Cirrhotic Cardiomyopathy

Journal of the American College of Cardiology © 2010 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 56, No. 7, 2010 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2009.12.075

STATE-OF-THE-ART PAPER

Cirrhotic Cardiomyopathy 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储 Rome and Trieste, Italy; and Richmond, Virginia Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by an abnormal and blunted response to physiologic, pathologic, or pharmacologic stress but normal to increased cardiac output and contractility at rest. As many as 50% of cirrhotic patients undergoing liver transplantation show signs of cardiac dysfunction, and 7% to 21% of deaths after orthotopic liver transplantation result from overt heart failure. In this review, we critically evaluate the existing literature on the pathophysiology and clinical implications of cirrhotic cardiomyopathy. (J Am Coll Cardiol 2010;56:539–49) © 2010 by the American College of Cardiology Foundation

More than 50 years ago, it was noted that persons with alcohol-related cirrhosis had increased cardiac output, and it was attributed to either impaired thiamine utilization or the presence of an endogenous vasodilator (1). Cardiac hypertrophy and cardiomyocyte edema in the absence of coronary artery disease, hypertension, or valvular disease were next described in an autopsy series of subjects with cirrhosis (2). Subsequent studies described an impaired hemodynamic response to physiologic (exercise) and pharmacologic stress despite a high resting cardiac output (3). These findings were then confirmed in animal models of alcoholic cirrhosis and found to be related to decreased myocardial contractile function (4), and finally were corroborated by additional human studies (5,6). This syndrome is formally described as cirrhotic cardiomyopathy, which is defined as chronic cardiac dysfunction in patients with cirrhosis characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities, in the absence of known cardiac disease and irrespective of the causes of cirrhosis, although some etiologies (e.g., iron overload and alcohol consumption) further impact on myocardial structure and function. This syndrome is considered to be related to both portal hypertension and cirrhosis (7) and is characterized by intrinsic alterations in myocardial function.

From the *Department of Clinical Medicine, University Campus Bio-Medico, Rome, Italy; †Virginia Commonwealth University, VCU Pauley Heart Center, Richmond, Virginia; ‡Department of Cardiology, II School of Medicine, University “La Sapienza,” Ospedale Sant’Andrea, Rome, Italy; §Department of Physiology and Pathology, University of Trieste, Trieste, Italy; and the 储Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, VCU School of Medicine, Richmond, Virginia. The authors have reported that they have no relationships to disclose. Manuscript received November 11, 2009; accepted December 16, 2009.

Pathophysiology Vascular Dysfunction Systemic vascular resistance and cardiac dysfunction. Advanced liver disease is associated with marked changes in systemic vascular resistance. In a model of pre-sinusoidal portal hypertension in rats, splanchnic arterial vasodilation is observed and is accompanied by a decreased contractile response to nitroprusside or isoproterenol and impaired myocyte calcium signaling, showing that portal vascular change and portosystemic shunting cause cirrhotic cardiomyopathy independent, at least in part, of parenchymal liver disease (8 –10). Sinusoidal portal hypertension, in contrast, is characterized by increased hepatic sinusoidal resistance to blood flow. This has both a fixed component due to fibrotic disruption of the architecture and a dynamic component due to changes in the contractility of the hepatic stellate cells and myofibroblasts in the hepatic sinusoids (11). These cells are sensitive to a number of vasoactive mediators, for example, endothelins, prostaglandins, and nitric oxide (NO). Sinusoidal NO production is impaired in subjects with cirrhosis because of increased caveolin expression (12,13). In contrast, there is an increased NO drive in the peripheral arterial circulation, especially in the splanchnic bed, that causes vasodilation. Other mediators implicated in the splanchnic arterial vasodilation seen in cirrhosis include carbon monoxide (CO) and endogenous cannabinoids (14,15). The resting hyperdynamic state in cirrhosis reflects, therefore, an initial appropriate response to splanchnic arterial vasodilation (15,16). Volume expansion. In patients with cirrhosis, blood volume expansion occurs before ascites formation. With progressive hepatic decompensation, there is a redistribution of this expanded blood volume with a relative decrease in the central circulation and increment in the

540

Zardi et al. Cirrhotic Cardiomyopathy

splanchnic bed (17). Moreover, despite an absolute increase in blood volume, there is marked accAMP ⴝ cyclic adenosine tivation of sodium (Na⫹) and wamonophosphate ter retentive pathways, which becGMP ⴝ cyclic guanosine come more pronounced as monophosphate cirrhosis worsens. This is driven iNOS ⴝ inducible nitric mainly by the state of progressive oxide synthase arterial vasodilation and imbalance MAPK ⴝ mitogen-activated protein kinase between the blood volume on one hand and the space it has to ocNOS ⴝ nitric oxide synthase cupy on the other (Fig. 1). Arterial compliance. Peripheral RyR2 ⴝ ryanodine receptor arterial vasodilation and arterial SNS ⴝ sympathetic nervous system compliance are closely associated. With progression of cirrhosis, TIPS ⴝ transjugular intrahepatic portosystemic there is a decrease in the thickness shunt of the vessel walls as well as a decrease in total vascular wall area (14). The vascular tone is also decreased, possibly because of reduced smooth muscle mass secondary to NO overproduction or altered endothelial function as well as alterations in extracellular matrix turnover (18). Increased expression of large conductance, calcium-activated potassium (K⫹) channel ␣ subunits have also been implicated as a cause of vascular remodeling and altered arterial compliance in cirrhosis (14). Abbreviations and Acronyms

Figure 1

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

Epidemiology, Natural History, and Clinical Presentation Limited information is available about the epidemiology of cirrhotic cardiomyopathy in humans, as its diagnosis is difficult because of near normal cardiac function at rest. The majority of patients are diagnosed during phases of clinical decompensation of cirrhosis in which they present with features of diastolic heart failure and/or high-output heart failure (5) (Table 1). The actual prevalence of this condition is unknown. Therefore, not much is known also regarding the natural history of the disease. The condition is undoubtedly well tolerated and asymptomatic for months to years, and in many cases the symptoms are not easily distinguished from those of the underlying disease. Similarly, the natural history in terms of response to treatment and prognosis is unclear. Increased arterial compliance in cirrhosis leads to a functional hypovolemia (decreased pre-load) despite a volume overload in absolute terms. The blunted cardiac response of cirrhotic cardiomyopathy fails to overcome the decrease in effective circulating volume because of arterial vasodilation. Conversely, splanchnic arterial vasodilation unloads the ventricle and may mask the presence of ventricular insufficiency. Autonomic dysfunction and impaired volume and baroreceptor reflexes may also contribute to the blunted cardiac response. In a calcium tetrachloride model

Clinical Basis of Blunted Cardiac Response

In the setting of liver cirrhosis and portal hypertension, a wide spectrum of factors, such as volume expansion and hyperdynamic circulation, contribute to electrophysiological abnormalities, diastolic dysfunction, and systolic dysfunction. Cardiomyocyte plasma membrane abnormalities, cytokines, growth factors, and autonomic impairment are also implied in this process. With advanced liver disease, these factors can lead to cardiac failure. ATPase ⫽ adenosine triphosphatase; CO ⫽ cardiac output.

