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266 L. Stern et al.
testing with MBR and MFR (both corrected
and uncorrected) showed high diagnostic accuracy for detection of CAV grades 2 and 3, and
uncorrected MFR > 2 identified low-risk patients
with an annual mortality risk of less than 5%.
Whereas left ventricular ejection fraction lower
than 45% and MFR < 1.7 were associated with
increased annual all-cause mortality (up to
51%). As such, the finding of high-risk features
on PET imaging may prompt consideration of
retransplantation before patients develop significant heart failure complications [35]. CMR,
with the assessment of myocardial perfusion
reserve, is also an accurate modality for detecting epicardial and microvascular CAV (Class
IIb, Level of Evidence C) compared to invasive
coronary angiography [36]. Additional CMR
features, including increased T2 values, which
are associated with myocardial edema, and
increased extracellular volume and late gadolinium enhancement (LGE), which are associated with increased fibrosis, are associated with
grade 2 or 3 CAV [37, 38]. Increased LGE is
independently associated with increased mortality and major adverse cardiac events [38].
However, the utility of CMR for CAV surveillance is limited by cost, poor imaging quality
with rapid heart rates in a denervated heart allograft, and concern for accumulation of gadolinium in the brain after repeated exposure [39].
Although there are limitations of CCTA, including limited visualization of vessels < 2 mm, it
may be a reasonable alternative in patients who
have had complications from conventional coronary angiography or for assessment of variant
coronary anatomy (Class IIa, Level of Evidence
]). A meta-analysis of thirteen prospective
B [25
CCTA studies of 615 HTx patients demonstrated
a sensitivity of 94%, specificity of 92%, negative
predictive value of 99%, and positive predictive
value of 67% for detecting a stenosis ≥ 50% on
an invasive coronary angiogram [40]. The addition of quantitative plaque has also been shown
to improve sensitivity for the detection of CAV
[41]. Historically, CCTA has been techni-
cally limited by higher resting heart rates posttransplant. However, newer generation CCTA
scanners yield technically adequate results in
the post-HTx population, and in fact, quality
may even be better than for native hearts due to
reduced heart rate variability of the denervated
cardiac allograft [42].
Management
Medical
Prevention and treatment options for CAV
include medical therapies, modulation of the
immune system, mechanical therapies including percutaneous intervention, and redo-HTx.
The 3-hydroxy-3 methylglutaryl coenzyme A
reductase inhibitor, pravastatin, was shown in
prospective clinical trials to reduce the incidence
of CAV, reduce cholesterol levels, reduce cardiac rejection with hemodynamic compromise,
and increase survival at 1-year post-transplant
[43]. This study was supported by another prospective trial of simvastatin, a similar drug,
which demonstrated superior 8-year survival
and freedom from CAV compared to a control
group [44]. Studies of PCSK9 inhibitors demonstrate safety and efficacy in stabilizing coronary
intimal hyperplasia [45]. Most recently, outcomes of EVOLVD (Cholesterol lowering with
EVOLocumab to prevent cardiac allograft vasculopathy in De-novo HTx recipients) trial have
shown that treatment of HTx recipients with
a PCSK9 inhibitor, evolocumab, for 1 year in
addition to statin therapy, substantially reduced
LDL cholesterol but did not reduce maximal
coronary intimal thickness, suggesting that
mechanisms other than dyslipidemia, including
inflammation and low-grade rejection, should
be addressed to mitigate CAV [46]. In another
trial, the use of vitamins C and E showed no
progression of CAV (compared to placebotreated control patients) [47]. Given the risk of
development of CAV and the likely contribution
of traditional risk factors to the development of
CAV, low-dose aspirin is generally advised posttransplant. The use of induction agents at the
time of HTx, including T cell depleting agents
and interleukin (IL)-2 receptor antagonists, may
lead to reduced rates of CAV (see Chap. 13).
