JACC: HEART FAILURE VOL. 7, NO.

2, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

MINI-FOCUS ISSUE: CARDIAC CONSEQUENCES OF NON-CARDIAC DISEASE

STATE-OF-THE-ART REVIEW

Heart Failure and Liver Disease

Cardiohepatic Interactions

Andrew Xanthopoulos, MD, PHD,a Randall C. Starling, MD, MPH,a Takeshi Kitai, MD, PHD,b
Filippos Triposkiadis, MD, PHDc

ABSTRACT

Heart failure (HF) and liver disease often co-exist. This is because systemic disorders and diseases affect both organs
(alcohol abuse, drugs, inflammation, autoimmunity, infections) and because of complex cardiohepatic interactions. The
latter, which are the focus of this review, include the development of acute cardiogenic liver injury and congestive hep-
atopathy in HF as well as cardiac dysfunction and failure in the setting of liver cirrhosis, nonalcoholic fatty liver disease, and
sequelae following liver transplantation. The emerging role of altered liver X receptor signaling in the pathogenesis of
HF comorbidities as well as of the intestinal microbiome and its metabolites in HF and liver disease are fruitful areas for
future research. (J Am Coll Cardiol HF 2019;7:87–97) © 2019 by the American College of Cardiology Foundation.

H eart failure (HF) and liver disease often co-

exist (1) because of systemic disorders and
diseases that affect both organs (alcohol
abuse, drugs, inflammation, autoimmunity, infec-
tions) as well as because of complex cardiohepatic in-
teractions. HF may lead to liver disease, which
adversely affects prognosis and complicates manage-
ment of HF. Conversely, liver disease per se may
cause cardiac dysfunction and failure in the absence
of other cardiovascular abnormalities (1,2). Following
a brief summary of the hepatic circulation, this review
discusses the pathophysiology, characteristics, and
clinical significance of cardiohepatic interactions.
The role of liver X receptor (LXRs) in HF co-
morbidities and the emerging role of gut microbiota
are also discussed (3,4) (Table 1).
other. The hepatic arterial buffer response repre-
sents the ability of the hepatic artery to compensate
for changes in portal flow (7). An increase in hepatic
arterial blood flow is capable of buffering 25% to
60% of decreased portal flow (8,9). Total hepatic
blood flow ranges between 800 and 1,200 ml/min,
equivalent to approximately 100 ml/min per 100 g
of liver wet weight (10). Although liver mass con-
stitutes 2.5% of total body weight, the liver receives
25% of cardiac output (5). On entering the liver,
blood from the portal vein and hepatic artery mix
and flows through sinusoids, in contact with hepa-
tocytes, and subsequently through the hepatic
veins. The hepatic veins carry blood to the inferior
vena cava, which carries blood to the right side of
the heart (11).

HEPATIC CIRCULATION HEPATIC INJURY IN HEART FAILURE

The liver receives blood from the portal vein and MECHANISMS. Ischemia reperfusion injury is
hepatic artery (Figure 1) (5,6). Receiving blood from characterized by cellular damage caused by
2 vessels protects the liver: If 1 source fails, the hypoperfusion-induced hypoxia, which is paradoxi-
liver continues to function as it is supplied by the cally exacerbated after restoration of oxygen delivery

From the aDepartment of Cardiovascular Medicine, Heart and Vascular Institute, Kaufman Center for Heart Failure, Cleveland
Clinic, Cleveland, Ohio; bDepartment of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan; and
the cDepartment of Cardiology, Larissa University General Hospital, Larissa, Greece. The authors have reported that they have no
relationships relevant to the contents of this paper to disclose.

Manuscript received September 20, 2018; accepted October 4, 2018.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2018.10.007

