Download Predicting cardiovascular complications after liver transplantation

LIVER TRANSPLANTATION 17:7-9, 2011
EDITORIAL
Predicting Cardiovascular Complications After
Liver Transplantation: 007 to the Rescue?
Hongqun Liu and Samuel S. Lee
Liver Unit, University of Calgary, Calgary, Canada
Received October 19, 2010; accepted November 5, 2010.
See Article on Page 23
Recipients of orthotopic liver transplantation (OLT) are
at increased risk of developing cardiovascular complications.1 Indeed, such complications occur in 25% to
70% of patients after OLT.2 For example, radiographic
evidence of pulmonary edema is observed in 22% to
56% of transplant recipients during the first postoperative month.2 Moreover, mortality associated with
cardiac causes accounts for up to 7% of deaths in the
early- to medium-term posttransplant period.2 In some
centers, all cardiovascular events are the third-leading
cause of death after infection and rejection. Most liver
transplant recipients have advanced cirrhosis. Such
patients’ cardiovascular status before transplantation
is generally abnormal, so they may respond poorly to
the stress of transplantation. Moreover, as a result of
immunosuppressive drug therapy or other reasons,
several cardiovascular risk factors, including hypertension, diabetes, hyperlipidemia, and obesity, are prevalent in OLT recipients.1
Because of this situation, the ability to predict which
individuals will develop cardiovascular events during
and after liver transplantation is hugely important in
the patient selection process. Transplant candidates
undergo a rigorous pretransplant workup that includes
a careful cardiovascular history and investigations such
as standard or dobutamine stress echocardiography,
nuclear heart scans, and even coronary angiography if
there is any lingering doubt about the presence of atherosclerotic coronary artery disease (CAD). Despite all
this, every transplant center sees significant morbidity
and mortality from cardiovascular complications in
transplant recipients, including some with a puzzling,
inexplicably severe event such as myocardial infarction
or heart failure in the absence of any known predisposing risk factor or background.
Cardiovascular events after transplantation can be
broadly categorized into 4 major areas: CAD, peripheral
vascular disease (particularly stroke), heart failure, and
arrhythmia. Some of the heterogeneity in the literature is
easily explained by the variable inclusion of these complications. More recently, at least some of the previously
unexplained cases of heart failure after transplantation
have been suspected to be due to a syndrome known as
cirrhotic cardiomyopathy.3 In the future, consensus definitions of exactly what constitutes cardiovascular complications [including subdivisions into cardiac, coronary
vascular, and peripheral vascular complications (stroke)]
would vastly decrease the heterogeneity of results and
thus allow significant progress in the field.
Liver transplantation stresses the cardiovascular
system,4,5 and limited cardiac reserve preoperatively
may be associated with poor outcomes postoperatively.6 Several previous studies have examined predictive factors for cardiovascular events in OLT recipients. Dec and colleagues7 found that cardiovascular
complications occurred in more than 70% of liver
transplant recipients. A multivariate analysis showed
that preexisting cardiac disease and older age at
transplantation were the only independent predictors
of a major complication. A recent study8 focused on
the development of CAD events in the perioperative
period (defined as up to 30 days after transplantation)
and found that a history of stroke, CAD, postoperative
sepsis, and increased interventricular septal thickness were markers of poor perioperative cardiac
Abbreviations: CAC, coronary artery calcium; CAD, coronary artery disease; MELD, Model for End-Stage Liver Disease; OLT,
orthotopic liver transplantation; SPECT, single-photon emission computed tomography.
Address reprint requests to Samuel S. Lee, M.D., Liver Unit, University of Calgary, 3330 Hospital Drive Northwest, Calgary, AB T2N 4N1,
Canada. Telephone: þ1-403-220-8457; FAX: þ1-403-270-0995; E-mail: [email protected]
DOI 10.1002/lt.22224
View this article online at wileyonlinelibrary.com.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2011 American Association for the Study of Liver Diseases.
V
8 LIU AND LEE
outcomes. Perioperative beta-blocker usage was significantly protective.
Our recent retrospective study9 included 197
patients who underwent OLT; 82 of these patients
(42%) suffered 1 or more cardiovascular complications during the first 6 postoperative months. Radiographically or clinically evident pulmonary edema was
the commonest complication. After adjustments for
age and sex, a multivariate analysis indicated that the
independent predictors of cardiovascular complications were an intraoperative cardiovascular event, a
preoperative history of cardiac disease or hypertension, and the integrated Model for End-Stage Liver
Disease (MELD) score (the MELD score plus adjustments for age and serum sodium). Neither the original
MELD score nor the MELD score adjusted for serum
sodium was an independent predictor of cardiovascular complications.
There continues to be great interest in finding a preoperative cardiovascular or imaging test that provides
accurate predictive ability for postoperative cardiovascular events. Using coronary angiography as a goldstandard test, Davidson and coworkers10 evaluated
single-photon
emission
computed
tomography
(SPECT) scanning. They found that the sensitivity of
SPECT imaging was only 37%, and the specificity was
63%. The positive predictive value was only 22%, and
the negative predictive value was 77%. It is, therefore,
clear that SPECT scanning is unreliable as a predictive test for OLT patients.
The transplantation guidelines of the American
Association for the Study of Liver Diseases recommend an evaluation for CAD if liver transplant candidates are more than 50 years old, are diabetic, are
chronic smokers, or have a clinical or family history
of heart disease.11 Those guidelines recommend dobutamine stress echocardiography. However, the performance characteristics of that test are not well
established in this population. A positive result with
dobutamine stress echocardiography should be confirmed with cardiac catheterization.
