2015).

    PubMed  Google Scholar 

  42. Zamirian, M. et al. Reduced myocardial reserve in cirrhotic patients: an evaluation by dobutamine stress speckle tracking and tissue Doppler imaging (TDI) echocardiography. J. Cardiovasc. Thorac. Res. 11, 127–131 (2019).

    PubMed  PubMed Central  Google Scholar 

  43. Rimbas, R. C. et al. New definition criteria of myocardial dysfunction in patients with liver cirrhosis: a speckle tracking and tissue doppler imaging study. Ultrasound Med. Biol. 44, 562–574 (2018).

    PubMed  Google Scholar 

  44. Moller, S., Wiese, S., Halgreen, H. & Hove, J. D. Diastolic dysfunction in cirrhosis. Heart Fail. Rev. 21, 599–610 (2016).

    PubMed  Google Scholar 

  45. Dowsley, T. F. et al. Diastolic dysfunction in patients with end-stage liver disease is associated with development of heart failure early after liver transplantation. Transplantation 94, 646–651 (2012).

    PubMed  Google Scholar 

  46. Tsiompanidis, E. et al. Liver cirrhosis-effect on QT interval and cardiac autonomic nervous system activity. World J. Gastrointest. Pathophysiol. 9, 28–36 (2018).

    PubMed  PubMed Central  Google Scholar 

  47. Huang, W. A., Dunipace, E. A., Sorg, J. M. & Vaseghi, M. Liver disease as a predictor of new-onset atrial fibrillation. J. Am. Heart Assoc. 7, e008703 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Adejumo, A. C. et al. Predictors, burden and impact of cardiac arrhythmias among patients hospitalized with end-stage liver disease. Heart Lung 49, 73–79 (2020).

    PubMed  Google Scholar 

  49. Chokesuwattanaskul, R. et al. Liver transplantation and atrial fibrillation: a meta-analysis. World J. Hepatol. 10, 761–771 (2018).

    PubMed  PubMed Central  Google Scholar 

  50. Berzigotti, A., Seijo, S., Reverter, E. & Bosch, J. Assessing portal hypertension in liver diseases. Expert Rev. Gastroenterol. Hepatol. 7, 141–155 (2013).

    CAS  PubMed  Google Scholar 

  51. Bosch, J., Groszmann, R. J. & Shah, V. H. Evolution in the understanding of the pathophysiological basis of portal hypertension: how changes in paradigm are leading to successful new treatments. J. Hepatol. 62, S121–S130 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Groszmann, R. J. et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N. Engl. J. Med. 353, 2254–2261 (2005).

    CAS  PubMed  Google Scholar 

  53. Ripoll, C. et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133, 481–488 (2007).

    CAS  PubMed  Google Scholar 

  54. Ripoll, C. et al. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J. Hepatol. 50, 923–928 (2009).

    PubMed  PubMed Central  Google Scholar 

  55. Moitinho, E. et al. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology 117, 626–631 (1999).

    CAS  PubMed  Google Scholar 

  56. D’Amico, G., Garcia-Pagan, J. C., Luca, A. & Bosch, J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 131, 1611–1624 (2006).

    PubMed  Google Scholar 

  57. Moller, S. & Bendtsen, F. The pathophysiology of arterial vasodilatation and hyperdynamic circulation in cirrhosis. Liver Int. 38, 570–580 (2018).

    PubMed  Google Scholar 

  58. Bolognesi, M., Di Pascoli, M., Verardo, A. & Gatta, A. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J. Gastroenterol. 20, 2555–2563 (2014).

    PubMed  PubMed Central  Google Scholar 

  59. Moller, S., Kimer, N., Barlose, M. & Bendtsen, F. Pathophysiological-based treatments of complications of cirrhosis. Scand. J. Gastroenterol. 55, 383–394 (2020).

    PubMed  Google Scholar 

  60. Schrier, R. W. Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am. J. Med. 119, S47–S53 (2006).

    CAS  PubMed  Google Scholar 

  61. Moller, S., Henriksen, J. H. & Bendtsen, F. Ascites: pathogenesis and therapeutic principles. Scand. J. Gastroenterol. 44, 902–911 (2009).

    PubMed  Google Scholar 

  62. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J. Hepatol. 53, 397–417 (2010).

    Google Scholar 

  63. Gines, P. et al. Hepatorenal syndrome. Nat. Rev. Dis. Primers 4, 23 (2018).

    PubMed  Google Scholar 

  64. Angeli, P., Garcia-Tsao, G., Nadim, M. K. & Parikh, C. R. News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document. J. Hepatol. 71, 811–822 (2019).

    PubMed  Google Scholar 

  65. Velez, J. C. Q., Therapondos, G. & Juncos, L. A. Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat. Rev. Nephrol. 16, 137–155 (2020).

    CAS  PubMed  Google Scholar 

  66. Sole, C., Pose, E., Sola, E. & Gines, P. Hepatorenal syndrome in the era of acute kidney injury. Liver Int. 38, 1891–1901 (2018).

    CAS  PubMed  Google Scholar 

  67. Puthumana, J. et al. Urine interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis in patients with cirrhosis: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 15, 1003–1013.e3 (2017).

    CAS  PubMed  Google Scholar 

  68. Best, L. M. et al. Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst. Rev. 9, CD013103 (2019).

    PubMed  Google Scholar 

  69. Mandorfer, M. et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 146, 1680–1690.e1 (2014).

    CAS  PubMed  Google Scholar 

  70. Krowka, M. J. et al. International Liver Transplant Society practice guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation 100, 1440–1452 (2016).

    PubMed  Google Scholar 

  71. Cartin-Ceba, R. & Krowka, M. J. Pulmonary complications of portal hypertension. Clin. Liver Dis. 23, 683–711 (2019).

    PubMed  Google Scholar 

  72. Koch, D. G. & Fallon, M. B. Hepatopulmonary syndrome. Clin. Liver Dis. 18, 407–420 (2014).

    PubMed  Google Scholar 

  73. Iqbal, S., Smith, K. A. & Khungar, V. Hepatopulmonary syndrome and portopulmonary hypertension: implications for liver transplantation. Clin. Chest Med. 38, 785–795 (2017).