Zardi et al. Cirrhotic Cardiomyopathy

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

541

Clinical of Cirrhotic Cardiomyopathy Table 1Presentation Clinical Presentation of Cirrhotic Cardiomyopathy Diagnostic Methods

Clinical Signs

Diagnostic Criteria

Echocardiography Dynamic magnetic resonance cardiac imaging Radionuclide angiography multigated acquisition Myocardial perfusion imaging with gating Systolic time intervals (measured through simultaneous recording of electrocardiogram, phonocardiogram, and external carotid arterial pulse tracing using multichannel photographic recording system)

High-output heart failure under resting conditions Blunted cardiac response to stress Diastolic dysfunction Systolic dysfunction

E/A ratio ⱕ1 Prolonged deceleration time (⬎200 ms) Prolonged isovolumetric relaxation time (⬎80 ms) Enlarged left atrium Decreased pattern of contractility Decreased wall motion Increased wall thickness Resting ejection fraction ⬍55% Ratio of pre-ejection period to LV ejection time is prolonged

Electrocardiography after necessary adjustment

Prolonged QT time Disturbances of excitation-contraction coupling

⬎0.44 s (rate-corrected)

Cardiac serum markers

Presence of BNP concentration Elevated pro-BNP concentration Presence of troponin I concentration

Elevation correlates with cirrhosis, cardiac dysfunction, and prolonged QT time Elevation correlates with low ventricular stroke volume and increased LV mass index

Vasodilator serum markers

Serum levels of Nitric oxide Carbon monoxide Endocannabinoids Endothelin-3 PGI2 Adrenomedullin

They are imbalanced in cirrhosis during hepatic decompensation phase

Vasoconstrictor serum markers

Serum levels of Angiotensin Endothelin-1 Vasopressin

They are imbalanced in cirrhosis during hepatic decompensation phase

BNP ⫽ brain natriuretic peptide; LV ⫽ left ventricular; PGI2 ⫽ prostacyclin.

of cirrhosis, rapid correction of the functional hypovolemia with saline infusion caused a rapid drop in cardiac output (19). The human corollary of this experiment is the development of heart failure and pulmonary hypertension after rapid increase in venous return after transjugular intrahepatic portosystemic shunt (TIPS) or liver transplantation (20). Therefore, the presence of a reduced cardiac workload, favored by splanchnic arterial vasodilation, which is in turn caused by progressive hepatic decompensation, may mask cardiac insufficiency. In fact, echocardiography often shows that patients with decompensated cirrhosis have normal cardiac function; however, physiologic or pharmacological stress, bacterial infections (e.g., spontaneous bacterial peritonitis), TIPS, or liver transplantation may unmask alterations in myocardial function, thus revealing the presence of cirrhotic cardiomyopathy. A broad spectrum of cardiac alterations characterizes the clinical presentation of cirrhotic cardiomyopathy (Fig. 2), that may be distinctively viewed as a high-output heart failure (Table 1) (21,22), although the chronological sequence in which abnormalities develop is not fully defined. Electrophysiologic changes. Multiple electrical abnormalities have been recognized in cirrhosis (QT-interval abnormalities, electrical and mechanical dyssynchrony, chronotropic incompetence) whose development seems linked to autonomic dysfunction (defects in the sympathetic nervous system [SNS] and vagal impairment), severe portal hypertension and liver dysfunction, cytokines, and endotoxins (23,24). These electric abnormalities are independent of the cause of cirrhosis.

QT-INTERVAL PROLONGATION. Prolongation of the QTinterval is well known to increase the risk for ventricular tachyarrhythmias. Prolongation of the QT-interval (⬎0.44 s) is seen even with mild increments in portal pressure in subjects with cirrhosis (24) and in noncirrhotic patients with portal hypertension, whereas a further increase has been described after TIPS insertion (21). Both delayed repolarization of cardiomyocytes due to K⫹ channel abnormalities and sympathoadrenergic hyperactivity may contribute to QT-interval prolongation (23,25). The QT-interval dispersion has been associated with the severity of liver dysfunction (26). It also varies from daytime to nighttime, probably reflecting diurnal variations in autonomic tone, circulatory status, and respiratory and oxygen demand (26). The QTinterval corrects itself in only 50% of subjects after a liver transplant (23). A recalculation of QT intervals based on heart rate and other liver-related parameters are now indicated to better dissect out the contribution of changes in QT-interval to heart-related morbidity and mortality in subjects with cirrhosis (27). According to some authors, QT-interval prolongation might be an important sign helpful to identify patients with cirrhosis at risk of cirrhotic cardiomyopathy (22). ELECTRICAL AND MECHANICAL DYSSYNCHRONY. Some cases of sudden death from ventricular arrhythmias have been reported in patients treated with vasopressin during variceal bleeding or when undergoing plasma exchange (28). In animal models, chronic ligation of the portal vein has been shown to reduce excitation-contraction coupling due to decreased density of the L-type calcium channel (10). Disturbances of

542

Figure 2

Zardi et al. Cirrhotic Cardiomyopathy

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

Clinical View on Relationship Between Clinical and Instrumental Abnormalities and Cardiac Function

Progressive deterioration of cardiac function in cirrhosis may be recognized by means of clinical, electrocardiographic (ECG), and echocardiographic abnormalities whose severity is predictive of contemporary seriousness of heart failure. CO ⫽ cardiac output.

excitation-contraction coupling have also been observed in cirrhotic patients with QT-interval prolongation, which may be attributable to defective K⫹ channel function in ventricular cardiomyocytes (29). The role of changes in intracellular calcium (Ca2⫹) and potassium (K⫹) in the extracellular milieu particularly after variceal hemorrhage and blood transfusion in mediating electromechanical dyssyncrony remains to be fully elucidated. Inotropic and chronotropic incompetence. In a study of cirrhotic subjects without ascites, Na⫹ loading caused an increased end-systolic volume even though the resting hemodynamics were relatively normal (6). After the development of ascites, there was more overt evidence of contractile dysfunction despite a decrease in both afterload (arterial vasodilation) and pre-load (venous return) (6). Both hypertensive and normotensive subjects with compensated cirrhosis show a reduction in cardiac index and an increase in systemic vascular resistance (30). These data have been considered to represent underlying “pump dysfunction.” The hearts of cirrhotic subjects show a blunted ability to increase heart rate or left ventricular ejection fraction after appropriate stimulation with exercise, drug infusion, or postural challenge (31). These data are corroborated by other studies where an infusion of atrial natriuretic factor in cirrhotic subjects led to a decrease in stroke volume and cardiac index despite an increase in heart rate (32). Another cause of decreased cardiac response to exercise is a decrease in maximal heart rate. This is closely correlated with the decreased cardiac output response. It is hypothe-

