Enrico M. Zardi, MD,* Antonio Abbate, MD, PHD,† Domenico Maria Zardi, MD,‡Aldo Dobrina, MD,§ Domenico Margiotta, MD,* Benjamin W. Van Tassel, PHARMD,†Antonella Afeltra, MD,* Arun J. Sanyal, MD�
ublished by Elsevier Inc. doi:10.1016/j.jacc.2009.12.075
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ore than 50 years ago, it was noted that persons withlcohol-related cirrhosis had increased cardiac output, and itas attributed to either impaired thiamine utilization or theresence of an endogenous vasodilator (1). Cardiac hyper-rophy and cardiomyocyte edema in the absence of coronaryrtery disease, hypertension, or valvular disease were nextescribed in an autopsy series of subjects with cirrhosis (2).ubsequent studies described an impaired hemodynamicesponse to physiologic (exercise) and pharmacologic stressespite a high resting cardiac output (3).These findings were then confirmed in animal models of
lcoholic cirrhosis and found to be related to decreasedyocardial contractile function (4), and finally were corrob-
rated by additional human studies (5,6).This syndrome is formally described as cirrhotic cardio-yopathy, which is defined as chronic cardiac dysfunction
n patients with cirrhosis characterized by blunted contrac-ile responsiveness to stress and/or altered diastolic relax-tion with electrophysiological abnormalities, in the absencef known cardiac disease and irrespective of the causes ofirrhosis, although some etiologies (e.g., iron overload andlcohol consumption) further impact on myocardial struc-ure and function.
This syndrome is considered to be related to both portalypertension and cirrhosis (7) and is characterized by
ntrinsic alterations in myocardial function.
rom the *Department of Clinical Medicine, University Campus Bio-Medico, Rome,taly; †Virginia Commonwealth University, VCU Pauley Heart Center, Richmond,irginia; ‡Department of Cardiology, II School of Medicine, University “Laapienza,” Ospedale Sant’Andrea, Rome, Italy; §Department of Physiology andathology, University of Trieste, Trieste, Italy; and the �Division of Gastroenterology,epatology and Nutrition, Department of Internal Medicine, Virginia Common-ealth University, VCU School of Medicine, Richmond, Virginia. The authors have
deported that they have no relationships to disclose.
Manuscript received November 11, 2009; accepted December 16, 2009.
athophysiology
ascular Dysfunction
ystemic vascular resistance and cardiac dysfunction.dvanced liver disease is associated with marked changes in
ystemic vascular resistance. In a model of pre-sinusoidal portalypertension in rats, splanchnic arterial vasodilation is observednd is accompanied by a decreased contractile response toitroprusside or isoproterenol and impaired myocyte calciumignaling, showing that portal vascular change and portosys-emic shunting cause cirrhotic cardiomyopathy independent, ateast in part, of parenchymal liver disease (8–10).
Sinusoidal portal hypertension, in contrast, is characterizedy increased hepatic sinusoidal resistance to blood flow. Thisas both a fixed component due to fibrotic disruption of therchitecture and a dynamic component due to changes in theontractility of the hepatic stellate cells and myofibroblasts inhe hepatic sinusoids (11). These cells are sensitive to a numberf vasoactive mediators, for example, endothelins, prostaglan-ins, and nitric oxide (NO). Sinusoidal NO production is
mpaired in subjects with cirrhosis because of increased caveo-in expression (12,13). In contrast, there is an increased NOrive in the peripheral arterial circulation, especially in theplanchnic bed, that causes vasodilation. Other mediatorsmplicated in the splanchnic arterial vasodilation seen inirrhosis include carbon monoxide (CO) and endogenousannabinoids (14,15).
The resting hyperdynamic state in cirrhosis reflects,herefore, an initial appropriate response to splanchnicrterial vasodilation (15,16).olume expansion. In patients with cirrhosis, bloodolume expansion occurs before ascites formation. Withrogressive hepatic decompensation, there is a redistri-ution of this expanded blood volume with a relative
ecrease in the central circulation and increment in the
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540 Zardi et al. JACC Vol. 56, No. 7, 2010Cirrhotic Cardiomyopathy August 10, 2010:539–49
splanchnic bed (17). Moreover,despite an absolute increase inblood volume, there is marked ac-tivation of sodium (Na�) and wa-ter retentive pathways, which be-come more pronounced ascirrhosis worsens. This is drivenmainly by the state of progressivearterial vasodilation and imbalancebetween the blood volume on onehand and the space it has to oc-cupy on the other (Fig. 1).Arterial compliance. Peripheralarterial vasodilation and arterialcompliance are closely associated.With progression of cirrhosis,there is a decrease in the thicknessof the vessel walls as well as adecrease in total vascular wall area
14). The vascular tone is also decreased, possibly because ofeduced smooth muscle mass secondary to NO overproductionr altered endothelial function as well as alterations in extra-ellular matrix turnover (18). Increased expression of largeonductance, calcium-activated potassium (K�) channel �ubunits have also been implicated as a cause of vascularemodeling and altered arterial compliance in cirrhosis (14).
