Hemodynamic alterations in cirrhosis and portal hypertension

Article information

Clin Mol Hepatol. 2010;16(4):347-352

Publication date (electronic) : 2010 December 31

doi : https://doi.org/10.3350/kjhep.2010.16.4.347

Moon Young Kim ¹, Soon Koo Baik ¹, Samuel S. Lee ²

¹Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

²Liver Unit, University of Calgary, Calgary, AB, Canada.

Corresponding author: Soon Koo Baik. Department of Internal Medicine, Yonsei University Wonju College of Medicine, 162 Ilsan-dong, Wonju 220-701, Korea. Tel. +82-33-741-1223, Fax. +82-33-745-6782, baiksk@medimail.co.kr

Received 2010 November 06; Revised 2010 November 21; Accepted 2010 November 25.

Abstract

Portal hypertension (PHT) is associated with hemodynamic changes in intrahepatic, systemic, and portosystemic collateral circulation. Increased intrahepatic resistance and hyperdynamic circulatory alterations with expansion of collateral circulation play a central role in the pathogenesis of PHT. PHT is also characterized by changes in vascular structure, termed vascular remodeling, which is an adaptive response of the vessel wall that occurs in response to chronic changes in the environment such as shear stress. Angiogenesis, the formation of new blood vessels, also occurs with PHT related in particular to the expansion of portosystemic collateral circulation. The complementary processes of vasoreactivity, vascular remodeling, and angiogenesis represent important targets for the treatment of portal hypertension. Systemic and splanchnic vasodilatation can induce hyperdynamic circulation which is related with multi-organ failure such as hepatorenal syndrome and cirrhotic cadiomyopathy.

Keywords: Portal hypertension; Hyperdynamic circulation; Hepatic stellate cell; Endothelial cell; Intrahepatic vascular resistance

INTRODUCTION

Cirrhosis has been considered to be silent and static. However, we have recently recognized that cirrhosis is actually a tumultuous and dynamic disease. Cirrhosis is the final result of hepatic fibrosis and is reversible in the middle stages of development between fibrogenesis and fibrolysis. This disease leads to hemodynamic disorders that can have widespread impacts in the body according to the severity of the cirrhosis. Hemodynamic alterations including portal hypertension and hyperdynamic circulation are the main cause of morbidity and mortality in patients with cirrhosis.1-3 The pathophysiologic process of portal hypertension consists of three components: intrahepatic circulation, systemic (splanchnic) circulation, and collateral circulation. Additionally, continuous abnormalities in systemic circulation induce hyperdynamic circulation.4,5

Portal pressure is due to intrahepatic resistance and portal blood flow, and is defined as a function of flow and resistance across the hepatic vasculature (pressure=flow×resistance). Development of portal hypertension can be influenced by changes in resistance and flow in the hepatic vasculature. Increased resistance of portal blood flow in cirrhotic liver induces portal venous dilatation and congestion of portal venous flow, leading to elevated portal pressure. Subsequently, portosystemic collaterals develop to counterbalance the increased resistance in portal blood flow, and induce an increase in venous return to heart which results in increased portal venous inflow. This hyperdynamic splanchnic circulation contributes to the maintaince and aggravation of portal hypertension.4 Increased intrahepatic resistance results from both vasoconstriction and fibrosis. Vasoconstriction is a reversible and dynamic condition which contributes up to 25% of increased resistance (Fig. 1).5-7

Figure 1

Hepatic stellate cell (HSC) activation. (A) In the quiescent state, HSCs do not contract. (B) In an activated state, the number and contractility of HSCs increase and induce changes in sinusoidal structure and intrahepatic resistance.

