Document Detail

Hemodynamic alterations in cirrhosis and portal hypertension.
Jump to Full Text
MedLine Citation:
PMID:  21415576     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Moon Young Kim; Soon Koo Baik; Samuel S Lee
Related Documents :
11771686 - Influence of ph and oxygen on copper corrosion in simulated uterine fluid.
16678256 - Pegylated albumin-heme as an oxygen-carrying plasma expander: exchange transfusion into...
23272766 - First-attack pediatric hypertensive crisis presenting to the pediatric emergency depart...
21568416 - Distribution of standing-wave errors in real-ear sound-level measurements.
649636 - Intra-articular pressure as a factor in initiating ulnar drift.
11126266 - Ventilator-induced lung injury leads to loss of alveolar and systemic compartmentalizat...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  The Korean journal of hepatology     Volume:  16     ISSN:  1738-222X     ISO Abbreviation:  Korean J Hepatol     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-03-18     Completed Date:  2011-06-28     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101211947     Medline TA:  Korean J Hepatol     Country:  Korea (South)    
Other Details:
Languages:  eng     Pagination:  347-52     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Collateral Circulation / physiology
Endothelial Cells / metabolism
Hemodynamics
Hepatic Stellate Cells / metabolism
Hypertension, Portal / etiology*
Liver Circulation / physiology
Liver Cirrhosis / etiology*
Splanchnic Circulation / physiology
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Korean J Hepatol
Journal ID (publisher-id): KJHEP
ISSN: 1738-222X
ISSN: 2093-8047
Publisher: The Korean Association for the Study of the Liver
Article Information
Download PDF
Copyright © 2010 by The Korean Association for the Study of the Liver
open-access:
Received Day: 06 Month: 11 Year: 2010
Revision Received Day: 21 Month: 11 Year: 2010
Accepted Day: 25 Month: 11 Year: 2010
Print publication date: Month: 12 Year: 2010
Electronic publication date: Day: 31 Month: 12 Year: 2010
Volume: 16 Issue: 4
First Page: 347 Last Page: 352
ID: 3304610
PubMed Id: 21415576
DOI: 10.3350/kjhep.2010.16.4.347

Hemodynamic alterations in cirrhosis and portal hypertension
Moon Young Kim1
Soon Koo Baik1
Samuel S. Lee2
1Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
2Liver Unit, University of Calgary, Calgary, AB, Canada.
Correspondence: 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

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

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 ETA 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).