    PubMed  Google Scholar 

  74. Savale, L., Watherald, J. & Sitbon, O. Portopulmonary hypertension. Semin. Respir. Crit. Care Med. 38, 651–661 (2017).

    PubMed  Google Scholar 

  75. Sitbon, O. et al. Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respir. Med. 7, 594–604 (2019).

    CAS  PubMed  Google Scholar 

  76. Swanson, K. L., Wiesner, R. H., Nyberg, S. L., Rosen, C. B. & Krowka, M. J. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am. J. Transpl. 8, 2445–2453 (2008).

    CAS  Google Scholar 

  77. Krowka, M. J., Swanson, K. L., Frantz, R. P., McGoon, M. D. & Wiesner, R. H. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 44, 1502–1510 (2006).

    PubMed  Google Scholar 

  78. AbuHalimeh, B., Krowka, M. J. & Tonelli, A. R. Treatment barriers in portopulmonary hypertension. Hepatology 69, 431–443 (2019).

    PubMed  Google Scholar 

  79. Jayakumar, A. R., Rama Rao, K. V. & Norenberg, M. D. Neuroinflammation in hepatic encephalopathy: mechanistic aspects. J. Clin. Exp. Hepatol. 5, S21–S28 (2015).

    PubMed  Google Scholar 

  80. Bajaj, J. S. Hepatic encephalopathy: classification and treatment. J. Hepatol. 68, 838–839 (2018).

    PubMed  Google Scholar 

  81. Cordoba, J. et al. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF). J. Hepatol. 60, 275–281 (2014).

    PubMed  Google Scholar 

  82. Bjerring, P. N., Gluud, L. L. & Larsen, F. S. Cerebral blood flow and metabolism in hepatic encephalopathy–a meta-analysis. J. Clin. Exp. Hepatol. 8, 286–293 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. Bajaj, J. S. et al. Minimal hepatic encephalopathy and mild cognitive impairment worsen quality of life in elderly patients with cirrhosis. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2020.03.033 (2020).

  84. Nardelli, S. et al. Muscle alterations are associated with minimal and overt hepatic encephalopathy in patients with liver cirrhosis. Hepatology 70, 1704–1713 (2019).

    PubMed  Google Scholar 

  85. Hanai, T. et al. Sarcopenia predicts minimal hepatic encephalopathy in patients with liver cirrhosis. Hepatol. Res. 47, 1359–1367 (2017).

    CAS  PubMed  Google Scholar 

  86. Vilstrup, H. et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 60, 715–735 (2014).

    PubMed  Google Scholar 

  87. Dirchwolf, M. & Ruf, A. E. Role of systemic inflammation in cirrhosis: from pathogenesis to prognosis. World J. Hepatol. 7, 1974–1981 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. Seo, Y. S. & Shah, V. H. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin. Mol. Hepatol. 18, 337–346 (2012).

    PubMed  PubMed Central  Google Scholar 

  89. Chia, S. et al. Intra-arterial tumor necrosis factor-α impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans. Arterioscler. Thromb. Vasc. Biol. 23, 695–701 (2003).

    CAS  PubMed  Google Scholar 

  90. Rajesh, M. et al. CB2-receptor stimulation attenuates TNF-α-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am. J. Physiol. Heart Circ. Physiol. 293, H2210–H2218 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Balasubramaniyan, V. et al. Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G145–G152 (2012).

    CAS  PubMed  Google Scholar 

  92. Maciejewski, J. P. et al. Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J. Clin. Invest. 96, 1085–1092 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Bulotta, S., Barsacchi, R., Rotiroti, D., Borgese, N. & Clementi, E. Activation of the endothelial nitric-oxide synthase by tumor necrosis factor-α. A novel feedback mechanism regulating cell death. J. Biol. Chem. 276, 6529–6536 (2001).

    CAS  PubMed  Google Scholar 

  94. McClain, C. J., Barve, S., Deaciuc, I., Kugelmas, M. & Hill, D. Cytokines in alcoholic liver disease. Semin. Liver Dis. 19, 205–219 (1999).

    CAS  PubMed  Google Scholar 

  95. Bird, G. L., Sheron, N., Goka, A. K., Alexander, G. J. & Williams, R. S. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann. Intern. Med. 112, 917–920 (1990).

    CAS  PubMed  Google Scholar 

  96. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nawaz, R. et al. HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN- ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflamm. Res. 66, 477–486 (2017).

    CAS  PubMed  Google Scholar 

  98. Thenappan, T. et al. A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am. J. Respir. Crit. Care Med. 183, 1080–1091 (2011).

    PubMed  Google Scholar 

  99. Zhang, J. et al. The role of CX(3)CL1/CX(3)CR1 in pulmonary angiogenesis and intravascular monocyte accumulation in rat experimental hepatopulmonary syndrome. J. Hepatol. 57, 752–758 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Sztrymf, B. et al. Cirrhotic rats with bacterial translocation have higher incidence and severity of hepatopulmonary syndrome. J. Gastroenterol. Hepatol. 20, 1538–1544 (2005).

    CAS  PubMed  Google Scholar 

  101. Varga, Z. V. et al. Disruption of renal arginine metabolism promotes kidney injury in hepatorenal syndrome in mice. Hepatology 68, 1519–1533 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Shah, N. et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. J. Hepatol. 56, 1047–1053 (2012).

    CAS  PubMed  Google Scholar 

  103. Karagiannakis, D. S., Vlachogiannakos, J., Anastasiadis, G., Vafiadis-Zouboulis, I. & Ladas, S. D. Frequency and severity of cirrhotic cardiomyopathy and its possible relationship with bacterial endotoxemia. Dig. Dis. Sci. 58, 3029–3036 (2013).

