Aorta In Marfan Syndrome Research Articles

Complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice

Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.

Abstract 16995: Distensibility and Aortic Growth Rate Predict Type B Aortic Dissection in Marfan Syndrome

Introduction: Marfan syndrome (MFS) is associated with high aortic growth rate (GR) and incidence of aortic dissection (AD), including delayed type B AD (TBAD) after prophylactic root repair. Elevated aortic stiffness has been investigated as a biomarker in MFS, but it remains uncertain how stiffness relates to GR and risk of AD. Vascular deformation mapping (VDM) is a technique that uses clinical CT angiography (CTA) to yield accurate, 3D maps of aortic growth over surveillance (VDM-G). This technique can also be used to assess aortic stiffness via quantification of cyclic wall stretch between systole and diastole (VDM-D) using multi-phasic dynamic CTA. Research Question: Is distensibility of the descending thoracic aorta associated with aortic GR or development of TBAD in MFS patients? Goal: The aim of this study was to analyze stiffness of the descending thoracic aorta in MFS and its association with aortic GR and occurrence of TBAD. Methods: We identified 36 adult MFS patients with dynamic CTA studies (>1 year interval) between 2004-2020. Growth was quantified by VDM-G, and linearized descending aortic stiffness by VDM-D - via calculation of distensibility - as the ratio of cyclic aortic surface area change (AR) over pulse pressure [(AR-1)/PP]. Results: Patients were 38.9 ± 12.1 years old, 58% were male and 25 (69%) had prior ascending repair. Mean CT follow-up interval was 5.7 ± 3.4 years and 8 developed TBAD during follow-up with pre-dissection diameter of 31.12 ± 6.01 mm at tear location. Age (β -0.4, 95%CI: -0.07, -0.01, p=0.015) and baseline diameter (β 0.10, 95%CI: 0.02, 0.18, p=0.017 ) independently predicted GR on multivariable analysis, but distensibility did not (p=0.38). Both distensibility (OR 0.02, 95% CI: 0.00, 0.68, p=0.03) and GR (OR 8687.05, 95% CI: 1.43, 5x10^7, p=0.04) were independent predictors of TBAD during follow-up, but diameter was not (p=0.49). Conclusion: Aortic stiffness and growth rate are likely predictors of type B aortic dissection in MFS.

Recurrent aneurysm 11 years after thoracoabdominal aortic replacement due to recanalization of intercostal arteries of the wrapping native aorta in Marfan syndrome: a case report

BackgroundPersistent blood flow is common in aortic aneurysms following endovascular repair. However, the recanalization of thrombosed intercostal arteries after open aortic repair is rare. We report a case of aortic aneurysm recurrence 11 years after thoracoabdominal aortic replacement resulting from recanalization of the intercostal arteries like a type II endoleak in a patient with Marfan syndrome.Case presentationA 50-year-old woman with Marfan syndrome presented with left-sided back pain after meals. She underwent abdominal aortic replacement at 35 years of age, distal aortic arch and thoracoabdominal aortic replacement for type B chronic aortic dissection at 38 years of age, and aortic root to the remnant arch replacement with a mechanical valve conduit for type A acute aortic dissection at 43 years of age, which resulted in complete replacement of the entire aorta with prosthetic grafts. The patient has been taking warfarin since then. The prothrombin time-international normalized ratio levels were controlled almost within the range of 1.5–2.5 during the follow-up period, but it was elevated up to 3.4 at 1 month before she felt back pain and kept high at 4.2 on admission. Enhanced computed tomography (CT) revealed an aneurysm between the descending graft and the remaining native aortic wall, compressing the esophagus. However, there were no abnormal findings on the CT performed 10 months prior to admission. Surgery revealed that the orifices of the intercostal arteries were patent with backflow. We closed the patent intercostal arteries using nonabsorbable sutures. The patient’s postoperative course was uneventful, and the CT performed 1 year later showed no aneurysmal recurrence.ConclusionsHere, we describe a rare case of recurrent aortic aneurysm long term after graft replacement due to recanalization of the intercostal arteries of the remaining aortic wall. Our findings suggest that closing all orifices of the intercostal arteries during aortic repair, regardless of backflow, could prevent delayed reopening; systemic anticoagulation after aortic replacement may be a risk factor for recanalization, and that postoperative periodic CT follow-up is essential, especially in patients receiving anticoagulant therapy.

