Cardiovascular risk stratification in the noncardiac solid organ transplant candidate

Abstract

Purpose of review

Solid organ transplantation (SOT) has become a widely accepted therapy for end-stage disease across the spectrum of thoracic and abdominal organs. With contemporary advances in medical and surgical therapies in transplantation, candidates for SOT are increasingly older with a larger burden of comorbidities, including cardiovascular disease (CVD). CVD, in particular, is a leading cause of morbidity and mortality in SOT candidates with end-stage disease of noncardiac organs [1].

Recent findings

Identification of coronary artery disease (CAD), heart failure, and valvular disease are important in noncardiac SOT to ensure both appropriate peri-transplant management and equitable organ allocation. Although the American College of Cardiology (ACC) and the American Heart Association (AHA) have published guidelines and recommendations for the perioperative cardiovascular evaluation of patients undergoing noncardiac surgery, the implications of both symptomatic and asymptomatic CVD differ in patients with end-stage organ failure being considered for SOT when compared to the general population.

Summary

Herein, we review the epidemiology, diagnosis, and evidence for the management of CVD in kidney and liver transplantation, combining current guidelines from the 2012 ACC/AHA scientific statement on cardiac disease evaluation in SOT with more contemporary evidenced-based algorithms.

INTRODUCTION

The average age of solid organ transplantation (SOT) candidates has increased significantly in the current era, with a particular increase in the proportion of patients over 65 years old (Fig. 1) [2]. This demographic shift is associated with an increase in the prevalence of pretransplant comorbidities including hypertension (HTN) and diabetes (DM). For example, in 2019, 38% of kidney transplant candidates had underlying diabetes, which had increased from 31% in 2009. Furthermore, in liver transplantation (LT), nonalcoholic fatty liver disease (NAFLD) is expected to become the most common indication for LT within the next decade [3]. As a result, an increasing number of patients with coronary artery disease (CAD) risk factors that are associated with the metabolic syndrome observed in patients with NAFLD such as insulin resistance and HTN will be considered for LT [4]. Taken together, the prevalence of CAD in these SOT populations is high and will continue to increase, underscoring the need for appropriate screening and management to optimize peri- and posttransplant outcomes.

FIGURE 1.

Trends in the age of patients at time of listing for solid organ transplant in the contemporary era.

GOALS OF CARDIOVASCULAR RISK STRATIFICATION IN SOLID ORGAN TRANSPLANTATION CANDIDATES

The goals of assessing cardiovascular disease (CVD) risk in SOT candidates are twofold. First, at the patient level, the screening of SOT candidates – even those that are asymptomatic – may identify significant CVD such that risk of thoracic or abdominal surgery alone would be prohibitive and lead to poor patient outcomes. In other words, a patient may be deemed not a candidate for SOT as the potential risk of surgery could outweigh its benefits. Second, evaluation of CVD risk allows for prioritization of organs to those candidates who will achieve maximum long-term benefits without their longevity being limited by cardiovascular comorbidities. Globally, preoperative evaluation is intended to identify those SOT candidates who have an active cardiovascular comorbidity including acute coronary syndromes, heart failure (HF), arrhythmia, or valvular disease that may compromise their posttransplant outcome.

RENAL TRANSPLANTATION

In the first section, we summarize key data and recommendations for risk stratification of renal transplant candidates with regard to CAD, HF, valvular disease, and pulmonary HTN. A summary of relevant American College of Cardiology (ACC)/American Heart Association (AHA) guidelines can be found in Table 2.

Table 2.

ACC/AHA Guidelines for Liver Transplant Candidates [1]

Coronary artery disease	Consider stress testing in liver transplant candidate with multiple CAD risk factors.	(Class IIb; Level of Evidence C).
Coronary artery disease/heart failure	Liver transplant candidates with an LVEF < 50%, ischemic LV dilatation, exercise-induced hypotension, angina, or known ischemia should be referred to cardiology for management.	(Class I; Level of Evidence B).
Pulmonary hypertension	Perform resting echocardiography in liver transplant candidates to quantify LV function and screen for PH and/or intrapulmonary shunt.	(Class IIb; Level of Evidence C).

ACC, American College of Cardiology; AHA, American Heart Association.

