REVIEW
Cardiac Morbidity and Mortality Related to Orthotopic
Liver Transplantation
George Therapondos,1 Andrew D. Flapan,2 John N. Plevris,3 and Peter C. Hayes3
This article briefly discusses the cardiac status of liver transplant recipients and their preoperative cardiac evaluation. It
describes in detail perioperative and early and late postoperative complications as well as the cardiac problems associated
with immunosuppression. The preoperative cardiovascular
status of patients is important in determining how they cope
with the stresses imposed by liver transplantation. Minor
early cardiac events are common and may influence longer
term cardiac morbidity. Immunosuppressive therapy may
have short term effects but is likely to adversely affect long
term cardiac risk. (Liver Transpl 2004;10:1441–1453.)
M
ost liver transplant recipients are patients with liver
cirrhosis. The most common cardiac condition
that affects these patients is cirrhotic cardiomyopathy, a
poorly defined condition that was recognized only
recently. Patients with this condition will respond poorly
to the stresses of liver transplantation or procedures such as
transjugular intrahepatic stent shunt insertion. It is
beyond the scope of this review to describe in detail the
abnormalities found in cirrhotic cardiomyopathy, but it is
important to highlight its importance in the cardiovascular
complications seen following liver transplantation. In
addition, one has to remember the importance of preexisting cardiac disease due to coronary artery disease
(CAD), genetic hemochromatosis, and alcoholic cardiomyopathy. The issue of CAD is particularly important
with the advent of orthotopic liver transplantation (OLT)
for recipients over the age of 50 years. Death from nonhepatic causes such as infections, neurologic causes, and
more specific to this article, cardiac causes, has become
more apparent. Data analysis from the United Network
for Organ Sharing showed a slightly reduced survival in
patients over the age of 50 years and especially in patients
over the age of 60 years.1
In this review, we briefly discuss the cardiac status of liver
transplant recipients and their preoperative cardiac evaluation, but we describe in detail their perioperative and postoperativecomplicationsandthecardiaccomplicationsof immunosuppression, as well as longer-term cardiac problems.
Preoperative Cardiac Status and Conditions
Predisposing to Cardiac Complications
Cirrhotic Cardiomyopathy
Cirrhotic cardiomyopathy is the term used to describe
the impaired cardiac contractility under conditions of
stress (exercise or pharmacological) in patients with cirrhosis. Its cause is not yet known, but the recognition
that cardiac failure after OLT is an important cause of
morbidity and mortality has highlighted the problem.
To date there is no single diagnostic test that can identify patients with this condition and predict who will
develop postoperative complications.2
The first description of baseline abnormal cardiac status was made by Kowalski and Abelmann,3 who described
elevated cardiac output in a group of cirrhotic patients,
although the same authors failed to detect an attenuated
response in these patients after exercise.4 Occult cardiomyopathy with depression of left ventricular (LV) function in
response to pressure and volume overload was first
described in a small group of alcoholic patients with cirrhosis and normal cardiac resting function.5 In that article,
the development of global LV dysfunction in 4 patients
may have been caused by the presence of this occult cardiomyopathy, which was masked by the preoperative
hemodynamic state but which can become evident posttransplant with the development of significant volume
loading and increased afterload. In cirrhosis, left atrial
diameters have been found to be increased, whereas right
atrial size is considered to remain unchanged.6 For a
detailed discussion of cirrhotic cardiomyopathy, the reader
is referred to the review by Moller and Henriksen.7
Abbreviations: CAD, coronary artery disease; OLT, orthotopic
liver transplantation; LV, left ventricular; HPS, hepatopulmonary
syndrome; PPH, portopulmonary hypertension; PAP, pulmonary
artery pressure; HCM, hypertrophic cardiomyopathy; TEE, transesophageal echocardiography; EF, ejection fraction; PRS, postreperfusion syndrome.
From the 1Department of Medicine, Division of Gastroenterology,
University of Toronto, Toronto General Hospital, Toronto, ON, Canada; and the 2Liver Unit and 3Cardiology Unit, Royal Infirmary of
Edinburgh, Edinburgh, UK.
Address reprint requests to G. Therapondos, 9-220 EN, Division of
Gastroenterology, Department of Medicine, Toronto General Hospital,
200 Elizabeth St, Toronto M5G 2C4, Canada. Telephone: 416 340
3834; FAX: 416 340 5019; E-mail: george.therapondos@utoronto.ca
Copyright © 2004 by the American Association for the Study of
Liver Diseases
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/lt.20298
Liver Transplantation, Vol 10, No 12 (December), 2004: pp 1441–1453
1441
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Therapondos et al.
Ischemic Heart Disease
The prevalence of CAD increases with age.8 Evaluation
of all patients for liver transplantation is therefore
important for the detection of CAD, not only because
of the operative risks but also because of the reduced
long-term survival of these patients given the limited
donor pool. Plotkin et al.9 recorded 50% mortality
when patients with a history of CAD underwent liver
transplantation. Carey et al.10 documented a 27% incidence of moderate or severe CAD in liver transplant
candidates over 50 years of age, with diabetes being the
most important predictive risk factor.
