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25520 Medical Adherence and Outcomes After Heart Transplant
immunosuppression and increased incidence of
late acute rejections, as reported by De Geest
et al. [5].
Adherence and Heart Transplant Outcomes
Depending on the definition of adherence and
the metrics employed, studies have provided
wide ranges of adherence estimates in organ
transplant recipients. A recent systematic review
on the topic in HTx recipients provides an overview of this heterogeneity in reporting [4]. The
authors demonstrate that adherence was reported
to be 25% in 1 study, between 25 and 40% in
5 studies, and the majority of studies (9 of
them) noted an adherence rate between 50 and
80% [4]. Non-adherence is widely recognized
to impact various post-transplant outcomes. A
study by De Geest et al. stratified patients into
different “compliance” groups based on several
compliance-related variables into “excellent
compilers” (84%), “minor subclinical noncompliers” (7%), and “moderate subclinical noncompliers” (9%), which showed a 1.19, 14.28,
and 22.22% incidence of late acute rejections,
respectively [5]. Dobbels et al. found that nonadherence was significantly associated with
the development of cardiac allograft vasculopathy (CAV) [3]. Farmer et al. showed a significant association between both moderate and
high adherence and improved mortality rates at
5–10 years [6]. Similarly, a retrospective study
using claims data from a single, large national
pharmacy chain (claims data from 2013 to
2016) and post-transplant follow-up data from
the OPTN database showed that after adjusting
for covariates, the odds of having a surviving
graft were almost double for adherent patients
than for non-adherent patients (OR:1.94, 95%
CI 1.58–2.37; p < 0.001) [7]. Other notable factors associated with graft survival included
having three or fewer post-index prescriptions for chronic conditions (OR: 4.33, 95% CI
3.55–5.27; p < 0.001) and filling immunosuppressants digitally (OR: 2.25, 95% CI 1.13–4.48,
p < 0.001) [7].
Factors Associated with Poor Medical Adherence
Various factors are associated with medication adherence rates, and Hussain et al. have
broadly and aptly divided them into five categories: sociodemographic, behavioral, medication-obtaining support, mental/emotional
well-being, and health/transplant-related factors
[4]. In the socio-demographic category, factors
associated with better adherence include older
age and female gender, while longer time since
transplant, African ancestry, and lower monthly
income are associated with non-adherence [4].
In the behavioral category, non-compliance with
other behavioral recommendations is a marker
for poorer medical compliance [4]. Examples of
such are the consumption of soft-boiled unpasteurized eggs and unpasteurized milk as well as
being a current/recent smoker. In the support
category, patients appear to demonstrate better adherence if they fill their medications digitally, have better social support, and improve
their health literacy by getting help with reading
health-related educational materials [4]. In the
mental/emotional status category, lower adherence is observed in those with higher self-care
disability, poorer psychosocial functioning,
higher depression scores, avoidant attachments,
and distrust of medications and healthcare systems [4]. Finally, in terms of health/transplant-
related factors, improved medical compliance
correlates with the need for fewer concomitant
prescriptions for other chronic conditions [4].
Compliance with Lifestyle Habits
In addition to medication adherence, lifestyle
habits can also adversely affect organ survival
[8–10]. Oftentimes, due to time limits, these
factors are not adequately reviewed during posttransplant follow-up appointments, and as such,
emphasis on their importance is lost. Studies
have shown that among solid organ transplant
patients, HTx recipients exhibit some of the
highest non-adherence rates to physical exercise,
256 A. P. Nikolova
with estimated rates of 34–49% [8–11]. Similar
trends are reported for non-adherence to dietary
recommendations (rates 23–46%) and missed
or canceled appointment rates (up to the astronomical 94%) [9]. Alcohol and tobacco use has
been reported in approximately 4.9–27.8% and
3.2–9.1% of HTx recipients, respectively [12].
Helmy et al. further revealed that up to 39.9%
of HTx recipients did not apply sun protection
as recommended to prevent skin cancer [8].
However, there is a paucity of studies on how
these various risk categories interact, co-exist,
and influence one another.
