Sirolimus as Primary Immunosuppression Attenuates Allograft Vasculopathy With Improved Late Survival and Decreased Cardiac Events After Cardiac Transplantation

Topilsky, Yan; Hasin, Tal; Raichlin, Eugenia; Boilson, Barry A.; Schirger, John A.; Pereira, Naveen L.; Edwards, Brooks S.; Clavell, Alfredo L.; Rodeheffer, Richard J.; Frantz, Robert P.; Maltais, Simon; Park, Soon J.; Daly, Richard C.; Lerman, Amir; Kushwaha, Sudhir S.

doi:10.1161/circulationaha.111.040360

Cited by 104 publications

(81 citation statements)

References 41 publications

(60 reference statements)

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“…can attenuate the progression of CAV after HTx (17,18). However, there have only been two previous trials investigating the effect of everolimus on CAV progression among de novo HTx recipients (6,7), and both studies investigated the effect of such therapy in combination with either full-dose or reduced CNI exposure.…”

mentioning

confidence: 99%

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

Arora

Andreassen

Andersson

et al. 2015

American Journal of Transplantation

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Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12‐month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7–11 weeks after HTx or standard cyclosporine immunosuppression. Ninety‐five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm3 and 13.8 ± 28.0 mm3 [all p‐values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor‐1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus‐based CNI‐free can potentially be considered in suitable de novo HTx recipients.

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mentioning

confidence: 99%

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

Arora

Andreassen

Andersson

et al. 2015

American Journal of Transplantation

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“…CAV is a major cause of long-term mortality following heart transplantation [1][2][3][4][5][6][7][8][9][10] . CAV may affect up to 50% of patients 5 years after transplantation [11] .…”

Section: The Pathogenesis Of Cav: An Inflammatory Perspectivementioning

confidence: 99%

“…The use of sirolimus (SIR) has been proposed as a substitute for CNIs in cardiac transplant patient based on its role in renal function preservation and prevention of chronic allograft vasculopathy [76][77][78] . In fact, SIR, can prevent vascular remodeling and neointimal proliferation, two key components of CAV, by inhibiting smooth muscle cell (SMC) and fibroblast proliferation [7,28,[79][80][81][82][83][84][85][86] . SIR has been shown to reduce the incidence of acute rejection among renal-transplant recipients and to prevent CAV in animals [87] .…”

Section: Mtor and Mtor Inhibitorsmentioning

confidence: 99%

Effects of Immunosuppressive agents on neutrophils inflammatory response in humans: An inflammatory perspective on coronary allograft vasculopathy

White

2016

Inflamm Cell Signal

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Cardiac transplantation (CTx) has improved survival in patients with advanced heart failure. Unfortunately, the conditional survival remains less than 15 years. The primary cause of mortality at 5 years following a CTx is the development of accelerated coronary atherosclerosis named coronary allograft vasculopathy (CAV). The neutrophils likely play an important role in this diffuse inflammatory process. Nevertheless, the contribution of the neutrophils on the pathogenesis of CAV is poorly understood. Regardless of their essential contribution for the prevention of graft rejection, immunosuppressive drugs (IDs) may have detrimental effects via some pro-inflammatory activities. This review presents the role of neutrophils on vascular inflammation and on the biologic effects of diverse immunosuppressive agents including mTOR inhibitors in the context of the pathophysiology of CAV. We investigated the impact of different IDs on the inflammatory responses of isolated human neutrophils harvested from healthy controls and herein, we reported on some novel characteristics of everolimus (EVE) on isolated neutrophils in comparison with other immunosuppressive agents. These biologic effects may contribute to their beneficial effects on the allograft vasculature and consequently on the prevention of CAV.

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“…However, the retrospective nature of the design and the differences in criteria for the therapy changes, make the results less generalizable [153] . Moreover, a recent study reported that late conversion to PSIs is associated with necrotic plaque core and calcification of the plaque [154] .…”

Section: Proliferation Signal Inhibitorsmentioning

confidence: 99%

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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Sirolimus as Primary Immunosuppression Attenuates Allograft Vasculopathy With Improved Late Survival and Decreased Cardiac Events After Cardiac Transplantation

Cited by 104 publications

References 41 publications

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

Effects of Immunosuppressive agents on neutrophils inflammatory response in humans: An inflammatory perspective on coronary allograft vasculopathy

Diagnosis and management of coronary allograft vasculopathy in children and adolescents

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