The Hyperdynamic Circulation of Chronic Liver Dias:From the Patient to the Molecule
Yasuko Iwakiri1,2,3and Roberto J.Groszmann1,2
The hyperdynamic circulatory syndrome obrved in chronic liver dias is a great example of rearch that originated from clinical obrvations and progresd in the last50years from the patient to the experimental laboratory.Our knowledge has evolved from the patient to the molecule,using experimental models that rve as a source for understanding the com-plex pathophysiological mechanisms that govern this complex syndrome.We now know that progressive vasodilatation is central to the detrimental effects obrved in multiple organs.
Although nitric oxide has been shown to be the primary vasodilator molecule in the effects, other molecules also participate in the complex mechanisms of vasodilatation.This review summarizes three major areas:first,clinical obrvation in patients;cond,experimental models ud to study the hyperdynamic circulatory syndrome;and third,the vasodilator molecules that play roles in vascular abnormalities obrved in portal hypertension.
胶体果胶铋胶囊说明书
(H EPATOLOGY2006;43:S121-S131.)
“Today’s catch-phra is“‘from bench to bedside’”and
university medical centres are struggling with the promo-tion of [There are examples] where astute obrvations of small group of patients have
been the starting point of voyages of scientific discov-ery—from,as it were,the bedside to the bench—but in
—Sir Keith Peters,FRCP
T he hyperdynamic circulatory syndrome obrved in chronic liver dias is a great example of re-
成绩英语arch that originated from clinical obrvations by astute bedside investigators2and progresd in the last 50years from the patient to the experimental laboratory. In this fascinating journey,investigators have gone from the patient to the molecule,and en route established a strong intermediate relay station in experimental models that have rved and still rve as the source readily avail-able to understand the complex pathophysiological mech-anisms that govern this complex syndrome.
The hyperdynamic syndrome should be better called “progressive vasodilatory syndrome,”becau vasodilatation is the factor that brings about all the vascular changes and finally leads to the multiorgan involvement obrved as a conquence of this hemodynamic change.Early in the cour,investigators recognized the primary importance of vasodilatation in the initiation of this syndrome,and consid-erable effort and resources were invested infinding the vaso-dilatory molecule(s).Finally,at the beginning of the1990s it became evident that a recently discovered molecule involved in a multiple biological mechanisms was the main culprit.3 As a rule in biology,a single agent cannot explain a whole syndrome.However,it became evident that nitric oxide,a biologically active gas,is the main molecule responsible for vasodilatation and the multiple organ malfunctions that characterize hyperdynamic circulation.4In the last15years, we have learned a lot about the patients,the experimental model,and the molecules that are the“prime movers”of the hyperdynamic state.We here review our current knowledge of this cardinal syndrome.
The Patient
In1953,bad on the clinical obrvation that patients with cirrhosis frequently showed“warm extremities,cu-
Abbreviations:NO,nitric oxide;cGMP;Cyclic Guanosine Monophosphate;
NOS,nitric oxide syntha;eNOS,endothelial nitric oxide syntha;nNOS,neu-
ronal nitric oxide syntha;iNOS,inducible nitric oxide syntha;BH4,tetrahydro-
biopterin;ET-1,endothelin-1;PGI2,prostacyclin;EDHF,endothelium-derived
hyperpolarizing factor;TNF-␣,tumor necrosis factor alpha;H2S,hydrogen sulfide.
From the1Hepatic Hemodynamic Laboratory,VA Connecticut Healthcare Sys-
tem,West Haven,CT;and the2Section of Digestive Dias and3Department of
Pharmacology,Yale University School of Medicine,New Haven,CT.
Dr.Iwakiri is supported by National Institutes of Health K01award(K01森林的早晨
DK067933-01)and has been Named New Investigator Award from Yale Liver
Center(P30DK34989).Dr.Groszmann is supported by a VA Merit Review
Award.
Address reprint requests to:Roberto J.Groszmann,M.D.,FRCP,Digestive
Dia Section/111H,VA Medical Center,950Campbell Avenue,West Haven,
CT06516.szmann@yale.edu;fax:203-937-3873.
Copyright©2006by the American Association for the Study of Liver Dias.
