Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling

The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (n = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (n = 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of MYOCD and MYH11 in SMCs, and an upregulation of COL1A1/2 in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that TGFB1 was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly TGFBR2) and SMAD genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of TGFB1, the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation.

Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms

Aortic aneurysm, including thoracic aortic aneurysm and abdominal aortic aneurysm, is the second most prevalent aortic disease following atherosclerosis, representing the ninth‐leading cause of death globally. Open surgery and endovascular procedures are the major treatments for aortic aneurysm. Typically, thoracic aortic aneurysm has a more robust genetic background than abdominal aortic aneurysm. Abdominal aortic aneurysm shares many features with thoracic aortic aneurysm, including loss of vascular smooth muscle cells (VSMCs), extracellular matrix degradation and inflammation. Although there are limitations to perfectly recapitulating all features of human aortic aneurysm, experimental models provide valuable tools to understand the molecular mechanisms and test novel therapies before human clinical trials. Among the cell types involved in aortic aneurysm development, VSMC dysfunction correlates with loss of aortic wall structural integrity. Here, we discuss the role of VSMCs in aortic aneurysm development. The loss of VSMCs, VSMC phenotypic switching, secretion of inflammatory cytokines, increased matrix metalloproteinase activity, elevated reactive oxygen species, defective autophagy, and increased senescence contribute to aortic aneurysm development. Further studies on aortic aneurysm pathogenesis and elucidation of the underlying signaling pathways are necessary to identify more novel targets for treating this prevalent and clinical impactful disease.

Initial Angiotensin Receptor Blocker Response in Young Marfan Patients Decreases After 3 Years of Treatment

Marfan syndrome is caused by mutations of the fibrillin-1 gene, which weakens the connective tissue integrity. Since 2003, bioavailability regulations of TGF-ß through fibrillin alterations have been presumed of being the culprit mechanisms for aortic aneurysm development. We present the analysis of our single-center Marfan children and adolescents cohort to assess the influence of age, sex, degree of cardiovascular involvement and dosage on losartan effectivity. This prospective longitudinal registered echocardiographical investigation (EudraCT 2009-016139-36) of 49 patients with an average follow-up of 72 months focused on aortic root z-scores, elasticity, and yearly progression rates. The 33 patients under medication with losartan showed an aortic root z-score reduction during the first 36 months compared to 22 patients without medication presenting constant mild progression. Yet, results diminished under losartan thereafter, adding up to similar progressions over 72 months in both groups (0.07 ± 0.10/year versus 0.04 ± 0.11/year). Although male patients exhibited higher root z-scores, progression with and without medication was comparable to females and not age-dependent. In conclusion, losartan evoked a significant aortic root z-score regression in young Marfan patients over the first 3 years, but this effect mitigated thereafter. The initial improvement concurred with ameliorated elasticity; lower stiffness levels predicted better clinical outcome, but likewise only up to 36 months. Sex differences in dilatation severity were observed but neither age nor sex had significant influence on progression rates. Losartan dosages were gradually increased in more severely affected patients and provided an equal rate of root progression over 72 months in comparison to patients under losartan treatment with lesser baseline dilatation severity.

Giant splenic artery aneurysm treated surgically with spleen and pancreas preservation

Aneurysms of the splenic artery represent a rare clinical entity, even though they account for 60-70% of all visceral artery aneurysms. Splenic artery aneurysms larger than 5 cm are extremely rare, and they are considered to be giant. Possible causes of splenic artery aneurysm development include: trauma, hormonal and local hemodynamic changes in pregnancy, portal hypertension, arterial degeneration, infection and postsplenectomy occurrence. Surgical treatment of giant splenic artery aneurysms includes procedures that frequently require pancreatectomy and splenectomy. We present a case of a 10.2 cm giant splenic artery aneurysm, firmly adhered to the pancreas, which was treated surgically, with spleen and pancreas preservation. SIMILAR CASES PUBLISHED: Although many cases on treatment of giant splenic artery aneurysm have been published, the majority have described additional visceral resections associated with aneurysmectomy, which is in contrast with our report. Furthermore, aneurysms reaching 10 cm in size were extremely rare.

