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138 E. Kransdorf et al.
41. Augustine SM, Yeo CJ, Buchman TG, Achuff SC,
Baumgartner WA. Gastrointestinal complications in
heart and in heart-lung transplant patients. J Heart
Lung Transplant. 1991;10(4):547–55; discussion
55–6.
42. Lv S, Ru S. The prevalence of malnutrition and its
effects on the all-cause mortality among patients
with heart failure: a systematic review and metaanalysis. PLoS ONE. 2021;16(10):e0259300.
43. Shiner CT, Woodbridge G, Skalicky DA, Faux SG.
Multidisciplinary inpatient rehabilitation following heart and/or lung transplantation-examining
cohort characteristics and clinical outcomes. PMR.
2019;11(8):849–57.
44. Kobashigawa JA, Leaf DA, Lee N, Gleeson MP, Liu
H, Hamilton MA, et al. A controlled trial of exercise
rehabilitation after heart transplantation. N Engl J
Med. 1999;340(4):272–7.
Maintenance Immunosuppression Strategies in Heart Transplantation
Jignesh Patel and Krishan Patel
12
Abstract
Advancements in immunosuppression therapies have transformed the landscape of heart
transplantation and significantly improved
outcomes for transplant recipients. Modern
immunosuppression strategy hinges on
deploying a combination of immunosuppressive agents; this chapter will cover the
different categories of maintenance immunosuppressive agents used in heart transplant patients, their clinical utility, and
strategies involving different combinations
of these agents to adjust to various clinical
phenotypes.
Keywords
Heart failure · Heart transplantation ·
Immunosuppression · Rejection · Induction ·
Cardiac allograft vasculopathy · Outcomes
J. Patel (*) · K. Patel
Cedars-Sinai Smidt Heart Institute, Los Angeles,
CA, USA
e-mail: jignesh.patel@cshs.org
K. Patel
e-mail: krishan.patel@cshs.org
Clinical Pearls
• While there is no accepted universal protocol
for immunosuppression, common standard
practice consists of “triple” therapy consisting of a calcineurin inhibitor, an anti-proliferative agent, and corticosteroids.
• Corticosteroid wean-to-off protocols are suc-
cessful in a majority of patients at low risk
for rejection with best results occurring when
initiated within the first year post-transplant.
• Tacrolimus is generally preferred to cyclo-
sporine due to reduced rejection and a more
tolerable adverse effect profile.
• Common side effects of calcineurin inhibitors
include hypertension, nephrotoxicity, hyperglycemia, hyperlipidemia, and neurotoxicity.
Calcineurin inhibitors are metabolized by
•
the cytochrome P-450 liver enzyme pathway
and thus are susceptible to interactions, most
notably with cytochrome P-450 inhibitors
such as the –azole antifungals and grapefruit
juice.
• Within the antiproliferatives, mycophenolate
mofetil (MMF) is superior to azathioprine
with improved survival, decreased incidence
of rejection and a reduced adverse effect
profile.
• Common side effects of the antiproliferatives
include myelosuppression, fluid retention and
nausea/vomiting.
© 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_12
139
140 J. Patel and K. Patel
• The proliferation signal inhibitors everolimus/sirolimus are superior to MMF in retarding cardiac allograft vasculopathy and may
also enable early weaning of calcineurin
inhibitors; however, they have also been associated with impaired wound healing and renal
insufficiency as they potentiate calcineurin
inhibitor nephrotoxicity.
• Immunosuppression regimens should be individualized to each patient’s risk profile and
medical history.
Introduction to Transplant Immunosuppression
Initial immunosuppressive efforts in human cardiac transplantation were hindered by poor outcomes that resulted from suboptimal regimens,
with the result frequently being overwhelming
infection or allograft rejection. Initially, at the
advent of modern cardiac transplantation, 1-year
survival in the 1970s hovered around 50% [1].
