Sporadic Aortic Aneurysm Research Articles

Family History of Aortic Disease Has No Effect on Outcomes of Fenestrated-branched Endovascular Aortic Repair in Patients with Complex Aortic Aneurysms

Prior reports have indicated an increased risk of aneurysm-related complications after endovascular repair in patients with familial aortic aneurysms. The aim of this study was to evaluate outcomes of fenestrated-branched endovascular aortic repair (F-BEVAR) for the treatment of complex abdominal (CAAAs) and thoracoabdominal aortic aneurysms (TAAAs) in patients with familial history of aortic aneurysms or dissections (FAA). The clinical data of 506 consecutive patients (69% male; 74 ± 8 years old) enrolled in a prospective non-randomized study to investigate outcomes of F-BEVAR for the treatment of CAAAs and TAAAs between 2013 and 2022 was reviewed. Outcomes were analyzed in patients with FAA affecting a first or second-degree relative and compared with patients with sporadic aortic aneurysms (SAAs). Endpoints included differences in the distribution of aortic disease, procedural metrics, 30-day mortality, and major adverse events (MAEs), patient survival, and mid-term stent-graft-related outcomes. There were 68 patients (13%) with FAAs and 438 (87%) with SAAs. Both groups had similar cardiovascular risk factors, history of aortic dissection, and aneurysm extent. FAA patients had significantly (P < .05) longer fluoroscopy time (82 vs 71 minutes) and higher radiation dose (1782 vs 1210 mGy). Technical success was achieved in 94.1% of the FAA group and in 96.6% of SAA group (P = .51). Median follow-up was 19 months. There was no difference in 30-day mortality and MAEs, and long-term patient survival, freedom from aortic-related mortality, and freedom from secondary interventions. Patients with FAA had higher sac shrinkage >5mm as compared with patients with SAAs (P = .006). FB-EVAR was performed with high technical success, low mortality, and low incidence of MAEs regardless of the presence of FAAs. There was no difference in the distribution of aortic disease nor in stent graft-related outcomes.TableVariablesFAA (n = 68)SAA (n = 438)P valueAneurysm type (Crawford class)0.862 Extent I4 (8.0)23 (7.4) Extent II22 (44.0)103 (33.1) Extent III8 (16.0)47 (15.1) Infrarenal short neck0 (0.0)1 (0.2) Pararenal18 (26.5)125 (28.6)30-day mortality1 (1.5)4 (0.9)1.00030-day MAESpinal cord injury0.588 No62 (91.2)411 (94.3) Motor (able to ambulate)2 (2.9)7 (1.6) Non-ambulatory4 (5.9)18 (4.1)Myocardial infarction2 (2.9)10 (2.3)1.000Major stroke0 (0.0)3 (0.7)1.000Respiratory failure5 (7.4)12 (2.8)0.111Acute kidney injury0.016 No61 (89.7)396 (90.8) Creatinine >2 but no dialysis3 (4.4)34 (7.8) Temporary dialysis3 (4.4)2 (0.5) Permanent dialysis1 (1.5)4 (0.9)Long-term secondary intervention17 (25.4)96 (22.5)0.721Aneurysm sac behavior Stable17 (25.4)199 (47.2)0.001 Enlarged >5 mm3 (4.5)33 (7.8)0.471 Shrunk >5 mm47 (70.1)189 (44.8)<0.001Final sac diameter53.8 (14.9)59.3 (15.1)0.006FAA, Familial history of aortic aneurysms or dissections; MAE, major adverse event; SAA, sporadic aortic aneurysms.Data are presented as number (%) or mean (standard deviation).Boldface P values indicate statistical significance. Open table in a new tab

Aortic Cellular Diversity and Quantitative Genome-Wide Association Study Trait Prioritization Through Single-Nuclear RNA Sequencing of the Aneurysmal Human Aorta.

Mural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue. Single-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. We sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes JUN, LTBP4 (latent transforming growth factor beta-binding protein 1), and IL34 (interleukin 34) in fibroblasts, ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4), and GLRX in vascular smooth muscle cells, as well as LRP1 in macrophage populations. Using nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.

Early Detection of Aortic Degeneration in a Mouse Model of Sporadic Aortic Aneurysm and Dissection Using Nanoparticle Contrast-Enhanced Computed Tomography.

