Numerical knockouts-In silico assessment of factors predisposing to thoracic aortic aneurysms.
Numerical knockouts-In silico assessment of factors predisposing to thoracic aortic aneurysms.
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DOI：
10.1371/journal.pcbi.1008273
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发表时间：
2020-10
影响因子：
4.3
通讯作者：
Humphrey JD
中科院分区：
文献类型：
--
作者：
Latorre M;Humphrey JD
无数的危险因素包括不受控制的高血压、衰老和多种基因突变导致胸主动脉瘤的发展和扩大。对临床数据的详细分析和对小鼠模型的纵向研究继续提供对这些潜在致死性疾病的自然史的深入了解。然而，由于在大多数情况下多种风险因素并存，很难将许多不同因素的个别影响分离出来，也很难理解它们是如何共同作用的。在本文中，我们使用了胸主动脉瘤发生和进展的数据信息计算模型，以单独和组合的方式对比关键的诱发风险因素;这些因素包括弹性纤维完整性的局部损失、异常胶原重塑、平滑肌收缩力降低、细胞外基质的机械感知或机械调节功能障碍沿着叠加的高血压和主动脉老化。在大多数情况下，细胞功能或基质完整性的轻度至重度局部丧失会引起不同程度的胸主动脉局部扩张，在易感风险因素共存的情况下，扩张通常会加剧。模拟表明，第一次，受损的平滑肌收缩性的影响是更重要的功能失调mechanosensing和mechanoregulation的矩阵比血管水平的控制直径，而且，功能失调mechanobiological控制可以产生病变的情况下，受损的弹性纤维的完整性。因此，特别令人关注的是，如马凡氏综合征中的Rheumin-1等成分的损失可能会损害弹性纤维的完整性和机械传感。动脉瘤是导致严重残疾和死亡的动脉壁的局部扩张。对临床数据的详细分析继续提供了对这些潜在致命疾病的自然史的深入了解，无数的风险因素包括不受控制的高血压，衰老和各种遗传突变有助于它们的发展和扩大。然而，由于这些风险因素在大多数情况下同时存在，很难将个别影响孤立出来，也很难理解它们如何共同作用。在本文中，我们使用计算模型的胸主动脉瘤的启动和进展，对比关键的诱发因素，无论是在隔离和组合，以及叠加高血压和老化。本研究从小鼠模型中恢复了许多发现，但新的和重要的观察结果有望指导体内和离体研究，因为我们试图理解并最终更好地治疗这些复杂的多因素病变，并最终以数据为依据的患者特定计算最终是前进的方向。
Myriad risk factors–including uncontrolled hypertension, aging, and diverse genetic mutations–contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing. Aneurysms are local dilatations of the arterial wall that are responsible for significant disability and death. Detailed analyses of clinical data continue to provide insight into the natural history of these potentially lethal conditions, with myriad risk factors–including uncontrolled hypertension, aging, and diverse genetic mutations–contributing to their development and enlargement. Yet, because of the co-existence of these risk factors in most cases, it has been difficult to isolate individual effects or to understand how they act in combination. In this paper, we use a computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing factors both in isolation and in combination as well as with superimposed hypertension and aging. The present study recovers many findings from mouse models but with new and important observations that promise to guide in vivo and ex vivo studies as we seek to understand and eventually better treat these complex, multi-factorial lesions, with data-informed patient-specific computations eventually the way forward.
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DOI：
10.1016/j.ijengsci.2014.08.003
发表时间：
2014-12-01
影响因子：
6.6
作者：
Cyron, C. J.;Humphrey, J. D.
通讯作者：
Humphrey, J. D.
影响因子：
2.6
作者：
de Wit, Aletta;Vis, Kelly;Jeremy, Richmond W.
通讯作者：
Jeremy, Richmond W.
DOI：
10.1161/hypertensionaha.115.06262
发表时间：
2016-05
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Bersi MR;Bellini C;Wu J;Montaniel KRC;Harrison DG;Humphrey JD
通讯作者：
Humphrey JD
DOI：
10.12945/j.aorta.2017.17.003
发表时间：
2017-02-01
期刊：
Aorta (Stamford, Conn.)
影响因子：
--
作者：
Brownstein, Adam J;Ziganshin, Bulat A;Elefteriades, John A
通讯作者：
Elefteriades, John A
DOI：
10.1093/imammb/dqq001
发表时间：
2010-12-01
影响因子：
1.1
作者：
Cardamone, L.;Valentin, A.;Humphrey, J. D.
通讯作者：
Humphrey, J. D.