Cardiovascular complications of cirrhosis

[Guest guest]

Cardiovascular complications of cirrhosis

Gut Feb 2008;57:268-278

S Møller, J H Henriksen

Department of Clinical Physiology 239, Hvidovre Hospital, University

of Copenhagen, Copenhagen, Denmark

“….The deterioration of the liver function is followed by a

decreased renal blood flow and glomerular filtration rate, and

increased sodium and water reabsorption, and may progress into the

hepatorenal syndrome, a functional and reversible renal impairment in

severely ill patients…â€

CONCLUDING COMMENTS

Cardiovascular complications in cirrhosis may arise on the basis of

combined humoral, nervous and haemodynamic changes. Cirrhotic

cardiomyopathy suggests a systolic and diastolic dysfunction and

electrophysiological abnormalities. It is different from alcoholic

heart muscle disease and appears to be unmasked by procedures that

stress the heart, such as pharmacological vasoconstriction, exercise,

and by insertion of TIPS (Box 1).59 Potential diagnostic tools

primarily include echocardiography and ECG (table 5). The

cardiovascular complications in cirrhosis and cirrhotic

cardiomyopathy may be part of a multiorgan syndrome that affects the

patients' prognosis.1 2 No specific treatment can be recommended, and

is largely empiric and supportive. Caution should be exercised with

respect to stressful procedures, such as large volume paracentesis

without adequate plasma volume expansion, TIPS insertion,

peritoneovenous shunting and surgery.4 Cardiac failure is an

important cause of mortality after liver transplantation. On the

other hand, liver transplantation has been shown to reverse systolic

and diastolic dysfunction and the prolonged Q-T interval.69 Thus,

although the post-transplant pathophysiological mechanisms are

complex, liver transplantation appears to be an effective treatment

of the cardiovascular complications of cirrhosis.

Improvement of left ventricular contractility with ACE inhibitors

should be done with care, as this may provoke severe arterial

hypotension. β-Blockers have been shown to reduce acutely the

prolonged Q-T interval and may, in addition to the cardioprotective

effects, be of benefit.79 82 However, effects on morbidity and

mortality remain to be shown in longitudinal studies.

Future studies should be directed towards a delineation of the

clinical importance of cardiovascular complications and cirrhotic

cardiomyopathy, and randomised to examine benefits of the treatments

outlined above.

Box 1: Key points of cirrhotic cardiomyopathy

* Present in the face of a hyperkinetic circulation with a

combined systolic and diastolic dysfunction together with

electrophysiological abnormalities.

* Different from alcoholic heart muscle disease

* Systolic dysfunction demasked by physical or pharmacological

stress

* Diastolic dysfunction detected by echocardiographic measurement

of the E/A ratio

* Q-T interval prolongation assessed on the ECG and adjusted

adequately

* Treatment is non-specific and directed towards the left

ventricular heart failure

ABSTRACT

Cardiovascular complications of cirrhosis include cardiac dysfunction

and abnormalities in the central, splanchnic and peripheral

circulation, and haemodynamic changes caused by humoral and nervous

dysregulation. Cirrhotic cardiomyopathy implies systolic and

diastolic dysfunction and electrophysiological abnormalities, an

entity that is different from alcoholic heart muscle disease. Being

clinically latent, cirrhotic cardiomyopathy can be unmasked by

physical or pharmacological strain. Consequently, caution should be

exercised in the case of stressful procedures, such as large volume

paracentesis without adequate plasma volume expansion, transjugular

intrahepatic portosystemic shunt (TIPS) insertion, peritoneovenous

shunting and surgery. Cardiac failure is an important cause of

mortality after liver transplantation, but improved liver function

has also been shown to reverse the cardiac abnormalities. No specific

treatment can be recommended, and cardiac failure should be treated

as in non-cirrhotic patients with sodium restriction, diuretics, and

oxygen therapy when necessary. Special care should be taken with the

use of ACE inhibitors and angiotensin antagonists in these patients.

The clinical significance of cardiovascular complications and

cirrhotic cardiomyopathy is an important topic for future research,

and the initiation of new randomised studies of potential treatments

for these complications is needed.