FBN1 knockout promotes cervical artery dissection by inducing N-glycosylation alternation of extracellular matrix proteins in rat VSMCs

FBN1 mutation promotes the degeneration of microfibril structures and extracellular matrix (ECM) integrity in the tunica media of the aorta in Marfan syndrome. However, whether FBN1 modulates cervical artery dissection (CAD) development and the potential molecular mechanisms of abnormal FBN1 in CAD remains elusive. In this study, FBN1 deficiency participated in the development of CAD and influenced the proliferation, apoptosis, and migration of vascular smooth muscle cells. FBN1 knockout induced alternations in mRNA levels of the transcriptome, protein expression of the proteome, and abundance of N-glycosylation of the N-glycoproteome. Comprehensive analysis of multiple omics showed up-regulation in mRNA levels of ECM proteins; yet, both the ECM protein levels and relative abundance of N-glycosylation were decreased. Moreover, we performed in vivo experiments to confirm the altered glycosylation of proteins in vascular smooth muscle cells. In conclusion, FBN1 deletion in vascular smooth muscle cells can result in altered N-glycosylation of ECM protein, which were critical for the stability of ECM and the process of CAD. This may open the way for a novel therapeutic strategy to treat people with CAD.

IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome.

Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.

Outcome of aortic dissection affecting the descending aorta in Marfan Syndrome

Abstract Introduction Marfan syndrome (MFS) is a connective tissue disorder related to FBN1 mutations. The main cardiac feature of this syndrome is the enlargement and the dissection of the ascending aorta. Close monitoring of the aortic root diameters and its preventive replacement has allowed improving life expectancy of these patients in the last decades. However, there is paucity of data about the outcome of aortic dissection affecting the descending aorta and its markers of poor evolution. Purpose To characterize patients with MFS and dissection involving the descending aorta. To compare baseline characteristics and the clinical outcome between patients with isolated type B dissection (Group B) and patients with type A dissection with residual B dissection (Group A). Methods Retrospective longitudinal analysis of patients that attended our Marfan unit between 2001 and 2021 with an aortic event involving the descending aorta. Clinical data were collected from electronic health records. Results From the global cohort of adults with Marfan syndrome seen at our centre, we identified a total of 37 adults (11.5% of the overall cohort) that had an acute aortic event with involvement of the descending aorta. 20 (54.1%) were type A aortic events and 17 (45.9%) were isolated type B dissections. Cardiovascular risk factors were similarly distributed in both groups but there was a significant higher percentage of women in Group B (35.0% vs 76.5%, p=0.012) (Figure 1). Acute management of the aortic event implied surgery in 17 (85.0%) patients in Group A and in 5 (29.4%) patients in Group B (p=0.001). In Group B, interventions were 3 TEVAR and 2 open surgeries. 2 (5.4%) patient died during the acute phase, 1 (5.0%) in Group A and 1 (5.9%) in Group B (p=ns).The remaining 35 patients (19 in Group A, 16 in Group B) were followed-up for 10.4±6.7 years. 10 patients died during follow-up (6 in Group A, 4 in Group B). In Group A, 2 patients died of sudden death, 2 patients died in the perioperative setting of aortic surgery, and 2 patients died of an aortic rupture. In Group B, 3 patients died in the perioperative setting of aortic surgery and 1 of an intracranial hemorrhage. The proportions of aortic events during follow-up (death, distal redissection, proximal dissection, distal intervention or aortic root surgery) in both groups are described in Figure 2. Median survival free of reintervention or death (non-related to initial event) was 7.5 years in the overall cohort; 8.2 years in Group A and 2.2 years in Group B (log rank p=0.04) (Figure 2). Conclusions Patients with Marfan syndrome and aortic dissection involving the descending aorta have a poor clinical outcome, with high rates of reintervention, redissection or death. Although Group B required less often surgery during the acute phase, worst survival free of reintervention or death was observed during follow-up. Funding Acknowledgement Type of funding sources: None.