Vasoreactivity such as vasoconstriction in hepatic circulation and vasodilation in systemic circulation plays a major role in pathophysiology of portal hypertension.8 Recently, vascular structural changes including vascular remodeling and angiogenesis have been identified as additional important compensatory processes for maintaining and aggravating portal hypertension.9 Vascular remodeling is an adaptive response of the vessel wall that occurs in response to chronic changes in the environment such as shear stress.10 Angiogenesis promoted through both proliferation of endothelial and smooth muscle cells also occurs as response to increased pressure and flow. In this report, we review new concepts of pathophysiology and hemodynamic alterations associated with portal hypertension and cirrhosis.

Intrahepatic circulation

Vasoregulatory imbalances and increased intrahepatic resistance

Hepatic stellate cells (HSCs) play a central role in producing dynamic components of intrahepatic resistance by causing sinusoidal vasoconstriction through "contractile machinery" and relaxation in response to the interaction between sinusoidal endothelial cells (SECs) and HSCs; their paracrine effects are accomplished through endothelin-1 (ET-1) and nitric oxide (NO).11 Normally, ET-1 is secreted from SECs and acts on ET_A receptors on HSCs leading to HSC contraction. Conversely, NO released from SECs by endothelial NO synthase (eNOS) induces relaxation of HSCs through the guanylate catalase pathway. Consequently, the balance between the ET-1 and NO accounts for the control of sinusoidal flow. However, in cirrhotic liver, the overproduction of ET-1 and increased susceptibility to autocrine ET-1 leading to activated HSCs result in increasing HSC contraction.12 In addition, multiple derangements in eNOS-derived NO generation by SECs contribute to impaired sinusoidal relaxation and increased intrahepatic resistance (endothelial dysfunction).13-15 Although eNOS protein levels appear to be unchanged, SECs show a prominent increase in the inhibitory protein caveolin binding to eNOS with concomitant decreased calmodulin binding, which may contribute to NOS dysfunction.13,16 Furthermore, recent studies have shown impaired phosphorylation and activation of eNOS mediated through alterations in G-protein coupled receptor signaling and defects in endogenous inhibitors of NOS, which suggest that multiple molecular defects likely contribute to a significant deficiency in hepatic NO production during cirrhosis.17 Sinusoidal vasoconstriction is due not only to diminished NO production by SECs, but also resistance of HSCs to NO due to defects in the guanylate cyclase signaling pathway.18,19 Animal experiments have demonstrated that activation of hepatic eNOS can improve portal hemodynamics in cirrhotic rat liver.8 Furthermore, a recent study evaluated the effects of simvastatin on intrahepatic vascular tone acting as an eNOS activator in humans.20 Patients who received simvastatin showed increased hepatic venous NO products and decreased hepatic vascular resistance without untoward systemic vascular effects.20

Sinusoidal Remodeling and Angiogenesis

HSC density and coverage of the sinusoidal lumen are increased in cirrhosis. The contractile nature and long cytoplasmic processes of HSCs encircling endothelial cells induce sinusoidal vessel constriction with increased vascular resistance termed "sinusoidal vascular remodeling". The characteristics of sinusoidal remodeling are distinct from process of fibrosis, collagen deposition of HSC.21,22 In this process, HSC motility and migration is absolutely required to promote enhanced coverage of HSCs around a SECs-lined sinusoid.

While Transforming growth factor-β (TGF-β) is largely recognized for its contribution to HSC-based collagen deposition, there is significant crosstalk between TGF-β and PDGF involved in HSCs motility. Indeed, these signals may converge at the level of c-abl tyrosine kinase.23,24 A number of signaling pathways mediate HSC recruitment to vessels in vascular remodeling and angiogenesis including PDGF, TGF-β, angiopoietins, and NO. Platelet derived growth factor (PDGF) is probably the most critical factor in the recruitment of pericytes to newly formed vessels.25 SECs also undergo substantive phenotypic changes in cirrhosis that likely contribute to changes in sinusoidal structure. Indeed, recent studies have identified a number of alterations in SEC phenotypes.26

