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


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

In This Article

Coronary Artery Disease

The prevalence of coronary artery disease (CAD) is rising among LT candidates.[7] Approximately 25% of LT candidates with traditional coronary risk factors (eg hypertension, hypercholesterolemia) may have moderate CAD (stenosis ≥50%) even while asymptomatic,[8] and those with severe CAD have increased cardiac mortality despite coronary interventions.[9] LT candidates with diabetes mellitus (DM) or ≥2 traditional cardiac risk factors are most likely to have obstructive CAD,[10–12] and those with nonalcoholic steatohepatitis (NASH) and renal dysfunction are most likely to have critical coronary stenosis.[13–16] Multivessel CAD (versus no CAD) has been associated with increased mortality and postoperative hemodynamic instability even in the absence of severe stenosis;[17] however, recent data have shown that severity or extent of CAD does not impact post-LT survival, if appropriately revascularized.[8,18]

Ischemic evaluation with exercise stress testing has poor predictive value in LT candidates[19–25] due to a limited ability to exercise to target heart rate; thus pharmacologic stress testing is frequently required.[26] Even in the absence of exercise, LT candidates may not achieve target heart rate due to impaired chronotropy on dobutamine stress echocardiography (DSE). DSE has been shown to have low sensitivity (13%) and low negative predictive value (75%) in the ESLD population.[20,21,23–25] Pharmacologic vasodilator (eg regadenoson) stress testing also has limited utility in LT candidates due to the chronic vasodilatory state exhibited by patients with ESLD.[22] This may effectively "decrease" available coronary flow reserve and result in both false-positive perfusion defects and false-negative studies.[19,27–30]

Cardiopulmonary exercise testing (CPET) with measurement of maximum aerobic capacity (maximum oxygen consumption [VO2] max or VO2 peak) and ventilatory or anaerobic threshold may provide additional prognostic information for LT candidates.[31] A reduction in aerobic capacity has been shown to predict outcomes in LT candidates waiting for LT[32] and at 90[33] and 100 days post-LT.[34] The 6-minute walk test (6MWT) is easily performed measuring the distance a patient can walk in that time frame. It has been shown to be predictive of outcomes in multiple conditions including cardiac and pulmonary. In LT candidates, a 6MWT distance of <250 m is associated with an increased risk of death after transplant, and for each 100-m increase in the distance achieved there is an adjusted 42% improvement in survival rates.[35] The challenge in applying these tests is the need for specialized equipment and technicians (CPET) or the length of time it takes to conduct the test (6MWT), which poses a barrier to frequent longitudinal measurement and limits their utility in the outpatient setting.

The utilization of coronary artery calcium (CAC) scoring via computed tomography (CT) angiography has demonstrated that 30% of LT candidates have at least moderate (≥50% stenosis) asymptomatic CAD.[12,36] A CAC score >400 Hounsfield Units is predictive of significant CAD requiring revascularization[36] and of 1-month post-LT cardiovascular complications.[37]

Given the overall low sensitivity of noninvasive testing in patients with ESLD, coronary angiography, invasive or noninvasive, remains the criterion standard for detection of CAD. Noninvasive coronary CT angiography (CCTA) may be an acceptable alternative to invasive angiography in patients with normal body habitus who are able to lie still, can perform required breath-holding maneuvers, and have a regular nontachycardic rhythm.[12,38,39] In the general population, CCTA has a very high sensitivity (≈90%) and negative predictive value (≈95%) for excluding significant CAD.[40] Thus, a normal scan result effectively excludes obstructive CAD and may limit the need for further investigation.[41] To date, there have been no reports comparing CCTA and invasive coronary angiography for detecting CAD in liver transplant recipients.[42] Invasive coronary angiography can be performed safely in LT candidates even with renal dysfunction and elevated bleeding risk.[43–45] Invasive angiography via a transradial approach, if possible, is the preferred method in LT candidates, to improve hemostasis and reduce periprocedural complications.[46–48]

In patients with ESLD and concomitant kidney disease, there is a risk of acute kidney injury following intravenous contrast administration. Patients with end-stage renal disease who are on chronic dialysis without expectation of renal recovery may be candidates for angiography, because there is no additional risk to renal function. Patients with normal renal function do not seem to be at a higher risk of developing contrast-induced nephropathy (CIN) despite concomitant ESLD.[48] There are minimal available data that examine the risk of CIN after angiography in patients with ESLD. In general, risk factors for CIN include prior recent contrast exposure, high contrast volume, reduced left ventricular ejection fraction, acute kidney injury, baseline serum creatinine > 1.5 mg/dL, reduced creatinine clearance, DM, hypotension, and advanced age.[49] Patients who develop CIN may also be at risk for worse cardiovascular outcomes.[50] Effective treatment and preventative strategies for CIN have not been specifically studied in ESLD, but limiting iodinated contrast volume dose and administering adequate periprocedural volume expansion are in line with current practice guideline recommendations.[51] Given the medical complexity of this patient population, a multidisciplinary discussion between nephrology, cardiology, and the transplant team is required prior to performing angiography in patients with chronic kidney disease and ESLD.

Revascularization of obstructive CAD may improve symptoms and cardiovascular mortality, and in cases where the burden of obstructive CAD would prohibit LT in an otherwise appropriate surgical candidate.[18,29,52–55] Revascularization, necessitating the need for dual antiplatelet therapy (DAPT), can be performed safely and can improve post-LT outcomes similar to those in LT candidates without significant CAD.[56,57] Management of thrombocytopenia and coagulopathies as well as minimizing the sheath size may reduce vascular and bleeding complications after invasive angiography.[58] Bare metal stents are typically preferred in LT candidates to minimize the duration of DAPT. The current standard of care is for 1 year of DAPT after both bare metal and drug-eluting stents. In patients requiring noncardiac surgery, such as LT, the current recommendation is to wait a minimum of 1 month after bare metal and 6 months after drug-eluting stent placement.[59] In the future, newer generation drug-eluting stents may require a shorter duration of therapy. In select patients, coronary artery bypass grafting (CABG) may be performed prior to LT.[52,60,61] Advanced age, female gender, and the presence of clinical heart failure or ascites are predictors of mortality after CABG in cirrhosis; however, these data must be interpreted with caution given low representation of cirrhotic patients in surgical study cohorts.[61] Patients who have been revascularized with CABG 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. Nonrevascularized obstructive severe multivessel CAD is an absolute contraindication for LT (Table 1).