The course in most cirrhotic patients is dominated by complications

to portal hypertension, such as bleeding from oesophageal varices and

ascites with the development of spontaneous bacterial peritonitis,

renal impairment and encephalopathy. Some patients, however, seem to

die of causes unrelated to these complications. A closer clinical

look shows that a number of these patients display signs of

cardiovascular disturbances secondary to vasodilatation, with palmar

erythema and reddish skin, raised and bounding pulse, and a low

systemic blood pressure indicating a hyperdynamic circulation.1 2 The

hyperdynamic syndrome was first described >50 years ago and comprises

increased heart rate, cardiac output and plasma volume, and reduced

systemic vascular resistance and arterial blood pressure.1-3 The

hyperdynamic syndrome is today a well-characterised element in the

clinical appearance of the cardiovascular complications of cirrhosis

and portal hypertension of various aetiologies.1 2 Experimental and

clinical findings of impaired cardiac function have led to the

introduction of the new clinical entity, cirrhotic cardiomyopathy,

but cardiac dysfunction is not seen in all patients, especially not

in those with less advanced disease, and its clinical significance is

still under discussion.4 This review will primarily centre on

clinical and pathophysiological aspects of the circulatory and

cardiac complications of advanced cirrhosis.

THE CIRCULATION IN CIRRHOSIS

An increase in cardiac output can be attributed to an increase in

venous return, heart rate and myocardial contractility, all of which

are controlled by the autonomic nervous system. Vasodilatation (low

systemic vascular resistance), the presence of arteriovenous

communications, expanded blood volume and increased sympathetic

nervous activity may further raise the cardiac output; most of these

pathophysiological mechanisms are active in advanced cirrhosis.1 2 In

the early stages, the presence of a hyperdynamic circulation is often

not apparent. However, with the progression of the liver disease,

there is an overall association between the severity of the cirrhosis

and the degree of hyperdynamic circulation. Studies on circulatory

changes with posture suggest that the patients are mostly

hyperdynamic in the supine position.3 5 6 Blood and plasma volumes

are raised in advanced cirrhosis, but the distribution between

central and non-central vascular areas is unequal.7 8 Thus, by

different techniques it has been established that the central and

arterial blood volume-that is, the blood volume in the heart, lungs

and central arterial tree-is most often decreased, whereas the non-

central blood volume, in particular the splanchnic blood volume, is

increased in animals and patients with cirrhosis (see table 1).2 7 9

10 The effective arterial blood volume (ie, the circulatory

compartment sensed by baroreceptors) and the central circulation time

(ie, central blood volume relative to cardiac output) are

substantially reduced and bear a significant relationship to poorer

survival in advanced cirrhosis.11

Total vascular compliance as well as arterial compliance (ie, an

increase in intravascular volume relative to an increase in

transmural blood pressure) are increased in cirrhosis with the degree

of decompensation.12 13 The altered static and dynamic

characteristics of the wall of large arteries are closely associated

with the circulatory and homoeostatic derangement.7 13 14 Arterial

compliance depends on the properties of the elastic and smooth muscle

of the arterial wall and represents an important coupling between the

heart and the arterial system with respect to relocation of

intravascular volume.14 The changes in arterial mechanics are

reversible at least in part.13 An element in the elevated arterial

compliance in advanced cirrhosis is the reduced arterial blood volume

and blood pressure.7 Arterial compliance expresses the stroke volume

relative to the pulse pressure and is directly related to the

severity of cirrhosis.13 14 However, in contrast to the systemic

vascular resistance, arterial compliance may be determined

independently of flow and pressure by pulsewave velocity.14 In

addition, the arterial compliance in cirrhosis seems to be affected

by vasoactive forces as it correlates directly with the vasodilator

calcitonin gene-related peptide (CGRP) and inversely with

catecholamines.13 The arteriolar tone adjusts the level of the blood

pressure and may thereby influences large artery compliance. Recent

data suggest that the hyperdynamic circulation is mainly caused by

circulatory alterations in the splanchnic area.15 Thus, arteriolar

vasodilatation would be a more localised event, whereas the elevation

in arterial compliance may be more systemic.7 Arterial compliance may

therefore be an integral variable for vascular responsiveness,

together with the systemic vascular resistance. Arterial compliance

is easy to determine and elevated in advanced cirrhosis. Besides a

relationship to age, body size, sex and the level of arterial blood

pressure, arterial compliance is directly related to the severity of

cirrhosis, the hyperdynamic circulatory derangement and abnormal

volume distribution. Its role in clinical hepatology, however,

remains to be established.