Figure 1 Clinical Basis of Blunted Cardiac Response
In the setting of liver cirrhosis and portal hypertension, a wide spectrum of factorslogical abnormalities, diastolic dysfunction, and systolic dysfunction. Cardiomyocytment are also implied in this process. With advanced liver disease, these factors
imited information is available about the epidemiology ofirrhotic cardiomyopathy in humans, as its diagnosis isifficult because of near normal cardiac function at rest. Theajority of patients are diagnosed during phases of clinical
ecompensation of cirrhosis in which they present witheatures of diastolic heart failure and/or high-output heartailure (5) (Table 1). The actual prevalence of this conditions unknown. Therefore, not much is known also regardinghe natural history of the disease. The condition is undoubt-dly well tolerated and asymptomatic for months to years,nd in many cases the symptoms are not easily distinguishedrom those of the underlying disease. Similarly, the naturalistory in terms of response to treatment and prognosis isnclear. Increased arterial compliance in cirrhosis leads to aunctional hypovolemia (decreased pre-load) despite a vol-me overload in absolute terms. The blunted cardiac re-ponse of cirrhotic cardiomyopathy fails to overcome theecrease in effective circulating volume because of arterialasodilation. Conversely, splanchnic arterial vasodilationnloads the ventricle and may mask the presence of ven-ricular insufficiency. Autonomic dysfunction and impairedolume and baroreceptor reflexes may also contribute to thelunted cardiac response. In a calcium tetrachloride model
as volume expansion and hyperdynamic circulation, contribute to electrophysio-ma membrane abnormalities, cytokines, growth factors, and autonomic impair-ad to cardiac failure. ATPase � adenosine triphosphatase; CO � cardiac output.
f cirrhosis, rapid correction of the functional hypovolemiaith saline infusion caused a rapid drop in cardiac output
19). The human corollary of this experiment is the devel-pment of heart failure and pulmonary hypertension afterapid increase in venous return after transjugular intrahepaticortosystemic shunt (TIPS) or liver transplantation (20).Therefore, the presence of a reduced cardiac workload,
avored by splanchnic arterial vasodilation, which is in turnaused by progressive hepatic decompensation, may maskardiac insufficiency. In fact, echocardiography often showshat patients with decompensated cirrhosis have normalardiac function; however, physiologic or pharmacologicaltress, bacterial infections (e.g., spontaneous bacterial peri-onitis), TIPS, or liver transplantation may unmask alter-tions in myocardial function, thus revealing the presence ofirrhotic cardiomyopathy.
A broad spectrum of cardiac alterations characterizes thelinical presentation of cirrhotic cardiomyopathy (Fig. 2),hat may be distinctively viewed as a high-output heartailure (Table 1) (21,22), although the chronological se-uence in which abnormalities develop is not fully defined.lectrophysiologic changes. Multiple electrical abnormal-
ties have been recognized in cirrhosis (QT-interval abnor-alities, electrical and mechanical dyssynchrony, chrono-
ropic incompetence) whose development seems linked toutonomic dysfunction (defects in the sympathetic nervousystem [SNS] and vagal impairment), severe portal hyper-ension and liver dysfunction, cytokines, and endotoxins23,24). These electric abnormalities are independent of the
linical Presentation of Cirrhotic CardiomyopathyTable 1 Clinical Presentation of Cirrhotic Cardiomyopathy
Diagnostic Methods Clinical S
EchocardiographyDynamic magnetic resonance cardiac imagingRadionuclide angiography multigated acquisitionMyocardial perfusion imaging with gatingSystolic time intervals (measured through
simultaneous recording of electrocardiogram,phonocardiogram, and external carotidarterial pulse tracing using multichannelphotographic recording system)
T-INTERVAL PROLONGATION. Prolongation of the QT-nterval is well known to increase the risk for ventricularachyarrhythmias. Prolongation of the QT-interval (�0.44 s)s seen even with mild increments in portal pressure inubjects with cirrhosis (24) and in noncirrhotic patients withortal hypertension, whereas a further increase has beenescribed after TIPS insertion (21). Both delayed repolar-zation of cardiomyocytes due to K� channel abnormalitiesnd sympathoadrenergic hyperactivity may contribute toT-interval prolongation (23,25). The QT-interval disper-
ion has been associated with the severity of liver dysfunc-ion (26). It also varies from daytime to nighttime, probablyeflecting diurnal variations in autonomic tone, circulatorytatus, and respiratory and oxygen demand (26). The QT-nterval corrects itself in only 50% of subjects after a liverransplant (23). A recalculation of QT intervals based oneart rate and other liver-related parameters are now
ndicated to better dissect out the contribution of changesn QT-interval to heart-related morbidity and mortalityn subjects with cirrhosis (27). According to some au-hors, QT-interval prolongation might be an importantign helpful to identify patients with cirrhosis at risk ofirrhotic cardiomyopathy (22).
