Lakhasly

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.

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 recent cohort, 2.8%
of the adult population was treated with long-term immunosuppressive medications,
consistent with prior self-reported estimates (2, 3). 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). 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.
Hypertrophy is frequently seen in association with diastolic
dysfunction and represents an important marker for adverse
remodeling (5, 6). Much of the focus on immunosuppressioninduced
cardiac remodeling has been on the effects on cardiac
hypertrophy in native or transplanted hearts (7–9) (Table 1).
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. Cyclosporine (CsA) binds to cyclophilin A,
forming a complex with high affinity for calcineurin, which
in turn inhibits its nuclear translocation. This is hypothesized
to inhibit activation of NFAT-mediated hypertrophy (59).
Tacrolimus binds to FK506-binding protein (FKBP12) to
inhibit calcineurin activity driving reduced NFAT-mediated
transcription of hypertrophic genes.
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). However, these
data were challenged by the failure of CsA to prevent
hypertrophy in several models of hypertension or pressure
overload (16, 35, 61). Tacrolimus has also yielded mixed results.
In murine models of genetic hypertrophic cardiomyopathy,
tacrolimus exacerbated cardiac hypertrophy (37). 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).
Some hypothesized that the mixed results were driven by
variability in hypertrophic signaling from genetic/sarcomericdriven
hypertrophic signaling vs. adaptive chemical or afterloaddriven
hypertrophy (37, 59). This hypothesis is somewhat
weakened by mixed data for transverse aortic constriction
rodent models.
Subsequent investigations suggested that CsA-induced
effects on hypertrophic remodeling may be driven by increased
fibrosis. Multiple studies have shown that CsA treatment
led to increases in MMP2, MMP9, and Collagen I in dose
dependent manner (20–22, 63). Rat hearts treated with CsA
exhibited increased fibrosis/collagen content (64). 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). The in
vitro findings suggest that increased fibrosis is not a result of
calcineurin-induced hypertension.
Notwithstanding some of the conflicting data in animal
models, the data from humans have been fairly consistent
as to the effects of CsA and tacrolimus on human hearts.
Endomyocardial biopsies from heart or liver transplant patients
treated with CsA showed structural distortion, increased
fibrosis, and increased collagen levels (25, 26). Furthermore,
patients treated with CsA and tacrolimus had hypertrophy or
increased LV mass on autopsy or imaging (8, 26, 27, 39, 40).
A clinical trial investigating the effect of CsA in patients with
hypertrophic cardiomyopathy was initiated, but it is unclear
if the study was completed and findings, if any, were not
published (66).
Despite some earlier reports of amelioration of cardiac
hypertrophy by CNI, there is no clear evidence in humans
to corroborate this finding. Supported by in vitro and human
data, a consistent signal of increased hypertrophy and fibrosis
associated with CNI treatment is observed (23, 28). 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.
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. There are notable differences between sirolimus
and everolimus (67). Everolimus is the 40-O-(2-hydroxyethyl)
derivative of sirolimus, and differs in its subcellular distribution,
pharmacokinetics and binding affinity. Compared to sirolimus,
everolimus has higher bioavailability and shorter half-life. Both
drugs form a complex with FKBP-12, which binds mTOR.
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). Clinically this has translated into differences in side effect
profile and potency of each drug.
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).
Sirolimus has been shown to reduce cardiac hypertrophy and
fibrosis in animal models of pressure overload, uremia, and
adriamycin induced cardiomyopathy (42, 43, 71). 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). Cellular data suggest that attenuation of
adverse cardiac remodeling by mTOR inhibitors may be related