Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

Gupta, Shuchita

doi:10.4172/2329-6607.1000123

Cited by 5 publications

(9 citation statements)

References 74 publications

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“…Whereas an intense suppression of immunological response involving activation of CD4+ cells prevents rejections and thus organ failure early after HTx, the continuation of a strong elimination of CD4+ cells years following HTx may contribute to higher mortality. Therefore, continuous adjustments of immunosuppressive therapy strategies as well as close monitoring of immunological status in the blood are important actions at every time stage after HTx.Immunological status, together with the side-effects of drug therapy, cardiovascular risk factors and donor and recipient demographics at the time point of HTx procedure influence the onset of transplant vasculopathy[23]. Interestingly, the present study showed that there were no significant differences in the prevalence of transplant vasculopathy between survivors and non-survivors at the time point of the last follow-up.…”

contrasting

confidence: 46%

“…In contrast to BB which application has been associated with better long-term outcomes after HTx, the use of diltiazem did not show any advantage with regard to survival despite a similar reduction of heart frequencies as under BB [26]. Although it is known that diltiazem enhances CsA and tacrolimus concentrations in the blood and thus reduces the need of higher CsA and tacrolimus doses [27] and has positive effects on transplant vasculopathy [23] and cardiopulmonary performance [28], giving preference to BB therapy in a selected group of patients could be advantageous considering results from this study.…”

Section: Discussionmentioning

confidence: 84%

“…Since survivors presented significantly less frequent transplant vasculopathy less than five years after HTx compared with non-survivors in this study, this finding suggests that, not just the presence of transplant vasculopathy is critical for survival, but much more the time point of its development. It is known that the immune mechanisms and the influence of immunomodulating drug therapy prevail in the development of transplant vasculopathy at early stages, whereas classical cardiovascular risk factors may play a greater role later in the time course[23]. In the present patient population typical cardiovascular risk factors at follow-up were equally distributed across both groups.…”

mentioning

confidence: 74%

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Predisposing factors for late mortality in heart transplant patients

Alyaydin¹,

Welp²,

Reinecke³

et al. 2021

Cardiol J.

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Background: Because of the growing prevalence of terminal heart failure on the one hand and organ shortage on the other hand, an optimal care of heart transplant recipients based on the knowledge of potential risk factors not only early, but also in a long-term course after heart transplantation is of great importance. Therefore, the aim of the present study was to identify predisposing factors for late mortality in this patient collective. Methods: Data from long-term heart transplant patients collected during follow-up visits in the current center were retrospectively analyzed. Clinical, laboratory, including immune monitoring and apparative examination results were studied with regard to all-cause mortality. Results: 172 patients after heart transplantation (mean: 13.2 ± 6.4 years) were divided into two groups: survivors (n = 133) and non-survivors (n = 39). In comparison with survivors, non-survivors were characterized by significantly more pronounced renal insufficiency with more frequent dialysis, anemia and worse functional status. Additionally, non-survivors obtained hearts from relevantly more obese donors. In a multivariate Cox regression analysis the following parameters were shown to be independent risk factors for increased mortality: CD4 percentage < 42%, C-reactive protein ≥ 0.5 mg/dL, presence of rejections requiring therapies in the past, onset of cardiac allograft vasculopathy < 5 years following heart transplantation with no use of beta-blockers. Conclusions: Low CD4+ cell percentages, sustained inflammation, relevant organ rejections, early onset of transplant vasculopathy and no use of beta-blockers are risk factors for higher mortality in a long-term follow-up after heart transplantation.

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contrasting

confidence: 46%

Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 74%

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Predisposing factors for late mortality in heart transplant patients

Alyaydin¹,

Welp²,

Reinecke³

et al. 2021

Cardiol J.

