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326 19. Cardiovascular assessment before liver transplantation
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CHAPTER
20
Predicting cardiovascular complications after
liver transplantation
Harini Gurram
1,
*, Jennifer Jo
1,
* and Lisa B. VanWagner
1,2
1
Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of
Medicine, Chicago, IL, United States
2
Department of Preventive Medicine, Division of Epidemiology, Northwestern
University Feinberg School of Medicine, Chicago, IL, United States
Introduction
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality after liver transplantation (LT)
[14]. In the current transplant era, surgical techniques and infection prevention have improved while the popu-
lation of patients listed for LT is older, more frail, and have a higher critical illness burden
[5]. This may be why
CVD has overtaken infection and allograft failure as the most common etiology of early mortality after LT
(
Fig. 20.1) [3]. Accurate risk estimation of cardiovascular complications following LT is paramount to guide allo-
cation of limited donor organs and to maximize the survival benefit of transplant recipients. This chapter will
discuss the epidemiology of cardiovascular complications after liver transplant, the natural history of CVD in LT
recipients, and the tools for assessing cardiovascular risk in liver transplant candidates.
Epidemiology and established risk factors for cardiovascular complications in liver transplantation
CVD encompasses the diagnoses of coronary heart disease (CHD), stroke, heart failure (HF), peripheral vascu-
lar disease (PVD), arrhythmias, and valvular heart disease (VHD)
[6]. The prevalence of CVD complications after
LT is actually increasing and up to 30% of liver transplant recipients will have a CVD complication within 1 year
of LT
[3,5,7]. Additionally, CVD is the leading cause of early morality after LT with an estimated 30-day mortal-
ity rate of 1.2%
[3,7]. In comparison, the 30-day mortality rates of other intra-abdominal sur geries such as laparo-
scopic cholecystectomy and Whipple are 0.2% and 0.3%, respectively
[3]. Major adverse cardiovascular events
(MACE) occur in about 10% of inpatient admissions within 90 days after LT, and the majority of these are non-
coronary events including atrial fibrillation (AF), HF, thromboembolism, and stroke
[4]. The natural history of
these events will be discussed later in the chapter (
Fig. 20.3).
The development of CVD in LT recipients is affected by both modifiable and nonmodifiable risk factors
(
Table 20.1). Nonmodifiable risk factors that contribute to the development of CVD include male sex, older age,
family history, and black race
[8]. Modifiable risk factors incl ude elevated blood pressure, diabetes, obesity, dysli-
pidemia, and smoking. End-stage liver disease (ESLD) introduces additional risk factors that also lead to the
development of CVD. As the liver plays a critical part in lipid and glucose homeostasis, liver dysfunction can
lead to the development of accelerated atherosclerosis and CVD
[9,10]. A study by Keeling et al. found that the
prevalence of coronary artery disease (CAD) in asymptomatic ESLD patients was much higher than expected;
* Authors Harini Gurram and Jennifer Jo contributed equally to this chapter.
327
Cardio-Hepatology.
DOI:
https://doi.org/10.1016/B978-0-12-817394-7.00002-4 © 2023 Elsevier Inc. All rights reserved.
https://t.me/medicina_free
only 9.2% of patients had normal coronary arteries and 33.8% had greater than 50% stenosis of the coronary
arteries
[11].
The confluence of traditional cardiac risk factors and liver specific risk factors is well demonstrated in nonalco-
holic steatohepatitis (NASH). NASH is an obesity related condition associated with metabolic syndrome and is
the most common indication for liver transplant in women, and the second most common indication overall, and
leading indication among women, in the United States
[12,13]. The proposed pathophysiology between NASH
and the development of CVD is multifactorial and multidirectional with significant overlap of risk factors
[14].
The exact mechanisms are unknown, but the systemic inflamm ation associated with nonalcoholic fatty liver dis-
ease (NAFLD) leads to endothelial dysfunction, angiogenesis associated with plaque formation and vulnerability,
hypercoagulability, and a proatherogenic lipid profile all of which may lead to subclinical myocardial dysfunc-
tion, coronary artery calcification, and increased thrombosis which contribute to the development of CVD
(
Fig. 20.2) [1518].