Systemic and splanchnic circulation

Vasoregulatory imbalances in the splanchnic circulation

In contrast to diminished intrahepatic bioavailability of NO, splanchnic (and systemic) circulation shows a relative excess in regional NO generation.8 This increased production is largely endothelium-dependent,27 and is thought to be evidence of eNOS activation in splanchnic endothelium. Some studies have shown that eNOS activation by the angiogenic growth factor, vascular endothelial growth factor (VEGF), may be a primary factor in initial eNOS activation which demonstrates interesting links between vasodilating angiogenesis and vascular remodeling.28 Bacterial translocation during cirrhosis increases tumor necrosis factor-α (TNF-α) production which can also induce the increase of systemic NO production.29-31 Therefore, increased NO production in systemic and splanchnic circulation contributes to decreased systemic vascular resistance and resultant hyperdynamic circulation. This in turn results in sodium retension and ascites mediated by a reduction of effective circulating volume, stimulation of sympathetic system, an activation of the renin-angiotensin-aldosteron system, and an increase of antidiuretic hormone release (Fig. 2).

Figure 2

Pathogenesis of hyperdynamic circulation in cirrhosis and portal hypertension.

CO, cardiac output; eNOS, endothelial nitric oxide synthetase; NO, nitric oxide; HO, heme oxygenase; CM, carbon monoxide; TNF-α, tumor necrosis factor-α; RAA, rennin-angiotensin-aldosteron; SNS, sympathetic nerve system; ADH, anti-diuretic hormone; VEGF, vascular endothelial growth factor; HE, hepatic encephalopathy; CCM, cirrhotic cardiomyopathy; HRS, hepatorenal syndrome; HPS, hepatopulmonary syndrome.

Vascular remodeling of systemic vessels in portal hypertension

Vascular remodeling is a long-term adaptive response to chronic changes in blood flow. Chronic increases in flow with dilation of the vascular channel are implicated in endothelial-based signals that mediate restructuring of the vessel, thereby allowing for chronic increases in vessel diameter and capacity for high volume flow. This change has been demonstrated in peripheral vessels including experimental models of portal hypertension which may be related to activation of eNOS.10,32

Collateral circulation

Vasoregulatory imbalances in collateral circulation

The development of portosystemic shunts and collateral circulation such as esophageal and hemorrhoidal collateral vessels is a compensatory response to decompress the portal circulation and hypertension, but unfortunately contributes to significant morbidity and mortality. Vasodilation of pre-existing collateral vessels results in increased collateral blood flow and volume. The mechanism of collateral vessel regulation still remains unclear. The control of collateral circulation could be a key in managing complications of portal hypertension, therefore, experimental studies are performed.33

Angiogenesis and vascular remodeling in collateral circulation

In addition to vasodilatation, the collateral circulatory bed develops through angiogenesis. Angiogenesis occurs through the proliferation of endothelial and smooth muscle cells in addition to vasculogenesis. Vasculogenesis refers to the recruitment of endothelial progenitor cells for the de novo synthesis of vessels.34 Angiogenesis and vasculogenesis are also influenced by NO and highly dependent on VEGF as the growth factor exerting pleiotropic effects to promote new vessel formation.35,36 Indeed, VEGF promotes vasodilation, vascular remodeling, and angiogenesis in part through NO-dependent or independent mechanisms. In animal models, neutralizing antibodies inhibited portosystemic shunting by blocking VEGF receptor 2, which further highlights the importance of VEGF and NO for increased portosystemic collateralization in portal hypertension.37 In addition, multikinase inhibitors such as sorafenib result not only in decreases of portosystemic shunts and improvement of portal hypertension but also inactivation of HSCs. This is under active investigation,37-39 however, more studies are needed for clinical application.