The pulmonary vascular resistance is often decreased in cirrhosis,

except in the 2-4% of the patients with portopulmonary

hypertension.16 Some patients exhibit characteristic vascular

abnormalities with arteriovenous shunts and intrapulmonary

dilatations.1 16 Ventilatory lung function and diffusion are impaired

in the majority of the patients, and the combination of vascular

abnormalities, reduced transfer factor and low arterial oxygen

saturation has been termed the hepatopulmonary syndrome.16 In

patients with cirrhosis, the reduced transfer factor correlates with

the low pulmonary blood volume, which suggests that central

underfilling also plays a role in the impairment of pulmonary

function.17

Pathophysiology of splanchnic arteriolar vasodilatation

Arteriolar vasodilatation in cirrhosis and portal hypertension may be

brought about by a combination of overproduction of circulating

vasodilators, vasodilators of intestinal or systemic origin,

vasodilators that escape degradation in the diseased liver or bypass

the liver through portosystemic collaterals, reduced resistance to

vasoconstrictors and increased sensitivity to vasodilators.1 2

According to " the arterial vasodilation hypothesis " , splanchnic

arteriolar vasodilation leads to reduction of the systemic vascular

resistance, central arterial underfilling with effective

hypovolaemia, activation of vasoconstrictor systems, such as the

sympathetic nervous system (SNS), the renin-angiotensin-aldosterone

system (RAAS), vasopressin, endothelins (ETs) and neuropeptide Y, and

hence development of a hyperkinetic circulatory state.1 8 18 Thus,

most of the haemodynamic changes summarised in table 1 and figure 1

can be explained by this theory. The predominantly splanchnic

vasodilation in cirrhosis precedes the increase in cardiac output and

heart rate, and it has recently been shown experimentally that mild

increases in portal pressure upregulate nitric oxide synthase

(eNOS).19 With the progression of the disease, the splanchnic

vasodilatation becomes more pronounced and the hyperdynamic

circulation may no longer be sufficient to correct the effective

hypovolaemia.20 21 The splanchnic circulation is less sensitive to

the effects of angiotensin II, noradrenaline and vasopressin because

of the surplus of vasodilators which may play a role in the

development of the vascular hyporesponsiveness to vasoconstrictors.22

The arterial blood pressure is mainly maintained by vasoconstriction

in the renal, cerebral and hepatic vascular beds where there seems to

be a diminished release of nitric oxide (NO) from endothelial

cells.15 23

To explain the vasodilatation in the systemic circulation, recent

research has focused especially on substances such as NO, CGRP and

adrenomedullin, but natriuretic peptides, interleukins, hydrogen

sulphide, ETs and endocannabinoids have also been implicated (table

2).1 Blockade of NO formation in animal models and cirrhotic patients

significantly increases arterial blood pressure and decreases plasma

volume, sodium retention and forearm blood flow.24 25 Taken together,

there is a growing body of evidence that systemic NO production is

increased and precedes the development of the hyperdynamic

circulation in cirrhosis, thereby playing a major role in the

arteriolar and splanchnic vasodilation and vascular hyporeactivity.15

In addition, vascular endothelial growth factor (VEGF) seems to

stimulate angiogenesis and the development of portosystemic

collaterals, and blockade of the VEGF receptor-2 has been shown

experimentally to inhibit this process and revert portal hypertension

and the hyperdynamic circulation.19 26 In addition, recent studies

have suggested that the haem oxygenase-carbon monoxide pathway

mediates hyporeactivity to phenylephrine in splanchnic vessels.27

CGRP and adrenomedullin are powerful vasodilating peptides, which are

both elevated in cirrhosis, especially in those patients with ascites

and the hepatorenal syndrome correlating with markers of central

hypovolaemia.1 Hydrogen sulphide is a gaseous transmitter with potent

vasodilating properties, which has recently been implicated in

vascular abnormalities in cirrhosis.28 New experimental data suggest

that defective rho-kinase signalling may also contribute to the

hypocontractility in cirrhosis.29 Thus, the excess of vasodilators

combined with an inadequate haemodynamic response to vasoconstrictors

may explain the vasodilatatory state and vascular hyporeactivity in

cirrhosis combined with a hyperdynamic circulation, but the

pathophysiological mechanisms behind the development of the

hyperdynamic circulation in cirrhosis may be multifarious, as listed

in table 3.