The prevalence of angiographically proven CAD in
patients with end-stage liver disease is not clearly
defined. CAD in patients with primary biliary cirrhosis
has been reported in a few small series and in isolated
case reports, questioning the relationship between elevated serum lipids and pathogenesis. Crippin et al.11
studied 312 patients with primary biliary cirrhosis and
showed that although life expectancy was decreased, the
incidence of atherosclerotic death was not statistically
higher than an age- and gender-matched control group.
This study showed that patients without risk factors,
such as nonsmoking females without hypertension, diabetes, and family history of premature CAD, have a
very low prevalence of moderate or severe CAD. However, the findings of this study may be biased by the fact
that patients with symptomatic CAD could have been
excluded from referral to this tertiary liver transplant
center.
Donovan et al.12 evaluated the range of cardiovascular abnormalities in patients undergoing evaluation for
liver transplantation and assessed ischemia during
dobutamine stress echocardiography. Fewer than 10%
of patients had evidence of significant ventricular dysfunction or valvular disease on preoperative echocardiography and only 3 out of 190 patients had significant
coronary artery disease. Once again, one has to be aware
of the possibility of referral bias in all of these studies.
The mechanisms for the major cardiac perioperative
events in patients with CAD remain ill defined. Possible
explanations for myocardial infarction include coronary vasospasm or thrombotic coronary occlusion, perhaps secondary to the hypercoagulable state that exists
after liver transplantation.13
Alcohol-Related Cardiomyopathy
Many patients with cirrhosis and a history of alcohol
abuse will have overt alcohol-related LV dysfunction,
but in general, standard cardiac evaluation will have
screened these patients out prior to transplantation.
Therefore, most liver transplant studies show a low
incidence of this condition. Alcoholic cardiomyopathy
occurs in patients with alcohol abuse, the majority of
whom do not have clinically evident cirrhosis. UrbanoMarquez et al.14 found that this type of cardiomyopathy
occurred commonly among actively drinking persons
with chronic alcoholism and that alcohol produced toxicity in cardiac muscle in a dose dependent manner.
Portopulmonary Hypertension and
Hepatopulmonary Syndrome
Portopulmonary hypertension (PPH) and hepatopulmonary syndrome (HPS) are pulmonary vascular
changes associated with chronic liver disease.15 HPS is
defined as the presence of the combination of advanced
liver disease, hypoxemia (PaO2 ⬍ 70 mm of Hg) or
alveolar-arterial oxygen gradient ⬎ 20 mm of Hg, and
pulmonary vascular dilatation.15 The reported prevalence of HPS varies widely, from 5% to 29%, and likely
because of the inconsistency of the defining criteria.16
Although initially a contraindication to liver transplantation, now liver transplantation is considered the treatment of choice for HPS, and reversal of HPS has been
described in both deceased donor transplant recipients
and living donor patients.17 The presence of HPS has a
major influence on survival in patients with cirrhosis,
especially in those with Child-Turcotte-Pugh class C.18
Mortality has been shown to be as high as 41% over a
2.5-year period.19 Data indicates a relationship between
the severity of hypoxemia and hospitalization mortality
posttransplant.15,20 – 22
The etiology of this syndrome remains unclear,
although it has been shown that endothelial-derived
nitric oxide synthase may play a critical role in its pathogenesis.23 – 26
PPH is defined as the presence of mean pulmonary
artery pressure (PAP) ⬎ 25 mm of Hg, pulmonary
vascular resistance ⬎ 120 dyne/cm – 5, and pulmonary
capillary wedge pressure ⬍ 15 mm of Hg in patients
with advanced liver disease.15 Management of patients
with PPH remains controversial. It appears that
patients with very high PAP (systolic PAP ⬎ 80 mm of
Hg) are at an increased risk from perioperative death.
Krowka et al.27 studied the relationship between cardiopulmonary-related mortality and untreated PPH in
43 patients who underwent OLT. Overall mortality
was 35%, with most of these deaths occurring because
of cardiopulmonary dysfunction. Cardiopulmonary
mortality was associated with a greater pretransplant
mean PAP, pulmonary vascular resistance, and
transpulmonary gradient. Mean PAP of 50 mm of Hg
or greater was associated with 100% mortality. No
mortality was reported in patients with a pre-OLT
OLT-Related Cardiac Morbidity and Mortality
mean PAP ⬍ 35 mm of Hg. This is supported by data
from Birmingham, England, which suggest that mild or
moderate PPH does not affect the outcome after OLT
and that even severe PPH is not an absolute contraindication to OLT,28 although the number of such
patients in their study was small and the issue remains
controversial. A recent paper describing the experience
of several centers confirmed that the primary reason for
denial of OLT was indeed the severity of PPH.15 The
authors felt that their data supported previous observations27 that mean PAP greater than 35 mm of Hg and
pulmonary vascular resistance greater than 250 dyne/s/
cm – 5 are associated with increased post-OLT cardiopulmonary mortality.