Another potentially nonmodifiable cardiovascular risk factor unique to ESLD is cirrhotic cardiomyopathy
(CCM). CCM is a clinical syndrome seen in 40%50% of patients with ESLD and is characterized by increased
cardiac output and reduced ventricular response to stress in the absence of other known cardiac disease
[19].
CCM is discussed in detail below, but notably presence of CCM pretransplant increases risk significantly for
TABLE 20.1 Risk factors for cardiovascular disease events.
Nonmodifiable risk factors Modifiable risk factors Liver transplant specific risk factors
Male sex Obesity Donation after cardiac death
Age . 55 Diabetes mellitus Cold ischemia time
Family history of cardiovascular disease Elevated blood pressure MELD score
Black race Dyslipidemia Higher BMI of donor
Cirrhotic cardiomyopathy Smoking
Coronary artery disease burden
NASH cirrhosis
FIGURE 20.1 Causes of early (30 day) mortality after liver transplantation. CVD, cardiovascular disease; OPTN, organ procurement and
transplantation network. Source: Adapted from VanWagner LB, et al. High early cardiovascular mortality after liver transplantation. Liver Transpl.
2014;20(11):13061316.
328 20. Predicting cardiovascular complications after liver transplantation
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CVD events in the perioperative and postoperative period [20]. While there is evidence that LT can reverse CCM,
the blunted cardiac response characteristic of CCM may be unmasked by perioperative and intraoperative stres-
sors (i.e., clamping the hepatic vein, infusion of fluids) and may precipitate clinical HF
[2123].
LT introduces several risk factors that also increase the likelihood of developing CVD. Liver donor factors
such as donor body mass index (BMI), donation after cardiac death, and longer graft cold ischemia time are asso-
ciated with early perioperative CVD risk
[4]. Immunosuppression after LT also increases the incidence of meta-
bolic complications that increase the risk of developing CVD
[4,15,16,24]. Based on the current system of liver
allocation, which is based on a “sickest first” policy in the United States, the population of patients receiving liver
transplants is more likely to be older and critically ill and thus more likely to have both clinical and subclinical
CVD which will have an impact on per ioperative and postoperative CVD events.
Natural history and timing of cardiovascular events in liver transplantation
Perioperative complications
Preload and cardiac output
Maintaining adequate preload and subsequently adequate cardiac output to appropriately perfuse tissues is a
necessary component of LT. This can pose a challenge as intraoperatively many factors can cause significant
hypovolemia and decreased preload such as hemorrhage, third space losses, and ascites production
[5,25]. The
conventional surgical technique itself requires clamping of the inferior vena cava (IVC) and portal vein which
can lead to significantly decreased preload in the anhepatic phase of LT. The piggy-back surgical technique pro-
motes better hemodynamic stability as the IVC is not fully obstructed, though this method can cause renal dys-
function and difficulties with surgical dissection due to portal hypertension and splanchnic congestion
[26].In
anticipation of, or in response to hemodynamic instability intraoperatively, patients are often aggressively fluid
resuscitated, which can conversely lead to hypervolemia. As such, significantly decreased or increased preload
can impair myocardial contractility leading to decreased cardiac output and impaired tissue perfusion (
Fig. 20.3).
Electrolyte derangements
Intraoperative electrolyte imbalances such as hypocalcemia, hypomagnesemia, hypokalemia, and hyperkale-
mia can occur due to multiple factors during LT. These severe derangements can in turn instigate cardiac dys-
function and arrhythmias
[21,27]. Thus close electrolyte monitoring, and rapid man agement of identified
abnormalities is important.
As mentioned previously, LT often involves large volume fluid resuscitation, particularly of citrated blood
products which can result in citrate toxicity. Citrate binds free calcium that has been shown to cause ionized
FIGURE 20.2 Pathophysiology of the relationship between liver disease and cardiovascular disease. This highlights the multifactorial and
multidirectional of the complex relationship between the development of liver disease and cardiovascular disease.