88 Xanthopoulos et al. JACC: HEART FAILURE VOL. 7, NO. 2, 2019

Heart Failure and Liver Disease FEBRUARY 2019:87–97

ABBREVIATIONS (12, Online Refs. 1,2). Hepatic ischemia
AND ACRONYMS reperfusion injury in HF is characterized by
early activation of Kupffer cells, late activa-
ACE = angiotensin-converting
enzyme
tion of polymorphonuclear cells (“neutro-
philic hepatitis”), intracellular calcium
ARB = angiotensin receptor
blocker overload, cytokines and chemokines, oxida-
CMR = cardiac magnetic tive stress, mitochondrial damage, and
resonance disruption of liver microcirculation (12,13).
ECMO = extracorporeal Nitric oxide has a protective effect (13). The
membrane oxygenation histopathological liver lesion is centrilobular
HF = heart failure coagulative necrosis in zone 3, which may
HT = heart transplantation extend to mid-zonal hepatocytes (14).
LS = liver stiffness Another mechanism is hepatic congestion.
LT = liver transplantation Absence of valves in hepatic veins allows the
LVEF = left ventricular ejection increased inferior caval pressure to impact
fraction the sinusoidal bed causing centrilobular
LXR = liver X receptor congestion, sinusoidal dilation, and peri-
MRA = mineralocorticoid venular fibrosis (1,14). The major damage
receptor antagonist occurs in zone 3 of Rappaport acinus, which
NAFLD = nonalcoholic fatty surrounds the central vein, with respect to
liver disease
the periportal region (zone 1) (14). Cen-
RXR = retinoid X receptors trilobular liver cell necrosis can extend to
VAD = ventricular assist device peripheral areas and is followed by the
deposition and spread of connective tissue, bridging
one central vein to the other, ultimately leading to
cirrhosis (1).
ACUTE CARDIOGENIC LIVER INJURY. The preva-
lence of hepatic dysfunction in acute HF is 20% to
T A B L E 1 What Is New in the Present Paper Compared to Other Reviews of
This Topic
1. New pathophysiological insights regarding the development of cardiac
dysfunction in liver disease
2. Novel risk stratification tools (ventriculoarterial coupling, new vasoactive
peptides)
3. Potential treatment options
A. Liver X receptors
A section is devoted to the role of liver X receptor (LXRs) in the development
of heart failure (HF) risk factors and comorbidities and consequently HF.
An interesting association is observed between LXRs and conventional HF
risk factors, such as hypertension, atherosclerosis, and obesity and
diabetes. Hence, LXRs may constitute a promising future target for HF
research and management.
B. Microbiota
The emerging role of microbiota in the setting of HF and liver disease is of
great importance. The liver is the first organ exposed to all molecules from
the intestines and the increased hepatic inflammation caused by increased/
changes in exposure to bacterial byproducts or metabolites due to either
intestinal edema or changes in the gut microbiota (and maybe especially
trimethylamine N-oxide [TMAO]), which are also produced in the liver and
associated with both HF and liver disease. Hence, microbiota affect the
heart–liver axis through a number of mechanisms including lipid and
glucose metabolism, cholesterol, bile acids, and inflammation
4. Recent consensus recommendations (71)
5. Recent randomized study with b-blockers in cirrhotic cardiomyopathy and a brief
discussion about the advantages and disadvantages of b-blocker use in
cirrhotic cardiomyopathy (60)
6. The current review is accompanied by 5 figures and Online Figure 1, which depict
important pathophysiological mechanisms and proposed management
algorithms.
30% (15). Although acute cardiogenic liver injury
(formerly, hypoxic hepatitis, ischemic hepatitis, or
shock liver) was conventionally considered the result
of cardiogenic shock, there is evidence that this is not
the sole responsible incident (2,16, Online Ref. 3).
Patients having chronic congestion or portal hyper-
tension, may exhibit acute cardiogenic liver injury
even after mild circulatory disturbances (Figure 2A)
(16, Online Refs. 4,5). In chronic congestion, hepato-
cytes compensate for impaired blood flow by
increasing oxygen extraction. However, with inade-
quate liver perfusion in HF, this compensatory
mechanism is exhausted, leading to hepatocellular
hypoxia and necrosis (17, Online Ref. 5). Thus, in
addition to hypoperfusion, the additional presence of
liver congestion is required for the development of
acute cardiogenic liver injury.
Diagnosis is based on: 1) setting: cardiac, circula-
tory, or pulmonary failure; 2) aminotransferase
levels, usually >20 times the upper limit of normal;
and 3) exclusion of other causes of liver damage. If
these 3 criteria are met, there is no need for liver bi-
opsy (18).
Cardiogenic liver injury often remains asymptom-
atic (1). Occasionally, patients exhibit symptoms and
signs resembling acute viral hepatitis (19). Laboratory
tests show increased alanine aminotransferase and
lactate dehydrogenase, usually 1 to 3 days after hemo-
dynamic deterioration. An alanine aminotransferase-
to-lactate dehydrogenase ratio <1.5 denotes cardio-
genic acute liver injury (20). Frequently, patients
exhibit a bleeding diathesis derived from deficiency of
liver coagulation factors (21). An increase in bilirubin
denotes hepatocellular injury or cholestasis. Renal
dysfunction is often present (Online Ref. 3).
Abdominal ultrasonography can be supportive in
the diagnosis. Dilation of inferior vena cava and
suprahepatic veins due to passive congestion is sug-
gestive of acute cardiogenic liver injury (22). Other
imaging techniques such as computed tomography
(CT) or cardiac magnetic resonance (CMR), may help
exclude other causes of liver injury (23). Liver biopsy
is helpful under conditions where the underlying
cause remains unclear (23).
Management focuses on the underlying acute HF
(19). Oxygen should be considered in hypoxemic pa-
tients and intravenous inotropes in persistent hypo-
perfusion (Online Ref. 6). There is much to learn
about newly designed liver-assisted devices, plasma
exchange, and hepatocyte transplantation (24).
Although some patients survive the acute event
and aminotransferases returns to normal values
within 3 to 7 days (Online Ref. 5), mortality remains
high (25,26).
JACC: HEART FAILURE VOL. 7, NO. 2, 2019 Xanthopoulos et al. 89
FEBRUARY 2019:87–97 Heart Failure and Liver Disease