Although one would assume that PPH resolves after
OLT, and there have been cases in which this has been
described,29–34 there have also been cases in which PPH
did not resolve35–37 or even recurred after transplant.38,39
Hemochromatosis
Patients with hemochromatosis may present with overt
cardiac disease but may also develop cardiac failure postoperatively. A case report by Levine and Kindscher40 highlights the case of a patient with undiagnosed hemochromatosis who developed progressive cardiac problems and
died very soon after transplantation.
It is well documented that patients with hepatic iron
overload have worse 1-year survival than those undergoing transplantation for other conditions. A total of 37
patients from 5 U.S. liver transplant centers were identified,41 and their 1- and 5-year survival rates after OLT
were 58% and 40%, respectively, compared with 79%
and 65%, respectively, in liver transplant for all indications on the United Network for Organ Sharing Registry performed around the same period. A total of 22%
of deaths were due to cardiac causes. Cardiac disease
was the most common cause of death more than 1 year
after OLT, with 3 of 37 patients dying of myocardial
infarction. A further patient died of cardiac arrest in the
setting of renal failure. A study from San Francisco,
California,42 investigated 9 patients with hemochromatosis who had no detectable preexisting cardiac disease.
Only 2 patients were known to have the disease before
liver transplantation. Postoperatively, 3 of 9 patients
developed congestive heart failure and 4 patients had
arrhythmias. In the control group, only 3 of 18 patients
experienced posttransplantation cardiac complications.
Although the association of iron overload with
dilated cardiomyopathy and congestive heart failure43 is
well known, the association between iron overload and
atherosclerotic disease is much more controversial.43 – 47
1443
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is regarded as a
relative contraindication to OLT because the hemodynamic changes associated with liver transplantation
(e.g., decreased systemic vascular resistance, hypervolemia) exacerbate the hemodynamic disturbances of the
underlying cardiomyopathy. However, transesophageal
echocardiography (TEE) is ideal in demonstrating that
ventricular volumes are low despite high pulmonary
capillary wedge pressure, and Harley et al.48 report on 2
patients with HCM who underwent successful OLT
without complications using TEE as a guide to fluid
replacement.
Cardiac Evaluation of Patients Undergoing
OLT
A schema for the investigation of liver transplant recipients was devised by Plevak,49 who proposed dobutamine stress echocardiography in patients who have the
presence of a clinical predictor for CAD.
In general, 2-dimensional and contrast echocardiography are recommended to assess LV function, to estimate PAP, and to exclude intrapulmonary shunting,
although this is not routinely practiced by all centers
and its value in routine screening pretransplant has not
been established.
Patients with an impaired ejection fraction (EF)
should be referred for angiography, although the cutoff
EF is not known. Patients found to have PPH on echocardiography should undergo right heart catheterization to accurately measure pressures and to assess the
severity of PPH. Careful assessment of right ventricular
function is critical, but with current improvements in
surgical technique and anesthetic expertise as well as the
availability of epoprostenol, the presence of PPH
should no longer be considered an absolute contraindication to transplantation, although it still remains a
considerable challenge, especially if the PPH is moderate or severe.50
Intraoperative Considerations and
Complications
Preload
Maintaining the high cardiac output of liver transplant
recipients is essential to ensure adequate perfusion of
tissues. However, maintaining this high cardiac output
can only be accomplished by maintaining preload,
which may be difficult given that the operation itself is
associated with major changes in volume and afterload.51 Intraoperatively, cardiac output may be
decreased by reduced preload or impaired myocardial
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Therapondos et al.
contractility. Hemorrhage, third space losses, and
ongoing ascites production can cause hypovolemia.
The venous return can be further compromised by
clamping of the inferior vena cava. Conversely, aggressive fluid replacement can cause significant volume
overload.
Electrolyte Imbalance
Blood loss can be significant, and infusion of large
amount of fluids as well as blood products may potentially result in citrate toxicity. Citrate binds calcium,
which may cause ionized hypocalcemia and transient
myocardial dysfunction. It has been shown that
patients with end-stage liver disease develop acute ionic
hypocalcemia with concomitant hemodynamic depression as manifested by a reduced cardiac index, stroke
index, and LV work index,52 when receiving citrated
blood products during the course of hepatic transplantation.
Cardiac arrhythmias may be precipitated by electrolyte abnormalities such as hypomagnesemia, which has
been described as occurring invariably during OLT53
and has also been associated with hypokalemia and
hypocalcemia.54 Immediately before unclamping, the
donor liver is flushed to clear the potassium-rich conservative solution, air, and debris. The patient’s temperature decreases abruptly at the time of reperfusion
(approximately 0.9°C). If potassium contained in the
cold storage solution is not cleared immediately, an
acute rise in serum potassium may occur, with subsequent toxic effects.
The decrease in preload with cross-clamping of the
inferior vena cava may lead to reduced perfusion of
tissues above the diaphragm and even lower perfusion
of organs below the diaphragm due to venous congestion. The absence of normal hepatic function, the initially poor function of the newly grafted liver and the
low body temperature may further exacerbate acidemia
by greatly reducing the metabolism of citrate, lactate,
and other acids.
