Contemporary Reviews in Cardiovascular Medicine

Gastrointestinal and Liver Issues in Heart Failure

Varun Sundaram, MD; James C. Fang, MD

AbstractHeart failure affects 23 million people worldwide and continues to have a high mortality despite advancements
in modern pharmacotherapy and device therapy. HF is a complex clinical syndrome that can result in the impairment of
endocrine, hematologic, musculoskeletal, renal, respiratory, peripheral vascular, hepatic, and gastrointestinal systems.
Although gastrointestinal involvement and hepatic involvement are common in HF and are associated with increased
morbidity and mortality, their bidirectional association with HF progression remains poorly fathomed. The current
understanding of multiple mechanisms, including proinflammatory cytokine milieu, hormonal imbalance, and anabolic/
catabolic imbalance, has been used to explain the relationship between the gut and HF and has been the basis for many
novel therapeutic strategies. However, the failure of these novel therapies such as antitumor necrosis factor- has resulted
in further complexity. In this review, we describe the involvement of the gastrointestinal and liver systems within the HF
syndrome, their pathophysiological mechanisms, and their clinical consequences. (Circulation.2016;133:1696-1703.
DOI: 10.1161/CIRCULATIONAHA.115.020894.)
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Key Words: gastrointestinal tract heart failure

H eart failure (HF) is a systemic disorder caused by the inabil-

ity of the heart to accommodate the venous return and to
maintain sufficient cardiac output to meet the bodys metabolic
needs.1 These hemodynamic perturbations result in a state of
systemic inflammation with well-described and well-studied
consequences in a variety of other organ systems, including
the renal, cerebral, musculoskeletal, and immune systems. In
contrast, the gastrointestinal and hepatic systems have received
less attention, although gastrointestinal symptoms are common.
With increasing clinical efforts to resuscitate the advanced HF
patient, a greater appreciation and a better understanding of the
gastrointestinal and hepatic manifestations of HF are needed.2,3
With some notable exceptions, gastrointestinal and hepatic
involvement in heart disease has historically received little
attention from cardiologists.4 Mechanisms of gastrointestinal
and hepatic dysfunction remain poorly understood despite
the common presence of gastrointestinal-related symptoms
and the increased morbidity and mortality associated with
their presence. The specific involvement of the gastrointesti-
nal system in HF results in a bidirectional relationship that
has been called the cardiointestinal syndrome.5 For example,
the systemic volume overload characteristic of HF is gener-
ally accompanied by concomitant gut edema, which can
lead to bacterial translocation into the systemic circulation.
Consequent monocyte activation and excessive cytokine
release result in systemic inflammation, increased symptoms,
and disease progression.6
In this review, we describe the current state of understand-
ing of the gastrointestinal and hepatic systems in HF. Although
nutritional status is also relevant in this discussion, we refer
the reader to other excellent reviews of nutritional aspects of
chronic disease.7,8
The Gut in HF
Gastrointestinal System as a Venous Reservoir
Studies of implantable hemodynamic monitors to manage HF
patients document that acute decompensated HF was not asso-
ciated with weight gain in 33% to 46% of patients. Moreover,
pulmonary artery pressures were noted to rise days to weeks
before acute decompensated HF hospitalization in the absence
of weight gain.911 This phenomenon has been attributed to
shifts between total extracellular fluid volume and effective
circulating volume. The venous system contains up to 70%
of the total blood volume. The compliance of the splanchnic
veins is much higher than that of the peripheral venous system,
and hence they act as a relatively greater venous reservoir. The
splanchnic veins have a large number of -1 and -2 recep-
tors and therefore are responsive to the sympathetic nervous
system.12 In HF, the amplified sympathetic nervous system
activation leads to a decrease in the capacitance of splanchnic
veins and a shift of fluid out of the splanchnic veins, thereby
increasing the effective circulating volume. This shift increases
the preload without increasing total body volume and exagger-
ates the hemodynamic effects of sodium and water retention
(Figure1).14 These splanchnic hemodynamic changes may also
be responsible for the abdominal discomfort, nausea, constipa-
tion, and diarrhea common in advanced HF.

From Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH (V.S.); and Division of Cardiovascular
Medicine, University of Utah Health Science Center, Salt Lake City (J.C.F.).
Correspondence to James C. Fang, MD, FACC, FAHA, Division of Cardiovascular Medicine, 30 N 1900 E, Salt Lake City, UT 84132. E-mail
james.fang@hsc.utah.edu
(Circulation. 2016;133:1696-1703. DOI: 10.1161/CIRCULATIONAHA.115.020894.)
2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.115.020894

1696
 Sundaram and Fang Gut and Liver in Heart Failure 1697
Figure 1. Gastrointestinal system as a venous reservoir. Adapted
from Fallick et al.13
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Cardiointestinal Syndrome
Common gastrointestinal manifestations of HF include
anorexia, early satiety, and abdominal pain; in patients with
advanced HF, ascites, protein-losing enteropathy (PLE), and
cachexia may be present. Historically, these symptoms have
been attributed to poor abdominal organ perfusion or edema
and have not been considered operational in the pathophysi-
ology of HF. However, the gut is a large immunologic organ
and may contribute to the proinflammatory cytokine milieu of
HF (Figure2). The failing heart is associated with systemic
immune activation, and levels of proinflammatory cytokines
predict HF survival.15,16 However, the direct pathological link
between the two has yet to be clearly elucidated.17
The intestine serves as an important immunologic bar-
rier and represents the largest mass of lymphoid tissue in
the body, containing >106 lymphocytes per 1 g tissue.18
More than 60% of the total immunoglobulin produced daily
is secreted in the gastrointestinal tract.19 There is increas-
ing evidence that altered gut morphology and function,
for example, increased gut permeability, in HF can alter
this immunologic barrier and play an important role in the
chronic inflammatory process.
Figure 2. Pathophysiology of cardiointestinal syndrome.
Increased gut permeability in HF appears to be a con-
sequence of gut edema and gastrointestinal hypoperfusion.