Coronary artery disease risk stratification in renal transplant candidates

Patients with end-stage renal disease (ESRD) have a significantly higher risk of CAD than the general population, with over 40% of their all-cause mortality being attributable to an underlying cardiovascular cause [5]. Because of the prevalence of underlying CAD, the incidence of myocardial infarction (MI) while awaiting renal transplantation is as high as 16% after 3 years, and the majority of deaths within 30 days of transplant are attributable to perioperative MI [6]. Current consensus from the ACC/AHA suggests a need for further diagnostic testing regardless of functional status and symptoms based upon the presence of three or more of the following risk factors: diabetes, known CVD, > 1 year on dialysis, left ventricular hypertrophy, age over 60, smoking, HTN, and hyperlipidemia [Class IIb; Level of Evidence C] [1].

Exercise treadmill testing without associated imaging is largely unhelpful in this patient population due to high false negative rates and difficulty in identifying ischemia on electrocardiogram (EKG) tracing in the presence of left ventricular hypertrophy [7]. Regadenoson is the most commonly used pharmacologic agent for vasodilator-based myocardial perfusion imaging. Although this agent is partially renally excreted, it is safe and Food and Drug Administration approved in patients with low glomerular filtration rates with only a slightly higher risk of GI side effects, which can be ameliorated with aminophylline administration [8]. Dobutamine stress echo can also be used as an imaging modality, though its use may be limited by uncontrolled HTN. More recently, other imaging modalities such as cardiac computed tomography (CT) ± coronary artery calcium scoring as well as cardiac magnetic resonance imaging have been studied to assess burden and location of obstructive CAD, but evidence remains limited in this population.

Treatment of CAD in patients with ESRD awaiting renal transplantation is similar to that of patients without kidney disease in terms of risk factor modification and secondary prevention. A recently published posthoc analysis of the ISCHEMIA-chronic kidney disease (CKD) trial, including transplant candidates with chronic, stable coronary syndromes and at least moderate ischemia, found no significant difference in all-cause mortality or nonfatal MI between those randomized to an invasive strategy of angiography and/or revascularization versus medical therapy alone [9]. For those patients who require revascularization, studies of patients with multivessel disease and CKD suggest some survival benefit with coronary artery bypass grafting as compared to percutaneous coronary intervention (PCI). The current KDOQI guidelines recommend surgical revascularization for left main or significant three-vessel disease [10,11]. For those in whom PCI is felt to be the optimal strategy, drug eluting stents are preferred to bare metal stents due to the increased risk of restenosis, which is higher at baseline in patients with ESRD compared to the general population [12]. Once listed for renal transplantation, there is no clear consensus on the optimal frequency and modality of surveillance testing. Although current KDOQI guidelines recommend yearly testing in patients awaiting transplantation, the benefit of this approach, particularly in low-risk patients, is uncertain [Class IIB; Level of Evidence C] [1].

Heart failure and the renal transplant recipient

The ACC/AHA guidelines currently recommend preoperative evaluation of left ventricular function using standard transthoracic echocardiography for all solid organ transplant candidates [1]. Due to the hemodynamic perturbations associated with dialysis as well as shared risk factors, HF has been estimated to affect up to 36% of patients with ESRD and those on dialysis may develop HF at rates as high as 7% per year [13,14]. These patients can exhibit both diastolic and systolic dysfunction, with each 1% reduction in left ventricular ejection fraction associated with a 2.7% increase in mortality risk [15]. HF in renal transplant candidates should be treated with guideline-directed medical therapy, though optimization of HF regimens may be limited in those patients with advanced CKD who are not yet dialysis dependent. For those with LVEF ≤35% despite GDMT, right and left heart catheterization should be performed for HF prognostication and to identify potential targets of surgical or percutaneous revascularization, ideally with low or no contrast. If LVEF remains low despite aggressive medical therapy, dual organ transplantation, and/or primary prevention ICD should be considered.

Valvular heart disease and end stage renal disease

Valvular heart disease, particularly degenerative calcification, is much more prevalent in patients with CKD than the general population as a result of dysregulated calcium and phosphate metabolism [16]. The incidence of calcific aortic and mitral valve disease, in particular, is directly related to time on dialysis and often progresses rapidly [1]. Mitral and aortic disease should be managed in renal transplant candidates according to the established ACC/AHA guidelines [17]. On the basis of their elevated surgical risk, patients with ESRD should be considered for transcatheter aortic valve replacement for definitive therapy of severe aortic stenosis prior to renal transplantation. Decision-making around surgical versus percutaneous approaches, however, should be individualized and made in conjunction with an interventional cardiologist and cardiac surgeon. In patients with significant primary or secondary mitral regurgitation, initial attempts at volume optimization should be made either with diuretic therapy or with titration of dialysis. If the mitral regurgitation fails to improve, the patient should be evaluated for either percutaneous or surgical repair, though mortality remains high regardless of the approach [18,19].

