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Received: 25 July 2017    Accepted: 11 September 2017

DOI: 10.1111/liv.13589

REVIEWS

The pathophysiology of arterial vasodilatation and

hyperdynamic circulation in cirrhosis

Søren Møller1  | Flemming Bendtsen2

1
Department of Clinical Physiology and
Nuclear Medicine, Center for Functional and Abstract
Diagnostic Imaging and Research, University Patients with cirrhosis and portal hypertension often develop complications from a
of Copenhagen, Copenhagen, Denmark
2
variety of organ systems leading to a multiple organ failure. The combination of liver
Gastro Unit, Medical Division, Faculty of
Health Sciences, Hvidovre Hospital, University failure and portal hypertension results in a hyperdynamic circulatory state partly owing
of Copenhagen, Copenhagen, Denmark
to simultaneous splanchnic and peripheral arterial vasodilatation. Increases in circula-
Correspondence tory vasodilators are believed to be due to portosystemic shunting and bacterial trans-
Søren Møller, MD, DMSc, Department of
location leading to redistribution of the blood volume with central hypovolemia. Portal
Clinical Physiology and Nuclear Medicine,
Centre for Functional Imaging and Research, hypertension per se and increased splanchnic blood flow are mainly responsible for
Copenhagen University Hospital, Hvidovre,
the development and perpetuation of the hyperdynamic circulation and the associated
Denmark.
Email: soeren.moeller@regionh.dk changes in cardiovascular function with development of cirrhotic cardiomyopathy, au-
Funding information tonomic dysfunction and renal dysfunction as part of a cardiorenal syndrome. Several
Professor Søren Møller was supported by of the cardiovascular changes are reversible after liver transplantation and point to the
grants from the Novo Nordisk Foundation,
The Capital Region of Copenhagen and The pathophysiological significance of portal hypertension. In this paper, we aimed to re-
University of Copenhagen. view current knowledge on the pathophysiology of arterial vasodilatation and the
Handling Editor : Frank Tacke ­hyperdynamic circulation in cirrhosis.

KEYWORDS
cardiac dysfunction, liver failure, multi-organ syndrome, portal hypertension

1 | INTRODUCTION characteristic hyperdynamic circulation with an increased cardiac

Patients with decompensated cirrhosis and portal hypertension
typically present with one or several of the classical complications
such as oesophageal varices, presence of ascites and sand renal
1,2
failure. Clinically, the patients often show signs of vasodilation
with characteristic changes in splanchnic as well as in systemic
3-5
­haemodynamics. Among splanchnic haemodynamic changes are
an increased splanchnic inflow together with an increase in the
post-­sinusoidal resistance leading to an increase in portal pres-
sure reflected by measurement of hepatic venous pressure gradi-
ent.6,7 In addition, patients with cirrhosis typically present with a
output, increased heart rate, and low systemic vascular resistance
(SVR) and low arterial blood pressure.8-10 From a haemodynamic
point of view, the patients exhibit a vascular hyporeactivity with a
generalized increased vascular compliance.11,12 The peripheral ar-
terial vasodilatation hypothesis was launched nearly 40 years ago
and was based on the assumption of a progressive splanchnic arte-
rial vasodilatation that induced abnormalities in splanchnic and sys-
temic haemodynamics.13 An important consequence of the arterial
vasodilatation was an increased portal venous inflow contributing
to increased portal pressure.4,14 In the systemic circulation, the arte-
rial vasodilatation leads to reduced central blood volume mimicking

Abbreviations: ACLF, acute-on-chronic liver failure; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; BRS, baroreflex sensitivity; CGRP, calcitonin gene-related peptide; CRP,
C-reactive protein; EIVPD, ejection-induced ventricular pressure difference; eNOS, endothelial nitric oxide synthase; HBF, hepatic blood flow; HRS, hepatorenal syndrome; HSC, hepatic stellate
cell; hsTnT, high sensitive troponin T; HVR, hepatic vascular resistance; IL, interleukin; LPS, lipopolysaccaride; MELD, model of end-stage liver disease; mIBG, metaiodobenzyl-guanidine; PAMPs,
pathogen-associated molecular patterns; PRR, pattern recognition receptors; RAAS, renin-angiotensin-aldosterone system; RAI, relative adrenal insufficiency; SEC, sinusoidal endothelial cell;
SIRS, systemic inflammatory response syndrome; SNS, sympathetic nervous system; SVR, systemic vascular resistance; TDI, tissue Doppler imaging; TIPS, transjugular intrahepatic portosystemic
shunt; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.

