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traditional risk factors [71] and provides superior discrimination of patients at interm ediate risk of CAD [72]. The

utility of CACS in LT candidates was investigated in three studies

[18,73,74]. Kemmer et al. demonstrated that it

is an useful tool for noninvasive screening of low-risk LT candidates

[73], but head-to-head comparison to other

noninvasive screening tests and assessment of CACS cost-effectiveness has not been performed to date. Another

study did show that CACS . 400 was an independent predictor of cardiovascular complications within the first-

month post-LT

[74].

In the recent years, the utility of a standard non-ECG gated CT chest performed for noncardiac indications

was examined for CACS assessment in the general population

[75]. The CAC estimation has been based on a

visual Weston score (range 012) that was shown to correlate well with Agatston score and to predict well the

all-cause and CVD mortality

[75,76]. A retrospective analysis based on 953 LT candidates who underwent ICA,

identified 54 patients who had non-gated CT chest and there was a strong correlation between Agatston and

Weston scores. The authors suggested this imaging modality as a possible tool for risk stratification of LT candi-

dates

[77].

Coronary computed tomography angiography (CCTA) is a noninvasive contrast method, alternative of ICA,

with a 95% sensitivity and 83% specificity for detection of obstructive CAD ($50% stenosis) in the general popu-

lation

[78]. When CCTA was included in the algorithm for assessment of patients with stable chest pain, it

resulted in a significantly lower rate of deaths from CAD or nonfatal MI than standard care, which was attrib-

uted to implementation of appropriate treatment

[79]. The accuracy of CCTA in LT candidates was comparable

to DSE in one study with CCTA showing NPV of 95% for major post-LT cardiac events and 100% for postopera-

tive major coronary events while for DSE they were 91% and 96%, respectively

[80]. Major challenges of CCTA

are the requirement for adequate heart rate control, the need to stay still and follow breathing instructions, and

the requirement to tolerate beta-blockers or sublingual nitroglycerin. One study in LT candidates reported no

changes in renal function (mean glomerular filtration rate of 90 6 43 mL/min pre-CT and 92 6 45 mL/min post-

CT [P 5 .19]) and no episodes of hypotension after administration of nitroglycerin prior to CCTA

[81], but the

rate of these complications requires further investigation. Additionally, studies have reported that the test may

be nondiagnostic in more than one-quarter of patients due to inadequate images, which could be explained with

the inability for breath holding due to ascites and baseline tachycardia in some patients with cirrhosis

[81,82].

Fractional flow reserve is nowadays considered as the gold standard for the assessment of hemodynamic sig-

nificance of equivocal or intermediate coronary lesions (50%70% stenosis) and can guide decisions regarding

percutaneous coronary intervention (PCI). It is usually measured as part of the ICA, but mounting evidence for

the last years has shown that noninvasive assessment of fractional flow reserve by CT can be a better predictor of

the need for revascularization or of major adverse cardiac events than CCTA

[83]. Thus, unnecessary ICA can be

prevented. This technique, however, has not been yet investigated in LT candidates and is not widely available.

Invasive coronary angiography

ICA is the gold standard for the evaluation of CAD that allows performance of PCI when appropriate. All LT

candidates with positive noninvasive cardiac tests as well as those with prior history of CAD, reduced left ven-

tricular ejection fraction (LVEF) on echocardiogram , 50%, and perhaps those with long-standing T2DM with

concomitant end-organ damage should be referred for ICA. Due to lack of clear guidelines, every transplant cen-

ter has different algorithm of CAD screening and various indications for ICA. At this point, the only concrete

consensus recommendation of multidisciplinary experts was an absolute contraindication for LT in the setting of

non-revascularized obstructive severe multivessel CAD

[84]. As outlined above, recent evidence suggests that

when compared to LT candidates without CAD, those with revascularized obstructive CAD had similar post-LT

survival within the first 2 years regardless of disease severity

[25,26].