Other vasoactive substances released from hypoxic
tissues may also potentially cause depression in ventricular function, although data to support this are lacking.
Hypophosphatemia has been reported after hepatectomy in live liver donors,55 after major liver resection,56 and after fulminant liver failure.57 This may
have significant cardiac effects such as reversible cardiomyopathy and depressed vascular responses to
vasopressors.58 Cardiac complications such as acute
pulmonary edema have been reported in these
donors.55
Postreperfusion Syndrome
Hemodynamic instability can be severe during reperfusion of the graft. Postreperfusion syndrome (PRS) is
defined as a decrease in mean arterial pressure of at least
30% for 1 minute within the first 5 minutes after reperfusion and is accompanied by a decrease in heart rate.
PRS occurs in up to 30% of patients and may lead to
cardiac arrest. It is thought to arise because of a further
reduction of systemic vascular resistance, in addition to
myocardial depression,59 and may be exacerbated by
the loss of volume due to bleeding and mechanical
blood flow issues such as anastomotic problems.60
Aggarwal et al.61 studied the relationship between
hypotension and the reperfusion of the new graft in 69
patients. They observed that in the group of patients
who developed significant hypotension at reperfusion,
there was a significant decrease in systemic vascular
resistance. In most patients (not just the ones with
hypotension) cardiac filling pressures rose and cardiac
output at 5 minutes after reperfusion was decreased by
16%.
An ischemia and anoxic-induced hepatic failure
experimental rat model to study the effects of liver
injury on myocardial function showed that there was a
reduction in heart rate and coronary flow and an
increase in calculated coronary vascular resistance. This
metabolic profile is similar to that seen at reperfusion of
the new liver and can cause direct myocardial dysfunction of the isolated perfused rat heart.62 However, caution should be exercised when extrapolating these findings to humans. It is not known whether myocardial
depressant factors released from the graft at the time of
reperfusion contribute to cardiac depression, but it has
been suggested that LV function may be compromised
at that time. Despite this, the evidence from a study by
De La Morena et al.63 concluded that PRS was caused
by insufficient increase in preload and not by an alteration in LV dysfunction, although they did detect a
decrease in LV compliance in the group that had developed PRS. Right ventricular dysfunction, as demonstrated by the presence of a rise in central venous and
pulmonary pressures and embolization of air and
thrombi,64 has been suggested, but again, De Wolf et
al.65 failed to demonstrate this during uncomplicated
OLT using venovenous bypass. In summary, there is no
evidence from clinical studies in humans that myocardial ischemia occurs at reperfusion despite some animal
model data.
Other
Complications such as air embolism66 and thromboembolism67 have been described in cases when OLT took
OLT-Related Cardiac Morbidity and Mortality
place with intraoperative TEE monitoring. In general,
these studies are small and the true incidence of these
complications remains unknown.
Steltzer et al.68 identified regional contraction
abnormalities using 2-dimensional TEE during liver
transplantation. In addition, echogenic contrast indicative of air embolism was seen in all of their patients.
A number of case reports have documented intravascular and / or intracardiac thrombus formation during
the dissection or anhepatic phase of OLT.69,70 In particular, Gologorsky et al.67 describes pulmonary thromboembolism with subsequent right ventricular dysfunction in a report of 7 patients out of a total of 577 OLTs,
most of which had been monitored by TEE intraoperatively. It was hypothesized that this occurred because
of an excessive activation of the coagulation system
immediately after graft reperfusion.
In a large retrospective study of 146 patients by Dec
et al.,71 there were no intraoperative deaths and major
cardiovascular complications were uncommon. Ventricular tachycardia occurred in 3 patients, with an
additional 2 patients experiencing ventricular fibrillation. PRS occurred in 20% of patients requiring shortterm pressor support.
Early Postoperative Cardiac Complications
In this section, we describe the cardiac complications
that occur in the first 3 months after OLT. Several
systemic hemodynamic changes that occur in the postOLT period impose a major stress on the cardiovascular
system. Substantial increases in blood pressure72 – 74 and
peripheral vascular resistance have been documented
after OLT.74 This is likely to be caused by the restoration of normal liver function and portal pressure as well
as by the hypertensive side effects of calcineurin inhibition.
Cardiovascular complications immediately after
liver transplantation have been reported to be as high
70%.71 New dilated cardiomyopathy is reported in
3.4% of posttransplant patients,71 but has not been
fully characterized.
Johnston et al.75 reported that 48 out of the 110
patients in their series from Birmingham, England had
a 1st cardiovascular event within 3 months of transplant. In our prospective study, the incidence of cardiac
complications was 25%.76
Dec et al.71 conducted a retrospective review of the
records of all liver recipients in their center from 1983
to 1992. They studied 146 patients and described 4
cardiovascular deaths (1 from previously unrecognized
severe pulmonary hypertension, 1 from hypoxemia due
to intrapulmonary shunting, and 2 unexplained). In a
1445
study from Berlin, Germany,77 of 546 adult liver transplant recipients, reintubation after OLT was performed
for cardiac reasons in 9.1% of patients.