    CAS  PubMed  Google Scholar 

  104. Liu, H., Ma, Z. & Lee, S. S. Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Gastroenterology 118, 937–944 (2000).

    CAS  PubMed  Google Scholar 

  105. Yang, Y. Y., Liu, H., Nam, S. W., Kunos, G. & Lee, S. S. Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: interaction between TNFα and endocannabinoids. J. Hepatol. 53, 298–306 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Gaskari, S. A., Liu, H., D’Mello, C., Kunos, G. & Lee, S. S. Blunted cardiac response to hemorrhage in cirrhotic rats is mediated by local macrophage-released endocannabinoids. J. Hepatol. 62, 1272–1277 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Padillo, F. J. et al. Anti-TNF-α treatment and bile duct drainage restore cellular immunity and prevent tissue injury in experimental obstructive jaundice. Int. J. Immunopathol. Pharmacol. 20, 855–860 (2007).

    CAS  PubMed  Google Scholar 

  108. Sheen, J. M. et al. Combined intraperitoneal and intrathecal etanercept reduce increased brain tumor necrosis factor-alpha and asymmetric dimethylarginine levels and rescues spatial deficits in young rats after bile duct ligation. Front. Cell Neurosci. 10, 167 (2016).

    PubMed  PubMed Central  Google Scholar 

  109. Shah, N. et al. Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis. Liver Int. 33, 398–409 (2013).

    CAS  PubMed  Google Scholar 

  110. Yi, H. et al. The association of lipopolysaccharide and inflammatory factors with hepatopulmonary syndrome and their changes after orthotopic liver transplantation. J. Thorac. Dis. 6, 1469–1475 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. Rodrigo, R. et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139, 675–684 (2010).

    CAS  PubMed  Google Scholar 

  112. Ochoa-Sanchez, R. & Rose, C. F. Pathogenesis of hepatic encephalopathy in chronic liver disease. J. Clin. Exp. Hepatol. 8, 262–271 (2018).

    PubMed  PubMed Central  Google Scholar 

  113. Rai, R. et al. Reversal of low-grade cerebral edema after lactulose/rifaximin therapy in patients with cirrhosis and minimal hepatic encephalopathy. Clin. Transl. Gastroenterol. 6, e111 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Jain, L. et al. Serum endotoxin, inflammatory mediators, and magnetic resonance spectroscopy before and after treatment in patients with minimal hepatic encephalopathy. J. Gastroenterol. Hepatol. 28, 1187–1193 (2013).

    CAS  PubMed  Google Scholar 

  115. Fallon, M. B., Abrams, G. A., McGrath, J. W., Hou, Z. & Luo, B. Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome. Am. J. Physiol. 272, G779–G784 (1997).

    CAS  PubMed  Google Scholar 

  116. Raevens, S. & Fallon, M. B. Potential clinical targets in hepatopulmonary syndrome: lessons from experimental models. Hepatology 68, 2016–2028 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. Oberti, F. et al. Prevention of portal hypertension by propranolol and spironolactone in rats with bile duct ligation. J. Hepatol. 26, 167–173 (1997).

    CAS  PubMed  Google Scholar 

  118. Pacher, P., Beckman, J. S. & Liaudet, L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315–424 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Gracia-Sancho, J. et al. Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 47, 1248–1256 (2008).

    CAS  PubMed  Google Scholar 

  120. Vasquez-Vivar, J., Whitsett, J., Martasek, P., Hogg, N. & Kalyanaraman, B. Reaction of tetrahydrobiopterin with superoxide: EPR-kinetic analysis and characterization of the pteridine radical. Free Radic. Biol. Med. 31, 975–985 (2001).

    CAS  PubMed  Google Scholar 

  121. Ungvari, Z. et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat. Rev. Cardiol. 15, 555–565 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Szabo, C., Ischiropoulos, H. & Radi, R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat. Rev. Drug Discov. 6, 662–680 (2007).

    CAS  PubMed  Google Scholar 

  123. Matei, V. et al. The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis. Hepatology 44, 44–52 (2006).

    CAS  PubMed  Google Scholar 

  124. Morales-Ruiz, M. et al. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology 125, 522–531 (2003).

    CAS  PubMed  Google Scholar 

  125. Shah, V. et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 117, 1222–1228 (1999).

    CAS  PubMed  Google Scholar 

  126. Hernandez-Guerra, M. et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology 43, 485–491 (2006).

    CAS  PubMed  Google Scholar 

  127. Nickovic, V. P. et al. Oxidative stress, NOx/l-arginine ratio and glutathione/glutathione S-transferase ratio as predictors of ‘sterile inflammation’ in patients with alcoholic cirrhosis and hepatorenal syndrome type II. Ren. Fail. 40, 340–349 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Terao, M. et al. Serum oxidative/anti-oxidative stress balance is dysregulated in potentially pulmonary hypertensive patients with liver cirrhosis: a case control study. Intern. Med. 54, 2815–2826 (2015).

    CAS  PubMed  Google Scholar 

  129. Vercelino, R. et al. N-acetylcysteine effects on genotoxic and oxidative stress parameters in cirrhotic rats with hepatopulmonary syndrome. Basic Clin. Pharmacol. Toxicol. 102, 370–376 (2008).

    CAS  PubMed  Google Scholar 

  130. Tieppo, J. et al. Quercetin administration ameliorates pulmonary complications of cirrhosis in rats. J. Nutr. 139, 1339–1346 (2009).

    CAS  PubMed  Google Scholar 

  131. Montoliu, C. et al. 3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis. Am. J. Gastroenterol. 106, 1629–1637 (2011).

    CAS  PubMed  Google Scholar 

  132. Gorg, B. et al. Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy. Hepatology 52, 256–265 (2010).

    PubMed  PubMed Central  Google Scholar 

  133. Vallance, P. & Moncada, S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 337, 776–778 (1991).

    CAS  PubMed  Google Scholar 

  134. Cahill, P. A., Redmond, E. M., Hodges, R., Zhang, S. & Sitzmann, J. V. Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats. J. Hepatol. 25, 370–378 (1996).

