Advanced Aortic Disease Research Articles

Abstract 15530: Single-cell Analysis in Aortic Aneurysmal Tissue From Patients With Marfan Syndrome Reveals Increased Tgf-beta Production but Downregulation of Downstream Canonical Tgf-beta Signaling Pathways

Background: Marfan syndrome (MFS) is caused by mutations in the gene for fibrillin-1 ( FBN1 ); however, the mechanisms by which these mutations cause aortic aneurysms are poorly understood. Although it was hypothesized previously that dysregulation of the complex TGF-β signaling pathway leads to aortic aneurysm formation, FBN1 mutations appear to have a paradoxical effect on TGF-β signaling in MFS. In this study, we evaluated cell-specific TGF-β expression in non-immune cells in MFS aortic tissue. Methods: We performed single-cell RNA sequencing of ascending aortic aneurysm tissues from MFS patients (n=3) undergoing aneurysm repair and age-matched, non-aneurysmal control tissue from cardiac transplant donors and recipients (n=4). Non-immune cells were separated out from the data and analyzed using the Seurat package in R. Differentially expressed genes were identified using edgeR. Results: Conserved gene expression was used to identify populations of smooth muscle cells (SMCs; n=6), fibroblasts (n=3), and endothelial cells (ECs; n=3). We found that TGFB1 was significantly upregulated in quiescent fibroblasts (identified by increased expression of DCN , LUM , and complement factors) with log2FC of 1.30 and FDR 8.25x10 -8 , as well as in activated fibroblasts (identified by increased expression of genes involved in blood vessel repair and healing including ACTA2 , NOTCH3 , THBS2 , and PDGFRB ) with log2FC of 1.25 and FDR 6.15x10 -22 . Despite this increase in TGFB1 , expression of TGF-β receptor genes (predominately TGFBR2 ) as well as downstream SMAD genes was downregulated significantly in the SMC, fibroblast, and endothelial cell clusters. Finally, genes involved in the non-canonical TGF-β pathway, including ERK , JNK, and p38, were not differentially expressed in non-immune cells in MFS compared with control tissues. Conclusion: Increased expression of TGFB1 in non-immune cells in MFS was driven by two clusters of fibroblasts. Despite this, our data do not support associated upregulation of other genes in the canonical or non-canonical TGF-β pathways and in fact support downregulation of canonical TGF-β signaling in non-immune cells of aneurysmal tissues from MFS patients with advanced aortic disease.

6126Peripheral aneurysms in Marfan patients are common and are related to age and advanced aortic disease

Abstract Background Peripheral aneurysms are not included in the diagnostic criteria for Marfan syndrome (MFS); however, their real prevalence in MFS is unknown. Furthermore, they are commonly seen in other genetic entities such as Loeys-Dietz syndrome. We aimed to investigate the prevalence of peripheral aneurysm in Marfan syndrome. Methods Patients with clinical criteria of Marfan syndrome and identified FBN1 mutation were evaluated. Only patients with either MRI or CT angiography assessing peripheral vessels were included in this study. MRI and CT angiography studies were retrospectively evaluated to detect the presence of peripheral aneurysms. Aortic dissection-related arterial dilations were excluded. Aortic events and those related to aneurysm complications were collected during follow-up. Results Two hundred and nine patients with Marfan and FBN1 mutation were evaluated. Of these 136 (65.1%) had undergone either MRA or CTA with peripheral artery study during follow-up. Mean age at the last follow-up visit was 42.4±14.1yrs; 54.4% were men, and mean follow-up 7.3±3.1 years. Sixty-six aneurysms were identified in 42 (30.9%) patients. The most common locations were the iliac arteries in 23. The rest were: renal (7), vertebral (5), splenic (5), coeliac (3), brachiocephalic (1), subclavian (3), carotid (3), axillary (2), internal mammary (3), femoral (2), hypogastric (3), bronchial (2), coronary (1), hepatic (1), lumbar (1), gastroduodenal (1) and popliteal (1). Twenty-six patients (61.9%) had more than one peripheral aneurysm, and only 4 required surgery. Patients with peripheral aneurysms were older (47.2±14.3yrs vs 40.2±13.6yrs, p=0.06) and more frequently men (69.0% vs 47.9% p=0.026). Although patients with peripheral aneurysms did not more frequently have aortic dissection (16.7% vs 17.0%, p=0.586), they did more frequently have aortic surgery (73.8% vs 47.9% p=0.05). Conclusions Peripheral aneurysms are present in one third of Marfan syndrome patients and are related to age and more advanced aortic disease. Systematic use of whole-body vascular assessment in Marfan patients can provide a comprehensive evaluation of the entire arterial system, identifying other sites of vascular involvement at risk of potential complications, and the subgroup of patients with more aggressive vascular disease expression.