At this stage, the only viable immunosuppressive techniques were the use of azathioprine, a
purine analogue, and total body irradiation, both
with many adverse effects. In the subsequent
30 years, improved donor heart management,
refinement of donor and recipient selection
methods, and the introduction of the calcineurin-inhibiting agent cyclosporine, followed by
even more successful immunosuppressive agents
and regimens, has improved survival considerably. With 1-year survival at 90%, a 5-year survival rate of approximately 70%, and a median
survival in excess of 11 years, developments in
immunosuppression have enabled heart transplantation (HTx) to become a definitive option
for selected patients with end-stage heart failure
[2]. There are three possible outcomes in the
use of immunosuppressive drugs, some or all
of which may overlap: the desired immunosuppressive effects, adverse effects of immunodeficiency such as infection and malignancy, and
non-immune toxicities such as diabetes, hypertension, and renal insufficiency. In particular,
malignancy is one of the most common causes
of death post-cardiac transplant, accounting for
24% of deaths after 5 years [2]. The impaired
immunoregulation that results from immunosuppression is synergistic with carcinogens
such as nicotine or ultraviolet light exposure
and oncogenic viruses such as the Epstein–Barr
virus (EBV) and the papillomavirus (HPV) [3].
Lymphoproliferative diseases, skin cancers, and
Kaposi sarcoma have a particularly high incidence relative to the general population.
In this field, it has always been crucial to
maintain a delicate balance between the risk of
rejection and the risk of immunosuppressionrelated adverse effects. Minimizing immunosuppression and immunosuppression-associated
complications without sacrificing efficacy are
the goals of post-transplantation management.
Modern immunosuppression strategy hinges
on the deployment of a combination of immunosuppressive agents, with each affecting a different pathway of T-cell activation (Fig. 12.1).
This chapter will cover the different categories
of maintenance immunosuppressive agents used
in HTx patients, their clinical utility, and strategies involving different combinations of these
agents.
Immunosuppressive agents commonly used
in HTx patients and their mechanisms of action
and common side effects are listed in Table
12.1, which gives trade names, pharmacology,
necessary adjustments for renal or hepatic dysfunction, and dosing and general monitoring
guidelines for each of the drugs. Table 12.2 lists
the major adverse effects of immunosuppressive
drugs.
Immunosuppressive Agents for Maintenance Regimens
Immunosuppression regimens can be generally
defined as induction, maintenance, or rejection
regimens. Whereas “rejection” regimens refer
to agents specifically used to treat rejection episodes (covered in Chap. 19), and “induction”
refers to a brief period of intense perioperative
immunosuppression, and will be covered later
in Chap. 13, maintenance therapy refers to the
ongoing immunosuppressive regimen that a
12 Maintenance Immunosuppression Strategies …
141
Fig. 12.1 Diagram of mechanisms of action of common immunosuppressants in heart transplant. Through
various pathways, the drugs inhibit T-cell proliferation. Abbreviations G1 (first growth phase), S (synthesis of DNA), G2 (second growth phase), and M
(cell division) represent the phases of the cell cycle.
APC, antigen-presenting cell; CDK, cyclin-dependent
kinase; IL-2, interleukin-2; IL-2R, interleukin-2 receptor; IL-2R Ab, interleukin-2-receptor antibody; MHC,
cardiac transplant patient must undergo for the
rest of their lives, to prevent rejection.
Remarkably, there remains no accepted uniform protocol for maintenance immunosuppression in cardiac transplant patients. The most
major histocompatibility complex; MMF, mycophenolate
mofetil; mRNA, messenger RNA; NF-AT, nuclear factor
of activated T cells; TCR, T-cell receptor; TOR, target
of rapamycin protein. Reused with own rights according to Springer Nature Policy, Kobashigawa JA, Patel
JK. Immunosuppression for heart transplantation: where
are we now? Nature Clinical Practice Cardiovascular
Medicine. 2006; 3(4): 203–12
common long-term regimen consists of a triple
therapy regimen, consisting of a corticosteroid, calcineurin inhibitor, and antiproliferative.
