Digestive and Liver Disease
Volume 39, Issue 6 , Pages 507-515, June 2007

Cirrhotic cardiomyopathy

Department of Internal Medicine, Catholic University of Rome, Italy

Received 10 June 2006; accepted 11 December 2006.

Article Outline

Abstract 

Decompensated liver cirrhosis is characterized by a peripheral vasodilation with a low-resistance hyperdynamic circulation. The sustained increase of cardiac work load associated with such a condition may result in an inconstant and often subclinical series of heart abnormalities, constituting a new clinical entity known as “cirrhotic cardiomyopathy”.

Cirrhotic cardiomyopathy is variably associated with baseline increase in cardiac output, defective myocardial contractility and lowered systo-diastolic response to inotropic and chronotropic stimuli, down-regulated β-adrenergic function, slight histo-morphological changes, and impaired electric “recovery” ability of ventricular myocardium.

Cirrhotic cardiomyopathy is usually clinically latent or mild, likely because the peripheral vasodilation significantly reduces the left ventricle after-load, thus actually “auto-treating” the patient and masking any severe manifestation of heart failure.

In cirrhotic patients, the presence of cirrhotic cardiomyopathy may become unmasked and clinically evident by certain treatment interventions that increase the effective blood volume and cardiac pre-load, including surgical or transjugular intrahepatic porto-systemic shunts, peritoneo-venous shunts (LeVeen) and orthotopic liver transplantation. Under these circumstances, an often transient overt congestive heart failure may develop, with increased cardiac output as well as right atrial, pulmonary artery and capillary wedge pressures.

Keywords: Cardiomyopathy, Hyperdynamic circulation, Liver cirrhosis, QT interval, Ventricular recovery

 

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1. Introduction 

Until the late 1980s, the patient with liver cirrhosis was considered somehow “protected” against cardiovascular involvement due to the favourable pattern of the main ischemic risk factors (i.e. hypotension, hypolipemia, low platelet count, impaired coagulation). The possibility of heart dysfunction in cirrhosis, first described in 1953 [1], was regarded as just related to the eventual metabolic complications of alcohol intake or haemochromatosis. This point of view, however, has been overtaken by a series of experimental and clinical findings that have been accumulating over the last decades.

Clear experimental and clinical evidence states that liver cirrhosis is characterized by a sustained peripheral vasodilation due to a wide number of vasoactive substances. The lowered systemic vascular resistance results in a reduction of effective circulating plasma volume and blood pressure, and in an enhancement of heart rate, cardiac output and sympathetic tone (“hyperdynamic” circulation), with an eventual sustained reduction of cardiac after-load [2], [3], [4], [5].

Such a condition may be associated with an inconstant and often subclinical constellation of cardiovascular abnormalities, such as resting tachycardia and baseline increased cardiac output [1], reduced myocardial contractility with a blunted systo-diastolic response to inotropic and chronotropic stimuli [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], down-regulation of β-adrenergic receptor function [23], [24], [25], slight histological changes [26], [27], [28], [29], increase of brain natriuretic peptide (BNP) [30], [31], [32], [33] and serum troponin [34], impaired electric “recovery” ability of ventricular myocardium [35], [36], [37], [38], [39].

Taking into consideration the wide variability of these different aspects, a new clinical entity has been recently recognized [40], [41], [42], [43], [44], [45], [46], known as “cirrhotic cardiomyopathy” (CC), term first introduced by Lee et al. [40].

A precise definition of CC is still difficult because of the variability of its clinical expressions and the uncertainty of the underlying pathophysiological mechanisms. CC may be referred to as “A chronic cardiac dysfunction in patients with cirrhosis, characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electro-physiological abnormalities, in absence of any known cardiac disease”, as stated by a consensus of international experts during the World Congress of Gastroenterology 2005, held in Montreal. The definitive diagnostic criteria are yet to be agreed upon, since the consensus group is still working on it, and the results are to be released in late 2006.

Currently [46], diagnosis of CC requires the presence of one or more of the following criteria: (a) baseline increased cardiac output, but blunted ventricular response to stress; (b) systolic and/or diastolic dysfunction; (c) absence of overt left ventricular failure at rest and (d) electrophysiological abnormalities, including chronotropic incompetence and prolonged QT interval.