LECTRICAL AND MECHANICAL DYSSYNCHRONY. Someases of sudden death from ventricular arrhythmias have beeneported in patients treated with vasopressin during varicealleeding or when undergoing plasma exchange (28). In animalodels, chronic ligation of the portal vein has been shown to
educe excitation-contraction coupling due to decreased den-
Diagnostic Criteria
sting conditions E/A ratio �1Prolonged deceleration time (�200 ms)Prolonged isovolumetric relaxation time (�80 ms)Enlarged left atriumDecreased pattern of contractilityDecreased wall motionIncreased wall thicknessResting ejection fraction �55%Ratio of pre-ejection period to LV ejection time is prolonged
tion coupling�0.44 s (rate-corrected)
on
Elevation correlates with cirrhosis, cardiac dysfunction, andprolonged QT time
Elevation correlates with low ventricular stroke volume andincreased LV mass index
They are imbalanced in cirrhosis during hepaticdecompensation phase
They are imbalanced in cirrhosis during hepaticdecompensation phase
igns
der restress
ontrac
tiontionentrati
ity of the L-type calcium channel (10). Disturbances of
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542 Zardi et al. JACC Vol. 56, No. 7, 2010Cirrhotic Cardiomyopathy August 10, 2010:539–49
xcitation-contraction coupling have also been observed inirrhotic patients with QT-interval prolongation, which maye attributable to defective K� channel function in ventricularardiomyocytes (29). The role of changes in intracellularalcium (Ca2�) and potassium (K�) in the extracellular milieuarticularly after variceal hemorrhage and blood transfusion inediating electromechanical dyssyncrony remains to be fully
lucidated.notropic and chronotropic incompetence. In a study ofirrhotic subjects without ascites, Na� loading caused anncreased end-systolic volume even though the restingemodynamics were relatively normal (6). After the devel-pment of ascites, there was more overt evidence of con-ractile dysfunction despite a decrease in both afterloadarterial vasodilation) and pre-load (venous return) (6). Bothypertensive and normotensive subjects with compensatedirrhosis show a reduction in cardiac index and an increasen systemic vascular resistance (30). These data have beenonsidered to represent underlying “pump dysfunction.”he hearts of cirrhotic subjects show a blunted ability to
ncrease heart rate or left ventricular ejection fraction afterppropriate stimulation with exercise, drug infusion, orostural challenge (31). These data are corroborated byther studies where an infusion of atrial natriuretic factor inirrhotic subjects led to a decrease in stroke volume andardiac index despite an increase in heart rate (32).
Another cause of decreased cardiac response to exercise isdecrease in maximal heart rate. This is closely correlated
Figure 2 Clinical View on Relationship Between Clinical and In
Progressive deterioration of cardiac function in cirrhosis may be recognized by meand echocardiographic abnormalities whose severity is predictive of contemporary
ith the decreased cardiac output response. It is hypothe- (
ized that impaired cardiovascular reflex regulation andiminished sensitivity to SNS activation might contribute tohe observed chronotropic incompetence (33).
iastolic dysfunction. Diastolic dysfunction in cirrhosisas first reported in 1997 (5). Although some diastolic
lterations may precede the systolic disturbances, bothorms of dysfunction may develop simultaneously in cir-hotic patients. Eccentric left ventricular hypertrophy devel-ps in bile duct ligated rats in conjunction with develop-ent of a hyperdynamic syndrome; this is associated with
ncreased collagen content and increased ventricular stiffness34) that induces a prolonged, slowed, or incomplete ven-ricular relaxation. Diastolic dysfunction has also beeneported in noncirrhotic portal hypertension and in patientsith ascites but without cardiac hypertrophy (35). Whereas
he increased venous return seen after TIPS is expected toncrease myocardial stretch and thus stroke volume, in atudy of alcohol-related cirrhosis, diastolic dysfunction wasnmasked by TIPS causing, in some cases, pulmonarydema and heart failure (36). Diastolic dysfunction may alsoesult from impaired myocardial relaxation. This is relatedo the on-off rate of Ca2� from troponin and the rate athich Ca2� returns to the sarcoplasmic reticulum through
he Ca2�–adenosine triphosphatase pump or Na�/Ca2�
xchanger. Interestingly, after paracentesis, patients withirrhosis show an improvement of diastolic dysfunction, asemonstrated by an increased ratio of early to late diastoliclling (E/A ratio) and a decreased deceleration time (5)
ental Abnormalities and Cardiac Function
clinical, electrocardiographic (ECG),sness of heart failure. CO � cardiac output.
