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The aorta is the ‘greatest artery’, through which oxygenated blood is delivered from the left ventricle to end organs with each cardiac cycle (200 million litres of blood transported in an average lifetime). The aorta can be affected by a wide spectrum of acute factors (such as cocaine use, weight lifting and trauma) and chronic acquired and/or genetic conditions (such as systemic arterial hypertension and phaeochromocytoma), which variously lead to increased aortic wall stress. The medial layer of the aorta can also be subject to abnormalities (such as Marfan syndrome, bicuspid aortic valve, inflammatory vasculitis, atherosclerosis and infections). Despite important advances in diagnostic and therapeutic interventions, data derived from registries and population-based studies highlight that the burden of aortic diseases remains high. Therefore, specific resources need to be allocated to design and implement preventive strategies (healthy lifestyles, modifications to cardiovascular risk factors, and educational and screening programmes) at individual and community levels. In this Review, we discuss the epidemiology, management and outcomes of the most common aortic diseases, namely, aortic aneurysms and acute aortic syndromes.In this Review, Bossone and Eagle discuss the epidemiology, management and outcomes of the most common aortic diseases: aortic aneurysms and acute aortic syndromes, including aortic dissection.

Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL , which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32–1.54, P = 3.3 × 10 −20 ). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images. Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples.

Aortic disease has many forms including aortic aneurysm and dissection, aortic coarctation or abnormalities in aortic function, such as loss of aortic distensibility. Genetic analysis in humans is one of the most important experimental approaches in uncovering disease mechanisms, but the relative infrequency of thoracic aortic disease compared with other cardiovascular conditions such as coronary artery disease has hindered large-scale identification of genetic associations. In the past decade, advances in machine learning technology coupled with large imaging datasets from biobank repositories have facilitated a rapid expansion in our capacity to measure and genotype aortic traits, resulting in the identification of dozens of genetic associations. In this Review, we describe the history of technological advances in genetic discovery and explain how newer technologies such as deep learning can rapidly define aortic traits at scale. Furthermore, we integrate novel genetic observations provided by these advances into our current biological understanding of thoracic aortic disease and describe how these new findings can contribute to strategies to prevent and treat aortic disease.Advances in machine learning technology in the past decade have accelerated the discovery of genetic loci associated with aortic disease. In this Review, Lindsay and colleagues discuss how emerging insights into the genetic architecture of aortic disease can improve the accuracy of disease prediction and facilitate the discovery of new therapeutic targets.

Understanding the complex interplay between morphologic and hemodynamic features in aortic dissection is critical for risk stratification and for the development of individualized therapy. This work evaluates the effects of entry and exit tear size on the hemodynamics in type B aortic dissection by comparing fluid–structure interaction (FSI) simulations with in vitro 4D-flow magnetic resonance imaging (MRI). A baseline patient-specific 3D-printed model and two variants with modified tear size (smaller entry tear, smaller exit tear) were embedded into a flow- and pressure-controlled setup to perform MRI as well as 12-point catheter-based pressure measurements. The same models defined the wall and fluid domains for FSI simulations, for which boundary conditions were matched with measured data. Results showed exceptionally well matched complex flow patterns between 4D-flow MRI and FSI simulations. Compared to the baseline model, false lumen flow volume decreased with either a smaller entry tear (− 17.8 and − 18.5%, for FSI simulation and 4D-flow MRI, respectively) or smaller exit tear (− 16.0 and − 17.3%). True to false lumen pressure difference (initially 11.0 and 7.9 mmHg, for FSI simulation and catheter-based pressure measurements, respectively) increased with a smaller entry tear (28.9 and 14.6 mmHg), and became negative with a smaller exit tear (− 20.6 and − 13.2 mmHg). This work establishes quantitative and qualitative effects of entry or exit tear size on hemodynamics in aortic dissection, with particularly notable impact observed on FL pressurization. FSI simulations demonstrate acceptable qualitative and quantitative agreement with flow imaging, supporting its deployment in clinical studies.

It is well known that blood exhibits non-Newtonian viscosity, but it is generally modeled as a Newtonian fluid. However, in situations of low shear rate, the validity of the Newtonian assumption is questionable. In this study, we investigated differences between Newtonian and non-Newtonian hemodynamic metrics such as velocity, vorticity, and wall shear stress. In addition, we investigated cardiovascular transport using two different approaches, Eulerian mass transport and Lagrangian particle tracking. Non-Newtonian solutions revealed important differences in both hemodynamic and transport metrics relative to the Newtonian model. Most notably for the hemodynamic metrics, in-plane velocity and vorticity were consistently larger in the Newtonian approximation for both arterial and venous flows. Conversely, wall shear stresses were larger for the non-Newtonian case for both the arterial and venous models. Our results also indicate that for the Lagrangian metrics, the history of accumulated shear was consistently larger for both arterial and venous flows in the Newtonian approximation. Lastly, our results also suggest that the Newtonian model produces larger near wall and luminal mass transport values compared to the non-Newtonian model, likely due to the increased vorticity and recirculation. These findings demonstrate the importance of accounting for non-Newtonian behavior in cardiovascular flows exhibiting significant regions of low shear rate and recirculation.