Endovascular conversion into aorto-uniiliac configuration of acute failed endovascular aneurysm repair is associated with better one-year survival rates compared to open conversion

BackgroundOpen conversions (OC) due to failed endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) are technically demanding because of preexisting prostheses and advanced aortic disease. This study evaluates the feasibility and outcomes of aorto-uniiliac endografting (AUI) as an alternative treatment option in acute failed EVAR. MethodsFrom March 1995 through February 2012, 26 patients underwent acute conversion of failed EVAR at our tertiary care university center. All data were prospectively entered in our institutional database. Outcomes included 30-day or in-hospital mortality, postoperative complications, and mid-term survival. ResultsDuring the investigation period, a total of 692 patients received EVAR at our institution, while five of the 26 patients with acute conversion (19.2%) had an initial EVAR at an outlying institution and were referred for treatment. Therefore, our estimated institutional rate of acute conversions was 3% (21 of 692 EVAR). OC were performed in 14 patients (53.8%), while 12 patients underwent AUI (46.2%). An average time of 20.3 months (median: 18.6; interquartile range Q1–Q3: 0.0–38.6) elapsed between the initial EVAR and the acute conversion. All acute AUI conversion procedures were completed successfully. The 30-day mortality following acute conversions was 42.3% and since the use of AUI, it could be reduced to 33.3%. Kaplan–Meier estimates revealed a survival advantage for AUI at one year (p = 0.046), but the benefit was lost by mid-term follow-up (p = 0.103). ConclusionsAUI for the treatment of acute failed EVAR represents a feasible and less invasive alternative to OC, and is associated with better one-year survival rates.

Aortic biomechanics by magnetic resonance: Early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?

BackgroundPrevious studies demonstrated the usefulness of MRI in the evaluation of aortic biomechanics in Marfan patients with aortic dilatation. However, these parameters have not been well studied in earlier stages of aortic disease. The present work aimed to study aortic biomechanics: aortic distensibility (AD) and pulse wave velocity (PWV), by MRI in Marfan patients without advanced aortic disease. MethodsEighty consecutive Marfan patients were compared with 36 age- and sex-matched controls. MRI images at the level of ascending, descending and abdominal aorta were used to determine AD and PWV. ResultsMarfan patients (27 men; age: 32.0±10.5years; mean aortic root diameter: 37.2±4.6mm) had lower AD at all levels (ascending 2.6±2.1 vs. 6.2±3.7mmHg−1·10−3, p<0.001; descending 3.1±2.0 vs. 8.3±4.2, p<0.001; and abdominal 4.5±2.2 vs. 14.0±5.2, p<0.001), higher aortic arch PWV (8.1±6.5 vs. 4.3±1.8m/s, p<0.01) and ascending-to-abdominal PWV (6.1±3.0 vs. 4.7±1.5m/s, p<0.01) compared with controls. Thirty-five Marfan patients had a non-dilated aortic root (mean aortic root diameter: 34.5±3.8mm). In multivariable analyses, after adjustment for age, pulse pressure and aortic dimensions, AD remained lower and PWV higher in Marfan patients; even Marfan patients with non-dilated aortic root showed impaired aortic biomechanics compared with controls. Z-score for ascending AD<−3.5 distinguished Marfan patients from controls with 82.5% sensitivity and 86.1% specificity. ConclusionsAortic biomechanics by MRI were abnormal in the entire aorta in Marfan patients. Moreover, Marfan patients without dilated aortic root showed clear impairment of aortic biomechanics, which suggests that they may be used as early markers of aortic involvement in these patients.