329Natural history and timing of cardiovascular events in liver transplantati on
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hypocalcemia in LT patients. Marquez et al. found that specifically in the absence of a functional liver, serum cit-
rate increased 20-fold after transfusion of citrated blood products causing acute ionic hypocalcemia. This resulted
in significant decreases in the endpoints of cardiac index, stroke index, and left ventricular stroke work index
during the course of LT
[28].
The magnesium ion is important in maintaining cardiovascular homeostasis, and administration of magne-
sium has been shown to improve myocardial contractility, augment the inotropy of catecholamines, and improve
coronary blood flow. Scott et al. in their study of nine patients found that ionized hypomagnesemia occurs dur-
ing hepatic transplantation and correlates with increased plasma citrate concentrations
[29]. Hypomagnesemia
occurred most prominently during the dissection and anhepatic stages of surgery and returned to baseline by
two hours after graft reperfusion. Given that these changes occur in the most hemodynamically unstable periods
of the surgery, they can further increase the likelihood of cardiac arrhythmias
[29]. Additionally, hypomagnese-
mia is associated with hypokalemia and hypocalcemia which are also electrolyte abnormalities that can predis-
pose to arrhythmias
[27].
Hyperkalemia is of particular concern during the graft reperfusion phase of hepatic transplantation. Usually,
potassium returns to prerevascularization levels within a couple of minutes of revascularization. However, in
some patients this does not occur resu lting in hyperkalemic cardiac arrest. Nakasuji et al. found that the most
important donor-related mechanism of hyperkalemia was that the preservation solution containing high potas-
sium levels was released into circulation immediately after revascularization
[30]. Flushing the portal vein or
hepatic artery with vena cava venting can decrease the amount of potassium released during this time
[30].
Other risk factors that are associated with clinically significant hyperkalemia include higher baseline potassium,
red blood cell transfusion, organ recovery after cardiac death, longer warm ischemia time, and longer donor hos-
pital stay
[31].
Postreperfusion syndrome
One of the most hemodynamically unstable periods of time during LT is immediately post graft reperfusion
when the IVC and portal vein are unclampe d. Aggarwal et al. first described postreperfusion syndrome (PRS)
and defined it as a decrease in mean arterial pressure . 30% below the baseline value for at least one minute
within five minutes after reperfusion
[32]. This syndrome occurs in 30% of patients and can lead to cardiac dys-
function and even cardiac arrest. Aggarwal et al. also found in their study of 69 patients that patients after graft
reperfusion had a 16% decrease in cardiac output
[32].
Hilmi et al. further stratified and modified the definition of PRS into mild and significant forms
[33]. Mild PRS
was defined as a decrease in blood pressure and/or heart rate , 30% of the anhepatic level, lasting # 5 minutes,
and responsive to calcium chloride (1 g intravenously) and/or epinephrine intravenous boluses (#100 μg) with-
out requiring continuous infusion of vasopressor agents. Significant PRS was defined as a decrease in blood pres-
sure more than 30% of the anhepatic level, asystole, hemodynamically significant arrhythmia, or requiring
vasopressor infusion intraoperatively. Other presentations of significant PRS included prolonged (defined as
greater than 30 minutes) or recurrent (defined as reappearing within 30 minutes after resolution) fibrinolysis that
required treatment with antifibrinolytic agents
[33].
The mechanism of PRS is thought to occur from ventriculoarterial decoupling due to the large amount of
blood coming to the heart from the liver. It is also thought that inflammatory mediators released from the graft
can cause sudden increases in pulmonary artery pressure and pulmonary vasculature resistive indices which can
cause global reductions in systemic vasculature resistance (SVR)
[34]. Acosta et al. found that both patients with
and without PRS had increases in right ventricular contractility after graft reperfusion, but those without PRS
concomitantly decreased afterload to promote ventriculoarterial coupling and thus better ventricular mechanical
efficiency
[35]. Those patients with PRS had less of an ability to change afterload in response to the acute change
in preload thus leading to circulatory dysfunction
[35]. Furthermore, identified risk factors of PRS are largely
related to graft recipient factors including age, Model for End-Stage Liver Disease (MELD) score, high creatinine,
high potassium, low calcium, and low hemoglobin
[34].