F I G U R E 1 Representation of the Splanchnic Vasculature

The splanchnic system receives nearly 25% of the cardiac output. Approximately one-fourth of the splanchnic arterial flow goes directly to the
liver through the hepatic artery; the remaining three-fourths reaches the liver after perfusing the pre-portal organs. The pre-portal veins
anastomose to form the portal vein. The portal vein and hepatic artery enter the liver at its hilum and ramify into progressively smaller vessels
before emptying into the hepatic sinusoids. Post-sinusoidal blood flows through the hepatic veins, which drain into the inferior vena cava.
The hepatic artery and the arteries of the pre-portal splanchnic organs have mean pressures of approximately 90 mm Hg. The portal venous
pressure is 7 to 10 mm Hg, which is only slightly higher than the pressure in the sinusoids. Reprinted with permission from Gelman and
Mushlin (6).

CONGESTIVE HEPATOPATHY. The incidence of a predominance of cholestatic enzymes (32,33, Online

congestive hepatopathy is 15% to 65% in severe HF
(27–29, Online Refs. 4,7) and probably higher in can-
didates for left ventricular assist device (LVAD) im-
plantation (30). Underlying pathophysiology includes
increased hepatic venous pressure, decreased hepatic
blood flow, and decreased arterial oxygen saturation
(Figure 2B) (2, Online Refs. 8,9). Congenital heart dis-
ease and Fontan circulation represent other pop-
ulations of patients at risk to develop liver disease (31).
Signs and symptoms are obscured by concomitant
right HF (19). In end-stage biventricular HF, specific
cardiomyopathies (i.e., restrictive, constrictive) or
severe tricuspid regurgitation, the differential diag-
nosis from chronic liver disease or cirrhosis can be
challenging. A pulsatile liver reflects tricuspid regur-
gitation, whereas loss of this pulsation progression to
secondary “cardiac liver fibrosis” (19, Online Ref. 4).
Apart from clinical examination, diagnosis
congestive hepatopathy is based on blood examina-
tions, abdominal ultrasonography and histologic ex-
amination of the liver. Patients typically present with
Ref. 7). Often congestive hepatic and renal dysfunc-
tions co-exist (hepatorenal reflex) (34,35).
Characteristic conventional imaging findings
include dilation of inferior vena cava and hepatic
veins; loss of normal triphasic hepatic venous wave-
form; retrograde hepatic venous opacification during
the early phase of intravenous contrast material in-
jection; and a predominantly peripheral heteroge-
neous pattern of hepatic enhancement due to
stagnant blood flow (36). Extensive fibrosis can be
seen in chronic or severe cases. Hyperenhancing
regenerative nodules retaining hepatobiliary contrast
agents are often present (36). Elastography enables
noninvasive measurement of liver mechanical prop-
erties through observation of shear-wave propagation
(37). Increasing fibrosis stage is associated with
increased liver stiffness, which can be exploited by
of ultrasonographic and CMR elastographic methods
(37).
Key findings in liver biopsy are atrophy or necrosis
or both, most pronounced in the central third of the
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Heart Failure and Liver Disease FEBRUARY 2019:87–97