strum
ans ofseriou
Table 1). In fact, parvalbumin improves diastolic dysfunc-
ion (37), suggesting that improved hemodynamic outcomesfter albumin infusion in subjects with spontaneous bacterialeritonitis may be partly due to a direct effect on theyocardium. Clinically, subjects with a thicker ventricle andore severe diastolic dysfunction are more likely to have
eart failure after liver transplantation (22). The diastolicysfunction tends to return to normal 6 to 12 months afterliver transplant (38).
ystolic dysfunction. A number of animal and human studiesn cirrhosis have shown evidence that systolic function ispparently normal or even increased at rest, yet becomesmpaired after stress, exercise, or other forms of stimuli (4–6).entricular function is impaired after pharmacologically in-uced stress in patients with alcoholic cirrhosis (39). Severaltudies of cirrhotic patients showed a decreased cardiac re-ponse with inotropic and chronotropic incompetence afterharmacologic or exercise-induced increase in afterload oreart rate (22,31); in fact, contrary to the expected increase, leftentricular ejection fraction did not change.
Although the systolic dysfunction has been attributedo the effects of alcohol on the myocardium in subjectsith cirrhosis, it is also present in those with nonalco-olic causes of cirrhosis (4), as has been evaluated byssessing ventricular contractile performance, at rest andfter exercise, through the measurement of systolic timentervals (derived from the simultaneous tracings oflectrocardiogram, carotid artery pulse, and phonocardio-ram) (28) (Table 1). In these cirrhotic patients, totallectromechanical systole was prolonged because of theengthening of systolic time intervals influenced by elec-romechanical coupling such as electromechanical delaynd pre-ejection period, probably related to a reducedesponse to the adrenergic drive (28).
Systolic dysfunction, however, worsens with increasingiver failure. The presence of ascites does not affect theystolic dysfunction, and it is also unaffected by thera-eutic paracentesis (5). It has been suggested that systolicysfunction may be influenced by pre-load, afterload, andiastolic dysfunction, but reduced myocardial reserve and
mpaired oxygen extraction (probably due to the localmbalanced NO production and function) emerge to behe main factors (22).
Recently, endocannabinoids have been implicated asotential cause of impaired myocardial contractility in aarbon tetrachloride mouse model of cirrhosis (40).
athogenic Mechanisms
he series of cardiac alterations that characterize thelinical presentation of cirrhotic cardiomyopathy dependn the several pathogenic mechanisms listed in theollowing text.
mpaired Receptor Function
everal potential molecular causes for impaired myocardialunction in cirrhosis have been identified. These include
hanges in cardiomyocyte plasma membranes, �-adrenoceptor (
ensity and function, altered K� channels, altered L-typea2� channels, and altered Na�/Ca2� exchanger (41).ole of cardiomyocyte plasma membrane changes. In a
tudy of a bile duct-ligated cirrhotic rat model, cardiomyocytesad significant increases in plasma membrane cholesterolontent and cholesterol-to-phospholipid molar ratio resultingn a decrease in plasma membrane fluidity compared withham-operated controls (42). In this model, cyclic adenosineonophosphate (cAMP) production in response to adrenergic
timulation was decreased; this was restored with correction ofhe membrane fluidity (Fig. 3). In a separate study of choles-atic cirrhotic rats, bile acid itself decreased plasma membraneuidity in cardiac ventricles (43).ole of ventricular �-adrenoceptors. The observed de-
rease in chronotropic and inotropic responses to �-drenergic stimulation (9) in cirrhosis may be due to eitherecreased �-adrenergic receptor density or function. Indeed, aecrease in �-adrenoceptor density has been observed concom-
tantly with the changes in membrane fluidity noted in thereceding text (42). The decrease in membrane fluidity fromncreased cholesterol further impairs signaling from the re-
aining receptors after ligand binding by inhibition of-adrenergic receptor coupling with stimulatory G proteins
44). Given the key role of altered membrane fluidity in-adrenergic receptor dysfunction and the presence of de-reased membrane fluidity in many animal models of cirrhosis,t appears that defective �-adrenergic receptor function isniversally present in cirrhotic cardiomyopathy.ole of ventricular muscarinic receptors. Five muscarinic
cetylcholine receptor subtypes are known: M1, M3, and5 muscarinic receptors couple to stimulate phospholipase, whereas M2 and M4 muscarinic receptors inhibit ad-
nylyl cyclase (44). However, only M2 and M3 receptors arexpressed in heart tissue, and M1, M2, and M3 receptorsre detected in vascular endothelial cells (45). In particular,uscarinic receptors reside in both the atria and ventricles
ut have a greater density in the former (46). They are morerevalent in the endocardium than in the epicardium.uscarinic receptors exist on T tubules in cardiomyocytes,
oronary arteries (including small vessels), and endothelialell membranes of capillaries. Muscarinic receptors arebundant on sinoatrial and atrioventricular nodal cells (47).he antagonistic effects of muscarinic versus �-adrenergic
timulation are well described in ventricular myocytes (48).n a rat model of bile duct ligated cirrhosis, investigatorseported blunted muscarinic (M2) responsiveness and de-ective signal transduction to cAMP (49).