Cardiac arrest and arrhythmia
VanWagner et al. conducted a retrospective study of 54,697 LT recipients in which 1576 died and analyzed the
prevalence and predictors of early (30-day) CVD mortality. Of these patients, 303 (19.2%) suffered cardiac arrest
and 140 of those patients had perioperative cardiac arrests (
Table 20.2). Though death from arrhythmia was one
of the definitions of CVD mortality in this study, it was not shown to be a leading cause of mortality [3].
Donovan et al. found perioperative arrhythmias occurred in 10 (14%) of their LT study patients
[36]. Dec et al.
330 20. Predicting cardiovascular complications after liver transplantation
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conducted a smaller retrospective study of 146 patients in which there were no intraoperative deaths and only
five patients suffered from either ventricular tachycardia or fibrillation
[37]. More recently, Koshy et al. reported
an incidence of cardiac arrest or ventricular arrhythmias in 6.4% of 408 LT recipients
[27].
Air embolism and thromboembolism
The intraoperative complications of air embolism and thromboembolism have mainly been identified in cases
utilizing intraoperative transesophageal echocardiography (TEE). Though thought to be rare occurrences, knowl-
edge of these complications remains limited given that the information has largely been extracted from case
reports and small studies.
Intraoperative TEE monitoring can help with placement of the percutaneous bypass canula for venovenous
bypass (VVB) and aid in identifying associated life-threatening complications such as air embolism and thrombo-
embolism
[38,39]. Sakai et al. found in a retrospective review that only two patients out of 360 LT patients were
found to have air embolism
[40]. Golgorsky et al. found seven patients out of 577 to have pulmonary thromboem-
bolism with right ventricular dysfunction immediately after graft reperfusion thought to be due to excessive acti-
vation of the coagulation system after graft reperfusion
[41]. Xia et al. found that eight of 426 patients who
underwent LT with intraoperative TEE monitoring were found to have incidental intracardiac thromboemboli
and identified two independent risk factors for this: symptomatic or surgically treated portal hypertension and
intraoperative hemodialysis
[42].
Donor factors related to perioperative cardiovascular events
VanWagner et al.’s retrospective study of 54,697 LT recipients in which 1576 died, as mentioned above, identi-
fied donor risk factors associated with early perioperative CVD mortality. Those included higher BMI (19.1 6
6.5 kg/m
2
), donation after cardiac death, and longer graft cold ischemia time (8.3 6 3.3 hours). ( Table 20.1) With
every one-hour increase in cold ischemia time, the odds ratio of overall CVD mortality increased 1.04. This study
did not find donor characteristics of smoking, alcohol dependency, or cocaine use to be related to early perioper-
ative CVD mortality
[3].
Postoperative complications
Early (90-day period)
Cardiac function
Studies involving cardiac function after LT seem to differ in regard to normalization of cardiac output and
index. Henderson et al. and Hadengue et al. found in their small studies (n 5 1723) that cardiac output and car-
diac index remain elevated after LT. Henderson et al. examined cardiac output at the post-LT 1-year and 2-year
time points to arrive at that conclusion
[43,44]. In contrast, Gadano et al. studied 68 LT patients and found that
TABLE 20.2 Causes of death for patients who died of cardiac arrest within 30 days of liver transplantation.
Secondary causes of death for patients who died of cardiac arrest within 30 days of liver transplantation
Secondary cause of
CVD-related mortality
All early CVD
deaths (n 5 633)
All cardiac arrests (n 5 303) Perioperative cardiac
arrests (n 5 140 or 46.2%)
Postoperative cardiac
arrests (n 5 163 or 53.7%)
Infection/sepsis 46 (7.3%) 20 (6.6%) 3 (2.1%) 17 (10.4%)
Graft failure 30 (4.7%) 16 (5.3%) 4 (2.9%) 12 (7.4%)
Hemorrhage 32 (5.1%) 19 (6.3%) 9 (6.4%) 10 (6.1%)
Operative 14 (2.2%) 7 (2.3%) 5 (3.6%) 2 (1.2%)
Renal failure 18 (2.8%) 11 (3.6%) 3 (2.1%) 8 (4.9%)
Unknown/none 475 (75.0%) 225 (74.3%) 113 (80.7%) 112 (68.7%)
Other
a
18 (2.8%) 5 (1.7%) 3 (2.1%) 2 (1.2%)
a
Other 5 malignancies (n 5 1), suicide/trauma (n 5 0), drugs/toxins (n 5 0), and other (n 5 4) for cardiac arrest deaths and malignancies (n 5 1), suicide/trauma (n 5 1), drugs/
toxins (n 5 0), and other (n 5 16).