570  |  wileyonlinelibrary.com/journal/liv

© 2017 John Wiley & Sons A/S. Liver International. 2018;38:570–580.
Published by John Wiley & Sons Ltd
MØLLER and BENDTSEN
a physiological effective hypovolemia.15 Despite intense activation
of endogenous vasoconstrictive systems, the patients inevitably de-
velop arterial hypotension partly due to reduced vascular respon-
siveness to vasoconstrictors.16,17 Along with the progression of the
disease, the circulation becomes more and more hyperdynamic until
a certain limit. The cardiac output cannot increase further and arterial
blood pressure continues to decreases with activation of vasocon-
strictors and augmented renal sodium and water retention.18 These
patients develop ascites and with the progression and development
of hyponatremia the ascites become refractory to treatment.19,20
The arterial vasodilatation hypothesis accounts for some of the
mechanisms underlying the progressive stage of decompensation in
cirrhosis, but other factors such as cardiac dysfunction contribute
to the reduction of effective hypovolemia in advanced cirrhosis and
the cirrhotic heart fails to compensate for the pronounced arterial
vasodilatation.21,22 Within the recent years, bacterial translocation
has been suggested to play a major role in terms of bacterial expres-
sion of pathogen-­associated molecular patterns (PAMPs).23,24 The
purpose of the present review is to highlight contemporary knowl-
edge on the pathophysiology of development of the hyperdynamic
circulation in patients with decompensated cirrhosis.
2 | LIVER FAILURE
2.1 | Hepatocellular dysfunction
The loss of functional liver cell mass and development of liver dysfunc-
tion leads to decreased metabolism of potential harmful vasodilators,
which induces a peripheral arterial vasodilatation. The hepatocytes
have essential physiological functions in terms of synthesis, metabo-
lism, clearance, and inactivation of drugs, hormones, alcohol, toxic and
vasoactive substances.25 One of the essential functions of the liver is
the synthesis of plasma proteins of importance for oncotic pressure
(albumin), immune system (C-­reactive protein [CRP], complement) and
coagulation (fibrogen, coagulation factors 2,7 and 10). The metabolic
function is often impaired in patients with acute-­on-­chronic liver fail-
ure (ACLF) owing to apoptosis of the hepatocytes.26 When exposed to
toxic substances such as alcohol or viruses, activation of hepatic stel-
late cells (HSCs) among others initiate fibrogenesis and, subsequently
cirrhosis.27 Along with this process, the metabolic function becomes
increasingly disturbed and the hepatic clearance of a number of vaso-
active substances such as atrial natriuretic peptide (ANP), glucagon,
renin, angiotensin II, substance P, vasopressin and aldosterone are im-
paired.28 The importance of hepatocellular dysfunction as an essen-
tial component in the development of the hyperdynamic circulation
in cirrhosis is evidenced by the predictive value of the MELD score
for development of a hyperdynamic circulation in cirrhotic patients
undergoing liver transplantation.9
2.2 | Development of portal hypertension
A prerequisite for the development of the hyperdynamic circulation
is the presence of portal hypertension. According to the hydraulic
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      571
Key points
• Liver dysfunction and portal hypertension are important
determinants of the hyperdynamic circulation.
• Arterial vasodilatation is a major pathophysiological
factor.
• The hyperdynamic circulation affects many organ ­systems
including the heart.
• The hyperdynamic state may affect the prognosis of the pa-
tients and are partly reversible after liver transplantation.
• Future research should be directed towards better insight
in the pathophysiological process and the effects of
­established and new pharmacological principles on
survival.
equivalent of the law of Ohm (U = R•I), the portal pressure is de-
termined by hepatic vascular resistance (HVR) as well as the hepatic
blood flow (HBF). HVR can be divided into fixed and dynamic or cel-
lular components.
Fixed components of the hepatic vascular resistance in cirrhosis
comprise initially fibrogenesis with increasing amount of fibrosis and
development of regeneration nodules in addition to steatosis and
thrombosis.14,27
Dynamic components of the hepatic vascular resistance comprise
cells with paracrine and autocrine effects such as hepatic sinusoidal
endothelial cells (SEC) and cells with contractile properties such as
HSC and smooth muscle cells.29 SECs interact with components in the
portal blood absorbed from the intestines. Thus, exposure to different
bacterial components such as bacterial DNA and lipopolysaccharides
(LPS) induces cell injury and inflammation.30 SEC shows constitu-
tive expression of endothelial NO-­synthase (eNOS) stimulated by
increased HBF, shear stress and paracrine factors such as vascular
endothelial growth factor (VEGF),31,32 see Figure 1. NO production
decreases HVR and thereby portal pressure and contribute to the
regulation of the sinusoidal blood flow and pressure in the cirrhotic
liver.29,31 HSCs are located in the space of Disse and crosstalk with
SEC. Reduced NO production by SEC leads to HSC activation charac-
terized by enhanced contractility of HSC, which represent an essen-
tial dynamic component of the sinusoidal haemodynamic resistance
in cirrhosis.30
The homeostasis of the HBF is essential both from a metabolic
and haemodynamic point of view. HBF equals the ratio of the he-
patic venous pressure gradient and the post-­sinusoidal resistance.
Normally, the hepatic vascular compliance is adequate to preserve
the portal pressure at a constant level. But in cirrhosis, the combi-
nation of an increased systemic vascular compliance and increased
portosystemic shunting with increased hepatic inflow, and reduced
hepatic vascular compliance result in a dramatic increase in portal
pressure.33 Thus, both fixed and dynamic components of the HVR
and haemodynamic components contribute to the development of
portal hypertension.
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572       MØLLER and BENDTSEN