    CAS  PubMed  Google Scholar 

  135. Battista, S. et al. Hyperdynamic circulation in patients with cirrhosis: direct measurement of nitric oxide levels in hepatic and portal veins. J. Hepatol. 26, 75–80 (1997).

    CAS  PubMed  Google Scholar 

  136. Bolognesi, M. et al. Haeme oxygenase mediates hyporeactivity to phenylephrine in the mesenteric vessels of cirrhotic rats with ascites. Gut 54, 1630–1636 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Morales-Ruiz, M. et al. Increased nitric oxide synthase expression in arterial vessels of cirrhotic rats with ascites. Hepatology 24, 1481–1486 (1996).

    CAS  PubMed  Google Scholar 

  138. Angeli, P. et al. The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites. Liver Int. 25, 429–437 (2005).

    CAS  PubMed  Google Scholar 

  139. Chen, Y. C. et al. Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats. Hepatology 39, 1075–1087 (2004).

    CAS  PubMed  Google Scholar 

  140. Mookerjee, R. P. et al. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology 45, 62–71 (2007).

    CAS  PubMed  Google Scholar 

  141. Kasumov, T. et al. Plasma levels of asymmetric dimethylarginine in patients with biopsy-proven nonalcoholic fatty liver disease. Metabolism 60, 776–781 (2011).

    CAS  PubMed  Google Scholar 

  142. Vizzutti, F. et al. ADMA correlates with portal pressure in patients with compensated cirrhosis. Eur. J. Clin. Invest. 37, 509–515 (2007).

    CAS  PubMed  Google Scholar 

  143. Fiorucci, S. et al. The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. Hepatology 42, 539–548 (2005).

    CAS  PubMed  Google Scholar 

  144. Norris, E. J., Larion, S., Culberson, C. R. & Clemens, M. G. Hydrogen sulfide differentially affects the hepatic vasculature in response to phenylephrine and endothelin 1 during endotoxemia. Shock 39, 168–175 (2013).

    CAS  PubMed  Google Scholar 

  145. Fiorucci, S., Zampella, A., Cirino, G., Bucci, M. & Distrutti, E. Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators. Am. J. Physiol. Heart Circ. Physiol. 312, H21–H32 (2017).

    PubMed  Google Scholar 

  146. Vairappan, B. Endothelial dysfunction in cirrhosis: role of inflammation and oxidative stress. World J. Hepatol. 7, 443–459 (2015).

    PubMed  PubMed Central  Google Scholar 

  147. Xie, G. et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142, 918–927.e6 (2012).

    Google Scholar 

  148. Iwakiri, Y., Shah, V. & Rockey, D. C. Vascular pathobiology in chronic liver disease and cirrhosis – current status and future directions. J. Hepatol. 61, 912–924 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Poisson, J. et al. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J. Hepatol. 66, 212–227 (2017).

    CAS  PubMed  Google Scholar 

  150. Horn, T., Christoffersen, P. & Henriksen, J. H. Alcoholic liver injury: defenestration in noncirrhotic livers–a scanning electron microscopic study. Hepatology 7, 77–82 (1987).

    CAS  PubMed  Google Scholar 

  151. DeLeve, L. D., Wang, X., Kanel, G. C., Atkinson, R. D. & McCuskey, R. S. Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis. Am. J. Pathol. 173, 993–1001 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Deleve, L. D., Wang, X. & Guo, Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48, 920–930 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Marrone, G., Shah, V. H. & Gracia-Sancho, J. Sinusoidal communication in liver fibrosis and regeneration. J. Hepatol. 65, 608–617 (2016).

    PubMed  PubMed Central  Google Scholar 

  154. Fernandez-Iglesias, A. & Gracia-Sancho, J. How to face chronic liver disease: the sinusoidal perspective. Front. Med. 4, 7 (2017).

    Google Scholar 

  155. Yokomori, H. et al. Vascular endothelial growth factor increases fenestral permeability in hepatic sinusoidal endothelial cells. Liver Int. 23, 467–475 (2003).

    CAS  PubMed  Google Scholar 

  156. Funyu, J., Mochida, S., Inao, M., Matsui, A. & Fujiwara, K. VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells. Biochem. Biophys. Res. Commun. 280, 481–485 (2001).

    CAS  PubMed  Google Scholar 

  157. May, D. et al. A transgenic model for conditional induction and rescue of portal hypertension reveals a role of VEGF-mediated regulation of sinusoidal fenestrations. PLoS ONE 6, e21478 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Pacher, P., Batkai, S. & Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58, 389–462 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Batkai, S. et al. Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Am. J. Physiol. Heart Circ. Physiol. 293, H1689–H1695 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Hegde, V. L. et al. Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells. Mol. Pharmacol. 74, 20–33 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Osei-Hyiaman, D. et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 115, 1298–1305 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Mendez-Sanchez, N. et al. Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease. Liver Int. 27, 215–219 (2007).

    CAS  PubMed  Google Scholar 

  163. Varga, Z. V. et al. β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. Br. J. Pharmacol. 175, 320–334 (2018).

    CAS  PubMed  Google Scholar 

  164. Rajesh, M. et al. Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis. J. Leukoc. Biol. 82, 1382–1389 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Batkai, S. et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 21, 1788–1800 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Habib, A. et al. Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver. Gut 68, 522–532 (2019).

    CAS  PubMed  Google Scholar 

  167. Teixeira-Clerc, F. et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat. Med. 12, 671–676 (2006).

    CAS  PubMed  Google Scholar 

  168. Munoz-Luque, J. et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J. Pharmacol. Exp. Ther. 324, 475–483 (2008).

    CAS  PubMed  Google Scholar 

  169. Julien, B. et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 128, 742–755 (2005).

    CAS  PubMed  Google Scholar 

  170. Maccarrone, M. et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36, 277–296 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Pacher, P., Steffens, S., Hasko, G., Schindler, T. H. & Kunos, G. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat. Rev. Cardiol. 15, 151–166 (2018).