However, there remains controversy over which
specific agents and combinations of agents are
142 J. Patel and K. Patel
(continued)
cells < 3000–4000
Major drug
interaction with
allopurinol
Polymorphisms
in TMPT may
Monitoring
No currently
available monito-
Intra and post:
Solumedrol 5–10
ring tool except
clinical response
mg/kg pre- or
intraoperatively
and 5–7 mg/
kg in 3 divided
doses over next
24 h; then rapidly
tapered from 1 to
0.3 mg/kg/day at
3–6 mo to 0.1 mg/
kg/day at 6 mo
For rejection:
prednisone 1–3
mg/kg/day PO for
3–7 day or solu-
medrol 3–10 mg/
kg/day IV; Lower
Monitoring of
levels not clini-
doses have been
used successfully
1–2 mg/kg per
day PO or IV
cally available
Dose is decreased
if white blood
Rarely used > 3
mg/kg
IV and oral the
same dose
increase effect
Dosing
Oral Intravenous Comments
×
renal/hepatic
dysfunction
Consider pred-
nisolone if hepatic
Processed in the
liver and metabo-
Generic
Drug Trade name(s) Pharmacology Adjustment for
Table 12.1 Overview of commonly used immunosuppressive drugs in cardiac transplantation, including both maintenance and induction agents
Prednisone Deltasone
×
dysfunction
No
lites excreted in
the urine
Prednisolone Generic Prednisone is
converted to Pred-
nisolone in liver
×
×
No
Prednisolone have
4–5 times potency
of hydrocortisone
Medrol Prednisone and
Solumedrol
Methylpredniso-
lone
× ×
Decrease doses
for renal dysfun-
ction and lower
to 6-mercapto-
purine, which is
Azathioprine Imuran Converted in liver
dose range for
hepatic dysfun-
ction
inactivated by
xanthine oxidase
or TMPT predo-
minantly in the
liver
12 Maintenance Immunosuppression Strategies …
Monitoring
Monitoring of
MPA levels is
controversial,
but trough levels
of 2.5–5.0 μg/
mL have been
suggested
CSA inhibits
enterohepatic
circulation of
MPA, decreasing
exposure and
levels
500–1500 mg
BID
Higher doses have
been used when
monitoring trough
MPA levels
IV and oral the
same dose
Abbott TDX
assay most com-
monly used
CSA trough
levels have been
routinely used
with levels of
Dosing is high
early after trans-
plantation and
gradually decrea-
ses over time
Drugs that inhibit
CYP-3A4 and
1–2 mg/kg per day in 2 divided doses
or as continuous infusion
300–350 ng/ml
early postopera-
tively decreasing
to 100–200 by
1 year
p-GP may result
in significantly
higher levels
IV dose is 1/3–1/4
of oral dose
Levels at 2 h
postdose appear
to more accura-
tely estimate area
under the curve
IV may be best
administered in
2–6 h infusions
143
(continued)
and may result in
lower doses
Dosing
Oral Intravenous Comments
renal/hepatic
Drug Trade name(s) Pharmacology Adjustment for
Table 12.1 (continued)
dysfunction
≤1000 mg BID × ×
Rapidly hydroly-
zed to mycophe-
Generic
MMF Cellcept
nolic acid (MPA)
and MPA to its
gluronide, which
is excreted in
urine and bile
4–8 mg/kg per
day in 2 divided
doses
Hepatic dysfun-
ction:
Decrease dose by
half and follow
levers
Oil-based
formulation
has unpredicta-
ble absorption
secondary to need
Generic
Calcineurin inhibitors
Cyclosporine
Oil-based Sandimmune
for emulsification
by bile salts
Modified for
more predictable
absorption
Both forms exten-
sively metaboli-
Neoral
Gengraf
Other generics
Modified (oil-ba-
sed formulation is
not bioequivalent
to modified prepa-
ration)
zed by CYP-3A4
and are substrates
and inhibitors of
p-GP
144 J. Patel and K. Patel
Monitoring
Whole-blood
levels of 10–15