Pulmonary Edema
Pulmonary edema that is commonly seen postoperatively may be multifactorial and secondary to significant
transfusion requirements, increased capillary permeability, and prolonged intubation. Atrial arrhythmias
may be due to volume overload, anemia, and fever.
Snowden et al.78 identified a high incidence of postoperative radiological pulmonary edema (47%) that
was associated with deterioration in gaseous exchange,
elevated PAP, increased duration of ventilator dependence, and increased intensive care stay. A total of 18%
of patients developed edema immediately after surgery
and an additional 29% developed edema during the
next 16 – 20 hours. There was no association with fluid
replacement or an increased incidence of postoperative
pleural effusions. Although there was a greater number
of patients with more severe liver disease in the group
that developed pulmonary edema, there were no statistically significant differences between the physical characteristics and liver disease severity of the patients who
developed pulmonary edema and the patients who did
not.
Plevak et al.79 showed that 22% of liver transplant
recipients had noninfective pulmonary infiltrates either
at initial or subsequent intensive care unit admissions.
Donovan et al.12 found that out of 71 transplant
patients there were 39 patients (56%) with pulmonary
edema, all of whom required diuretics. One patient had
a myocardial infarction, 4 patients had acute LV dysfunction, and 10 patients (14%) had an arrhythmia
(mostly atrial).
Dec et al.71 described pulmonary edema that was
common but tended to be short lived and usually
resolved in the first 72 hours. Unlike these series, a
study of 176 pediatric liver transplants from Madrid,
Spain,80 described infrequent pulmonary edema (7
cases); this may reflect the differences in the preoperative hemodynamic status of this patient population
compared with an adult group.
Dilated Cardiomyopathy
A group from the Mayo Clinic81 reviewed the records of
754 patients undergoing liver transplantation and identified 7 patients who developed a reversible dilated cardiomyopathy in the first 5 days posttransplant. This was
associated with pulmonary edema and it was felt to be
unexplained, but it clearly documented myocardial dys-
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Therapondos et al.
function with a median LV EF of 20%. The median age
of the group was 37 years and none of these patients had
any significant intraoperative cardiac events or a cardiac
history. A total of 6 of the 7 patients had normal LV
function preoperatively with a median EF of 60%; 6 of
the 7 patients had complete clinical and echocardiographic resolution of heart failure. Subsequent follow-up for a median duration of 15 months showed no
recurrence of clinical failure and a stable ejection fraction. Only 1 patient died of cardiac causes.
Thromboembolism
A single study by Sankey et al.82 identified massive
pulmonary platelet thromboembolism as a common
cause of sudden perioperative death following liver
transplantation, by studying necropsy tissues from
patients who died within 10 days after OLT. Whether
this has wider implications is unknown.
Myocardial Infarction
Myocardial infarction is a relatively rare phenomenon,
presumably because of the efforts made during the preoperative cardiac evaluation of patients to detect CAD.
Dec et al.71 detected myocardial ischemic events in 5%
of patients in their series, although cardiovascular mortality was less than 3%.
Despite this evidence and the preoperative screening, Rubin et al.83 found a higher incidence of ischemic
electrocardiography changes (T-wave or ST-wave
changes) with symptoms in a group of 45 consecutive
patients undergoing OLT (6 / 45; 13%) than in a group
of patients undergoing major intraabdominal surgery
(1 / 28; 4%). The transplant patients were younger than
the patients in the comparison group, but there was no
difference in gender.
Cardiac Function After Liver Transplantation
Several human studies found a persistence of the
increased cardiac output84 – 86 of cirrhosis for up to 2
years post-OLT,85 while others reported a complete
recovery.87,88 An echocardiographic study by Park et
al.88 showed a reduction in the cardiac index by 35% at
1 – 13 months after OLT. A prospective trial of 28
patients,89 followed-up for a mean period of 17
months, showed that systemic, renal, and most splanchnic circulatory alterations were restored to normal, with
blood pressure greatly increased, which is likely to be
due to the restoration of normal liver function as well as
a side effect of calcineurin treatment.
An increase in circulating endothelin in the early
postoperative period90 has been proposed as one of the
mechanisms by which these changes may occur, and the
resultant increase in afterload could be responsible for
heart failure seen in these patients. With time, there
may be adaptation to the increased afterload and hence
improvement in cardiac function. Changes in levels of
vasoactive intestinal peptide, calcitonin gene-related
peptide,91 and endotoxin92 have also been proposed to
have a similar role in the altered hemodynamic changes
during and after liver transplantation.
At present, there is no reliable method to identify
patients susceptible to cardiac complications. However,
in our prospective study of 40 liver transplant recipients, we identified raised preoperative serum brain
natriuretic peptide levels as a predictor of cardiac failure
in the early posttransplantation period.76
Two echocardiographic studies evaluated cardiac
function after liver transplantation. Acosta et al.93 demonstrated that 21 months after OLT, 20% of patients
had altered systolic or diastolic ventricular function.