sized that impaired cardiovascular reflex regulation and diminished sensitivity to SNS activation might contribute to the observed chronotropic incompetence (33). Diastolic dysfunction. Diastolic dysfunction in cirrhosis was first reported in 1997 (5). Although some diastolic alterations may precede the systolic disturbances, both forms of dysfunction may develop simultaneously in cirrhotic patients. Eccentric left ventricular hypertrophy develops in bile duct ligated rats in conjunction with development of a hyperdynamic syndrome; this is associated with increased collagen content and increased ventricular stiffness (34) that induces a prolonged, slowed, or incomplete ventricular relaxation. Diastolic dysfunction has also been reported in noncirrhotic portal hypertension and in patients with ascites but without cardiac hypertrophy (35). Whereas the increased venous return seen after TIPS is expected to increase myocardial stretch and thus stroke volume, in a study of alcohol-related cirrhosis, diastolic dysfunction was unmasked by TIPS causing, in some cases, pulmonary edema and heart failure (36). Diastolic dysfunction may also result from impaired myocardial relaxation. This is related to the on-off rate of Ca2⫹ from troponin and the rate at which Ca2⫹ returns to the sarcoplasmic reticulum through the Ca2⫹–adenosine triphosphatase pump or Na⫹/Ca2⫹ exchanger. Interestingly, after paracentesis, patients with cirrhosis show an improvement of diastolic dysfunction, as demonstrated by an increased ratio of early to late diastolic filling (E/A ratio) and a decreased deceleration time (5) (Table 1). In fact, parvalbumin improves diastolic dysfunc-

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

tion (37), suggesting that improved hemodynamic outcomes after albumin infusion in subjects with spontaneous bacterial peritonitis may be partly due to a direct effect on the myocardium. Clinically, subjects with a thicker ventricle and more severe diastolic dysfunction are more likely to have heart failure after liver transplantation (22). The diastolic dysfunction tends to return to normal 6 to 12 months after a liver transplant (38). Systolic dysfunction. A number of animal and human studies on cirrhosis have shown evidence that systolic function is apparently normal or even increased at rest, yet becomes impaired after stress, exercise, or other forms of stimuli (4 – 6). Ventricular function is impaired after pharmacologically induced stress in patients with alcoholic cirrhosis (39). Several studies of cirrhotic patients showed a decreased cardiac response with inotropic and chronotropic incompetence after pharmacologic or exercise-induced increase in afterload or heart rate (22,31); in fact, contrary to the expected increase, left ventricular ejection fraction did not change. Although the systolic dysfunction has been attributed to the effects of alcohol on the myocardium in subjects with cirrhosis, it is also present in those with nonalcoholic causes of cirrhosis (4), as has been evaluated by assessing ventricular contractile performance, at rest and after exercise, through the measurement of systolic time intervals (derived from the simultaneous tracings of electrocardiogram, carotid artery pulse, and phonocardiogram) (28) (Table 1). In these cirrhotic patients, total electromechanical systole was prolonged because of the lengthening of systolic time intervals influenced by electromechanical coupling such as electromechanical delay and pre-ejection period, probably related to a reduced response to the adrenergic drive (28). Systolic dysfunction, however, worsens with increasing liver failure. The presence of ascites does not affect the systolic dysfunction, and it is also unaffected by therapeutic paracentesis (5). It has been suggested that systolic dysfunction may be influenced by pre-load, afterload, and diastolic dysfunction, but reduced myocardial reserve and impaired oxygen extraction (probably due to the local imbalanced NO production and function) emerge to be the main factors (22). Recently, endocannabinoids have been implicated as potential cause of impaired myocardial contractility in a carbon tetrachloride mouse model of cirrhosis (40). Pathogenic Mechanisms The series of cardiac alterations that characterize the clinical presentation of cirrhotic cardiomyopathy depend on the several pathogenic mechanisms listed in the following text. Impaired Receptor Function Several potential molecular causes for impaired myocardial function in cirrhosis have been identified. These include changes in cardiomyocyte plasma membranes, ␤-adrenoceptor

Zardi et al. Cirrhotic Cardiomyopathy

543

density and function, altered K⫹ channels, altered L-type Ca2⫹ channels, and altered Na⫹/Ca2⫹ exchanger (41). Role of cardiomyocyte plasma membrane changes. In a study of a bile duct-ligated cirrhotic rat model, cardiomyocytes had significant increases in plasma membrane cholesterol content and cholesterol-to-phospholipid molar ratio resulting in a decrease in plasma membrane fluidity compared with sham-operated controls (42). In this model, cyclic adenosine monophosphate (cAMP) production in response to adrenergic stimulation was decreased; this was restored with correction of the membrane fluidity (Fig. 3). In a separate study of cholestatic cirrhotic rats, bile acid itself decreased plasma membrane fluidity in cardiac ventricles (43). Role of ventricular ␤-adrenoceptors. The observed decrease in chronotropic and inotropic responses to ␤adrenergic stimulation (9) in cirrhosis may be due to either decreased ␤-adrenergic receptor density or function. Indeed, a decrease in ␤-adrenoceptor density has been observed concomitantly with the changes in membrane fluidity noted in the preceding text (42). The decrease in membrane fluidity from increased cholesterol further impairs signaling from the remaining 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 decreased membrane fluidity in many animal models of cirrhosis, it appears that defective ␤-adrenergic receptor function is universally present in cirrhotic cardiomyopathy. Role of ventricular muscarinic receptors. Five muscarinic acetylcholine receptor subtypes are known: M1, M3, and M5 muscarinic receptors couple to stimulate phospholipase C, whereas M2 and M4 muscarinic receptors inhibit adenylyl cyclase (44). However, only M2 and M3 receptors are expressed in heart tissue, and M1, M2, and M3 receptors are detected in vascular endothelial cells (45). In particular, muscarinic receptors reside in both the atria and ventricles but have a greater density in the former (46). They are more prevalent in the endocardium than in the epicardium. Muscarinic receptors exist on T tubules in cardiomyocytes, coronary arteries (including small vessels), and endothelial cell membranes of capillaries. Muscarinic receptors are abundant on sinoatrial and atrioventricular nodal cells (47). The antagonistic effects of muscarinic versus ␤-adrenergic stimulation are well described in ventricular myocytes (48). In a rat model of bile duct ligated cirrhosis, investigators reported blunted muscarinic (M2) responsiveness and defective signal transduction to cAMP (49). However, as discussed previously, plasma membrane alterations in cirrhosis models may impair all post-receptor cardiomyocyte systems involving cAMP. The potential role of altered M1 and M3 receptors in cirrhotic cardiomyopathy remains to be described. Role of ventricular Kⴙ channels. Ventricular K⫹ channels are activated by a fall in cytoplasmic adenosine triphosphate concentration and function as a voltageindependent “brake” to modulate myocyte depolarization (50). Activation of K⫹ channels is essential for both early