F I G U R E   1   The role of stellate cells, sinusoidal endothelial cells and fibrogenesis in altered haemodynamics after liver injury. Hepatic stellate
cells are activated into myofibroblasts that deposit scar matrix in the Space of Disse. This increases the amount fibrotic tissue as part of the fixed
component of the hepatic vascular resistance. Shear stress on the sinusoidal wall activates NO release from the sinusoidal endothelial cells that
further stimulate the hepatic stellate cells and other endothelial cells. Release of vascular endothelial growth factor (VEGF) from hepatocytes
and hepatic stellate cells stimulate hepatic angiogenesis

inflow.4,42 This further augments the portal pressure and stimulates

2.3 | Arterial vasodilatation
2.3.1 | Vasodilators
There is a considerable amount of evidence for an arteriolar splanch-
nic vasodilatation as a general pathophysiological basis for the portal
hypertension pathophysiology and development of the hyperdynamic
circulatory changes.4,34 The modified “peripheral arterial vasodilation
hypothesis” combines arterial underfilling with a forward increase
in hepatosplanchnic capillary pressure and filtration with increased
35
lymph formation. Of the many potential vasodilators involved, the
most important are listed in Table 1. NO is of particular interest since
it is referred to as one of the most potent vasodilators involved in
the regulation of vascular tone,36 but others may also play important
roles in the fine tuning of the balance between vasoconstricting and
vasodilating forces.37 This delicate homeostatic balance in cirrhosis is
directed towards a continued systemic vasodilatation despite intense
activation of vasoconstrictor systems.38 From a pathophysiologic
point of view, diverse explanations can be given relating to changes
in receptor affinity, receptor down-­regulation and post-­receptor de-
fects, but these mechanisms should be revealed in future studies.39
The pathophysiological coupling between early hepatic failure
and portal hypertension on the one hand and the development of
systemic and splanchnic vasodilatation and the hyperdynamic syn-
drome on the other is still not fully understood. As mentioned above,
an increased intrahepatic resistance leads to portal hypertension
29
and development of portosystemic shunts. The combination of
hepatic failure and portosystemic shunts by-­passing blood away
from the liver increases circulating vasodilators such as NO, arachi-
donic acid metabolites, calcitonin gene-­related peptide (CGRP) and
others (Table 1).36,40,41 An augmented vasodilatation increases plas-
ma-­ and blood volumes and cardiac output and lead to a hyperdy-
namic circulatory state that further increases splanchnic and hepatic
overproduction and liberation of vasodilators by shear stress pref-
erentially in the splanchnic circulation.36,43 In experimental as well
as in human portal hypertension, splanchnic vasodilatation leads to
a reduced SVR, a decreased effective blood volume and reduced
arterial blood pressure with activation of potent vasoconstricting
systems such as the sympathetic nervous system (SNS), the renin-­
angiotensin-­aldosterone system (RAAS) and non-­osmotic release of
vasopressin.8,16,22
Although the pathophysiology and the role of arterial vasodilata-
tion in cirrhosis is complex, there is definite experimental and clinical
evidence that it precedes the counter-­regulatory neurohumoral acti-
vation and the renal sodium and fluid retention. From a clinical point
of view, the hyperdynamic syndrome can be considered a prerequisite
for the development of the multi-­organ failure involving many organ
systems. Disturbed pulmonary function and haemodynamics is termed
the hepatopulmonary syndrome, disturbed cerebral perfusion is typ-
ically seen in patients with hepatic encephalopathy, pronounced re-
duced renal blood flow and glomerular filtration are characteristics of
the hepatorenal syndrome (HRS), and impaired corticosteroid release
is essential in relative adrenal insufficiency (RAI) as covered later42,44
(see Figure 2).
2.3.2 | Inflammation
Patients with cirrhosis are more susceptible to bacterial infections
for several reasons. In addition to a general immune dysfunction, an
increased intestinal permeability facilitates bacterial overgrowth.45,46
These mechanisms contribute to translocation of bacteria from the
gastrointestinal tract to the mesenteric lymph nodes.45,47 In particular,
Gram-­negative bacteria and bacterial products affect the haemody-
namic balance and accentuates the hyperdynamic circulatory state.
Bacteria in the splanchnic lymph nodes, in the ascitic fluid or in the
MØLLER and BENDTSEN |
      573