Although none of the patients presented with an EF ⬍
50%, and EF remained within normal limits, the number of patients with an EF ⬍ 60% increased. There
were no significant differences between patients with
and without alcoholic etiology. The authors comment
that despite an abnormal EF, these patients did not have
cardiac symptoms. There was a significant decrease in
diastolic function, with mean values at the lower limits
of normality and an increase in the number of patients
with abnormal values. Our prospective study confirmed
a deterioration of diastolic cardiac function 3 months
after OLT, although again, this was not associated with
symptoms of cardiac failure.76
Sampathkumar et al.81 hypothesized that cirrhotic
cardiomyopathy may be reversible after OLT, because
the 7 patients in their series who developed postoperative myocardial depression all recovered. This potential
for reversibility is also suggested by the correction of
prolonged QT intervals after OLT.94
Donovan et al.12 identified 4 patients who developed global LV dysfunction (EF ⫽ 20%) within the 1st
postoperative week. All these patients had normal preoperative LV function, and 3 of the 4 patients had a
history of alcoholic liver disease.
Nasraway et al.95 studied a group of 96 liver transplant recipients between 1984 and 1992, and recorded
hemodynamic and oxygen transport variables during
the first 2 postoperative days. The mortality of this
study was 15%, with the most common cause of death
being multiorgan failure (36%). Cardiovascular failure
was seen in 21.4%. The decrease in cardiac function
seen in nonsurvivors was most marked during the first
12 postoperative hours, and survivors were character-
OLT-Related Cardiac Morbidity and Mortality
ized by higher levels of mean arterial pressure, systemic
vascular resistance, LV stroke work index, cardiac
index, and oxygen delivery when compared with nonsurvivors in both preoperative and postoperative periods. The decrease in systemic blood flow following
transplantation was mainly attributable to a decrease in
ventricular function, as reflected by decreases in stroke
output and work. These findings indicate that nonsurvivors of OLT experience early postoperative cardiac
failure relative to survivors. This finding does not seem
to be exclusive to OLT patients, because Shoemaker et
al.96 made a similar observation in a study of 708 highrisk surgical patients.
The reduced cardiac performance in the nonsurvivors could neither be explained by inadequate preload
nor by excessive afterload and, therefore, the only plausible explanation remains an intrinsic depression of
myocardial contractility. Moreover, the fact that the
cardiac index was reduced in nonsurvivors as compared
with survivors, both preoperatively, suggests that nonsurvivors may have had less pretransplant cardiac
reserve.
A reduction in the postoperative ventricular function in OLT patients may also be explained by the fact
that during OLT an inflammatory response develops,
which is accompanied by the release of circulating
mediators such endotoxin and tumor necrosis factor–␣;
both of these mediators have been implicated as myocardial depressants during acute illness.97 – 101
Long-Term Cardiovascular Risk
In contrast to the early postoperative cardiac complications of OLT, which are mostly due to the hemodynamic and / or cardiac status of patients with cirrhosis
and the hemodynamic changes seen after transplant,
the long-term cardiac risks are almost entirely due to
CAD. However, in contrast to renal transplant recipients, the incidence of atherosclerotic cardiovascular disease complications after OLT has been reported not to
be statistically different than in the age- and gendermatched general population,102,103 although hypertension and diabetes were more frequent.103 In contrast to
these data, Johnston et al.104 calculated that the relative
risk of ischemic cardiac events was 3.07, with the relative risk of cardiac death at 2.56 when compared with
an age- and gender-matched population without transplants. Patients with evidence of heart disease had been
excluded from the transplant waiting list and this group
of patients did not include smokers. They found that
moderate hypertension and hyperlipidemia were more
detrimental in patients after OLT compared with nontransplant patients, and recommended that close atten-
1447
tion to modifying these risk factors should be paid in
this population.
In an analysis of the 1st year posttransplant of the
first 215 adult OLTs in the University of Toronto
(1985 – 1991), there were 3 deaths from cardiovascular
causes (1.4% of patients),105 but others have shown that
14% of late deaths (more than 1 year) post-OLT are
due to cardiovascular causes.106
Long-term cardiovascular mortality in 1 series was
2.6%,107 which was similar to a study by Pruthi et al.,108
who identified 8 patients who had cardiovascular deaths
in a group of 299 patients (2.6%) who had survived
more than 3 years after OLT. However, this represented 21% of all deaths in this group, which is similar
to Neuberger,109 who identified cardiovascular death as
the most common cause of death (22%) in 617 adult
liver patients 5 or more years after OLT. Again, similar
figures were obtained by Rabkin et al.,110 who included
all patients who survived for longer than 1 year after
transplantation and showed that cardiovascular mortality was less than 1%.
Despite the lack of conclusive evidence for increased
long-term risk of cardiovascular disease in liver transplant recipients, it is common sense to assume that the
longer these patients survive, the higher the prevalence
of clinically significant cardiovascular disease will be.
Liver graft recipients are at an increased risk from
hypercholesterolemia, hypertension, and diabetes.