544

Figure 3

Zardi et al. Cirrhotic Cardiomyopathy

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

Molecular Basis of Blunted Cardiac Response

Gap-junction linked cardiomyocytes in which plasma membrane, myosin-actin cross-bridge, and sarcoplasmic reticulum are clearly depicted. This picture elucidates the following cardiomyocyte abnormalities: 1) reduced cholesterol plasma membrane content and alteration in cholesterol-to-phospholipid molar ratio; 2) downregulation of myocardial ␤-adrenoceptor density and a dysfunction of adrenergic intracellular signaling by G protein, adenylyl cyclase, and cyclic adenosine monophosphate (cAMP); 3) alteration of muscarinic receptors (in particular, receptor M2 inhibits adenylyl cyclase, and receptors M1 and M3 are linked to intracellular signaling pathways, including phospholipase C); and 4) the density of K⫹ channels is reduced, probably because of plasma membrane alterations. The receptor function is stimulated by calcitonin gene-related peptide and adenosine, while noradrenaline, 5-hydroxytryptamine, neuropeptide Y, angiotensin II, and endothelin-1 show inhibitory action. ATP ⫽ adenosine triphosphate; RyR2 ⫽ ryanodine receptor Ca2⫹ release channels.

and final repolarization. The K⫹ channel activators (calcitonin gene-related peptide, adenosine, and so forth) promote hyperpolarization and relaxation whereas inhibitors (noradrenaline, 5-hydroxytryptamine, neuropeptide Y, angiotensin II, endothelin-1, and so forth) cause depolarization and contraction. A rat model of bile duct ligated cirrhosis found decreased current density for all 3 types of K⫹ channels in isolated ventricular myocytes (Ca2⫹-independent transient outward K⫹ current, delayed rectifying K⫹ current, and inward rectifying K⫹ current) (25). As a consequence of the decreased K⫹ current density, cirrhotic rats exhibited a longer duration of baseline action potential as compared with ventricular myocytes of sham-operated rats (25). These observations may contribute to the QT-interval prolongation previously described in cirrhotic patients. A rapid change from a “short” to a “long” action potential command waveform may cause an immediate decrease in peak Ca2⫹-dependent current and a marked slowing of its decline (51). Therefore, a marked prolongation of the action potential might maintain the cardiomyocyte in a contracted state and

impair relaxation (49). The inwardly rectifying background K⫹ current is believed to be the main ionic current responsible for setting the resting membrane potential in mammalian heart cells and also to influence the late phase of repolarization (52); therefore, the inwardly rectifying background K⫹ current may have some effect on cardiomyocyte inotropy depending on the overall status of regulation of intracellular Ca2⫹ concentration, the key driver of the myocardial contractility. Role of extracellular and sarcoplasmic reticulum calcium channels. In cardiac myocytes, depolarization of the plasmalemma opens L-type voltage-gated Ca2⫹ channels that cause activation of Ca2⫹-stimulated Ca2⫹ release from the sarcoplasmic reticulum through ryanodine receptors (RyR2). Phosphorylation of RyR2 and decreased sarcoplasmic reticulum Ca2⫹ can decrease the calcium available for release (53). The decline of Ca2⫹ content and the consequent myocardial relaxation occur through Ca2⫹ reuptake in the sarcoplasmic reticulum and expulsion of Ca2⫹ from the cytosol into the extracellular space by adenosine triphosphate-driven calcium pumps and ion gradientdependent Na⫹/Ca2⫹ exchangers. A decrease in initial

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

Ca2⫹ entry as well as decreased Ca2⫹-stimulated Ca2⫹ release have been noted in cardiac myocytes in a bile duct ligated model of cirrhosis (54) (Fig. 4). A decrease in density of L-type channels and sarcolemmal calcium content has been reported in other studies (16). Crosstalk between sarcolemmal L-type Ca2⫹ channels and the sarcoplasmic reticulum might be fundamentally important to ensure adequate Ca2⫹ kinetics for long-term excitation-contraction coupling. Dysregulation of this process remains to be described in detail. Role of Naⴙ/Ca2ⴙ exchanger. The Na⫹/Ca2⫹ exchanger plays an important role in maintaining a balance between Ca2⫹ influx and efflux. The Na⫹/Ca2⫹ exchanger is present in all “external” membranes and exchanges 3 Na⫹ ions for 1 Ca2⫹ ion (or 4 Na⫹ ions for 1 Ca2⫹ ion) (55). The Na⫹/Ca2⫹ exchanger is, therefore, responsible for maintenance of steady-state intracellular free Ca2⫹ concentration, although a small fraction of the Ca2⫹ transport also depends on a sarcolemmal Ca2⫹ adenosine triphosphatase (56). Since excess Ca2⫹ influx contributes to cardiomyocyte apoptosis (57), abnormalities of the Na⫹/Ca2⫹ exchanger

Figure 4

Zardi et al. Cirrhotic Cardiomyopathy

545

might contribute the cirrhotic cardiomyopathy. This, however, remains to be elucidated. Molecular Mediators of Impaired Myocardial Function in Cirrhosis Role of carbon monoxide. Carbon monoxide is an endogenously produced short-lived gas that favors splanchnic arterial vasodilation. Cirrhosis may stimulate carbon monoxide production through activation of the SNS, increased levels of norepinephrine, or increased cytokinemia from the enhanced portal venous bacteremia and endotoxemia. Carbon monoxide may decrease ventricular contractility through increased cyclic guanosine monophosphate (cGMP) and depressed calcium influx. In a rat model of bile duct-ligated cirrhosis, heme oxygenase messenger ribonucleic acid transcription, protein expression, and total heme oxygenase activity were significantly upregulated in cirrhotic rat hearts but not in sham-operated control rat hearts (58). Role of cannabinoids and their receptors. Endocannabinoids (e.g., anandamide) are lipids that are the endogenous ligands for cannabinoid receptors (59). Several mammalian tissues express 1 of 2 types of cannabinoid receptors: CB1,

Molecular Basis of Blunted Cardiac Response

Gap-junction linked cardiomyocytes in which plasma membrane, myosin-actin cross-bridge, and sarcoplasmic reticulum are clearly depicted. This picture elucidates the following cardiomyocyte abnormalities: 1) L-type voltage-gated Ca2⫹ channels contribute to the Ca2⫹ influx across the cell during depolarization; the dysfunction of cardiomyocyte ␤-adrenoceptor is implied in inhibition of ryanodine receptor Ca2⫹ release channels (RyR2) by a Ca2⫹/calmodulin pathway leading to reduction of intracellular Ca2⫹ concentration; 2) increased levels of carbon monoxide (CO) stimulate guanylyl cyclase in cirrhosis; this process leads to hyperexpression of cyclic guanosine monophosphate (cGMP) that inhibits Ca2⫹ release by sarcoplasmic reticulum; 3) cannabinoids receptor 1 (CB1) inhibition of ␤-adrenoceptor function has been reported; and 4) the increased circulating levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1-␤ stimulate inducible nitric oxide synthase (iNOS), leading to nitric oxide (NO) production; the NO induces apoptosis and inhibits RyR2, reducing Ca2⫹ current.

