The protein known as mammalian target of rapamycin (mTOR) plays vital roles in protein synthesis, and hence in growth and cell proliferation, including the proliferation of immune response cells and neoplastic cells. The paths through which it acts have two main branches that start from mTOR complexes known as mTORC1/RAPTOR and mTORC2/RICTOR. The former is inhibited by sirolimus (rapamycin), everolimus, and their analogues, while the latter is not. Despite not inhibiting mTORC2/RICTOR, the sirolimus family are known collectively as mTOR inhibitors, and also as proliferation signal inhibitors (PSIs).1

mTOR inhibitors are attractive for post-transplantation therapy because their antiproliferative properties appear to combine immunosuppression with reductions in the risk or progression of proliferative post-transplantation complications, notably malignancy2 and allograft vasculopathy.3,4 When replacing antimetabolites in triple therapy in conjunction with calcineurin inhibitors (CNIs) and steroids, mTOR inhibitors have been reported to decrease the progression of cardiac allograft vasculopathy without increasing the incidence of acute rejection;4–6 and as replacements or partial replacements of CNIs they have been found both to attenuate the progression of allograft vasculopathy after heart transplantation (HT)7 and to reduce the incidence of malignancy after kidney transplantation.8

Kushwaha et al.9 have presented results suggesting that mTOR inhibitors may actually bring about the reversion of another common life-threatening post-HT complication, left ventricular hypertrophy (LVH).10 In a retrospective study in which 83 patients with a CNI as primary immunosuppressor were compared over 1 year with 58 for whom a CNI was replaced with sirolimus because of nephrotoxicity and/or allograft vasculopathy, the authors found that LV mass index (LVMI) decreased significantly from 99 to 93 g/m2 in the sirolimus group while increasing slightly in the CNI group, and that left atrial volume index, an indirect measure of diastolic function, decreased significantly in the sirolimus group while increasing significantly in the CNI group. Moreover, the reduction in LVMI was almost entirely found in the 13 sirolimus-treated patients with LVH at baseline, among whom average LVMI fell by 24 g/m2. These results are in keeping with reports that in mice sirolimus reduces overload-induced LVH and fibrosis, and reverses associated alterations of gene expression;11,12 and that in kidney transplant patients with allograft nephropathy, replacement of CNIs with sirolimus may bring about the regression of LVH independently of blood pressure changes.13

Kushwaha et al. tentatively attribute the observed regression of LVH to the direct action of sirolimus on myocardium rather than to any influence on hypertension, the main cause of LVH in HT patients.14 They base this conclusion on the fact that although blood pressure fell in the sirolimus group and not in the CNI group (doubtless because of the withdrawal of CNIs in the former), the blood pressure changes in the sirolimus group were not correlated with LVMI; and on the observation that the number of endomyocardial biopsy cells stained by a polyclonal antibody against the cell cycle inhibitor p27Kip1 increased in a group of 22 sirolimus-treated patients but not in a group of nine CNI-treated patients. In this respect, one misses the presentation of data on whether the p27Kip1-positive cell count correlated with the degree of LVH regression. Also, although increased p27Kip1 synthesis is not entirely unexpected (being a known effect of mTOR inhibition),15 it is a pity that the results of labelling with polyclonal antibody were not backed up by reverse transcription–PCR or expression array studies. Such studies might have confirmed alteration of the complex pathway between mTOR and p27Kip1, and thrown light on whether alteration of other signalling pathways might also have been involved in the observed regression of LVH. Given the central physiological roles of mTOR, it is certainly on the cards that its inhibition has as yet unknown consequences,16 and that any such consequences may include effects that are relevant to LVH.

Even if sirolimus does induce LVH regression in addition to its antitumoural, antivasculopathic, and immunosuppressive effects, it is not a panacea. As might be expected, given the very fundamental functions of mTOR, the administration of mTOR inhibitors has been associated with numerous adverse side effects with varying degrees of manageability, including hyperlipidaemia, defective wound healing, oedema, bacterial infections, acne, pneumonitis, and proteinuria.17 Together with the immunosuppressive action of mTOR inhibitors, these effects call for great caution to be exercised in regard to the tacit suggestion of Kushwaha et al. that sirolimus may be a valid therapeutic approach to LVH in non-transplant patients.