26721 Cardiac Allograft Vasculopathy
Anti-thymocyte globulin (ATG), a commonly
used T cell depleting agent, has shown delayed
onset of CAV [47] and decreased CAV progression by IVUS parameters between baseline and
1-year post-transplant [48]. Different approaches
to maintenance immunosuppression have shown
differences in the development of CAV. The
purine inhibitor mycophenolate mofetil (MMF),
in combination with the calcineurin inhibitor
(CNI) cyclosporine, showed a decreased incidence of CAV [49]. Clinical trials using the
proliferation signal inhibitors (PSI) sirolimus or
everolimus in conjunction with CNI have shown
reduced rates of CAV compared to maintenance
immunosuppressive regimens with CNI in combination with purine antagonist. Everolimus, in
combination with cyclosporine, showed lower
rates of CAV compared to cyclosporine with
azathioprine [50]. Sirolimus, in combination
with cyclosporine, showed lower rates of CAV
compared to cyclosporine in combination with
azathioprine [51]. High-dose everolimus in combination with cyclosporine showed harm in one
trial, but low-dose everolimus with cyclosporine
showed decreased CAV progression by IVUS
and similar mortality compared to cyclosporine
with MMF [52]. Everolimus showed efficacy
over MMF for CAV in subpopulations, including women, diabetics, patients over age 60, and
patients with higher cholesterol levels [53].
Another study examined low-dose everolimus
with reduced dose cyclosporine versus standard
dose cyclosporine with MMF. Low-dose CNI
was withdrawn, and PSI dose increased to target
levels 7–11 weeks post-transplant. This study
also demonstrated a lower CAV burden in the
PSI arm [54, 55]. Immunomodulation with photopheresis may reduce rates of CAV due to the
reduction of rejection episodes. Patients treated
empirically with photopheresis for the first
6 months post-transplant had reduced rates of
acute rejection without increased risk of infection. Using photopheresis in the treatment of
patients with rejection with hemodynamic compromise or recurrent rejection decreased the risk
of subsequent significant rejection episodes [56].
Reduction of rejection and the inflammatory
state may lead to decreased rates of CAV,
although this has not formally been studied in a
clinical trial format.
Interventional
CAV is generally a pan-arteritis, but it can present with focal stenosis. Percutaneous intervention and stent placement are generally temporary
measures for CAV. Data with newer everolimus
DES suggest durability of stented segments with
low rates of target lesion revascularization [57,
58]. Prior attempts at revascularization by coro-
nary artery bypass grafting (CABG) surgery
resulted in high post-surgical mortality and low
rates of survival one year after CABG [59, 60].
CAV is the main cause of need for redo-HTx.
Annually, 2–3% of HTx recipients are redo HTx
recipients. Unfortunately, survival after a redo
HTx is reduced compared to an index HTx. For
adult recipients, 1-year survival after redo HTx
is approximately 70%, and 10-year survival is
38% [61]. Redo transplant for acute rejection
results in poor post-transplant survival and is not
recommended. However, patients undergoing
redo HTx for stable CAV have comparable posttransplant survival to primary transplants [62].
In summary, CAV is one of the major com-
plications after an HTx that contributes to graft
failure and significant morbidity and mortality.
Improvement in post-HTx immunosuppression,
imaging technology, and risk stratification techniques will lead to improved quality of life and
longevity after transplant. Investigations into
other types of immunosuppressants, including
targeting of interleukin (IL-6), down-regulation
of the immune system by impairing T cell costimulation, and targeting components of the
innate immune system may augment the current regimen of agents used in induction and
maintenance immunosuppression. Furthermore,
insights into the immune mechanisms of CAV
may have an impact on native atherosclerosis
as there may be an immune component to the
development of native atherosclerosis in nontransplant patients.
268 L. Stern et al.
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Transplant Reports. 2020;7:12–7.
Long-Term Complications in Heart Transplantation
Lily Stern, Evan Kransdorf, and Yosef Manla
22
Abstract
Heart transplantation requires longitudinal
follow-up to monitor for potential long-term
complications. The focus of this chapter
is the diagnosis and management of other
potential long-term complications, including
malignancy, hypertension, renal dysfunction,
hyperlipidemia, diabetes, osteoporosis, and
gastrointestinal complications.
