Sirolimus As Primary Immunosuppressant Reduces Left Ventricular Mass and Improves Diastolic Function of the Cardiac Allograft

Raichlin, Eugenia; Chandrasekaran, Krishnaswamy; Kremers, Walter K.; Frantz, Robert P.; Clavell, Alfredo L.; Pereira, Naveen L.; Rodeheffer, Richard J.; Daly, Richard C.; McGregor, Christopher G.A.; Edwards, Brooks S.; Kushwaha, Sudhir S.

doi:10.1097/tp.0b013e318189049a

Cited by 47 publications

(27 citation statements)

References 45 publications

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“…In various other hypertrophy models as well as humans, rapamycin attenuates HCM (27,32,38). However, rapamycin has negative inotropic effects in our study as well as in other models (28).…”

Section: Discussioncontrasting

confidence: 45%

ThePTPN11loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling

Schramm¹,

Fine

Edwards³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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The identification of mutations in PTPN11 (encoding the protein tyrosine phosphatase Shp2) in families with congenital heart disease has facilitated mechanistic studies of various cardiovascular defects. However, the roles of normal and mutant Shp2 in the developing heart are still poorly understood. Furthermore, it remains unclear how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome (also termed Noonan Syndrome with multiple lentigines), which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). In normal hearts, Shp2 controls cardiomyocyte size by regulating signaling through protein kinase B (Akt) and mammalian target of rapamycin (mTOR). We hypothesized that Shp2 LOF mutations dysregulate this pathway, resulting in HCM. For our studies, we chose the Shp2 mutation Q510E, a dominant-negative LOF mutation associated with severe early onset HCM. Newborn mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth displayed increased cardiomyocyte sizes, heart-to-body weight ratios, interventricular septum thickness, and cardiomyocyte disarray. In 3-mo-old hearts, interstitial fibrosis was detected. Echocardiographically, ventricular walls were thickened and contractile function was depressed. In ventricular tissue samples, signaling through Akt/mTOR was hyperactivated, indicating that the presence of Q510E-Shp2 led to upregulation of this pathway. Importantly, rapamycin treatment started shortly after birth rescued the Q510E-Shp2-induced phenotype in vivo. If rapamycin was started at 6 wk of age, HCM was also ameliorated. We also generated a second mouse model in which cardiomyocyte-specific Q510E-Shp2 overexpression started after birth. In contrast to the first model, these mice did not develop HCM. In summary, our studies establish a role for mTOR signaling in HCM caused by Q510E-Shp2. Q510E-Shp2 overexpression in the cardiomyocyte population alone was sufficient to induce the phenotype. Furthermore, the pathomechanism was triggered pre- but not postnatally. However, postnatal rapamycin treatment could still reverse already established HCM, which may have important therapeutic implications.

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“…In various other hypertrophy models as well as humans, rapamycin attenuates HCM (27,32,38). However, rapamycin has negative inotropic effects in our study as well as in other models (28).…”

Section: Discussioncontrasting

confidence: 45%

ThePTPN11loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling

Schramm¹,

Fine

Edwards³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…[7]. Also, studies have shown that rapa served as immunosuppressive drugs in both experimental models and clinical transplantation [21][22][23], but their combined effects on graft survival have not been investigated previously, which forms the focus of this study. Here we reported that CCR5 blockade in combination with rapa prevent both acute and chronic rejection in a fully MHC-mismatched murine model up to 90 days.…”

Section: Discussionmentioning

confidence: 99%

Retracted: CCR5 blockade in combination with rapamycin prolongs cardiac allograft survival in mice