The renal effects of replacing CNIs with mTOR inhibitors are particularly controversial. Although mTOR inhibitors are not themselves nephrotoxic, and their substitution for CNIs therefore reduces renal insult, there have been reports that total withdrawal of CNIs increases the risk of kidney graft rejection,18 while partial withdrawal is called into question by reports that mTOR inhibitors potentiate the nephrotoxicity of CNIs.17 Other studies have observed improved renal function without increased rejection risk in the total absence of CNIs,3,19 or that renal function improved when low-level CNI administration accompanied administration of an mTOR inhibitor. Since the increased rejection risk seems mainly to affect patients in their first post-transplant year, some authors have recommended that mTOR inhibitors be used in conjunction with low-level CNI administration during this period.17

Another factor to be taken into account is the possible desirability of administering mTOR inhibitors together with additional drugs that counteract some of the mechanisms by which the cell responds to mTOR inhibition. It is known that there is a negative feedback loop whereby inhibition of mTORC1 by sirolimus increases AKT activation, which tends to restore mTOR activity;20 and Carracedo et al.21 have recently reported that cancer patients exhibit a second negative feedback loop, with similar effects, involving the mitogen-activated protein kinase pathway.

Kushwaha et al.'s findings open up exciting perspectives for the treatment of post-HT LVH. They call for more thorough evaluation in randomized trials that allow overall assessment of the pros and cons of mTOR inhibitor therapy. mTOR inhibitors certainly seem to have a role to play in the management of transplant patients; in the coming years, further research must characterize that role more fully.

Conflict of interest: M.G.C.-L. reports having received grant support from Wyeth, Novartis and Astellas Pharma.