CVD, cardiovascular disease; LT, liver transplantation.
Adapted from VanWagner LB, et al. High early cardiovascular mortality after liver transplantation. Liver Transpl. 2014; 20(11):13061316.
331Natural history and timing of cardiovascular events in liver transplantati on
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those transplanted for cirrhosis had a significantly decreased cardiac index 1-year post-LT compared to the first
six postoperative months. Cardiac index in this study was found to be increased in those patients who had sepsis
or anemia
[45]. Park et al. also found a reduction in cardiac index in 12 out of 13 post-LT patients that were fol-
lowed up with echocardiography 113 months post-LT and concluded that LT improves hemodynamic changes
often associated with chronic liver disease
[46].
When discussing left ventricular ejection fraction (LVEF) in particular, Nicolau-Raducu et al. found in a cross-
sectional study of 389 LT patients that 24 patients decreased their LVEF .10% from baseline and 11 of those
patients had severe decreases in LVEF ,40%. Two patients followed in this study died from intractable HF
within one year of transplantation, but the majority of patients had improvement in their cardiac function
[47].
Nasraway et al. conducted a retrospective study of 96 LT patients to describe the hemodynamic and oxygen
transport patterns in survivors versus nonsurvivors post-LT. The mortality rate following LT was 15%, and it
seemed that nonsurvivors had a decrease in cardiac index compared to survivors, particularly within the first
12 hours postoperatively. Since SVR and pulmonary artery wedge pressure did not significantly differ between
survivors and nonsurvivors, it is most compelling that intrinsic depression of myocardial contractility is causing
the discrepancy in cardiac index between these two groups and could mean these patients had less cardiac
reserve preoperatively
[48].
Additionally, patients with less cardiac reserve preoperatively may be at an increased risk of HF due to the
inflammatory response that develops during LT. Release of inflammatory mediators such as endotoxin and
tumor necrosis factor have been identified as being independent myocardial depressants during critical illness
[4852].
CCM is defined as cardiac dysfunction in cirrhotic patients manifested by subclinical alterations in cardiac
function and no known cardiac disease
[19]. Given the hyperdynamic state and systemic vasodilation that occurs
in cirrhosis, CCM may not be frequently detected preoperatively though postoperative complications can ensue.
After transplantation, physiological increases in preload and afterload can incite acute left ventricular systolic
and diastolic dysfunction in these patients without overt CCM preoperatively. In a review by Izzy et al., it is
summarized that CCM may not necessarily improve post-LT as previously thought, and some studies suggest
that diastolic function can remain the same or even worsen
[53]. The World Congress of Gastroenterology in
Montreal in 2005 provided the initial diagnostic criteria for CCM involving echocardiographic measures for eval-
uation of systolic and diastolic dysfunction, along with additional supportive criteria. These criteria have now
become outdated with significant advances in cardiovascular imaging and with the need for more comprehensive
testing. Izzy and VanWagn er et al. recently proposed new recommendations in 2019 on behalf of the Cirrhotic
Cardiomyopathy Consortium
[19]. The new criteria recommend assessment of global longitudinal strain along
with modified guidelines for evaluation of advanced diastolic dysfunction to better capture patients with CCM
in a preoperative evaluation. It is also recommended by this group that postoperatively, any patients with evi-
dence of pretransplant systolic or diastolic dysfunction based on these criteria should be followed with serial
echocardiograms with tissue Doppler imaging and strain imaging at 6, 12, and 24-month post-transplant inter-
vals. This can expectantly bette r identify those patients with persistent cardiac dysfunction and who may subse-
quently benefit from early interventions such as tighter blood pressure control and specific antihypertensives to
prevent further cardiac remodeling
[19,53].