Neutrophil extracellular traps (NETs) play an important role in abdominal aortic aneurysm (AAA) formation; however, the underlying molecular mechanisms remain unclear. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) may exert therapeutic effects on AAA through their immunomodulatory and regenerative abilities. This study aimed to examine the role and mechanism of MSC-EVs in regulating the development of NET-mediated AAA. Excessive release of NETs was observed in patients with AAA, and the levels of NET components were associated with the clinical outcomes of the patients. Datasets from the Gene Expression Omnibus database were analyzed and revealed that the PI3K/AKT pathway and ferroptosis were strongly associated with NETosis during AAA formation. Further experiments verified that NETs promoted AAA formation by inducing ferroptosis in smooth muscle cells (SMCs) by inhibiting the PI3K/AKT pathway. The PI3K agonist 740 Y-P, the ferroptosis inhibitor ferrostatin-1, and Padi4 deficiency significantly prevented AAA formation. MSC-EVs attenuated AAA formation by reducing NET release in an angiotensin II-induced AAA mouse model. In vitro experiments revealed that MSC-EVs reduced the release of NETs by shifting NETosis to apoptosis. Our study indicates an important role for NET-induced SMC ferroptosis in AAA formation and provides several potential targets for AAA treatment. Vascular disease: Stem cell packets help reduce artery bulge Tiny membrane-bound packets of biomolecules secreted by stem cells in the bone marrow umbilical cord can reduce the development of dangerous bulges or ballooning in the aorta, the body’s largest artery. Liang Chen of China’s Shanghai Jiao Tong University School of Medicine and colleagues report that these stem cell-derived vesicles help to prevent such bulges, known as aneurysms, in mice through their effects on a type of immune cell called neutrophils, which release networks of DNA and protein at sites of inflammation. The neutrophil-produced molecules induced a type of cell death in the smooth muscle cells of the arterial wall, but the stem cell-secreted vesicles helped to suppress this process. These findings could lead to new therapies for people suffering from aortic aneurysm, a condition that can lead to life-threatening ruptures if left untreated.

Thoracic aortic dissection (TAD) is a catastrophic disease with high mortality and morbidity, characterized by fragmentation of elastin and loss of smooth muscle cells. However, the underlying pathological mechanisms of this disease remain elusive because there are no appropriate animal models, limiting discovery of effective therapeutic strategies. We treated mice on C57BL/6 and FVB genetic backgrounds with β-aminopropionitrile monofumarate (BAPN), an irreversible inhibitor of lysyl oxidase, for 4 wk, followed by angiotensin II (Ang II) infusion for 24 h. We found that the BAPN plus Ang II treatment induced formation of aortic dissections in 100% of mice on both genetic backgrounds. BAPN without Ang II caused dissections in few FVB mice, but caused 87% of C57BL/6 mice to develop TAD, with 37% dying from rupture of the aortic dissection. Moreover, a lower dose of BAPN induced TAD formation and rupture earlier with fewer effects on body weight. Therefore, we have generated a reliable and convenient TAD model in C57BL/6 mice for studying the pathological process and exploring therapeutic targets of TAD.

Inflammatory mediators such as cytokines and chemokines are crucially involved in the development of abdominal aortic aneurysm (AAA). Here we report that CaCl 2 application into abdominal aorta induces AAA with intra-aortic infiltration of macrophages as well as enhanced expression of chemokine (C-C motif) ligand 3 (CCL3) and MMP-9. Moreover, infiltrating macrophages express C-C chemokine receptor 5 (CCR5, a specific receptor for CCL3) and MMP-9. Both Ccl3 −/− mice and Ccr5 −/− but not Ccr1 −/− mice exhibit exaggerated CaCl 2 -inducced AAA with augmented macrophage infiltration and MMP-9 expression. Similar observations are also obtained on an angiotensin II-induced AAA model. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl 2 -treated Ccl3 −/− mice. On the contrary, CCL3 treatment attenuates CaCl 2 -induced AAA in both wild-type and Ccl3 −/− mice. Consistently, we find that the CCL3–CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl 2 -induced AAA by suppressing MMP-9 expression. Inflammatory cytokines and chemokines are involved in the development of abdominal aortic aneurysm (AAA). Here the authors show that CCL3 prevents the development of CaCl 2 -induced AAA by suppressing MMP-9 expression.

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets. Aortic aneurysm and dissection, the major problem linked to Marfan syndrome (MFS), lacks effective pharmacological treatment. Here, the authors show that the NO pathway is overactivated in MFS and that inhibition of guanylate cyclase and cGMP-dependent protein kinase reverts MFS aortopathy in mice.

Due to the symptoms, patients with acute type A aortic dissection are first seen by the ambulance service and diagnosed at the emergency department. How often an aortic dissection occurs in an emergency department per year has been studied. The incidence in the emergency department may be used as a quality marker of differential diagnostics of acute chest pain. A multi-institutional retrospective study with the municipal Berlin hospital chain Vivantes and its Department of Pathology and the Charité - University Medicine Berlin was performed. From the Berlin Hospital Society, the annual numbers of publicly insured emergency patients were obtained. Between 2006 and 2016, 631 aortic dissections were identified. The total number of patients treated in the emergency departments (n = 12,790,577) was used to calculate the “emergency department incidence.” The autopsy data from six clinics allowed an estimate on how many acute type A aortic dissections remained undetected. Across all Berlin hospitals, the emergency department incidence of acute type A aortic dissection was 5.24 cases in 100,000 patients per year. In tertiary referral hospitals and, particularly, in university hospitals the respective incidences were markedly higher (6.7 and 12.4, respectively). Based on the autopsy results, about 50% of the acute type A aortic dissection may remain undetected, which would double the reported incidences. Among different hospital types the emergency department incidences of acute type A aortic dissection vary between 5.93/100,000 and 24.92/100,000. Aortic dissection; Incidence; Emergency Department; Epidemiology