Neibauher et al20 compared HF patients with recent-onset
peripheral edema with stable nonedematous patients with
HF and healthy volunteers. Bowel edema was not measured
directly, and peripheral edema was used as an indirect reli-
able marker of bowel edema. They observed significantly
higher concentrations of endotoxins (lipopolysaccharide /
liposomal binding protein ratio) in patients with edematous
HF compared with nonedematous patients with HF. Patients
with presumed gut edema had bacterial or lipopolysaccharide
translocation to the systemic circulation. Once in the circula-
tion, it is surmised that lipopolysaccharide binds to lipid-bind-
ing protein, producing a complex that interacts with CD14
and Toll-like signaling receptors, initiating increased cytokine
production. Also in this study, patients with edematous HF
had significantly higher plasma concentrations of C-reactive
protein, tumor necrosis factor (TNF)-, soluble TNF recep-
tor-1 and -2, interleukin-6, and soluble CD14 than the other
2 groups. Importantly, the study demonstrated normalization
of endotoxins levels (lipopolysaccharide) in edematous HF
patients after intensive diuresis.20 Although this study sug-
gests that gut edema incites a proinflammatory response in
HF, it may be confounded by the level of illness of the patients
with edematous HF (eg, the edematous patients had greater
baseline hyponatremia and abnormal renal function and uric
acid levels) compared with the nonedematous patients. Other
investigators have found similar observations.21,22 Tang et al23
showed that elevated fasting plasma levels of trimethylamine-
N-oxide in HF, a downstream metabolite of gut microbiota,
was associated with a 3.4-fold increased risk for mortality,
indicating that alteration in microbial composition in the gut
could potentially lead to progression of the disease. However,
these observations may be epiphenomenon, and causality has
not been established. Intestinal mucosal ischemia also may
lead to increased gut permeability and bacterial translocation.
Using intragastric Pco2 as marker of splanchnic hypoperfu-
sion, Krack et al24 demonstrated elevated levels of intragastric
Pco2 and inflammatory markers in patients with congestive
HF patients low-level and peak exercise.
These findings suggest a potential role for bacterial decon-
tamination of the gut in patients with HF. A randomized trial
of probiotics in patients with HF is testing this hypothesis and
assessing their effect on inflammatory markers and clinical
progression of disease.25
Cardiac Cachexia
Cardiac cachexia has been described as a catabolic state char-
acterized by unintentional and nonedematous weight loss of
>7.5% of premorbid body weight over 6 months.26 The preva-
lence of cardiac cachexia in HF cohorts has been reported to
be as high as 45%.27 Cardiac cachexia is associated with poor
survival independently of functional capacity, left ventricular
systolic function, or peak oxygen consumption. The annual
mortality in cachectic HF patients may be as high as 20% to
30%.28
Anker and coworkers29 have suggested that cachexia in HF is
driven by an increase in the factors that promote protein and fat
tissue degradation. While showing an upregulation of hormonal
 1698CirculationApril 26, 2016
factors (norepinephrine, epinephrine, TNF and cortisol levels)
that promote catabolism, they also demonstrated an inadequate
anabolic response (eg, reduced dehydroepiandrosterone, insulin,
and testosterone levels), signifying an anabolic/catabolic imbal-
ance in cachectic HF patients. Anorexia, early satiety, and poor
gastrointestinal absorption of foods and nutrients in HF may fur-
ther exacerbate this anabolic/catabolic imbalance.7,8
The relationship between cardiac cachexia and gastroin-
testinal function may also be partially mediated through endo-
crine pathways. Ghrelin, a growth hormonereleasing peptide,
is secreted from stomach and circulates in the bloodstream.30
Ghrelin is the endogenous ligand for the growth hormone
secretagog receptor and stimulates growth hormone secretion.
Growth hormone and insulin-like growth factor are anabolic
hormones; elevated serum growth hormone levels with normal
or low insulin-like growth factor-1 levels have been described
in HF patients with cachexia.31 Growth hormone secretagog
receptor has been detected in heart and blood vessels, in addi-
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tion to the hypothalamus and pituitary.
Ghrelin is an appetite stimulatory peptide, and its levels
are increased by fasting and decreased by feeding. Nagaya
et al32 measured circulating ghrelin levels in 74 patients with
HF; plasma ghrelin levels did not differ between HF patients
and control subjects. However, plasma ghrelin levels were
higher in cachectic HF patients compared with noncachec-
tic patients and correlated negatively with body mass index.
This observation suggests that increased circulating ghre-
lin levels may be a compensatory response to an anabolic/
catabolic imbalance in HF patients with cachexia. Small
studies have demonstrated that administration of ghrelin
induces weight gain by decreasing fat use and increasing
carbohydrate use through a growth hormoneindependent
mechanism. In animal models, intravenous administration of
ghrelin has been shown to decrease systemic vascular resis-
tance and to increase cardiac output.33
Figure 3. Pathophysiology of cardiac cachexia.
Increased intestinal permeability and translocation of
endotoxin in HF may be an important stimulus for release of
TNF, another mediator of cardiac cachexia. Despite encourag-
ing preliminary experiences with the TNF antagonist etan-
ercept in HF,34 the experience with etanercept in rheumatoid
arthritis led to the current warning that HF may be precipitated
or worsened by this drug. Other approaches to block TNF
have also not been successful. In the Anti-TNF Therapy
Against Congestive Heart Failure (ATTACH) trial, infliximab,
a chimeric monoclonal antibody to TNF, increased HF hos-
pitalizations.35 A singular reason for the failure of the anti-
TNF is unlikely. Some have surmised that TNF production
is an epiphenomenon in HF and not complicit in the disease
progression. However, a signal for harm was noted in these tri-
als, suggesting that perhaps TNF toxicity may be have been
enhanced. Antibody binding may have increased the circulat-
ing time of TNF or even produced a rebound effect, result-
ing in even higher levels of TNF. Alternatively, TNF may
be adaptive; evidence also suggests that TNF may promote
vascular nitric oxide production, attenuate stress-induced
apoptosis, and decrease the toxicity of prolonged sympathetic
activation. These alternative explanations could explain the
increased rates of HF hospitalization in those receiving high
doses of infliximab.36,37
To summarize, the pathophysiology of cardiac cachexia is
complex, and multiple mechanisms (Figure3) are likely oper-
ational. Although chronic inflammation plays an important
role, the gastrointestinal system is likely central to its patho-
physiology in that anorexia, malnutrition, and malabsorption
interact with hormonal disturbances such as ghrelin excretion
and other imbalances of anabolic, as well as catabolic systems.