T A B L E   1   Vasodilating and vasoconstricting forces involved in state to advanced stages of end-­stage liver disease and the increased
disturbed haemodynamics in cirrhosis (alphabetic order) systemic inflammation constitutes an additional aetiology of ACLF.
Vasodilator systems Bacterial translocation of viable bacteria takes place, in particu-
Adenosine lar, in the decompensated cirrhotic state.46 Gram-­negative bacteria,

Adrenomedullin PAMPs bacterial products, such as lipopolysaccharide are associated

with a hyperdynamic circulation and selective intestinal decontamina-
Arachidonic acid metabolites (thromboxane—A2, leukotriens,
epoxyeicosatrienoic acids (EET), prostacyclin (PGI2) and others) tion with norfloxacin decreases vascular NO production and the sys-

Atrial natriuretic peptide temic hyperdynamic circulation.51 However, rifaximin does not seem
to have obvious beneficial effect on the systemic haemodynamics,
Bradykinin
hyperdynamic circulation or renal function in cirrhosis.52
Brain natriuretic peptide
Calcitonin gene-­related peptide
Carbon monoxide
3 | PATHOPHYSIOLOGY OF THE
Endocannabinoids
HYPERDYNAMIC CIRCULATION
Endothelin-­3 (ET-­3) IN CIRRHOSIS
Endotoxin
Enkephalins As mentioned above, reduced hepatic clearance and presence of por-
Glucagon tosystemic shunts increase the circulating levels of vasodilators and
Histamine PAMPs in particular in severely ill patients with ACLF.22,53 The physi-
Hydrogen sulphide ological correlate to systemic vasodilatation is a reduction of the SVR
Interleukins and a functional central hypovolemia and arterial hypotension.29,42

Natriuretic peptide of type C (CNP) Through baroreceptor reflex activation, the SNS, RAAS and the vaso-
pressin system are all activated leading to an increase in heart rate,
Nitric oxide
stroke volume and cardiac output.54-56 However, arterial hypotension
Substance P
persists because of reduced vascular responsiveness to vasoconstric-
Tumour necrosis factor-­α (TNF-­α)
tors.57,58 Increased cardiac output augments flow-­mediated endothe-
Vasoactive intestinal polypeptide
lial production and liberation of, in particular NO into the systemic
Vasoconstrictor systems
circulation.30 This further augments the vasodilatation and increases
Angiotensin II in cardiac output4,59 and therefore systemic NO overproduction can
Adrenaline and noradrenaline be considered a result of a primary hyperdynamic circulation.43 NO
Endothelin-­1 (ET-­1) production may precede the hyperdynamic circulation and increased
Neuropeptide Y shear stress could therefore be considered a feed-­forward mechanism
Renin-­angiotensin-­aldosterone system enhancing further NO production. In addition to mechanical stimuli
Sympathetic nervous system as shear stress, pro-­inflammatory cytokines (TNF-­α) contribute to

Vasopressin (Copeptin) ­NO-­mediated vasodilatation,60,61 Figure 2.