Keywords
Heart failure · Heart transplantation ·
Rejection · Cardiac allograft vasculopathy ·
Malignancy · Outcomes · Infection
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
• Malignancy due to chronic immunosup-
pression is a major limitation to long-term
survival and is more than twice as common
compared to the non-transplant population; more common malignancies post-heart
transplant include skin cancer, lung cancer and post-transplant lymphoproliferative
disease.
• Common medical problems after transplan-
tation include calcineurin inhibitor-induced
hypertension, diabetes and renal dysfunction;
steroid-induced osteoporosis, peptic ulcer
disease, and hyperlipidemia.
• Diarrhea, nausea, and leukopenia are com-
mon side effects from the anti-metabolite
mycophenolate mofetil and may require dose
reduction and, in severe cases, transition to
an enteric-coated formulation.
•
After the first three months post-transplant,
proliferation signal inhibitors such as sirolimus or everolimus can be considered in place
of anti-metabolites for recurrent rejection,
donor-specific antibodies, cardiac allograft
vasculopathy, malignancy, and cytomegalovirus infection. Side effects of these medications may limit general use.
• Proliferation signal inhibitors may be used
in place of calcineurin inhibitors (along with
mycophenolate mofetil) in carefully selected
patients with significant renal dysfunction
© 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_22
271
272 L. Stern et al.
(renal sparing immunosuppression) and
metastatic malignancy, although with an
increased risk of rejection.
Outpatient Management
There are a number of factors that are important
to the long-term management of heart transplant
(HTx) patients. Generally, maintenance immunosuppression is most intense in the first months
after transplant. The risk for rejection and infection is highest early post-transplant. Therefore,
outpatient follow-up is the most intense. Patients
generally require the involvement of caregivers to
assist with medication administration, medication
adherence, and transportation to frequent clinic
visits. As the risk of rejection decreases over
time, target trough levels of immunosuppressant
medications are lowered. Decrement in cardiac
function may be asymptomatic, and therefore,
cardiac function and lab work, including echocardiography and renal function, are frequently
assessed during follow-up [1]. Many programs
use a combination of triple immunosuppressant
medications, including a calcineurin inhibitor,
anti-proliferative medications, and prednisone. If
a patient avoids rejection, maintains normal left
ventricular (LV) systolic function, and does not
develop donor-specific antibodies, patients can
start to wean prednisone off by 6 months, but
usually are not weaned off until 12 months post
transplant. After surgery, a patient’s functional
status often improves with cardiac rehabilitation. Nevertheless, complications often arise and
are actively managed by the transplant team with
close multidisciplinary involvement.
Malignancy
The main limitations to long-term survival after
an HTx are CAV, graft failure, infection, and
malignancy [1]. The use of chronic immunosuppression after transplant to prevent allograft
rejection increases the risk of malignancy in
the long term. Recipients of HTx may have a
pre-existing history of malignancy that, after
transplant and on immunosuppression, predisposes them to recurrence of their primary
malignancy. Youn et al. recently reported in their
study of patients with pre-transplant malignancies that during a median follow-up of 8.6 years
post-transplant, patients with pre-transplant
malignancy compared to those without showed
a significantly higher incidence of posttransplant malignancies (43.8 vs. 20.8%, p < 0.001),
including 9.6% (n = 7) of cancer recurrence.
However, comparable 10-year survival, 10-year
freedom from rejection, CAV, or non-fetal major
adverse cardiac events were recorded, underlying that a history of pre-transplant malignancy
should not disqualify patients from HTx listing
[2]. For patients with pre-existing cancer with a
high risk of recurrence, HTx should be delayed
for an adequate time, as opined by oncology, to
ensure patients remain free from cancer recurrence. High-risk cancers include melanoma,
breast and colorectal cancer. Although data is
limited, there is possible transmission of malignant oncogenic cells from donor to recipient.