546

Zardi et al. Cirrhotic Cardiomyopathy

expressed in the brain and in several peripheral tissues including heart, endothelial cells (hepatic sinusoidal endothelial cells), smooth muscle cells, and perivascular nerves; and CB2, expressed in immune system cells. Cannabinoids induce splanchnic arterial vasodilation and have negative inotropic effects on cardiac contractility in cirrhosis. In a rat model of bile duct ligated cirrhosis, increased endocannabinoid signaling blunted the ventricular responsiveness to ␤-adrenergic stimuli by the CB1 receptor (60). A study in a rat model of carbon tetrachloride-induced cirrhosis showed that increased activity of the endocannabinoid/CB1 receptor system directly impaired cardiac contractility, whereas endocannabinoid/CB1 receptor blockade restored the normal contractile function (40). The negative inotropic effect of CB1 receptor might be the result of L-type calcium channel inhibition and cAMP reduction. Role of NO. Nitric oxide is produced in cardiac microvascular endothelial cells and cardiomyocytes from either constitutive or inducible nitric oxide synthase (NOS), which catalyses the conversion of L-arginine to L-citrulline. Cardiomyocytes principally express endothelial NOS, localized near invaginations of the plasmalemma termed caveolae, and neuronal NOS, localized on the sarcoplasmic reticulum (61). A third isoform, the inducible nitric oxide synthase (iNOS), may be expressed upon stimulation with inflammatory mediators. While NO synthesized by neuronal NOS and endothelial NOS has cardioprotective effects through improvement of perfusion and inhibition of apoptosis, NO derived from iNOS has a cardiotoxic effect through the suppression of muscle wall contractility and induction of apoptosis (62). Nitric oxide is released in a pulsatile manner from the beating heart. Changes in ventricular filling induce parallel increases or decreases in cardiac NO synthesis, which, in turn, modulate the function of ion channels and transporters involved in cardiac excitation-contraction coupling (63). Preliminary observations indicated that NO overproductioninduced hyperdynamic circulation in cirrhosis and the consequent splanchnic arterial vasodilation masked the presence of blunted cardiac function (19,20). However, experimental studies on cirrhotic animal models revealed the link between NOS, NO, and blunted cardiac response. Van Obbergh et al. (64) first elucidated the role of NOS in cirrhotic cardiomyopathy by demonstrating that treatment with the nonspecific NOS inhibitor, L-NMMA (N omega-monomethyl-Larginine), significantly increased ventricular contractility of isolated working hearts in cirrhotic rats. Thereafter, Liu et al. (65) showed that high levels of NO were cardiodepressant and that the heart and aorta of cirrhotic rats expressed high levels of iNOS messenger ribonucleic acid and endothelial NOS, respectively. Some lines of evidences support the role of tumor necrosis factor-␣ as a potent inducer of iNOS and, thereby, NO production (66). Conversely, NO stimulation of soluble guanylyl cyclase produces a 160- to 400-fold increase in cGMP as the second messenger effector and may cause bradycardia by blocking L-type channels and impairing the responsiveness of cardiac pacemaker cells to

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

adrenergic stimuli (54,66). Overproduction of NO and neuronal NOS overactivity may impair RyR2 function through both classic cGMP-signaling and direct redox modification of specific thiol residues in the RyR2 protein (63). In a rat model of bile duct-ligated cirrhosis, both tumor necrosis factor-␣ and interleukin-1␤ exerted a negative inotropic effect in control papillary muscles through an NO-dependent mechanism, leading to the hypothesis that NO production played an important role in the pathogenesis of cirrhotic cardiomyopathy (65). Other molecular pathways have also been investigated to explain the role of NO in cirrhotic cardiomyopathy. Peroxynitrite is a reactive oxygen species, formed by the reaction of NO with superoxide anion (O2⫺), that may inhibit cardiac function through nitration (or S-nitrosation) of cardiac contractile proteins, such as actin (67). In a rat model of bile duct ligated cirrhosis, increased protein nitration in cardiac tissue was associated with reduced chronotropic function (68). In a separate study of L-NAME (NG-L-nitro-arginine methyl ester) and N-acetylcysteine, decreased cardiac nitrotyrosine levels favored normalization of cardiac function and further confirmed the inhibitory effect of nitration. Role of Apoptosis in Impaired Myocardial Function in Cirrhosis Apoptosis is a key cellular process that plays an important role of myocardial remodeling in heart failure (69). Mitogen-activated protein kinases (MAPKs) are signaling proteins that respond to a variety of stimuli. Of the MAPK family, p38-MAPK is particularly involved with growth, proliferation, differentiation, and apoptosis (70). Several cirrhosis-inducing agents specifically activate p38-MAPK in myofibroblasts (71). Gene transfer techniques show that the p38-MAPK isoform, p38␣, contributes to cell death after ischemia and cardiomyocyte apoptosis (72). A selective p38␣/p38␤ isoform inhibitor, SB203580, protects cardiac myocytes from ischemic damage, further confirming the pro-apoptotic role for p38␣ (73). These effects are due to inhibition of the ␣ rather than the ␤ isoform (74). Transforming growth factor-␤ is a potent pro-fibrogenic and pro-apoptotic cytokine that causes its effects through smad proteins and non-smad pathways, including the p38 MAPK and JUN NH2-terminal kinases. These, as well as transforming growth factor-␤ activity, are increased in cirrhosis. Prognosis The patient with cirrhosis is a severely ill patient with an overall unfavorable prognosis if liver transplant is not safely performed. While cirrhosis directly provides an increased risk of cancer, bleeding, or infection, additional conditions may worsen the already poor prognosis of such patients. As previously stated, impaired cardiac function is often undiagnosed in cirrhosis yet leads to an increased risk of death especially in the setting of acute decompensated cirrhosis, conditions in which the inability of increasing cardiac