Hyperdynamic circulation

The hyperdynamic circulation is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure in cirrhotic patients.40-43 These hemodynamic alterations are initiated by systemic and splanchnic vasodilatation, and eventually lead to abnormalities of the cardiovascular system and several regional vascular beds including ones involved in hepatic, splanchnic, renal, pulmonary, skeletal muscle and cerebral circulation.5

Clinical features and pathogenesis

Hyperdynamic circulation is clinically presents with tachycardia, hypotension, and bounding pulses. Although hyperdynamic circulation per se is not distressing to the patient, this phenomenon is clinically relevant due to its propensity to aggravate or precipitate some of the complications associated with portal hypertension. Severity of hyperdynamic circulation correlates with advancing liver failure with patients with end-stage liver failure generally showing the greatest extent of peripheral vasodilatation and increased cardiac output.41-44 Thus, virtually all patients with decompensated cirrhosis show evidence of hyperdynamic circulation. However, the presence of portal hypertension, rather than liver failure, is essential for the development of hyperdynamic circulation. Since the gut and liver receive a third of the entire cardiac output, hyperdynamic circulation directly or indirectly contributes to two of the most troublesome complications of cirrhosis: ascites and variceal bleeding. In concert with the increased total cardiac output, mesenteric blood flow also increases.45,46 Moreover, studies in both humans and animal models of cirrhosis or portal hypertension confirm that mesenteric hyperemia is due not only to a passive increase in blood flow as part of the increased cardiac output, but also to mesenteric vasodilatation. In other words, the percentage of overall cardiac output perfusing the mesenteric organs also increases.42,43,45,46 Recently, bacterial infection has been recognized as a risk factor for precipitating variceal bleeding.47 The underlying mechanism of this curious observation remains unknown, but it has been suggested that humoral substances released during the course of sepsis, including endotoxins and cytokines such as TNF-α, intensify the hyperdynamic circulation and thus increase blood flow through varices. The exact pathogenic mechanisms leading to hyperdynamic circulation remain to be definitively determined. Several factors to date have been hypothesized to be involved, including humoral substances, central neural activation, tissue hypoxia, and hypervolemia.48

Multi-organ involvement

Heart

Cirrhotic cardiomyopathy was first described in the late 1960s although it was mistakenly attributed to latent or subclinical alcoholic cardiomyopathy for many years.49-51 Despite an increased baseline cardiac output, cirrhotic patients have a suboptimal ventricular response to stress. These individuals show blunted systolic and diastolic contractile responses to stress in conjunction with evidence of ventricular hypertrophy or chamber dilatation, and electrophysiological abnormalities including prolonged QT intervals. The pathogenesis of this syndrome is multifactorial and includes diminished β-adrenergic receptor signal transduction,2,52-55 cardiomyocyte cellular plasma membrane dysfunction, and increased activity or levels of cardio-depressant substances such as cytokines, endogenous cannabinoids, and nitric oxide.51 Although cirrhotic cardiomyopathy is usually clinically mild or silent, overt heart failure can be precipitated by stress from liver transplantation or transjugular intrahepatic portosystemic shunt insertion. Recent studies suggest that the presence of cirrhotic cardiomyopathy may contribute to the pathogenesis of hepatorenal syndrome precipitated by spontaneous bacterial peritonitis,56 acute heart failure after insertion of transjugular intrahepatic portosystemic shunts,57,58 and increased cardiovascular-associated morbidity and mortality after liver transplantation.59

The Kidney

Renal vasoconstriction is characteristic in kidney with splanchnic vasodilation and hyperdynamic circulation, and may be responsible for the development of hepatorenal syndrome. Renal vasoconstriction develops as a consequence of effective hypovolemia and ensuing neurohumoral activation.60 This provides the rationale for treating hepatorenal syndrome with albumin infusion and vasoconstrictors (terlipressin, norepinephrine, or midodrine).61

The Lung and Brain

Vasodilatation in the lung leads to ventilation perfusion mismatch and even arterio-venous shunts in the pulmonary circulation; these result in hepatopulmonary syndrome, characterized by marked hypoxemia.62,63 In some cases, this may evolve into the opposite situation with markedly increased pulmonary vascular resistance seen in portopulmonary hypertension.64 This is thought to develop through endothelial dysfunction and vascular remodeling of the pulmonary circulation.65 Changes in cerebral blood flow and vascular reactivity associated with portal hypertension are considered to contribute and facilitate some of the brain abnormalities of hepatic encephalopathy.