ng/ml early after
transplantation
and 5–10 ng/
ml by 1 year are
targets
Doses are high
early after
transplantation
and decrease over
time
Drugs that inhibit
CYP3A4 or p-GP
may result in
0.01–0.02 mg/kg per day in 2 divided
doses or as continuous infusion
higher levels
Whole-blood
trough levels of
4–15 ng/ml
Coadministration
with CSA may
2 mg/day in 1
dose (may be
preceded by
a single 6-mg
loading dose)
increase CSA
levels as much as
100%
Dose 4 h apart
with CSA or
tacrolimus
monitor is 3–8
0.75 mg BID Therapeutic drug
ng/ml
Early renal insuf-
ficiency seen
when used with
sd-CSA. rd-CSA
recommended
Dosing
Oral Intravenous Comments
renal/hepatic
Drug Trade name(s) Pharmacology Adjustment for
Table 12.1 (continued)
0.05–0.1 mg/
kg per day in 2
divided doses
dysfunction
Follow levels for
hepatic dysfun-
ction
Metabolized by
CYP-3A4 and
are substrates and
Generic
Tacrolimus Prograf
inhibitors of p-GP
×
≤33% ↓ if hepatic
dysfunction
p-GP substrate
mTOR inhibitors
Sirolimus Rapamune CYP-3A4 and
×
≤33% ↓ if hepatic
dysfunction
CYP-3A4 and
p-GP substrate
Certican (EU)
Everolimus Zotress (US)
org/10.1161/01.CIR.0000150332.42276.69; American Heart Association.
Simon F. Shakar, Ronald Zolty, et al., Drug Therapy in the Heart Transplant Recipient: Part II: Immunosuppressive Drugs, Circulation, 110 (25), 3858–3865, https://doi.
CNI, calcineurin inhibitor; CSA, cyclosporine; CYP, cytochrome P450; MMF, mycophenolate mofetil; p-GP, p-glycoprotein; rd-CSA, reduced-dose cyclosporine; sd-CSA,
standardized-dose cyclosporine; TOR, target of rapamycin; TMPT, thiopurine methyltransferase. Reused with permission from JoAnn Lindenfeld, Geraldine G. Miller,
12 Maintenance Immunosuppression Strategies …
145
Table 12.2 Overview of major adverse effects of immunosuppressive drugs used in cardiac transplantation—listed
by frequency scoring
Steroid AZA MMF CSA TAC SIR EVR
Potential for drug–drug interactions 1 1 1 4 4 4 4
Hypertension 2 4 3 2
Diabetes 3 1–2 2–3
Obesity 2
Hyperlipidemia
Renal insufficiency 3 3 4
a
2 3 3 3–4 3–4
b
Osteoporosis 3 1–2 1–2 1–2
Avascular necrosis 1
Poor wound healing 2 2
c
1–2
Neurological minor tremors, paresthesias 3 3
Neurological major seizures, cerebritis 1 1
Hirsutism 2 3
Alopecia 1 2
Gingival hyperplasia 3
d
GI
2 3 2 3 3 3
Hepatic toxicity 2 1 2 1 1
Hypomagnesmia 3 3
Hyperkalemia 2 2 2
Hyperuricemia 3 3 3
Anemia 2 3 3 3
Thrombocytopenia 1 2 3 3 3
Neutropenia 3 3 3 3
Cushingoid features 3
Cytokine release syndrome—mild
Cytokine release syndrome—severe
Serum sickness
AZA, azithoprine; CSA, cyclosporine; EVR, everolimus; GI, gastrointestinal; MMF, mycophenolate mofetil; SIR,
sirolimus; TAC, tacrolimus
1, rare (<5%); 2, common (5–15%); 3, very common; 4, most patients
a. Hyperlipidemia defined as: (↑ total cholesterol, ↑↑LDL cholesterol, ↑ triglycerides) (16–50%)
b. When used concomitantly with cyclosporine
c. Wound healing (especially early after operation), >50%
d. GI problems: diarrhea, nausea, vomiting
Reused with permission from JoAnn Lindenfeld, Geraldine G. Miller, Simon F. Shakar, Ronald Zolty, et al., Drug
Therapy in the Heart Transplant Recipient: Part II: Immunosuppressive Drugs, Circulation, 110 (25), 3858–3865,
https://doi.org/10.1161/01.CIR.0000150332.42276.69; American Heart Association
146 J. Patel and K. Patel
most effective. This section will cover the most
commonly used immunosuppressive agents in
maintenance regimens.