Zardi et al. Cirrhotic Cardiomyopathy

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49

output likely contributes to unfavorable outcomes (28). The impaired cardiac output may indeed favor a decrease in renal perfusion contributing to the pathogenesis of hepatorenal syndrome (75). That is favored by the ensuing sympathetic activation that tries to increase cardiac contractility but stimulates renal sodium and water retention also through the activation of the renin-angiotensin-aldosterone system (76). Furthermore, when there is a rapid hemodynamic change (e.g., after TIPS or liver transplantation), the increased filling pressure may favor the development of congestive heart failure. That is due both to the impaired diastolic relaxation, already present but still unrevealed, that causes elevated ventricular pressure thus favoring left atrium dilation, and to the impaired heart rate and intrinsic alterations of myocardium contractility. The ensuing blunted cardiac function causes a decrease in the effective circulatory volume, which induces a further increase in sodium retention. Thus, increasing sodium excretion through diuretics, aldosterone-blockers especially, leads to improved function (77). The ␤-adrenergic blockers are often used for patients with cirrhosis to reduce the portal hypertension and prevent the gastroesophageal variceal hemorrhage; ␤-blockers also ameliorate the cardiac contraction and function, both reducing QT-interval prolongation time and opposing the downregulation of ␤-adrenoceptor density (44). However, no longitudinal studies of diuretics and ␤-blockers for cirrhotic cardiomyopathy are available. Conflicting results have also been obtained by the use of angiotensin-II receptor antagonists, which, despite a good increase in sodium excretion without a change in renal and systemic hemodynamics (78), have not produced substantial clinical results after long-term treatment (79). On the contrary, according to some authors, angiotensin-converting enzyme inhibitors could be of benefit (77), but further studies are necessary to prove their efficacy in cirrhotic cardiomyopathy. Because of the rapid shift of a large volume of blood from the splanchnic area to the heart, TIPS, used to treat refractory ascites and gastroesophageal variceal hemorrhage, often produces a worsening of the cardiac function in patients with cirrhosis, especially in those with impaired cardiac diastolic function (E/A ratio ⱕ1) (80). Liver transplantation is also associated with cardiovascular complications (affecting almost 25% of patients), and patients with an abnormal heart function during surgery are at higher risk for post-operative pulmonary edema (81,82). An improvement after liver transplant is expected and validates the concept that the cardiomyopathy is truly cirrhotic in origin (38). A study of 40 patients with cirrhosis undergoing liver transplantation reported the disappearance of left ventricular hypertrophy and diastolic dysfunction as well as normalization of systolic response and exercise capacity during stress (38). In case of concomitant severe cardiomyopathy, heart transplantation has been considered (83).

547

Potential Therapeutic Approaches No accepted pharmacologic treatment for cirrhotic cardiomyopathy exists. Liver transplant is the cure for cirrhosis and is likely to cure the associated cardiomyopathy. While waiting for targeted clinical trials, general knowledge and considerations used for heart failure should be applied to patients with cirrhosis (84). Agonists of farnesoid X receptor (a gene involved in intrahepatic generation of vasodilator hydrogen sulfide) and NCX-1000 (a new compound that releases NO in the liver) are interesting new attempts aimed at correcting the diminished production of endogenous hepatic vasodilators during cirrhosis (85,86), but their usefulness is not yet clear in cirrhotic cardiomyopathy. At present, investigations on the gene expression pattern of the cardiomyocyte adrenergic pathway in animal models of cirrhosis are an attempt to better understand the causes of the blunted cardiac response (87). New gene-targeting pharmacological strategies might be the future direction toward which research will move.

Conclusions A significant proportion of patients with cirrhosis affected by ascites, volume overload, and signs of hyperdynamic circulation have normal resting echocardiographic parameters but abnormal cardiac responses during exertion, stress, TIPS, or liver transplantation, consistent with the existence of a cirrhotic cardiomyopathy (81). Strict diagnostic criteria for cirrhotic cardiomyopathy are lacking, and this syndrome is often not recognized. Inability to increase cardiac output when necessary is likely a cofactor in cirrhosis complications such as hepatorenal syndrome or shock. No specific treatment or management strategies has been tested for patients with cirrhotic cardiomyopathy. The presence of the cardiomyopathy should be suspected in patients with worsening hemodynamics, and such patients may benefit from more aggressive monitoring and treatment of the underlying pathology leading to decompensation, and close monitoring during procedures likely to cause decompensation (i.e., TIPS, paracentesis, transplant). Clinical trials in this area are eagerly awaited. In the meantime, management of cirrhotic cardiomyopathy, once identified, should follow the recommendations of the American College of Cardiology/ American Heart Association guidelines for the treatment of patients with heart failure (84). A better comprehension of both the complex hemodynamic changes during cirrhosis and the molecular pathways involved in the contractile dysfunction of the cardiomyocyte may lead to improved care of patients with cirrhotic cardiomyopathy. Reprint requests and correspondence: Dr. Enrico M. Zardi, Università “Campus Bio-Medico,” Via Àlvaro del Portillo, Rome 200-00128, Italy. E-mail: [email protected].