However, the inconstant and variable association of the different clinical features and the often poor symptomatic reflexes of this clinical condition do not allow CC to be referred to as a true “hepato-cardiac syndrome” (for instance, like the well known hepato-renal or hepato-pulmonary syndromes).

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2. Cardiac dysfunction in CC 

2.1. Basal cardiac alterations 

The histo-morphological alterations of the heart in CC are mild and non-specific, including myocardial hypertrophy, interstitial and cellular oedema, patchy fibrosis, nuclear vacuolation, pigmentation, exudation, mild flogosis [26], [27], [28], [29] and a heart mass within normal values [47].

Resting diastolic right cavities dimensions were inconsistently reported to be reduced (as a result of central blood compartment depletion) or slightly increased, with an eccentric hypertrophy when the cardiac pre-load is augmented [9], [17], [18], [19], [21], [47], [48], [49], [50], [51], [52], [53], although the pulmonary artery systolic pressure seems to be unmodified.

Mild increases in resting left atrial and both end-systolic and end-diastolic left ventricle volumes have been reported too [17], [47], [48], [49], [50], [51], [52]. Some authors, however, [9], [20], [21] were unable to confirm the alterations of left ventricular diastolic diameters, probably because the low peripheral vascular resistance facilitates the left ventricular performance by reducing the after-load.

2.2. Impairment of ventricular contractility 

Much more significant in CC is the impairment of chronotropic and inotropic cardiac performance under physical exercise (namely isometric), or pharmacological, mental and postural stress [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22].

Under these conditions, an increase in end-systolic diameters and end-diastolic pressures, and a blunted increase in heart rate, ejection fraction, cardiac index and stroke volume have been reported in comparison to controls, concerning both right and left ventricles. In particular, the pharmacological response to norepinephrine, angiotensin II, dobutamine and vasopressin is decreased [8], [10], [12], [13], [14], and the cardiac output does not increase after infusion of ouabain [6].

Moreover, the non-invasive analysis of systolic time intervals disclosed that an important parameter in assessing left ventricular contractile function such as the ratio between pre-ejection period (PEP) and left ventricular ejection time (LVET) is decreased in cirrhotic patients, due to a shortened PEP and a prolonged LVET [11], [21]. The duration of mechanical systole is normal, but its relationship with the duration of the electrical systole is altered [54]. The pattern of such changes tends to suggest the existence of an abnormal electromechanical coupling rather than a plain ventricular mechanical failure [39].

The indicators of cardiac pre-load, such as atrial natriuretic factor [55] and ventricular BNP [30], [31], [32], [33], are known to be often increased in CC. However, ventricular remodelling and pressure load hypertrophy play a considerable role in eliciting BNP release by cardiac ventricles; in this way, BNP may represent a marker of left ventricular dysfunction rather than just an indicator of volume overload [33]. BNP levels closely correlate [32] with indicative parameters of cardiac function (plasma volume, heart rate and QT interval) and with the severity of liver disease (Child score, hepatic venous pressure gradient and serum albumin) but not with those characteristic of the hyperdynamic circulation (cardiac output and systemic vascular resistance). These results tend to support the concept of CC as a specific cardiac disorder peculiar to cirrhosis rather than an adaptive response to the increased cardiac work load due to the hyperdynamic circulation [33], [40], [41], [42], [43], [44], [45], [46].

2.3. Impairment of diastolic compliance 

CC is also associated with a complex series of abnormalities in diastolic function (alterations of relaxation and ventricular filling pattern). Indeed, diastolic disturbances appear to be so common that many authors contend that some degree of diastolic dysfunction is present in virtually every patient with cirrhosis [16], [18], [20], [22].

Diastolic dysfunction manifests as a stiff, noncompliant ventricle, and is often observed in patients with some degree of left ventricular hypertrophy or dilation [47], [56]. The diastolic alterations may precede the systolic disturbances.

In particular, the subjects with decompensated cirrhosis and ascites often show a significantly reduced E/A ratio (early (E) or late (A) ventricular filling peak flow velocity), considered an early marker of cardiac involvement [16], [18].