Pulmonary Edema
The occurrence of pulmonary edema seems to occur most frequently immediately post-transplantation. There
are many factors that likely together contribute to this complication including significant volume resuscitation,
increased capillary permeability, and prolonged intubation
[36].
Donovan et al. found that 39 (56% of those that suffered complications) patients after transplantation had chest
radiographic appearance of pulmonary edema requiring postoperative diuretic therapy in all of those cases. This
did not correlate with the volume of blood products transfused suggesting again that development of pulmonary
edema is a mu ltifactorial process
[36].
Snowden et al. aimed to determine the incidence of radiological pulmonary edema in LT patients in relation to
the perioperative and postoperative courses. Of the 34 patients’ imaging, 47% showed evidence of postoperative
radiological pulmonary edema which was associated with deterioration in gaseous exchange, elevated pulmo-
nary artery pressure, and increased duration of ventilator dependence and intensive care unit stay. Eighteen per-
cent of patients that had pulmonary edema immediately postoperatively had greater transfusion requirements
and pulmonary artery pressures perioperatively. Another 29% of patients had radiologic evidence of pulmonary
332 20. Predicting cardiovascular complications after liver transplantation
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edema 1620 hours post-LT, but this group did not have a correlation with increased volume resuscitation needs
intraoperatively
[54].
Samstein et al. found that pulmonary edema was more common in recipients of decea sed donor liver trans-
plant (DDLT) than with living donor liver transplant (LDLT). Though the majority of the above studies found
pulmonary edema as a more immediate complication postoperatively, Samstein et al. followed patients more lon-
gitudinally and found in their study of 471 DDLTs and 565 LDLTs that within the first year, the incidence of pul-
monary edema was 9% of LDLTs versus 17% of DDLTs and the overall incidence after 10 years was 10% of
LDLTs versus 36% of DDLTs. The higher probability of pulmonary edema in DDLT recipients could be due to
the increased inflammatory response with deceased donors due to more prominent ischemia-reperfusion injury
and/or due to the possibility of higher severity illness in DDLT recipients
[55].
Dilated cardiomyopathy
Dec et al. found that 3.4% of 146 patients had a postoperative complication of dilated cardiomyopathy [37].
Sampathkumar et al. reviewed 754 LT patients and found seven patients that developed reversible dilated cardio-
myopathy post-transplantation without an identifiable cause. The patients had four-chamber dilation on echocar-
diography with decreased LVEF to 20% from a preoperative median of 60%, but this ultimately improved to a
median of 50%. All of these patients required supportive care involving mechanical ventilation, afterload reduc-
tion, inotropic support, and intensive care unit monitoring during the acute event but at 15-month follow-up did
not have recurrence of HF
[56].
Cardiac arrest and arrhythmia
VanWagner et al. identified 163 (53.7%) patients that suffered from early 30-day postoperative cardiac arrests
out of 303 total cardiac arrests within the perioperative and early postoperative periods (
Table 20.2). A large pro-
portion (68.7%) of these early cardiac arrests were due to unknown secondary causes, but the known identified
causes were infection/sepsis (10.4%), graft failure (7.4%), hemorrhage (6.1%), renal failure (4.9%), and operative
causes (1.2%)
[3]. As several causes of perioperative cardiac arrhythmia were described above, this arrhythmia
risk can persist after LT due to the stress of surgery itself along with other factors including ongoing parasympa-
thetic impairment, post-transplant reperfusion, chronic immunosuppression, and electrophysiological abnormali-
ties of CCM such as QT prolongation, chronotropic incompetence, and electromechanical uncoupling
[27,53,57].
VanWagner et al. found that at the 30-day and 90-day post-transplantation time points, atrial fibrillation (AF)
was the most common reason for hospital readmission (
Fig. 20.4) [4]. Similarly, Patel et al. found that the most
common cardiovascular event 4 weeks post transplantation in 59 (20.5%) patients out of 348 was cardiac arrhyth-
mia with the most common being AF, followed by symptomatic bradycardia and supraventricular tachycardia
[58].
FIGURE 20.3 Timeline of major cardiovascular risk in the post-transplant period. This highlights the time course of the main cardiovascu-
lar complications after liver transplantation. CHD, coronary heart disease; MI, myocardial infarction.
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