548

Zardi et al. Cirrhotic Cardiomyopathy

REFERENCES

1. Shorr E, Zweifach BW, Furchgott RF, Baez S. Hepatorenal factors in circulatory homeostasis. IV. Tissue origins of the vasotropic principles, VEM and VDM, which appear during evolution of hemorrhagic and tourniquet shock. Circulation 1951;3:42–79. 2. Lunseth JH, Olmstead EG, Abboud F. A study of heart disease in one hundred eight hospitalized patients dying with portal cirrhosis. Arch Intern Med 1958;102:405–13. 3. Gould L, Shariff M, Zahir M, Di Lieto M. Cardiac haemodynamics in alcoholic patients with chronic liver disease and presystolic gallop. J Clin Invest 1969;48:860 – 8. 4. Caramelo C, Fernandez-Muñoz D, Santos JC, et al. Effect of volume expansion on hemodynamics, capillary permeability and renal function in conscious, cirrhotic rats. Hepatology 1986;6:129 –34. 5. Pozzi M, Carugo S, Boari G, et al. Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites. Hepatology 1997;26:1131–7. 6. Wong F, Liu P, Lilly L, Bomzon A, Blendis L. Role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis. Clin Sci (Lond) 1999;97:259 – 67. 7. Donovan CL, Marcovitz PA, Punch JD, Bach DS, Brown KA, Lucey MR. Two dimensional and dobutamine stress echocardiography in the preoperative assessment of patients with end-stage liver disease prior to orthotopic liver transplantation. Transplantation 1996;61:1180 – 8. 8. Benoit JN, Womack WA, Hernandez L, Granger DN. “Forward” and “backward” flow mechanisms of portal hypertension. Relative contributions in the rat model of portal vein stenosis. Gastroenterology 1985;89:1092– 6. 9. Battarbee HD, Farrar GE, Spears RP. Responses to hypotension in conscious rats with chronic portal venous hypertension. Am J Physiol Gastrointest Liver Physiol 1990;259:48 –55. 10. Zavecz JH, Bueno O, Maloney RE, O’Donnell JM, Roerig SC, Battarbee HD. Cardiac excitation-contraction coupling in the portal hypertensive rat. Am J Physiol Gastrointest Liver Physiol 2000;279: 28 –39. 11. Zardi EM, Dobrina A, Ambrosino G, Margiotta D, Polistina F, Afeltra A. New therapeutic approaches to liver fibrosis: a practicable route? Curr Med Chem 2008;15:1628 – 44. 12. Sanyal AJ, Bosch J, Blei A, Arroyo V. Portal hypertension and its complications. Gastroenterology 2008;134:1715–28. 13. Hendrickson H, Chatterjee S, Cao S, Morales Ruiz M, Sessa WC, Shah V. Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver. Am J Physiol Gastrointest Liver Physiol 2003;285:652– 60. 14. Bolognesi M, Sacerdoti D, Piva A, et al. Carbon monoxide-mediated activation of large conductance calcium-activated potassium channels contributes to mesenteric vasodilatation in cirrhotic rats. J Pharmacol Exp Ther 2007;321:187–94. 15. Woitas RP, Heller J, Stoffel-Wagner B, Spengler U, Sauerbruch T. Renal functional reserve and nitric oxide in patients with compensated liver cirrhosis. Hepatology 1997;26:858 – 64. 16. Bernardi M, Fornalè L, Di Marco C, et al. Hyperdynamic circulation of advanced cirrhosis: a re-appraisal based on posture-induced changes in hemodynamics. J Hepatol 1995;22:309 –18. 17. Levy M, Wexler MJ. Renal sodium retention and ascites formation in dogs with experimental cirrhosis but without portal hypertension or increased splanchnic vascular capacity. J Lab Clin Med 1978;91: 520 –36. 18. Sarkar R, Meinberg EG, Stanley JC, Gordon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res 1996;78:225–30. 19. Ferna´ndez-Muñoz D, Caramelo C, Santos JC, Blanchart A, Hernando L, Lo´pez-Novoa JM. Systemic and splanchnic hemodynamic disturbances in conscious rats with experimental liver cirrhosis without ascites. Am J Physiol 1985;249:316 –20. 20. Van der Linden P, Le Moine O, Ghysels M, Ortinez M, Devière J. Pulmonary hypertension after transjugular intrahepatic portosystemic shunt: effects on right ventricular function. Hepatology 1996;23: 982–7. 21. Møller S, Dümcke CW, Krag A. The heart and the liver. Expert Rev Gastroenterol Hepatol 2009; 3:51– 64. 22. Møller S, Henriksen JH. Cardiovascular complications of cirrhosis. Postgrad Med J 2009;85:44 –54.

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49 23. Bernardi M, Calandra S, Colantoni A, et al. Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors. Hepatology 1998;27:28 –34. 24. Hendrickse MT, Triger DR. Vagal dysfunction and impaired urinary sodium and water excretion in cirrhosis. Am J Gastroenterol 1994;89: 750 –7. 25. Ward CA, Ma Z, Lee SS, Giles WR. Potassium currents in atrial and ventricular myocytes from a rat model of cirrhosis. Am J Physiol 1997;273:537– 44. 26. Hansen S, Møller S, Bendtsen F, Jensen G, Henriksen JH. Diurnal variation and dispersion in QT interval in cirrhosis: relation to haemodynamic changes. J Hepatol 2007;47:373– 80. 27. Zambruni A, Di Micoli A, Lubisco A, Domenicali M, Trevisani F, Bernardi M. QT interval correction in patients with cirrhosis. J Cardiovasc Electrophysiol 2007;18:77– 82. 28. Zambruni A, Trevisani F, Caraceni P, Bernardi M. Cardiac electrophysiological abnormalities in patients with cirrhosis. J Hepatol 2006;44:994 –1002. 29. Henriksen JH, Fuglsang S, Bendtsen F, Christensen E, Møller S. Dyssynchronous electrical and mechanical systole in patients with cirrhosis. J Hepatol 2002;36:513–20. 30. Gentilini P, Romanelli RG, Laffi G, et al. Cardiovascular and renal function in normotensive and hypertensive patients with compensated cirrhosis: effects of posture. J Hepatol 1999;30:632– 8. 31. Kelbaek H, Rabøl A, Brynjolf I, et al. Haemodynamic response to exercise in patients with alcoholic liver cirrhosis. Clin Physiol 1987;7: 35– 41. 32. La Villa G, Lazzeri C, Pascale A, et al. Cardiovascular and renal effects of low-dose atrial natriuretic peptide in compensated cirrhosis. Am J Gastroenterol 1997;92:852–7. 33. Gerbes AL, Remien J, Jüngst D, Sauerbruch T, Paumgartner G. Evidence for down regulation of beta-2 adrenoreceptors in cirrhotic patients with severe ascites. Lancet 1986;1:1409 –11. 34. Inserte J, Perello´ A, Agullo´ L, et al. Left ventricular hypertrophy in rats with biliary cirrhosis. Hepatology 2003;38:589 –98. 35. Valeriano V, Funaro S, Lionetti R, et al. Modification of cardiac function in cirrhotic patients with and without ascites. Am J Gastroenterol 2000;95:3200 –5. 36. Huonker M, Schumacher YO, Ochs A, Sorichter S, Keul J, Rössle M. Cardiac function and haemodynamics in alcoholic cirrhosis and effects of the transjugular intrahepatic portosystemic stent shunt. Gut 1999; 44:743– 8. 37. Coutu P, Bennett CN, Favre EG, Day SM, Metzger JM. Parvalbumin corrects slowed relaxation in adult cardiac myocytes expressing hypertrophic cardiomyopathy-linked-tropomyosin mutations. Circ Res 2004;94:1235– 41. 38. Torregrosa M, Aguadé S, Dos L, et al. Cardiac alterations in cirrhosis: reversibility after liver transplantation. J Hepatol 2005;42:68 –74. 39. Limas CJ, Guiha NH, Lekagul O, Cohn JN. Impaired left ventricular function in alcoholic cirrhosis with ascites. Ineffectiveness of ouabain. Circulation. 1974;49:755– 60. 40. Ba´tkai S, Mukhopadhyay P, Harvey-White J, Kechrid R, Pacher P, Kunos G. Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Am J Physiol Heart Circ Physiol 2007;293:1689 –95. 41. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 2008;70:23– 49. 42. Ma Z, Meddings JB, Lee SS. Membrane physical properties determine cardiac beta-adrenergic receptor function in cirrhotic rats. Am J Physiol 1994;267:87–93. 43. Gazawi H, Ljubuncic P, Cogan U, Hochgraff E, Ben-Shachar D, Bomzon A. The effects of bile acids on beta-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes. Biochem Pharmacol 2000;59:1623– 8. 44. Ma Z, Lee SS, Meddings JB. Effects of altered cardiac membrane fluidity on beta-adrenergic receptor signalling in rats with cirrhotic cardiomyopathy. J Hepatol 1997;26:904 –12. 45. Wang Z, Shi H, Wang H. Functional M3 muscarinic acetylcholine receptors in mammalian hearts. Br J Pharmacol 2004;142:395– 408. 46. Brodde OE, Bruck H, Leineweber K, Seyfarth T. Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart. Basic Res Cardiol 2001;96:528 –38.