Pulmonary hypertension in renal transplant candidates

Pulmonary hypertension (PH) is another common comorbidity that is estimated to affect up to 30–60% of patients with CKD [20]. Risk factors for the development of pre and postcapillary PH in ESRD include chronic hypervolemia, anemia, and arteriovenous fistulas, all of which contribute to pulmonary artery endothelial dysfunction and ultimately pulmonary vascular disease [21]. Group II PH, or that attributable to left heart disease, is the most common type of PH in patients with renal failure owing to the progressive systolic and diastolic dysfunction as described above. Arteriovenous fistulas which are associated with high cardiac output and high pulmonary vascular flow may also contribute to significant PH, such that closure of AV fistulas peri-renal transplantation may improve PH. Pulmonary vasodilators have not been well studied in this population, but may be considered in patients with Group I PAH under the care of a PH specialist with consideration of avoidance of those therapies which are renally cleared. Assessment of candidacy for renal transplantation in patients with PH is of paramount importance to identify those patients with prohibitive or irreversible PH, such that renal transplant may have limited long-term success. Expert consensus supports performing a right heart catheterization in those patients with persistent, moderate, or severe elevation in estimated pulmonary artery systolic pressure by transthoracic echo (PASP > 45 mmHg) [22]. Efforts should be made to perform right heart catheterization ideally after volume optimization. In those with AV fistulas, hemodynamics should be measure with and without AVF occlusion to quantify the contribution of the AVF to the elevated pulmonary pressure.

LIVER TRANSPLANTATION

In this final section, we summarize key data and recommendations regarding risk stratification for liver transplant candidates with regard to CAD, cirrhotic cardiomyopathy and PH. A summary of relevant ACC/AHA guidelines can be found in Table 2.

Cardiovascular disease assessment of liver transplant candidates

CVD is the number one cause of early death following LT. Asymptomatic obstructive CAD is estimated to affect up to 25% of LT candidates, with an even higher prevalence in patients being evaluated for LT due to NASH [23]. Because of chronotropic incompetence and systemic vasodilation, use of exercise, dobutamine, and vasodilator stress testing all have limited sensitivity and specificity in the patient with end stage liver disease. As a result, coronary angiography – either noninvasively with CCTA or invasively with left heart catheterization – remains the gold standard for the diagnosis of CAD in a patient with cirrhosis [24^■■]. If obstructive CAD is identified, revascularization has been shown to improve outcomes – even in patients with stable asymptomatic CAD [25]. Importantly, the ACC/AHA guidelines recommend routine involvement of cardiovascular clinicians in the care of LT candidates, particularly in those with abnormal transthoracic echocardiograms or EKG findings (Class IIb, Level of Evidence C). In this group of patients, as well as those with diabetes and two or less risk factors for CAD but without NASH, CCTA with calcium scoring can be considered for risk stratification. If CCTA is abnormal or if CCTA is contraindicated, invasive angiography should be performed. In those low-risk individuals with only one ACC/AHA risk factor, stress echocardiography should provide a sufficient screening tool. In those patients less than 40 years old without CAD risk factors who have excellent functional capacity, further ischemic work up is not required. Annual screening for modifiable CVD risk factors in LT candidates is reasonable.

Management of cirrhotic cardiomyopathy prior to liver transplant

The unmasking of cirrhotic cardiomyopathy – defined as cardiac dysfunction that develops with end-stage liver disease in the absence of prior heart disease – is a common cause of early readmission following LT [26]. Prior to LT, end-stage liver disease physiology is typically characterized by a high output, low systemic vascular resistance state. Cirrhotic cardiomyopathy can be identified in the setting of abnormal LVEF and/or abnormal global longitudinal strain [26]. Although an LVEF < 40% is generally considered a contraindication to isolated LT, reassessment of LV function at 6-month intervals in combination with appropriate GDMT may reveal interval improvement in LV function to permit reassessment for isolated LT. In clinical practice, uptitrating GDMT in this population may be limited due to relatively lower blood pressures from systemic vasodilation.

Assessment of pulmonary hypertension in end stage liver disease

Portopulmonary hypertension (PoPH) —or pulmonary arterial HTN associated with portal HTN – is thought to affect 2–10% of patients with liver disease, both cirrhotic and noncirrhotic [27]. Screening for PoPH is important in LT candidates, as significant PoPH is a contraindication to LT and any degree of PoPH may affect pre and posttransplant survival [28,29]. Transthoracic echo can be used as an initial screening modality, with expert consensus that an RVSP > 45 mmHg or other findings consistent with PoPH and/or RV dysfunction should prompt referral for right heart catheterization [30]. Invasive hemodynamic findings of elevated mPAP (>20mmHg) with a normal PCWP (<15 mmHg) in the presence of portal HTN (hepatic wedge to vein gradient > 5 mmHg) is diagnostic of PoPH. Those patients with mPAP > 35 mmHG should be referred to a PH specialist to determine whether they are a candidate for PH- specific therapies. If their mPA pressure can be lowered to < 35mmHg with a PVR < Woods Units, they can be considered for LT [31].