Hypercholesterolemia has been reported to be prevalent
in 31% – 46% of patients after 1 – 3.5 years following
transplantation. Other factors that may contribute to
an increased risk of cardiovascular disease in the longterm include early postoperative complications such as
hypotension, myocardial infarction, pulmonary embolism, and arrhythmias. Dec et al.71 reported that survival at 5 years was reduced in those patients who had
cardiac events in their early posttransplantation course.
In summary, cardiac death is relatively uncommon
in long-term liver transplant patients, but it is one of the
most important causes of mortality.
Cardiac Toxicity Associated With
Immunosuppression
Tacrolimus and Hypertrophic Cardiomyopathy
Whittington et al.,111 in a review of pediatric liver transplantation, described 2 patients who developed congestive heart failure on tacrolimus, which resolved after
discontinuation of the drug. This is the first report of
tacrolimus cardiotoxicity, but the issue became much
more widely appreciated after the publication by Atkison et al.112 of the first description of the development
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Therapondos et al.
of hypertrophic cardiomyopathy associated with
tacrolimus treatment in 5 pediatric patients who underwent liver transplantation or liver and small bowel
transplantation. These changes were noted mainly as a
result of routine 2-dimensional echocardiography
within 2 months of the initiation of tacrolimus therapy
and only 2 of these patients were symptomatic. Tacrolimus concentrations in these patients were relatively
high (between 11.5 and 30.6 ng/mL). These cardiac
changes resolved with either discontinuation of the
tacrolimus or when drug trough levels were kept low.
A number of similar case reports describing cardiac
hypertrophy associated with tacrolimus treatment followed.113 – 115 These reports described both symptomatic patients but also described unexpected postmortem
findings. Their findings tended to involve patients in
the first few months after OLT, apart from the report by
Pappas et al.,115 who described 3 pediatric transplant
recipients (2 liver, 1 liver and small bowel) that developed significant cardiomyopathy 15, 96, and 60
months after their second transplant. Tacrolimus dose
reduction and beta-blockers failed to alleviate the cardiomyopathy in these patients; therefore, the patients
were changed to sirolimus, which resulted in an
improvement in their echocardiographic parameters.
The issue still remains controversial and most of the
available evidence comes from retrospective series and
case reports. To date, there has only been 1 prospective
randomized study investigating this issue. Therapondos
et al.76 noted that the tacrolimus group had a more
unfavorable cardiac profile than the cyclosporine
group. Brain natriuretic peptide, which was used as a
serum marker of cardiac failure, and indices of cardiac
dysfunction such as heart rate variability were worse in
the tacrolimus group post-op. It was hypothesized that
perhaps tacrolimus does have a more adverse cardiac
profile, although clinical events are relatively rare. Prior
to this study, our group sought evidence of cardiotoxicity in our adult patients treated with tacrolimus.116 A
total of 12 patients were studied and we found a variety
of abnormalities on 2-dimensional echocardiography.
Out of 4 patients with abnormal postoperative echocardiograms, only 1 patient developed an unexplained cardiomyopathy after a prolonged intensive care unit
admission with prolonged sepsis. She was the only one
of our patients to have received intravenous tacrolimus
and she gradually improved on cyclosporine, which had
actually been started because of tacrolimus-associated
leukopenia. Cardiotoxicity following intravenous
tacrolimus has also been described by Cox et al.117 who
identified sinus bradycardia in a 15-year-old orthotopic
liver transplant recipient.
Nakata et al.118 studied 32 patients who underwent
living related donor liver transplantation. A total of 13
of the 32 patients (50.6%) showed LV hypertrophy
within the first 2 weeks, and they demonstrated that
tacrolimus blood levels above 15 ng/mL were associated
with LV wall thickening. It is important to note, however, that no patients showed clinically significant cardiac hypertrophy and that LV thickness returned to
normal by week 4 after OLT.118 Chang et al.119 compared a small number of pediatric liver transplant recipients on tacrolimus with patients on cyclosporine and
found HCM only in tacrolimus patients.
Other studies, however, did not find evidence that
tacrolimus was more likely to cause HCM than cyclosporine. In a large retrospective study from Pittsburgh,120 the authors attempted to determine the prevalence of HCM in adult transplant recipients. They
investigated nonheart transplant recipients who
received tacrolimus and found that the overall prevalence of HCM was 0.1% in the entire group of tacrolimus-treated patients, and they concluded that the prevalence of HCM in the tacrolimus-treated adult
transplant population is similar to that reported in general population studies. Khanna et al.121 examined cardiac findings at autopsy in adults and children following liver transplantation and tacrolimus therapy and
compared their findings with autopsy findings in
patients who died of end-stage liver disease without
liver transplantation. The mean weight of the heart in
both groups was comparable, but was higher than in the
normal population. This study confirmed the findings
of the echocardiographic study by Park et al.,88 and they
concluded that LV hypertrophy was associated with the
hemodynamic changes seen in cirrhosis rather than
tacrolimus treatment. Roberts et al.,122 from the University of Nebraska, reviewed autopsy hearts from 19
patients who had received tacrolimus for minimum of 1
week prior to death following OLT and compared them
with hearts from patients who had received cyclosporine and with a non-OLT control group. They identified
that cardiomegaly with preferential septal hypertrophy
was common at autopsy in both adult and pediatric
liver transplant patients but did not identify tacrolimus
as more likely to cause it than cyclosporine.
