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measured by the E/A ratio 28 days after the procedure predicted survival 1 year later. However, on multivariate

analysis, only the day 28 E/A ratio remained a significant predictor of death. During the first year of follow-up

after TIPS, the authors found that 60% of patients with an E/A ratio # 1 died, whereas no mortality was

observed in the patients with E/A ratio . 1.

Rabie et al.

[58], combining their results from Toronto with the Italian cohort [50], unsurprisingly reported

very similar findings. They examined a broad range of cardiac echo variables.

This combined study revealed several phenomena: (1) An E/A ratio of # 1wasapredictorofmortality.(2)The

increased mortality in those with an E/A ratio # 1 was due to both cardiac- and noncardiacrelated causes. (3)

Patients with E/A ratio of # 1 were less likely to clear ascites if TIPS was inserted to treat refractory ascites. We

agree with the authors’ postulation that patients with diastolic dysfunction were unable to handle the increased pre-

load after TIPS

[59]. Thus, the relative underfilling of the effective arterial circulating volume persists after TIPS with

resultant slow clearance of the ascites. There were three cardiac deaths post-TIPS insertion in this study; all of these

deaths happened in those with E/A ratio # 1 while no cardiac death was observed in those with E/A ratio . 1.

Rabie and coworkers

[12] found that in univariate analysis, age, serum creatinine, MELD score, and an E/A

ratio of # 1 were significant in predicting survival

[60]. However, on multivariate analysis again only an E/A

ratio # 1 was predictive of death after TIPS. Although patients with E/A ratio of . 1 had significantly lower

serum creatinine at baseline and 6 months after TIPS, multivariate analyses demonstrated that an E/A ratio of

# 1 was the only predictor of slow clearance of ascites.

All these data suggest that physicians need to assess cardiac function, particularly paying attention to the pres-

ence of diastolic dysfunction before TIPS insertion in cirrhotic patients. Moreover, post-TIPS surveillance should

also include cardiac monitoring with echocardiography to assess diastolic function. Those with E/A, 11 must be

carefully followed. Physicians also need to carefully weigh whether the benefits outweigh the potential risks of

the TIPS procedure in patients with borderline cardiac function.

Cardiac function, especially diastolic function, plays a very important role in the prediction of patient outcome

after TIPS. What about biomarkers reflecting heart injury? Recently, Vasatova and colleagues investigated cardiac

markers including high sensitivity cardiac troponin T (hs-cTn T), myoglobin glycogen phosphorylase BB isoen-

zyme (GPBB) and heart type of fatty acid binding protein (FABP). Univariable cox regression analysis showed

that higher hs-cTn T and FABP before TIPS were associated with poor survival, while Child-Pugh score, gender

or age had no correlation with one-year mortality after TIPS. No relationship was found between morta lity and

preprocedural serum GPBB and myoglobin. Cox multivariable proportional hazard regression showed that pre-

procedural hs-cTnT and postprocedural FABP are significant predictors of one-year mortality

[61].

Liver transplantation

Cirrhotic cardiomyopathy undoubtedly plays a significant role in both morbidity and mortality outcomes

before, during, and after liver transplantation. However, these subtopics are well covered in other chapters, and

the reader is referred to those. Specifically,

Chapter 19 deals with the cardiovascular workup and management

before liver transplantation.

Chapter 20 details the anesthesia considerations in patients with end-stage liver fail-

ure and cirrhotic cardiomyopathy during the perioperative and immediate postoperative periods. Finally,

Chapter 21 elucidates the major adverse cardiovascular events after liver transplantation and in particular man-

agement and ways of predicting which patients will develop cardiac events posttransplantation.

Hepatorenal syndrome

Hepatorenal syndrome (HRS) is a functional renal failure due to intense renal vasoconstriction that frequently

develops in patients with ascites (see also

Chapter 18). There are two types of HRS: type 1, which is often precipi-

tated by a bacterial infection, especially spontaneous bacterial peritonitis (SBP), and is characterized by a rapidly

progressive impairment of renal function. Type 2 HRS is characterized by a stable or slowly progressive renal fail-

ure so that its main clinical consequence is not acute renal failure, but refractory ascites, and its prognosis is better

than type 1 HRS. There is a relationship between cardiac output, HRS, and patient survival. It has been proposed

that cardiac dysfunction in cirrhosis is a major determinant of the course of patients who develop HRS

[62].

How to predict the development of HRS is very important. Ruiz-del-Arbol and colleagues

[63] investigated

the systemic and hepatic hemodynamics in patients with SBP. They compared the patients with renal failure

with those without renal failure and found that insufficient cardiac response to infection in patients with SBP

contributed to the development of hepatorenal syndrome after infection resolution. Patients with acute renal fail-

ure (hepatorenal syndrome) demo nstrated significantly less cardiac reserve than those whose renal function

remained unimpaired. Not only did cardiac output measured after resolution of infection decline in the group

224 15. Cirrhotic cardiomyopathy

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with renal failure (compared with no change in the renal-unimpaired group), but even the baseline cardiac out-

put in HRS patients was lower than the no-HRS cohort.

These observ ations point at adequate cardiac function as a primary det erminant of renal function in cirrhotic

patients with SBP. Interestingly, the MAP dropped significantly in the renal failure patients, while the patients

without hepatorenal syndrome, vascular resistance had no significant change. As is well known, pressur-

e 5 flow 3 resistance. Thus, these data imply that the drop in cardiac output is responsible for the decreased

MAP, and thus reduced renal perfusion. In other words, cardiac function is at least as important as peripheral

vessel status in the pathogenesis of acute renal dysfunction associated with SBP. It is also noteworthy that liver

function did not play an important role in renal failure, because the baseline Child-Pugh sc ores were similar in

patients who developed HRS versus those who did not

[63,64].