Can Frozen Elephant Trunk Cure Type I Dissection Confined to Thoracic Aorta in Marfan Syndrome?

This study sought to evaluate the long-term impact of frozen elephant trunk (FET) on the distal aorta of patients with Marfan syndrome (MFS) who had type I dissection confined to the thoracic aorta (above the diaphragmatic hiatus). Between 2003 and 2016, 42 patients with MFS (Ghent or revised Ghent criteria) (age 33.3 ± 8.9 years; 27 men; 64.3%) sustaining type I dissection above the diaphragmatic hiatus involving the aortic arch (22 acute; 52.4%) underwent total arch replacement and FET. Dissection extended distally to the mid-descending aorta in 32 (76%) and to above the diaphragmatic hiatus in 10 (24%) patients. Operative mortality was 4.8% (2 of 42). Follow-up was 100% at 6.3 ± 3.0 years. Maximal aortic sizes at the mid-descending aorta, diaphragmatic hiatus, renal arteries, and largest segment of abdominal aorta were 22.8, 21.1, 19.1, and 19.9 mm preoperatively and 23.1, 22.0, 19.8, and 22.4 mm on the latest computed tomographic angiography. Dilation and complete remodeling of the distal aorta occurred in 10.0% (4 of 40) and 90% (36 of 40) of patients, respectively. One late death occurred, and 3 distal reoperations were performed. Preoperative abdominal aortic maximal aortic size was predictive of distal dilatation (mm) (hazard ratio, 1.78; P= .021) and reoperation (≥25 mm vs <25 mm) (hazard ratio, 12.88; P= .037). At 10 years, freedom from dilation, reoperation, and death were 69.8%, 78.1%, and 90.0%, respectively. At 8 years, the rates of death, reoperation, and reoperation-free survival were 10%, 11%, and 79%, respectively. The FET technique has a positive remodeling impact on type I dissection confined to the thoracic aorta in patients with MFS. This study adds evidence supporting the safety and durability of this extended approach for type I aortic dissection in MFS.

Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome.

Fibrillin-1 is an elastin-associated glycoprotein that contributes to the long-term fatigue resistance of elastic fibers as well as to the bioavailability of transforming growth factor-beta (TGFβ) in arteries. Altered TGFβ bioavailability and/or signaling have been implicated in aneurysm development in Marfan syndrome (MFS), a multi-system condition resulting from mutations to the gene that encodes fibrillin-1. We recently showed that the absence of the latent transforming growth factor-beta binding protein-3 (LTBP-3) in fibrillin-1-deficient mice attenuates the fragmentation of elastic fibers and focal dilatations that are characteristic of aortic root aneurysms in MFS mice, at least to 12weeks of age. Here, we show further that the absence of LTBP-3 in this MFS mouse model improves the circumferential mechanical properties of the thoracic aorta, which appears to be fundamental in preventing or significantly delaying aneurysm development. Yet, a spinal deformity either remains or is exacerbated in the absence of LTBP-3 and seems to adversely affect the axial mechanical properties of the thoracic aorta, thus decreasing overall vascular function despite the absence of aneurysmal dilatation. Importantly, because of the smaller size of mice lacking LTBP-3, allometric scaling facilitates proper interpretation of aortic dimensions and thus the clinical phenotype. While this study demonstrates that LTBP-3/TGFβ directly affects the biomechanical function of the thoracic aorta, it highlights that spinal deformities in MFS might indirectly and adversely affect the overall aortic phenotype. There is a need, therefore, to consider together the vascular and skeletal effects in this syndromic disease.

Imaging of the Postsurgical Aorta in Marfan Syndrome.