Cyclosporine
Although most reports describe tacrolimus-associated
cardiomyopathy, there is a report from Mead et al.123
(in abstract form only), describing 2 pediatric liver
transplant recipients (ages 3 and 9 months) who developed cardiomyopathy while receiving cyclosporine
microemulsion (Neoral). A change to a different cyclosporine formulation resulted in resolution of the cardio-
OLT-Related Cardiac Morbidity and Mortality
myopathy. In addition to this, a study to assess the
incidence of myocardial hypertrophy in patients after
unrelated donor bone marrow transplantation found
that changes in the LV mass index were greater with
cyclosporine therapy than with tacrolimus therapy
(56% vs. 20%) although this was not associated with
any significant clinical events.124
Corticosteroids
It may be important to note that all the patients
described in these reports were treated with corticosteroids in the early stages post – liver transplantation.
Brand et al.125 from the Netherlands described 3 premature infants who developed hypertrophic cardiomyopathy during high-dose dexamethasone treatment for
bronchopulmonary dysplasia, and these authors postulated that immunomodulating mechanisms may be
involved in the pathogenesis of this disorder.
Pediatric heart transplant recipients are routinely
followed by echocardiography to assess the function
and development of the transplanted heart. A study by
Scott et al.113 demonstrated that on average an
implanted heart is thicker than normal with decreased
end diastolic volume. However, they found no significant difference in the degree of cardiac hypertrophy
between the tacrolimus and the cyclosporine-treated
groups. They postulated that the observed cardiac
hypertrophy may have been due to the effects of steroids, which have already been demonstrated to have
that affect in this age group.126
Long-Term Cardiovascular Risk Associated
With Immunosuppression
An evaluation of cardiovascular risk after liver transplantation at 1 year post-OLT found that tacrolimus
was associated with a less adverse cardiovascular risk
profile than cyclosporine.127 Similar findings were
reported by another group,128 who investigated the
3-year post – liver transplant incidence of hypertension,
hyperlipidemia, diabetes mellitus, and cardiovascular
disease in 2 cohorts of liver transplant recipients who
received either tacrolimus or cyclosporine. At 3 years
after OLT, 18% of patients had evidence of cardiovascular disease in the cyclosporine group, compared with
0% in the tacrolimus group.
In summary, although tacrolimus may be associated
with relatively rare occurrences of HCM and cardiac
failure in the first few months post-OLT, it appears that
in the longer term, it may have a less adverse cardiovascular risk profile.
1449
Other Immunosuppressive Agents
Mycophenolate mofetil has been used in liver transplantation as a calcineurin inhibitor-sparing agent,
especially in cases of renal impairment.129 Data indicate
that the incidence of hypertension decreases after the
introduction of mycophenolate mofetil with a potential
improvement in cardiovascular risk profile.130
Sirolimus (Rapammune) has been reported to be
associated with pleural and pericardial effusions in a
small number of patients post-OLT. In addition, there
are concerns regarding a high rate of lipid disorders.
The University of Miami experience showed a 55.2%
rate of dyslipidemia, with most of these patients requiring drug therapy.131 Although peripheral edema is common with sirolimus therapy, it is thought that this is
due to a capillary leak mechanism rather than cardiac
toxicity.132
Infections
Transplant recipients are susceptible to unusual opportunistic infections. Cytomegalovirus infection has been
reported as a cause of myocarditis, which led to biventricular failure, which was remedied by ganciclovir
treatment.133 Purulent pericarditis due to Legionella
pneumophila134 and infective endocarditis have also
been described.135
Chagas disease (infection with Trypanosoma cruzi),
which can lead to cardiomyopathy, is a potential problem in organ recipients. Transmission from donor to
recipient has been reported in Latin America, but only
in renal transplant patients.136 There has been only 1
report of such transmission in the United States for a
liver transplant recipient, who died of multiorgan failure unrelated to T. cruzi infection;137 therefore, it
appears that the real risk to most liver recipients is
exceedingly small.
Summary
Liver transplantation imposes stresses on the cardiovascular system of patients with liver disease. The underlying
hemodynamic and cardiac status of patents with cirrhosis
is important in determining which patients will cope with
this stress. Minor intraoperative morbidity and early cardiac complications are relatively common and may have
an impact on longer-term cardiac problems. Major cardiac
events do occur perioperatively and in the early postoperative period, but are much less common in these time
periods. Calcineurin inhibitors and corticosteroids may
cause short-term complications and certainly have a longer-term adverse cardiac risk profile. The true magnitude of
1450
Therapondos et al.
the potential long-term cardiac problems that could face
liver transplant recipients may not yet be fully appreciated;
our efforts should currently be directed at modifying the
known cardiovascular risk factors affecting these patients.
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