    CAS  PubMed  Google Scholar 

  172. Pacher, P. & Mechoulam, R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog. Lipid Res. 50, 193–211 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Batkai, S. et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat. Med. 7, 827–832 (2001).

    CAS  PubMed  Google Scholar 

  174. Moezi, L. et al. Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors. Br. J. Pharmacol. 149, 898–908 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Simoes, E. S. A. C., Miranda, A. S., Rocha, N. P. & Teixeira, A. L. Renin angiotensin system in liver diseases: friend or foe? World J. Gastroenterol. 23, 3396–3406 (2017).

    Google Scholar 

  176. Herath, C. B. et al. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis. J. Hepatol. 47, 387–395 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Vilas-Boas, W. W. et al. Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis. World J. Gastroenterol. 15, 2512–2519 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Grace, J. A., Herath, C. B., Mak, K. Y., Burrell, L. M. & Angus, P. W. Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. Clin. Sci. 123, 225–239 (2012).

    CAS  Google Scholar 

  179. Rockey, D. C. & Weisiger, R. A. Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology 24, 233–240 (1996).

    CAS  PubMed  Google Scholar 

  180. Schneider, A. W., Kalk, J. F. & Klein, C. P. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology 29, 334–339 (1999).

    CAS  PubMed  Google Scholar 

  181. Bataller, R. et al. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology 125, 117–125 (2003).

    CAS  PubMed  Google Scholar 

  182. Paizis, G. et al. Up-regulation of components of the renin-angiotensin system in the bile duct-ligated rat liver. Gastroenterology 123, 1667–1676 (2002).

    CAS  PubMed  Google Scholar 

  183. Yoshiji, H. et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 34, 745–750 (2001).

    CAS  PubMed  Google Scholar 

  184. Ruiz-del-Arbol, L. et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 42, 439–447 (2005).

    CAS  PubMed  Google Scholar 

  185. Pereira, R. M. et al. The renin-angiotensin system in a rat model of hepatic fibrosis: evidence for a protective role of angiotensin-(1-7). J. Hepatol. 46, 674–681 (2007).

    CAS  PubMed  Google Scholar 

  186. Bansal, S., Lindenfeld, J. & Schrier, R. W. Sodium retention in heart failure and cirrhosis: potential role of natriuretic doses of mineralocorticoid antagonist? Circ. Heart Fail. 2, 370–376 (2009).

    CAS  PubMed  Google Scholar 

  187. Hartupee, J. & Mann, D. L. Neurohormonal activation in heart failure with reduced ejection fraction. Nat. Rev. Cardiol. 14, 30–38 (2017).

    CAS  PubMed  Google Scholar 

  188. Chayanupatkul, M. & Liangpunsakul, S. Cirrhotic cardiomyopathy: review of pathophysiology and treatment. Hepatol. Int. 8, 308–315 (2014).

    PubMed  PubMed Central  Google Scholar 

  189. Moller, S., Henriksen, J. H. & Bendtsen, F. Pathogenetic background for treatment of ascites and hepatorenal syndrome. Hepatol. Int. 2, 416–428 (2008).

    PubMed  PubMed Central  Google Scholar 

  190. Zablocki, D. & Sadoshima, J. Angiotensin II and oxidative stress in the failing heart. Antioxid. Redox Signal. 19, 1095–1109 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Yanagisawa, M. et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411–415 (1988).

    CAS  PubMed  Google Scholar 

  192. Moller, S., Emmeluth, C. & Henriksen, J. H. Elevated circulating plasma endothelin-1 concentrations in cirrhosis. J. Hepatol. 19, 285–290 (1993).

    CAS  PubMed  Google Scholar 

  193. Pinzani, M. et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 110, 534–548 (1996).

    CAS  PubMed  Google Scholar 

  194. Moore, K. et al. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N. Engl. J. Med. 327, 1774–1778 (1992).

    CAS  PubMed  Google Scholar 

  195. Chuang, C. L. et al. Endotoxemia-enhanced renal vascular reactivity to endothelin-1 in cirrhotic rats. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G752–G761 (2018).

    CAS  PubMed  Google Scholar 

  196. Chuang, C. L. et al. Lipopolysaccharide enhanced renal vascular response to endothelin-1 through ETA overexpression in portal hypertensive rats. J. Gastroenterol. Hepatol. 30, 199–207 (2015).

    CAS  PubMed  Google Scholar 

  197. Fritz, J. S., Fallon, M. B. & Kawut, S. M. Pulmonary vascular complications of liver disease. Am. J. Respir. Crit. Care Med. 187, 133–143 (2013).

    PubMed  PubMed Central  Google Scholar 

  198. Correale, M. et al. Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand? Vasc. Health Risk Manag. 14, 253–264 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Du, Q. H. et al. Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats. World J. Gastroenterol. 19, 2065–2072 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Hathaway, C. K. et al. Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade. Proc. Natl Acad. Sci. USA 112, 5141–5146 (2015).

    CAS  PubMed  Google Scholar 

  201. Iglarz, M. & Clozel, M. Mechanisms of ET-1-induced endothelial dysfunction. J. Cardiovasc. Pharmacol. 50, 621–628 (2007).

    CAS  PubMed  Google Scholar 

  202. Zhan, S., Chan, C. C., Serdar, B. & Rockey, D. C. Fibronectin stimulates endothelin-1 synthesis in rat hepatic myofibroblasts via a Src/ERK-regulated signaling pathway. Gastroenterology 136, 2345–2355.e1-e4 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhan, S. & Rockey, D. C. Tumor necrosis factor α stimulates endothelin-1 synthesis in rat hepatic stellate cells in hepatic wound healing through a novel IKK/JNK pathway. Exp. Cell Res. 317, 1040–1048 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Liu, C. Q. et al. Thromboxane prostanoid receptor activation impairs endothelial nitric oxide-dependent vasorelaxations: the role of rho kinase. Biochem. Pharmacol. 78, 374–381 (2009).

