Introduction
Medications that target and downregulate the immune system are utilized for the
prevention and treatment of a variety of conditions, including neoplasms, autoimmune
diseases, and acute rejection after solid organ transplantation (1).In a rat
model of myocardial infarction, everolimus improved postinfarct
remodeling (72) although in the recently published
CLEVER-ACS trial of patients with myocardial infarction,
there everolimus treatment had no effect on myocardial
remodeling (73).Herein, we focus on the cardiovascular
effects and mechanistic underpinnings of calcineurin inhibitors (CNI), mammalian
target of rapamycin (mTOR) inhibitors, and purine synthesis inhibitors (Figure Hypertrophy and fibrosis
Cardiac hypertrophy is a feature of adverse cardiac
remodeling that may be driven by genetic or acquired factors.In addition to the well described
increased risk of infection and malignancy in chronically immunosuppressed patients,
many of these agents exhibit direct effects on the cardiovascular system including risk
of left ventricular (LV) hypertrophy, myocardial fibrosis, arrhythmia, hypertension,
dyslipidemia, and coronary atherosclerosis (4).Calcineurin inhibitors
Calcineurin, a calcium and calmodulin-dependent
phosphatase, plays a pivotal role in cardiac hypertrophy by
translocating to the nucleus and dephosphorylating NFAT,
allowing it to transcribe genes to activate hypertrophy in
cardiomyocytes.In early animal experiments, CsA successfully prevented
or attenuated cardiac hypertrophy in mice overexpressing
contractile elements (10, 29), genetic predispositions to
hypertrophy (19), and treatment with exogenous chemical
signals promoting hypertrophy (11, 15, 60).In animal
models of hypertrophy induced by phenylephrine stimulation,
spontaneously hypertensive rats, or aortic banding, tacrolimus
treatment had variable effects, with exacerbation or amelioration
of the hypertrophic phenotype (16, 38, 61, 62).Tacrolimus binds to FK506-binding protein (FKBP12) to
inhibit calcineurin activity driving reduced NFAT-mediated
transcription of hypertrophic genes.mTOR inhibitors
mTOR inhibitors, such as sirolimus and everolimus, inhibit
mammalian target of rapamycin complex I, thereby inhibiting
downstream pathways driving cell growth, proliferation, and
survival.Cellular data
highlight that the increase in LV mass may be driven primarily
by CNI-induced increase in fibrosis and collagen deposition
rather than cardiomyocyte remodeling.However, everolimus binding to FKBP-12 is ~3-fold weaker
than that of sirolimus, leading to significant differences in
inhibition of mTORC2 activation and downstream effects (68,
69).Sirolimus has been shown to reduce cardiac hypertrophy and
fibrosis in animal models of pressure overload, uremia, and
adriamycin induced cardiomyopathy (42, 43, 71).Similar data
of increased collagen deposition in response to tacrolimus
treatment was observed in human induced pluripotent stem cellderived
cardiac organoids treated with tacrolimus (65).This class of drugs has garnered significant interest in
solid organ transplantation owing to salutary effects on renal
function, allograft vasculopathy and malignancy risk (70).Hypertrophy is frequently seen in association with diastolic
dysfunction and represents an important marker for adverse
remodeling (5, 6).Cyclosporine (CsA) binds to cyclophilin A,
forming a complex with high affinity for calcineurin, which
in turn inhibits its nuclear translocation.Tacrolimus has also yielded mixed results.