However, as discussed previously, plasma membranelterations in cirrhosis models may impair all post-receptorardiomyocyte systems involving cAMP. The potential rolef altered M1 and M3 receptors in cirrhotic cardiomyopathyemains to be described.ole of ventricular K� channels. Ventricular K� chan-els are activated by a fall in cytoplasmic adenosineriphosphate concentration and function as a voltage-ndependent “brake” to modulate myocyte depolarization
50). Activation of K� channels is essential for both early
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544 Zardi et al. JACC Vol. 56, No. 7, 2010Cirrhotic Cardiomyopathy August 10, 2010:539–49
nd final repolarization. The K� channel activatorscalcitonin gene-related peptide, adenosine, and so forth)romote hyperpolarization and relaxation whereas inhib-tors (noradrenaline, 5-hydroxytryptamine, neuropeptide, angiotensin II, endothelin-1, and so forth) causeepolarization and contraction. A rat model of bile duct
igated cirrhosis found decreased current density for all 3ypes of K� channels in isolated ventricular myocytesCa2�-independent transient outward K� current, de-ayed rectifying K� current, and inward rectifying K�
urrent) (25). As a consequence of the decreased K�
urrent density, cirrhotic rats exhibited a longer durationf baseline action potential as compared with ventricularyocytes of sham-operated rats (25). These observationsay contribute to the QT-interval prolongation previ-
usly described in cirrhotic patients.A rapid change from a “short” to a “long” action potential
ommand waveform may cause an immediate decrease ineak Ca2�-dependent current and a marked slowing of itsecline (51).Therefore, a marked prolongation of the action potential
Figure 3 Molecular Basis of Blunted Cardiac Response
Gap-junction linked cardiomyocytes in which plasma membrane, myosin-actin crossfollowing cardiomyocyte abnormalities: 1) reduced cholesterol plasma membrane cmyocardial �-adrenoceptor density and a dysfunction of adrenergic intracellular sig3) alteration of muscarinic receptors (in particular, receptor M2 inhibits adenylyl cying phospholipase C); and 4) the density of K� channels is reduced, probably becgene-related peptide and adenosine, while noradrenaline, 5-hydroxytryptamine, neutriphosphate; RyR2 � ryanodine receptor Ca2� release channels.
ight maintain the cardiomyocyte in a contracted state and d
mpair relaxation (49). The inwardly rectifying background� current is believed to be the main ionic current respon-
ible for setting the resting membrane potential in mam-alian heart cells and also to influence the late phase of
epolarization (52); therefore, the inwardly rectifying back-round K� current may have some effect on cardiomyocytenotropy depending on the overall status of regulation ofntracellular Ca2� concentration, the key driver of the
yocardial contractility.ole of extracellular and sarcoplasmic reticulum calcium
hannels. In cardiac myocytes, depolarization of the plas-alemma opens L-type voltage-gated Ca2� channels that
ause activation of Ca2�-stimulated Ca2� release fromhe sarcoplasmic reticulum through ryanodine receptorsRyR2). Phosphorylation of RyR2 and decreased sarcoplas-ic reticulum Ca2� can decrease the calcium available for
elease (53). The decline of Ca2� content and the conse-uent myocardial relaxation occur through Ca2� reuptaken the sarcoplasmic reticulum and expulsion of Ca2� fromhe cytosol into the extracellular space by adenosineriphosphate-driven calcium pumps and ion gradient-
e, and sarcoplasmic reticulum are clearly depicted. This picture elucidates thet and alteration in cholesterol-to-phospholipid molar ratio; 2) downregulation ofby G protein, adenylyl cyclase, and cyclic adenosine monophosphate (cAMP);and receptors M1 and M3 are linked to intracellular signaling pathways, includ-f plasma membrane alterations. The receptor function is stimulated by calcitonintide Y, angiotensin II, and endothelin-1 show inhibitory action. ATP � adenosine
-bridgontennalingclase,
ause oropep
ependent Na�/Ca2� exchangers. A decrease in initial
a2� entry as well as decreased Ca2�-stimulated Ca2�
elease have been noted in cardiac myocytes in a bile ductigated model of cirrhosis (54) (Fig. 4). A decrease in densityf L-type channels and sarcolemmal calcium content haseen reported in other studies (16). Crosstalk betweenarcolemmal L-type Ca2� channels and the sarcoplasmiceticulum might be fundamentally important to ensuredequate Ca2� kinetics for long-term excitation-contractionoupling. Dysregulation of this process remains to beescribed in detail.ole of Na�/Ca2� exchanger. The Na�/Ca2� exchangerlays an important role in maintaining a balance betweena2� influx and efflux. The Na�/Ca2� exchanger is present
n all “external” membranes and exchanges 3 Na� ions for 1a2� ion (or 4 Na� ions for 1 Ca2� ion) (55). Thea�/Ca2� exchanger is, therefore, responsible for mainte-
ance of steady-state intracellular free Ca2� concentration,lthough a small fraction of the Ca2� transport also dependsn a sarcolemmal Ca2� adenosine triphosphatase (56).ince excess Ca2� influx contributes to cardiomyocytepoptosis (57), abnormalities of the Na�/Ca2� exchanger
Figure 4 Molecular Basis of Blunted Cardiac Response
Gap-junction linked cardiomyocytes in which plasma membrane, myosin-actin crossfollowing cardiomyocyte abnormalities: 1) L-type voltage-gated Ca2� channels contomyocyte �-adrenoceptor is implied in inhibition of ryanodine receptor Ca2� releasCa2� concentration; 2) increased levels of carbon monoxide (CO) stimulate guanylphosphate (cGMP) that inhibits Ca2� release by sarcoplasmic reticulum; 3) canna4) the increased circulating levels of tumor necrosis factor (TNF)-alpha and interleuproduction; the NO induces apoptosis and inhibits RyR2, reducing Ca2� current.