CONCLUSION

SOT candidates with end-stage renal or hepatic disease are at a high risk of perioperative cardiovascular morbidity and mortality. Pretransplant ischemic evaluation should be guided by the presence of CAD risk factors and functional status. HF in this patient population should be managed aggressively with guideline-directed medical therapy. Screening for pulmonary HTN and pulmonary vascular disease is important for risk stratification, assessment of candidacy, and appropriate referral for PH-specific therapies. If patients are deemed to have active, concomitant CVD, collaboration with cardiology, and/or pulmonary vascular disease specialists are of paramount importance to assure appropriate diagnostic testing as well as determination of whether single or dual organ transplantation should be pursued.

Table 1.

ACC/AHA Guidelines for Renal Transplant Candidates [1]

Coronary artery disease	Preoperative 12-lead EKG in patients with known cardiovascular disease or with any cardiovascular symptoms.	(Class I; Level of Evidence C).
	Preoperative 12-lead EKG in patients without known cardiovascular disease or without any cardiovascular symptoms.	(Class IIa; Level of Evidence C).
	Annual 12-lead EKG after listing for kidney transplantation.	(Class IIb; Level of Evidence C).
	Noninvasive stress testing in kidney transplantation candidates on the basis of multiple CAD risk factors.	(Class IIb, Level of Evidence C).
	The role of nonconkitetrast CT calcium scoring and/or cardiac CT angiography in pretransplant risk stratification is uncertain.	(Class IIb; Level of Evidence B).
	The role of periodic screening for myocardial ischemic in asymptomatic kidney transplantation candidates while listed for transplant is uncertain.	(Class IIb; Level of Evidence C).
	In kidney transplant candidates, LVEF < 50%, evidence of ventricular chamber enlargement, exercise induced hypotension, angina, or known ischemia should prompt referral to a cardiologist for the management of ischemic heart disease.	(Class I; Level of Evidence B).
	Revascularization prior to transplant should be considered in patient who meet the 2011 ACC/AHA Guidelines [1].	(Class I; Level of Evidence B).
	CABG is preferred to PCI to in kidney transplant candidates with multivessel CAD and diabetes mellitus.	(Class IIa; Level of Evidence B).
	In patients with ESRD, CABG may be considered in the presence of significant (>50%) left main stenosis, significant 3 vessel disease (≥70%), or significant disease (≥70%) in the proximal LAD and one other epicardial vessel.	(Class IIb; Level of Evidence B).
	Prophylactic revascularization in patients with stable CAD that will not improve symptoms or survival is not recommended prior to transplant surgery.	(Class III; Level of Evidence B).
Heart failure	Echocardiographic assessment of left ventricular function in potential kidney transplant candidates.	(Class IIa; Level of Evidence B).
Valvular disease	Consider yearly echocardiogram in patients with ESRD and moderate aortic stenosis.	(Class IIb; Level of Evidence C).
Pulmonary hypertension	If significant pulmonary hypertension is identified on echocardiographic screening of a kidney transplant candidate, evaluate for secondary causes (eg, obstructive sleep apnea, left heart disease).	(Class IIa; Level of Evidence C).
	If significant pulmonary hypertension is identified on screening echocardiogram (eRVSP > 45mmHg or other evidence of RV pressure/volume overload) consider right heart catheterization.	(Class IIb; Level of Evidence C).
	If PAH is diagnosed on right heart catheterization in the absence of a secondary cause, consider referral to a pulmonary vascular disease specialist.	(Class IIa; Level of Evidence C).

ACC, American College of Cardiology; AHA, American Heart Association; CABG, coronary artery bypass grafting; EKG, electrocardiogram; PCI, percutaneous coronary intervention.

KEY POINTS.

• In the contemporary era, solid organ transplant candidates are increasingly older with a greater burden of comorbidities.

• Peri-transplant screening for coronary artery disease, valvular heart disease, heart failure, and pulmonary hypertension are of paramount importance to ensure optimal posttransplant outcomes and equitable distribution of organs.

• Collaboration with cardiologists and/or pulmonologists is recommended in patients with active cardiovascular disease or pulmonary hypertension to guide peri-transplant care and ensure appropriate management.