Despite concerns for bleeding complications with ICA due to baseline coagulopathy and thrombocytopenia in

cirrhotic patients, the majority of studies to date have shown that ICA is safe with low rate of major bleeding epi-

sodes post-catheterization (0%2.4%)

[23,8588].Only5%7% of the patients in these studies received fresh fro-

zen plasma before the procedure

[8587]. It is noteworthy that recent practice guidance by the American

Gastroenterology Association recommended against using international normalized ratio (INR) for perioperative

bleeding risk stratification

[89]. It recommended fibrinogen level of more than 120 mg/dL and platelets level of

more than 50,000/μL to be aimed for before invasive interventions in this patient population. One study reported

more pseudoaneurysms and a greater need for blood transfusions post-catheterization in cirrhotic patients com-

pared to those without liver disease

[90]. Transradial arterial approach was proven safe and effective among LT

candidates undergoing left heart catheterization with fewer vascular and bleeding complications [88,91] and is

recommended by current consensus guidelines in conjunction with smaller size sheaths

[84]. Worsening of renal

314 19. Cardiovascular assessment before liver transplantation

III. Cardiovascular system in liver failure

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function was reported in 0.9%2.8% [23,88,92]. In patients with advanced chronic kidney disease, nephrology

consult and standard preventive measures are recommended before ICA

[84].

Management of coronary artery disease in liver transplantation candidates

Although initial small studies have demonstrated a very high risk of early and late post-LT morbidity and mortal-

ity among patients with proven CAD before transplant

[93,94], subsequent analyses of larger cohorts have not con-

firmed these findings when patients with CAD were appropriately treated

[25,95]. A cohort study that included 630

patients who underwent ICA prior to LT followed by coronary intervention when appropriate, demonstrated similar

post-LT survival among patients with and without obstructive CAD (defined as $ 50% stenosis of one or more ves-

sels), which persisted after adjustment for donor and recipient risk factors

[25]. CAD severity did not impact sur-

vival either. Importantly, no difference in survival of LT recipients was noted among angiographically proven

revascularized CAD regardless of number of vessels involved, severity, and extent of CAD compared to recipients

without CAD

[26]. Multivessel CAD predicted early post-LT mortality when compared to patients without CAD in

one study

[24], but did not increase mortality in comparison to single-vessel CAD in another study [25].Comparison

between some of the studies will be impacted by improved management of CAD over the last decades.

In the general population, low-dose aspirin and high-intensity statin therapy are recommended for all patients

with stable CAD

[96]. However, limited data exist on their use, efficacy, and safety in patients with decompensated

cirrhosis awaiting LT. Recent retrospective analysis of 84 patients with angiographically proven CAD noted signifi-

cant underutilization of both aspirin and statin with only 36% and 23% of the patients, respectively, receiving this

therapy as indicated

[97]. This finding remained when analyses were applied to those with multivessel CAD where

77% were on aspirin and 65% on statin. Both patients with and without CAD had similar lipid profiles. This is in

concordance with previous knowledge that cholesterol is a surrogate marker of liver synthetic function and

decreases with disease advancement

[98], although this fact does not refute the need for statins in patients with cir-

rhosis and CAD. Importantly, aspirin was safe with no episodes of acute gastrointestinal bleeding (GIB) or worsen-

ing renal function and only non-clinically relevant drop in platelet count was noted

[97]. Similarly, statin use was

not associated with increased risk of hepatic decompensation or mortality

[97]. However, definite conclusion regard-

ing aspirin and statins’ safety cannot be drawn only based on this study due to its small sample size and retrospec-

tive design. Randomized controlled trial (RCT) assessing the use of statins for prevention of variceal rebleeding

among patients with decompensated cirrhosis reported two patients who developed rhabdomyolysis (2.9%) and one

(1.4%) had elevation of transaminases requiring discontinuation while on simvastatin 40 mg daily

[99].High-dose

pravastatin (80 mg daily) in patients with hypercholesterolemia and well-compensated stable liver disease, which

excluded patients with decompensated cirrhosis, showed pravastatin was safe and well-tolerated

[100].