Zhang

et al. 2009

Clinical and Experimental Immunology

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SummaryBoth chemokine receptor 5 (CCR5) blockade and rapamycin (rapa) are effective in modulating transplant immunity and led to prolonged allograft survival, yet a great many grafts were ultimately lost to acute rejection. In this study we examined the inhibition of CCR5 in combination with the treatment with rapa in cardiac transplantation. Fully major histocompatibility complexmismatched murine cardiac allograft models were randomized to five groups. They were administered with anti-CCR5 antibody or control antibody and rapa or phosphate-buffered saline (PBS), respectively. An additional group was treated with anti-CCR5 antibody, rapa and anti-CD25 antibody. Allograft rejection was investigated by flow cytometric analyses and enzyme-linked immunospot assay. Allografts treated with anti-CCR5 antibody plus rapa showed significantly prolonged survival (83 Ϯ 3 days, P < 0·001) compared with control antibody plus PBS-treated allografts (6 Ϯ 1 days). Treatment with anti-CCR5 monoclonal antibody (mAb) plus rapa inhibited significantly the progression of chronic rejction. Further analysis of donor hearts in the anti-CCR5 antibody plus rapa-treated group demonstrated increased infiltration of CD4 + CD25 + forkhead box P3 + regulatory T cells, and depletion of CD25 + cells resulted in acute rejection of allografts in 18 Ϯ 1 day. CCR5 blockade in combination with rapa is effective in preventing acute and chronic rejection in a robust murine model. This effect is mediated by CD25 + T cell recruitment and control of T lymphocyte proliferation.

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“…Stallone, et al showed that SRI introduction along with CNI withdrawal improved graft survival and reduced interstitial/vascular α-smooth muscle actin expression, slowing down the progression of allograft injury in renal transplant recipients. 32) Kushwaha, et al showed in HTx recipients that conversion from CNI to SRL decreased LVMI along with increased 14) Little has been reported about the anti-proliferative effect of EVL except for several studies in renal transplant recipients. Paoletti, et al showed in a randomized controlled study that EVL therapy along with reduced CyA was effective in the reduction of LVM among renal transplant recipients, mainly due to reduced LV wall thickness, 34) which was consistent with our results.…”

Section: )mentioning

confidence: 99%

“…[8][9][10][11][12] Clinical studies also showed that SRL had an advantage in the improvement of LVH compared with conventional calcineurin inhibitors (CNI) when used as an immunosuppressant in heart or kidney transplant recipients. [13][14][15] However, little is known about how the next generation mTOR inhibitor derivative everolimus (EVL) affects LVM. 13,16,17) EVL has become thus far a major mTOR inhibitor for immunosuppression therapy because of its superiority in terms of fewer adverse effects compared to SRL.…”

Section: Eft Ventricular Hypertrophy (Lvh) Is Observed In Pa-mentioning

confidence: 99%

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

et al. 2016

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SummaryEverolimus (EVL), one of the mammalian targets of rapamycin, is a next generation immunosuppressant that may have accessory anti-proliferative effects in heart transplant (HTx) recipients. However, little is known about the clinical relationship between EVL and regression of cardiac hypertrophy. A total of 42 HTx recipients received EVL therapy at post-HTx 150 days on median and had been followed at our institute for > 1 year between 2008 and 2014 [EVL (+) group]. We also observed 18 patients without EVL from post-HTx 150 days for 1 year [EVL (-) group]. There were no significant differences in baseline variables between the two groups. Left ventricular mass index (LVMI) and the ratio of early transmitral filling velocity to the peak early diastolic mitral annular motion velocity (E/e') decreased significantly during 1-year EVL treatment compared with the EVL (-) group. There were no differences in blood pressure and medications between the 2 groups. Improvement of LVMI and the E/e' ratio was not associated with trough levels of calcineurin inhibitors or EVL, but correlated with each baseline value. In conclusion, this EVL-incorporated immunosuppressant regimen attenuated cardiac hypertrophy as well as diastolic dysfunction in HTx recipients. (Int Heart J 2016; 57: 204-210)

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Sirolimus As Primary Immunosuppressant Reduces Left Ventricular Mass and Improves Diastolic Function of the Cardiac Allograft

Abstract: Withdrawal of CNI and replacement with SRL in cardiac transplant recipients results in a decrease in LV mass and improvement in diastolic function. SRL may be useful to attenuate LVH and improve cardiac allograft diastolic function.

Cited by 47 publications

References 45 publications

ThePTPN11loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling

ThePTPN11loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling

Retracted: CCR5 blockade in combination with rapamycin prolongs cardiac allograft survival in mice

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

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