Interventional Strategies to Improve Adherence in Heart Transplant Recipients
Multiple interventional strategies have been
explored with the goal of improving transplant
recipients’ adherence. These have included
mobile health strategies (mHealth) with electronic monitoring feedback, pharmacist-led interventions, and cognitive education [13]. They
have been modestly associated with improved
compliance metrics [4]. A small single-center
randomized control trial of 137 HTx recipients
(mHeart trial) tested an mHealth-based tool vs
conventional follow-up to improve patient adherence [14]. Metrics assessed included patients’
experience of therapeutic regimens (including
the degree of inconvenience related to taking
medication, patients’ knowledge of their regimen intakes, drug names, drug doses, and drug
indications [14]. This small pilot study showed
that an mHealth-based strategy significantly
improved adherence in HTx recipients [14].
Additionally, the study showed a significant
reduction in the number of patients needing to
travel to the clinic for follow-up appointments
with the clinical pharmacist [14]. Similarly,
findings from a systematic review by Marcelino
indicated that a psycho-educational intervention
program exerted a positive impact on adherence
in HTx recipients [15]. Such strategy was tested
in a randomized control trial (The MAESTROTx
trial), which included 205 heart, liver, and lung
transplant recipients who were randomized to a
control vs interventional group [16]. The intervention group received staged multicomponent
tailored behavioral interventions (visits 2–4)
based on social cognitive theory and the transtheoretical model (e.g., electronic monitoring
feedback, motivational interviewing) [16]. The
control group received usual care and attended
visits 1–5 only. The intervention group had a
16% higher dosing adherence post-intervention (95.1 vs. 79.1%; p < 0.001), resulting in
odds of adherence being five times higher [16].
This effect was sustained at the end of followup (similar results for timing adherence). The
5-year clinical event-free survival was 82.5 versus 72.5% in the intervention vs control groups
(p = 0.18) [16]. A systematic review focusing
on renal, heart, and liver transplant recipients
revealed that a combination of interventions may
be effective for long-term immunosuppressant
adherence of solid organ recipients [17]. A study
by Shi et al. reviewed interventions tested by
randomized controlled trials to improve adherence in solid organ transplant recipients and
found that such tools significantly improved the
pooled risk ratios for overall adherence, dosing
adherence, and timing adherence compared to
controls [13]. Interestingly, these interventions
lead to no significant improvement in immunosuppressant blood concentration [13].
The COVID-19 pandemic ushered in the
greater utilization of telehealth as healthcare
professionals were forced to limit face-to-face
in-person visits. The adoption of this technology was specifically important for the HTx
recipients who were more vulnerable to higher
morbidity and mortality consequences due to
CVOID-19 infections. Multiple small singlecenter studies showed the feasibility of his strategy in the transplant population [18]. Despite
increasing telehealth utilization, several factors,
such as technological infrastructure, reimbursement, and limited patient digital literacy, can
hinder the adoption of remote care. Future studies are needed to determine the impact of this
modality on post-HTx outcomes.
25720 Medical Adherence and Outcomes After Heart Transplant
Future Directions
Although preliminary findings from small studies demonstrate promising data on the effectiveness of some interventions to improve patient
adherence, further large-scale studies are needed
in this realm. While some adherence tools have
been associated with good patient satisfaction,
others have been shown to suffer from a high
attrition rate [4]. Additionally, none of the interventions tested have been shown to improve
patient survival or other medical outcomes [4].
Future studies should carefully evaluate the
ongoing adherence rate to these novel tools over
time.
References
1. Velleca A, Shullo MA, Dhital K, Azeka E, Colvin
M, DePasquale E, et al. The International Society
for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J
Heart Lung Transplant. 2023;42(5):e1-141.
2. De Bleser L, Dobbels F, Berben L, Vanhaecke J,
Verleden G, Nevens F, et al. The spectrum of nonadherence with medication in heart, liver, and lung
tranplant patients assessed in various ways. Transpl
Int. 2011;24(9):882–91.
3. Dobbels F, De Geest S, Van Cleemput J, Droogne
W, Vanhaecke J. Effect of late medication noncompliance on outcome after heart transplantation: a 5-year follow-up. J Heart Lung Transplant.
2004;23(11):1245–51.