circulation stimulate monocytes and lymphocytes to liberation of
pro-­inflammatory cytokines such as tumour necrosis factor-­α (TNF-­α)
and interleukin (IL)-­6 in indirectly NO as part of a “cytokine storm.”36
Bacteria also express PAMPs, which is accumulated in the systemic
circulation because of impaired hepatic clearance.48 PAMPs are rec-
ognized by the pattern recognition receptors (PRRs) expressed in
immune cells and epithelia and this inflammatory response further
augments the vasodilatory and hyperdynamic state.22,46 The systemic
inflammatory response syndrome (SIRS) denotes a condition some-
times seen in patients with cirrhosis. It includes fever, increased heart
rate, respiratory failure, an activated immune system and sepsis with
confirmed bacterial etiology,49,50 see Figure 2. Recently, a new modi-
fied version of the arterial vasodilatation hypothesis has been pro-
posed, “The systemic inflammation hypothesis” of decompensation
of cirrhosis, HRS and ACLF.22 According to this hypothesis, bacterial
translocation affects the course of cirrhosis from the compensated
Bile acids may exert a suppressive effect on the cardiovascular
system. Recently, Desai et al62 found that high concentrations of bile
acids were associated with increased ejection fraction and shorten-
ing fraction of the left ventricle but lower heart rate. The same group
recently used a double knockout model (Fxr−/−; Shp−/−) to show sim-
ilarities between experimental severe bile acid overload and human
cirrhotic cardiomyopathy.62 They found that electrocardiographic and
ultrasonographic features of cardiomyopathy resolved with reversal
of liver injury and the authors proposed a new term “cholecardia” to
describe the cardiodepressant effects of bile acids. These results con-
vincingly argue for a direct and reversible effect of bile acids on cardio-
myocytes. However, most of the studies on the effects on bile acids on
the heart come from experimental studies and more data are need in
human hyperdynamic circulation and cirrhotic cardiomyopathy.63
Vasodilatation leads to impaired vascular reactivity, responsive-
ness to vasoconstrictors and, hence, increased arterial compliance of
the vascular system, which is directly related to the degree of the hy-
perdynamic circulation and degree of arterial hypotension.64 Together
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574       MØLLER and BENDTSEN
with altered mechanical properties of large and small arteries, this
manifests in changed arterial pressure profiles. Thus, the arterial pul-
sation in cirrhosis seems qualitatively changed with reduced pulse
reflections, which may protect against manifest cardiac failure in ad-
vanced cirrhosis.65 This knowledge could be utilized since analysis of
the arterial diastolic reflected waveform by calculation of the diastolic
augmentation index seems to predict hyperdynamic circulation, for ex-
ample, in patients undergoing liver transplantation.66
Activation of the RAAS and other sodium-­water retaining mech-
anisms subsequently expand plasma volume and increase cardiac
preload leading to a further increase in stroke volume and cardiac out-
put.16,67 This may in turn lead to an increase in splanchnic flow and
portal venous inflow into the liver and tend to further increase the
portal pressure.68 Recently, McAvoy et al68 by magnetic resonance an-
giography observed increased hepatic arterial flow and increased liver
blood flow and reduced renal blood flow indicating a dysregulated
splanchnic vasodilatation causing extrasplanchnic vasoconstriction as
part of a splanchnic steal phenomenon. Previously, it has been shown
by Caraceni et al69 that systemic vasodilatation, for example, in femo-
ral skeletal muscles also contributes to the hyperdynamic circulation.
From a pathophysiological point of view, it is unclear which events
that initiate the hyperdynamic circulation and the coupling to splanch-
nic haemodynamics. Thus, in patients with compensated cirrhosis,
features of hyperdynamic circulation are more developed in patients
with clinical significant portal hypertension than in those with a lesser
degree of portal hypertension. 10
In portal-­hypertensive rats, a hy-
perdynamic circulation partly depends on central neural c-­fos gene
expression through the afferent pathway from the gut to the central
cardiovascular-­regulatory nuclei and portal hypertension signals to
F I G U R E   2   Illustration of mechanisms
of development of the hyperdynamic
syndrome in advanced cirrhosis and portal
hypertension. Portal hypertension, liver
failure and immunological incompetence
facilitate bacterial translocation with
release of pathogen-­associated molecular
patterns (PAMPs), and cytokines (tumour
necrosis factor-­α (TNF-­α, interleukin-­
1β (IL1B) and other vasodilators
including NO. A preferential splanchnic
vasodilatation leads to activation of
vasoconstrictive systems such as the
sympathetic nervous system, the renin-­
angiotensin-­aldosterone system and others,
central hypovolemia, and cardiovascular
dysfunction and gradually development of
a hyperdynamic syndrome
the central nuclei via capsaicin-­sensitive vagal afferent nerves.56,70
Therefore, direct neural pathways from the gut and the liver to the
brain seem to contribute to the hyperdynamic circulatory state.
Similarly, it has been experimentally shown that atrophy of mesenteric