Cardiac pre-load has been reported to be increased in cirrhosis, but it could also be normal or even reduced [45], depending on hydration status, posture, central blood volume contraction and therapy. The alterations of cardiac pre-load and the central volume underfilling do have a significant impact on diastolic function in cirrhosis. In fact, large volume paracenteses, which, at least in short term, are able to increase the blood return to the heart, may result in an improvement of E/A ratio [16], [18]. Moreover, the studies of the hemodynamic effect of transjugular intrahepatic porto-systemic shunts (TIPS) in cirrhotic patients with different effective blood volume demonstrate that the procedure results in a significant increase of diastolic function (i.e. end-diastolic left ventricular volumes and E/A ratio) only in the patients with more pronounced effective hypovolemia [57].

2.4. Impairment of electric ventricular recovery 

An impaired electric ventricular recovery, with a significant prolongation of QT interval on basal ECG, has been reported in patients with liver cirrhosis [1], [35], [36], [37], [38], [39].

Ventricular “recovery” may be roughly defined as the whole of the electro-metabolic processes occurring in the myocardial cells after their depolarisation, aimed to regain the electric excitability. On basal surface electrocardiogram, the length of the “active” phase of the electric cardiac cycle (from the earliest ventricular depolarisation to the latest repolarisation) is measured by the duration of the QT interval. For this reason, the length of the QT interval, corrected according the heart rate (QTc), is considered a reliable routine assessment of ventricular recovery ability [58], thus representing a sensitive marker of early myocardial involvement in different clinical conditions. In general population, QT prolongation is associated with an increased arrhythmic risk [59], [60], [61], [62].

The prolonged QTc in cirrhosis may therefore be considered a marker of CC, and may be of potential use in clinical screening. An exhaustive analysis of the significance and the pathogenesis of QT prolongation in cirrhosis may be found in the fine report by Zambruni et al. [39].

Nowadays, the significance of the alterations of the electric ventricular recovery has been further reviewed. The existence of a “physiological” slight QT variability among the 12 surface conventional ECG leads has been recently demonstrated in healthy subjects [63], [64], reflecting underlying regional variation in myocardial recovery ability. In this way, QT dispersion (QTd) has been simply defined as the interlead QTc variability, that is the difference between the maximum and minimum QTc intervals, as measured from the 12-lead electrocardiogram [64].

Since a well-nourished and performing myocardium should exhibit no particular regional alterations, the existence of an abnormal QT dispersion, far from being a simple recording artefact, is widely acknowledged as a sensitive, subclinical marker of myocardial damage [63], [64]. Moreover, an increase in QTd by itself may be responsible for the augmented arrhythmic risk observed in healthy patients with prolonged QT interval [63], [64], [65], [66], [67], [68], possibly leading to dangerous events.

The actual existence of a significant QTd increase in decompensated cirrhosis is object of inconsistent preliminary reports [38], [69], [70], and the matter therefore deserves further extensive and controlled studies.

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3. Clinical features and diagnosis of CC 

CC is usually clinically latent or mild, likely because the peripheral vasodilation significantly reduces the left ventricle after-load, thus actually “auto-treating” the patient and masking any severe manifestation of heart failure.

In cirrhotic patients, the presence of CC may become unmasked and clinically evident by certain treatment interventions acutely rising the effective blood volume and cardiac pre-load, including surgical porto-systemic shunts [71], [72], TIPS [57], [70], [73], [74], [75], [76], [77], [78], [79], [80], peritoneo-venous shunts (LeVeen) [81] and orthotopic liver transplantation (OLT) [82], [83], [84], [85], [86]. Under these circumstances, an often transient overt congestive heart failure may develop, with increased cardiac output, as well as right atrial, pulmonary artery and capillary wedge pressures.

The worsening of cardiac function after OLT is however transient, since the hyperdynamic circulation appears to be reversible in the months following OLT, with a normalization of peripheral vascular resistances, cardiac pre-load, basal and post-stress systolic function, and an improvement of ventricular hypertrophy and electrical recovery [69], [83], [84], [85], [86], [87], [88], [89].

In the absence of firm and established diagnostic criteria [46], the clinical recognition of CC depends on a high level of awareness for the presence of this syndrome. In this way, the exact prevalence of CC still remains unknown.