4. Hussain T, Nassetta K, O’Dwyer LC, Wilcox JE,
Badawy SM. Adherence to immunosuppression
in adult heart transplant recipients: a systematic
review. Transplant Rev. 2021;35(4):100651.
5. De Geest S, Abraham I, Moons P, Vandeputte M,
Van Cleemput J, Evers G, et al. Late acute rejection
and subclinical noncompliance with cyclosporine
therapy in heart transplant recipients. J Heart Lung
Transplant. 1998;17(9):854–63.
6. Farmer SA, Grady KL, Wang E, McGee EC Jr,
Cotts WG, McCarthy PM. Demographic, psychosocial, and behavioral factors associated with survival after heart transplantation. Ann Thorac Surg.
2013;95(3):876–83.
7. Boghani S, Kirkham H, Witt EA, Hira N, Cherikh
WS, Wilk AR, et al. Medication adherence and graft
survival among kidney transplant recipients. J Drug
Assess. 2019;8(sup1):6.
8. Helmy R, Duerinckx N, De Geest S, Denhaerynck
K, Berben L, Russell CL, et al. The international
prevalence and variability of nonadherence to the
nonpharmacologic treatment regimen after heart
transplantation: findings from the cross-sectional
BRIGHT study. Clin Transplant. 2018;32(7):e13280.
9. De Geest S, Dobbels F, Martin S, Willems K,
Vanhaecke J. Clinical risk associated with appointment noncompliance in heart transplant recipients.
Prog Transplant. 2000;10(3):162–8.
10. Duerinckx N, Burkhalter H, Engberg SJ, Kirsch
M, Klem ML, Sereika SM, et al. Correlates and
outcomes of posttransplant smoking in solid
organ transplant recipients: a systematic literature review and meta-analysis. Transplantation.
2016;100(11):2252–63.
11. Brocks Y, Zittermann A, Grisse D, Schmid-Ott G,
Stock-Gießendanner S, Schulz U, et al. Adherence of
heart transplant recipients to prescribed medication
and recommended lifestyle habits: a single-center
experience. Prog Transplant. 2017;27(2):160–6.
12. Lieb M, Weyand M, Seidl M, Erim Y. Protocol: prospective single-centre clinical observational study on
electronically monitored medication non-adherence,
its psychosocial risk factors and lifestyle behaviours
after heart transplantation: a study protocol. BMJ
Open. 2020;10(10):e038637.
13. Shi YX, Liu CX, Liu F, Zhang HM, Yu MM, Jin YH,
et al. Efficacy of adherence-enhancing interventions
for immunosuppressive therapy in solid organ transplant recipients: a systematic review and meta-analysis based on randomized controlled trials. Front
Pharmacol. 2020;11:578887.
14. Gomis-Pastor M, Mirabet Perez S, Roig Minguell E,
Brossa Loidi V, Lopez Lopez L, Ros Abarca S, et al.
Mobile health to improve adherence and patient
experience in heart transplantation recipients: the
mHeart trial. In: Healthcare. MDPI; 2021. p. 463.
15. Marcelino CAG, Díaz LJR, da Cruz DM.
The effectiveness of interventions in managing treatment adherence in adult heart transplant
patients: a systematic review. JBI Evid Synth.
2015;13(9):279–308.
16. Dobbels F, De Bleser L, Berben L, Kristanto P,
Dupont L, Nevens F, et al. Efficacy of a medication
adherence enhancing intervention in transplantation:
the MAESTRO-Tx trial. J Heart Lung Transplant.
2017;36(5):499–508.
17. De Bleser L, Matteson M, Dobbels F, Russell C,
De Geest S. Interventions to improve medicationadherence after transplantation: a systematic review.
Transpl Int. 2009;22(8):780–97.
18. Wang CW, Ha N, Duarte M, Sherman CB.
Telemedicine implementation in Solid Organ
Transplant (SOT) clinics is associated with satisfaction among patients and providers but increased burden on staff. Am J Transplant. 2022;868–9
Cardiac Allograft Vasculopathy
Lily Stern, Evan Kransdorf, and Yosef Manla
21
Abstract
Cardiac allograft vasculopathy (CAV) is one
of the major complications after heart transplantation (HTx) that contributes to graft
failure and significant morbidity and mortality. This chapter explores the epidemiology,
pathophysiology, and clinical features, as
well as diagnosis, medical and surgical management of CAV. Advancements in post-HTx
immunosuppression, imaging technology,
and risk stratification techniques will lead to
improved quality of life and longevity after
transplant.