Oxidative stress and unfolded protein response (UPR) in advanced aortic disease from Marfan Syndrome (MFS) transgenic mice

We investigated the occurrence and mechanisms of oxidative stress in aortae from MFS mouse model (mgÄFBN1). Aortic dilation, elastic fiber rupture and collagen deposition markedly increased from 3–6 months(mo). ROS production (by 3 methods) increased in aortae from 6‐mo, but not 1 or 3‐mo‐old MFS mice, mainly at crossa. Nox4 mRNA increased after 1mo, while Nox2 only at 6mo. To assess oxidative stress mechanisms, we investigated UPR markers in MFS aortae. Expression of KDEL chaperones increased at 6mo, but not 1 or 3mo. Protein disulfide isomerase(PDI), which associates with and regulates Nox(es), equally increased. Also, PDI expression topography correlated with ROS production sites (DMPO adduct antibody), mainly at adventitia in crossa and media in abdominal aorta. Adventitial PDI switch in crossa correlated with diffuse collagen accumulation. Moreover, yeast‐two‐hybrid screening disclosed PDI interaction with fibrillin‐1(FBN1); in cultured fibroblasts, such association was mainly intra, but not extracellular. FBN1 immunodetection decreased by~80% and co‐localized with PDI in MFS adventitia. PDI/UPR marker changes were not systemic and absent in kidney and liver. Losartan prevented aortic remodeling, but ROS production remained increased in aorta at 6mo. Thus, ROS production increases with MFS aortic disease progression, in close temporal and topographic correlation with PDI expression and UPR.

Selective Use of Off-Pump Coronary Bypass Surgery Reduces Mortality and Neurologic Morbidity Associated with High-Risk Coronary Bypass Surgery: A 400-Case Comparative Experience

The frequency of use of off-pump coronary artery bypass (CAB) surgery to surgically treat coronary artery disease has varied greatly from center to center and from surgeon to surgeon because of preference, training, and experience. We report an experience with 400 consecutive isolated CAB procedures selectively managed with on-pump or off-pump surgery, according to the perceived potential for aortic embolization or stroke as determined by clinical and imaging determinations. The off-pump CAB group (46 patients) was 7.1 years older (P < .05) and had an 11% lower ejection fraction (P < .03) than the on-pump group. There was no difference in gender, urgency of surgery, hemodynamic stability, angina class, or incidence of prior myocardial infarction. All 400 patients underwent intraoperative transesophageal echocardiography, and many underwent an epiaortic study to supplement image quality. Patients without palpable or imaged advanced aortic disease or deemed to be at clinically high risk for stroke (advanced age, prior strokes, or advanced cerebrovascular or peripheral vascular disease) underwent on-pump procedures requiring 55 minutes of aortic ischemia and 97 minutes of high-flow, high-pressure bypass on average. All others underwent off-pump procedures. The numbers of grafts per patient were similar (3.2 on-pump, 2.8 off-pump; = ns). There was no in-hospital or 30-day mortality in either group. Using the New York State risk-adjustment algorithm, we found the predicted mortality rate for the off-pump group was higher (2.24% on-pump versus 5.54% off-pump, P = .008). The postoperative length of stay was longer in the off-bypass group (3.67 days versus 4.31 days, P = .003). The frequencies of hospital readmission and perioperative complications (renal, pulmonary, infection, bleeding, cardiac, neurologic) were similar, and there were no postoperative strokes in either group. The selective use of off-pump surgery safely managed patients at higher risk for perioperative stroke and associated embolic multisystem organ failure and death. Individual surgeon and center-wide use of a selective approach is recommended as an alternative to a single-procedure nonselective approaches.

A simple technique for aortic cannulation in organ donors with advanced aortic disease

Cannulation of the abdominal aorta in organ donors with advanced arteriosclerotic disease or extensive trauma may be problematic owing to difficulty in securing a watertight tie around the diseased aorta, the danger of creating a false passageway in the aorta, and the risk of breaking off plaque particles that can advance into the arteries of donated organs. Cannulation problems can be avoided in these challenging donors by using a simplified technique for cannulation of the thoracic aorta in which a Foley catheter is passed down around the aortic arch, the balloon is inflated, and cool flushing is initiated.