Fluoroquinolone-Induced Aortic Injury

According to clinical studies, the use of fluoroquinolone antibacterial agents is associated with such rare, but serious adverse reactions as aortic injuries. The aim of the study was to analyse scientific literature data on the risk of aortic injury during fluoroquinolone treatment. The analytical review showed that the risk factors for fluoroquinolone-induced aortic injury are male gender, age over 45 years, underlying aortic disease, as well as smoking and associated atherosclerosis. Clinical and morphological forms of fluoroquinolone-associated aortic injuries include dilatation (aneurysm development), dissection, and rupture. The analysis of data on the association between aortic injuries and the use of most common fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) showed that development of aneurysm and dissection was most often observed for levofloxacin, and least often for ciprofloxacin. The mechanism of aortic injury is due to fluoroquinolone-mediated activation of matrix metalloproteinases which damage elastic components of vascular walls, as well as reduction in lysyl oxidase expression and collagen synthesis. The ability of fluoroquinolones to form complexes with magnesium ions reduces the availability of magnesium to the cell enzyme systems, which delays synthesis of extracellular matrix structural proteins, leads to metalloproteinase activation and calcification of the vascular walls. Prevention, early detection, and timely management of the above-mentioned issues depend on the awareness of different medical specialists about the risks of aortic injury associated with the use of fluoroquinolone antibiotics.

Visceral segment aortic thrombus is associated with proximal aortic degeneration after infrarenal abdominal aortic aneurysm repair

Objective To identify predictors of aortic aneurysm formation at or above an infrarenal abdominal aortic aneurysm repair. Methods A total of 881 infrarenal abdominal aortic aneurysm repairs were identified at a single institution from 2004 to 2008; 187 of the repairs were identified that had pre-operative and post-operative computed tomography imaging at least one year or greater to evaluate for aortic degeneration following repair. Aortic diameters at the celiac, superior mesenteric, and renal arteries were measured on all available computed tomographic scans. Aortic thrombus and calcification volumes in the visceral and infrarenal abdominal aortic segments were calculated. Multivariable modeling was used with log transformed variables to determine potential predictors of future aortic aneurysm development after infrarenal abdominal aortic aneurysm repair. Results Of the 187 patients in the cohort, 100 had an open abdominal aortic aneurysm repair while 87 were treated with endovascular repair. Proximal aortic aneurysms developed in 26% ( n = 49) of the cohort during an average of 72 ± 34.2 months of follow-up. After multivariable modeling, visceral segment aortic thrombus on pre-operative computed tomography imaging increased the risk of aortic aneurysm development above the infrarenal abdominal aortic aneurysm repair within both the open abdominal aortic aneurysm (hazard ratio 2.04, p = 0.033) and endovascular repair (hazard ratio 3.31, p = 0.004) cohorts. Endovascular repair was independently associated with a higher risk of future aortic aneurysm development after infrarenal abdominal aortic aneurysm repair when compared to open abdominal aortic aneurysm (hazard ratio 2.19, p = 0.025). Conclusions Visceral aortic thrombus present prior to abdominal aortic aneurysm repair and endovascular repair are both associated with an increased risk of future proximal aortic degeneration after infrarenal abdominal aortic aneurysm repair. These factors may predict patients at higher risk of developing proximal aortic aneurysms that may require complex aortic repairs.

Recurrent Heart Failure in a Patient With the Parachute Device Implantation: A Case Report

Background: The parachute device is made to isolate of the aneurysm to exclude the dysfunctional myocardium might be a promising concept to improve clinical prognosis. However, the clinical practice revealed the device might result in death and worsen heart failure (HF). Case presentation: Herein, we report a male subject who received parachute device implantation after the ventricular aneurysm development caused by myocardial infarction. Even with standard treatment, the patient was still hospitalized for six times because of heart failure in the next 19 months and passed away before the transplantation was scheduled. This is a very rare case that a HF subject received parachute device implantation with early death.Conclusions: The progressive maladaptive remodeling would delay the reendothelialization of the device. The subsequent device displacement may enhance the mitral regurgitation and result in poor clinical outcome.Clinical Trial Registration: PARACHUTE China Approval Trial, NCT02240940, Registered September 16, 2014, https://clinicaltrials.gov/ct2/show/NCT02240940