To further clarify the relationship between cardiac function and HRS, Ruiz-del-Arbol et al. performed another

study. They found that there were significant differences between patients with HRS and those without in ten

variables at baseline which included MAP, cardiac output, stroke volume, stroke work, urinary sodium excretion,

plasma renin activity, plasma concentrations of aldosterone and norepinephrine, wedged hepatic venous pres-

sure, and hepatic venous pressure gradient. However , on multivariate analysis, of the 10 variables showing sig-

nificant differences between groups, only plasma renin activity and cardiac output remained independently

associated with the development of hepatorenal syndrome.

They also documented that the baseline peripheral vascular resistance was decreased to the same extent in the

two groups. Again, this implies that it is the decreased cardiac output that reduces arterial pressure which trig-

gers the renal vasoconstriction and HRS. The authors observed these phenomena: (1) baseline cardiac output was

significantly lower in patients who later developed HRS; (2) development of hepatorenal syndrome further

reduced cardiac output. These observations indicate that the progression of circulatory dysfunction in cirrhosis is

due to a reduction in cardiac output. They therefore concluded that hepatorenal syndrome is the result of a

decrease in cardiac output in the setting of a severe arterial vasodilation

[65]. With these observations in mind,

physicians need to carefully monitor patients whose cardiac output is lower or whose cardiac output is reduced

during severe infections such as SBP.

Adrenal insufficiency

Adrenal insufficiency is defined as deficient production or action of glucocorticoids resulting from either a

structural damage of adrenal glands, “‘primary adrenal failure,”’ or an impairment o f the hypothalamicpitui-

tary axis or “‘secondary adrenal disease.”’ The literature generally supports the existence of adrenal insuffi-

ciency in cirrhosis

[66]. “Hepato-adrenal syndrome” was first proposed by Fontan in 1956 [67] and reexamined

by Marik et al. recently

[68]. These authors suggested the diagnostic criteria for adrenal i nsufficiency in cirrho-

sis: A random (stress) cortisol level ,20 μg/dL in a highly stressed patient (respiratory failure, hypotension);

or a random cortisol level ,15 μg/dL or a 30-min level ,20 μg/dL post-lowdose (1 μg) cosyntropin. Based

on these criteria, 66% of patients with chronic liver disease had adrenal insufficiency

[68].Inareviewarticle,

Fede et al. postulated that 26%64% of cirrhotic patients with ascites have adrenal insufficiency

[66].Thesame

group also demonstrated that the degree of adrenal dysfunction correlates with the severity o f liver disease. In

their series, adrenal insufficiency was present in 28% of ChildPugh class A patients, 58% in class B and 88%

in class C

[69].

On the one hand, there is cardiac dysfunction in cirrhotic patients; on the other hand, a high percentage of

patients with cirrhosis have ad renal insufficiency. Therefore, a cardioadrenal axis has been postulated to exist

in cirrhosis. According to this hypothesis, adrenal insufficiency-related cardiac dysfunction appears to be similar

in many aspects to cirrhotic cardiomyopathy: (1) both cirrhotic cardiomyopathy and adrenal insufficiency-

associated cardiomyopathy do not have symptoms, but may become clinically evident under stressful conditions.

(2) Under challenge, cardiac reserve cannot meet increased circulatory demands in both cirrhosis and adrenal

insufficiency, and patients manifest clinically overt heart failure. (3) Down-regulation of beta-adrenergic receptors

is a common feature in both clinical entities and may contribute to myocardial hyporesponsiveness. (4) QT inter-

val prolongation is a common clinical characteristic in both CCM and adrenal insufficiency. (5) Finally, patients

with cirrhotic cardiomyopathy, if adrenal insufficiency also coexists, may be mo re susceptible to develop overt

cardiac dysfunction

[70].

Physicians may wish to consider that for those whose cirrhotic cardiomyopathy is not responsive to treatment, cor-

ticosteroid supplementation may be helpful. However, the existence of true adrenal insufficiency in cirrhosis is not

universally accepted, and some doubters remain. Moreover, the postulated cardioadrenal axis in cirrhosis remains

hypothetical, so like many subtopics in cardiovascular complications of cirrhosis, this area too needs further study.

225Morbidity/mortality after cardiovascular challenges

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Cirrhotic cardiomyopathy and prognosis

Cirrhosis progresses at variable rates to end-stage liver failure. Deaths from hepatic failure, variceal bleeding

and infection are common in advanced cirrhosis. It is easy to understand that the worse the liver function, the

higher the mortality rate when challenged by TIPS and surgery

[71,72]. For example, variceal bleeding causes

10%15% mortality in cirrhotic patients with Child-Pugh class A, 20%30% in Child-Pugh B, and 40%50% in

Child-Pugh C patients

[71].

All deaths, of course, ultimately involve some form of cardiac arrest as an agonal event and patients with cir-

rhosis are not an exception. However, whether cardiac dysfunction predicts the prognosis in cirrhotic patients

needs to be clarified.

Krag et al.

[73] prospectively investigated 24 patients with cirrhosis and ascites. They analyzed the relationship

between cardiac systolic function, hepatorenal syndrome, and survival in these patients. Cardiac function was

evaluated by gated myocardial perfusion imaging for assessment of cardiac index (CI) and cardiac volumes. The

authors found that in the patients whose CI was ,1.5 L/min/m

, renal blood flow and glomerular filtration rate

(GFR) were significantly lower and serum creatinine was significantly higher compared with those whose CI was

higher than 1.5 L/min/m

; The number of patients who developed hepatorenal syndrome type 1 within 3

months was higher in the group with low CI than in those with high CI. Furthermore, patients with the lowest

CI had significantly poorer survival at 3, 9, and 12 months compared to those with a higher CI (

Fig. 15.1).

