Cardiac morbidity and mortality related to orthotopic liver transplantation
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.)
Most 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 postoperative complications and the cardiac complications of immunosuppression, as well as longer-term cardiac problems.
Preoperative Cardiac Status and Conditions Predisposing to Cardiac Complications
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
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
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. Urbano-Marquez 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 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
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
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
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 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.
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
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.
Complications such as air embolism66 and thromboembolism67 have been described in cases when OLT took 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 short-term 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 post-OLT 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 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 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.
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 dysfunction 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.
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 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 characterized 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 high-risk 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–α; 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 gender-matched 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 attention 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 long-term 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 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.
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 cardiomyopathy. 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
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.
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
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.
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 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.