ight contribute the cirrhotic cardiomyopathy. This, how-ver, remains to be elucidated.
olecular Mediators of Impairedyocardial Function in Cirrhosis
ole of carbon monoxide. Carbon monoxide is an endo-enously produced short-lived gas that favors splanchnicrterial vasodilation. Cirrhosis may stimulate carbon monoxideroduction through activation of the SNS, increased levels oforepinephrine, or increased cytokinemia from the enhancedortal venous bacteremia and endotoxemia. Carbon monoxideay decrease ventricular contractility through increased cyclic
uanosine monophosphate (cGMP) and depressed calciumnflux. In a rat model of bile duct-ligated cirrhosis, hemexygenase messenger ribonucleic acid transcription, proteinxpression, and total heme oxygenase activity were significantlypregulated in cirrhotic rat hearts but not in sham-operatedontrol rat hearts (58).ole of cannabinoids and their receptors. Endocannabi-oids (e.g., anandamide) are lipids that are the endogenous
igands for cannabinoid receptors (59). Several mammalianissues express 1 of 2 types of cannabinoid receptors: CB1,
e, and sarcoplasmic reticulum are clearly depicted. This picture elucidates theto the Ca2� influx across the cell during depolarization; the dysfunction of cardi-nels (RyR2) by a Ca2�/calmodulin pathway leading to reduction of intracellular
ase in cirrhosis; this process leads to hyperexpression of cyclic guanosine mono-receptor 1 (CB1) inhibition of �-adrenoceptor function has been reported; and
)-1-� stimulate inducible nitric oxide synthase (iNOS), leading to nitric oxide (NO)
-bridgributee chanyl cyclbinoidskin (IL
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546 Zardi et al. JACC Vol. 56, No. 7, 2010Cirrhotic Cardiomyopathy August 10, 2010:539–49
xpressed in the brain and in several peripheral tissuesncluding heart, endothelial cells (hepatic sinusoidal endo-helial cells), smooth muscle cells, and perivascular nerves;nd CB2, expressed in immune system cells. Cannabinoidsnduce splanchnic arterial vasodilation and have negativenotropic effects on cardiac contractility in cirrhosis. In a rat
odel of bile duct ligated cirrhosis, increased endocannabi-oid signaling blunted the ventricular responsiveness to-adrenergic stimuli by the CB1 receptor (60). A study in a
at model of carbon tetrachloride-induced cirrhosis showedhat increased activity of the endocannabinoid/CB1 recep-or system directly impaired cardiac contractility, whereasndocannabinoid/CB1 receptor blockade restored the nor-al contractile function (40). The negative inotropic effect
f CB1 receptor might be the result of L-type calciumhannel inhibition and cAMP reduction.ole of NO. Nitric oxide is produced in cardiac microvas-
ular endothelial cells and cardiomyocytes from either con-titutive or inducible nitric oxide synthase (NOS), whichatalyses the conversion of L-arginine to L-citrulline. Car-iomyocytes principally express endothelial NOS, localizedear invaginations of the plasmalemma termed caveolae,nd neuronal NOS, localized on the sarcoplasmic reticulum61). A third isoform, the inducible nitric oxide synthaseiNOS), may be expressed upon stimulation with inflam-atory mediators. While NO synthesized by neuronal NOS
nd endothelial NOS has cardioprotective effects throughmprovement of perfusion and inhibition of apop-osis, NO derived from iNOS has a cardiotoxic effecthrough the suppression of muscle wall contractility andnduction of apoptosis (62). Nitric oxide is released in aulsatile manner from the beating heart. Changes in ven-ricular filling induce parallel increases or decreases inardiac NO synthesis, which, in turn, modulate the functionf ion channels and transporters involved in cardiacxcitation-contraction coupling (63).