The diagnosis of CC may be confirmed by pharmacological or physical stress tests, since static tests can be insufficient.

A golden standard for diagnosis of CC is still lacking. Tests of diastolic function by echocardiographic indices (such as E/A ratio) or dynamic magnetic resonance cardiac imaging may represent the best available screening tests to diagnose the syndrome, particularly in patients undergoing significant interventional or pharmacological stresses. The identification of patients at risk of developing cardiac failure following OLT has been attempted by QT prolongation [69] or dobutamine stress echocardiography [90], but no preoperative echographic parameter can be considered an absolutely reliable predictor.

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4. Pathogenetic mechanisms of CC 

Chronic alcohol consumption is positively able to induce a dilated cardiomyopathy by either direct ethanol cardiotoxicity or breakdown product acetaldehyde [91], [92], [93], interfering with excitation–contraction coupling and inotropism. However, the heart involvement in alcoholic and non-alcoholic cirrhosis has no strictly specific features, sharing a substantially identical echocardiographic and histological pattern [11], [15], [16], [22], [44].

Therefore, the heart abnormalities occurring in cirrhosis may not be regarded simply as a complication of alcoholic liver disease but they should be considered as a specific cardiac dysfunction [33].

Several pathogenetic mechanisms may be involved in the pathogenesis of CC.

4.1. Autonomic dysfunction and β-adrenergic down-regulation 

In the subjects suffering from liver cirrhosis, a deep alteration of the autonomic adrenergic function has been reported [24], [25], [94], which correlates to the severity of the disease.

In these patients, both inotropic and chronotropic responses to β-adrenergic agonist stimulation are actually diminished. In this way, the response to norepinephrine, angiotensin II and dobutamine is decreased [8], [12], [13], [14], and no significant heart rate increase occurs during Valsalva maneuver, ice-cold skin stimulation or mental stress [7]. Moreover, the dose of isoproterenol required for heart rate to increase 25beats/min is significantly higher in cirrhotic patients than in controls [95], [96]. The response to posture variations is reduced too, due to a blunted barreflex function, with a tendency to orthostatic hypotension, and no significant increase in heart rate during tilting test [17], [97], [98], [99], [100]. The data of a blunt chronotropic and inotropic cardiac response in cirrhosis were also confirmed in animal models [101], [102].

A significant down-regulation of the β-adrenergic receptors, which has been demonstrated in cirrhosis [101], [103], [104], may account for the above-mentioned clinical and experimental data.

The mechanism of β-adrenergic receptor desensitization in cirrhosis is controversial. The adrenergic dysfunction in cirrhosis is characterized by an enhanced sympathetic tone and by increased circulating catecholamine levels [24], [25], [105], triggered by low arterial pressure and reduced central arterial volume. Probably, the long-term exposure to sustained spilled-over norepinephrine levels [104] may cause a β-adrenergic receptor desensitization, sequestration and down-regulation [101]. Such mechanisms may eventually result in a decrease of the β-receptor density on the plasma membrane [18], [103], [106], [107], [108], and of the affinity for epinephrine [109], [110].

The cell membrane fluidity is critical in the correct function of several membrane-bound receptors, including β-adrenergic ones [111]. In fact, a decreased membrane fluidity (due to an increased cholesterol content and cholesterol/phospholipid ratio) in the cardiomyocytes of bile duct-ligated rats was reported to be associated with a blunted β-adrenergic receptor response, with an alteration of the signal transduction pathway [109], [111] and of the conductance of the gap–junction channels [109], [112], [113].

The adrenergic dysfunction may exert a role in the development of the inotropic ventricular disturbances, since the alteration of cardiac β-adrenergic receptor and its post-receptor signal transduction pathway (namely G-protein expression and function, and GTP-dependent activation of the second messager cAMP) are critical in the cardiac excitation–contraction coupling [114], [115]. In fact, the interaction between the activated β-adrenergic receptors and G-protein leads to the contractile response through the activation of membrane L-type Ca++ channels [41], [115], as well as to conformational changes of troponin-I, which accelerate myocardial relaxation [41].