Caution should be considered in donors with
a history of renal cell carcinoma with vascular invasion, melanoma, choriocarcinoma, and
sarcomas (3). Malignancy may be discovered
in organ donors after the process or at the time
of organ transplant. The rate of de novo malignancy is approximately two-fold higher in
transplant recipients compared to the general
population [4]. Common malignancies after
HTx include skin cancer, lung cancer, and anogenital cancer, post-transplant lymphoproliferative disease (PTLD), and Kaposi’s sarcoma. In
a recent analysis of the International Society for
Heart and Lung Transplantation registry, the risk
of any de novo solid malignancy between years
1 and 5 after transplantation was 10.7%, with
the cumulative incidence for skin cancer and
non-skin solid cancers of 7.0 and 4.0%, respectively [5]. Proposed mechanisms for increased
rates of de novo malignancy include direct
effects of immunosuppression, reduced immune
surveillance, and expansion of atypical cells. In
addition, oncogenic viruses may proliferate in
the setting of immunosuppression and contribute to the development of malignancy. Viruses
27322 Long-Term Complications in Heart Transplantation
including Epstein-Barr (EBV), human herpes
virus 8 (HHV-8), human papillomavirus (HPV),
human T-cell lymphotropic virus 1 (HTLV-
1), and Merkel cell polyomavirus (MCV)
have associations with specific malignancies.
Survival after diagnosis of malignancy depends
on many factors, including the size of the tumor,
local or distant spread of the tumor, aggressiveness of the tumor, and ability of the patient to
tolerate treatments directed against the tumor.
Cardiac transplants may require more intense
immunosuppression because of the risk of death
with graft loss. Animal studies suggest that calcineurin inhibitors (CNI) may promote cancer
through increased production of transforming
growth factor (TGF) beta [6].
PTLD represents a heterogeneous group of
lymphoproliferative disorders. EBV infection
is associated with PTLD. EBV-seronegative
recipients receiving transplants from EBVseropositive donors are at elevated risk for the
development of PTLD. With EBV infection,
B cells incorporate EBV DNA into the cellular genome, decreasing the rate of apoptosis
and leading to cellular proliferation. EBV DNA
load is suggestive in the right clinical context
for PTLD. Imaging studies, including fluorodeoxyglucose (FDG)-positron emission tomography, can assess hypermetabolic tissue, but
ultimately, diagnosis of PTLD is made on histopathology. In a recent analysis of the ISHLT
registry, it was reported that 3.8% of the patients
developed PTLD within 10 years of transplantation. Independent risk factors of PTLD development within 3 years of transplantation included
male recipient, EBV donor-positive–recipientnegative match, while maintenance therapy
with cyclosporine vs tacrolimus at initial discharge was associated with a lower incidence.
It was also observed that PTLD development
within 3 years of transplantation set patients as
a significant mortality risk (HR: 2.42 [95% CI:
2.01–2.91]; P < 0.001) [7]. The risk of PTLD is
highest in the first year after transplant when
immunosuppression is most intense. Common
sites of PTLD in HTx recipients include lung,
GI tract, liver, lymph nodes, and disseminated
disease. In heart–lung transplant recipients,
PTLD is primarily found in the lung. Symptoms
are variable with PTLD. PTLD can present with
fever, fatigue, malaise, recurrent infections that
do not respond to antibiotic therapy, lymphadenopathy, or with significant organ dysfunction. Low grade PTLD is generally treated with
a significant reduction of immunosuppressive
therapies. Reduction of EBV can be attempted
with the antiviral agent acyclovir or ganciclovir.
In high-risk patients, prophylaxis with anti-viral
agents can be considered. For the treatment of
neoplastic B cells, several approaches are possible, including the use of chemotherapy, anti-B
cell therapy with rituximab, the use of proliferation signal inhibitors (PSI, and withdrawal of
one immunosuppressant agent), and tumor
resection [8]. When the reduction or withdrawal
of immunosuppressant therapies is not effective,
mortality from PTLD is high. Kaposi’s sarcoma
is associated with HHV-8 and occurs in men
at rates 3-fold higher than is seen in women.
Lesions typically affect the legs and cause
lymphedema. Skin cancers include squamous
cell and basal cell carcinomas, melanoma, and
Merkel cell carcinoma. Factors that mitigate the
risk of skin cancer development include ultraviolet radiation, fair skin, pre-transplant history
of skin cancer or actinic keratosis, geographic
location, intensity, duration, and type of immunosuppressant therapy. The use of voriconazole
for the treatment of fungal infection has been
associated with the development of aggressive
squamous cell carcinomas [9]. Nicotinamide,
an amide form of Vitamin B3, has been shown
to prevent cutaneous skin cancer in animal studies [10] and in immunocompetent patients [11].