    CAS  PubMed  Google Scholar 

  205. Rosado, E. et al. Interaction between NO and COX pathways modulating hepatic endothelial cells from control and cirrhotic rats. J. Cell Mol. Med. 16, 2461–2470 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Graupera, M. et al. Sinusoidal endothelial COX-1-derived prostanoids modulate the hepatic vascular tone of cirrhotic rat livers. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G763–G770 (2005).

    CAS  PubMed  Google Scholar 

  207. Iwakiri, Y. & Groszmann, R. J. Vascular endothelial dysfunction in cirrhosis. J. Hepatol. 46, 927–934 (2007).

    CAS  PubMed  Google Scholar 

  208. Graupera, M. et al. Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers. Hepatology 37, 172–181 (2003).

    CAS  PubMed  Google Scholar 

  209. Laffi, G., La Villa, G., Pinzani, M., Marra, F. & Gentilini, P. Arachidonic acid derivatives and renal function in liver cirrhosis. Semin. Nephrol. 17, 530–548 (1997).

    CAS  PubMed  Google Scholar 

  210. Rimola, A. et al. Urinary excretion of 6-keto-prostaglandin F1α, thromboxane B2 and prostaglandin E2 in cirrhosis with ascites. Relationship to functional renal failure (hepatorenal syndrome). J. Hepatol. 3, 111–117 (1986).

    CAS  PubMed  Google Scholar 

  211. Hou, M. C. et al. Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: role in the hyperdynamic circulation. Hepatology 27, 20–27 (1998).

    CAS  PubMed  Google Scholar 

  212. Nascimento, M. et al. Hepatic injury induced by thioacetamide causes aortic endothelial dysfunction by a cyclooxygenase-dependent mechanism. Life Sci. 212, 168–175 (2018).

    CAS  PubMed  Google Scholar 

  213. Lacout, A. et al. Roles of cyclooxygenase 2 and hepatic venous flow in patients with HHT or hepatopulmonary syndrome. Med. Hypotheses 83, 302–305 (2014).

    CAS  PubMed  Google Scholar 

  214. Tang, X. et al. Cyclooxygenase-2 regulates HPS patient serum induced-directional collective HPMVEC migration via PKC/Rac signaling pathway. Gene 692, 176–184 (2019).

    CAS  PubMed  Google Scholar 

  215. Chang, C. C. et al. Selective cyclooxygenase inhibition by SC-560 improves hepatopulmonary syndrome in cirrhotic rats. PLoS ONE 12, e0179809 (2017).

    PubMed  PubMed Central  Google Scholar 

  216. Awdish, R. L. & Cajigas, H. R. Early initiation of prostacyclin in portopulmonary hypertension: 10 years of a transplant center’s experience. Lung 191, 593–600 (2013).

    CAS  PubMed  Google Scholar 

  217. Oliver, M. I. et al. Autonomic dysfunction in patients with non-alcoholic chronic liver disease. J. Hepatol. 26, 1242–1248 (1997).

    CAS  PubMed  Google Scholar 

  218. Perez-Pena, J. et al. Autonomic neuropathy in end-stage cirrhotic patients and evolution after liver transplantation. Transpl. Proc. 35, 1834–1835 (2003).

    CAS  Google Scholar 

  219. Milovanovic, B. et al. Autonomic dysfunction in alcoholic cirrhosis and its relation to sudden cardiac death risk predictors. Gen. Physiol. Biophys. 28, 251–261 (2009).

    PubMed  Google Scholar 

  220. Yokoyama, A. et al. Prolonged QT interval in alcoholic autonomic nervous dysfunction. Alcohol. Clin. Exp. Res. 16, 1090–1092 (1992).

    CAS  PubMed  Google Scholar 

  221. Henriksen, J. H., Moller, S., Ring-Larsen, H. & Christensen, N. J. The sympathetic nervous system in liver disease. J. Hepatol. 29, 328–341 (1998).

    CAS  PubMed  Google Scholar 

  222. Iga, A., Nomura, M., Sawada, Y., Ito, S. & Nakaya, Y. Autonomic nervous dysfunction in patients with liver cirrhosis using 123I-metaiodobenzylguanidine myocardial scintigraphy and spectrum analysis of heart-rate variability. J. Gastroenterol. Hepatol. 18, 651–659 (2003).

    PubMed  Google Scholar 

  223. Dillon, J. F. et al. The correction of autonomic dysfunction in cirrhosis by captopril. J. Hepatol. 26, 331–335 (1997).

    CAS  PubMed  Google Scholar 

  224. Hendrickse, M. T. & Triger, D. R. Vagal dysfunction and impaired urinary sodium and water excretion in cirrhosis. Am. J. Gastroenterol. 89, 750–757 (1994).

    CAS  PubMed  Google Scholar 

  225. Moller, S. & Henriksen, J. H. Review article: pathogenesis and pathophysiology of hepatorenal syndrome–is there scope for prevention? Aliment. Pharmacol. Ther. 20, 31–41 (2004).

    CAS  PubMed  Google Scholar 

  226. Gerbes, A. L., Remien, J., Jungst, D., Sauerbruch, T. & Paumgartner, G. Evidence for down-regulation of beta-2-adrenoceptors in cirrhotic patients with severe ascites. Lancet 1, 1409–1411 (1986).

    CAS  PubMed  Google Scholar 

  227. Lee, S. S. et al. Desensitization of myocardial β-adrenergic receptors in cirrhotic rats. Hepatology 12, 481–485 (1990).

    CAS  PubMed  Google Scholar 

  228. Ceolotto, G. et al. An abnormal gene expression of the β-adrenergic system contributes to the pathogenesis of cardiomyopathy in cirrhotic rats. Hepatology 48, 1913–1923 (2008).

    CAS  PubMed  Google Scholar 

  229. Di Stefano, C., Milazzo, V., Milan, A., Veglio, F. & Maule, S. The role of autonomic dysfunction in cirrhotic patients before and after liver transplantation. Review of the literature. Liver Int. 36, 1081–1089 (2016).