The muscarinic cholinergic parasympathetic system exerts a negative inotropic and chronotropic counterbalance against the β-adrenergic stimulation. However, an overactivity of the parasympathetic nervous system may not be considered as a major factor in the genesis of CC, since the muscarinic receptor function is blunted in the myocardium of cirrhotic rats [116], likely as a result of a post-M2-receptor defect. Moreover, Captopril seems to correct the parasympathetic dysfunction in cirrhosis [117], indicating that the vagal dysfunction may be partially caused by the neuromodulation of angiotensin II, representing therefore a compensatory mechanism of the blunted β-adrenergic function.

4.2. Nitric oxide and carbon monoxide 

Increased nitric oxide (NO) production plays an important role in the peripheral arterial vasodilation and the hyperdynamic circulation of cirrhosis [118], [119], [120].

An elevated level of inflammatory cytokines (IL1-β, IL6, IL8, endothelins, TNF-α, bile acids) and of gut-derived bacterial endotoxins may be responsible for the increased NO production in cirrhosis [43], [44], [121], [122], [123], [124], [125], through the activation of NO synthase.

NO may exert a role in the complex interaction between the β-adrenergic function and the regulation of calcium channels. In fact, NO may inhibit [123], [126], [127], [128], [129], [130] the β-adrenergic stimulation of cAMP and activate the guanylate–cyclase mediated cGMP production, which in turn is able to block the extracellular calcium influx through the L-type channels.

Moreover, NO-mediated oxidative inflammatory response is known to result in significant post-translational protein nitrations, able to modulate catalytic activity, cell signalling and cytoskeletal organization [131]. Since a correct β-adrenergic function is critical in modulating the myocardial contractility, any abnormalities in the β-adrenergic receptor signal transduction pathway might lead to the impairment of cardiac systolic and diastolic function which characterizes CC. Although, to date, a direct link between cytokines and endotoxins and CC has not been yet established, such substances may be able to interfere with cardiac contractility and chronotropic response [126], [127], [132], [133], [134], [135]. The role of NO in reducing cardiac contractility is further confirmed by the effects of l-NMMA–arginine (a non-selective NOS blocker that is able to increase the positive inotropic effect of isoproterenol and increase left ventricular pressure) [136], [137], nitroprusside (a NO-donor vasodilator that further decreases cardiac contractility) [133] and methylene blue (a guanylate–cyclase inhibitor that prevents the negative inotropic effect of nitroprusside) [133].

Carbon monoxide (CO) is a result of the bio-processing of haeme to biliverdin by the haeme oxygenase (HO) system. It is able to activate guanylate–cyclase, resulting in cGMP production [138], [139], [140]. Since cGMP may have a cardiodepressant action, also the activation of HO–CO–cGMP pathway may exert a role in the pathogenesis of CC.

In fact, an increased expression of inducible HO and cGMP levels was demonstrated in left ventricle of bile duct-ligated rats, whose isolated papillary muscles did exhibit a blunted contractility [140]. The treatment with Zn-protoporphyrine IX (an HO inhibitor) reduced cGMP levels, thus normalizing the myocardial inotropic ability [140].

4.3. Endocannabinoids 

Endogenous cannabinoids may exert a vasodilatory effect by the activation of two G-protein coupled inhibitory receptors (CB1 and CB2) in the vascular endothelium [129], [130]. The potential role of endocannabinoids in decreasing the vascular tone in cirrhosis is suggested by several observations. An increased production of endogenous cannabinoids (such as anandamide) has been demonstrated in monocyte of cirrhotic rats [141], [142], probably as a result of bacterial endotoxins [143]. Moreover, the infusion of monocytes from cirrhotic rats decreases the mean arterial pressure of normal rats, while the administration of CB1 antagonists to cirrhotic rats is able to increase the total peripheral resistances and decrease both mesenteric blood flow and portal venous pressure [141], [142].

The role of endocannabinoids in sustaining the vasodilation of cirrhosis is further amplified by their ability to induce apoptosis in hepatic stellate cells, with a potential effect in altering the microcirculation of the liver and enhancing the development of portal hypertension and hyperdynamic circulation [144].