Keywords
Heart failure · Heart transplantation · Chronic
rejection · Cardiac allograft vasculopathy ·
Surveillance · Trajectory score
L. Stern · E. Kransdorf (*) · Y. Manla
Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
e-mail: Evan.kransdorf@cshs.org
L. Stern
e-mail: Lily.stern@cshs.org
Y. Manla
e-mail: Yosef.manla@cshs.org;
Yosef.manla1@gmail.com
Clinical Pearls
• Cardiac allograft vasculopathy (CAV) is one
of the major causes of death limiting the
long-term survival after heart transplantation
• CAV is a chronic form of rejection, best
characterized as a diffuse immune-mediated
pan-arteritis with non-immune factors also
contributing to risk.
• CAV often remains asymptomatic due to
denervation of the donor heart, which blunts
angina pain. Symptomatic CAV may present
with dyspnea, left ventricular dysfunction,
restrictive physiology, or even sudden cardiac
death.
• The gold standard for diagnosis of CAV is
the coronary angiogram, with surveillance
protocols varying from annually to protocols
at specific year marks.
•
Intravascular ultrasound (IVUS) during a
baseline and 1-year angiogram is performed
at some centers. The change in first-year
IVUS measurement of maximal intimal
thickness (MIT) is a predictor for subsequent
angiographic development of CAV and other
poor outcomes at 5 years.
• Through the use of artificial intelligence and
machine learning, a CAV trajectory score was
developed and can be calculated at 1-year
post-heart transplant to assist with risk stratification of patients for the development of
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
J. Kobashigawa (ed.), Clinical Guide to Heart Transplantation, https://doi.org/10.1007/978-3-031-88290-6_21
259
260 L. Stern et al.
CAV and the need for protocol-scheduled
coronary angiograms. In this assessment,
donor age, donor male sex, donor tobacco
consumption, recipient dyslipidemia, class II
anti-HLA DSAs, and acute cellular rejection
(> 2R), are independently associated with
higher CAV risk trajectories.
• Medical strategies to abrogate CAV include
the administration of statins and targeted use
of proliferation signal inhibitors (PSIs) such
as sirolimus/everolimus.
• Interventional options for CAV include the
placement of drug-eluting stents, but these
are usually temporary measures; the only
definitive solution is re-transplantation.
Epidemiology
Cardiac allograft vasculopathy (CAV), known
as chronic allograft rejection, imposes a significant long-term morbidity and mortality burden
on heart transplant (HTx) recipients and is one
of the leading causes of death post-transplant
[1]. The incidence of CAV increases in a progressive manner over time. Per the latest registry
report from the ISHLT [1], for adult HTx recipients, the prevalence of CAV is 7.7% at 1-year
post-transplant, 29% at 5 years post-transplant,
and 46.8% at 10 years post-transplant. Younger
recipient age is associated with an increased risk
of CAV, possibly due to more robust immune
systems or the lack of CAV screening with angiography in older recipients who have a propensity for renal dysfunction [1]. Older donor age
has been associated with the development of
CAV [2]. In a 2019 ISHLT registry study, donors
over age 49 were noted to have a higher prevalence of traditional cardiac risk factors, and the
risk of CAV was higher at 5 and 10-year followups [3]. Additionally, the female sex of either
donor or recipient is associated with decreased
risk for development of CAV within 5 years
post-transplant. The hazard ratio for the development of CAV with the female donor-female
recipients is 0.72 when compared to the male
donor-male recipients [1].