The hepatic circulation

From a haemodynamic point of view, the hepatic vascular resistance

and portal inflow determine the level of portal pressure. Factors

that determine the hepatic vascular resistance include both

structural and dynamic components. Among the structural components

are histological characteristics such as steatosis, fibrosis and

regeneration nodules. Dynamic structures include cells with

contractile properties such as hepatic stellate cells, myofibroblasts

and smooth muscle cells.30 Portal venous inflow is mainly determined

by the degree of splanchnic vasodilation. In healthy subjects, the

hepatic blood flow equals the splanchnic blood flow, but patients

with portal hypertension have a substantial portosystemic collateral

circulation, and an increased mesenteric inflow of up to several

litres per minute has been reported (table 1). Thus, a large part of

the increased cardiac output is returned through portosystemic

collaterals. The azygous blood flow is especially important, as the

azygous vein drains oesophageal varices and an increase in azygous

flow is associated with an increased risk of variceal bleeding.11 β-

Blockers, nitrates, octreotide, terlipressin, etc. can reduce the

increased splanchnic blood flow pharmacologically, and infusion of

these drugs may in some patients partially reverse the hyperkinetic

mesenteric circulation. As outlined above, there seems to be a

defective sinusoidal eNOS-derived production of NO.15 In addition,

recent investigations of endogenous vasoactive substances have

focused especially on ET-1, angiotensin II, catecholamines and

leukotrienes in the increased hepatic-sinusoidal resistance.1 30 The

haemodynamic imbalance with a predominant sinusoidal constriction may

contribute significantly to the development of portal hypertension

and be an important target for treatment.

Volume distribution and circulatory dysfunction

Imbalance between vasodilating and vasoconstricting forces in

cirrhosis contributes to an abnormal distribution of volume, vascular

resistance and flow. Although the cardiac output is increased,

thereby reflecting substantial vasodilatation, it covers

hyperperfused, normoperfused and hypoperfused vascular beds. Thus, in

the kidney, vasoconstriction prevails and plays a pivotal role along

with the development of hepatic decompensation. Liver dysfunction,

central hypovolaemia, arterial hypotension and neurohumoral

activation of particularly the RAAS and SNS with renal

vasoconstriction is of major importance.1 20 The increased plasma

volume in cirrhosis should therefore be considered secondary to the

activation of neurohumoral mechanisms consequent on mainly splanchnic

vasodilatation, low arterial blood pressure and reduced central and

arterial blood volume.

Central hypovolaemia and arterial hypotension may be ameliorated by

infusion of plasma expanders. During volume expansion, most cirrhotic

patients respond with a further reduction in systemic vascular

resistance rather than an increase in arterial blood pressure.7 9 The

infusion of hyperosmotic solutions or albumin in cirrhosis results

initially in a shift of fluid from the interstitial space into the

plasma volume, with expansion of the latter.7 9 Irrespective of

severity, volume expansion produces a rise in stroke volume and

cardiac output. In early cirrhosis there is a proportional expansion

of the central and non-central parts of the blood volume, whereas in

late cirrhosis, expansion is mainly confined to the non-central part,

with a proportionally smaller increase in cardiac output, probably

because of cardiac dysfunction and abnormal vascular compliance.9 31

Similar effects are seen after infusion of a plasma protein solution,

whereas infusion of packed red blood cells may be less efficient

possibly because of a difference in the trapping of NO and shear

stress.1

When therapeutic paracentesis is done in decompensated cirrhosis

without administration of plasma expanders, about 75% of patients

will develop what is termed paracentesis-induced circulatory

dysfunction.32 This condition is characterised by a pronounced

activation of the RAAS and SNS, which reflects central hypovolaemia.