Beta-blockers are recommended as first-line therapy after acute coronary syndrome, and for management of

angina pectoris and AF

[96]. NSBBs (propranolol, nadolol, and carvedilol) are the mainstay therapy for primary

and secondary prophylaxis of variceal bleeding with essential part of their effect being the β2-blockade that

causes splanchnic vasoconstriction and thus decreases portal inflow

[101]. However, cardioselective β1-blockers

are usually preferred in patients with CA D in the general population. One cohort study from Taiwan compared

the use of NSBBs versus β1-selective blockers in cirrhotic patients after MI

[102]. At 2-year follow-up, the use of

β1-selective blockers was associated with lower incidence of major cardiac events while there was no difference

in all- cause mortality and liver outcomes. Perioperative use of beta-blockers (propranolol and metoprolol) dem-

onstrated protective effect against adverse cardiac events and death within the first-month post-LT

[57]. Overall,

the selection of beta-blocker in cirrhotic patients with CAD should be a combined decision between cardiology

and hepatology and based on the primary treated problem and patient’s comorbidities.

Small studies have shown that PCI is effective and safe in LT candidates with obstructive CAD

[26,103].A

single-center study that analyzed different strategies of screening for CAD among LT candidates over three periods

of time demonstrated that more aggressive approach with increased rate of ICA and PCI resulted in reduction of

MI rate within the first-year post-LT from 8.0% to 0.6% and improved 1-year all-cause mortality from 16% to 6%

[92]. Bare-metal stents may be preferred over drug-eluting stents (DES) in order to minimize dual antiplatelet ther-

apy (DAPT) to 30 days and reactivate patients on the transplant list, thereafter, instead of the minimum recom-

mended duration of 6 months with DES.

[84] The data of DAPT in LT candidate’s safety are limited. One study

reported 2/16 cirrhotic patients developed fatal variceal bleeding while on DAPT.

[104] Another study compared

80 cirrhotic patients who were treated with medical management only and 68 who received stents and were started

on DAPT

[105]. Treatment with stents and DAPT was associated with a higher incidence of acute GIB at both 1-

and 2-year follow-up with no effect on all-cause mortality. There was no difference in GIB rate between those who

received bare-metal stents and DES despite that most of the patients received DES (76.5%). A recent cohort study

315Introduction

III. Cardiovascular system in liver failure

https://t.me/medicina_free

showed increased GIB with DAPT at 1-year post-MI but decreased recurrent MI when cirrhotic patients were com-

pared to non-cirrhotic patients

[106].

When PCI is not feasible, coronary artery bypass grafting (CABG) may be performed before [107111] or

simultaneously with LT

[112] in well-selected patients. The major challenge is that current evidence relies on case

series or small sample size studies that also included in their analyses various other cardiac procedures per-

formed in patients with cirrhosis. Overall, postoperative outcomes for pre-LT CABG were significantly worse in

those with ChildTurcottePugh (CTP) class B and C with up to 43% perioperative mortality in class B

[108]

and 67%100% mortality in class C [108110]. There was a correlation between CTP class and adverse postoper-

ative outcomes with suggested cutoff for CTP . 7

[108,110]. Other predictors of mortality after CABG in a large

cohort study, that included 0.2% patients with cirrhosis, were ascites (OR 3.80), age . 60 (OR 2.21), female gender

(OR 1.92), and presence of HF (OR 1.75)

[111]. It is recommended that LT candidates with prior history of CABG

should undergo LVEF assessment and ischemic testing by ICA

[84].

In aggregate, CAD is common among LT candidates with prevalence likely exceeding that of the general pop-

ulation. Burden of traditional cardiovascular risk factors and NASH etiology is the major risk factors to be con-

sidered during risk stratification. The most widely used tests for CAD screening are DSE and SPECT. Both tests

have low sensitiv ity, but good NPV in low-risk individuals. Data on efficacy of CACS and CCTA are limited yet

promising. Major advantages and disadvantages of screening tests are summarized in

Table 19.4. Medical man-

agement of CAD and PCI, if indicated, should be promptly applied in order to reduce post-LT mortality.