Published online in Wiley InterScience(www.).
DOI10.1002/hep.20993
Potential conflict of interest:Nothing to report.合适的近义词
S121
taneous vascular spiders,wide pul pressure,and capil-lary pulsations in the nail beds,”Kowalski and Abelmann 2first demonstrated that cirrhosis is associated with a hy-perdynamic circulatory syndrome.This study demon-strated an increa in cardiac output and a decrea in peripheral vascular resistance in patients with alcohol-in-duced cirrhosis.The findings were reproduced in su描写母亲的作文
b-quent studies 5;however,the recognition of the harmful effect of this syndrome on multiple organs was only rec-ognized years later.4We know now that vasodilatation is central to the detrimental effect obrved in veral vital organs 4and that the multi-organ failure obrved in chronic liver dias is in large part attributable to this progressive vasodilatation.The harmful effects obrved in the systemic circulation and veral other vital organs always originate via the vasodilatory state.Whereas in the heart,the splanchnic,the pulmonary,and the cerebral circulation,the deleterious effects are mediated by the hyperdynamic circulation itlf,in other organs such as the kidney and the brain (such as in chronic encephalop-athy);it is a respon to vasodilatation in the other circu-latory beds (Fig.1).
The Systemic Circulation,the Heart.In this circu-latory bed the evidence of this syndrome is usually first obrved.“Warm extremities,cutaneous vascular spiders,wide pul pressure,and capillary pulsations in the nail beds”are common findings in patients with overt liver dias.However,over the years we have learned that the patients are hyperdynamic before the syndrome be-comes clinically evident.The systemic circulatory syn-drome ems condary to changes occurring in regional vascular beds.Any change in peripheral vascular resis-tance is rapidly compensated by changes in cardiac out-put.6This point is clearly en in experiments and in patients with arterioveno
us fistulae wherein opening of the fistula is enough to increa the cardiac output.How-ever,in portal hypertension,the progressive reduction in peripheral resistance is slower,and compensatory mecha-nisms,such as sodium and water retention with expansion of the plasma volume,play a fundamental role in perpet-uating and aggravating the hyperdynamic syndrome.We believe that the initial vasodilatation occurs in the splanchnic circulation and that the heart respon is di-rectly related to a combination of splanchnic vasodilata-tion and expansion of the plasma volume together with an incread venous return to the heart,in large part,through portal-systemic shunts (Fig.2).Although vaso-dilatation is esntial as the initiating factor,no hyperdy-namic circulation occurs without expansion of the plasma volume and portal-systemic shunting.7,8In the long run,the heart behaves as in other forms of high cardiac output syndrome:Initial compensation according to the degree of individual cardiac rerve,followed sooner or later by some degree of cardiac insufficiency.The cardiac index is usually higher than normal (Ͼ4L/min/m 2)but insuffi-cient to maintain arterial pressure on the face of progres-sive vasodilatation.9Interestingly,high cardiac output failure is reversible once the initial cau leading to the high cardiac output is treated.This reversal has been ob-rved also in patients with cirrhosis after liver transplan-tation.10,11
The Hyperdynamic Splanchnic Circulation.The hyperdynamic splanchnic circulation is central to the
de-velopment of the syndrome,and although is commonly recognized as a complication of cirrhosis,it should be better conceptualized as a complication of portal
hyper-
Fig. 1.Vasodilatation:the source of all evils.*Chronic en-cephalopathy is associated with a reduced brain blood flow.The mech-anism is probably similar to what is obrved in the renal circulation.
S122IWAKIRI AND GROSZMANN HEPATOLOGY,February 2006
tension.It has been obrved in all forms of portal hyper-tension caud by a condition other than cirrhosis and confirmed in different experimental models of portal hy-pertension (Table 1);therefore,it cannot be considered solely a complication of cirrhosis.