It is mainly caused by a paracentesis-induced splanchnic arteriolar

vasodilatation and brings about a further reduction in the systemic

vascular resistance.33 Intravenous infusion of albumin has been shown

to prevent complications caused by circulatory dysfunction and may

prevent development of renal failure and rapid occurrence of ascites,

and prolong survival.32 Recent studies have shown, however, that

administration of vasoconstrictors such as terlipressin or

noradrenaline may be effective alone or especially in combination

with albumin.34 35 Paracentesis-induced circulatory dysfunction is

thus an example of a cirrhotic condition where complications

attributable to a potentially reduced effective blood volume can be

prevented by a specific volume expansion.

The deterioration of the liver function is followed by a decreased

renal blood flow and glomerular filtration rate, and increased sodium

and water reabsorption, and may progress into the hepatorenal

syndrome, a functional and reversible renal impairment in severely

ill patients (table 1).20 However, glomerular hyperfiltration has

been described in some patients with preascitic cirrhosis.36

Recently, a new concept has been put forward in the

pathophysiological explanation of renal dysfunction as a circulatory

dysfunction characterised by insufficient cardiac output leading to

effective hypovolaemia.20 21 This concept is supported by data from a

longitudinal study in non-azotaemic cirrhotic patients suggesting

that circulatory dysfunction with a decrease in cardiac

output_combined with splanchnic arterial vasodilatation and

activation of the RAAS contribute to renal dysfunction and the

hepatorenal syndrome.20 37 Angiotensin II mainly acts on the efferent

arteriole, and a low dose of an ACE inhibitor may induce a

significant reduction in glomerular filtration and a further

reduction in sodium excretion, even in the absence of a change in

arterial blood pressure. This suggests that the integrity of the RAAS

is important for the maintenance of renal function in cirrhotic

patients and that RAAS overactivity does not solely contribute to the

adverse renal vasoconstriction. Treatment of the hepatorenal syndrome

is directed towards improving liver function by liver

transplantation, arterial hypotension and central hypovolaemia, and

reducing renal vasoconstriction, for instance with the combined use

of splanchnic vasoconstrictors such as terlipressin and plasma

expanders such as human albumin.20

The circulation of the extremities

The cutaneous and muscular circulations may be increased in patients

with cirrhosis.1 Palmar erythema, spider naevi and potatory face were

early recognised as clinical signs of cutaneous hyperperfusion. These

types of circulatory abnormalities illustrate capillary

hyperperfusion and the presence of arteriovenous fistulae. Muscular

circulation is reported to be increased, normal and reduced in

patients with cirrhosis.38 39 Evaluation of brachial and femoral

artery blood flow by Doppler techniques has failed to disclose a

clear hyperdynamic perfusion of the limbs.38 39 Recently, however, it

has been shown that blockade of NOS causes peripheral

vasoconstriction in the forearm in cirrhosis and that this system

contributes in the regulation of the peripheral vascular tone and to

the hyperdynamic state.25 Estimates of skin blood flow by nuclear

medicine techniques have shown normal capillary skin blood flow in

cirrhotic patients.40

The techniques used are hampered by various caveats relating to the

methods in use and experimental circumstances. Venous occlusion

plethysmography with forearm and leg measurements may give a

combination of cutaneous and muscular blood flow, but this method has

also given identical baseline values in patients and controls.41 We

still have only a faint impression of the haemodynamics of the

peripheral circulation in cirrhosis, and the cutaneous and muscular

circulations in cirrhosis are important topics for further research.

At present it can be concluded that the increased cardiac output in

patients with cirrhosis covers systemic vascular beds with various

degrees of perfusion, owing to an imbalanced state of

vasoconstriction and vasodilatation. The exact distribution of the

increased cardiac output to the different organs, tissues and types

of vessels remains to be clarified.