Corticosteroids
Corticosteroids, or simply steroids, are among
the first immunosuppressive agents ever used
in clinical transplantation, and, to this day,
remain a cornerstone of post-transplant management. They exert potent immunosuppressive
and anti-inflammatory effects. Uniquely, they
play a major role in the induction phase immediately post-transplant, during maintenance, and
as part of anti-rejection regimens. While highly
effective for the prevention and treatment of
acute rejection, their long-term use is associated
with a number of adverse effects. For this reason, many centers attempt to wean prednisone,
the most commonly used maintenance steroid,
by 12 months post-transplant except for multiorgan transplant recipients or those with certain
etiologies of their original cardiomyopathy, like
sarcoidosis or giant cell myocarditis [4].
Mechanism of Action
Corticosteroids act by altering the transcriptional regulation of multiple genes that affect
leukocytes (T and B lymphocytes, granulocytes, macrophages, and monocytes) as well as
endothelial cell function [5]. The major effect
on lymphocytes is mediated by inhibition of
the transcription factor activator protein 1 and
nuclear factor kappa B (NF-kB), which negatively affect the expression of several genes,
including those controlling cytokine production, growth factors, and adhesion molecules.
Furthermore, steroids cause a decrease in the
production of vasoactive/chemoattractant factors and lipolytic/proteolytic enzymes in nonlymphoid cells. Downstream, this results in
inhibition of neutrophil adhesion to endothelial
cells, prevention of macrophage differentiation,
and down-regulation of endothelial function.
Glucocorticoids also exert their anti-inflammatory effects through inducing the release of lipocortin, which acts by inhibiting phospholipase
A2, in turn suppressing the production of prostaglandins and leukotrienes [6, 7].
Adverse Eects
While effective at preventing rejection, steroids are associated with a significant number of
long-term adverse effects. Hypertension, poor
wound healing, gastric ulcers, emotional lability,
cataracts, and proximal myopathy are all associated with corticosteroid therapy. Furthermore,
cosmetic side effects such as hirsutism, acne,
moon facies, easy bruising, skin fragility, “buffalo hump,” and truncal obesity may also occur.
From a metabolic point of view, hyperlipidemia,
salt and water retention, diabetes mellitus, osteopenia, and growth retardation in children may
result [6, 8]. If high-dose steroids are administered long-term, chronic adrenal suppression
may result (via negative feedback mechanisms).
Adrenal insufficiency may also follow a steroid
taper or physiologic “stress” (illness, surgical
procedures, infections).
Calcineurin Inhibitors: Cyclosporine and Tacrolimus
The calcineurin inhibitors (CNIs), which include
cyclosporine and tacrolimus, have become cornerstones of maintenance immunosuppressive
therapy for transplant patients. Cyclosporine is a
lipophilic undecapeptide which was initially isolated from the fungus Tolypocladium inflatum.
The discovery of cyclosporine and subsequent
use in HTx in the late 1970s enabled survival
rates to drastically improve. Tacrolimus, in contrast, was more recently discovered in 1987 and
only since the late 2000s has it become widely
used in HTx patients. Tacrolimus is a macrolide
and is produced by the fungus Streptomyces
usukubaensis; it has a very similar mode of
action to cyclosporine and is frequently used as
an alternative to it.