Protein-Losing Enteropathy
Hypoalbuminemia/hypoproteinemia is a common condition
in patients with HF and is an independent predictor of poor
 Sundaram and Fang Gut and Liver in Heart Failure 1699
prognosis.38 It is most often related to malnutrition, inflamma-
tion, and cachexia, but other causal factors include hemodilu-
tion, liver dysfunction, proteinuria, and PLE.
PLE, a condition characterized by gastrointestinal loss of
proteins, is often underappreciated in HF. The pathophysiology
of HF-related PLE is related to gut edema and rupture of intesti-
nal lacteals from elevated central venous pressures.39 Increased
gut epithelial permeability subsequently leads to protein leak-
age into the gut lumen. PLE has also been described in other
cardiac conditions associated with elevated right-sided filling
pressures, including constrictive pericarditis, tricuspid regurgi-
tation, and congenital heart disease.40 Although PLE in HF is a
consequence of elevated right-sided filling pressures, it can in
turn increase pulmonary capillary wedge pressures as a result
of low colloid oncotic pressure.41 Small studies have shown
that coadministration of albumin with diuretics in refractory
diuretic-resistant edema confers modest clinical benefit, a find-
ing that warrants confirmation with large, prospective studies.42
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The first step in the evaluation of patients with hypopro-
teinemia is to exclude other common causes like malnutrition
or liver and renal disease. The most commonly used and reli-
able method to determine enteric protein loss is to determine
the clearance of -1 antitrypsin (A1AT) from plasma. A1AT is
a protein synthesized in the liver that is resistant to proteolysis
or degradation in the gut, thereby allowing its intact elimina-
tion and detection in feces. The measurement of A1AT clear-
ance requires both blood and stool samples. Elevated A1AT
clearance suggests excessive gastrointestinal protein loss dis-
tal to pylorus. Patients with PLE generally have A1AT clear-
ance values >50 mL/24 h (normal, <27 mL/24 h). The positive
predictive value of the test has been found to be 97.7%, and the
negative predictive value is 75%.43,44 Technetium 99mlabeled
human serum albumin scintigraphy can also identify protein
loss in the gut, but its use is limited to research.45
The cornerstone of treatment for PLE in HF involves
treating the underlying disease. Davidson et al46 demonstrated
reversal of PLE after pericardial stripping in a small case series
of patients with constrictive pericarditis. There are also reports
of reversal of PLE with orthotopic heart transplantation.47
Alteration in the Pharmacokinetics and
Pharmacodynamics of HF Drugs as a Result of
Gastrointestinal Issues
Gut involvement in HF not only causes worsening of symp-
toms and clinical progression but also potentially compli-
cates HF treatment by decreasing intestinal absorption of HF
drugs. Several mechanisms are attributed to cardiointestinal
syndrome that are implicated in the decreased permeability
of drugs from gut lumen to intestinal epithelial cells to por-
tal circulation in HF.48 Such mechanisms include edematous
changes in the intestinal wall, increased thickness of the bowel
tissues as a result of collagen deposition, and intestinal dam-
age from chronic hypoperfusion.22,49 The proinflammatory
cytokine milieu can also alter the expression of various drug-
metabolizing enzymes and transporters.50,51
Drugs are transported from intestinal lumen to epithelial
cells through either transcellular or paracellular tight junctions.
Evidence suggests that the integrity of paracellular tight junc-
tions to carbohydrates may be damaged in patients with HF.22,48
Although most HF drugs are lipophilic and transported via the
transcellular junctions, intestinal transport of certain hydrophilic
HF drugs such as lisinopril is via paracellular tight junctions,
which may be impaired in HF.48,52 Gut edema may also alter
the rate of absorption of certain drugs such as loop diuretics.53
However, this effect appears to be variable even within the same
drug class. For instance, the rate of absorption of oral furosemide
is delayed in the presence of gut edema, but this phenomenon is
not observed with torsemide and bumetanide.54
Involvement of the Liver in HF
Chronic HF can result in a congestive hepatopathy, which is
related to a chronically congested liver and generally is not
directly related to alterations in cardiac output. Congestive
hepatopathy is the most common cause of liver dysfunction in
HF, more common than reduced cardiac output. In HF, elevated
central venous pressure is transmitted to the sinusoidal bed
without any significant attenuation owing to a lack of hepatic
venous valves. Sinusoids are small endothelium-lined capil-
laries in the liver that have open pores, which greatly increase
the permeability of the liver.55 Elevated venous pressures can
hence cause sinusoidal congestion, resulting in peri-sinusoidal
edema, which decreases oxygen diffusion to the hepatocytes.
Sinusoidal congestion can also cause exudation of protein-rich
fluid into the space of Disse. Excess fluid in the space of Disse
is usually drained into hepatic lymphatics, but when the lymph
formation exceeds the capacity of the lymphatics, high-protein
fluid may ooze from the surface of the liver and drain into the
peritoneal cavity. This phenomenon causes high-protein-con-
centration ascites (typically >2.5 g/dL) and distinguishes car-
diac ascites from other types. The relatively high concentration
of protein in patients with cardiac ascites could be caused by the
relatively modest elevations of portal pressure in patients with
cardiac ascites compared with liver cirrhosis or lower protein
levels in patients with intrinsic cirrhosis (caused by more com-
promised synthetic function) than patients with cardiac asci-
tes.56 Persistent congestion over years can further compromise
oxygen supply, leading to fibrosis. Fibrosis is a wound-healing
response to chronic liver injury and can result in cirrhosis if
left untreated.57 Chronic intrahepatic venous stasis can also pre-
dispose to intrahepatic thrombi, which can accelerate fibrosis
and eventually lead to cirrhosis.58 The various patterns of liver
involvement in HF are mentioned in Table 1.