Interestingly, MELD score had no role in prediction of mortality in these patients. Based on these studies, it may

be useful to monitor cardiac function be monitored to estimate prognosis, especially for those who have systolic

or diastolic dysfunction, or both (

Fig. 15.2).

Pathogenic mechanisms

The pathogenic mechanisms of CCM are multifactorial and in many respects differ from other noncirrhotic

causes of heart failure. The development of cirrhotic cardiomyopathy therefore has its own process.

FIGURE 15.2 Cellular pathogenic mechanisms in cirrhotic cardiomyocytes. AC, adenylylcyclase; ATP, adenosine triphosphate; cAMP,

3’,5’-cyclic adenosine monophosphate; cGMP, 3’5’-cyclic guanosine monophosphate; Gβ, Gγ, Gαs, Gi, G-protein subunit; GC, guanylate

cyclase; GTP, guanosine-5’-triphosphate; MHC, myosin heavy chain; PBL, phospholamban; PKA, protein kinase G; pPBL, phosphorylated PBL;

ROS, reactive oxygen species; SR, sarcoplasmic reticulum.

226 15. Cirrhotic cardiomyopathy

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Patients with cirrhosis have portal hypertension and gastrointestinal congestion which results in bacterial

translocation; the translocated bacteria release toxic products such as lipopolysaccharide (LPS) into the circula-

tion, that is, endotoxemia. LPS stimulates pro-inflammatory cytokines such as tumor necrosis factor alpha

(TNFα)

[74,75], interleukin 1 beta (IL-1β) [75] and vasodilators such as nitric oxide (NO) [75], carbon monoxide

(CO)

[76], prostacyclin (PGI

) [77] and glucagon [78]. These vasodilators cause vasodilatation, arterial hypoten-

sion, and overactivation of the sympathetic nervous system. The overdriven β-adrenergic receptor eventually

becomes desensitized, which contributes to cardiac dysfunction.

TNFα

TNF-α is the most important pro-inflammatory cytokine that has a negative inotropic effect on myocardium [79].

It exerts a concentration- and time-dependent negative inotropic effect on cardiac contractility

[80]. LPS and factors

such as other cytokines in the circulation significantly induces TNF-α expression [81]. The Lee lab demonstrated

that TNF-α is significantly increased in cirrhotic murine hearts

[75].Yangetal.foundthatTNF-α is a key mediator

of cardiodepression in cirrhosis. Anti-TNF-α antibody or knockdown of the TNF-α gene restores the cardiac con-

tractility in the cirrhotic heart

[74]. Another strong evidence is that perfusing TNF-α to isolated rat hearts signifi-

cantly decreases the heart rate (2 83%), contractile force (220%), and velocity of relaxation (218%)

[79].

These studies demonstrated that the mechanism of the inhibitory effects of TNF-α on cardiac contractility is

complex. Yang et al. demonstrated that the inhibitory mechanism of TNF- α on cardiac contractility is via

NFκBiNOS and p38MAPK signaling pathways; Jude and coworkers proposed that the inhibition of cardiac con-

tractility by TNF-α is through the activation of protein kinase C (PKC) because chelerythrine, a PKC inhibitor,

significantly restored the TNF-α-inhibited cardiac contractility. Another study found that TNF-α in a low, patho-

physiologically relevant concentration has inhibitory effects on cardiac contractile response to catecholamines by

blocking α- and β-adrenoceptors. Furthermore, low concentration of TNF-α also reduces intracellular calcium

transients

[82]. Cardiomyocytes from adult cats were treated with TNFα which significantly decreased the levels

of peak intracellular calcium during the systolic contraction sequence

[74]. This study further demonstrated that

TNFα directly altered the intracellular calcium homeostasis, not through NO, nor an arachidonic acid pathway.

β-Adrenergic signaling

Cardiac-adrenergic signaling is one of the main regulators of cardiac contractility. Adrenergic receptors

increase adenylyl cyclase activity through stimulatory G proteins. Increased production of cAMP in turn results

in an increase in calcium influx and contractile force mainly through activation of protein kinase A (PKA). Lee

and colleagues in 1990 demonstrated that compared with sham-operated controls, cirrhotic rats needed a signifi-

cantly higher dose of isoprenaline to raise basal heart rate by 50 beats/min and the maximal heart rate response

is lower (104 6 29 vs. 158 6 61 beats/min). Furthermore, myocardial β-adrenoceptor density is significantly lower

in cirrhotic rats and the dissociation constant is higher. Our further analysis showed that it is the density of β1-

adrenergic receptor that is downregulated in the cirrhotic heart; this is entirely responsible for the myocardial

hyporesponsiveness to catecholamines observed in cirrhosis

[83].

Because of the difficulty in obtaining human heart tissue , Gerbes et al. measured the density of β-adrenocep-

tors on human lymphocytes, which are believed to parallel the status of cardiac hat it is the density of β1-adra-

drenoceptor density on lymphocytes was significantly low er in patients with severe ascites

[84]. Further studies

demonstrated that not only the density/sensitivity of β-adrenoceptors is decreased, but also its postreceptor sig-

naling pathway is blunted in cardiac tissue of cirrhotic rats. Postreceptor impairment includes the content and

function of stimulatory Gs-proteins

[85], uncoupling of the β-adrenoceptor-ligand complex from G protein [86],

and responsiveness of adenylyl cyclase to stimuli

[85,87].