sympathetic innervation contributes to splanchnic vasodilatation.4,71
Results of these experimental studies suggest that portal hypertension
per se also activates central nervous mechanisms and that neural con-
tribution is an essential factor for the development of hyperdynamic
circulation.71 Recently, in a large patient population comprising 410
cirrhotic patients, we found by principal components analysis that a
hyperdynamic circulation was independently associated with a higher
hepatic venous pressure gradient, a higher HBF and presence of as-
cites.8 Furthermore, presence of central hypovolemia was associated
with HBF and hepatic vascular resistance. Therefore, development of
the hyperdynamic circulation and central hypovolemia seem mainly
explained by changes in portal pressure and HBF.8 Although there
seems to be a close correlation between parameters of portal and sys-
temic haemodynamics, it can be discussed what is the chicken and
what is the egg. However, the findings support that a backward shear
stress on splanchnic resistance vessels lead to splanchnic vasodila-
tation and consequently systemic vasodilatation and hyperdynamic
­circulation,72 see Figure 1.
4 | THE HYPERDYNAMIC CIRCULATION
AND THE HEART
Some patients with advanced cirrhosis may exhibit a dysfunctional
heart. Thus, patients with refractory ascites and imminent renal
MØLLER and BENDTSEN
dysfunction may show a declining cardiac output.73,74 In addition,
pharmacological treatment (eg with ß-­blockers) may attenuate the hy-
perdynamic circulatory state and further lower the arterial blood pres-
sure.75,76 Low arterial blood pressure is also associated with increased
mortality and with the development of ascites.77 This emphasizes
that the use of beta-­blockers may be harmful in some patients with
advanced fluid retention and renal dysfunction, but clear evidence is
lacking and future research is needed in this field78-80.
The concept of a cardiac dysfunction in cirrhosis has led to the
clinical entity Cirrhotic cardiomyopathy. This term denotes a chronic
cardiac dysfunction characterized by a blunted contractile respon-
siveness to stress and altered diastolic relaxation with electrophysi-
ological abnormalities, such as prolongation of the Q-­T interval.81
Cirrhotic cardiomyopathy may affect the prognosis and aggravate the
course of the disease during invasive procedures such as the inser-
tion of a transjugular intrahepatic portosystemic shunt (TIPS) and liver
82,83
transplantation.
There are a number of morphometric changes in the heart char-
acterize cirrhotic cardiomyopathy. These changes include an increase
in the left atrial volume and high rates of right-­ventricular abnormal-
ities, which is related to the degree of liver failure but apparently not
to the aetiology of the liver disease.84-86 Similarly, there seems to be
a trend towards an increased left ventricular end-­diastolic volume in
cirrhotic patients, but variable results have been obtained.87-89 Several
clinical and autopsy studies have reported left ventricular hypertrophy
owing to a combination of the hyperdynamic circulation, activation of
the RAAS, and increased circulating levels of endotoxins, cytokines
and bile acids, all facilitating myocardial remodelling.85,86,88,90-92 The
morphometric changes in the myocardial mass tend to increase the
stiffness of the ventricle, which affects the emptying of the ventricle,
thereby contributing to diastolic dysfunction.93 Hypertrophy and dif-
fuse fibrosis can be revealed both macroscopically and microscopically.
Moreover, it has been suggested that the finding of cardiomyocytes of
varied diameters, irregularly shaped nuclei and unusual pigmentation
in cardiac biopsies from cirrhotic hearts may represent early micro-
scopic changes in cirrhotic cardiomyopathy.94
4.1 | Systolic dysfunction
Although the heart appears hyperdynamic with increased cardiac
output, stroke volume and ejection fraction, a systolic dysfunction
may become manifest under conditions of haemodynamic or pharma-
cological stress. This leads to a further increase in the end-­diastolic
ventricular pressures after stress and an increased stroke index and
95,96
left ventricular ejection fraction. Recently, Yotti and Ripoll et al
assessed systolic function in patients with cirrhosis by echo-­Doppler
M-­mode measurement of ejection intraventricular pressure differ-
ence (EIVPD), a new sensitive measure of systolic function. The au-
thors found that systolic function as measured by EIVPD was related
to the severity of the liver disease expressed as MELD score, presence
of ascites, SNS activity, heart rate variability and treatment with beta-­
blockers. In an interventional sub-­study, an increase in cardiac after-
load by infusion of phenylephrine resulted in a decrease in systolic
|
      575
function and cardiac output and the changes markers of inflamma-
tion.97 Results of this and other studies suggest that the function of
the hyperdynamic left ventricle in cirrhosis is related to the severity of
the liver disease and activation of SNS and that treatment with beta-­
blockers significantly affects cardiac systolic function.9 The use of
potent vasoconstriction drugs such as terlipressin reduces heart rate
and cardiac output, an effect that could be considered an ameliora-
tion of the hyperdynamic circulation.98 However, at the same time,