F I G U R E 2 Mechanisms of Liver Injury in Heart Failure

(A) Acute cardiogenic liver injury usually develops following severe liver hypoxia in the setting of liver congestion (i.e., cardiogenic shock).
(B) Congestive hepatopathy results from chronic liver congestion associated with chronic liver hypoxia (i.e., chronic severe congestive
heart failure).

hepatic lobule and most prominent immediately
adjacent to the central vein (2). Notably, this pattern
of necrosis and/or atrophy significantly decreases
toward the lobule periphery (Online Refs. 8,10).
Diuretics are the mainstay of treatment (Online
Ref. 11). Percutaneous mechanical
conjunction with inotropic therapy may occasionally
be necessary (Online Ref. 11). Surgical treatment
should be considered in cases with constrictive peri-
carditis, tricuspid regurgitation or stenosis, and
ischemic cardiomyopathy (38). When appropriate,
support in implantation of a LVAD and heart transplantation
JACC: HEART FAILURE VOL. 7, NO. 2, 2019 Xanthopoulos et al. 91
FEBRUARY 2019:87–97 Heart Failure and Liver Disease

F I G U R E 3 Cardiac, Liver, and Circulatory Dysfunction in Cirrhotic Cardiomyopathy

CO ¼ cardiac output; DT ¼ deceleration time of transmitral flow; E/A ¼ transmitral early (E)-to-late (A) flow velocity ratio; LA ¼ left atrial;
LV ¼ left ventricular; LVEDV ¼ left ventricular end-diastolic volume; LVEF ¼ left ventricular ejection fraction; QT, interval; QT ¼ electro-
cardiographic interval.