Membrane fluidity

Membrane fluidity, the mobility of lipid moieties in the lipid bilayer of the plasma membrane, plays an impor-

tant role in cellular functions including carrier-mediated transport, ion exchange, energy transfer, and regulation

of enzyme activity

[88]. Wu and colleagues found that less membrane fluidity decreased cAMP content, and

227Membrane fluidity

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-K

-ATPase activity in cardiomyocytes and disturbed myocardial function [89]. The membrane fluidity is

abnormal in both red blood cells

[90] and platelets [91] in cirrhotic patients which may mimic the membrane flu-

idity of cardiomyocytes in cirrhotic patients. There is no direct study on biochemical and biophysical properties

of cardiomyocytes in cirrhotic patients. However, Ma et al.

[85] found that the fluidity of plasma membrane is

impaired in heart cells in cirrhotic rats. The impaired plasma membrane fluidity in cirrhotic heart changes the

functions of membrane-bound receptors including β-adrenergic receptors

[85]. Restoration of these abnormalities

in vitro results in normalization of blunted response of β-adrenergic receptors [85]. Alterations in membrane flu-

idity may also play a role in abnormal function of other membrane-bound components in cirrhotic cardiomyo-

cytes including ion channels, Mg

(21)

-ATPase, and acetylcholinesterase [92]. Our lab demonstrated the ion

channel changes such as K

and Ca

channels. The significant decrease in K

currents and L-type Ca

chan-

nels [93,94] required further investigation.

Bile acids

The concentrations of total bile acids, glycocholic acid, glycochenodeoxycholic acid, taurocholic acid, tauroche-

noxycholic acid, and tauroursodeoxycholic acid (TUDCA) are significantly increased in patients with early cirrhosis

compared to those with chronic hepatitis

[52]. The levels of total and individual bile acids are diagnostic markers

of cirrhosis. Furthermore, the levels of total bile acids, primary conjugated bile acids, and TUDCA parallel the pro-

gression of cirrhosis

[95]. Increase in bile acids has been shown to affect heart rate and contractility [96].

Desai and colleagues studied the role of bile acids in cirrhotic cardiomyopathy (see also

Chapter 16).

Farnesoid X receptor (Fxr), a bile acid receptor and small heterodimer partner, a downstream target of Fxr, were

doubly-knocked out (DKO) in mice, which creates a model for bile acid overload. They Compared DKO mice to

adult wild type and found that DKO mice manifested the following abnormalities: increased the ratio heart

weight/tibial length; increased the size of cardiomyocytes; induced the core cytoskeletal proteins, α/β actin and

α/β tubulin; decreased left ventricular internal diameter (LVID) in diastole and in systole; decreased cardiac out-

put; prolonged QTc and PR intervals on ECG; slowed heartbeat (bradycardia); decreased myosin heavy chain

(MHC) α isoform; activated apoptotic pathways; and elevated serum cardiac troponin-2 levels. All these changes

match the clinical symptoms of cirrhotic cardiomyopathy

[97]. Moreover, bile acids are sufficient to mimic the

heart dysfunction phenotype observed in DKO mice. Furthermore, pathological levels of bile acids are sufficient

to cause metabolic reprogramming: suppressing fatty acid oxidation regulators such as Pgc1α, m-Cpt1, Nrf-1,

Nrf-2 and Tfam; suppressing glucose oxidation inhibitors, such as Pdk4 and thus, switching the metabolite from

fatty acid to glucose

[97].

Bile acids overload also inhibits adenylyl cyclase, which may contribute to blunted cardiac contractility in

jaundiced patients

[98].

Gazawi et al. proposed three mechanisms of bile acids on cardiomyopathy: β-adrenoceptor, membrane fluid-

ity, and reactive oxygen species (ROS). They studied the effects of different concentration of bile acids on the

heart and found that 10

M of bile acids decreases the density of cardiac β-adrenoceptor; 10

M reduces both

receptor density and affinity and furthermore, reduces membrane fluidity

[99]. They did not find the effect of

bile acids on ROS at the pathophysiological concentration. These results suggest that bile acids, at concentrations

equivalent to the plasma/serum total or estimated free bile acid concentration, plays a pathogenetic role in the

etiology of cardiomyopathy.

Nitric oxide

NO is significantly increased in cirrhotic patients [30]. NO negatively regulates cardiac contractile function

[75]. NO is involved in several types of cardiac dysfunction including sepsis, myocarditis, cardiac transplant

rejection, and dilated cardiomyopathy

[100]. NO donors exert a negative inotropic effect and enhance diastolic

relaxation. Nonspecific nitric oxide synthases (NOS) inhibitors increase cardiac contractility

[75,101]. NO activates

guanylyl cyclase which catalyzes GTP to produce cGMP. cGMP has negative inotropic effects. Another study

demonstrated that NOS1 knockout or using NOS1 inhibitor significantly increased basal contraction both in left

ventricular myocytes and in vivo compared with controls. Thi s study further found that compared with controls,

NOS1 disruption increased L-type Ca

current density, increased Ca

influx and a sarcoplasmic reticulum cal-

cium load, increase [Ca2 1 ]i transient peak amplitude

[102]. Furthermore, NO inhibits the positive inotropic and

228 15. Cirrhotic cardiomyopathy

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chronotropic responses to β-adrenergic receptor stimulation [100]. Our study demonstrated that NO was signifi-

cantly increased in serum and heart in cirrhotic rats. The increased NO has a negative inotropic effect in isolated

left ventricular papillary muscles of cirrho tic rats

[75]. Increased levels of cGMP in cirrhotic ventricles and ele-

vated serum and cardiac levels of cytokines like TNF-α suggest a cytokine/NO/cGMP pathway for this effect

[75]. Possible effects of NO on cardiac function in physiological and some pathophysiological states were exten-

sively reviewed previously

[101,103].