Pathophysiology
CAV is generally thought to be a diffuse pan
arteritis with concentric, longitudinal intimal
thickening of the epicardial coronary arteries
[4]. It can involve the coronary microvasculature as well. While CAV is generally a diffuse
process, it can manifest in ways similar to native
coronary artery disease with focal stenosis. The
pathophysiology and molecular basis for CAV
include contributions from immune responses to
the donor heart including atherosclerotic mechanisms, ischemia–reperfusion injury, and particular infections [5
mechanisms include atherosclerotic mechanisms and traditional risk factors for coronary
atherosclerosis, which are frequent after HTx
and include hypertension, hyperlipidemia, obesity, renal dysfunction, and glucose intolerance
(diabetes). Tissue damage may occur during the
process of HTx and include donor physiologic
changes due to the processes of brain death, cardiac arrest, heart procurement, and ischemia–
reperfusion at the time of heart implantation.
Elements of the adaptive and innate immune
systems likely contribute to the development of
CAV. Human leukocyte antigen (HLA) shedding during heart implantation can lead to indirect allorecognition with internalization and
processing of donor-soluble HLA by recipient
antigen-presenting cells, leading to T-cell stimulation. Heat shock proteins may be detected by
toll-like receptors and promote the maturation of
dendritic cells. Complement deposition, namely
C3d and C4d deposition, are associated with
antibody-mediated rejection and CAV [6]. Over
time, alloimmune interactions will lead to T and
B cell stimulation, the release of pro-inflammatory cytokines, and a state of vascular inflammation. Endothelial cells that line transplanted
coronary arteries are the main point of contact
and communication between the recipient blood
and the transplanted graft and, thus, maybe the
primary antigenic stimulus for the initiation
and progression of CAV. Donor-specific antibodies (DSA) can develop in the transplanted
graft, particularly after episodes of cellular and/
] (Fig. 21.1). Non-immune
21 Cardiac Allograft Vasculopathy
261
Fig. 21.1 A diagram demonstrating the collaboration
and interaction of alloimmune-dependent and independent factors that influence the pathogenesis of transplant
vasculopathy. Abbreviations Ag antigen, CD cluster of differentiation, eNOS endothelial nitric oxide synthase, and
or antibody-mediated rejection. The presence of
DSA, particularly in major histocompatibility
complex (MHC) type II antigens, is associated
with CAV and poor outcomes after HTx [7–10].
In addition to DSA, non-HLA antibodies, many
of which are expressed on endothelial cells, are
likely involved in the development of CAV and
include anti-angiotensin II type I receptor [11],
anti-MHC class I chain-related A [12], MHC
class I chain-related B, as well as adhesion and
trafficking receptors. In addition, vimentin is
also expressed on endothelial cells thus antivimentin antibodies have been associated with
CAV [13]. Moreover, inflammatory modulators
may influence cytokine signaling and the development of CAV [14, 15]. Infections, such as
breakthrough cytomegalovirus (CMV) infections
SMC smooth muscle cell. Reused with permission Daniel
Schmauss, Michael Weis, Cardiac Allograft Vasculopathy:
Recent Developments, Circulation, 117(16), 2131–214,
https://doi.org/10.1161/CIRCULATIONAHA.107.711911;
American Heart Association
despite prophylactic antiviral treatment, may
also influence the development of CAV [16, 17].
Clinical Features
As the process of HTx causes denervation of
the transplanted graft, cardiac angina is typically absent, and CAV may present insidiously.
Shortness of breath or atypical symptoms may
accompany CAV, but CAV may be asymptomatic. CAV may present with left ventricular systolic dysfunction, but even with severe
CAV, left ventricular systolic function may be
preserved. Significant CAV is often accompanied by restrictive allograft physiology,
defined as symptomatic heart failure with either
262 L. Stern et al.
echocardiographic or hemodynamic abnormalities on right heart catheterization. This form
of CAV with restrictive cardiac physiology is
felt secondary to microvascular disease [18].
Echocardiographic parameters consistent with
restrictive allograft physiology in adults include
E to A velocity ratio > 2, decreased isovolumic
relaxation time < 60 ms, and shortened mitral
valve deceleration time < 150 ms. Restrictive
hemodynamics on right heart catheterization
include right atrial pressure > 12 mmHg, pulmonary capillary wedge pressure > 25 mmHg,
and cardiac index < 2 L/minute/square meter. A
consensus statement was published in 2011 by
the International Society for Heart and Lung
Transplant (ISHLT) that established a working
formulation of standardized nomenclature for
CAV (Table 21.1). By this form of classification, CAV can be divided into non-significant
(CAV0), mild (CAV1), moderate (CAV2), and
severe (CAV3) disease, which includes significant restrictive cardiac physiology due to microvascular disease [19].