JACC Vol. 56, No. 7, 2010 August 10, 2010:539–49 47. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008;118:863–71. 48. Caulfield MP. Muscarinic receptors-characterization, coupling and function. Pharmacol Ther 1993;58:319 –79. 49. Jaue DN, Ma Z, Lee SS. Cardiac muscarinic receptor function in rats with cirrhotic cardiomyopathy. Hepatology 1997;25:1361–5. 50. Noma A. ATP-regulated K⫹ channels in cardiac muscle. Nature 1983;305:147– 8. 51. Bouchard RA, Clark RB, Giles WR. Effects of action potential duration on excitation-contraction coupling in rat ventricular myocytes. Action potential voltage-clamp measurements. Circ Res 1995; 76:790 – 801. 52. Nichols CG, Makhina EN, Pearson WL, Sha Q, Lopatin AN. Inward rectification and implications for cardiac excitability. Circ Res 1996; 78:1–7. 53. Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM. Ca2⫹/ calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2⫹ leak in heart failure. Circ Res 2005;97:1314 –22. 54. Ward CA, Liu H, Lee SS. Altered cellular calcium regulatory systems in a rat model of cirrhotic cardiomyopathy. Gastroenterology 2001; 121:1209 –18. 55. Bridge JH, Smolley JR, Spitzer KW. The relationship between charge movements associated with ICa and INa-Ca in cardiac myocytes. Science 1990;248:376 – 8. 56. Crespo LM, Grantham CJ, Cannell MB. Kinetics, stoichiometry and role of the Na-Ca exchange mechanism in isolated cardiac myocytes. Nature 1990;345:618 –21. 57. Chen X, Zhang X, Kubo H, et al. Ca2⫹ influx-induced sarcoplasmic reticulum Ca2⫹ overload causes mitochondrial-dependent apoptosis in ventricular myocytes. Circ Res 2005;11;97:1009 –17. 58. Liu H, Song D, Lee SS. Role of heme oxygenase-carbon monoxide pathway in pathogenesis of cirrhotic cardiomyopathy in the rat. Am J Physiol Gastrointest Liver Physiol 2001;280:68 –74. 59. De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol 2004;141: 765–74. 60. Gaskari SA, Liu H, Moezi L, Baik SK, Lee SS. Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Br J Pharmacol 2005;146:315–23. 61. Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci U S A 1999;96:657– 62. 62. Kim YM, Bombeck CA, Billiar TR. Nitric oxide as a bifunctional regulator of apoptosis. Circ Res 1999; 84:253– 6. 63. Seddon M, Shah AM, Casadei B. Cardiomyocytes as effectors of nitric oxide signalling. Cardiovasc Res 2007;75:315–36. 64. Van Obbergh L, Vallieres Y, Blaise G. Cardiac modifications occurring in the ascitic rat with biliary cirrhosis are nitric oxide related. J Hepatol 1996;24:747–52. 65. Liu H, Ma Z, Lee SS. Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Gastroenterology 2000;118:937– 44. 66. Herring N, Danson EJ, Paterson DJ. Cholinergic control of heart rate by nitric oxide is site specific. News Physiol Sci 2002;17:202– 6. 67. Gow AJ, Farkouh CR, Munson DA, Posencheg MA, Ischiropoulos H. Biological significance of nitric oxide-mediated protein modifications. Am J Physiol Lung Cell Mol Physiol 2004;287:262– 8. 68. Mani AR, Ippolito S, Ollosson R, Moore KP. Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis. Hepatology 2006;43:847– 86.

Zardi et al. Cirrhotic Cardiomyopathy

549

69. Anselmi A, Gaudino M, Baldi A, et al. Role of apoptosis in pressure-overload cardiomyopathy. J Cardiovasc Med (Hagerstown) 2008;9:227–32. 70. Kerkela R, Force T. p38 mitogen-activated protein kinase: a future target for heart failure therapy? J Am Coll Cardiol 2006;48:556 – 8. 71. Parsons CJ, Takashima M, Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol 2007;22:79 – 84. 72. Ren J, Zhang S, Kovacs A, Wang Y, Muslin AJ. Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. J Mol Cell Cardiol 2005;38:617–23. 73. Saurin AT, Martin JL, Heads RJ, et al. The role of differential activation of p38-mitogen activated protein kinase in preconditioned ventricular myocytes. FASEB J 2000;14:2237– 46. 74. Sabio G, Arthur JS, Kuma Y, et al. p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J 2005;24:1134 – 45. 75. Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42: 439 – 47. 76. Wong F. Cirrhotic cardiomyopathy. Hepatol Int 2009;3:294 –304. 77. Pozzi M, Ratti L, Guidi C, et al. Potential therapeutic targets in cirrhotic cardiomyopathy Cardiovasc Haematolog Disord Drug Targets 2007;7:21– 6. 78. Wong F, Liu P, Blendis L. The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis. Hepatology 2002;35:1449 –58. 79. Gonzalez-Abraldes J, Albillos A, Banares R, et al. Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Gastroenterology 2001;121:382– 8. 80. Cazzaniga M, Salerno F, Pagnozzi G, et al. Diastolic dysfunction is associated with poor survival in patients with cirrhosis with transjugular intrahepatic portosystemic shunt. Gut 2007;56:869 –75. 81. Ripoll C, Catalina MV, Yotti R, et al. Cardiac dysfunction during liver transplantation: incidence and preoperative predictors. Transplantation 2008;85:1766 –72. 82. Tiukinhoy-Laing SD, Rossi JS, Bayram M, et al. Cardiac hemodynamic and coronary angiographic characteristics of patients being evaluated for liver transplantation. Am J Cardiol 2006;98:178 – 81. 83. Hsu RB, Chang CI, Lin FY, et al. Heart transplantation in patients with liver cirrhosis. Eur J Cardiothorac Surg 2008;34:307–12. 84. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53: 1343– 82. 85. Renga B, Mencarelli A, Migliorati M, et al. Bile-acid-activated farnesoid X receptor regulates hydrogen sulfide production and hepatic microcirculation. World J Gastroenterol 2009;15:2097–108. 86. Fiorucci S, Antonelli E, Brancaleone V, et al. NCX-1000, a nitric oxide-releasing derivative of ursodeoxycholic acid, ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver. J Hepatol 2003;39:932–9. 87. Ceolotto G, Papparella I, Sticca A, et al. An abnormal gene expression of the ␤-adrenergic system contributes to the pathogenesis of cardiomyopathy in cirrhotic rats. Hepatology 2008;48:1913–23. Key Words: cardiomyocyte y vascular dysfunction y cirrhosis y portal hypertension.