Carbon monoxide

CO is mainly produced in the body through the action of heme oxygenases. These enzymes are responsible

for converting heme to biliverdin and CO. Like NO, CO activates soluble guanylate cyclase which catalyzes GTP

to produce cGMP, a cardiodepressant

[104,105]. Raju and coworkers found that the expression of inducible heme

oxygenase (HO-1) mRNA was increased in the right ventricle in a canine model of congestive heart failure

[106].

Our previous study demonstrated the increases of mRNA and protein expression of HO-1 in left ventricles of

bile duct-ligated rats, which was associated with an increase in cGMP levels

[76]. Furthermore, we found that

zinc protoporphyrin IX, an HO inhibitor, restores the elevated cGMP levels in cirrhotic heart and reverse the

inhibited contractility of the cirrhotic rat papillary muscle. These findings suggest the involvement of an HO-CO-

cGMP pathway in the development of cirrhotic cardiomyopathy.

It is well known that L-type calcium channels are essential for cardiac contractility

[107]. Abramochkin et al.

found that CO binds with cytochrome c oxidase which subsequent increase ROS production. ROS inhibits cardiac

L-type calcium channels. Another ion channel that CO modulates is cardiac sodium channel (I

): CO decreases

the peak density of I

. Thus, CO may affect some cardiac ionic currents and therefore modulates the cardiac

electrical activity and contractility

[108]. CO also activates soluble guanylate cyclase and subsequent increases the

intracellular content of cGMP which inhibits cardiac contractility

[75,76].

Myosin heavy chain isoform shift

There are two types of MHC in the heart: α-MHC and β-MHC. β-MHC predominantly expressed in late fetal

life and α-MHC predominantly expressed in the adult. In adult rats, more than 70% MHC is α-MHC isoform

[109]. Compared with α-MHC, β-MHC has lower APTase activity with slow twitch [110]. β-MHC dramatically

slows the overall rate of the stretch activation response compared to that of α-MHC isoform; specifically, the rate

of force decay of β-MHC was approximately twofold slower and the rate of delayed force development was

approximately 2.5-fold slower compared with that of α-MHC

[111].

α-MHC to β-MHC switch plays a significant role in cardiac dysfunction in several noncirrhotic types of heart

failure

[109]. Rundell and colleagues tested the myosin isoform shift in experimental diabetes and found that the

cardiac content of α-MH C in diabetes was decreased significantly at 6 wk (41% 6 4.1 vs 77.8% 6 3.3, P , .05) and

continuously decreased at 12 wk (32.5% 6 2.9 vs 73.6% 6 2.5, P , .05) of diabetes. They further demonstrated a

linear decrease in cardiac tension cost with decreased α-MHC content

[109].

The depression of tension cost in this rodent model of diabetes could be fully explained by the altered myosin

isoform distribution. Exercise training delays the isoform shift from α-MHC to β-MHC and also delays the ons et

of overt heart failure in the spontaneously hypertensive rat model of heart failure and thus improves survival

[112]. Lowes et al. found that an increase of α-MHC and a decrease in β-MHC improves left ventricular function

in patients with idiopathic dilated cardiomyopathy

[113].

Our recent publication demonstrated the MHC isoform shift from α-MHC dominant in control rats to β-MHC

dominant in cirrhotic animals

[114] which is similar to the shift in diabetic cardiomyopathy [109]. Rundell et al.

found a linear decrease in cardiac tension cost with decreased α-MHC content. Our study found that the max i-

mum twitch force is decreased following the decrease in α-MHC content in cirrhotic heart; both the rate of rise

and fall of contraction were reduced. Moreover, the maximal force-generating capacity was reduced, and the ino-

tropic effect of increased stimulus frequency was significantly attenuated.

The exact cellular mechanism underlying the MHC isoform change remains unclear. Studies from the Desai

lab demonstrated that high-dose bile acids in a murine model of cholestasis are associated with a similar α-MHC

to β-MHC isoform change and may be mediated via a G-protein coupled receptor GPCR-5

[97,115].

229Myosin heavy chain isoform shift

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The role of ion channels in cirrhotic cardiomyopathy

It is well known that the calcium channel plays an essential role in cardiac contraction. Our previous study

showed that it is the plasma membrane channels that have pathological phenotype, not the calcium system

within the cardiomyocytes. The protein expression of L-type Ca

channels in cirrhotic heart is reduced com-

pared with controls, and the peak inward Ca2 1 current was significantly less. At all membrane potentials exam-

ined, the current densities of L-type Ca

channels from cirrhotic heart are consistently lower. In comparison

with the calcium channels in plasma membrane, the protein expression and messenger RNA transcription for sar-

coplasmic reticulum Ca

-pump adenosine triphosphatase [SERCA2] and calcium-induced release channels are

quantitatively unchanged, and the ryanodine binding characteristics and Ca2 1 uptake are also unaltered

[94].

Using the fluorescence (Fluo-4) method, we found that the steady-state diastolic calcium fluorescence is not

different between Sham and BDL myocytes, However, the maximum calcium transient was significantly smaller

in cirrhotic cardiomyocytes (P , .001). Time to peak calcium transient in cirrhotic cardiomyocytes is clearly longer

than that in the cardiomyocytes from sham control (P , .05)

[114]. Furthermore, contractile force of right ventricu-

lar trabeculae at calcium .0.5 mM and the maximum contractile force are significantly attenuated in cirrhotic tra-

beculae compared with that in sham controls (P , .001).

In addition to the L-type calcium channel change that plays a key role in reduced contractility, potassium

channels also show differences in cirrhotic cardiomyocytes compared with controls. Our previous study showed

that the density of expression of I

, a calcium-independent transient outward K 1 current, and I

sus

, a delayed rec-

tifier K 1 current is decreased. These decreases contribute to the prolonged Q-T interval of the electrocardiogram

that has been described in cirrhotic patients

[93].