ABNORMALITIES IN THE REGULATION OF THE CIRCULATION

Autonomic dysfunction

Cirrhosis is often associated with autonomic neuropathy which has

become evident from studies of haemodynamic responses to standard

cardiovascular reflex tests, such as heart rate variability and

isometric exercise.3 5 42 Most studies on these issues have found a

high prevalence of autonomic dysfunction in cirrhosis with

associations with liver dysfunction and survival.43 44 The autonomic

dysfunction may be temporary, arises as a consequence of liver

dysfunction and seems reversible after liver transplantation.45 Most

studies have focused on defects in the SNS, but the importance of

vagal impairment for sodium and fluid retention has been shown.3 42

43 Sympathetic responses to exercise are clearly impaired.46 47

Similarly, blood pressure responses to orthostasis are impaired,

probably because of a blunted baroreflex function in advanced

cirrhosis.5 48 Abnormal cardiovascular responses to vasoconstrictors

have been reported in patients with cirrhosis,1 and there is

experimental evidence that haem oxygenase mediates hyporeactivity to

phenylephrine in the mesenteric vessels of cirrhotic rats with

ascites.27 Administration of captopril partly corrects the

parasympathetic dysfunction in cirrhosis, which indicates that the

vagal component is to a certain extent caused by neuromodulation with

angiotensin II.43 Involvement of the RAAS is also supported by data

that show normalisation of cardiac responses to postural changes

after administration of canrenone, an aldosterone antagonist, to

compensated cirrhotic patients.48 Interestingly, the vasoconstrictor

hyporeactivity seems to be reversible by such antioxidants as vitamin

C, which indicates that oxidative stress plays a role in vascular

hyporeactivity and that antioxidant therapy could possibly have a

role in these complications in cirrhosis.49

The pathophysiological basis underlying the autonomic dysfunction in

cirrhosis is unknown, but relationships to the severity of the liver

disease, mortality and reversibility after liver transplantation

point to hepatic metabolism and increased NO production, and reduced

vasoconstrictor sensitivity with postreceptor defects. This provides

some explanation for the vascular hyporeactivity in cirrhosis (fig 2).

