Cardiac preservation using ex vivo organ perfusion: new therapies for the treatment of heart failure by harnessing the power of growth factors using BMP mimetics like THR-184.

IF 2.8 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Frontiers in Cardiovascular Medicine Pub Date : 2025-03-18 eCollection Date: 2025-01-01 DOI:10.3389/fcvm.2025.1535778
William D Carlson, Dattatreyamurty Bosukonda, Peter C Keck, Philippe Bey, Shannon N Tessier, Frederic R Carlson
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引用次数: 0

Abstract

As heart transplantation continues to be the gold standard therapy for end-stage heart failure, the imbalance between the supply of hearts, and the demand for them, continues to get worse. In the US alone, with less than 4,000 hearts suitable for transplant and over 100,000 potential recipients, this therapy is only available to a very few. The use of hearts Donated after Circulatory Death (DCD) and Donation after Brain Death (DBD) using ex vivo machine perfusion (EVMP) is a promising approach that has already increased the availability of suitable organs for heart transplantation. EVMP offers the promise of enabling the expansion of the overall number of heart transplants and lower rates of early graft dysfunction. These are realized through (1) safe extension of the time between procurement and transplantation and (2) ex vivo assessment of preserved hearts. Notably, ex vivo perfusion has facilitated the donation of DCD hearts and improved the success of transplantation. Nevertheless, DCD hearts suffer from serious preharvest ischemia/reperfusion injury (IRI). Despite these developments, only 40% of hearts offered for transplantation can be utilized. These devices do offer an opportunity to evaluate donor hearts for transplantation, resuscitate organs previously deemed unsuitable for transplantation, and provide a platform for the development of novel therapeutics to limit cardiac injury. Bone Morphogenetic Protein (BMP) signaling is a new target which holds the potential for ameliorating myocardial IRI. Recent studies have demonstrated that BMP signaling has a significant role in blocking the deleterious effects of injury to the heart. We have designed novel small peptide BMP mimetics that act via activin receptor-like kinase (ALK3), a type I BMP receptor. They are capable of (1) inhibiting inflammation and apoptosis, (2) blocking/reversing the epithelial-mesenchymal transition (EMT) and fibrosis, and (3) promoting tissue regeneration. In this review, we explore the promise that novel therapeutics, including these BMP mimetics, offer for the protection of hearts against myocardial injury during ex vivo transportation for cardiac transplantation. This protection represents a significant advance and a promising ex vivo therapeutic approach to expanding the donor pool by increasing the number of transplantable hearts.

利用体外器官灌注保存心脏:利用生长因子的力量,利用像THR-184这样的BMP模拟物来治疗心力衰竭的新疗法。
由于心脏移植仍然是治疗终末期心力衰竭的金标准,心脏供应和需求之间的不平衡继续恶化。仅在美国,适合移植的心脏不到4000颗,而潜在的接受者超过10万,这种疗法只适用于极少数人。使用循环死亡(DCD)后捐赠的心脏和使用体外机器灌注(EVMP)的脑死亡(DBD)后捐赠的心脏是一种很有前途的方法,已经增加了心脏移植合适器官的可用性。EVMP提供了扩大心脏移植总数和降低早期移植物功能障碍率的希望。这些是通过(1)安全延长获取和移植之间的时间和(2)保存心脏的体外评估来实现的。值得注意的是,体外灌注促进了DCD心脏的捐赠,提高了移植的成功率。然而,DCD心脏遭受严重的收获前缺血/再灌注损伤(IRI)。尽管取得了这些进展,但可供移植的心脏中只有40%能够得到利用。这些设备确实为评估供体心脏移植提供了机会,使以前认为不适合移植的器官复苏,并为开发限制心脏损伤的新疗法提供了平台。骨形态发生蛋白(Bone Morphogenetic Protein, BMP)信号是一个具有改善心肌IRI潜力的新靶点。最近的研究表明,BMP信号在阻断心脏损伤的有害影响中起着重要作用。我们设计了一种新的小肽BMP模拟物,通过激活素受体样激酶(ALK3),一种I型BMP受体起作用。它们能够(1)抑制炎症和细胞凋亡,(2)阻断/逆转上皮-间质转化(EMT)和纤维化,(3)促进组织再生。在这篇综述中,我们探讨了新型治疗方法的前景,包括这些BMP模拟物,在心脏移植的体外运输过程中保护心脏免受心肌损伤。这种保护是一个重大的进步,也是一种有前途的体外治疗方法,通过增加可移植心脏的数量来扩大供体库。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Frontiers in Cardiovascular Medicine
Frontiers in Cardiovascular Medicine Medicine-Cardiology and Cardiovascular Medicine
CiteScore
3.80
自引率
11.10%
发文量
3529
审稿时长
14 weeks
期刊介绍: Frontiers? Which frontiers? Where exactly are the frontiers of cardiovascular medicine? And who should be defining these frontiers? At Frontiers in Cardiovascular Medicine we believe it is worth being curious to foresee and explore beyond the current frontiers. In other words, we would like, through the articles published by our community journal Frontiers in Cardiovascular Medicine, to anticipate the future of cardiovascular medicine, and thus better prevent cardiovascular disorders and improve therapeutic options and outcomes of our patients.
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