Clinical Manifestations
Most reports of the hepatic complications of HF date back to an
era before heart transplantation and mechanical circulatory sup-
port. However, involvement of the liver in HF is a contemporary
independent predictor of poor prognosis.59 In patients with HF
with preserved ejection fraction, right ventricular dysfunction
is common and may develop from contractile impairment and
afterload mismatch from pulmonary hypertension, which can
lead to liver dysfunction.60 Progression to liver cirrhosis can in
turn lead to intrinsic changes in myocardial structure and func-
tion, often described as cirrhotic cardiomyopathy, indicating a
vicious cycle of a cause-effect relationship.61
The most common symptom of hepatic involvement of
HF is abdominal discomfort, often localized to the right upper
 1700CirculationApril 26, 2016

Table 1. Patterns of Liver Involvement in HF

Condition Pathophysiology LFTs Other Testing Reversible?
Congestive hepatopathy Right-sided heart volume overload Modest increase Rarely required Yes
Hepatic fibrosis Prolonged congestion (usually years) with Modest increase HVPG Maybe
wound-healing response Liver biopsy
Liver-spleen scan
Hepatic cirrhosis End-stage fibrosis with liver synthetic Modest increase HVPG No
dysfunction and portal hypertension Liver biopsy
Liver- spleen scan
Ischemic hepatitis Acute hypotension and more likely with Dramatic elevation Rarely required Usually
decrease in cardiac output and concomitant
congestion
HF indicates heart failure; HVPG, hepatic venous pressure gradient; and LFT, liver function test.

quadrant. In the Evaluation Study of Congestive Heart Failure 250 times the upper limit of normal. These laboratory values
and Pulmonary Artery Catheterization Effectiveness (ESCAPE) usually return to normal within 7 to 10 days in the absence of
trial, 8% of hospitalized HF patients had abdominal discomfort any further hemodynamic insult. Serum bilirubin levels rarely
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as their chief complaint. Nausea, early satiety, and weight loss rise to >4 times the upper limit of normal, and serum alkaline
may also be present. Physical examination findings include phosphatase is usually within 2 times the upper limit of nor-
hepatic enlargement, ascites, jaundice, and signs of portal mal.67 Ischemic hepatitis generally has a benign and self-limited
hypertension. In a large case series of 175 patients in acute and course, but under rare circumstances, fulminant hepatic failure
chronic HF, hepatomegaly was present in 90% to 95%, ascites can occur.68 Management involves restoration of cardiac out-
in 17% to 25%, and splenomegaly in 7% to 20%.62 put and blood pressure while reducing central venous pressure
However, liver dysfunction in HF is usually asymptom- because there is no specific therapy for ischemic hepatitis.
atic and generally discovered on routine biochemical testing.
Hepatic laboratory abnormalities most commonly demon- Assessment of Hepatic Status in HF
strate cholestasis, are related to elevations in right atrial pres- In advanced HF, the degree of hepatic dysfunction should be
sure and severe tricuspid regurgitation, and correlate with quantified because cardiac surgery outcomes are poor in patients
increased serum natriuretic peptide levels. Chronic passive with cirrhosis; mortality in Child class C cirrhosis exceeds 50%.
congestion can also impair hepatic synthetic function, lead- Laboratory abnormalities suggestive of synthetic dysfunction
ing to prolonged prothrombin time and hypoalbuminemia. are particularly worrisome and should be aggressively inves-
Allen et al63 reviewed liver function tests of 2679 patients tigated.69,70 Evidence for portal hypertension by noninvasive
with symptomatic chronic HF from the Candesartan in Heart means, for example, liver-spleen scans or abdominal ultrasound,
Failure: Assessment of Reduction in Mortality and Morbidity suggests advanced liver disease but lacks sensitivity for signifi-
Program (CHARM) study and found that the most common cant hepatic dysfunction, for example, fibrosis. Transjugular
liver function test abnormalities were low albumin (18.3%), intrahepatic liver biopsy can be performed safely in patients with
elevated alkaline phosphatase (14.0%), and elevated total bili-
rubin (13.0%). Alanine aminotransferase and aspartate ami-
notransferase were less commonly abnormal in these patients.
Allen et al also noticed that in the CHARM study elevated
total bilirubin was one of the strongest independent predictors
of poor prognosis. The outcome of patients with congestive
hepatopathy is directly related to the severity of the underly-
ing heart disease. Effective treatment of HF can even reverse
early histological changes of passive hepatic congestion.64
Ischemic hepatitis refers to diffuse hepatic injury from a
sudden drop in cardiac output or perfusion pressure and may
be more likely in the presence of hepatic congestion. Seeto
et al65 noted that patients with traumatic hemorrhagic shock
did not develop ischemic hepatitis. In contrast, those patients
who developed ischemic hepatitis had high filling pressures
in addition to low cardiac output. These findings indicate
that ischemic hepatitis is more likely a consequence of both
hepatic congestion and a low cardiac output.66 Figure 4. Assessment of patients with cardiac cirrhosis being
From a laboratory perspective, ischemic hepatitis is charac- considered for advanced heart failure therapies. ALT indicates
terized by rapid increases in serum aminotransferases and lactate alanine transaminase; AST, aspartate transaminase; CABG, coro-
nary artery bypass surgery; PT, prothrombin time; TR, tricuspid
dehydrogenase, often to dramatic levels. The aminotransferases regurgitation; and VAD, ventricular assist device. Adapted from
peak 1 to 3 days after the hemodynamic insult and can rise to Gelow et al.71
 Sundaram and Fang Gut and Liver in Heart Failure 1701
Table 2. Commonly Used HF Drugs That Are Eliminated via
the Liver
Drugs Clearance
-Blockers
Carvedilol Liver
Metoprolol succinate Liver
Bisoprolol Liver, kidney
Nebivolol Liver, kidney
Angiotensin-converting enzyme inhibitors
Trandolapril Liver, kidney
Fosinopril Liver, kidney
Angiotensin receptor blockers
Losartan Predominantly liver (90%)
Candesartan Liver, kidney
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Heart failure (HF) drugs (aldosterone antagonists, hydralazine, isosorbide
dinitrate, other angiotensin-converting enzyme inhibitors) not mentioned above
predominantly have nonhepatic clearance.
advanced HF. Histological fibrosis is common and may affect
the decision to proceed with advanced therapies71 (Figure4).