For many years the dominant theory explaining portal hypertension in cirrhosis was the “backward flow”theory,which postulated that incread portal vascular resistance was the only cau for the increa in portal pressure.This
theory predicted a splanchnic hypodynamic circulation with incread menteric vascular resistance.Obrva-tions of a decread portal blood flow at the hepatic hilum supported this theory.12This hypodynamic or a normo-dynamic situation is obrved in early cirrhosis when por-tal hypertension is mainly attributable to an increa in intrahepatic vascular resistance,and portal-systemic col-laterals have not yet developed.In moderate to vere portal hypertension,however,when an extensive collat-eral circulation is prent,the obrvation of a decread portal blood flow entering the liver is misleading becau does not take into account portal flow diverted through the collateral circulation.In the late 1960s and early 1970s,a ries of stu
dies in patients with well-established cirrhosis suggested that the splanchnic circulation was hy-perdynamic.13-15However,in the early 1980s,when a methodology to evaluate regional hemodynamics and portal-systemic shunting in rodent models of portal hy-pertension was developed,the hemodynamic events that follow the induction of portal hypertension were un-equivocally demonstrated.16-18An increa in splanchnic blood flow together with an increa in portal vascular resistance were shown to contribute to portal hyperten-sion.17,18This process is called the “forward flow”theory,and it provides a rationale for the u of vasoconstrictors in patients with portal hypertension.
At that time,we coined the name “portal venous in-flow”for the splanchnic blood flow entering into the por-tal system to distinguish it from the portal blood
flow
Fig.2.Mechanisms leading to the hyperdynamic circulation.(1)Factors that are upregulated in early portal hypertension.(2)Physical stimuli that are upregulated by an increa in blood flow.(3)Factors that are unique to cirrhosis.
Table 1.Experimental Models of Portal Hypertension and
Hyperdynamic Circulation*
Rat
Portal Vein Constriction Groszmann et al.
Am J Physiol 1982;242:G156–G160Cirrhosis CCl 4威武不屈
Vorobioff et al.
Gastroenterology 1984;87:1120–1126Thioacetamide Hori et al.
Dig Dis Sci 1993;38:2195–2202Bile duct ligation
Lee et al.
Am J Physiol 1986;251:G176–G180Mou
鸭肉饭Portal vein constriction
Iwakiri et al.
Am J Physiol GI Liver Physiol 2002;283:G1074–G1081Chronic schistosomiasis
菠萝肉的家常做法Sarin et al.
Am J Physiol 1990;258:G365–G369Rabbit Portal vein constriction Cahill al.
Hepatology.1995;22(2):598–606Dog
Bile duct ligation
Levy M.
Am J Physiol.1977;233:F572–F585Bosch et al.
H EPATOLOGY 1983;3:1002–1007
*Reprentative publications for each model.
HEPATOLOGY,Vol.43,No.2,Suppl.1,2006IWAKIRI AND GROSZMANN S123
perfusing the liver.16Portal hypertension is the only known pathophysiological situation in which the portal bloodflow entering into the portal system is different from portal bloodflow perfusing the liver.
In veral studies,the hyperdynamic splanchnic circu-lation of the portal hypertensive patient has been demon-strated by using indirect techniques.19We believe the initial signal that triggers the quence vasodilatation-hy-perdynamic circulation is located in this bed and that the signal is the initial increa in portal pressure itlf(e Fig.2).20,21
The Hyperdynamic Pulmonary Circulation.The hyperdynamic circulation also affects the lungs.Pulmo-nary vasodilatation is associated with the hepatopulmo-nary syndrome,one of the most vere complications of chronic liver dias.Although the intrinsic mechanism that triggers this syndrome into its full expression is not fully known,local vasodilatation mediated by veral en-dothelial vasodilators,including nitric oxide and carbon monoxide,plays a major role.22This review de
als with the conquences of the systemic hyperdynamic syndrome on the different organs affected by the progression of chronic liver dias.Local factors in the pulmonary circulation may determine why only some patients develop the hepa-topulmonary syndrome.High cardiac output,by increas-ing shear stress in the pulmonary vascular endothelium and by shortening pulmonary and tissue transit time of red cells,23,24may contribute as well to the verity of the hepatopulmonary syndrome.