CONCLUSIONS

Portal hypertension is associated with vascular alterations in intrahepatic and systemic circulation. Extensive research has improved our understanding of the pathogenic mechanisms underlying hemodynamic derangement, allowing the development of novel treatment modalities. Future studies should focus on pharmacologic and genetic approaches to modulate vascular biologic systems to ameliorate complications and symptoms relating to hemodynamic alterations in patients with cirrhosis and portal hypertension.

Acknowledgements

This work was supported by a grant from Ministry for Health, Welfare and Family Affairs, Republic of Korea (no. A050021).

Abbreviations

HSCs

hepatic stellate cells

SECs

sinusoidal endothelial cells

ET-1

endothelin-1

nitric oxide

eNOS

endothelial NO synthase

cardiac output

heme oxygenase

carbon monoxide

TNF-α

tumor necrosis factor-α

RAA

rennin-angiotensin-aldosteron

SNS

sympathetic nerve system

VEGF

vascular endothelial growth factor

hepatic encephalopathy

CCM

cirrhotic cardiomyopathy

HRS

hepatorenal syndrome

HPS

hepatopulmonary syndrome

TGF-β

transforming growth factor-β

PDGF

platelet derived growth factor

References

1. Kim MY, Baik SK, Suk KT, Yea CJ, Lee IY, Kim JW, et al. Measurement of hepatic venous pressure gradient in liver cirrhosis: relationship with the status of cirrhosis, varices, and ascites in Korea. Korean J Hepatol 2008;14:150–158. 18617762.

2. Baik SK, Fouad TR, Lee SS. Cirrhotic cardiomyopathy. Orphanet J Rare Dis 2007;2:15. 17389039.

3. Baik SK. Assessment and current treatment of portal hypertension. Korean J Hepatol 2005;11:211–217. 16177547.

4. Guturu P, Shah V. New insights into the pathobiology of portal hypertension. Hepatol Res 2009;39:1016–1019. 19796039.

5. Kim MY, Baik SK. Pathophysiology of portal hypertension, what's new? Korean J Gastroenterol 2010;56:129–134. 20847603.

6. Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325–337. 4056346.

7. Kim MY, Baik SK. Hyperdynamic circulation in patients with liver cirrhosis and portal hypertension. Korean J Gastroenterol 2009;54:143–148. 19844149.

8. Langer DA, Shah VH. Nitric oxide and portal hypertension: interface of vasoreactivity and angiogenesis. J Hepatol 2006;44:209–216. 16297493.

9. Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Hepatology 2007;45:817–825. 17326208.

10. Fernández-Varo G, Ros J, Morales-Ruiz M, Cejudo-Martín P, Arroyo V, Solé M, et al. Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis. Am J Pathol 2003;162:1985–1993. 12759254.

11. Rockey DC, Shah V. Nitric oxide biology and the liver: report of an AASLD research workshop. Hepatology 2004;39:250–257. 14752845.

12. Reinehr RM, Kubitz R, Peters-Regehr T, Bode JG, Häussinger D. Activation of rat hepatic stellate cells in culture is associated with increased sensitivity to endothelin 1. Hepatology 1998;28:1566–1577. 9828221.

13. Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 1999;117:1222–1228. 10535886.

14. Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998;114:344–351. 9453496.

15. Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology 1998;28:926–931. 9755227.

16. Yokomori H, Oda M, Yoshimura K, Nomura M, Wakabayashi G, Kitajima M, et al. Elevated expression of caveolin-1 at protein and mRNA level in human cirrhotic liver: relation with nitric oxide. J Gastroenterol 2003;38:854–860. 14564631.