Endocannabinoids are also known to exert a negative inotropic effect on cardiac contractility [134], [145], [146]. This fact may have a pathogenic role in the development of CC, since CB1 antagonists have been reported to restore the blunted contractile response of isolated left ventricular papillary muscles from cirrhotic rats, while endocannabinoid re-uptake blockers enhance their relaxation [147].

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5. Treatment of CC 

As previously discussed, CC is often clinically asymptomatic, with a low intrinsic morbility and mortality. Therefore, treatment is normally unnecessary [44], [46], [130]; a careful follow-up of the patient is however particularly advisable during and after stressful clinical procedures.

The occurrence of ventricular failure in CC should be treated as in any other non-cirrhotic patient (bed rest, sodium restriction, oxygen, diuretics, after-load reduction, alcohol discontinuation, dosage reduction of QT prolonging drugs) [44], [46], [130], although the literature data dealing with the effect of any specific pharmacological treatment in CC or in experimental animal models are still insufficient.

Cardiac glycosides (digoxin, ouabain) did not show any significant therapeutic value [6], [44], [130]. The inotropic beta-agonists (dobutamine and isoproterenol) are poorly effective [8], [95], [96], [130], mainly because of the β-adrenergic desensitization.

Newer treatments with anti-cytokines or with amrinone or milrinone (phospho-dyesterase inhibitors which interfere with cAMP metabolization) may be of potential interest in patients with CC [148], but they require further clinical validation.

The patients suffering from cirrhosis and oesophageal varices are often under treatment with non-cardio-selective beta-blockers. Beta-blockers may improve the hyperdynamic syndrome through the reduction of the heart rate and ventricular electric recovery [149], [150], but they do have a well-known negative inotropic effect. Their gradual withdrawal should therefore be considered in overt clinical heart failure.

As previously discussed, CC appears to be fully reversible a few months after OLT, which is also able to correct QT prolongation [69], [83], [84], [85], [86], [87], [88], [89].

Cardiac pre-load is often increased in patients with cirrhosis but it may also be normal or even reduced [45]. Since the alterations of cardiac pre-load may have a role in affecting the ventricular performance in CC [57], every treatment able to normalize pre-load and restore an adequate effective circulating blood volume is potentially effective in treating CC.

In this way, large volume paracentesis may restore both systolic and diastolic ventricular function in decompensated cirrhotics [16], [18], and albumin administration has been reported to improve cardiac output as well as right atrium, pulmonary artery and left ventricular tele-diastolic pressures in patients with cirrhosis and spontaneous bacterial peritonitis [151].

Blood transfusions [152] and infusion of isotonic saline [153] or other plasma expanders such as dextran [102] did not, however, grant comparable results on the cardiac performance, while the central expansion by means of hyperosmotic solutions resulted in an increase of cardiac output [154]. These inconsistencies may be due to the limited pre-load reserve of cirrhotic patients and their decreased ability to modulate cardiac performance under various loading conditions.

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Conflict of interest statement 

None declared.

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Practice Points 


•Cirrhotic cardiomyopathy (CC) consists of a series of heart abnormalities, including baseline increased cardiac output, lowered systo-diastolic response to inotropic and chronotropic stimuli, down-regulated β-adrenergic function and impaired electric “recovery” ability of ventricular myocardium.

•CC is usually clinically latent or mild. It may become clinically evident (congestive heart failure) after some treatment interventions (i.e. surgical or transjugular intrahepatic porto-systemic shunts, peritoneo-venous shunts and orthotopic liver transplantation) rising the effective blood volume and cardiac pre-load.

•The pathogenesis of CC is still controversial, but a pathogenetic role may be ascribed to the autonomic dysfunction and β-adrenergic down-regulation, and the increased production of NO, CO, and endogenous cannabinoids.

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Research Agenda: 


•New research perpectives in CC may concern the pathogenetic role of endocannabinoids, bacterial infections and cytokines.

•It is still to be investigated how the cardiac involvement may affect the clinical outcome of interventional procedures and whether the cardiac parameters may be considered in cirrhosis cumulative survival predictive models.

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PII: S1590-8658(06)00647-5

doi:10.1016/j.dld.2006.12.014

Digestive and Liver Disease
Volume 39, Issue 6 , Pages 507-515, June 2007

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