Fig. 19.1 illustrates a proposed algorithm of CAD screening in LT candidates based on the available data.

Assessment of cardiac dysrhythmias

Atrial dysrhythmia

AF is the most common cardiac arrhythmia among LT candidates that has been associated with increased

intraoperative, early and late cardiac events post-LT

[3,113]. The impact of AF on survival is controversial with

most studies showing no impact on mortality

[113115], although one study reported greater risk of death at

both 1-month and 1-year post-LT

[116]. Various preexisting structural and functional heart abnormalities have

been identified as risk factors in cirrhotic patients with AF: LV hypertrophy

[113], CAD [115], valvular heart dis-

ease, LVEF , 50%

[117], and clinical HF [113]. Thus, a new diagnosis of AF in LT candidates should prompt fur-

ther cardiac evaluation or reevaluation

[84].

Prevalence and risk factors of atrial fibrillation in liver transplantation candidates

The reported incidence of AF in cirrhotic patients ranges from 3.1% over a 9-year follow-up [114] to 8.5% at 1-

year follow-up

[117], while prevalence of AF fluctuates widely between 0.15% to 11.2% [113,115,117,118]. This

TABLE 19.4 Advantages and disadvantages of screening tests.

Cardiac test Advantages Disadvantages

DSE Acceptable NPV for post-LT cardiac events; safe, widely

available, no radiation, simultaneous assessment of cardiac

structure and function at rest can be done; relatively inexpensive.

Low sensitivity for diagnosing CAD, high rate of

nondiagnostic tests due to inability to achieve target heart

rate.

SPECTMPI Acceptable NPV for post-LT cardiac events. Low sensitivity for diagnosing CAD, high rate of false

positive results in ascites, radiation exposure.

CACS Suitable for low-to-intermediate risk patients, non-contrast,

noninvasive, low-dose radiation exposure.

Non-calcified plaques cannot be detected, cost, insurance

coverage.

CCTA Suitable for intermediate-risk patients, noninvasive. Risk of contrast nephropathy and hypotension, radiation

exposure; requires heart rate control; reduced image quality

in up to 28%.

ICA Gold standard, allows PCI if indicated. Invasive, risk of bleeding and contrast nephropathy;

radiation exposure.

CACS, Coronary artery calcium score; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; DSE, dobutamine stress

echocardiogram; ICA, invasive coronary angiography; LT, liver transplantation; NPV, negative predictive value; SPECTMPI, single-photon emission computed

tomography- myocardial perfusion imaging.

316 19. Cardiovascular assessment before liver transplantation

III. Cardiovascular system in liver failure

https://t.me/medicina_free

large difference could be explained with diversity of the studied populations, different ethnicities, and utilized

AF definitions ranging from one-time review of available ECGs in one study

[118] to close cardiac follow-up of

the LT candidates where the highest prevalence was noted

[117]. A meta-analysis of seven cohort studies demon-

strated an estimated AF pooled prevalence of 5% in patients with cirrhosis and 2.4% among LT candidates

[119].

These findings confirm that AF prevalence in cirrhotic patients is at least comparable to that of the general popu-

lation, which has been reported to range from 1%

[120] to 5% in the western world [121,122]. It remains conten-

tious as to whether cirrhosis and its severity is a risk factor of AF with one study showing no association

between cirrhosis and MELD score with new-onset AF

[115], while another one demonstrated a 46% higher risk

for new-onset AF in cirrhotic compared to non-cirrhotic patients (HR 1.46; 95% CI 1.181.80) with men younger

than 65 years without comorbidities being at highest risk

[114]. A recent single-center retrospective analysis

based on 1727 patients demonstrated a definite association between liver disease severity and new-onset AF,

independent of other AF risk factors, with prevalence of 3.7% among those with MELD 610 that rose to 20.1%

in patients with MELD . 30

[117]. The authors of this study suggested two major underlying mechanisms to

explain this association: autonomic dysfunction resulting in decreased heart rate variability that is common in cir-

rhosis and worsens with severity of liver damage, and neurohormonal changes, such as elevation of vasoactive

intestinal peptide and galectin-3 levels that may trigger AF.

Patients with alcohol-associated cirrhosis are at increased risk of AF if they have enlarged left atrium related

to their prior alcohol use

[123]. NAFLD has been also associated with the greater risk of AF based on a meta-

analysis of five studies (pooled RR 2.06; 95% CI 1.10 3.85)

[124] but this finding was not confirmed in an analysis

of the Framingham Heart Study participants over a follow-up of 12 years

[125]. Among patients with T2DM,

NAFLD has increased more than sixfold AF incidence (adjusted OR 6.38; 95% CI 1.724.2, P 5 .005)

[126] and

about threefold (OR 3.04; 95% CI 1.546.02, P , .001)

[127] the prevalence of permanent AF even after adjustment

for other risk factors for AF. Possible pathogenic mechanisms for development of AF in NAFLD are systemic

inflammation, LV remodeling, autonomic dysfunction, and increased pericardial fat, which all have been associ-

ated with NAFLD

[43].

FIGURE 19.1 Proposed approach for evaluation of coronary artery disease in liver transplant candidates. *Patients with history of coro-

nary stent or coronary artery bypass grafting (CABG) need cardiology evaluation and left heart catheterization; **CAD evaluation of patients

with GFR ,30 is to be determined on case by case basis; and ***Triglyceride .150, LDL .130, total cholesterol . 200. CAD, Coronary artery

disease; FFR. fractional flow reserve; LHC, left heart catheterization; LT, liver transplantation; CABG, coronary artery bypass grafting; NASH,

nonalcoholic steatohepatitis; CT, computed tomography.

317Introduction

III. Cardiovascular system in liver failure

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Another important risk factor for AF is CCM, which manifests in these patients as diastolic dysfunction (DD),

a well-established risk factor for AF

[128].

Diagnosis and treatment of atrial fibrillation in liver transplantation candidates

After diagnosing AF on ECG, LT candidates should undergo full workup, including serum biochemistry to rule

out electrolyte abnormalities, chest radiography, thyroid function tests, echocardiography, and noninvasive stress

test to rule out CAD. Holter monitoring might be helpful when paroxysmal AF is suspected. Studies comparing

rate- versus rhythm-control strategies in cirrhotics are not available to date and patients should be referred to cardi-

ology for appropriate management according to current guidelines

[129,130]. Similarly, no evidence exists on effi-

cacy and safety of radiofrequency catheter ablation for the treatment of AF in patients with cirrhosis.

In contrast, the benefits, risks, and optimal methods of anticoagulation for ischemic stroke prevention in LT

candidates with AF have been addressed in recent studies

[131,132]. However, their results might not be applica-

ble to all cirrhotic patients globally as all studies were performed and based on Asian population. A study based

on the Taiwan National Health Insurance database demonstrated that patients with cirrhosis and AF had an

increased risk of both ischemic stroke (HR 1.10, P 5 .046) and intracranial hemorrhage (ICH) (HR 1.20, P 5 .043)

when compared to those without cirrhosis

[131]. This finding reflects the already known susceptibility of cirrhotic

patients to both thrombosis and coagulopathy due to deficiency of anticoagulant factors and increases in procoa-

gulants

[133]. Cirrhotic patients with CHA

-Vasc score $ 2 treated with warfarin were noted to have a signif-

icantly lower risk of ischemic stroke (HR 0.76; 95% CI 0.580.99) with similar ICH rate when compared to no

treatment group, while antiplatelet therapy had no effect on ischemic stroke risk

[131]. Warfarin is approved by

the US Food and Drug Administration (FDA) for use in patients with AF. Despite that, patients with CTP class B

and C were noted to have a higher incidence of major bleeding events per year when anticoagulated with warfa-

rin compared to those with class A cirrhosis (14.5% vs 4.9%, P , .001)

[134]. In contrast, a recent meta-analysis of

seven studies concluded that the use of anticoagulation in patients with AF and cirrhosis decreases the risk of

stroke by 58% (HR 0.58, 95% CI 0.350.96) with no increased risk of bleeding (HR 1.45, 95% CI 0.962.17)

[135].

It is notable that the achievement of true therapeutic effect of warfarin in patients with cirrhosis can be limited

by the fact that elevated INR is often observed in these patients.

Current guidelines for management of AF in the general population recommend the use of four direct oral antic-

oagulants (DOACs): dabigatran, rivaroxaban, apixaban, and end edoxaban over warfarin

[129], but the RCTs lead-

ing to their approval excluded patients with active liver disease or platelet count , 90,000/μL

[136139]. Currently,

none of the DOACs is permitted by the FDA for cirrhosis CTP class C and only apixaban and dabigatran are per-

mitted for cautious use with no dose adjustment in cirrhosis CTP class B. Small observational studies have shown

similar safety of DOACs (rivaroxaban and apixaban) compared to traditional anticoagulation

[140142]. A recent

large retrospective cohort study that included cirrhotic Asian patients with AF reported similar efficacy between

DOACs (apixaban, dabigatran, and rivaroxaban) and warfarin, but there was significantly lower risk of major

bleeding (2.9% vs 5.4%, P , .001) and GIB in the DOACs group (1.9% vs 3.6%, P 5 .003)

[132].However,mostof

the patients received low-dose DOACs (69% were on apixaban 2.5 mg twice daily; 89% on dabigatran 110 mg twice

daily; and 95% on rivaroxaban 1015 mg daily) per discretion of the prescribing physician and CTP score was not

calculated due to lack of this information in the database. Both rivaroxaban and dabigatran showed a lower risk of

major bleeding, but apixaban did not demonstrate this benefit, which could be explained with the higher propor-

tion of patients who received standard dose of apixaban. A recent RCT that compared rivaroxaban to warfarin for

management of acute non-neoplastic portal vein thrombosis among patients with compensated cirrhosis has also

demonstrated rivaroxaban was safe and superior to warfarin in clot dissolution

[143].

Besides bleeding concerns, warfarin and DOACs may pose a risk of liver injury. A meta-analysis of 29 RCTs

found no increased risk of drug-induced liver injury with DOACs when they were compared to standard antic-

oagulation or placebo (relative risk 0.90, 95% CI 0.721.13)

[144]. Similar results were noted when patients with

prior liver disease were included in a cohort study

[145]. In a large analysis based on US healthcare claims,

DOACs were associated with a lower risk of liver injury compared to warfarin, with dabigatran demonstrating

the lowest risk

[146]. In contrast, an analysis based on FDA reports of adverse events suggested that rivaroxaban

may have a higher risk of liver injury compared to other DOAC s and warfarin

[147].

All cirrhotic patients should undergo an esophagogastroduodenoscopy for variceal screening before initiation of

anticoagulation. Treatment of varices with NSBB or band ligation should be performed, if indicated. Experts in por-

tal hypertension tend to prefer NSBB in this setting for primary prophylaxis of variceal bleeding given concerns

about difficulty in managing bleeding of post-banding ulcers while on anticoagulation. An attractive alternative for

cirrhotic patients at high risk of stroke who cannot be anticoagulated due to high bleeding risk could represent the

318 19. Cardiovascular assessment before liver transplantation

III. Cardiovascular system in liver failure

https://t.me/medicina_free

non-pharmacological approach of left atrial appendage closure. However, conclusions regarding its benefit versus

risk are difficult to draw as studies to date have included only a small number of cirrhotic patients

[148].

An important point among LT candidates is the reversal of anticoagulation in the perioperative period or in

the setting of a major bleeding episode. Idarucizumab, a humanized monoclonal antib ody fragment, has shown a

rapid and complete reversal of dabigatran activity in patients with significant GIB

[149]. Andexanet was

approved by the FDA in 2018 for reversal of anticoagulation effect of apixaban and rivaroxaban. It has demon-

strated excellent effect in reducing factor Xa activity in patients with major bleeding

[150]. If a specific antidote is

not available, 4-factor prothrombin complex concentrate can be considered for fast reve rsal of factor Xa inhibitors

although the potential risk of early thrombotic events should be considered

[151].

Collectively, LT candidates with AF should undergo further evaluation in order to exclude underlying cardiac

pathology that could have triggered the AF. The prevalence of AF in cirrhotic patients appears to be at least simi-

lar to that of the general population and the risk may be increasing with higher MELD or with DD reflecting

CCM. The initiation and choice of anticoagulation should be based on a careful stratification between benefits

and risks. DOACs appear to be as safe as the standard anticoagulation with warfarin, but there is no sufficient

evidence to suggest that DOAC should be the preferred one in this population and patients with CTP class C

should not be prescribed DOACs at this time.

Ventric ular arrhythmias

Data about ventricular arrhythmias are very limited in patients with cirrhosis. However, prolongation of QT

interval is the most commonly reported electrophysiological abnormality in cirrhosis that reflects delayed ventric-

ular repolarization. The majority of studies investigating the significance of QT prolongation have assessed cor-

rected for heart rate QT (QTc) and define d it as QTc . 440 Ms. QT interval prolongation used to be one of the

supportive criteria for diagnosis of CCM

[63] with reported prevalence in patients with cirrhosis ranging between

33% and 83%

[152157]. The recent contemporary definition of CCM, which is an echocardiographic phenome-

non, has eliminated this electrocardiographic criterion

[63]. The preval ence of QTc prolongation progressively

increases from class A to class C cirrhosis

[152,153,158] and CTP score was noted to be an independent predic tor

of prolonged QTc

[154]. Although associated with alcoholic cirrhosis in some studies [154,158160], no correla-

tion with cirrhosis etiology was noted in other studies

[152,153,155]. It was demonstrated that chronic beta-

blockade selectively shortens QTc only in cirrhotic patients with QTc prolongation at baseline

[157]. Interestingly,

prolonged QTc before LT was associated with atrial arrhythmias and acute coronary syndrome post-LT in one

retrospective study that evaluated ECG abnormalities of 186 cirrhotic patients

[160]. Although associated with

ventricular arrhythmias and sudden death in the general population

[161], only a single study noted a correlation

between prolonged QTc and sudden cardiac death among patien ts with alcohol-associated liver disease

[159],

and these results have not been replicated by subsequent studies. On the contrary, all follow-up studies except

one

[153], showed no association with all-cause mortality post-LT [152,154,156]. However, a recent study showed

that QTc prolongation does not correlate with the myocardial changes noted on echocardiography

[162]. Another

study found that only QTc prolongation after LT impacts post-LT survival regardless of QTc length before LT

[156]. Sepsis was the predominant cause of death (43%) among these patients. Prolonged QTc was also noted to

be a predictor of 6-week mortality in cirrhotic patients with acute GIB

[163]. Thus, it could be speculated that

prolonged QTc effect on survival is reflective of the overall sickness of these patients but this should be investi-

gated in future studies.

Assessment of heart failure

Prevalence and risk factors

The AHA outlined, in 2013, four stages for development of HF; stage A (having risk factors for HF), stage B

(having myocardial structural changes without clinical symptoms and signs), stage C (developing clinical symp-

toms and signs), and stage D (refractory clinical presentation)

[164]. It is challenging to determine the prevalence

of clinical HF in LT candidates in view of selection bias where patients with symptoms of HF or LVEF , 50% are

often excluded from LT evaluat ion. However, subclinical cardiac dysfunction in patients with EF. 50% (e.g.,

reduced myocardial strain or DD) has been investigated in these patients. Two studies have shown that patients

with cirrhosis have normal myocardial strain

[165,166] though one study showed that in a subset of patients with

cirrhosis strain values may be decreased

[167]. Conversely, DD used to be considered very common in patients

319Introduction

III. Cardiovascular system in liver failure

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with end-stage liver disease with a prevalence exceeding 50% [168]. The recent, comprehensive, and strict criteria

for DD by the American Society of Echocardiography (ASE) led to significant decrease in the reported prevalence

of DD (

Table 19.5) [169]. Recent studies showed that DD affects 22%33% of patients with cirrhosis [170,171].A

notable entity for cardiac muscle dysfunction in these patients is CCM, which is defined as systolic or DD in

patients with cirrhosis in the absence of known heart disease. It is believed to be secondary to myocardial hyper-

trophy, myocardial fibrosis, and subendocardi al edema

[172]. The diagnostic criteria for this entity have been

recently revised by the CCM consortium, accounting for the recent developments in echocardiographic technol-

ogy (

Table 19.5) [63]. Prior data suggested that CCM or more specifically its diastolic component can increase the

risk for posttransplant HF

[173]. Recent data suggest that CCM per the new criteria (or new definition) increases

the risk for posttransplant cardiovascular disease (including HF) by almost twofold

[170]. The presence of meta-

bolic syndrome and its surrogates, which are common in these patients as outlined above, confers an additional

risk for HF, which has been illustrated from studies in the general population

[174].

Diagnosis and management of cardiac muscle dysfunction in liver transplantation candidates

Echocardiography remains the gold standard for the evaluation of cardiac muscle function. Ejection fraction

has long been the focus of echocardiographic assessment of LT candidates. In view of pronounced vasodilatory

status and consequently decreased afterload in patients with end-stage liver disease, ejection fraction is usually

normal or increased in these patients leading to overestimating the actual myocardial contractile function. This

concept has been validated by a recent large study that illustrated in patients with MELD . 20, posttransplant

mortality is associated with pretransplant EF of 50%60%, which is considered normal in general population

[175]. This highlights the need for an additional contractile surrogate, which has a better prognostic value such as

global longitudinal strain. Global longitudinal strain has been recommended by ASE since 2015. Strain represents

the myocardial shortening in systole in relation to myocardial fiber length in diastole; therefore, it is a negative

percent value but to minimize confusion, ASE recommends referring to changes in strain as change in the abso-

lute value

[176]. Table 19.5 illustrates the echocardiographic variables that need to be evaluated in the every LT

candidate to diagnose systolic dysfunction, DD and CCM).

It is noteworthy that although the data about the utility of magnetic resonance imaging in evaluation of car-

diac muscle function evaluation are currently limited, more data on its role in evaluating cardiac function in

ESLD can be anticipated

[177].

While patients with clinical HF or reduced LVEF are usually excluded from transplant consideration, patients

with reduced strain (absolute va lue , 18%) or with DD often make it to the transplant list. These patients are

technically in stage B in the development of HF. Therefore, although prospective data are lacking about these

patients, recent expert opinion consensus recommended that these patients should be followed up with echocar-

diography every 6 months while listed and continue to do so until 2 years posttransplant

[63]. The intent is to

detect and manage any worsening in cardiac function when it is still in the subclinical phase. Future studies are

needed to validate or revise this approach.

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TABLE 19.5 Echocardiographic assessment of cardiac function in liver transplant candidates.

Systolic dysfunction Diastolic dysfunction

Any of the following

• Decreased left ventricular ejection fraction (#50%)

• Decreased global longitudinal strain (absolute value , 18)

$ 3 of the following

• Septal e’ velocity , 7 cm/s

• E/e’ ratio . 15

• Left atrial volume index . 34 mL/m [2]

•

Tricuspid regurgitation velocity . 2.8 m/s in the absence of

portopulmonary hypertension

Presence of 2 criteria warrants further evaluation using other criteria such as E/A ratio during valsalva, isovolumetric relaxation time, left atrial strain, pulmonary vein

velocities, and left ventricular strain.

The presence of systolic or diastolic dysfunction according to these criteria in the absence of known cardiac disease is diagnostic of Cirrhotic Cardiomyopathy.

e’, Early diastolic mitral annular velocity; E, Peak velocity flow in early diastole; A, Peak velocity flow in late diastole.

320 19. Cardiovascular assessment before liver transplantation

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https://t.me/medicina_free

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