17. Liu S, Premont RT, Kontos CD, Zhu S, Rockey DC. A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nat Med 2005;11:952–958. 16142243.

18. Dudenhoefer AA, Loureiro-Silva MR, Cadelina GW, Gupta T, Groszmann RJ. Bioactivation of nitroglycerin and vasomotor response to nitric oxide are impaired in cirrhotic rat livers. Hepatology 2002;36:381–385. 12143046.

19. Perri RE, Langer DA, Chatterjee S, Gibbons SJ, Gadgil J, Cao S, et al. Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation. Am J Physiol Gastrointest Liver Physiol 2006;290:G535–G542. 16269521.

20. Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernández M, Garca-Pagán JC, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004;126:749–755. 14988829.

21. Friedman SL, Rockey DC, McGuire RF, Maher JJ, Boyles JK, Yamasaki G. Isolated hepatic lipocytes and Kupffer cells from normal human liver: morphological and functional characteristics in primary culture. Hepatology 1992;15:234–243. 1735526.

22. Maher JJ, Bissell DM, Friedman SL, Roll FJ. Collagen measured in primary cultures of normal rat hepatocytes derives from lipocytes within the monolayer. J Clin Invest 1988;82:450–459. 3042806.

23. Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, Limper AH, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004;114:1308–1316. 15520863.

24. Ceni E, Crabb DW, Foschi M, Mello T, Tarocchi M, Patussi V, et al. Acetaldehyde inhibits PPARgamma via H2O2-mediated c-Abl activation in human hepatic stellate cells. Gastroenterology 2006;131:1235–1252. 17030193.

25. Hellström M, Kalén M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999;126:3047–3055. 10375497.

26. Straub AC, Stolz DB, Ross MA, Hernández-Zavala A, Soucy NV, Klei LR, et al. Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver. Hepatology 2007;45:205–212. 17187425.

27. Wiest R, Shah V, Sessa WC, Groszmann RJ. NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. Am J Physiol 1999;276:G1043–G1051. 10198349.

28. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43(2 Suppl 1):S121–S131. 16447289.

29. Wiest R, Das S, Cadelina G, Garcia-Tsao G, Milstien S, Groszmann RJ. Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. J Clin Invest 1999;104:1223–1233. 10545521.

30. Liu H, Ma Z, Lee SS. Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Gastroenterology 2000;118:937–944. 10784593.

31. Liu H, Song D, Lee SS. Increased nitric oxide synthase expression in aorta of cirrhotic rats. Life Sci 1999;64:1753–1759. 10353629.

32. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 1998;101:731–736. 9466966.

33. Lee FY, Colombato LA, Albillos A, Groszmann RJ. Administration of N omega-nitro-L-arginine ameliorates portal-systemic shunting in portal-hypertensive rats. Gastroenterology 1993;105:1464–1470. 8224649.

34. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 2004;95:343–353. 15321944.

35. Sumanovski LT, Battegay E, Stumm M, van der Kooij M, Sieber CC. Increased angiogenesis in portal hypertensive rats: role of nitric oxide. Hepatology 1999;29:1044–1049. 10094944.

36. Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006;130:1807–1821. 16697743.

37. Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodés J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol 2005;43:98–103. 15893841.

38. Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology 2004;126:886–894. 14988842.

39. Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 2009;49:1245–1256. 19137587.

40. Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec's cirrhosis. J Clin Invest 1953;32:1025–1033. 13096569.

41. Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an overview. Pharmacol Ther 2001;89:221–231. 11516477.

42. Lebrec D, Moreau R. Pathogenesis of portal hypertension. Eur J Gastroenterol Hepatol 2001;13:309–311. 11338055.

43. Garcia-Tsao G. Portal hypertension. Curr Opin Gastroenterol 2003;19:250–258. 15703565.

44. Braillon A, Cales P, Valla D, Gaudy D, Geoffroy P, Lebrec D. Influence of the degree of liver failure on systemic and splanchnic haemodynamics and on response to propranolol in patients with cirrhosis. Gut 1986;27:1204–1209. 3781335.

