Prevention of Acute Rejection and Allograft Vasculopathy by Everolimus in Cardiac Transplants Recipients: A 24-Month Analysis

Viganò, Mario; Tuzcu, Murat; Benza, Raymond L.; Boissonnat, P.; Haverich, Axel; Hill, James A.; Laufer, Guenther; Love, Robert B.; Parameshwar, Jayan; Pulpón, L. Alonso; Renlund, Dale G.; Abeywickrama, Kamal; Crétin, Nathalie; Starling, Randall C.; Eisen, Howard J.

doi:10.1016/j.healun.2007.03.005

Cited by 105 publications

(88 citation statements)

References 27 publications

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“…The results were confirmed at 24 months. 57 The RAD B253 data at 4 years showed that significantly fewer patients on everolimus had a major cardiovascular event related to cardiac allograft vasculopathy compared with patients treated with azathioprine. In addition, according to an economic analysis, everolimus is associated with a decrease of 57.2% in the average cost of treatment for such events.…”

Section: Endothelium Atherosclerosis and Heart Transplantationmentioning

confidence: 99%

Long-term outcome of everolimus treatment in transplant patients

Salvadori

Bertoni²

2011

TRRM

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Abstract:The authors review the use of everolimus in long-term studies both in renal and heart transplantation. The pharmacokinetic and pharmacodynamic differences between everolimus and its parent drug, sirolimus are discussed. The improved pharmacokinetic, in particular the improved bioavailability, the reduced half-time and the reduced binding to plasma protein makes everolimus the first choice among the proliferation signal inhibitors. Everolimus is given in almost all studies in association with cyclosporine, but fixed doses of this drug can cause nephrotoxicity. The first studies used everolimus and CsA in fixed doses, but later studies with reduced CsA doses revealed which revealed improved outcomes. Finally, therapeutic drug monitoring became the better choice for both drugs. Recently very high everolimus exposure allowed the use of very low CsA exposure with improvement of the worse side effects linked to the CsA standard dose. The Zeus study revealed a complete and safe CsA withdrawal, thanks to everolimus and mycophenolic acid. In heart transplantation, everolimus resulted in improved outcomes with respect to antiproliferative drugs such as mycophenolic acid and azathioprine. Along with antirejection properties, everolimus provided evidence for antiproliferative effects on several cells. This resulted in fewer viral infections (mainly CMV), anti-atherosclerotic properties (mainly important in heart transplantation, and antineoplastic effect. The latter activity resulted in lower cancer incidence in transplant patients treated by everolimus. An important piece of evidence for this activity is documented by the use of everolimus in the treatment of some cancers, including renal cancer, neuroendocrine cancers and hepatocellular cancers, also outside the field of transplantation.

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Section: Endothelium Atherosclerosis and Heart Transplantationmentioning

confidence: 99%

Long-term outcome of everolimus treatment in transplant patients

Salvadori

Bertoni²

2011

TRRM

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“…A 12 month clinical trial study found that cardiac transplant recipients treated with the mTOR inhibitor everolimus had significantly reduced intimal thickness compared to the azathioprine treated group [33]. Similarly, a 2-year study found everolimus treated patients had significantly reduced acute rejection and limited progression of TV [34]. Our results identify ERK as a new target of mTOR following activation by anti-MHC antibody and suggest that blocking of both mTORC1 and mTORC2 may be necessary to inhibit MHC class I mediated cell proliferation.…”

