Direct Anti-Inflammatory Mechanisms Contribute to Attenuation of Experimental Allograft Arteriosclerosis by Statins

Shimizu, Koïchi; Aikawa, Masamichi; Takayama, Kiyoshi; Libby, Peter; Mitchell, Richard N.

doi:10.1161/01.cir.0000092949.67153.74

Cited by 98 publications

(83 citation statements)

References 28 publications

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“…Nonetheless, efficacy and therapeutic benefit of statins in heart transplant recipients is established unequivocally [94][95][96][97][98][99][100]. In addition to their lipid lowering effects, statins exert their potential beneficial effects by their pleiotropic effects [101]. There are no definitive guidelines to guide therapy in transplant population.…”

Section: Dyslipidemiamentioning

confidence: 99%

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

Munagala¹,

Phancao²

2018

obm.transplant

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Heart transplant remains the gold standard therapy for patients with end stage heart disease and offers improved survival and quality of life. Significant progress has been achieved in improving one-year mortality after heart transplantation. Nonetheless, longterm graft survival has not changed significantly over the past few decades. Long term survival of heart transplant recipients is limited by chronic rejection, cardiac allograft vasculopathy (CAV), and malignancy. CAV is a major contributor for graft failure and mortality after the first year of in heart transplant recipients. CAV is a proliferative vasculopathy characterized by diffuse myointimal hyperplasia and progressive narrowing of the graft vessels. Both immune dependent and independent factors have been shown to contribute to the pathogenesis of CAV. Understanding these risk factors is essential in developing preventative and therapeutic strategies. Angiography with Intravascular ultrasound has become the key diagnostic tool in the early detection of CAV as well as prognostication. Echocardiographic assessment of allograft function in conjunction with coronary angiographic findings are used in assessing the severity of CAV. Adjustment of immunosuppression and statins remain the initial steps in the management of CAV. Retransplantation is the definitive treatment for severe CAV, however, the paucity of organs along with increased mortality associated with retransplantation makes it a less desirable option. Remarkable progress has been achieved in the understanding of pathogenesis, risk factors for CAV and plaque morphology. Nevertheless, significant knowledge gaps persist in scientific understanding of risk factors, pathogenesis, prevention and treatment of CAV. Further research is warranted to fill these gaps, develop diagnostic modalities to facilitate early detection of CAV, and management strategies to Improve graft tolerance and immune modulation. This review focuses on summarizing the pathogenesis and risk factors for CAV.

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Section: Dyslipidemiamentioning

confidence: 99%

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

Munagala¹,

Phancao²

2018

obm.transplant

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“…However, in some studies, other cholesterol-lowering drugs did not improve transplant outcome (27). While improved transplant survival may be related to the ability of statins to lower lipid levels, statins also have immuno modulatory properties that are independent of lipid-lowering effects (28)(29)(30) in monocytes (31)(32)(33)(34)(35)(36)(37)(38)(39) and T cells (33,34,40,41). Indeed, when treated with lipid-lowering agents, mice with normal lipid levels exhibited prolonged transplant survival (26).…”

Section: Hsd and Transplant Fatementioning

confidence: 99%

Impact of environmental factors on alloimmunity and transplant fate

Riella

Bagley

Iacomini

et al. 2017

Journal of Clinical Investigation

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“…ECs were isolated from the B/c murine hearts as described previously 32 and incubated for 72 hours with the peritoneal macrophages extracted from naive B6 WT or Mac-1 Ϫ/Ϫ mice. We performed flow cytometry analysis for costimulatory molecule expression of the B/c EC-primed macrophages as described below.…”

Section: Murine Ec Isolation and Coculture With Macrophagesmentioning

confidence: 99%

Leukocyte Integrin Mac-1 Promotes Acute Cardiac Allograft Rejection

et al. 2008

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Background— In allograft rejection, recipient leukocytes and alloantibodies first target donor endothelial cells. Although the leukocyte integrin Mac-1 (α Mβ2 , CD11b/CD18) facilitates cell–cell interactions among leukocytes and interactions between leukocytes and endothelial cells or platelets, its role in allograft survival and vasculopathy is incompletely defined. Methods and Results— This study examined parenchymal rejection and graft arterial disease after total allomismatched cardiac transplantation (BALB/c donor heart and B6 recipients) in wild-type (WT) and Mac-1-deficient (Mac-1 −/− ) recipients. Recipient Mac-1 deficiency attenuated parenchymal rejection and significantly prolonged cardiac allograft survival from 8.3±1.3 days in WT recipient allografts (n=18) to 13.8±2.3 days in Mac-1 −/− recipient allografts (n=6; P <0.0001). Accumulation of neutrophils and macrophages significantly decreased in Mac-1 −/− compared with WT recipients. Adoptive transfer of WT but not Mac-1 −/− macrophages to Mac-1 −/− recipients exacerbated parenchymal rejection and reduced allograft survival; in contrast, adoptive transfer of WT neutrophils did not affect graft survival. Mac-1 −/− macrophages expressed significantly lower levels of costimulatory molecules both in vivo and in vitro, and mixed lymphocyte reaction using alloantigen-primed Mac-1 −/− macrophages resulted in significantly lower antigen-presenting function than for WT macrophages. Tumor necrosis factor-α production also fell in cultures with Mac-1 −/− macrophages. Despite attenuation of acute rejection, recipient Mac-1-deficiency did not prevent late graft arterial disease. Conclusions— These studies demonstrate critical participation of Mac-1 in alloresponses during cellular allograft rejection. These observations establish a molecular target for modulating recipient responses to prolong graft survival.

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Direct Anti-Inflammatory Mechanisms Contribute to Attenuation of Experimental Allograft Arteriosclerosis by Statins

Cited by 98 publications

References 28 publications

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis

Impact of environmental factors on alloimmunity and transplant fate

Leukocyte Integrin Mac-1 Promotes Acute Cardiac Allograft Rejection

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