Titin and collagen isoforms

Titin, a giant protein, of 3 MDs molecular weight and over 1.5-μm length [116], functions as a molecular

spring which is responsible for the passive elasticity of relaxed striated muscle and plays an essential role in

myofibrillar assembly

[117]. The structure of titin domains is essential for cardiomyocyte to function. Because

titin spans the entire sarcomere, its length and elasticity largely determine the passive tension of the ventricle

[118]. Titin has two isoforms, N2BA and N2B. In normal hearts, the ratio of N2BA:N2B is typically 70:30 [119].

The predominant titin isoform in patients with end-stage dilated cardiomyopathy is the longer, softer N2BA,

which correlated with the increase of en d diastolic volume on ultrasonography. Our animal study did not show

any isoform difference in the rat cirrhotic heart

[117]. However, we found that the involvement of titin in the

pathogenesis of cirrhotic cardiomyopathy is through the decreased phosphorylation of titin which contributes to

the increased stiffness and thus diastolic dysfunction.

Our data are consistent with the results of Slater and colleagues in a noncirrhotic animal model of heart fail-

ure. They found that metformin significantly increased the phosphorylation of N2B in transverse aortic constric-

tion 1 deoxycorticosterone acetate-induced cardiac dysfunction in mice and improved the cardiac function

[120].

Using carboxypeptidase cathepsin A transgenic (CatA-TG) mouse to create a cardiac hypertrophy model, Hohl

et al. found that the type I/type III collagen ratio was shifted toward higher abundance of collagen I fibers and

the left ventricular end-diastolic volume was significantly increased

[121]. Our study in bile duct-ligated cirrhotic

rats also showed a significant shift of collagen from type III toward type I, the stiffer isoform

[117]. This shift aug-

ments diastolic stiffness

[117].

Endocannabinoids

Cardiac endocannabinoids are synthesized from membrane phospholipids in the heart. Endocannabinoids

have several receptors such as CB1, CB2, transient receptor potential V1 (TRPV1), peroxisome proliferator-

activated receptors, and G-protein-coupled receptor

[122]. Among them, CB1 plays an important role in the car-

diovascular system: cannabinoids induce hypotension and bradycardia

[123]. Furthermore, anandamide, one of

the main endogenous agonists of CB1, decreases cardiac systolic force in a dose-dependent manner. This inhibi-

tion is reversed by AM-251, a CB1 antagonist.

230 15. Cirrhotic cardiomyopathy

III. Cardiovascular system in liver failure

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In cirrhotic rats, the plasma level of an endogenous cannabinoid, anandamide, and the anandamide content in

macrophages is significantly increased

[124]. Combined with the inhibitory effects of endocannabinoid on cardiac

contractility, we postulated that endocannabinoid plays an important role in cirrhotic cardiomyopathy. We first

evaluated the CB1 receptor content in cirrhotic hearts. Compared with controls, the CB1 receptor expression is

protein level has no significant change. However, AM-251, a CB1 receptor antagonist, signifi cantly improved the

cardiac contractility in cirrhotic hearts. We speculated that the local cardiac production of endocannabinoids

plays a major role in cirrhotic cardiomyopathy

[125].

This hypothesis was verified in our later study which showed that the monocyte content is significantly

increased in cirrhotic heart, and the anandamide is also significantly increased in cirrhotic heart. Hemorrhage sig-

nificantly decreased arterial pressure and the rate of rise of left ventricular pressure (dP/dT). After hemorrhage,

dP/dT is quickly reversed in controls but the reversion is severely prolonged in BDL rats. AM-251 treatment sig-

nificantly restores the impaired response in cirrhotic rats. The increased anandamide is further increased in BDL

hearts after hemorrhage. Moreover, the monocytes are significantly increased before or after hemorrhage in cir-

rhotic heart compared with controls. Gadolinium chloride (GdCl

), a macrophage inhibitor, significantly reduced

cardiac endocannabinoid levels both at baseline and after hemorrhage. Like AM-251, GdCl

also restores cardio-

vascular response to hemorrhage in cirrhotic rats which implies that anandamide may be from monocytes in cir-

rhotic heart. Endocannabinoids from monocytes play an essential role in cardiac response to hemorrhage

[126].

Summary of mechanisms

In conclusion, pathogenic mechanisms are diverse and multifactorial. We believe the underlying major mecha-

nism is the leaky gut of cirrhosis, with bacterial translocation and resultant inflammatory phenotype. This

unleashes a chain of enhanced cardiodepressant factors such as cytokines, NO, CO, and endocannabinoids, and

reduces the major stimulatory pathways such as the β-conclusion, pathogenic mechanisms are diverse and also

contribute to membrane biochemical and biophysical changes which hinder receptor function in cardiomyocytes.

Cirrhosis is associated with defective protein synthetic function which leads to alterations in proteins such as

myosin and collagen isoforms. Finally, there is likely abnormal function of final common pathways such as NF-

Kappa B and intracellular calcium transients.

Management

Vasodilatation is a pathophysiological feature in cirrhosis and therefore, due to this “auto-treatment,” overt

ventricular failure is usually absent in the baseline state. However, physicians need to monitor cardiac function

when patients with cirrhosis face challenges such as TIPS, infection, or surgeries including liver transplantation.

The usual supportive management of heart failure such as bedrest, oxygen, and correction of fluid-electrolyte

and acid-base abnormalities should be instituted. Unfortunately, beyond these general measures, no specific

pharmacological or other medical treatments have yet been confirmed to be effective in treating CCM. The fol-

lowing drugs or substances have been investigated in human or animal studies.