Marfan syndrome is a heritable multisystem connective tissue disease and is the most common genetic cause of aortic disease. Guidelines for surgical repair and recommendations for surveillance imaging aim to prevent aneurysm rupture, aortic dissection, and death. Options for proximal aorta repair include the modified Bentall procedure and valve-sparing aortic root repairs. Hemiarch and total arch replacement are options for aortic arch repair, and the elephant trunk procedure is a special two-staged total arch repair facilitating future descending aorta repair. Endovascular repair is not currently considered an acceptable long-term treatment option in Marfan syndrome but may be performed when open repair is not feasible or in the acute setting as a bridge to definitive surgical treatment. After an initial surgery, patients remain at risk for new aortic dissection, propagation of a pre-existing aortic dissection, and new or enlarging aortic aneurysm. Anastomotic pseudoaneurysm is a potential postsurgical complication at multiple sites including proximal and distal aortic anastomoses, coronary anastomoses, and intercostal and visceral artery patches. Patients undergoing endovascular repair are at increased risk of endoleak and aortic dissection. CT and MR angiography are the main imaging modalities for surveillance of the aorta in Marfan syndrome and are capable of demonstrating these complications, as well as expected postsurgical appearances. 4D flow MRI is an emerging technique providing hemodynamic information that may risk-stratify aneurysms better than size alone and help predict future aortic events.

Aortic microcalcification is associated with elastin fragmentation in Marfan syndrome.

Marfan syndrome (MFS) is a connective tissue disorder in which aortic rupture is the major cause of death. MFS patients with an aortic diameter below the advised limit for prophylactic surgery (<5 cm) may unexpectedly experience an aortic dissection or rupture, despite yearly monitoring. Hence, there is a clear need for improved prognostic markers to predict such aortic events. We hypothesize that elastin fragments play a causal role in aortic calcification in MFS, and that microcalcification serves as a marker for aortic disease severity. To address this hypothesis, we analysed MFS patient and mouse aortas. MFS patient aortic tissue showed enhanced microcalcification in areas with extensive elastic lamina fragmentation in the media. A causal relationship between medial injury and microcalcification was revealed by studies in vascular smooth muscle cells (SMCs); elastin peptides were shown to increase the activity of the calcification marker alkaline phosphatase (ALP) and reduce the expression of the calcification inhibitor matrix GLA protein in human SMCs. In murine Fbn1C1039G/+ MFS aortic SMCs, Alpl mRNA and activity were upregulated as compared with wild-type SMCs. The elastin peptide-induced ALP activity was prevented by incubation with lactose or a neuraminidase inhibitor, which inhibit the elastin receptor complex, and a mitogen-activated protein kinase kinase-1/2 inhibitor, indicating downstream involvement of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation. Histological analyses in MFS mice revealed macrocalcification in the aortic root, whereas the ascending aorta contained microcalcification, as identified with the near-infrared fluorescent bisphosphonate probe OsteoSense-800. Significantly, microcalcification correlated strongly with aortic diameter, distensibility, elastin breaks, and phosphorylated ERK1/2. In conclusion, microcalcification co-localizes with aortic elastin degradation in MFS aortas of humans and mice, where elastin-derived peptides induce a calcification process in SMCs via the elastin receptor complex and ERK1/2 activation. We propose microcalcification as a novel imaging marker to monitor local elastin degradation and thus predict aortic events in MFS patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome.

Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue due to mutations in the fibrillin-1 gene (FBN1). This study aimed at characterizing microelastic properties of the ascending aortic wall and lung parenchyma tissues from wild type (WT) and age-matched Fbn1 hypomorphic mice (Fbn1(mgR/mgR) mice) to identify tissue-specific biomechanical effects of aging and disease in MFS. Atomic force microscopy was used to indent lung parenchyma and aortic wall tissues, using Hybrid Eshelby Decomposition analysis to extract layer-specific properties of the intima and media. The intima stiffened with age and was not different between WT and Fbn1(mgR/mgR) tissues, whereas the media layer of MFS aortas showed progressive structural and mechanical degradation with a modulus that was 50% softer than WT by 3.5months of age. Similarly, MFS mice displayed progressive structural and mechanical deterioration of lung tissue, which was over 85% softer than WT by 3.5months of age. Chronic treatment with the angiotensin type I receptor antagonist, losartan, attenuated the aorta and lung tissue degradation, resulting in structural and mechanical properties not significantly different from age-matched WT controls. By revealing micromechanical softening of elastin-rich aorta and lung tissues with disease progression in fibrillin-1 deficient mice, our findings support the use of losartan as a prophylactic treatment that may abrogate the life-threatening symptoms of MFS.

Genotype impacts survival in Marfan syndrome.

The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients. We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 ± 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 ± 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P < 0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to a DN effect (abnormal fibrillin-1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P < 0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014). Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation.