The Renal and Cerebral Circulation.The renal cir-culatory bed appears to be indirectly affected by the con-quences of the hyperdynamic state(Fig.1).The kidney responds to a perceived hypovolemia,in the only way it knows,by retaining sodium and water.In reality,progres-sive vasodilatation in the patients induces a state of“rel-ative hypovolemia.”Rather than a decrea in intravascular volume,the relative hypovolemia results from an increa of the vascular compartment caud by vasodilatation,leading to a reduction in central blood volume,and activation of vasoconstrictive and volume-retaining neurohumoral mechanisms that perpetuate the sodium and water retentive state.25-27In compensated cir-rhosis,in the face of progressive vasodilatation,the intra-vascular volume and the cardiac output increa to maintain arterial perfusion pressure.With the progression of the dia,vasodilatation is accentuated,and the car-diac output continues to increa.Eventually the cardiac respon is not enough to maintain perfusion pressure, the renal blo
odflow drops,and renal failure develops. This chain of events was recognized in the mid1970s by Dr.J.N.Cohn,who suggested that this syndrome of progressive vasodilatation,incread cardiac output,and renal failure should be called cardiocirculatory hepatorenal failure.28Recently,Ruiz-del-Arbol and others29have shown that the hepatorenal syndrome ems to develop when the heart cannot compensate any longer for the progressive decrea in peripheral resistance.This limita-tion can be attributable to different caus,30including the known effect of chronic high cardiac output,psis,or a decrea in the heart pre-load caud by the continu-ously increasing vasodilatation.Interestingly,Cohn et al.31also suggested that treatment of the systemic vascular dilatation could result in an improvement in renal func-tion.Again he has proved to be correct;chronic infusions of vasoconstrictors,especially vasopressin analogs,im-prove renal function in patients with hepatorenal syn-drome.32Infusions of the powerful vasoconstrictors not only improve systemic peripheral resistance but also,by constricting mainly the splanchnic bed,reduce portal pressure and increa renal perfusion pressure.
The relationship between the systemic vasodilatation of liver dias and the cerebral circulation is perhaps the most difficult to define.Decreas as well as increas in cerebral bloodflow have been described.33The increa in bloodflow has been mainly associated with acute liver failure;portal hyp
ertension and systemic vasodilatation have also been encountered.33The brain(as well as the kidney and the splanchnic circulatory bed)autoregulates bloodflow within a wide margin of arterial pressure and, as Guyton6had demonstrated,the heart output increas in respon to the demands of the regional circulations. Therefore,if an increa occurs in cerebral bloodflow,the driving force must be determined by local factors.Con-verly,in chronic liver dias,cerebral bloodflow is decread,and this decrea runs in parallel with the re-duction in renal bloodflow,suggesting that the mecha-nisms of this reduction are similar in the two vital organs.34Local disruptions of the autoregulatory mecha-nisms,a decrea in arterial perfusion pressure beyond the autoregulatory margins,and organ vasoconstriction in-duced by the activation of the neurohormonal compensa-tory respons are probably the causative factors. Although increasing systemic perfusion pressure is bene-ficial to the renal circulation,such an increa in systemic perfusion pressure may be detrimental to the brain.In acute liver failure,increas in cerebral bloodflow may lead to the development of brain edema.35However, whether in chronic encephalopathy an increa in sys-temic perfusion pressure may be beneficial is of interest. Experimental Models
The development of experimental models to study the hyperdynamic circulation has been of critical importance for our understanding of the syndrome.Although the
S124IWAKIRI AND GROSZMANN HEPATOLOGY,February2006
models result in different forms of liver dias,the com-mon denominator is portal hypertension.Vasodilatation and the hyperdynamic circulation have been obrved in all forms of portal hypertension(e Table1).We recently showed20that incread portal pressure is the initial signal that triggers the molecular mechanisms that initiate the vasodilatory stimulus leading to splanchnic vasodilatation (e Fig.2).The portal vein constricted model in the rat has rved as the“war hor,”in which the different stages of the portal hypertensive syndrome as well as the day-to-day changes leading to the hyperdynamic state have been studied.36,37It is a highly reproducible and predictable model.The model has shown that a decrea in peripheral resistance leads to a decrea in the central blood volume before the ont of sodium retention;retention of sodium ceas once the central blood volume returns to baline values.38
Although this model of pre-hepatic portal hyperten-sion mimics in many ways some of the most notable he-modynamic characteristics obrved in models of cirrhosis,it still lacks the verity and complexity of the multiple mechanisms leading to vasodilatation and the hyperdynamic circulation obrved in cirrhosis39,40(Fig.