Diagnosis
Invasive Assessment of Cardiac Allograft Vasculopathy
Due to the usually silent progression and
increased morbidity and mortality associated
with CAV, surveillance, and diagnosis of this
disease process is critical. The gold standard test
for diagnosis of CAV continues to be the conventional coronary angiogram. Interpretation of
lumen patency by conventional coronary angiography may give a false sense of security as the
lumen of the coronary artery may not be compromised until intimal thickening encroaches
and causes focal stenosis (Fig. 21.2). For this
reason, many institutions utilize intravascular
ultrasound (IVUS) or optical coherence tomography (OCT) in addition to conventional coronary angiography for the assessment of CAV
[20, 21]. Although a number of IVUS-based
parameters have been analyzed post-transplant,
change in maximal intimal thickness (MIT) of
a matched cross-sectional area of a coronary
Table 21.1 The International Society for Heart and Lung Transplantation nomenclature of cardiac allograft
vasculopathy
Grade of CAV Disease severity Angiographic findings
CAV0 No disease No detectable angiographic lesion
CAV1 Mild Angiographic LM <50%, or primary vessel with
CAV2 Intermediate Angiographic LM <50%; a single primary vessel >70%,
CAV3 Severe
Abbreviations CAV: cardiac allograft vasculopathy; ISHLT: International Society of Heart and Lung Transplantation;
LM: left main; LVEF: left ventricular ejection fraction
Reprinted from The Journal of Heart and Lung Transplantation, 29(7), Mandeep R. Mehra, Maria G. Crespo-Leiro,
Anne Dipchand, Stephan M. Ensminger, Nicola E. Hiemann, Jon Kobashigawa, Joren Madsen, Jayan Parameshwar,
Randall C. Starling, Patricia A. Uber, International Society for Heart and Lung Transplantation working formulation
of a standardized nomenclature for cardiac allograft vasculopathy—2010, 717–727, Copyright (2010), with permission from Elsevier
maximum lesion of <70%, or any branch stenosis
<70% (including diffuse narrowing) without allograft
dysfunction
or isolated branch stenosis >70% in branches of 2 systems, without allograft dysfunction
Angiographic LM >50%, or ≥2 primary vessels >70%
stenosis, or isolated branch stenosis >70% in all 3 systems; or ISHLT CAV1 or CAV2 with allograft dysfunction (defined as LVEF <45%, usually in the presence
of regional wall motion abnormalities) or evidence of
significant restrictive physiology
21 Cardiac Allograft Vasculopathy
263
Fig. 21.2 The top half demonstrates the progression of cardiac allograft vasculopathy as demonstrated by the right coronary artery angiogram at year
3 post-transplant compared to year 1. Note the multiple, diffuse stenoses (red arrows). The bottom half
demonstrates the progression of intimal thickness
(red arrow) as demonstrated by intravascular ultrasound at 52 weeks (1 year) post-transplant compared
artery from baseline (approximately 6 weeks
post-transplant) to 1-year post-transplant was a
reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events
(MACE), and development of angiographic
CAV through 5 years post HTx. Historically,
patients with an MIT increase of 0.5 mm or
greater in any matched site of a coronary artery
had a significantly higher incidence of death
or graft loss, nonfatal MACE, and a higher
to baseline (week 4 post-transplant). There was a difference of greater than 0.5 mm change between baseline and 1 year. Such a finding is highly prognostic for
poor long-term outcomes. Reused with permission
from Author, Outpatient Management and Long-Term
Complications in Heart Transplantation, Clinical guide
to heart transplantation, 171–183, 2017, Springer Nature.
https://doi.org/10.1007/978-3-319-43773-6_13
incidence of new angiographic CAV [22, 23].
A more recent, large single-center retrospective trial demonstrated that a baseline MIT of
0.64 mm at approximately 6 weeks post-transplant, consistent with donor-transmitted coronary artery disease, as well as a change in MIT
of at least 0.27 mm within the first year, were
independently associated with increased 5-year
mortality and development of CAV [24]. This
updated MIT threshold has been incorporated
264 L. Stern et al.
into the most recent HTx management guidelines (Class IIa, Level of Evidence B) [25].