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“…In addition to these antibody based therapies, pharmacologic agents blocking complement effector pathways like non-canonical NF-κB could be explored as putative strategies for inhibiting AV. Given the paucity of new therapies to reduce the development of AV [3], clinical studies to examine if either inhibition of activators of the MyD88 pathway or the complement activation are safe and effective in reducing AV should be considered.…”

Section: Conclusion and Therapeutic Potentialmentioning

confidence: 99%

“…Given its unique pathophysiological underpinnings involving alloimmune T cell activation, AV is clinically refractory to many repositioned agents intended for treating CAD [3]. Moreover, contemporary immunosuppressive regimens to halt alloimmune adaptive responses have yielded only incremental or no therapeutic benefit regarding secondary or tertiary prevention [4,5].…”

Section: Introductionmentioning

confidence: 99%

Innate immune mechanisms in transplant allograft vasculopathy

Jane‐wit¹,

Fang²,

Goldstein

2016

Current Opinion in Organ Transplantation

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Purpose of Review Allograft vasculopathy (AV) is the leading cause of late allograft loss following solid organ transplantation. Ischemia reperfusion injury (IRI) and donor specific antibody (DSA)-induced complement activation confer heightened risk for AV via numerous innate immune mechanisms including MyD88, HMGB1, and complement induced non-canonical NF-kB signaling. Recent Findings The role of MyD88, a signal adaptor downstream of the toll-like receptors (TLR), has been defined in an experimental heart transplant model, which demonstrated that recipient MyD88 enhanced AV. Importantly, triggering receptor on myeloid receptor 1(Trem1), a MyD88 amplifying signal, was present in rejecting human cardiac transplant biopsies and enhanced the development of AV in mice. HMGB1, a nuclear protein that activates TLRs, also enhanced the development of AV. Complement activation elicits assembly of membrane attack complexes (MAC) on endothelial cells which activate non-canonical NF-kB signaling, a novel complement effector pathway that induces pro-inflammatory genes and potentiates endothelial cell mediated alloimmune T cell activation, processes which enhance AV. Summary Innate immune mediators including HMGB1, MyD88, and non-canonical NFκB signaling via complement activation contribute to AV. These pathways represent potential therapeutic targets to reduce AV after solid organ transplantation.

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Reduction of Transplant Vasculopathy by Intraoperative Nucleic Acid-based Therapy in a Mouse Aortic Allograft Model

Arif

Franz

Remes

et al. 2018

Thorac cardiovasc Surg

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Background Transplant vasculopathy (TV) is the main limiting factor for long-term graft survival characterized by fibrosis, myofibroblast, and smooth muscle cell (SMC) proliferation. Decoy oligodeoxynucleotide (dODN) against the transcription factor activator protein-1 (AP-1) might interfere with the expression of AV-related genes that govern neointima formation. Methods Aortic allografts from DBA/2 mice were incubated with control buffer, consensus, or mutated control AP-1 dODN and were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg body weight [BW]) was administered daily. Explantation and histomorphometric and immunohistochemical evaluation was performed after 30 days. Matrix metalloproteinase (MMP) activity was visualized by gelatin in situ zymography. Results Intima-to-media (I/M) ratio and neointima formation were significantly reduced in the consensus AP-1 dODN treatment group by 37% (p < 0.05) and 67% (p < 0.01), respectively. SMC α-actin-2 staining and macrophage marker expression revealed a marked reduction in the neointima. I/M ratio was found to correlate with the number of tissue macrophages (p < 0.05). MMP and fibrosis marker expression were not significantly altered. Conclusion Intraoperative AP-1dODN utilization might be a strategy to preserve graft function after transplantation.

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Drugs for the Prevention and Treatment of Cardiac Allograft Vasculopathy

Cited by 5 publications

References 74 publications

Predisposing factors for late mortality in heart transplant patients

Predisposing factors for late mortality in heart transplant patients

Innate immune mechanisms in transplant allograft vasculopathy

Reduction of Transplant Vasculopathy by Intraoperative Nucleic Acid-based Therapy in a Mouse Aortic Allograft Model

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