2).Again,in all the models,splanchnic and systemic vasodilatation is the initial step leading to the hyperdy-namic syndrome(Fig.2).Whereas the involvement of the splanchnic and systemic circulation is obrved in all ex-perimental models,significant abnormalities in other re-gional beds are en only in some certain specific models and sometimes only after provocative maneuvers.33,41 Bloodflow autoregulation is very prominent in the brain,kidneys,and splanchnic circulation within a large margin of blood pressures values.6Within the autoregu-latory perfusion pressure margins,local metabolic changes modulate bloodflow in the circulatory beds. However,outside the margins,perfusion pressure be-comes the determinant of organ bloodflow.Disruption of the autoregulatory process,by derangement of the local milieu,allows inappropriate and detrimental end organ respons to the changes in systemic hemodynamics.Such disruption may occur even within the organs’autoregula-tory margins.
Clinical rearch pos critical questions that cannot be completely answered with human investigation.Results of animal rearch carried out to resolve the questions must be reexamined clinically to confirm their relevance to the human condition.Technological advances are pro-viding increasing opportunities to carry out investigations directly on portal hypertensive patients;however,inher-ent limitations make rearch with animal models esn-tial to elucidate basic mechanisms,improve diagnosis, and test potential therapies.The Molecules
Nitric Oxide.Nitric oxide(NO),an endothelial de-rived relaxing factor,is a key player in arterial vasodilata-tion in the splanchnic and systemic circulation,which leads to the hyperdynamic circulatory syndrome in portal hypertension.42-46NO caus vasodilatation by stimulat-ing soluble guanylyl cycla to generate cyclic guanosine monophosphate(cGMP)in vascular smooth muscle.47 NO is synthesized by a family of three nitric oxide synthas(NOS):constitutively expresd isoforms,en-dothelial NOS(eNOS),48and neuronal NOS (nNOS),49,50and inducible NOS(iNOS).51Among the isoforms,eNOS is the major enzymatic source of the vas-cular NO overproduction in the splanchnic arterial circu-lation.21,43,52Recent evidence suggest that nNOS,found in the neuron and vascular smooth muscle cells,is also upregulated in the menteric artery53,54and in aorta55 and plays a role in the development/maintenance of the hyperdynamic splanchnic circulation in experimental cir-rhosis.55The iNOS is synthesized de novo in a variety of cell types,including macrophages and vascular smooth muscle cells,only after induction by endotoxin and in-flammatory cytokines.56Interestingly,despite the pres-ence of endotoxemia in cirrhosis,iNOS is not detected in the splanchnic arterial vasculature in both portal vein li-gated and CCl4rats with cirrhosis.40,42,44,57However,in-cread iNOS expression was obrved in aorta isolated from rats with biliary cirrhosis.58,59
eNOS is Ca2ϩ/calmodulin-dependent and requires co-factors such as tetrahydrobiopterin(BH4)for its activ-ity.60In rats with cirrhosis,an increa in circulating endotoxin activates guanosine triphosphate(GTP)–cy-clohydrola I,which generates BH4production in mes-enteric arteries.This increa in BH4is associated with enhanced eNOS activity and eNOS-derived NO over-production in the menteric arterial beds.61
eNOS is regulated by complex protein–protein inter-actions and post-translational modification.60Among positive regulator proteins,Hsp9062and rine/threonine kinas Akt/protein kina B contribute to the activation of eNOS in the splanchnic arterial circulation in portal hypertensive rats.63Akt/protein kina B directly phos-phorylates eNOS at Ser1177(human)or Ser1179(bo-vine)and enhances its ability to generate NO.64-67 Various forms of stimuli,such as vascular endothelial growth factor,inflammatory cytokines,and mechanical forces by shear stress,stimulate the production of NO by this mechanism64-66in portal hypertension.21,58,63In the intestinal microcirculation,we obrved that vascular en-dothelial growth factor upregulates eNOS protein expres-
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