    PubMed  Google Scholar 

  230. Jaue, D. N., Ma, Z. & Lee, S. S. Cardiac muscarinic receptor function in rats with cirrhotic cardiomyopathy. Hepatology 25, 1361–1365 (1997).

    CAS  PubMed  Google Scholar 

  231. Moller, S. & Henriksen, J. H. Cirrhotic cardiomyopathy. J. Hepatol. 53, 179–190 (2010).

    PubMed  Google Scholar 

  232. Alvarado Tapias, E. et al. Short-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis. J. Hepatol. https://doi.org/10.1016/j.jhep.2020.03.048 (2020).

    Article  PubMed  Google Scholar 

  233. Provencher, S. et al. Deleterious effects of β-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 130, 120–126 (2006).

    CAS  PubMed  Google Scholar 

  234. Brito-Azevedo, A. et al. Propranolol improves endothelial dysfunction in advanced cirrhosis: the ‘endothelial exhaustion’ hypothesis. Gut 65, 1391–1392 (2016).

    PubMed  Google Scholar 

  235. Leithead, J. A. et al. Non-selective β-blockers are associated with improved survival in patients with ascites listed for liver transplantation. Gut 64, 1111–1119 (2015).

    CAS  PubMed  Google Scholar 

  236. Morsiani, C. et al. The peculiar aging of human liver: a geroscience perspective within transplant context. Ageing Res. Rev. 51, 24–34 (2019).

    CAS  PubMed  Google Scholar 

  237. Yusuf, S., Reddy, S., Ounpuu, S. & Anand, S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 104, 2746–2753 (2001).

    CAS  PubMed  Google Scholar 

  238. Papatheodoridi, A. M., Chrysavgis, L., Koutsilieris, M. & Chatzigeorgiou, A. The role of senescence in the development of nonalcoholic fatty liver disease and progression to nonalcoholic steatohepatitis. Hepatology 71, 363–374 (2020).

    CAS  PubMed  Google Scholar 

  239. Ramirez, T. et al. Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. J. Hepatol. 66, 601–609 (2017).

    CAS  PubMed  Google Scholar 

  240. Sheedfar, F., Di Biase, S., Koonen, D. & Vinciguerra, M. Liver diseases and aging: friends or foes? Aging Cell 12, 950–954 (2013).

    CAS  PubMed  Google Scholar 

  241. Lenti, M. V. et al. Mortality rate and risk factors for gastrointestinal bleeding in elderly patients. Eur. J. Intern. Med. 61, 54–61 (2019).

    PubMed  Google Scholar 

  242. Heidemann, J., Bartels, C., Berssenbrugge, C., Schmidt, H. & Meister, T. Hepatorenal syndrome: outcome of response to therapy and predictors of survival. Gastroenterol. Res. Pract. 2015, 457613 (2015).

    PubMed  PubMed Central  Google Scholar 

  243. Raevens, S. et al. Prevalence and outcome of diastolic dysfunction in liver transplantation recipients. Acta Cardiol. 69, 273–280 (2014).

    PubMed  Google Scholar 

  244. Wolff, J. L., Starfield, B. & Anderson, G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch. Intern. Med. 162, 2269–2276 (2002).

    PubMed  Google Scholar 

  245. Anstee, Q. M., Mantovani, A., Tilg, H. & Targher, G. Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 15, 425–439 (2018).

    PubMed  Google Scholar 

  246. Mantovani, A. et al. Nonalcoholic fatty liver disease is associated with ventricular arrhythmias in patients with type 2 diabetes referred for clinically indicated 24-hour Holter monitoring. Diabetes Care 39, 1416–1423 (2016).

    CAS  PubMed  Google Scholar 

  247. Ling, L. H., Kistler, P. M., Kalman, J. M., Schilling, R. J. & Hunter, R. J. Comorbidity of atrial fibrillation and heart failure. Nat. Rev. Cardiol. 13, 131–147 (2016).

    CAS  PubMed  Google Scholar 

  248. Watt, K. D., Pedersen, R. A., Kremers, W. K., Heimbach, J. K. & Charlton, M. R. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am. J. Transpl. 10, 1420–1427 (2010).

    CAS  Google Scholar 

  249. Ruggieri, A., Gagliardi, M. C. & Anticoli, S. Sex-dependent outcome of hepatitis B and C viruses infections: synergy of sex hormones and immune responses? Front. Immunol. 9, 2302 (2018).

    PubMed  PubMed Central  Google Scholar 

  250. Zhang, B. & Wu, Z. Y. Estrogen derivatives: novel therapeutic agents for liver cirrhosis and portal hypertension. Eur. J. Gastroenterol. Hepatol. 25, 263–270 (2013).

    PubMed  Google Scholar 

  251. Shimizu, I. Impact of oestrogens on the progression of liver disease. Liver Int. 23, 63–69 (2003).

    CAS  PubMed  Google Scholar 

  252. Lu, G. et al. Antioxidant and antiapoptotic activities of idoxifene and estradiol in hepatic fibrosis in rats. Life Sci. 74, 897–907 (2004).

    CAS  PubMed  Google Scholar 

  253. Lu, P. et al. Gender differences in hepatic ischemic reperfusion injury in rats are associated with endothelial cell nitric oxide synthase-derived nitric oxide. World J. Gastroenterol. 11, 3441–3445 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Sakamoto, M. et al. Estrogen upregulates nitric oxide synthase expression in cultured rat hepatic sinusoidal endothelial cells. J. Hepatol. 34, 858–864 (2001).

    CAS  PubMed  Google Scholar 

  255. Stanhewicz, A. E., Wenner, M. M. & Stachenfeld, N. S. Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan. Am. J. Physiol. Heart Circ. Physiol. 315, H1569–H1588 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Engelmann, C. et al. Loss of paraspinal muscle mass is a gender-specific consequence of cirrhosis that predicts complications and death. Aliment. Pharmacol. Ther. 48, 1271–1281 (2018).