Hepatic venous pressure measurement can be performed along
with transjugular liver biopsy and is currently the method of
choice for measurement of portal venous pressure. Normal por-
tal pressure ranges from 7 to 12 mmHg, and the pressure gradi-
ent between portal and hepatic veins ranges from 1 to 4 mmHg.
Wedged hepatic venous pressure has been found to closely
correlate with the portal pressure.72,73 A catheter is introduced
through the jugular vein to the hepatic vein and is advanced
until it can go no farther. The pressure measurements are then
taken in the free and wedged positions. The difference between
the wedge and free pressures gives the hepatic venous pressure
gradient (HVPG), which is the pressure difference between
the portal and inferior vena cava pressures. The sensitivity and
specificity of HVPG >6 mmHg for predicting stage 1 compen-
sative liver cirrhosis are 78% and 81%, respectively.74 Myers et
al75 measured HVPG in 83 patients with cardiac hepatopathy
and noticed that HVPG was normal in 81% of these patients.
The HVPG therefore allows the clinician to evaluate the cause
of ascites when present in HF. If the HVPG is low, then ascites
is likely attributable to passive hepatic congestion without cir-
rhosis from elevated right-sided pressures. If the HVPG is >6
mmHg with an elevated inferior vena cava pressure, cirrhosis
and concomitant portal hypertension are likely present.
The Model for End Stage Liver Disease (MELD) score
has also been used in a similar fashion to risk stratify patients
with advanced HF and to predict outcomes of HF patients
undergoing left ventricular assist device implantations and
heart transplantations. Kim et al76 used the MELD score and
its modifications, MELD-Na (includes serum sodium) and
MELD-X1 (excludes international normalized ratio in patients
who are receiving oral anticoagulation), to assess their useful-
ness as a prognostic tool in ambulatory HF patients with evi-
dence of liver dysfunction. In patients who were not receiving
anticoagulation, the MELD and MELD-Na scores were good
predictors of death, heart transplantation, or left ventricular
assist device implantation at 1 year.
Outcomes When Hepatic
Dysfunction Complicates HF
While preexisting severe liver dysfunction is associated with
poor outcomes after left ventricular assist device implantation,
patients with mild liver function test derangement improve their
liver function.77 A retrospective analysis (baseline liver function
tests: mean gamma glutamyl transpeptidase, 165 U/L; mean
alkaline phosphatase, 121 U/L; mean bilirubin, 2 mg/dL; mean
lactate dehydrogenase, 338 U/L; mean aspartate transaminase,
39 U/L; and mean alanine transaminase, 29 U/L) demonstrated
improvements in gamma glutamyl transpeptidase, alkaline phos-
phatase, and bilirubin levels within 3 months, whereas transami-
nases and lactate dehydrogenase took 12 months to normalize
after heart transplantation. This difference in time course was
probably related to the shift of fluid from the intrathoracic com-
partment to the systemic circulation, contributing to an increase
in effective circulating volume and thereby increasing blood
flow to the liver. Of note, patients with severe liver disease were
excluded from these studies.78 High postoperative mortality and
morbidity were observed in patients with established cirrhosis
who underwent advanced HF therapies. Improved risk stratifica-
tion and selection of patients with liver function test abnormali-
ties are critical for optimal outcomes after left ventricular assist
device implantation and heart transplantation.
Alteration in the Pharmacokinetics and
Pharmacodynamics of HF Drugs as a Result of
Cardiac Cirrhosis
Liver dysfunction in HF may alter the pharmacokinetics
and pharmacodynamics of HF drugs. In general, hydro-
philic -blockers are excreted unchanged by the kidneys,
and lipophilic -blockers are largely metabolized by the liver
(Table2).79 Figure5 shows the route of elimination of various
-blockers used in HF. The majority of angiotensin-convert-
ing enzyme inhibitors (except fosinopril) are excreted by the
kidneys; hence, drug toxicity is not a major concern in patients
with liver dysfunction. However, some angiotensin-convert-
ing enzyme inhibitors (eg, enalapril, ramipril) are prodrugs
that must be converted to an active metabolite in the liver by
esterification.81 However, there are few clinical data on the use
of such angiotensin-converting enzyme inhibitors in patients
with HF complicated by liver disease. The use of aldosterone
antagonists82 has been well established in patients with liver
cirrhosis, although there is a limited evidence base of their use
Figure 5. Route of elimination of -blockers used in heart failure.
Adapted with permission from Opie and Gersh.80 Copyright
2013, Elsevier. Authorization for this adaptation has been obtained
both from the owner of the copyright in the original work and from
the owner of copyright in the translation or adaptation
 1702CirculationApril 26, 2016
when there is concomitant HF. Ivabradine, an If current inhibi-
tor recently approved by US Food and Drug Administration
14. Anker SD, von Haehling S. Inflammatory mediators in chronic heart fail-
for the management of HF with reduced ejection fraction, is
contraindicated in patients with severe hepatic insufficiency.83
The commonly used HF drugs that have hepatic clearance are
listed in Table2.
Conclusions
There is convincing evidence that involvement of the gastroin-
testinal system and liver in HF is independently associated with
poor outcome. Recognizing the clinical and pathophysiological
importance of gastrointestinal symptoms should be part of the
routine evaluation of HF. When possible, gastrointestinal func-
tion should be optimized in HF through improved hemodynam-
ics and guideline-directed HF management. Other therapeutic
modalities directed at gastrointestinal and hepatic function in
HF such as alterations of gut flora, nutritional supplements, and
ghrelin in cardiac cachexia remain to be further explored. As
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advanced therapeutic options grow for patients with end-stage
HF, a thorough understanding of the impact of gastrointestinal
and liver complications of HF is increasingly important.
Disclosures
None.
References
1. Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine.
Philadelphia, PA: WB Saunders; 2015.
2. Mann DL. Mechanisms and models in heart failure: a combinatorial
approach. Circulation. 1999;100:9991008.
3. Braunwald E, Bristow MR. Congestive heart failure: fifty years of prog-
ress. Circulation. 2000;102(suppl 4):IV14IV23.
4. Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypoth-
esis. Lancet. 2000;356:930933. doi: 10.1016/S0140-6736(00)02690-8.
5. Sandek A, Rauchhaus M, Anker SD, von Haehling S. The emerging role
of the gut in chronic heart failure. Curr Opin Clin Nutr Metab Care.