Preliminary observations indicated that NO overproduction-nduced hyperdynamic circulation in cirrhosis and the con-equent splanchnic arterial vasodilation masked the presencef blunted cardiac function (19,20). However, experimentaltudies on cirrhotic animal models revealed the link betweenOS, NO, and blunted cardiac response. Van Obbergh et al.
64) first elucidated the role of NOS in cirrhotic cardiomyo-athy by demonstrating that treatment with the nonspecificOS inhibitor, L-NMMA (N omega-monomethyl-L-
rginine), significantly increased ventricular contractility ofsolated working hearts in cirrhotic rats. Thereafter, Liu etl. (65) showed that high levels of NO were cardiodepres-ant and that the heart and aorta of cirrhotic rats expressedigh levels of iNOS messenger ribonucleic acid and endo-helial NOS, respectively. Some lines of evidences supporthe role of tumor necrosis factor-� as a potent inducer ofNOS and, thereby, NO production (66). Conversely, NOtimulation of soluble guanylyl cyclase produces a 160- to00-fold increase in cGMP as the second messenger effectornd may cause bradycardia by blocking L-type channels and
mpairing the responsiveness of cardiac pacemaker cells to c
drenergic stimuli (54,66). Overproduction of NO andeuronal NOS overactivity may impair RyR2 functionhrough both classic cGMP-signaling and direct redoxodification of specific thiol residues in the RyR2 protein
63). In a rat model of bile duct-ligated cirrhosis, bothumor necrosis factor-� and interleukin-1� exerted a neg-tive inotropic effect in control papillary muscles through anO-dependent mechanism, leading to the hypothesis thatO production played an important role in the pathogen-
sis of cirrhotic cardiomyopathy (65).Other molecular pathways have also been investigated to
xplain the role of NO in cirrhotic cardiomyopathy. Per-xynitrite is a reactive oxygen species, formed by theeaction of NO with superoxide anion (O2�), that maynhibit cardiac function through nitration (or S-nitrosation)f cardiac contractile proteins, such as actin (67). In a ratodel of bile duct ligated cirrhosis, increased protein
itration in cardiac tissue was associated with reducedhronotropic function (68). In a separate study of L-NAMENG-L-nitro-arginine methyl ester) and N-acetylcysteine,ecreased cardiac nitrotyrosine levels favored normalizationf cardiac function and further confirmed the inhibitoryffect of nitration.
ole of Apoptosis in Impairedyocardial Function in Cirrhosis
poptosis is a key cellular process that plays an importantole of myocardial remodeling in heart failure (69).
itogen-activated protein kinases (MAPKs) are signalingroteins that respond to a variety of stimuli. Of the MAPKamily, p38-MAPK is particularly involved with growth,roliferation, differentiation, and apoptosis (70). Severalirrhosis-inducing agents specifically activate p38-MAPKn myofibroblasts (71). Gene transfer techniques show thathe p38-MAPK isoform, p38�, contributes to cell deathfter ischemia and cardiomyocyte apoptosis (72). A selective38�/p38� isoform inhibitor, SB203580, protects cardiacyocytes from ischemic damage, further confirming the
ro-apoptotic role for p38� (73). These effects are due tonhibition of the � rather than the � isoform (74). Trans-orming growth factor-� is a potent pro-fibrogenic andro-apoptotic cytokine that causes its effects through smadroteins and non-smad pathways, including the p38 MAPKnd JUN NH2-terminal kinases. These, as well as trans-orming growth factor-� activity, are increased in cirrhosis.
rognosis
he patient with cirrhosis is a severely ill patient with anverall unfavorable prognosis if liver transplant is not safelyerformed. While cirrhosis directly provides an increasedisk of cancer, bleeding, or infection, additional conditionsay worsen the already poor prognosis of such patients. As
reviously stated, impaired cardiac function is often undi-gnosed in cirrhosis yet leads to an increased risk of deathspecially in the setting of acute decompensated cirrhosis,
onditions in which the inability of increasing cardiac
utput likely contributes to unfavorable outcomes (28). Thempaired cardiac output may indeed favor a decrease in renalerfusion contributing to the pathogenesis of hepatorenalyndrome (75). That is favored by the ensuing sympatheticctivation that tries to increase cardiac contractility buttimulates renal sodium and water retention also throughhe activation of the renin-angiotensin-aldosterone system76). Furthermore, when there is a rapid hemodynamichange (e.g., after TIPS or liver transplantation), the in-reased filling pressure may favor the development ofongestive heart failure. That is due both to the impairediastolic relaxation, already present but still unrevealed, thatauses elevated ventricular pressure thus favoring left atriumilation, and to the impaired heart rate and intrinsiclterations of myocardium contractility. The ensuinglunted cardiac function causes a decrease in the effectiveirculatory volume, which induces a further increase inodium retention. Thus, increasing sodium excretionhrough diuretics, aldosterone-blockers especially, leads tomproved function (77). The �-adrenergic blockers areften used for patients with cirrhosis to reduce the portalypertension and prevent the gastroesophageal varicealemorrhage; �-blockers also ameliorate the cardiac contrac-ion and function, both reducing QT-interval prolongationime and opposing the downregulation of �-adrenoceptorensity (44). However, no longitudinal studies of diureticsnd �-blockers for cirrhotic cardiomyopathy are available.onflicting results have also been obtained by the use of
ngiotensin-II receptor antagonists, which, despite a goodncrease in sodium excretion without a change in renal andystemic hemodynamics (78), have not produced substantiallinical results after long-term treatment (79). On theontrary, according to some authors, angiotensin-convertingnzyme inhibitors could be of benefit (77), but furthertudies are necessary to prove their efficacy in cirrhoticardiomyopathy.
Because of the rapid shift of a large volume of blood fromhe splanchnic area to the heart, TIPS, used to treatefractory ascites and gastroesophageal variceal hemorrhage,ften produces a worsening of the cardiac function inatients with cirrhosis, especially in those with impairedardiac diastolic function (E/A ratio �1) (80).
Liver transplantation is also associated with cardiovascu-ar complications (affecting almost 25% of patients), andatients with an abnormal heart function during surgery aret higher risk for post-operative pulmonary edema (81,82).
An improvement after liver transplant is expected andalidates the concept that the cardiomyopathy is trulyirrhotic in origin (38). A study of 40 patients with cirrhosisndergoing liver transplantation reported the disappearancef left ventricular hypertrophy and diastolic dysfunction asell as normalization of systolic response and exercise
apacity during stress (38).In case of concomitant severe cardiomyopathy, heart
ransplantation has been considered (83).2
otential Therapeutic Approaches
o accepted pharmacologic treatment for cirrhotic cardio-yopathy exists. Liver transplant is the cure for cirrhosis
nd is likely to cure the associated cardiomyopathy. Whileaiting for targeted clinical trials, general knowledge and
onsiderations used for heart failure should be applied toatients with cirrhosis (84). Agonists of farnesoid X recep-or (a gene involved in intrahepatic generation of vasodilatorydrogen sulfide) and NCX-1000 (a new compound thateleases NO in the liver) are interesting new attempts aimedt correcting the diminished production of endogenousepatic vasodilators during cirrhosis (85,86), but their use-ulness is not yet clear in cirrhotic cardiomyopathy.
At present, investigations on the gene expression patternf the cardiomyocyte adrenergic pathway in animal modelsf cirrhosis are an attempt to better understand the causes ofhe blunted cardiac response (87). New gene-targetingharmacological strategies might be the future directionoward which research will move.
onclusions
significant proportion of patients with cirrhosis affectedy ascites, volume overload, and signs of hyperdynamicirculation have normal resting echocardiographic parame-ers but abnormal cardiac responses during exertion, stress,IPS, or liver transplantation, consistent with the existencef a cirrhotic cardiomyopathy (81). Strict diagnostic criteriaor cirrhotic cardiomyopathy are lacking, and this syndromes often not recognized. Inability to increase cardiac outputhen necessary is likely a cofactor in cirrhosis complications
uch as hepatorenal syndrome or shock. No specific treat-ent or management strategies has been tested for patientsith cirrhotic cardiomyopathy. The presence of the cardio-yopathy should be suspected in patients with worsening
emodynamics, and such patients may benefit from moreggressive monitoring and treatment of the underlyingathology leading to decompensation, and close monitoringuring procedures likely to cause decompensation (i.e.,IPS, paracentesis, transplant). Clinical trials in this area
re eagerly awaited. In the meantime, management ofirrhotic cardiomyopathy, once identified, should follow theecommendations of the American College of Cardiology/merican Heart Association guidelines for the treatment ofatients with heart failure (84). A better comprehension ofoth the complex hemodynamic changes during cirrhosisnd the molecular pathways involved in the contractileysfunction of the cardiomyocyte may lead to improved caref patients with cirrhotic cardiomyopathy.
eprint requests and correspondence: Dr. Enrico M. Zardi, Uni-ersità “Campus Bio-Medico,” Via Àlvaro del Portillo, Rome
548 Zardi et al. JACC Vol. 56, No. 7, 2010Cirrhotic Cardiomyopathy August 10, 2010:539–49
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ey Words: cardiomyocyte y vascular dysfunction y cirrhosis y portal