    PubMed  Google Scholar 

  257. Kim, S. M. et al. QT prolongation is associated with increased mortality in end stage liver disease. World J. Cardiol. 9, 347–354 (2017).

    PubMed  PubMed Central  Google Scholar 

  258. Kawut, S. M. et al. Clinical risk factors for portopulmonary hypertension. Hepatology 48, 196–203 (2008).

    PubMed  PubMed Central  Google Scholar 

  259. Rao, R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50, 638–644 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Miele, L. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 1877–1887 (2009).

    CAS  PubMed  Google Scholar 

  261. Bigatello, L. M. et al. Endotoxemia, encephalopathy, and mortality in cirrhotic patients. Am. J. Gastroenterol. 82, 11–15 (1987).

    CAS  PubMed  Google Scholar 

  262. Lin, R. S. et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J. Hepatol. 22, 165–172 (1995).

    CAS  PubMed  Google Scholar 

  263. Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J. Hepatol. 56, 1283–1292 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Seki, E. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).

    CAS  PubMed  Google Scholar 

  265. Bernardi, M. et al. Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors. Hepatology 27, 28–34 (1998).

    CAS  PubMed  Google Scholar 

  266. Xiang, X. et al. Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming of impaired regeneration pathways in mice. J. Hepatol. 72, 736–745 (2020).

    CAS  PubMed  Google Scholar 

  267. Swanson, K. L., Wiesner, R. H. & Krowka, M. J. Natural history of hepatopulmonary syndrome: impact of liver transplantation. Hepatology 41, 1122–1129 (2005).

    PubMed  Google Scholar 

  268. Krowka, M. J., Wiseman, G. A., Steers, J. L. & Wiesner, R. H. Late recurrence and rapid evolution of severe hepatopulmonary syndrome after liver transplantation. Liver Transpl. Surg. 5, 451–453 (1999).

    CAS  PubMed  Google Scholar 

  269. Casey, S., Schelleman, A. & Angus, P. Recurrence of hepatopulmonary syndrome post-orthotopic liver transplantation in a patient with noncirrhotic portal hypertension. Hepatology 58, 2205–2206 (2013).

    PubMed  Google Scholar 

  270. Krowka, M. J. et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl. 6, 443–450 (2000).

    CAS  PubMed  Google Scholar 

  271. Izzy, M., Oh, J. & Watt, K. D. Cirrhotic cardiomyopathy after transplantation: neither the transient nor innocent bystander. Hepatology 68, 2008–2015 (2018).

    PubMed  Google Scholar 

  272. Mittal, C., Qureshi, W., Singla, S., Ahmad, U. & Huang, M. A. Pre-transplant left ventricular diastolic dysfunction is associated with post transplant acute graft rejection and graft failure. Dig. Dis. Sci. 59, 674–680 (2014).

    PubMed  Google Scholar 

  273. Bargehr, J. et al. Preexisting atrial fibrillation and cardiac complications after liver transplantation. Liver Transpl. 21, 314–320 (2015).

    PubMed  Google Scholar 

  274. Zardi, E. M. et al. Cirrhotic cardiomyopathy in the pre- and post-liver transplantation phase. J. Cardiol. 67, 125–130 (2016).

    PubMed  Google Scholar 

  275. Wong, F., Leung, W., Al Beshir, M., Marquez, M. & Renner, E. L. Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation. Liver Transpl. 21, 300–307 (2015).

    PubMed  Google Scholar 

  276. Carrier, P., Debette-Gratien, M., Jacques, J. & Loustaud-Ratti, V. Cirrhotic patients and older people. World J. Hepatol. 11, 663–677 (2019).

    PubMed  PubMed Central  Google Scholar 

  277. Sharpton, S. R., Feng, S., Hameed, B., Yao, F. & Lai, J. C. Combined effects of recipient age and model for end-stage liver disease score on liver transplantation outcomes. Transplantation 98, 557–562 (2014).

    PubMed  PubMed Central  Google Scholar 

  278. Wong, V. W., Adams, L. A., de Ledinghen, V., Wong, G. L. & Sookoian, S. Noninvasive biomarkers in NAFLD and NASH – current progress and future promise. Nat. Rev. Gastroenterol. Hepatol. 15, 461–478 (2018).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

P.P. receives support from the Intramural Research Program of NIAAA/NIH (1ZIAAA000375-13).

Author information

Authors and Affiliations

  1. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA

    Csaba Matyas, Eszter Trojnar & Pal Pacher

  2. Department of Anesthesiology, Columbia University, New York, NY, USA

    György Haskó

  3. Department of Intensive Care Medicine and Burn Center, University Hospital Medical Center, Faculty of Biology and Medicine, Lausanne, Switzerland

    Lucas Liaudet

Authors
  1. Csaba Matyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. György Haskó
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucas Liaudet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eszter Trojnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pal Pacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.M., L.L. and P.P. researched data for the article. All authors discussed the content of the manuscript. C.M., L.L., E.T. and P.P. wrote the article, and all authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Pal Pacher.

Ethics declarations

Competing interests

The authors declare no competing interests

Additional information

Peer review information

Nature Reviews Cardiology thanks F. Triposkiadis, M. Klapholz and M. Bernardi for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Nonalcoholic fatty liver disease

Excessive accumulation of fat in the liver that is not related to alcohol consumption.

Nonalcoholic steatohepatitis

A subtype of nonalcoholic fatty liver disease characterized by liver inflammation and liver cell damage.

Alcoholic liver disease

Liver damage caused by alcohol consumption.

Transjugular intrahepatic portosystemic shunt

An artificial passage connecting the portal and hepatic veins.

Acute-on-chronic liver failure

A syndrome affecting patients with chronic liver disease that is characterized by systemic inflammation, organ failure and poor prognosis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matyas, C., Haskó, G., Liaudet, L. et al. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nat Rev Cardiol 18, 117–135 (2021). https://doi.org/10.1038/s41569-020-0433-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-020-0433-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing