Multidisciplinary Approach to Cardiac and Pulmonary Vascular Disease Risk Assessment in Liver Transplantation

An Evaluation of the Evidence and Consensus Recommendations

Lisa B. VanWagner; Matthew E. Harinstein; James R. Runo; Christopher Darling; Marina Serper; Shelley Hall; Jon A. Kobashigawa; Laura L. Hammel

Disclosures

American Journal of Transplantation. 2018;18(1):30-42.

Abstract and Introduction

Abstract

Liver transplant (LT) candidates today are older, have greater medical severity of illness, and have more cardiovascular comorbidities than ever before. In addition, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Cirrhotic cardiomyopathy, a condition characterized by increased cardiac output and a reduced ventricular response to stress, is present in up to 30% of patients with cirrhosis, thus challenging perioperative management. Current noninvasive tests that assess for subclinical coronary and myocardial disease have low sensitivity, and altered hemodynamics during the LT surgery can unmask latent cardiovascular disease either intraoperatively or in the immediate postoperative period. Therefore, this review, assembled by a group of multidisciplinary experts in the field and endorsed by the American Society of Transplantation Liver and Intestine and Thoracic and Critical Care Communities of Practice, provides a critical assessment of the diagnosis of cardiac and pulmonary vascular disease and interventions aimed at managing these conditions in LT candidates. Key points and practice-based recommendations for the diagnosis and management of cardiac and pulmonary vascular disease in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

Introduction

Cardiovascular complications are the leading cause of non-graft-related morbidity and mortality early after liver transplantation (LT).^[1–3] Accurate risk estimation of cardiovascular complications following LT is paramount to guide allocation of limited resources and improve clinical outcomes. However, patients with end-stage liver disease (ESLD) are poorly represented in current guidelines for preoperative cardiac evaluation and management in noncardiac surgeries.^[4,5] This has resulted in significant clinical management variations between transplant programs in the preoperative cardiac evaluation and management decisions of LT candidates when cardiac pathology is identified.

Prevalent cardiovascular disease increases mortality risk, but prognosis might be improved by optimal perioperative management involving multiple disciplines, including hepatology, cardiology, nephrology, pulmonology, anesthesia, critical care, and transplant surgery. It is with this in mind that a working group, endorsed by the American Society of Transplantation (AST) Liver and Intestinal (LICOP) and Thoracic and Critical Care (TCC COP) Communities of Practice, was organized whereby invited experts in the field of transplantation reviewed the diagnostic approaches and treatment strategies that presently exist in the evaluation and management of cardiac and pulmonary vascular disease among patients in need of LT. The goal was to develop a consensus of opinions, based on best available evidence, on optimal practices and to articulate a research agenda to focus on important unanswered questions.

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Next Section

Abstract and Introduction
Methods
Coronary Artery Disease
Heart Failure and Cardiomyopathy
Portopulmonary Hypertension
Cardiac Dysrhythmias
Valvular Heart Disease
Congenital Heart Disease
Role of Combined Heart Liver Transplantation
Summary
References

Table 1. Cardiac and pulmonary vascular disease contraindications to liver-alone transplantation: consensus recommendations ^a
Cardiac or pulmonary vascular condition	Absolute contraindications	Relative contraindications
Coronary artery disease	Nonrevascularized obstructive severe multivessel CAD	Nonrevascularized obstructive moderate CAD not involving left main or proximal LAD coronary arteries
Cardiomyopathy and heart failure	Left ventricular ejection fraction <40% Moderate to severe right heart failure	Left ventricular ejection fraction <50% Hypertrophic cardiomyopathy with resting left ventricular outflow tract obstruction
Portopulmonary hypertension	Severe pulmonary hypertension associated with right heart failure and/or not responsive to medical therapies	Moderate pulmonary hypertension with preserved right ventricular function not responsive to medical therapy
Cardiac arrhythmias	Recurrent ventricular arrhythmias	Recurrent unstable arrhythmias
Valvular heart disease	Severe irreversible valvular disease	Moderate pulmonary hypertension with preserved right ventricular function not responsive to medical therapy
Congenital heart disease	Congenital heart disease plus moderate to severe right heart failure not responsive to medical therapy	Congenital heart disease plus moderate pulmonary hypertension with preserved right ventricular function not responsive to medical therapy

CAD, coronary artery disease; LAD, left anterior descending.
^aExpert consultation with a cardiologist or pulmonary hypertension specialist familiar with liver transplantation surgery is recommended prior to decision making in all situations.

Table 2. Summary of recommendations and considerations for the assessment of cardiac and pulmonary vascular disease among liver transplant candidates with end-stage liver disease
Cardiac or pulmonary vascular condition	Diagnostic modality	Test operating characteristics^c		Special considerations in ESLD	GRADE recommendations
Cardiac or pulmonary vascular condition	Diagnostic modality	PPV	NPV	Special considerations in ESLD	GRADE recommendations
Coronary artery disease				LT candidates with DM or ≥2 traditional cardiac risk factors^a are most likely to have obstructive CAD	Consider invasive or noninvasive angiography if known CAD, abnormal noninvasive test or a high pretest probability of CAD (DM or ≥2 traditional risk factors) (2C)
	Noninvasive stress testing DSE Vasodilator testing^d	0%-33% 15%-22%	75%-100% 77%-100%	LT candidates may not achieve maximal chronotropy on pharmacologic stress testing Resting microvascular vasodilation limits available coronary flow reserve	The decision to pursue stress testing should be based on individualized evaluation of the candidate's pretest probability for having CAD (see above) (1C)
	Functional testing Cardiopulmonary exercise testing (CPET)	Unknown	Unknown	VO₂ max, a measure of CV fitness, is achieved in <35% of patients with ESLD; VO₂ peak can be used as a surrogate³¹ Anaerobic threshold (AT), a measure of cardiopulmonary reserve, can be obtained in >90% of patients with ESLD Reduction in VO₂ peak <15 mL/min per kg places a patient in class III-IV heart failure category and predicts poor prognosis Reduction in aerobic capacity predicts outcomes in waitlist candidates and at 90 and 100 d post-LT	For ambulatory patients, functional testing may be useful to identify those LT candidates who are at increased risk for poor outcomes and who may benefit from prehabilitation (2C)
	6-minute walk test (6MWT)	Unknown	Unknown	-AT <9.0 mL/min per kg is associated with reduced 90-d survival -AT of <9.2 mL/minute per kg is associated with increased length of hospital stay 6MWD < 250 meters is associated with increased risk of death For each 100-meter increase in 6MWD survival increases by 42% (HR, 0.58; P = .02)³⁵
	Noninvasive coronary CT angiography (CCTA) Coronary artery calcium (CAC) score	17%^b	95%^b	CAC score > 400 HU predicts: -Significant CAD requiring revascularization³⁶ -1 month post-LT complications (OR, 95% CI: 4.62, 1.1–18.7)³⁷	Consider CCTA in patients with normal body habitus who are able to lie still, perform required breath-holding maneuvers, and who have a regular nontachycardic rhythm (2C) In candidates with advanced CKD and suspected CAD, consultation with a nephrologist and standard preventive measures for contrast-induced nephropathy are recommended (1C)
	Invasive coronary angiography	NA	NA	Invasive angiography, when indicated, is safe despite coagulopathy and renal dysfunction.	To reduce bleeding complications, a transradial approach (if possible) and minimization of sheath size are recommended (1C) Bare metal stents are preferred to minimize duration of dual antiplatelet therapy, though drug-eluting stents may also be used (1C) In candidates with advanced CKD and suspected CAD, consultation with a nephrologist and standard preventive measures for contrast-induced nephropathy are recommended (1C) Patients who have been revascularized surgically with coronary artery bypass grafting should be treated based on their pretransplant assessment of left ventricular ejection fraction and ischemic testing. If testing yields a reduction in systolic function or evidence of ischemia, then invasive testing should be performed to assess graft patency (1C)
Cardiomyopathy and heart failure	2-Dimensional echocardiography (TTE)			May detect diastolic dysfunction (hallmark of CC)LVOTO > 36 mm Hg increases risk for intraoperative hypotension LVH may suggest subclinical myocardial diseaseIncreased LA volume is a predictor of future heart failure events	Preoperative TTE should be performed in all candidates to assess systolic and diastolic cardiac function and LVOTO (1C) Detected abnormalities require a multidisciplinary approach as to the cause of findings, further testing. and initiation of heart failure therapies (1C)Presence of CC should be considered in the decision-making process when listing patients for LT (2C)
	DSE			May detect systolic dysfunction manifested by a decrease in stroke volume or ejection fraction LVOTO may be inducible	The decision to pursue stress testing should be based on individualized evaluation of the candidate's pretest probability for having inducible systolic dysfunction (1C)
	12-lead ECG			QTc prolongation (>440 ms) is the hallmark of CC and predicts post-LT cardiac complications Impaired excitation contraction coupling may be seen in CC; clinical significance unknown	Treat reversible causes of prolonged QTc and avoid QT prolonging medications (1C)
	Functional testing Cardiopulmonary exercise testing (CPET) 6-minute walk test (6MWT)			Alteration of aerobic capacity (VO₂ peak) or ventilator efficiency (VE/VCO₂) is a sign of CC Reduced exercise tolerance is a sign of CC	For ambulatory patients, functional testing may be useful to identify those LT candidates who are at increased risk for poor outcomes and who may benefit from prehabilitation (2C)
Portopulmonary hypertension	2-Dimensional echocardiography (TTE)	Elevated right-sided and pulmonary pressures (RVSP > 40–50 mm Hg) In patients with PoPH, RVSP overestimates PAP at higher levels of RVSP (r = 0.43)⁹³			Referral for RHC if elevated RVSP (>40–50 mm Hg) or RV systolic dysfunction found on TTE (1C)
Portopulmonary hypertension	Right-side heart catheterization	MPAP>25 mm Hg, PVR >240 dynes/s per cm⁻⁵ with PCWP <15 mm Hg		MPAP >35 mm Hg and PVR >400 dynes/s/cm⁻⁵ on RHC is a contraindication to LT	POPH should only be diagnosed on RHC (1C) RHC should assess response to medical therapy of confirmed PoPH (1C) A multidisciplinary team approach with experts in anesthesia and pulmonary hypertension is critical in the management of patients with POPH (1C)
Cardiac arrhythmias	12-lead ECG	QTc prolongation:>0.45 s males or >0.47 s females		AF prevalence is 1%-6% in LT candidates and is associated with a 6-fold increased odds of post-LT complications Prolonged QTc may be acquired or congenital and is common in CC	Arrhythmia on ECG should prompt a thorough history and investigation of associated causes (1C) In patients with known dysrhythmias, perioperative hemodynamic monitoring with treatment readily at hand, such as transcutaneous or transvenous pacing, electrical cardioversion or defibrillation, and appropriate anti-arrhythmic drugs is recommended (1C)
Valvular heart disease	2-Dimensional echocardiography (TTE)	28% of LT candidates have mitral or triscuspid regurgitation		TR is associated with poorer post-LT outcomes Mild or moderate asymptomatic AS is not an absolute contraindication to LT	TTE should be performed in all patients to assess for valvular disease (1C) Intraoperative TEE may be a useful adjunct in the management of patients with valvular heart disease undergoing LT (2C)

1C, Oxford Center for Evidence Based Medicine level of evidence for all or none randomized controlled trials; 2C, Oxford Center for Evidence Based Medicine level of evidence for "outcomes" based research; 6MWD, 6-min walk distance; 6MWT, 6-min walk test; AF, atrial fibrillation; AS, aortic stenosis; AT, anaerobic threshold; CAD, coronary artery disease; CC, cirrhotic cardiomyopathy; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; DM, diabetes mellitus; DSE, dobutamine stress echocardiography; ECG, 12-lead electrocardiogram; ESLD, end-stage liver disease; HR, hazard ratio; HU, Hounsfield units; LA, left atrial; LT, liver transplant; LVH, left ventricular hypertrophy; LVOTO, left ventricular outflow tract obstruction; MPAP, mean pulmonary artery pressure; NA, nonapplicable; NPV, negative predictive value; OR, odds ratio; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PoPH, portopulmonary hypertension; PPV, positive predictive value; PVR, pulmonary vascular resistance; RHC, right heart catheterization; RV, right ventricle; RVSP, right ventricular systolic pressure; TTE, transthoracic echocardiogram; TR, tricuspid regurgitation; VO_{2 max}, maximum oxygen consumption; VO_{2 peak}, peak oxygen consumption; VE/VCO_s, minute ventilation/carbon dioxide production; VO, oxygen volume (oxygen consumption); VCO_2, carbon dioxide production.
^aTraditional risk factors for CAD include age (male > 45 y; female > 55 y), hypercholesterolemia, hypertension, tobacco use, and family history of early CAD (first-degree relative male < 55 y; female < 65 y).
^bEstimates taken from data in the general population⁴⁰; to date there are no data comparing CCTA to invasive coronary angiography in liver transplant candidates.
^cAs compared to invasive coronary angiography as criterion standard.