(HT) should be considered, especially if the liver
disease is attributed to advanced HF that can poten-
tially be reversed by an LVAD alone and/or with a
right VAD (RVAD) (Online Ref. 12).
A model for end-stage liver disease (MELD) has
been reported to predict mortality risk in patients
with end-stage liver disease (39,40) and adverse
events associated with VAD therapy (41,42). Alter-
native MELD scores, more attractive in HF patients,
are the MELD-XI and MELD-Naþ, excluding inter-
national normalized ratio and including sodium,
respectively (43). The MELD-XI is of prognostic sig-
nificance in patients with VAD support and anti-
coagulation therapy (44) and has been shown to
predict early mortality after cardiac transplantation
(45).
Prognosis depends on the underlying cardiac dis-
ease. However, increased liver biomarkers are asso-
ciated with abnormal hemodynamics and impaired
survival (27,33, Online Ref. 13). Increased liver stiff-
ness (46) and hypoalbuminemia (47) are also associ-
ated with adverse outcome.
Patients with hepatic dysfunction undergoing HT
may demonstrate significant improvement in liver
function. Nevertheless, irreversible hepatic cirrhosis
is considered an absolute contraindication for HT,
unless combined with liver transplantation (LT)
(Online Ref. 14).
92 Xanthopoulos et al.
Heart Failure and Liver Disease
T A B L E 2 Risk Factors Associated With Development of Heart Failure
Following Liver Transplantation
Categories Risk Factors (Ref. #)
Medical history Older age (Online Ref. 19)
Coronary artery disease (67)
Sex (female) (Online Ref. 19)
Hypertension (67, Online Ref. 18)
Alcohol use (67, Online Ref. 18)
Recent/remote smoker (Online Ref. 18)
Diabetes mellitus (Online Ref. 18)
Depression (Online Ref. 18)
MELD score (67, Online Refs. 18,19)
Framingham score (Online Ref. 18)
Chronic kidney disease (67)
Dialysis (Online Ref. 18)
Hepatitis C (67,71)
Amyloidosis (71)
Hemochromatosis (71)
Nonalcoholic steatohepatitis (67,71)
Laboratory parameters BUN (Online Ref. 18)
Creatinine concentration (67)
eGFR (Online Refs. 18,19)
Plasma sodium levels (Online Ref. 19)
High sensitivity troponin (Online Ref. 18)
Brain natriuretic peptide (Online Ref. 18)
Albumin level (67)
Electrocardiographic QTc >450 ms (Online Refs. 18,19)
parameters
Echocardiographic Diastolic dysfunction pre-transplantation (70)
parameters
LVEF pre-transplantation (70)
Hemodynamic parameters Mean arterial pressure #65 mm Hg (Online Refs. 18,19)
Mean pulmonary artery pressure $30 mm Hg
(Online Ref. 18)
Pulmonary capillary wedge pressure $15 mm Hg
(Online Ref. 18)
BUN ¼ blood urea nitrogen; eGFR ¼ estimated glomerular filtration rate; LVEF ¼ left ventricular
ejection fraction; MELD ¼ model for end-stage liver disease.
HEART FAILURE IN LIVER DISEASE
CIRRHOTIC CARDIOMYOPATHY. Cirrhotic cardiomy-
opathy is present in up to 50% of patients with
cirrhosis (48). It is a syndrome characterized by sys-
tolic dysfunction (blunted increase in stress cardiac
output with resting LVEF <55%), impaired diastolic
relaxation (early [E]-to-late [A] ratio <1.0, prolonged
deceleration time [>200 ms]), prolonged
volumetric relaxation time (>80 ms), and electro-
physiological disturbances such as prolonged QT C
interval (49) (Figure 3).
Cirrhotic cardiomyopathy has been attributed to a
cirrhotic proinflammatory state leading to increased
cardiomyocyte apoptosis and shift in myosin heavy
chain isoform from the a subtype to the weaker b
isoform (50). Circulatory abnormalities are predomi-
nantly due to liver-derived toxic factors causing
JACC: HEART FAILURE VOL. 7, NO. 2, 2019
FEBRUARY 2019:87–97
arterial dilation and hyperdynamic circulation (50).
With further progression of liver failure and arterial
dilation, the cardiac systolic reserve is exhausted.
From that point, the heart is unable to further in-
crease the cardiac output, resulting in arterial
underfilling and decreased effective circulatory vol-
ume (49–51).
This syndrome, which is initially asymptomatic, is
often misdiagnosed due to nonspecific symptoms
present in advanced liver cirrhosis, such as exercise
intolerance, fatigue, and dyspnea (52).
Various modalities of cardiac imaging have been
applied (53). Stress testing has been used to assess
systolic dysfunction and echocardiography to eval-
uate rest systolic dysfunction with strain techniques.
Echocardiography with tissue Doppler is the method
most preferred to detect diastolic dysfunction.
Experience with other modalities such as CT and CMR
is limited (51,53–56).
Prognosis is unfavorable, and specific therapies are
lacking (49). Several new vasoactive peptides
(copeptin, pro-adrenomedullin, pro-atrial natriuretic
peptide) have been reported to be associated with
portal pressure and systemic hemodynamics,
whereas galectin-3 is currently used as a marker
of fibrosis (Online Refs. 15,16). Ventriculoarterial
coupling has recently emerged as a novel risk strati-
fication tool for the outcome of cirrhotic patients after
LT (57). LT results in clinical improvement and may
cure cardiomyopathy. However, post-transplantation
prognosis depends on pre-transplantation identifica-
tion and management of cirrhosis with cardiomyop-
athy (see discussion below) (58).
Cirrhotic cardiomyopathy complicates several
treatment modalities used in cirrhosis and/or HF.
Although beta-blockers are contraindicated in
cirrhosis with refractory ascites (i.e., hypotension/
exaggeration of low renal perfusion), they shorten
the prolonged QT C interval and reduce bacterial
translocation from the gut (59). Moreover, a recent
randomized controlled trial in cirrhotic cardiomyop-
athy patients reported no differences between
metoprolol and placebo in cirrhosis-related and car-
diac outcomes during a 6-month follow-up (60).
iso- Angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs) are contra-
indicated because they may aggravate the systemic
vasodilatory state (52). Likewise, terlipressin, which
is used for the treatment of renal dysfunction
complicating liver disease, is contraindicated, as it
may further depress cardiac function (61). Finally,
diastolic dysfunction is associated with poorer prog-
nosis in patients treated by transjugular intrahepatic
portosystemic shunt (50).
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F I G U R E 4 Schematic Relating LXR Signaling to HF Development

In the cell nucleus, LXR form an obligate heterodimer complex with the RXR that binds to regulatory regions of target genes. Following ligand
binding, the LXR/RXR complex undergoes a conformational change that leads to the release of co-repressors and recruitment of co-
activators, which modulates target gene expression. Altered LXR/RXR signaling contributes to development of HF risk factors and co-
morbidities and, consequently, HF. HF ¼ heart failure; LXR ¼ liver X receptor; RXR ¼ retinoid X receptor.