terlipressin may exert a negative inotropic effect on the left ventricle
and therefore the over-­all effects on the cardio-­vascular system are
complex.96
With the use of modern echocardiographic techniques, impaired
systolic function can also be detected at rest. Such techniques include
tissue-­Doppler Imaging (TDI) and speckle tracking echocardiography
with possibility to detect the systolic and diastolic dysfunction while
the patient is at rest.99,100
Along with the progression of the liver dysfunction and the ar-
terial vasodilatation, the cardiac systolic performance may reach a
maximum. The cirrhotic heart seems hereafter unable further to in-
crease the cardiac output with the result of central underfilling and
effective hypovolemia,16,101 see Figure 2. Many cirrhotic patients with
end-­stage cirrhosis develop renal failure and there is evidence that
the terminal decline in cardiac output is related to the progression of
renal failure and survival.73,74 A cardiorenal interaction seems there-
fore to be a major determinant for the development of nephropathy
in cirrhosis.18,102-105
4.2 | Diastolic dysfunction
The term diastolic dysfunction relates to the filling of the left ven-
tricle and thereby directly to the stiffness or compliance of the
myocardial wall of the left ventricle.93 The increased stiffness is at-
tributed to cardiac hypertrophy, patchy fibrosis and subendothe-
lial edema.86,90,94,106,107 Presence of diastolic dysfunction can be
assessed by Doppler-­echo-­cardiography by measuring a decreased
E/A ratio and delayed early diastolic transmitral filling with prolonged
deceleration and isovolumetric relaxation times.92 The corresponding
characteristics are also indicated on the tissue-­Doppler and speckle
tracking echocardiography.92,99,108 The prevalence of diastolic dys-
function in cirrhosis may be up to 40%-­50% depending on the popu-
lation.108,110 The presence of diastolic dysfunction seems related to
severity of disease,111,112 development of complications83,111,113 and
­mortality.111,114 Moreover, diastolic dysfunction predicts the course
after TIPS insertion.115,116
97
4.3 | Neurocardiac abnormalities
Autonomic dysfunction in cirrhosis is expressed in different ways such
as, for example, conductance aberrations with prolonged Q-­T interval,
decreased heart rate variability and low baroreflex sensitivity.56 The
neurocardiac changes and autonomic dysfunction are closely related
to the hyperdynamic circulation and portal hypertension.56 Thus, we
have previously described a relation with the prolonged Q-­T interval
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576       MØLLER and BENDTSEN
and increased cardiac output, increased heart rate and decreased heart
rate variability.21,117-119 Decreased heart rate variability has been known
in cirrhosis for years with significant relations to clinical and haemody-
namic characteristics.119-121 In addition, autonomic dysfunction in cir-
rhosis is mirrored by presence of chronotropic incompetence, increased
sympathetic nervous system activity and decreased baroreflex sensitiv-
ity (BRS).122 During exercise, cirrhotic patients are unable to increase
their heart rate, which increases less in response to the activation of
the sympathetic nervous system.110 Chronotropic incompetence may
therefore be an important factor for the fading cardiac output at the
end-­stage when hypovolemia is aggravated.81 Reduced BRS can be
considered a vascular hyporeactivity to vasoconstrictors with an im-
paired response in blood pressure and changes in haemodynamics.122
Thus, impaired BRS is related to central haemodynamics, which points
to the assumption that autonomic dysfunction is associated with cardiac
dysfunction and the hyperdynamic circulation in cirrhosis.54 This is fur-
ther supported by the finding of an autonomic dysfunction reflected by
reduced cardiac noradrenaline uptake in patients with cirrhosis by the
55
use of mIBG-­scintigraphy. Therefore, the combination of chronotropic
incompetence and impaired BRS seems to involved in the augmented
increase in cardiac output in advanced stages of cirrhosis. Most of the
features of the autonomic dysfunction are reversible after liver trans-
plantation confirming the central role of hyperdynamic circulation and
portal hypertension in determining the neurocardiac abnormalities.56
4.4 | Biomarkers of cardiovascular dysfunction
Biomarkers of the cardiovascular system may reflect the underlying
mechanisms of vasodilatation (NO, CGRP) as well as cardiac failure
(natriuretic peptides, cardiac troponin-­1, high sensitive troponin T
(hsTnT) and cytokines), and counter-­regulation (RAAS, SNS and the
vasopressin system [copeptin]).37
In cirrhosis, brain natriuretic peptides (BNP and pro-­BNP) are re-
lated to disease severity, cardiac dysfunction (QT-­interval prolonga-
tion) and survival.123 Circulating atrial natriuretic peptides (ANP and
pro-­ANP) is increased in decompensated cirrhosis and is related to the
progression of liver dysfunction, portal hypertension and imbalance of
37,40,124
systemic haemodynamics.
Cardiac troponin I and hs-­TnT are cardiovascular markers, where
troponin I is increased in some patients with cirrhosis indicating sub-
125
clinical myocardial injury and impaired systolic function. Also in
patients with cirrhosis hs-­TnT has proved to be a strong independent
38