Arterial blood pressure and baroreceptor function in cirrhosis

The level of the arterial blood pressure, which depends on the

cardiac output and the systemic vascular resistance, is kept low

normal in cirrhosis as a circulatory compromise between the

vasodilatating and counter-regulatory vasoconstricting forces

affecting both vascular resistance and arterial compliance. There is

a relationship between the degree of arterial hypotension in

cirrhosis and the severity of disease, signs of decompensation, and

survival.1 11 SNS, RAAS, vasopressin and ET-1 are all important

vasoconstrictors involved in the maintenance of the arterial blood

pressure in cirrhosis.1 50 The impact of potent vasodilators has been

mentioned above. NOS blockade causes higher arterial blood pressure

in cirrhotic rats and reduces forearm blood flow in cirrhotic

patients.25 Inhibition of the endocannabinoid CB1 receptor raises

arterial blood pressure and cardiac contractility in experimental

cirrhosis, and anandamide increases the splanchnic vessel diameter,

flow and cardiac output and may thus contribute to the hyperkinetic

state and arterial hypotension in cirrhosis.51-53 The arterial blood

pressure possesses a circadian variation. In cirrhosis, the arterial

blood pressures are reduced during the day, whereas at night the

values are normal, which indicates an abnormal blood pressure

regulation.54 A resetting of the baroreceptors is still discussed in

human conditions in relation to wall tension of the fibroelastic

tissues in the vessels and stretch-induced activation of the sodium-

potassium channels.8 Whereas the baroreflex sensitivity (BRS) may be

normal in early cirrhosis,55 there is substantial evidence that BRS

is impaired in patients with advanced disease.56 57 Recently, we have

described relationships of the reduced BRS to determinants of the

central circulation and the RAAS. Together with a flat blood

pressure/heart rate slope as found during 24 h ambulatory blood

pressure monitoring, this indicates that low BRS contributes to the

dysregulation of the arterial blood pressure, although the precise

mechanism is unknown.54 57

CARDIAC DYSFUNCTION IN CIRRHOSIS

The expanded blood volume in advanced cirrhosis contributes to a

persistent increase in cardiac output, which may overload the

heart.58 In other circumstances, increased cardiac output and

augmented cardiac work would cause cardiac failure but, because of

the decreased afterload, as reflected by reduced systemic vascular

resistance and increased arterial compliance, left ventricular

failure may be latent in cirrhosis.4 13 59 Cardiac failure may become

manifest under strain or treatment with vasoconstrictors. This type

of cardiac dysfunction has been termed " cirrhotic cardiomyopathy " and

was for years erroneously attributed to alcoholic heart muscle

disease. At the 2005 World Congress of Gastroenterology at Montreal,

a working party of experts in the field was set up to work out a

classification system for cirrhotic cardiomyopathy. Essentials in the

definition are a chronic cardiac dysfunction in cirrhotic patients,

characterised by blunted contractile responsiveness to stress, and/or

altered diastolic relaxation with electrophysiological abnormalities

in the absence of other known cardiac disease (table 4), and a

consensus working group is developing a specific definition to be

published in 2008. Elements in cirrhotic cardiomyopathy include

impaired cardiac contractility with a systolic dysfunction, diastolic

dysfunction and electromechanical abnormalities with a prolonged Q-T

interval.4 59 Various electrophysiological mechanisms for the

conductance abnormalities and impaired cardiac contractility have

been suggested and include changes in the cardiomyocyte plasma

membrane with an increased cholesterol/phospholipid ratio, attenuated

function of the β-adrenergic pathway and greater activity of

inhibitory systems.4 Other studies have focused on negative inotropic

effects of NO, nitration of cardiac proteins, CO, endogenous

cannabinoids, bile acids, endotoxins and other systems.59 60

Cannabinoids are endogenous ligands including anandamide that binds

to cannabinoid receptors CB1 and CB2.4 51 The production may increase

in response to stress such as tachycardia and overload.61

Experimental studies have shown a negative inotropic effect of

anadamide in cirrhotic rats, which suggests that this system is

involved in cirrhotic cardiomyopathy.4 62 The haem oxygenase-CO

pathway has also been shown to play a role in the pathogenesis of

abnormal cardiac contractility in cirrhotic cardiomyopathy.4 27

Systolic dysfunction

In cirrhotic cardiomyopathy, the left ventricular end-diastolic

pressure increases after exercise, but the expected increases in

cardiac stroke index and left ventricular ejection fraction (LVEF)