45. Lee SS, Girod C, Valla D, Geoffroy P, Lebrec D. Effects of pentobarbital sodium anesthesia on splanchnic hemodynamics of normal and portal-hypertensive rats. Am J Physiol 1985;249:G528–G532. 4051000.

46. Vorobioff J, Bredfeldt JE, Groszmann RJ. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol 1983;244:G52–G57. 6849394.

47. Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, Burroughs AK. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1998;27:1207–1212. 9581672.

48. Li Y, Song D, Zhang Y, Lee SS. Effect of neonatal capsaicin treatment on haemodynamics and renal function in cirrhotic rats. Gut 2003;52:293–299. 12524416.

49. Murray JF, Dawson AM, Sherlock S. Circulatory changes in chronic liver disease. Am J Med 1958;24:358–367. 13520736.

50. Abelmann WH. Hyperdynamic circulation in cirrhosis: a historical perspective. Hepatology 1994;20:1356–1358. 7927272.

51. Baik SK, Lee SS. Cirrhotic cardiomyopathy: causes and consequences. J Gastroenterol Hepatol 2004;19(Suppl 7):S185–S190.

52. Lee SS, Marty J, Mantz J, Samain E, Braillon A, Lebrec D. Desensitization of myocardial beta-adrenergic receptors in cirrhotic rats. Hepatology 1990;12:481–485. 2169452.

53. Ma Z, Meddings JB, Lee SS. Membrane physical properties determine cardiac beta-adrenergic receptor function in cirrhotic rats. Am J Physiol 1994;267:G87–G93. 8048535.

54. Ma Z, Lee SS, Meddings JB. Effects of altered cardiac membrane fluidity on beta-adrenergic receptor signalling in rats with cirrhotic cardiomyopathy. J Hepatol 1997;26:904–912. 9126806.

55. Kim MY, Baik SK. Cirrhotic cardiomyopathy. Korean J Hepatol 2007;13:20–26. 17380071.

56. Ruiz-del-Arbol L, Urman J, Fernández J, González M, Navasa M, Monescillo A, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003;38:1210–1218. 14578859.

57. Naritaka Y, Ogawa K, Shimakawa T, Wagatsuma Y, Konno S, Katsube T, et al. Clinical experience of transjugular intrahepatic portosystemic shunt (TIPS) and its effects on systemic hemodynamics. Hepatogastroenterology 2004;51:1470–1472. 15362779.

58. Braverman AC, Steiner MA, Picus D, White H. High-output congestive heart failure following transjugular intrahepatic portal-systemic shunting. Chest 1995;107:1467–1469. 7750353.

59. Rayes N, Bechstein WO, Keck H, Blumhardt G, Lohmann R, Neuhaus P. Cause of death after liver transplantation: an analysis of 41 cases in 382 patients. Zentralbl Chir 1995;120:435–438. 7639030.

60. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151–1157. 2971015.

61. Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. J Hepatol 2003;38(Suppl 1):S69–S89. 12591187.

62. Rodriguez-Roisin R, Roca J, Agusti AG, Mastai R, Wagner PD, Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis. Am Rev Respir Dis 1987;135:1085–1092. 3579008.

63. Rodriguez-Roisin R, Agusti AG, Roca J. The hepatopulmonary syndrome: new name, old complexities. Thorax 1992;47:897–902. 1465744.

64. Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004;24:861–880. 15516683.

65. Fallon MB. Portopulmonary hypertension: new clinical insights and more questions on pathogenesis. Hepatology 2003;37:253–255. 12540774.

Article information Continued

(open-access, http://creativecommons.org/licenses/by-nc/3.0) :

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.