HEART FAILURE IN NONALCOHOLIC FATTY LIVER
DISEASE. Nonalcoholic fatty liver disease (NAFLD),
the most frequent liver disease, is characterized by
the accumulation of liver fat, >5% per liver weight, in
the presence of <10 g of daily alcohol consumption
(62). NAFLD promotes coronary atherosclerosis and
confers an increased risk for cardiomyopathy,
valvular calcification, arrhythmia, and some conduc-
tion defects (63, Online Ref. 17). Moreover, NAFLD
and its severity are independently associated with
increased risk of adverse outcomes in elderly patients
with acute HF (64). Although more research is needed
to identify the pathophysiology underlying the rela-
tionship between NAFLD and HF, screening for heart
diseases, risk assessment for diabetes, and a multi-
disciplinary approach for managing these patients
should be encouraged (65).
HEART FAILURE AFTER LIVER TRANSPLANTATION. HF
may occur early (#30 days) or late (>30 days) after LT
and it is accompanied by high mortality (66,67). Early
onset HF reflects surgical cardiovascular stress,
whereas late onset HF indicates coronary atheroscle-
rosis (68,69). Patients with pre-transplantation dia-
stolic dysfunction need close post-transplantation
follow-up for timely identification of HF (70). Risk
factors associated with the development of HF
following LT (70, Online Refs. 18,19) are summarized
in Table 2, whereas an algorithm for pre-
transplantation cardiac evaluation is shown in Online
Figure 1. Multimodality imaging (echocardiography,
CT, CMR) and timely implementation of HF therapies
are important for the management of liver trans-
plantation candidates (71).
LIVER AND DRUG METABOLISM
Acute liver injury, hepatic congestion, and especially
cardiac cirrhosis are associated with abnormalities of
hepatic drug metabolism (2). Abnormal hepatic drug
metabolism is also related to the severity of HF and is
improved after HF management (Online Ref. 20).
Drugs used for HF that exhibit hepatic metabolism
such as beta-blockers (carvedilol, metoprolol succi-
nate, bisoprolol, nebivolol), ACE inhibitors (trando-
lapril, fosinopril), and ARBs (candesartan, losartan)
should be used with caution (72). MRAs can be used in
cirrhosis with ascites, whereas ivabradine is contra-
indicated (Online Refs. 21,22). The question of
whether cardiac and noncardiac liver injury lead to
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Heart Failure and Liver Disease FEBRUARY 2019:87–97

C E NT R AL IL L U STR AT IO N Cardiac and Liver Dysfunction Often Co-Exist

Cardiogenic liver injury

Congestive hepatopathy

Systemic
disorders/diseases
• Alcohol abuse Liver
Cardiac • Drugs
Dysfunction • Inflammatory disorders Dysfunction
• Autoimmune diseases
• Infections

Cirrhotic cardiomyopathy
Non-alcoholic fatty liver disease
Post liver transplantation

Atherosclerosis
Hypertension
Insulin resistance
Diabetes Altered LXR signaling
Nephropathy

Xanthopoulos, A. et al. J Am Coll Cardiol HF. 2019;7(2):87–97.

Co-existence is the result of systemic disorders and diseases affecting both organs (e.g., alcohol abuse, drugs, inflammation, autoimmunity, infections) as well as
complex cardiohepatic interactions. The latter interactions include development of acute cardiogenic liver injury and congestive hepatopathy in HF as well as cardiac
dysfunction and HF in the setting of liver cirrhosis (cirrhotic cardiomyopathy), nonalcoholic fatty liver disease, and sequelae following liver transplantation. Finally,
altered LXR signaling may contribute to the pathogenesis of HF co-morbidities. HF ¼ heart failure; LXR ¼ liver X receptor.

the same pharmacokinetic abnormalities remains Transcriptional activity of LXRs is induced in