However, it was not demonstrated to be effective
for the prevention of skin cancer or actinic keratosis in a randomized control trial of solid organ
transplant recipients [12]. Lung cancer, particularly in patients with prior significant tobacco
exposure, is increased in HTx recipients.
Anogenital cancer occurs in 2–3% of transplant
recipients. Lesions may be multiple and extensive and may resemble genital warts. Screening
for the presence of malignancy after a HTx is
critical. Dermatologic evaluation should be done
to screen for skin cancer. There are no formal
274 L. Stern et al.
guidelines for cancer screening after a HTx, but
regular health maintenance screening would be
appropriate. As with CAV, the use of PSI instead
of anti-metabolite may be favorable in the context of malignancy. Transition to PSI may
decrease the risk of development of subsequent
malignancies after a HTx [13]. Additional indications for the use of PSI in this context include
the history of HTx rejection, development of
donor-specific antibodies, and viral infection
with CMV. Although PSI can cause proteinuria
kidney disease, it can be used instead of CNI in
a renal sparing effort; however, given concern
for possible increased risk of rejection, CNI
minimization with PSI may be a safer method
[14]. The use of PSI instead of CNI may also be
indicated for disseminated malignancies such as
PTLD. PSI use should be made on an individual
basis. Potential risks of PSI include increased
risk of fungal infection, fluid retention, risk of
venous thromboembolism, hypertriglyceridemia,
oral ulcers, proteinuria renal disease, nausea,
diarrhea, leukopenia, and pneumonitis.
General Medical Management
Cardiovascular Risk Factors
therapy is avoided. Hypertriglyceridemia can be
caused by PSI therapy, at times requiring cessation of PSI therapy. Hypertriglyceridemia can
usually be managed by agents, including fenofibrate or fish oil.
Renovascular
As with hypertension, CNI is known to lead
to gradual reduction of glomerular filtration
rate and lead to renal dysfunction with longterm use. Renal dysfunction occurs in 52% of
patients, with 15% on chronic dialysis [15]. CNI
toxicity can lead to acute renal dysfunction, so
trough levels of CNI are monitored closely.
While the mainstay of chronic immunosuppressant therapy remains the use of CNI, usually
in combination with an anti-metabolite immunosuppressant, CNI-free immunosuppressant
regimens can be used to avoid the long-term
nephrotoxic effects of CNI, although careful
consideration of the risks of possible rejection [14]. Nephrotoxins, in particular, NSAIDS,
should be avoided, if possible, post-transplant.
The use of colchicine for the treatment of gout
should be done with caution.
Risk factors for the development of heart disease
are quite prevalent after a HTx. Within five years
post-transplant, hypertension occurs in 92% of
patients, and hyperlipidemia occurs in 88% of
patients [15]. Hypertension is a known side effect
of treatment with CNI [16] and steroids. Salt
restriction is advisable, particularly at the earliest post-transplant, when steroid doses and CNI
target trough levels are highest. Hypertension
management using standard guidelines and
directed targets can be done with a number of
different anti-hypertensive agents. Calcium channel blockers in combination with angiotensinconverting enzyme inhibitors showed benefit
by IVUS-based parameters of CAV assessment
at one-year post-transplant [17]. Statin therapy
is recommended post-transplant, in part for the
treatment of hyperlipidemia. Due to drug-drug
interactions, high-dose, high-intensity statin
Endocrine
Another common risk factor that is often present prior to and post-HTx is glucose intolerance
and diabetes. Need for steroid use post-transplant requires adequate control of diabetes prior
to listing for a HTx. Use of high-dose steroids
post-transplant leads to diabetes in 30–40% of
patient’s post-transplant. Screening for ocular,
renal, and podiatric complications of diabetes should continue per usual recommendation.
Early high-dose steroids are weaned such that,
in one approach, patients are reduced to 10 mg
prednisone by three months post-transplant,
5 mg by six months post-transplant, and, if possible, weaned off the prednisone by one year
post-transplant. Many patients will experience
symptoms of steroid withdrawal, most often
manifest in muscle or joint aches or fatigue.