β-Adrenergic receptor blockers (β-blockers)

Because of the activated sympathetic system in cirrhotic patients [37], β-blockers play a role in protecting the

heart from damage resulting from overactivated sympathetic system. It is well documented that α- (carvedilol)

and β-(propranolol) blockers are effective in depression of portal hypertension and prophylaxis of variceal bleed-

ing in cirrhotic patients

[127].

As mentioned above, cardiovascular events occur in 25%70% of patients after liver transplantation. Chopra

et al.

[128] dem onstrated that during the perioperative period a significant catecholamine surge occurs, produc-

ing elevations in heart rate and blood pressure (BP). Safadi and colleagues tested the protective effects of

β-blocker in perioperative period in liver transplantation, they found β-blockers attenuate both the sympathetic

and neuroendocrine responses to stress perioperatively; they balance myocardial oxygen supply and demand

mismatch, reduce inflammatory markers and free radicals and therefore, β-blockers protected perioperative liver

transplantation patients from adverse cardiac outcomes. β-blocker significantly increased the probability of sur-

vival in early postoperative period (30 days) in liver recipients

[129] (Tables 15.315.5).

231Management

III. Cardiovascular system in liver failure

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TABLE 15.3 Studies assessing changes in systolic and diastolic function after liver transplantation.

SFirst author, year,

country

Total Sample

Size

Subjects

Age (x )

Male/Female

Time post-transplant Resultss Pre LT Post LT p

Acosta et al.

[130] Spain 30

NR/NR

21 months (x )

Range: 1340

months

1. SD: Increased incidence of EF , 55%

2. DD: Increased Incidence of E/A , 1

3. DD: Decrease in E/A (x )

EF , 55: 4/30

E/A , 1: 6/30

E/A (x ):1.32

EF , 55: 9/30

E/A , 1: 18/30

E/A (x ): 1.01

, 0.01

, 0.001

Therapondos et al. [131]

Scotland

49.8

18/22

Week 12

Weeks 1,2,4,8 Not

shown

1. SD: No change in EF (x )

2. DD: Decrease in E/A (x )

3. DD: Increased Isovolumetric relaxation time (x )

4. DD: Increased Interventricular septum thickness (x )

EF (x ): 72,72%

E/A (x ): 1.23

IVRT (x ): 100.3ms

IVS: 0.90 cm

EF (x ): 76, 73%

E/A (x ): 0.96

IVRT (x ): 117.2ms

IVS: 1.07 cm

, 0.001

, 0.05

, 0.03

Torregrosa et al. [40] Spain 40

56.5

23/17

9 months (x )

Range: 612months

1. SD: Improved physiologic stress response

a. elevated HR

b. elevated Cardiac index and Stroke volume index

2. SD: Improved baseline hemodynamics (decreased EF

(x )

3. DD: Increased Peak filling rate

4. DD: Decreased LAD (x )

5. DD: No change in E/A, or Deceleration time (x)

6. DD: No change in IVS (x )

Δ HR: 146%

Δ CI: 142%

Δ SVI: 11%

EF (x ): 73%

Δ PFR: 149%

E/A (x ): 1.1

DT (x ): 241 Ms

IVS: 10.4 mm

Δ HR: 165%

Δ CI: 198%

Δ SVI: 128%

EF (x ): 67%

Δ PFR: 193%

E/A (x ): 1.1

DT (x ): 232 Ms

IVS: 10.1 mm

0.01

0.02

0.007

0.04

Dowsley et al. [44] United

States

107

73/34

2.6 months (x )

Range: 06 months

1. SD: Increased incidence of EF , 50%

2. SD: Decrease in EF (x )

3. DD: Increase in E/E’ Ratio (x )

4. DD: No change in E/A (x )

5. DD: No change in IVS

EF , 50: 0/107

EF (x ): 68%

E/E’ (x ): 7.5

E/A (x ): 1.1

IVS: 11.3 mm

EF , 50: 28/107

EF (x ): 65%

E/E’: 8.6

E/A (x ): 1.1

IVS: 12.0 mm

0.004

0.0015

0.04

Khemakanok et al. [132]

Thailand

1.8 (pediatric)

9/11

36months

Weeks 12 Not

shown

1. SD: No change in incidence EF . 80.

2. SD: No change in EF (x )

3. DD: No change in incidence E/E’ . 12

4. DD: No change in E/E’ (x )

5. DD: No change in % Abnormal left ventricle geometry

EF . 80: 12/20

EF (x ): 74%

E/E’ . 12:12/20

E/E’ (x ):12.7

Abnormal: 19/20

EF . 80: 9/18

EF (x ): 75%

E/E’ . 12: 7/18

E/E’ (x ): 10.4

Abnormal: 17/18

Chen et al. [133] China 41

54.9

30/11

18.2 months(x )

1. SD: Decreased Left ventricle strain

a. Longitudinal and Circumferential LV Strain (x )

2. SD: No change in EF (x )

3. DD: Decreased left ventricle size

a. Decreased left ventricle end diastolic diameter and

volume (x )

4. DD: Decreased LV Mass(x )

5. DD: decreased RV End Diastolic Area (x )

6. DD:No change in E/A or E/E’ (x )

LS: 218.5%

CS: 216.5%

EF (x ): 66.1%

LVEDD: 4.8 cm

LVEDV: 91.4 mL

LVM: 214 g

E/A (x ):1.08

E/E’ (x ): 7.2

LS: 220.8%

CS: 218.7%

EF (x ):65.2%

LVEDD: 4.4 cm

LVEDV: 71.3 mL

LVM: 195.8 g

E/A (x ) 0.97

E/E’ 6.8

, 0.01

0.03

Sonny et al. [46] United

States

243

175/68

41 months (x )

Range: 852months

1. SD: No change in EF (x )

2. DD: Worsening of DD Grade

3. DD: Increased LVMI

4. No change in LAVI

EF (x ): 59%

LVMI: 92.8 g/m

LAVI: 33.0 m/m

EF (x ): 57%

k DD Grade: 40%

LVMI: 105.9 g/m

LAVI: 34.2 m/m

, 0.001

0.001

Gajanana et al. [47] United

States

47/26

371 days (x )

1. DD: No change in incidence of DD

2. DD: Improved DD Grade in 38%, Worse/no change DD

Grade in 62%

DD: 58% of sample/

DD: 58% of sample

k DD Grade: 62%

NS/

Junge et al.