Mechanism of Action
Cyclosporine and tacrolimus both function
by blocking calcium-activated calcineurin
(Fig. 12.1) [9, 10]. The agents are able to enter
14712 Maintenance Immunosuppression Strategies …
cells through diffusion and bind to different
immunophilins: cyclosporine binds to cyclophilin and tacrolimus to FK binding protein-12
(FKBP-12). This drug-immunophilin complex
proceeds to bind to calcineurin, a phosphatase
that dephosphorylates multiple molecules,
including nuclear factor of activated T cells (NFAT). In turn, dephosphorylated NF-AT translocates to the nucleus, where it binds to specific
DNA sites in the promoter regions of several
cytokine genes, including interleukin (IL)-2.
Through this series of actions, cyclosporine
and tacrolimus inhibit transcription of IL-2 and
other cytokines, tumor necrosis factor alpha
(TNF-a), granulocyte–macrophage colony-stimulating factor, and interferon-gamma [11]. In a
mechanism specific to cyclosporine, transforming growth factor-ß (TGF-ß) production is also
stimulated, augmenting its immunosuppressive
activity [12]. Furthermore, cyclosporine has
been found to suppress delayed-type hypersensitivity skin reactions to tuberculin in guinea-pigs
but appeared have no effects on antibody synthesis, suggesting a mechanism of immunosuppression specific to T cells.
Notes
Cyclosporine is available as oil-based or microemulsion formulations, as well as intravenous
solution (for post-operative administration).
Due to an improved pharmacokinetic profile
and clinical data, microemulsion preparations
are generally preferred over the older oil-based
formulations [13]. Indeed, randomized studies comparing the two demonstrated similar
survival at 2 years, but lower rates of treated
rejection in the microemulsion group [14–16].
Furthermore, the microemulsion formulation
exhibited better tolerance and fewer discontinuations, and allowed lower average doses
of corticosteroids compared to the oil-based
formulation.
Tacrolimus has become the most widely
used CNI in recent years, preferred over cyclosporine. There is evidence from uncontrolled
studies that tacrolimus results in lower rates of
rejection and fewer adverse effects as compared
to cyclosporine [17–19]. While there is no demonstrated difference in post-transplant survival
between tacrolimus and oil-based cyclosporine
[20, 21], randomized controlled trials show
patients on tacrolimus display lower moderatesevere cellular rejection rates at 6 months compared to those on microemulsion cyclosporine
[22]. Despite this, tacrolimus patients have been
noted to display a higher incidence of de novo
diabetes mellitus compared to microemulsion
cyclosporine.
Adverse Eects
While not an adverse effect per se, cyclosporine
treatment has been previously noted to mask the
clinical signs and symptoms of acute allograft
rejection, making endomyocardial biopsy essential for rejection surveillance.
Cyclosporine is also noted to cause acute or
chronic dose-related nephrotoxicity, with the
possible sequelae of arteriolar sclerosis and tubulo-interstitial fibrosis (see Table 12.2). In most
patients, hypertension and hyperlipidemia tend
to occur [23] and the development of de novo
diabetes mellitus is fairly common. Electrolyte
abnormalities are common, especially hyperkalemia, but are rarely life-threatening if renal
function remains intact. Hypertrichosis, which
occurs in at least 50% of patients, and gingival
hyperplasia are side effects seen with cyclosporine. Neurotoxic symptoms may also occur;
such manifestations include tremor, paresthesias, headache, seizures, mental status changes,
visual symptoms, and insomnia. Other possible
side effects include nausea, vomiting, cholestasis/cholelithiasis, and long-term, may accelerate
the development of osteoporosis (especially in
combination with corticosteroids).
Tacrolimus has been noted to exhibit a similar side effect profile to cyclosporine, although
the incidence of hyperlipidemia and hypertension are reduced (see Table 12.2) [20], while the
incidence of hyperglycemia and neurotoxicity is
relatively increased. There is some evidence to
suggest that the onset of diabetes may be more
common when tacrolimus is given with azathioprine compared to mycophenolate mofetil [24].