[Figure: see text].

Targeting the NLRP3 Inflammasome With Inhibitor MCC950 Prevents Aortic Aneurysms and Dissections in Mice.

BackgroundAortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide‐binding oligomerization domain–like receptor pyrin domain containing 3 (NLRP3)–caspase‐1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation.Methods and ResultsIn a model of sporadic aortic aneurysm and dissection induced by challenging wild‐type mice with a high‐fat, high‐cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge‐induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3–caspase‐1 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP‐9) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase‐1 directly activated MMP‐9 by cleaving its N‐terminal inhibitory domain. Moreover, the genetic knockdown of Nlrp3 or Casp‐1 in mice or treatment of mice with MCC950 diminished the challenge‐induced N‐terminal cleavage of MMP‐9, MMP‐9 activation, and aortic destruction.ConclusionsOur findings suggest that the NLRP3–caspase‐1 inflammasome directly activates MMP‐9. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.

Activation of Bone Marrow–Derived Cells and Resident Aortic Cells During Aortic Injury

BackgroundThe process of aortic injury, repair, and remodeling during aortic aneurysm and dissection is poorly understood. We examined the activation of bone marrow (BM)-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic aortic aneurysm and dissection. Materials and methodsWild-type C57BL/6 mice were transplanted with green fluorescent protein (GFP)+ BM cells. For 4 wk, these mice were either unchallenged with chow diet and saline infusion or challenged with high-fat diet and angiotensin II infusion. We then examined the aortic recruitment of GFP+ BM-derived cells, growth factor production, and the differentiation potential of GFP+ BM-derived and GFP− resident aortic cells. ResultsAortic challenge induced recruitment of GFP+ BM cells and activation of GFP− resident aortic cells, both of which produced growth factors. Although BM cells and resident aortic cells equally contributed to the fibroblast populations, we did not detect the differentiation of BM cells into smooth muscle cells. Interestingly, aortic macrophages were both of BM-derived (45%) and of non−BM-derived (55%) origin. We also observed a significant increase in stem cell antigen-1 (Sca-1)+ stem/progenitor cells and neural/glial antigen 2 (NG2+) cells in the aortic wall of challenged mice. Although some of the Sca-1+ cells and NG2+ cells were BM derived, most of these cells were resident aortic cells. Sca-1+ cells produced growth factors and differentiated into fibroblasts and NG2+ cells. ConclusionsBM-derived and resident aortic cells are activated in response to aortic injury and contribute to aortic inflammation, repair, and remodeling by producing growth factors and differentiating into fibroblasts and inflammatory cells.

Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice

Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency (Adamts-4−/−) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4−/− mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections

Aneurysms of the Ascending Aorta

Aneurysms of the ascending aorta present a special challenge to primary care physicians, internists, and cardiac surgeons because they remain asymptomatic until they present with either dissection or rupture. This review article is based on a selective search of the literature. In the elderly, aneurysms of the ascending aorta are mainly caused by atherosclerosis. In younger patients, the most common cause is Marfan syndrome; less commonly, younger patients may have Loeys-Dietz syndrome, non-syndromic familial aortic aneurysms, or aortic valve malformations. Genetic variants predisposing to the development of sporadic aortic aneurysms have recently been identified. The risk of rupture and dissection depends on the aortic diameter: when the diameter exceeds 55 mm, surgery improves the outcome, as the risk of surgical complications is lower than the mortality due to rupture or dissection. A more accurate prognosis can be obtained by normalizing the aortic diameter to the body surface area. For patients with Marfan syndrome or a bicuspid aortic valve, the indications for surgery should be determined on an individual basis, depending on additional risk factors. Randomized treatment trials are lacking. The medical management of aneurysms of the ascending aorta consists of monitoring the size of the aneurysm, controlling blood pressure, and treating any cardiovascular risk factors. Patients with Marfan syndrome benefit from preventive treatment with beta-blockers. Advances in the pathophysiological understanding of aortic aneurysms have led to the testing of new types of treatment, e.g., with AT1 antagonists. With the aid of a risk-based treatment strategy, surgery can be properly timed to prevent dissection, which is usually lethal when it occurs. More research is needed on the pathogenesis of this condition so that better preventive treatments can be developed.