27522 Long-Term Complications in Heart Transplantation
Rarely will steroid withdrawal symptoms prevent steroid weaning. At times, patients with
autoimmune disease may require higher than
usual maintenance doses of prednisone. The
presence of autoimmune disease does not appear
to affect long-term outcomes after a HTx [18].
Bone complications after HTx include osteoporosis, fracture, and osteonecrosis [avascular
necrosis (AVN)]. Risk factors for osteoporosis
include pre-transplant bone state and post-transplant bone loss. Advanced heart failure, chronic
heparin or loop diuretic use, chronic kidney disease, vitamin D deficiency, hyperparathyroidism,
hypogonadism, and reduced physical activity
can lead to low bone mineral density (BMD)
prior to transplant[19]. Post-transplant, bone loss
is greatest in the first year due to higher doses
of steroids and possibly due to higher CNI target trough levels (when cyclosporine is used in
maintenance immunosuppression). Steroids
cause reduced bone formation and increased
bone resorption. In one study of patients who
had annual spinal radiographs, a vertebral fracture was reported in 27% of patients in the first
two years after transplant [20]. Predictors of
fracture included age and pre-transplant BMD.
In another study, women with the lowest BMD
pre-transplant were at the highest risk of fracture, with most fractures occurring in the first
six months post-transplant [21]. Prevention of
falls, smoking cessation, early mobilization after
transplant, and regular weight-bearing exercise
are recommended. Treatment with Vitamin D
(particularly in those with Vitamin D deficiency)
and calcium is recommended prior to and posttransplant. Bisphosphonate therapy to prevent
bone loss should be considered in patients over
age 65, patients with a history of prior fragility
fracture, and those with BMD T scores below
negative 1.0. If bisphosphonate therapy is not
tolerated or if the patient has significant renal
insufficiency, calcitriol is an alternate option. If
calcitriol is prescribed, serum and urine calcium
levels should be monitored [22]. Treatment with
bisphosphonate therapy for osteoporosis may not
be required for more than one year after transplant. The use of chronic steroids post-transplant
is also associated with osteonecrosis. The risk of
AVN is <3% in patients maintained on doses of
prednisone less than 15 mg/day. Other risk factors for the development of AVN include excess
alcohol intake, systemic lupus erythematosus,
anti-phospholipid antibodies, trauma, sickle cell
disease, Gaucher disease, and decompression
disease. AVN often presents with weight-bearing
pain but can occur at rest or with night symptoms. Plain films may yield the diagnosis, but
magnetic resonance imaging (MRI) is the most
sensitive test for diagnoses of AVN. Treatment
options include non-operative and operative
options. Early-stage AVN may benefit from
medical therapy with bisphosphonates, statin
therapy to reduce the transition of bone marrow
pluripotent cells into fat cells, iloprost (prostacyclin) vasodilator therapy, and anticoagulation
when AVN is related to thrombophilia. Electrical
stimulation and hyperbaric oxygen were used for
early-stage AVN. Operative approaches include
joint preserving procedures or joint replacement.
Gastrointestinal
Gastrointestinal issues can occur post-HTx.
Early post-transplant, with the use of higher
doses of steroids, peptic ulcer disease and gastritis symptoms can be reduced by the use of
proton pump inhibition (PPI). PPI use is generally not required in the long term. Patients
on mycophenolate mofetil can have diarrhea
or nausea, which usually improves with dose
reduction; however, if ineffective, it usually
responds to transition to enteric-coated formulations. Patients maintained on azathioprine are at
risk for pancreatitis. Patients post-transplant are
at risk for cholelithiasis and diverticular disease.
In summary, major complications after
HTx, in addition to infection, rejection, and
CAV, include malignancy, hypertension, hyperlipidemia, renal disease, glucose intolerance,
bone and gastrointestinal disease. Advances in
techniques for immunosuppression minimization for renal disease, infection, or malignancy
improve the quality of life and longevity of HTx
patients. Potential alternative immunosuppression therapies, including T cell co-stimulation