[134] Germany 132

4.14 (pediatric)

70/62

1 year

1. DD: Decreased LV end Diastolic diameter (x z score)

2. DD: Decreased LVMI (x )

3. DD: Normalization of all cardiac indices in 92%

LVEDD (z-score,

x ): 0.98

LVMI (x ): 125.65/

LVEDD (z-score, x ):

0.08

LVMI (x ): 67.18

zscores ,2: 121/132

, 0.001

, 0.001/

SD, Systolic dysfunction; DD, diastolic dysfunction; EF, ejection fraction; E/A, ratio of early to late transmitral diastolic inflow velocity; IVS, interventricular septum; LVMI, left ventricular mass index; LAVI, left atrial volume index; E/E’, ratio of early

transmitral diastolic inflow to early mitral annular velocity; RV, right ventricle.

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Prolonged Q-T interval predicts severe ventricular tachyarrhythmias and sudden death in no ncirrhotic cardiac

conditions, but whether this applies to the cirrhotic patient with prolonged Q-T interval

[37] remains unknown.

Henriksen and colleagues reported that β-blocker administration acutely reduces prolonged QTc toward normal

values in patients with cirrhosis

[144] (Table 15.6).

There are some controversies over β-blocker usage in some specific groups of patients with cirrhosis. Krag and

colleagues believed that in hepatorenal syndrome, treatment with beta-blockers further decreases heart rate and

cardiac output and may therefore have deleterious effects on hemodynamics and renal function, consequently

reducing survival

[73].

Combination vasoconstrictors and albumin

For type 1 HRS, systemic vasoconstrictors combined with plasma expansion are currently the most used form

of pharmacologic therapy. The combined administration of intravenous albumin and vasoconstrictors (e.g., terli-

pressin and alfa-1 agonists) normalizes circulatory function and serum creatinine in most patients with type-1

hepatorenal syndrome. These effects, however, are rarely obtained when vasoconstrictors or intravenous albumin

are given alone

[65].

Splanchnic vasoconstrictors and albumin coadministration counteract the intense vasodilation in the splanch-

nic bed, thereby improving effective arterial blood volume. This improvement, in turn, suppresses the endoge-

nous vasoconstrictors (e.g., renin-angiotensin-aldosterone system [RAAS], SNS) that are responsible for renal

vasoconstriction. Albumin administration, by expanding the circulating blood volume, on the one hand, increases

cardiac preload and cardiac output and on the other hand, improves GFR

[150].

The RAAS is the most important system controlling BP, cardiovascular, and renal function. A lot of clinical

trials support that RAAS-blockade is the single most important cardioprotective strategy for cardiovascular dis-

eases

[151]. Since RAAS was activated in cirrhotic patients [152], it is rational to speculate that RAAS blockage

has cardiac protective effects on cirrhotic cardiomyopathy. The only RAAS related study on cirrhotic cardiomy-

opathy was done by Pozzi and colleagues

[153].

They administrated aldosterone antagonist potassium canrenoate to Child A postviral preascitic cirrhotic

patients. After 6 months of treatment, the authors found some improvement in left ventricular hypertrophy and

wall thickness, and a trend toward improved diastolic function indices, they suggested that 6 months were an

insufficient duration within which to see significant normalization of diastolic dysfunction; a longer course of

treatment is probably needed. Pozzi’s results indicated that drugs blocking the fibrogenic effects of the aldoste-

rone system are beneficial and also that cardiac remodeling might occur in cirrhosis.

TABLE 15.4 Prevalence of CCM in studies assessing cardiovascular function post-liver transplant.

Author

Year

Country

Total

sample

size

Subjects Etiology Cirrhosis severity Cardiac assessment

CCM

prevalence

(%)

Age (x )

Male/Female

Alcohol/

viral/other

Child

A/B/C

MELD

score (x )

Systolic or diastolic dysfunction; method of

assessment

Snowden

et al.

[135]

England

34 54.5

18/16

12/7/15 NR NR Clinically;

CXR , 24 Hrs Post op: Evidence of Pulmonary

Edema

47.1

Eimer et al.

[136] United

States

NR 55.8

NR NR 24 Clinical and SD;

Acute Post-op Heart Failure: Clinical: signs

symptoms HF 1 Echo: LV EF , 40% 1 CXR:

Pulmonary edema

7.0

Fouad et al.

[137] Canada

197 55.9

136/61

44/90/63 NR 19.4 Clinically;

Cardiac complications 06mo post op: Pulmonary

Edema(CXR) or CHF (Clinically)

34.5

Pimenta et al.

[138] Portugal

84 56

52/32

62/14/17 1/30/

SD;

Echo: Cardiac output , 4.5 L/min

28.9

Yataco et al.

[139] United

States

NR NR

292/438/

730

NR NR Clinical and SD;

030 day post op cardiovascular complication

confirmed by Echo: EF , 35% 1 LV dilation

1.2

NR, Not reported; SDS, systolic dysfunction; DD, diastolic dysfunction; CXR, chest x-ray; CHF, congestive heart failure; EF, ejection fraction, MELD, model for

endstage liver disease.

233Management

III. Cardiovascular system in liver failure

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