predictor of a poor long-­term outcome. Nevertheless, the specific
predictive and diagnostic value of cardiovascular biomarkers needs to
be thoroughly assessed in larger prospective studies to define their
role in the evaluation of cardiac dysfunction in patients with cirrhosis.
5 |  THE HYPERDYNAMIC CIRCULATION
AND THE KIDNEYS
Renal failure is a common complication in cirrhosis and ranges from
acute kidney injury (AKI) and chronic kidney disease to end-­stage liver
disease with development of HRS.101,105,126,127 HRS occurs in approxi-
mately 20% of patients with ascites and is largely functional with a
pronounced renal vasoconstriction in the face of a splanchnic arterial
vasodilatation.101 From a pathophysiological point of view, the major
three elements in the development of HRS are liver dysfunction, the
hyperdynamic circulatory state with low arterial blood pressure and
abnormal neurohumoral regulation.128 The SNS and RAAS are highly
activated in patients with HRS and associated with increased mortal-
ity.16,67,129,130 Administration of non-­selective beta-­blocker dampens
the hyperdynamic circulation and may negatively affect and further
reduce the low blood pressure and renal blood flow in patients with
HRS. It has been debated whether beta-­blockers may be harmful in
these patients and in patients with decompensated cirrhosis, but these
reservations have not been confirmed.80 With the progression of the
vasodilatation and reduction of the SVR, the cardiac output seems to
reach a maximal level.101,131 The result is a further reduction in CBV
and arterial blood pressure and this terminal decline in cardiac output
may augment the progression of renal failure.73,74,132 We have there-
fore recently put forward the hypothesis of the presence of a cardio-
renal syndrome in cirrhosis, which indicates that cardiac dysfunction in
cirrhosis is a major determinant of the course of patients who develop
HRS.18,133 In patients with cirrhosis, the term “cardiorenal” suggests
a condition in which progressive renal dysfunction is related to a de-
cline in cardiac systolic function.75,134 Therefore, considering the renal
changes in end-­stage liver disease as a cardiorenal syndrome compa-
rable to what is observed in, for example, patients with advanced car-
diac failure may increase our understanding on the pathophysiologic
course in chronic liver disease.
6 | RELATIVE ADRENAL INSUFFICIENCY
Patients with cirrhosis are susceptible to infections that may con-
tribute to and elicit severe complications including renal failure and
sepsis.135-137 From a haemodynamic point of view, there are many
similarities between full-­blown sepsis and advanced cirrhosis since
both conditions are characterized by a hyperdynamic circulatory
failure and signs of inflammation.42,138,139 RAI is defined by insuf-
ficient cortisol production of cortisol, which is a prerequisite for
an adequate stress response.140 RAI is observed in patients with
heart and kidney diseases in whom RAI is a risk factor in particu-
lar in those patients with sepsis owing to immune disorders.140,141
TNF-­α, IL-­6 and other cytokines suppress the pituitary ACTH se-
cretion and hence lead to inadequate adrenal cortisol secretion.142
In cirrhosis, RAI may be part of a hepato-­adrenal syndrome with
comparable cytokine-­induced disturbances in the pituitary-­adrenal
axis.142,143 Since patients with adrenal insufficiency often present
with cardiac dysfunction, we recently hypothesized that RAI may
contribute to cardiac dysfunction in cirrhosis as part of a cardio-
adrenal syndrome.143 Therefore, the relationship between develop-
ment of cardiac dysfunction, renal failure, and the hyperdynamic
circulation and RAI should be topic for future research in patients
with cirrhosis.
MØLLER and BENDTSEN
7 | CONCLUSION
Cirrhosis and portal hypertension lead to a splanchnic and peripheral
arterial vasodilatation with development of a hyperdynamic circulatory
state. From a pathophysiological point of view, increases in vasodilators
owing to portosystemic shunting and bacterial translocation augment
the hyperdynamic circulation and central hypovolemia. The hyperdy-
namic state results in a hyperdynamic multi-­organ syndrome that af-
fects many organ systems including the cardiovascular system with
development of a cirrhotic cardiomyopathy, autonomic dysfunction
and renal dysfunction as part of a cardiorenal syndrome. These haemo-
dynamic changes may affect survival and seem largely reversible after
liver transplantation. Several of the drugs used in the treatment of por-
tal hypertension including non-­selective beta-­blockers and terlipressin
beneficially affect the hyperdynamic circulation. Our understanding of
the pathophysiological processes is essential for future research in this
area and should be directed towards the effects of established and new
pharmacological principles on mortality in relation to precipitating fac-
tors and potential stressful procedures such as TIPS insertion.
CO NFLI CTS OF I NT E RE S T
The authors do not have any disclosures to report.
O RCI D
Søren Møller  http://orcid.org/0000-0001-9684-7764
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How to cite this article: Møller S, Bendtsen F. The
pathophysiology of arterial vasodilatation and hyperdynamic
circulation in cirrhosis. Liver Int. 2018;38:570–580.
https://doi.org/10.1111/liv.13589