unanswered (2).
FUTURE PERSPECTIVES
LIVER X RECEPTORS IN HEART FAILURE. Liver X
receptors (LXRs, including LXR a and LXR b) are
considered essential regulators of lipid and glucose
metabolism, cholesterol homeostasis, and inflamma-
tion (73, Online Ref. 23). LXRs bind to DNA as heter-
odimers with retinoid X receptors (RXR) (Figure 4).
LXR a is the dominant subtype expressed in the liver
and is also highly expressed in tissues that play roles
in cholesterol metabolism (intestine, adipose, kidney,
and adrenals).
response to elevated cellular levels of cholesterol.
Activation of LXRs normalizes reverse cholesterol
transport, prevents diabetes-induced inflammation,
and reduces the number of pro-inflammatory macro-
phages (Online Ref. 24). Direct cardiac effects of LXR
signaling include the decrease of cardiomyocyte hy-
pertrophy, loss (death), and fibrotic remodeling. LXRs
also stimulate angiogenesis within the myocardium
and increase the capacity for glucose uptake and
utilization (metabolic remodeling) (3).
The aforementioned widespread effects of the
LXRs provide an explanation for the contribution of
altered LXRs signaling to the pathogenesis of several
of HF co-morbidities, including atherosclerosis and
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FEBRUARY 2019:87–97 Heart Failure and Liver Disease

vascular disease, hypertension, diabetes, obesity, and
chronic kidney disease and consequently to HF (3,74,
Online Ref. 25).
LIVER DYSFUNCTION AND GUT MICROBIOTA. Gut
microbiota signature in chronic HF
compositional shifts with low bacterial richness and
depletion of bacteria with butyrate-producing po-
tential (75). Butyrate exerts local anti-inflammatory
effects in the gut mucosa and stimulates regulatory
T cells, also in the periphery (76). HF can induce in-
testinal ischemia in addition to liver injury, leading to
disruption of the mucosal epithelial barrier and
leakage of gut-derived toxic metabolites into sys-
temic circulation (77). As the liver is the first organ
exposed to toxic gut molecules, interaction between
gut and liver in the setting of HF has been an exciting
new research field. Trimethylamine (TMA) is an
organic compound generated by gut microbiota from
specific dietary nutrients (4,78, Online Ref. 26). TMA
is rapidly oxidized into trimethylamine N-oxide
(TMAO) by flavin monooxygenase (FMO) enzymes in
the liver and released into the circulation (4,78,79).
Although elevated TMAO levels seem to be associated
with poor prognosis in HF (80–82), further studies
exploring the generation and metabolism of TMAO in
this setting are warranted.
POTENTIAL THERAPEUTIC TARGETS. Experimental
studies have suggested that targeting LXRs may serve
as an addendum to HF management. However,
systemic LXR activation is complicated by hepatic
steatosis and hypertriglyceridemia (Online Ref. 27).
Nonetheless, several sophisticated pharmacological
strategies and nonsystemic drug routes have been
initiated and remain to be comprehensively explored.
As gut dysbiosis has been shown to contribute to
the pathogenesis of both HF and chronic kidney dis-
ease, it could be an effective therapeutic target for HF
with or without renal compromise (4). Diet modifi-
cation, prebiotics, and probiotics are major thera-
peutic tools used in current clinical practice, but there
are few data regarding the impact of these in-
undergoes terventions on HF (79, Online Ref. 26). The GutHeart:
Targeting Gut Microbiota to Treat Heart Failure
study will randomize 150 patients with stable HF
and a LVEF <40% to receive rifaximin, the probiotic
yeast Saccharomyces boulardii (catalog number
74012, American Type Culture Collection, Manassas,
Virginia), or no treatment (control) for 3 months.
The primary endpoint is baseline-adjusted LVEF as
measured by echocardiography after 3 months (83).
CONCLUSIONS
The heart and the liver are in close relation to each
other. Impairment of cardiac function may lead to
hepatic dysfunction and vice versa (Central
Illustration). Liver hypoperfusion and hepatic
congestion are the 2 central pathophysiological
mechanisms, both in acute cardiogenic liver injury
and hepatic congestion. Cirrhotic cardiomyopathy is a
syndrome that includes systolic, diastolic, and elec-
trophysiological abnormalities that develop in the
setting of liver cirrhosis. Altered LXR signaling con-
tributes to the development of HF comorbidities.
Because the liver is the first organ exposed to the gut
toxic molecules produced in HF, gut–liver interaction
in the setting of HF has been an exciting new research
field. Management of deranged cardiohepatic in-
teractions remains challenging.
ADDRESS FOR CORRESPONDENCE: Dr. Filippos Tri-
poskiadis, Department of Cardiology, Larissa Univer-
sity General Hospital, P.O. Box 1425, 411 10 Larissa,
Greece. E-mail: ftriposkiadis@gmail.com.

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KEY WORDS gut microbiota, heart failure,
interactions, liver, liver X receptor
A PP END IX For a supplemental figure and
references, please see the online version of this
paper.