A CAV trajectory model was recently devel-
oped to risk stratify patients for the development
of clinically significant CAV and associated
mortality over 10 years from transplant [26].
In an international multicenter study, 1301
HTx recipients were prospectively assessed for
the presence of allograft coronary disease and
stratified into 4 distinct CAV trajectories based
on disease found on angiography with IVUS
at baseline at 4–8 weeks and 1 year post HTx:
(1) no CAV over time (2) mild and late-onset
CAV, (3) early onset and progressive evolution
of CAV and (4) early onset with rapid evolution
of CAV. Recipient and donor characteristics,
including donor age, donor male sex, donor
tobacco consumption, recipient dyslipidemia,
class II anti-HLA DSAs, and acute cellular
rejection (>2R), were found to be independently
associated with higher risk trajectories. The
trajectory model was initially developed from
patients in Europe and then was validated on
patients in a large center in the United States.
The model found that not only were higher CAV
trajectories associated with higher rates of clinically significant CAV over time but also with
higher mortality (Fig. 21.3). As such, patients
with CAV trajectories 3 or 4 noted at 1-year
post-transplant should undergo more intensive
annual CAV surveillance. Recently, it was found
in a single-center study of 102 patients that
using an additive probability of >0.7 to be in
CAV trajectory scores 1 and 2 appears safe and
predictive to avoid annual angiograms within
5 years post-transplant [27]. Furthermore, the
CAV trajectory has the potential to serve as an
important surrogate for 10-year clinical outcomes in future trials.
Non-invasive Assessment of Cardiac Allograft Vasculopathy
Procedures such as conventional coronary
angiography and IVUS pose risks that accompany invasive tests. These risks include bleeding, infection, contrast-induced nephropathy,
peripheral vascular disease, risk of myocardial
infarction, dissection or damage of the coronary artery, stroke, and potential death from
the invasive test(s). Due to patient discomfort
and the inherent risks of invasive testing, noninvasive tests can be used to assess for CAV.
Non-invasive tests for CAV include exercise or
pharmacologic-based stress tests, positive emission tomography (PET) testing with myocardial
blood flow (MBF) and myocardial flow reserve
(MFR), cardiac magnetic resonance (CMR),
and coronary computed tomographic angiography (CCTA). Dobutamine stress echocardiography and single photon emission computed
tomography (SPECT) are less useful than other
non-invasive modalities such PET with MBF/
MFR, CMR, and CCTA for CAV surveillance
and evaluation due to relatively lower sensitivity
with high rates of false negative results [28–32].
The limited performance of SPECT may be
due to the diffuse and balanced nature of CAV.
Nevertheless, these modalities are still an option
for patients who are unable to undergo invasive
evaluation or other non-invasive modalities due
to cost or imaging limitations from rapid heart
rate in a denervated cardiac allograft due to the
lack of parasympathetic nervous system tone
(Class IIb, Level of Evidence B) [25]. In contrast, PET with MBF and MFR has shown promise for non-invasive surveillance and diagnosis
of macro and microvascular CAV [33, 34]. A
study evaluating patients who underwent PET
Fig. 21.3 Overall, 10-year survival probability according
to the CAV trajectory. Trajectories 3 and 4 were associated with higher mortality rates (10-year patient survival
of 73.43% [95% CI, 65.18–80.02] and 51.89% [95% CI,
38.76–63.51], respectively) in comparison with trajectories
1 and 2 that were characterized by 10-year patient survival of 80.01 (95% CI, 76.38–84.82) and 83.49% (95%
CI, 71.34–90.80), respectively (P < 0.001). Reprinted with
permission from Alexandre Loupy, Guillaume Coutance,
Guillaume Bonnet, Jan Van Keer, et al., Identification
and Characterization of Trajectories of Cardiac Allograft
Vasculopathy After Heart Transplantation: A PopulationBased Study, Circulation, 141(24), 1954–1967, and
https://doi.org/10.1161/CIRCULATIONAHA.119.044924;
American Heart Association
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26521 Cardiac Allograft Vasculopathy