are absent or subnormal, which indicates an inadequate response of

the ventricular reserve to a rise in ventricular filling pressure.63

A vasoconstrictor-induced increase of 30% in the left ventricular

afterload results in an approximate doubling in pulmonary capillary

wedge pressure, with no change in cardiac output.31 Recently, we have

shown by myocardial perfusion imaging that infusion of terlipressin

suppresses myocardial function, whereas the myocardial perfusion is

left unaffected.64 This response may be useful in diagnosing

cirrhotic cardiomyopathy. A similar pattern is seen after insertion

of a transjugular intrahepatic portosystemic shunt (TIPS), but the

raised cardiac pressures after TIPS tend to normalise with time.65 66

Some of these patients (12%) may develop manifest cardiac failure in

association with the TIPS insertion.67 Similar effects are seen after

infusion of plasma expanders. Infusion of a plasma protein solution,

however, increases cardiac output, as well as right atrial pressure,

pulmonary arterial pressure and pulmonary capillary wedge pressure,

whereas infusion of packed red blood cells may not produce a change

in these variables.1

The LVEF reflects systolic function, even though it is very much

influenced by preload and afterload. It has been reported to be

normal at rest in some studies and reduced in one study of a subgroup

of patients with ascites.31 63 68 After exercise, LVEF increases less

in cirrhotic patients than in controls (fig 3).59 63 69 The reduced

functional capacity may be attributed to a combination of blunted

heart rate response to exercise, reduced myocardial reserve and

profound skeletal muscle wasting with impaired oxygen extraction.46

47 In patients with advanced cirrhosis and severe vasodilatation,

activation of the RAAS, impaired renal function and a reduced

systolic function (a decrease in cardiac output) appear to be major

determinants for the development of the hepatorenal syndrome.37

Spontaneous bacterial peritonitis is a well-known risk factor for the

development of the hepatorenal syndrome, and after resolution of the

infection suppression of systolic function appears to be more

pronounced in patients who develop renal failure. Maintenance of

cardiac contractility thus appears to be an important factor in the

prevention of renal failure.70

Diastolic dysfunction

Many patients with cirrhosis exhibit various degrees of diastolic

dysfunction, which implies changes in myocardial properties that

affect left ventricular filling. Diastolic dysfunction may progress

to systolic dysfunction, although this has not been directly shown in

cirrhotic patients.31 71 The pathological basis of the increased

stiffness of the left ventricle seems to be cardiac hypertrophy,

patchy fibrosis and subendothelial oedema.4 31 69 Determinants of a

diastolic dysfunction on a Doppler echocardiogram are decreased E/A

ratio (the ratio of early to late (atrial) phases of ventricular

filling) and delayed early diastolic transmitral filling with

prolonged deceleration and isovolumetric relaxation times (table

4).31 68 72 In a number of studies, A wave and E wave velocities and

deceleration times are much increased and the E/A ratio is decreased

in cirrhotic patients, especially in those with ascites.68 72 Recent

studies of ventricular diastolic filling in cirrhosis support the

presence of a subclinical myocardial disease with diastolic

dysfunction, which, in ascitic patients, improves after paracentesis

and can be aggravated after TIPS.65 68 72 In these decompensated

patients, paracentesis seems to ameliorate diastolic, but not

systolic, function.68 Patients with TIPS with an E/A ratio <1 seem to

have a poorer survival rate than patients without signs of diastolic

dysfunction.73 Liver transplantation has recently been shown to

reverse cardiac changes, including diastolic dysfunction (fig 4).69

It has been proposed that diastolic dysfunction precedes systolic

dysfunction in early heart disease and that anti-aldosterone

treatment improves cardiac function. Pozzi et al recently

demonstrated that anti-aldosterone treatment with K-Canrenoate in

cirrhosis ameliorated cardiac structure by reducing left ventricular

wall thickness and volume, but had almost no effects on systolic and

diastolic functions.74 It is also possible that anti-aldosterone

treatment may have beneficial effects on catecholamine-induced

cardiac fibrosis, as described in heart failure.75

The clinical significance of diastolic dysfunction and its importance

in cirrhotic cardiomyopathy has been questioned, as overt cardiac

failure is not a prominent feature of cirrhosis. However, there are

several reports of unexpected death from heart failure following

liver transplantation, surgical portocaval shunts and TIPS.67 76

These procedures involve a rapid increase in cardiac preload. In a

less compliant heart, the diastolic dysfunction could be enough to

cause pulmonary oedema and heart failure. This is consistent with the

findings of Huonker et al,65 who reported an increase in pulmonary

artery pressure, preload and diastolic dysfunction after TIPS. In

patients with the hepatopulmonary syndrome and in children with

chronic hepatitis, an isolated right ventricular diastolic

dysfunction has been described and may play a role in the right

cardiac function and course of these patients.77 Thus, both left and

right diastolic dysfunction could account for part of the cardiac

dysfunction in cirrhotic cardiomyopathy.

Electromechanical abnormalities

There is a large body of evidence for electrophysiological

abnormalities in cirrhosis primarily comprising prolonged

repolarisation time and increased dispersion of the electromechanical

time interval.78 79 The sympathetic nervous activity influences the

heart rate and electromechanical coupling by several mechanisms:

noradrenaline binding to β-receptors, receptor-mediated G protein

interaction and, consequently, stimulation of adenylcyclase,

activation of cAMP-dependent phosphokinase A and channel

phosphorylation. Several receptor and postreceptor defects have been

described in cirrhosis with reduced β-receptor density and

sensitivity, and altered G protein and calcium channel functions.4 80

All these defects may explain both impaired chronotropic responses

and electromechanical uncoupling. The coupling between cardiac

contractions and the arterial system is of major importance for the

amount of work performed by the left ventricular myocardium, and

thereby for the strain on the heart.14 46 In addition, Ward et al

have shown a decrease in K+ currents in ventricular cardiomyocytes

from cirrhotic rats, which prolongs the Q-T interval.81 The prolonged

repolarisation time is reflected by a prolonged Q-T interval in a

substantial fraction of the patients with cirrhosis, which could lead

to ventricular arrhythmias and sudden cardiac death, but the evidence

from clinical studies is sparse.4 59 In cirrhotic patients, the

prolonged Q-T interval is significantly related to the severity of

the liver disease, portal hypertension, portosystemic shunts,

elevated brain-type natriuretic peptide (BNP) and pro-BNP, elevated

plasma noradrenaline and reduced survival.79 82 83 The prolongation

of the Q-T interval is partly reversible after liver transplantation

and β-blocker treatment (fig 5).45 82 The prolonged Q-T interval in

cirrhosis should be considered an element in the cirrhotic

cardiomyopathy and may be of potential use in identifying patients at

risk.