mentioning

confidence: 98%

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway

Jindra

Jin

Jácamo

et al. 2008

Biochemical and Biophysical Research Communications

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The aim of this study was to characterize the interaction between mTOR and ERK in primary endothelial cells (EC) following MHC class I and integrin ligation. Ligation of MHC class I molecules or integrins on the surface of EC leads to phosphorylation of ERK at Thr202/Tyr204. We utilized small interfering RNA (siRNA) blockade of mTOR and proteins involved in mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) to define a relationship between mTOR and ERK following MHC class I signaling. We found mTORC2 was responsible for MHC class I and integrin induced phosphorylation of ERK at Thr202/Tyr204. We corroborated these results demonstrating that long-term exposure to rapamycin also inhibited ERK pathway activation in response to MHC class I signaling. Our results demonstrate, for the first time, that engagement of either MHC class I or integrin on the surface of EC leads to ERK activation through an mTORC2-dependent pathway. KeywordsMHC; HLA class I; ERK; mTORC2; siRNA; Endothelial cells; Signal transduction mTOR plays an essential role in integrin and MHC class I-induced cell proliferation and survival through formation of two distinct multi-protein molecular complexes, mTORC1 and mTORC2 [1][2][3][4]. mTORC1 consists of mTOR in association with regulatory associated protein of mTOR (Raptor) and GβL [5]. mTORC1 phosphorylates p70 S6 Kinase and eukaryotic initiation factor 4E binding protein 1 which activate translational machinery to increase cell proliferation [6,7]. mTORC2 is composed of mTOR binding to rapamycin insensitive companion of mTOR (Rictor), GβL, stress-activated protein kinase-interacting protein 1 (Sin1) and the newly discovered associations with PRoline-Rich protein 5 (PRR5) or the synonymous protein observed with Rictor 1 (Protor-1), and P-REX1 [8][9][10][11][12]. mTORC2 activates Akt at Ser473, Rac GTPase, cell migration and effects reorganization of the actin cytoskeleton [11][12][13][14]. Recent work utilizing mouse knockout models emphasizes the importance of mTOR for growth and proliferation in development [15,16]. Homozygous mTOR (−/−) mice have * Corresponding author: Fax: + 1 310 206 3216; Email address: ereed@mednet.ucla.edu (E. F. Reed). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [17,18]. These data show both mTOR complexes are involved in signal transduction leading to cell proliferation, however, the mechanism(s) by which mTORC2 participates in mitogenic signaling remains less well defined. NIH Public AccessERK1/2 are members of a family of serine/threonine kinases activated by a variety of growth factors, cell surface receptors, int...

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“…They showed preservation of the coronary lumen at 1 year with significant lower incidence of CAV in the everolimus group compared to the aziathropine group. A sub-study published in 2007 confirmed the results at 24 mo [142] and the same group has also shown reduced incidence of cardiovascular events in the everolimus group [143] . Nevertheless, despite the promising results of these studies, all of them compared PSIs to Azathioprine, which is not used as first line therapy anymore and known to be associated to higher rate of rejection than newer immunosuppressive agents.…”

Section: Proliferation Signal Inhibitorsmentioning

confidence: 65%

Diagnosis and management of coronary allograft vasculopathy in children and adolescents

Dedieu

Greil

Wong

et al. 2014

WJT

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Coronary allograft vasculopathy remains one of the leading causes of death beyond the first year post transplant. As a result of denervation following transplantation, patients lack ischaemic symptoms and presentation is often late when the graft is already compromised. Current diagnostic tools are rather invasive, or in case of angiography, significantly lack sensitivity. Therefore a non-invasive tool that could allow early diagnosis would be invaluable.This paper review the disease form its different diagnosis techniques,including new and less invasive diagnostic tools to its pharmacological management and possible treatments. DEFINITION AND PHYSIOPATHOLOGYIn children, coronary allograft vasculopathy (CAV) remains the main limiting survival factor after heart transplantation and the major cause of mortality after the first year post transplant leading ultimately to graft loss [1,2] . One elegant etiological description of CAV is that of "immunologic mechanisms operating in a milieu of nonimmunologic risk factors" [3] . The process is believed to start off as a response to endothelial injury in the graft, originated by a complex interaction of multiple donor and recipient factors. The resulting endothelial dysfunction, leads to altered endothelial permeability and subsequent intimal hyperplasia as a consequence of the vascular remodeling originated by the inflammatory response. The immunologic events constitute the original trigger and noninflammatory events such as cytomegalovirus infection, ischemic time (reperfusion injury), increased donor age and classical cardiovascular risk factors (i.e., diabetes, dyslipidemias, smoking and hypertension), perpetuate the inflammatory response and increase the endothelial injury [4] . Typical lesions (Figures 1 and 2) consist of diffuse intimal proliferation leading to the development of luminal stenosis and small vessels occlusion which then limits blood supply to the graft causing chronic vascular injury and ultimately myocardial ischemia [5] . The lesions develop earlier and quicker than atherosclerotic lesions. REVIEW 276December 24, 2014|Volume 4|Issue 4|

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Prevention of Acute Rejection and Allograft Vasculopathy by Everolimus in Cardiac Transplants Recipients: A 24-Month Analysis

Cited by 105 publications

References 27 publications

Long-term outcome of everolimus treatment in transplant patients

Long-term outcome of everolimus treatment in transplant patients

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway

Diagnosis and management of coronary allograft vasculopathy in children and adolescents

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