2008;11:632639. doi: 10.1097/MCO.0b013e32830a4c6e.
6. Yndestad A, Dams JK, Oie E, Ueland T, Gullestad L, Aukrust P. Systemic
inflammation in heart failure: the whys and wherefores. Heart Fail Rev.
2006;11:8392. doi: 10.1007/s10741-006-9196-2.
7. Anker SD, Coats AJ. Cardiac cachexia: a syndrome with impaired survival
and immune and neuroendocrine activation. Chest. 1999;115:836847.
8. Anker SD, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol.
2002;85:5166.
9. Bourge RC, Abraham WT, Adamson PB, Aaron MF, Aranda JM Jr,
Magalski A, Zile MR, Smith AL, Smart FW, OShaughnessy MA, Jessup
ML, Sparks B, Naftel DL, Stevenson LW; COMPASS-HF Study Group.
Randomized controlled trial of an implantable continuous hemodynamic
monitor in patients with advanced heart failure: the COMPASS-HF study.
J Am Coll Cardiol. 2008;51:10731079. doi: 10.1016/j.jacc.2007.10.061.
10. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR,
Stevenson LW, Strickland W, Neelagaru S, Raval N, Krueger S, Weiner
S, Shavelle D, Jeffries B, Yadav JS; CHAMPION Trial Study Group.
Wireless pulmonary artery haemodynamic monitoring in chronic heart
failure: a randomised controlled trial. Lancet. 2011;377:658666. doi:
10.1016/S0140-6736(11)60101-3.
11. Ritzema J, Troughton R, Melton I, Crozier I, Doughty R, Krum H, Walton
A, Adamson P, Kar S, Shah PK, Richards M, Eigler NL, Whiting JS, Haas
GJ, Heywood JT, Frampton CM, Abraham WT; Hemodynamically Guided
Home Self-Therapy in Severe Heart Failure Patients (HOMEOSTASIS)
Study Group. Physician-directed patient self-management of left atrial
pressure in advanced chronic heart failure. Circulation. 2010;121:1086
1095. doi: 10.1161/CIRCULATIONAHA.108.800490.
12. Gelman S. Venous function and central venous pressure: a physiologic story.
Anesthesiology. 2008;108:735748. doi: 10.1097/ALN.0b013e3181672607.
13. Fallick C, Sobotka PA, Dunlap ME. Sympathetically mediated changes
in capacitance redistribution of the venous reservoir as a cause of
decompensation. Circ Heart Fail. 2011;4:669675. doi: 10.1161/
CIRCHEARTFAILURE.111.961789.
ure: an overview. Heart. 2004;90:464470.
15. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating
levels of tumor necrosis factor in severe chronic heart failure. N Engl J
Med. 1990;323:236241. doi: 10.1056/NEJM199007263230405.
16. Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal
C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD. Plasma cyto-
kine parameters and mortality in patients with chronic heart failure.
Circulation. 2000;102:30603067.
17. Mann DL. Inflammatory mediators and the failing heart: past, present, and
the foreseeable future. Circ Res. 2002;91:988998.
18. Brandtzaeg P, Halstensen TS, Kett K, Krajci P, Kvale D, Rognum TO,
Scott H, Sollid LM. Immunobiology and immunopathology of human
gut mucosa: humoral immunity and intraepithelial lymphocytes.
Gastroenterology. 1989;97:15621584.
19. Salminen S, Bouley C, Boutron-Ruault MC, Cummings JH, Franck A,
Gibson GR, Isolauri E, Moreau MC, Roberfroid M, Rowland I. Functional
food science and gastrointestinal physiology and function. Br J Nutr.
1998;80(suppl 1):S147S171.
20. Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus
M, Poole-Wilson PA, Coats AJ, Anker SD. Endotoxin and immune
activation in chronic heart failure: a prospective cohort study. Lancet.
1999;353:18381842. doi: 10.1016/S0140-6736(98)09286-1.
21. Krack A, Sharma R, Figulla HR, Anker SD. The importance of the gas-
trointestinal system in the pathogenesis of heart failure. Eur Heart J.
2005;26:23682374. doi: 10.1093/eurheartj/ehi389.
22. Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, von Haehling
S, Schroedl W, Karhausen T, Doehner W, Rauchhaus M, Poole-Wilson
P, Volk HD, Lochs H, Anker SD. Altered intestinal function in patients
with chronic heart failure. J Am Coll Cardiol. 2007;50:15611569. doi:
10.1016/j.jacc.2007.07.016.
23. Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, Wu Y,
Hazen SL. Prognostic value of elevated levels of intestinal microbe-gen-
erated metabolite trimethylamine-N-oxide in patients with heart failure:
refining the gut hypothesis. J Am Coll Cardiol. 2014;64:19081914. doi:
10.1016/j.jacc.2014.02.617.
24. Krack A, Richartz BM, Gastmann A, Greim K, Lotze U, Anker SD,
Figulla HR. Studies on intragastric PCO2 at rest and during exercise as a
marker of intestinal perfusion in patients with chronic heart failure. Eur J
Heart Fail. 2004;6:403407. doi: 10.1016/j.ejheart.2004.03.002.
25. Costanza AC, Moscavitch SD, Faria Neto HC, Mesquita ET. Probiotic
therapy with Saccharomyces boulardii for heart failure patients: a ran-
domized, double-blind, placebo-controlled pilot trial. Int J Cardiol.
2015;179:348350. doi: 10.1016/j.ijcard.2014.11.034.
26. Anker SD, Rauchhaus M. Insights into the pathogenesis of chronic heart fail-
ure: immune activation and cachexia. Curr Opin Cardiol. 1999;14:211216.
27. von Haehling S, Doehner W, Anker SD. Nutrition, metabolism, and the
complex pathophysiology of cachexia in chronic heart failure. Cardiovasc
Res. 2007;73:298309. doi: 10.1016/j.cardiores.2006.08.018.
28. Anker SD, Coats AJ. Cardiac cachexia: a syndrome with impaired survival
and immune and neuroendocrine activation. Chest. 1999;115:836847.
29. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ,
Poole-Wilson PA, Coats AJ. Hormonal changes and catabolic/anabolic
imbalance in chronic heart failure and their importance for cardiac
cachexia. Circulation. 1997;96:526534.
30. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K.
Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
Nature. 1999;402:656660. doi: 10.1038/45230.
31. Castellano G, Affuso F, Di Conza P, Fazio S. The GH/IGF-1 axis and heart
failure. Curr Cardiol Rev. 2009;5:203215.
32. Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H,
Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H, Yutani C, Kangawa
K. Elevated circulating level of ghrelin in cachexia associated with chronic
heart failure: relationships between ghrelin and anabolic/catabolic factors.
Circulation. 2001;104:20342038.
33. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, Hosoda
H, Hirota Y, Ishida H, Mori H, Kangawa K. Chronic administration of ghrelin
improves left ventricular dysfunction and attenuates development of cardiac
cachexia in rats with heart failure. Circulation. 2001;104:14301435.
34. Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman
AM, Mann DL. Results of targeted anti-tumor necrosis factor therapy with
etanercept (ENBREL) in patients with advanced heart failure. Circulation.
2001;103:10441047.
 Sundaram and Fang Gut and Liver in Heart Failure 1703
35. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF
Therapy Against Congestive Heart Failure Investigators. Randomized,
double-blind, placebo-controlled, pilot trial of infliximab, a chimeric
monoclonal antibody to tumor necrosis factor-alpha, in patients with
moderate-to-severe heart failure: results of the anti-TNF Therapy Against
Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133
3140. doi: 10.1161/01.CIR.0000077913.60364.D2.
36. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann
DL. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the
failing human heart. Circulation. 1996;93:704711.
37. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL,
Glembotski CC, Quintana PJ, Sabbadini RA. Tumor necrosis factor alpha-
induced apoptosis in cardiac myocytes. Involvement of the sphingolipid
signaling cascade in cardiac cell death. J Clin Invest. 1996;98:28542865.
doi: 10.1172/JCI119114.
38. Horwich TB, Kalantar-Zadeh K, MacLellan RW, Fonarow GC. Albumin
levels predict survival in patients with systolic heart failure. Am Heart J.
2008;155:883889. doi: 10.1016/j.ahj.2007.11.043.
39. Chan FK, Sung JJ, Ma KM, Leung YL, Yeung VT. Protein-losing enter-
opathy in congestive heart failure: diagnosis by means of a simple method.
Hepatogastroenterology. 1999;46:18161818.
40. Rychik J. Protein-losing enteropathy after Fontan operation. Congenit
Heart Dis. 2007;2:288300. doi: 10.1111/j.1747-0803.2007.00116.x.
Downloaded from http://circ.ahajournals.org/ by guest on November 20, 2017
41. Arques S, Ambrosi P. Human serum albumin in the clinical syn-
drome of heart failure. J Card Fail. 2011;17:451458. doi: 10.1016/j.
cardfail.2011.02.010.
42. Doungngern T, Huckleberry Y, Bloom JW, Erstad B. Effect of albumin on
diuretic response to furosemide in patients with hypoalbuminemia. Am J
Crit Care. 2012;21:280286. doi: 10.4037/ajcc2012999.
43. Biancone L, Fantini M, Tosti C, Bozzi R, Vavassori P, Pallone F. Fecal
alpha 1-antitrypsin clearance as a marker of clinical relapse in patients
with Crohns disease of the distal ileum. Eur J Gastroenterol Hepatol.
2003;15:261266. doi: 10.1097/01.meg.0000049990.68425.c8.
44. Becker K, Berger M, Niederau C, Frieling T. Individual fecal alpha 1-anti-
trypsin excretion reflects clinical activity in Crohns disease but not in
ulcerative colitis. Hepatogastroenterology. 1999;46:23092314.
45. Wang SJ, Tsai SC, Lan JL. Tc-99m albumin scintigraphy to monitor the
effect of treatment in protein-losing gastroenteropathy. Clin Nucl Med.
2000;25:197199.
46. Davidson JD, Waldmann TA, Goodman DS, Gordon RS Jr. Protein-losing
gastroenteropathy in congestive heart-failure. Lancet. 1961;1:899902.
47. Rueda Soriano J, Zorio Grima E, Arnau Vives MA, Osa Sez A, Martnez
Dolz L, Almenar Bonet L, Palencia Prez MA, Salvador Sanz A. Reversal
of protein-losing enteropathy after heart transplantation in young patients.
Rev Esp Cardiol. 2009;62:937940.
48. Ogawa R, Stachnik JM, Echizen H. Clinical pharmacokinetics of drugs in
patients with heart failure: an update (part 2, drugs administered orally). Clin
Pharmacokinet. 2014;53:10831114. doi: 10.1007/s40262-014-0189-3.
49. Arutyunov GP, Kostyukevich OI, Serov RA, Rylova NV, Bylova
NA. Collagen accumulation and dysfunctional mucosal barrier of
the small intestine in patients with chronic heart failure. Int J Cardiol.
2008;125:240245. doi: 10.1016/j.ijcard.2007.11.103.
50. Zordoky BN, El-Kadi AO. Modulation of cardiac and hepatic cytochrome
P450 enzymes during heart failure. Curr Drug Metab. 2008;9:122128.
51. Morgan ET. Impact of infectious and inflammatory disease on cytochrome
P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol
Ther. 2009;85:434438. doi: 10.1038/clpt.2008.302.
52. Kostis JB. Differences among ACE inhibitors. Am J Hypertens.
2010;23:1156. doi: 10.1038/ajh.2010.170.
53. Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC. Furosemide
absorption altered in decompensated congestive heart failure. Ann Intern
Med. 1985;102:314318.
54. Brater DC. Clinical pharmacology of loop diuretics in health and disease.
Eur Heart J. 1992;13 Suppl G:1014.
55. Sherlock S. The liver in heart failure; relation of anatomical, functional,
and circulatory changes. Br Heart J. 1951;13:273293.
56. Safran AP, Schaffner F. Chronic passive congestion of the liver in man:
electron microscopic study of cell atrophy and intralobular fibrosis. Am J
Pathol. 1967;50:447463.
57. Runyon BA. Cardiac ascites: a characterization. J Clin Gastroenterol.
1988;10:410412.
58. Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of con-
gestive hepatic fibrosis (cardiac cirrhosis). Hepatology. 1995;21:12321237.
59. van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen
DJ, Voors AA. Abnormal liver function in relation to hemodynamic profile
in heart failure patients. J Card Fail. 2010;16:8490. doi: 10.1016/j.
cardfail.2009.08.002.
60. Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart
dysfunction in heart failure with preserved ejection fraction. Eur Heart J.
2014;35:34523462. doi: 10.1093/eurheartj/ehu193.
61. Zardi EM, Abbate A, Zardi DM, Dobrina A, Margiotta D, Van Tassell BW,
Van Tassel BW, Afeltra A, Sanyal AJ. Cirrhotic cardiomyopathy. J Am
Coll Cardiol. 2010;56:539549. doi: 10.1016/j.jacc.2009.12.075.
62. Richman SM, Delman AJ, Grob D. Alterations in indices of liver function
in congestive heart failure with particular reference to serum enzymes. Am
J Med. 1961;30:211225.
63. Allen LA, Felker GM, Pocock S, McMurray JJ, Pfeffer MA, Swedberg
K, Wang D, Yusuf S, Michelson EL, Granger CB; CHARM Investigators.
Liver function abnormalities and outcome in patients with chronic heart
failure: data from the Candesartan in Heart Failure: Assessment of
Reduction in Mortality and Morbidity (CHARM) program. Eur J Heart
Fail. 2009;11:170177. doi: 10.1093/eurjhf/hfn031.
64. Giallourakis CC, Rosenberg PM, Friedman LS. The liver in heart failure.
Clin Liver Dis. 2002;6:94767, viii.
65. Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation
and pathogenesis. Am J Med. 2000;109:109113.
66. Henrion J, Descamps O, Luwaert R, Schapira M, Parfonry A, Heller F.
Hypoxic hepatitis in patients with cardiac failure: incidence in a coronary care
unit and measurement of hepatic blood flow. J Hepatol. 1994;21:696703.
67. Gitlin N, Serio KM. Ischemic hepatitis: widening horizons. Am J
Gastroenterol. 1992;87:831836.
68. Cohen JA, Kaplan MM. Left-sided heart failure presenting as hepatitis.
Gastroenterology. 1978;74:583587.
69. Klemperer JD, Ko W, Krieger KH, Connolly M, Rosengart TK, Altorki
NK, Lang S, Isom OW. Cardiac operations in patients with cirrhosis. Ann
Thorac Surg. 1998;65:8587.
70. Bizouarn P, Ausseur A, Desseigne P, Le Teurnier Y, Nougarede B, Train
M, Michaud JL. Early and late outcome after elective cardiac surgery in
patients with cirrhosis. Ann Thorac Surg. 1999;67:13341338.
71. Gelow JM, Desai AS, Hochberg CP, Glickman JN, Givertz MM,
Fang JC. Clinical predictors of hepatic fibrosis in chronic advanced
heart failure. Circ Heart Fail. 2010;3:5964. doi: 10.1161/
CIRCHEARTFAILURE.109.872556.
72. Bosch J, Mastai R, Kravetz D, Navasa M, Rods J. Hemodynamic evalua-
tion of the patient with portal hypertension. Semin Liver Dis. 1986;6:309
317. doi: 10.1055/s-2008-1040613.
73. Reynolds TB, Ito S, Iwatsuki S. Measurement of portal pressure and its
clinical application. Am J Med. 1970;49:649657.
74. Suk KT, Kim HC, Namkung S, Han SH, Choi KC, Park SH, Sung HT,
Kim CH, Kim SH, Ham YL, Kang HM, Kim DJ. Diagnostic accuracy of
hepatic venous pressure gradient measurement in the prediction of stage
1 compensated liver cirrhosis in patients with chronic hepatitis B. Eur J
Gastroenterol Hepatol. 2013;10:11701176.
75. Myers RP, Cerini R, Sayegh R, Moreau R, Degott C, Lebrec D. Cardiac
hepatopathy: clinical, hemodynamic, and histologic characteristics and
correlations. Hepatology. 2003;37:393400.
76. Kim MS, Kato TS, Farr M, Wu C, Givens RC, Collado E, Mancini DM,
Schulze PC. Hepatic dysfunction in ambulatory patients with heart failure:
application of the MELD scoring system for outcome prediction. J Am
Coll Cardiol. 2013;61:22532261. doi: 10.1016/j.jacc.2012.12.056.
77. Russell SD, Rogers JG, Milano CA, Dyke DB, Pagani FD, Aranda
JM, Klodell CT Jr, Boyle AJ, John R, Chen L, Massey HT, Farrar DJ,
Conte JV; HeartMate II Clinical Investigators. Renal and hepatic func-
tion improve in advanced heart failure patients during continuous-flow
support with the HeartMate II left ventricular assist device. Circulation.
2009;120:23522357. doi: 10.1161/CIRCULATIONAHA.108.814863.
78. Dichtl W, Vogel W, Dunst KM, Grander W, Alber HF, Frick M, Antretter
H, Laufer G, Pachinger O, Plzl G. Cardiac hepatopathy before
and after heart transplantation. Transpl Int. 2005;18:697702. doi:
10.1111/j.1432-2277.2005.00122.x.
79. Johnsson G, Regrdh CG. Clinical pharmacokinetics of beta-adrenorecep-
tor blocking drugs. Clin Pharmacokinet. 1976;1:233263.
80. Opie L, Gersh B. Drugs for the Heart. 8th ed. New York, NY: Elsevier; 2013.
81. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors.
Circulation. 1998;97:14111420.
82. Sungaila I, Bartle WR, Walker SE, DeAngelis C, Uetrecht J, Pappas C,
Vidins E. Spironolactone pharmacokinetics and pharmacodynamics in
patients with cirrhotic ascites. Gastroenterology. 1992;102:16801685.
83. Deedwani P. Selective and specific inhibition of If with ivabradine for the treat-
ment of coronary artery disease or heart failure. Drugs. 2013;73:15691586.
 Gastrointestinal and Liver Issues in Heart Failure
Varun Sundaram and James C. Fang

Circulation. 2016;133:1696-1703
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