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
No nitric oxide
eNOS endothelial NO synthase
CO cardiac output
HO heme oxygenase
CM carbon monoxide
TNF-α tumor necrosis factor-α
RAA rennin-angiotensin-aldosteron
SNS sympathetic nerve system
VEGF vascular endothelial growth factor
HE 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 KoreaKorean J HepatolYear: 20081415015818617762
2. Baik SK,Fouad TR,Lee SS. Cirrhotic cardiomyopathyOrphanet J Rare DisYear: 200721517389039
3. Baik SK. Assessment and current treatment of portal hypertensionKorean J HepatolYear: 20051121121716177547
4. Guturu P,Shah V. New insights into the pathobiology of portal hypertensionHepatol ResYear: 2009391016101919796039
5. Kim MY,Baik SK. Pathophysiology of portal hypertension, what's new?Korean J GastroenterolYear: 20105612913420847603
6. Bhathal PS,Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilatorsJ HepatolYear: 198513253374056346
7. Kim MY,Baik SK. Hyperdynamic circulation in patients with liver cirrhosis and portal hypertensionKorean J GastroenterolYear: 20095414314819844149
8. Langer DA,Shah VH. Nitric oxide and portal hypertension: interface of vasoreactivity and angiogenesisJ HepatolYear: 20064420921616297493
9. Lee JS,Semela D,Iredale J,Shah VH. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?HepatologyYear: 20074581782517326208
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 cirrhosisAm J PatholYear: 20031621985199312759254
11. Rockey DC,Shah V. Nitric oxide biology and the liver: report of an AASLD research workshopHepatologyYear: 20043925025714752845
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 1HepatologyYear: 199828156615779828221
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 ratGastroenterologyYear: 19991171222122810535886
14. Rockey DC,Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertensionGastroenterologyYear: 19981143443519453496
15. Gupta TK,Toruner M,Chung MK,Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic ratsHepatologyYear: 1998289269319755227
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 oxideJ GastroenterolYear: 20033885486014564631
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 hypertensionNat MedYear: 20051195295816142243
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 liversHepatologyYear: 20023638138512143046
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 activationAm J Physiol Gastrointest Liver PhysiolYear: 2006290G535G54216269521
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 cirrhosisGastroenterologyYear: 200412674975514988829
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 cultureHepatologyYear: 1992152342431735526
22. Maher JJ,Bissell DM,Friedman SL,Roll FJ. Collagen measured in primary cultures of normal rat hepatocytes derives from lipocytes within the monolayerJ Clin InvestYear: 1988824504593042806
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 fibrosisJ Clin InvestYear: 20041141308131615520863
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 cellsGastroenterologyYear: 20061311235125217030193
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 mouseDevelopmentYear: 19991263047305510375497
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 liverHepatologyYear: 20074520521217187425
27. Wiest R,Shah V,Sessa WC,Groszmann RJ. NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive ratsAm J PhysiolYear: 1999276G1043G105110198349
28. Iwakiri Y,Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the moleculeHepatologyYear: 2006432 Suppl 1S121S13116447289
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 contractilityJ Clin InvestYear: 19991041223123310545521
30. Liu H,Ma Z,Lee SS. Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated ratsGastroenterologyYear: 200011893794410784593
31. Liu H,Song D,Lee SS. Increased nitric oxide synthase expression in aorta of cirrhotic ratsLife SciYear: 1999641753175910353629
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 remodelingJ Clin InvestYear: 19981017317369466966
33. Lee FY,Colombato LA,Albillos A,Groszmann RJ. Administration of N omega-nitro-L-arginine ameliorates portal-systemic shunting in portal-hypertensive ratsGastroenterologyYear: 1993105146414708224649
34. Urbich C,Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biologyCirc ResYear: 20049534335315321944
35. Sumanovski LT,Battegay E,Stumm M,van der Kooij M,Sieber CC. Increased angiogenesis in portal hypertensive rats: role of nitric oxideHepatologyYear: 1999291044104910094944
36. Russo FP,Alison MR,Bigger BW,Amofah E,Florou A,Amin F,et al. The bone marrow functionally contributes to liver fibrosisGastroenterologyYear: 20061301807182116697743
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 ratsJ HepatolYear: 2005439810315893841
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 miceGastroenterologyYear: 200412688689414988842
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 ratsHepatologyYear: 2009491245125619137587
40. Kowalski HJ,Abelmann WH. The cardiac output at rest in Laennec's cirrhosisJ Clin InvestYear: 1953321025103313096569
41. Blendis L,Wong F. The hyperdynamic circulation in cirrhosis: an overviewPharmacol TherYear: 20018922123111516477
42. Lebrec D,Moreau R. Pathogenesis of portal hypertensionEur J Gastroenterol HepatolYear: 20011330931111338055
43. Garcia-Tsao G. Portal hypertensionCurr Opin GastroenterolYear: 20031925025815703565
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 cirrhosisGutYear: 198627120412093781335
45. Lee SS,Girod C,Valla D,Geoffroy P,Lebrec D. Effects of pentobarbital sodium anesthesia on splanchnic hemodynamics of normal and portal-hypertensive ratsAm J PhysiolYear: 1985249G528G5324051000
46. Vorobioff J,Bredfeldt JE,Groszmann RJ. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertensionAm J PhysiolYear: 1983244G52G576849394
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 hemorrhageHepatologyYear: 199827120712129581672
48. Li Y,Song D,Zhang Y,Lee SS. Effect of neonatal capsaicin treatment on haemodynamics and renal function in cirrhotic ratsGutYear: 20035229329912524416
49. Murray JF,Dawson AM,Sherlock S. Circulatory changes in chronic liver diseaseAm J MedYear: 19582435836713520736
50. Abelmann WH. Hyperdynamic circulation in cirrhosis: a historical perspectiveHepatologyYear: 199420135613587927272
51. Baik SK,Lee SS. Cirrhotic cardiomyopathy: causes and consequencesJ Gastroenterol HepatolYear: 200419Suppl 7S185S190
52. Lee SS,Marty J,Mantz J,Samain E,Braillon A,Lebrec D. Desensitization of myocardial beta-adrenergic receptors in cirrhotic ratsHepatologyYear: 1990124814852169452
53. Ma Z,Meddings JB,Lee SS. Membrane physical properties determine cardiac beta-adrenergic receptor function in cirrhotic ratsAm J PhysiolYear: 1994267G87G938048535
54. Ma Z,Lee SS,Meddings JB. Effects of altered cardiac membrane fluidity on beta-adrenergic receptor signalling in rats with cirrhotic cardiomyopathyJ HepatolYear: 1997269049129126806
55. Kim MY,Baik SK. Cirrhotic cardiomyopathyKorean J HepatolYear: 200713202617380071
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 peritonitisHepatologyYear: 2003381210121814578859
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 hemodynamicsHepatogastroenterologyYear: 2004511470147215362779
58. Braverman AC,Steiner MA,Picus D,White H. High-output congestive heart failure following transjugular intrahepatic portal-systemic shuntingChestYear: 1995107146714697750353
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 patientsZentralbl ChirYear: 19951204354387639030
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 cirrhosisHepatologyYear: 19888115111572971015
61. Arroyo V,Colmenero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current managementJ HepatolYear: 200338Suppl 1S69S8912591187
62. Rodriguez-Roisin R,Roca J,Agusti AG,Mastai R,Wagner PD,Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosisAm Rev Respir DisYear: 1987135108510923579008
63. Rodriguez-Roisin R,Agusti AG,Roca J. The hepatopulmonary syndrome: new name, old complexitiesThoraxYear: 1992478979021465744
64. Rodriguez-Roisin R,Krowka MJ,Herve P,Fallon MB. Pulmonary-Hepatic vascular Disorders (PHD)Eur Respir JYear: 20042486188015516683
65. Fallon MB. Portopulmonary hypertension: new clinical insights and more questions on pathogenesisHepatologyYear: 20033725325512540774

Article Categories:
  • Review

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

Previous Document:  Overexpression of microtubule-associated protein-1 light chain 3 is associated with melanoma metasta...
Next Document:  A comparative study of high-dose hepatic arterial infusion chemotherapy and transarterial chemoembol...