Finding the Road to Rome in Cardiac Allograft Vasculopathy Imaging Surveillance : Transplantation

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Finding the Road to Rome in Cardiac Allograft Vasculopathy Imaging Surveillance

Chih, Sharon MBBS, PhD1; Beanlands, Rob S.B. MD2; Moayedi, Yasbanoo MD, MHSc3; Ross, Heather J. MD, MHSc3

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doi: 10.1097/TP.0000000000004101

The purpose of clinical surveillance is to diagnose and prognosticate disease, ideally undertaken as the findings have significant bearing on patient care by directing preventive or treatment interventions. Cardiac surveillance after heart transplantation (HT) is routine for allograft function, rejection, and cardiac allograft vasculopathy (CAV). Although strategies for post-HT surveillance continue to evolve, particularly with the development of less invasive blood-based testing for rejection, the best screening approach for CAV remains unclear. There is a pressing need for effective solutions for CAV, underscored by a continuing high 50% transplant lifetime disease prevalence and being a predominant cause of late allograft failure and reason for retransplantation.1 Better surveillance is critical to bridging the management gap for CAV.

In 2010, the International Society for Heart and Lung Transplantation proposed universal invasive coronary angiography (ICA)–based definitions for CAV.2 This CAV 0–3 grading system has since been externally validated in large patient cohorts and shown to be prognostic.3 However, a major criticism of the reliance on ICA for CAV is the detection of disease at a late stage or missing disease, including early coronary intimal hyperplasia and microvascular dysfunction, which are both predictors of poorer outcomes. Additionally, regular ICA monitoring is limited as it is invasive, imparting risk and discomfort to patients. Adjunctive intravascular imaging early posttransplant has incremental value to ICA for identifying patient populations at increased risk of adverse cardiovascular events, including patients with donor transmitted atherosclerosis and rapidly progressive coronary intimal thickening within the first year of transplant.4,5 In these high-risk CAV patients, early treatment with a mammalian target of rapamycin inhibitor can attenuate disease progression.6 Beyond the early posttransplant period, routine invasive coronary screening has uncertain benefits. Similarly, invasive screening may be of limited value for patients who are already on a mammalian target of rapamycin inhibitor as their management is unlikely to be altered. Although the detection of late angiographic CAV is relevant for risk stratification, there are few effective treatment options apart from retransplantation.7 Percutaneous coronary revascularization is often undertaken for focal obstructive disease, but without strong accompanying data for improving clinical outcomes such as reducing myocardial infarction, graft dysfunction, death, or need for retransplant. Noninvasive imaging-guided ICA is a common approach for CAV surveillance in asymptomatic patients, particularly for patients who are outside the early 2–3-y posttransplant period. In addition to guiding invasive assessment, noninvasive imaging may also direct management decisions, including revascularization and retransplantation. The ideal noninvasive imaging modality for CAV surveillance has not been established. Several techniques are used clinically, including stress echocardiography, myocardial perfusion imaging (single-photon emission computed tomography [SPECT], positron emission tomography [PET], magnetic resonance imaging [MRI]), myocardial blood flow quantification (PET or MRI), and computed tomography coronary angiography (CTCA).8,9 Data supporting the use of these modalities are mostly derived from observational single-center studies. There have been no randomized controlled trials of noninvasive imaging surveillance for CAV or studies comparing different modalities.

The International Society for Heart and Lung Transplantation guidelines on CAV evaluation are undergoing revision with anticipated updates to existing recommendations for annual or biannual ICA (currently class I), intravascular ultrasound (currently class IIa), and noninvasive modalities (currently class IIa for stress echocardiography and SPECT and class IIb for CTCA).10 Although there are mounting data supporting specific techniques and approaches, variable access to testing, associated cost, and available management interventions influence physicians’ perceived risks and benefits of screening. These have contributed to a lack of clarity and practice standardization for CAV surveillance between institutions and even among physicians within the same institution.

We demonstrated clinical practice variability for CAV surveillance in an international online survey (Supplementary Data, SDC, completed by 72 respondents, predominantly from North America (61%) and Europe (21%). All institutions perform routine screening for CAV in asymptomatic HT patients with 76% performing testing lifelong. Almost all institutions (96%) undertake ICA for CAV surveillance, and more than half (59%) perform adjunctive intracoronary imaging such as intravascular ultrasound or optical coherence tomography (Figure 1). Most institutions (79%) also perform noninvasive imaging for CAV surveillance, but their selected modality differs (Figure 1) for reasons such as center expertise (43%), patient safety/comfort (40%), supporting data (19%), and cost (17%). Notably, stress echocardiography (88%), SPECT (78%), and CTCA (81%) are readily accessible, whereas perfusion PET (49%) and MRI (56%) are less available. These findings are noteworthy as variation in screening practices may underestimate CAV detection and incidence, which impedes our appreciation of the true burden of CAV as well as our understanding of clinical risk predictors, natural history of disease, patient outcomes, and the impact of management interventions.

Institutional practice for cardiac allograft vasculopathy surveillance. CAV, cardiac allograft vasculopathy; CT, computed tomography; IVUS, intravascular ultrasound; OCT, optical coherence tomography; PET, positron emission tomography; SPECT, single-photon emission tomography.

Our survey also sought to determine whether there is clinical equipoise on CAV surveillance. All clinicians believe CAV surveillance to be important and most (79%) screen patients lifelong. The majority (92%) are comfortable to undertake annual or biannual ICA in patients at low risk for procedural-related complications. However, opinions diverge on the duration of ICA monitoring post-HT, with only 50% indicating performing ICA in patients lifelong (Figure 2). Most clinicians (71%) are comfortable undertaking annual screening for CAV using noninvasive imaging instead of ICA. Similar to ICA monitoring, clinicians differ on noninvasive surveillance regarding time from transplant, but most of them seem comfortable using noninvasive imaging after 5 y posttransplant, including 26% who were comfortable with noninvasive imaging at any time posttransplant (Figure 2). A preferred noninvasive imaging modality is not apparent, and 49% of clinicians are comfortable using any available modality for CAV, including stress echocardiography, SPECT, PET, or CTCA (Figure 2). Overall, these opinions indicate a state of equipoise among clinicians on the approach for CAV surveillance, particularly in the later years from transplant.

Clinician opinion on cardiac allograft surveillance. CAV, cardiac allograft vasculopathy; CTCA, computed tomography coronary angiography; PET, positron emission tomography; SPECT, single-photon emission tomography.

The high clinical burden of CAV combined with treatment deficiencies for established disease emphasizes the need for vigilant and standardized surveillance after HT. Studies demonstrating diagnostic and prognostic utility for coronary and functional imaging in CAV have not compared modalities. Furthermore, efficacy endpoints have not consistently incorporated clinically meaningful outcomes, such as mortality, retransplantation, allograft dysfunction, heart failure, and revascularization. Hence, the ideal surveillance strategy for CAV is uncertain, and there is heterogeneity in institutional practice and clinician opinion on screening frequency, invasive versus noninvasive assessment, intracoronary imaging, and preferred noninvasive modality. Moreover, there is clinical equipoise. These factors provide clear impetus and justification for a randomized clinical trial to evaluate contemporary surveillance approaches on clinical outcomes and determine whether a noninvasive or invasive imaging strategy for CAV is ideal. The generation of high-quality clinical efficacy data is necessary to establish robust clinical surveillance for CAV diagnosis and risk stratification. Early disease detection and prognostication are in turn vital for advancing toward new patient-tailored therapies for CAV. Although many roads may lead to Rome, it is indeed time to find and travel on the best path forward for CAV surveillance.


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