The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective

Ostberg, Nicolai P; Zafar, Mohammad A.; Ziganshin, Bulat A.; Elefteriades, John A.

doi:10.3390/biom10020182

Cited by 107 publications

(112 citation statements)

References 146 publications

(205 reference statements)

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“…The identification of genetic variants that cause hereditary forms of aneurysm provides the opportunity to clearly define the molecular deficiencies that initiate this disease. Several recent reviews have summarized the current list of approximately 30 genes involved in the development of either syndromic or non-syndromic forms of TAA [ 14 , 184 , 185 , 186 ] ( Figure 1 B). Although criteria for inclusion vary, 11 genes are currently confirmed as “definitive” determinants of highly penetrant TAA based on the Clinical Genome Resource framework [ 187 ].…”

Section: Genes Associated With Syndromic and Non-syndromic Hereditmentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

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Section: Genes Associated With Syndromic and Non-syndromic Hereditmentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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“…Human genetic variants in the PCSK6 locus have been linked with increased blood pressure and aortic dissection [27,53], which are both known to be associated with aortic aneurysm formation [54,55]. The risk for development of aortic dissection and aneurysms is increased in patients with genetic diseases resulting in a defective TGFB-signaling [56], where PCSK6 is one of the key proteases involved in the TGFB1 axis [22,23].…”

Section: Discussionmentioning

confidence: 99%

Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice

Röhl

Suur

Lengquist

et al. 2020

Cells

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Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines, but their function in the vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques from symptomatic patients, localization to smooth muscle cells (SMCs) in the fibrous cap and positive correlations with inflammation, extracellular matrix remodeling and cytokines. Here, we hypothesize that PCSK6 could be involved in flow-mediated vascular remodeling and aim to evaluate its role in the physiology of this process using knockout mice. Pcsk6−/− and wild type mice were randomized into control and increased blood flow groups and induced in the right common carotid artery (CCA) by ligation of the left CCA. The animals underwent repeated ultrasound biomicroscopy (UBM) examinations followed by euthanization with subsequent evaluation using wire myography, transmission electron microscopy or histology. The Pcsk6−/− mice displayed a flow-mediated increase in lumen circumference over time, assessed with UBM. Wire myography revealed differences in the flow-mediated remodeling response detected as an increase in lumen circumference at optimal stretch with concomitant reduction in active tension. Furthermore, a flow-mediated reduction in expression of SMC contractile markers SMA, MYH11 and LMOD1 was seen in the Pcsk6−/− media. Absence of PCSK6 increases outward remodeling and reduces medial contractility in response to increased blood flow.

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“…43 Familial non-syndromic TAADs refers to the instance when one or more family member is also diagnosed with TAAD. 44 Research continuous to identify genetic causes of familial TAADs as 21% of TAAD patient have a positive family history of the condition. Interestingly, 21% appears to be an underestimate as many family members do not undergo the routine imaging to identify nonsymptomatic aneurysms.…”

Section: Non-syndromic Genetic Predispositionmentioning

confidence: 99%

Bio-chemo-mechanics of the thoracic aorta

2021

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The pathophysiology of thoracic aortic aneurysms and dissections are poorly understood, despite high mortality associated with the diseases. An evidence review was conducted to examine the biomechanical, chemical and genetic factors involved in thoracic aortic pathology. The composition of connective tissue and smooth muscle cell action can mediate important mechanical properties that allow the thoracic aorta to withstand and transmit pressures. Genetic syndromes can affect connective tissue and signalling proteins that interrupt smooth muscle function, leading to tissue failure. There are complex interplaying factors that maintain thoracic aortic function in health and disrupt in disease, signifying an area for extensive research.

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The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective

Cited by 107 publications

References 146 publications

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice

Bio-chemo-mechanics of the thoracic aorta

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