Some investigators have used different combinations to create evaluation systems. The combinations
include donor age, recipient age, creatinine, bilirubin,
prothrombin time, ischemia time, and so forth.12,13
These scoring systems are based mostly on MELD
variables. There is a correlation between the degree of
liver failure and the extent of cardiovascular abnormalities (particularly cirrhotic cardiomyopathy and
hyperdynamic circulation). Therefore, MELD components may predict cardiovascular events after liver
transplantation. However, some of the components
reported by Brandao et al.13 in these scoring systems
rely on postoperative data that are typically unavailable before transplantation; this limits their usefulness. Other shortcomings of previous studies of the
prediction of cardiovascular complications include
their retrospective nature, insufficient sample sizes,
and single-center design as well as the fact that some
are now more than 15 years old, so newer management/diagnostic modalities were not used.
LIVER TRANSPLANTATION, January 2011
It is obvious that patients with overt evidence of
heart disease are easily identified during the pretransplant selection process. However, because of the
marked peripheral vasodilatation of end-stage cirrhosis that autotreats a potentially latent heart failure,
cardiac abnormalities in patients with cirrhosis are
usually subclinical. Patients with subclinical or
asymptomatic heart disease create the greatest challenge in pretransplant risk stratification. A simple and
reliable marker for identifying such patients has been
unavailable until now.
In popular movie culture, many world-threatening
problems have been resolved by James Bond, Agent
007. In a case of life imitating art, this number (0.07)
is coincidentally the exact demarcation point of abnormality (in nanograms per milliliter) of the troponin
I assay used by Coss et al.14 in their study published
in this issue of Liver Transplantation. A multivariate
analysis of 230 transplant recipients showed that an
abnormal pretransplant troponin I level (>0.07 ng/
mL) was 1 of only 4 factors predicting postoperative
cardiovascular complications up to 8 years after
transplantation. The other 3 factors were a previous
cardiovascular history, smoking, and pretransplant
diabetes. These 3 factors have been previously
described in some studies, but the troponin I result is
novel. Pretransplant troponin I levels were increased
in approximately one-quarter of their patients and
correlated with markers of cardiac dysfunction/disease, such as left ventricular wall thickness and a low
ejection fraction.
Table 3 in Coss et al.’s article14 details the 7
patients who suffered perioperative cardiovascular
events. In this group, 2 cases illustrated the aforementioned unpredictable and often inexplicable
occurrence of cardiovascular events and the potential
utility of troponin I. A 19-year-old woman with only
diabetes as a risk factor but no smoking or cardiovascular history and a normal echocardiogram inexplicably developed congestive heart failure. A 43-year-old
woman with a smoking history but no other risk factor and again a normal echocardiogram suffered fatal
cardiac arrest. For both, elevated troponin I levels
were the only clue to underlying cardiac dysfunction
or disease.
Why should an abnormal troponin I value predict
cardiovascular outcomes after transplantation? Both
troponin I and T isoforms are elaborated by cardiomyocytes in response to conditions that injure or
severely stress the heart, such as ischemia, ventricular dilatation or failure, cardiomyopathy, and inflammation.15 In contrast to the troponin T isoform, the I
isoform is not dependent on glomerular filtration for
elimination and is thus unaffected by renal dysfunction. In Coss et al.’s study,14 neither troponin T nor
other serum markers of inflammation such as C-reactive protein showed any predictive value. On the other
hand, troponin I as a marker perhaps of cirrhotic cardiomyopathy may somehow indicate latent cardiac
dysfunction that is not recognized by conventional
screening methods.
LIVER TRANSPLANTATION, Vol. 17, No. 1, 2011
The limitations of this study, as the authors noted,
are its retrospective nature and relatively small number of patients. The latter means a risk of a type 2
error; other studies have demonstrated that MELD
scores and renal dysfunction are associated with cardiac complications after OLT.9,12,13 Another limitation
is that the authors did not calculate the sensitivity,
specificity, positive predictive value, or negative predictive value of the troponin I level. Finally, it might
have been interesting to determine if other serum
markers of cardiac distress or dysfunction, such as Btype or brain natriuretic peptide and pro-brain natriuretic peptide, are similarly predictive.
The cardiac calcium score, also called the coronary
artery calcium (CAC) score, uses computerized tomography to measure the buildup of calcium in the arterial wall plaque. CAC scoring has been most thoroughly evaluated in asymptomatic patients with an
intermediate risk of major adverse cardiovascular
events as predicted by the Framingham risk score. In
this population, the annual risk of CAD death or myocardial infarction is 0.4% with a CAC score of 0 to 99,
1.3% with a CAC score of 100 to 399, and 2.4% with
a CAC score higher than 399.16 The relative risk of all
coronary disease events is 1.9 with a CAC score of 1
to 99, 10.2 with a CAC score of 100 to 399, and 26.2
with a CAC score higher than 399.17 This diagnostic
modality merits examination in candidates for liver
transplantation.
Overall, the ability to identify patients at the highest
risk of death after liver transplantation has been
improved over the last several years. However, our
predictive ability remains relatively weak, so studies
such as this one will help tremendously. Because cardiovascular events are often fatal, using a simple
marker such as serum troponin I, if it is proven to be
valid in larger prospective studies, will help us to better identify and select patients who will do well after
transplantation. Better prediction and recipient selection will thus ultimately reduce mortality so that these
patients, like Agent 007, can ‘‘die another day.’’
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