References

1
Lee
CH
Inoki
K
Guan
KL
mTOR pathway as a target in tissue hypertrophy
Annu Rev Pharmacol Toxicol
 , 
2007
, vol. 
47
 (pg. 
443
-
467
)
2
Valantine
H
Is there a role for proliferation signal/mTOR inhibitors in the prevention and treatment of de novo malignancies after heart transplantation? Lessons learned from renal transplantation and oncology
J Heart Lung Transplant
 , 
2007
, vol. 
26
 (pg. 
557
-
564
)
3
Raichlin
E
Khalpey
Z
Kremers
W
Frantz
RP
Rodeheffer
RJ
Clavell
AL
Edwards
BS
Kushwaha
SS
Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients
Transplantation
 , 
2007
, vol. 
84
 (pg. 
467
-
474
)
4
Mancini
D
Pinney
S
Burkhoff
D
LaManca
J
Itescu
S
Burke
E
Edwards
N
Oz
M
Marks
AR
Use of rapamycin slows progression of cardiac transplantation vasculopathy
Circulation
 , 
2003
, vol. 
107
 (pg. 
1
-
6
)
5
Eisen
H
Tuzcu
E
Dorent
R
Kobashigawa
J
Mancini
D
Valantine von Kaeppler
H
Starling
RC
Sørensen
K
Hummel
M
Lind
JM
Abeywickrama
KH
Bernhardt
P
RAD B253 Study Group
Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplants recipients
N Engl J Med
 , 
2003
, vol. 
349
 (pg. 
847
-
858
)
6
Keogh
A
Richardson
M
Ruygrok
P
Spratt
P
Galbraith
A
O'Driscoll
G
Macdonald
P
Esmore
D
Muller
D
Faddy
S
Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial
Circulation
 , 
2004
, vol. 
110
 (pg. 
2694
-
2700
)
7
Raichlin
E
Bae
JH
Khalpey
Z
Edwards
BS
Kremers
WK
Clavell
AL
Rodeheffer
RJ
Frantz
RP
Rihal
C
Lerman
A
Kushwaha
SS
Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation
Circulation
 , 
2007
, vol. 
116
 (pg. 
2726
-
2733
)
8
Kauffman
HM
Cherikh
WS
Cheng
Y
Hanto
DW
Kahan
BD
Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies
Transplantation
 , 
2005
, vol. 
80
 (pg. 
883
-
889
)
9
Kushwaha
SS
Raichlin
E
Sheinin
Y
Kremers
WK
Chandrasekaran
K
Brunn
GJ
Platt
JL
Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
2742
-
2750
First published on September 11, 2008. doi:10.1093/eurheartj/ehn407
10
Goodroe
R
Bonnema
DD
Lunsford
S
Anderson
P
Ryan-Baille
B
Uber
W
Ikonomidis
J
Crumbley
AJ
VanBakel
A
Zile
MR
Pereira
N
Severe left ventricular hypertrophy 1 year after transplant predicts mortality in cardiac transplant recipients
J Heart Lung Transplant
 , 
2007
, vol. 
26
 (pg. 
145
-
151
)
11
Gao
XM
Wong
G
Wang
B
Kiriazis
H
Moore
XL
Su
YD
Dart
A
Du
XJ
Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis
J Hypertens
 , 
2006
, vol. 
24
 (pg. 
1663
-
1670
)
12
Shioi
T
McMullen
JR
Tarnavski
O
Converso
K
Sherwood
MC
Manning
WJ
Izumo
S
Rapamycin attenuates load-induced cardiac hypertrophy in mice
Circulation
 , 
2003
, vol. 
107
 (pg. 
1664
-
1670
)
13
Paoletti
E
Amidone
M
Cassottana
P
Gherzi
M
Marsano
L
Cannella
G
Effect of sirolimus on left ventricular hypertrophy in kidney transplant recipients: a 1-year nonrandomized controlled trial
Am J Kidney Dis
 , 
2008
, vol. 
52
 (pg. 
324
-
330
)
14
Ventura
HO
Malik
FS
Mehra
MR
Stapleton
DD
Smart
FW
Mechanisms of hypertension in cardiac transplantation and the role of cyclosporine
Curr Opin Cardiol
 , 
1997
, vol. 
12
 (pg. 
375
-
381
)
15
Kawamata
S
Sakaida
H
Hori
T
Maeda
M
Uchiyama
T
The upregulation of 27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines
Blood
 , 
1998
, vol. 
91
 (pg. 
561
-
569
)
16
Inoki
K
Ouyang
H
Li
Y
Guan
KL
Signaling by target of rapamycin proteins in cell growth control
Microbiol Mol Biol Rev
 , 
2005
, vol. 
69
 (pg. 
79
-
100
)
17
Zuckermann
A
Manito
N
Epailly
E
Fiane
A
Bara
C
Delgado
JF
Lehmkuhl
H
Ross
H
Eisen
H
Chapman
J
Valantine
H
Multidisciplinary insights on clinical guidance for the use of proliferation signal inhibitors in heart transplantation
J Heart Lung Transplant
 , 
2008
, vol. 
27
 (pg. 
141
-
149
)
18
Mulay
AV
Hussain
N
Fergusson
D
Knoll
GA
Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials
Am J Transplant
 , 
2005
, vol. 
5
 (pg. 
1748
-
1756
)
19
Bestetti
R
Theodoropoulos
TA
Burdmann
EA
Filho
MA
Cordeiro
JA
Villafanha
D
Switch from calcineurin inhibitors to sirolimus-induced renal recovery in heart transplant recipients in the midterm follow-up
Transplantation
 , 
2006
, vol. 
81
 (pg. 
692
-
696
)
20
O'Reilly
KE
Rojo
F
She
QB
Solit
D
Mills
GB
Smith
D
Lane
H
Hofmann
F
Hicklin
DJ
Ludwig
DL
Baselga
J
Rosen
N
mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt
Cancer Res
 , 
2006
, vol. 
66
 (pg. 
1500
-
1508
)
21
Carracedo
A
Ma
L
Teruya-Feldstein
J
Rojo
F
Salmena
L
Alimonti
A
Egia
A
Sasaki
AT
Thomas
G
Kozma
SC
Papa
A
Nardella
C
Cantley
LC
Baselga
J
Pandolfi
PP
Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
J Clin Invest
 , 
2008
, vol. 
118
 (pg. 
3065
-
3074
)
doi:10.1093/eurheartj/ehn407

Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Comments

0 Comments