Abstract 18897: Extracellular Signal-related Kinase Signaling and Smooth Muscle Cell Contractile Gene Expression are Uniformly Enhanced in the Aortic Root and Ascending Aorta in Marfan Syndrome

Introduction: Enhanced TGF-β signaling drives aortic root aneurysm development in Marfan syndrome (MFS) via the non-canonical (ERK) pathway in murine models, but ERK not been studied in human tissue. Conversely, blockade of canonical (Smad) TGF-β signaling is detrimental in MFS mice. Recently, TGF-β-induced increases in smooth muscle cell (SMC) contractile genes and collagen I (COL1) expression have been proposed to lead to aortic stiffness and dilatation in MFS. Hypothesis: We hypothesized that ERK signaling is enhanced in human MFS tissue and dictates the predilection of the aortic root to develop aneurysm by altering SMC gene expression. Methods and Results: Western blot of aortic root tissue from MFS patients with root aneurysms (4.67±0.09 cm) revealed 3.1-fold increased ERK activation relative to control aortic root (p=0.03, n=8). When compared to non-dilated MFS ascending (ASC) aorta (2.94±0.14 cm), there was no difference in ERK activation between the two regions. While RT-PCR of MFS root showed increased expression of the contractile gene regulator myocardin (2.4±0.07 fold, p=0.01), and of MYH11 (3.05±0.13 fold, p=0.03) ACTA2 (2.93±0.10 fold, p&lt;0.01), and SM22-α (1.88±0.13 fold, p=0.02) versus controls, these genes were not differentially expressed between MFS root and ASC. COL1 expression was increased in MFS root relative to controls (5.57±0.06 fold, p&lt;0.01) and MFS ASC (2.25±0.06 p&lt;0.01). In vitro treatment of cultured MFS aortic root SMCs (n=5 patients) with TGF-β and Smad-specific inhibitor (SB431542) failed to increase expression of MYOCD, MYH11, ACTA2, SM22-α or COL1, while co-treatment with TGF-β and ERK inhibitor (PD98059) induced significant increases in expression of these genes (5.4-, 2.6-, 2.7-, 1.4-, and 1.4- fold, respectively p&lt;0.05). Conclusions: ERK signaling is uniformly enhanced in MFS aortic root and ASC tissue, indicating that further study into aortic region-specific responses to cellular signals is needed to assess the development of focal aortic root aneurysm in MFS. Increased contractile gene expression is Smad-dependent and non-focal and thus does not clarify focal root aneurysm. COL1, while focally enhanced in the MFS root, is Smad-driven and suppressed by ERK, and may represent a compensatory response.

Early and Late Results of Graft Replacement for Dissecting Aneurysm of Thoracoabdominal Aorta in Patients With Marfan Syndrome

When treating dissecting aneurysm of the thoracoabdominal aorta surgically in patients with Marfan syndrome, we have usually performed graft replacement- including the entire thoracoabdominal aorta and reconstruction of all visceral branches, even if dilatation is mild in some segments-to avoid further aortic operations in the follow-up period. From October 1999 through July 2011, 20 consecutive patients with Marfan syndrome underwent repair of dissecting aneurysm of the thoracoabdominal aorta (median age, 45 years; range, 19-65 years). All patients underwent surgical intervention with cerebrospinal fluid (CSF) drainage and distal aortic and selective organ perfusion. Deep hypothermia was used in 13 patients for spinal cord protection. No in-hospital mortality was observed. One patient had temporary spinal cord ischemia but was fully recovered by discharge. Other complications included exploration for bleeding (n=1), prolonged ventilation (n=1), and graft infection (n=1). At a mean follow-up of 54 months (range, 9-129 months), 1 patient had died of interstitial pneumonia at 38 months postoperatively. Survival at 8% years was 91.2±9.0%. Two patients required additional aortic procedures (total arch replacement and aortic valve-sparing surgery). Actuarial rate of freedom from aortic operations at 8 years was 83.9%±10.5%, but no patient needed required repeated thoracotomy for an aortic procedure. Neither false nor patch aneurysms were observed using computed tomography (CT) during follow-up surveillance. Graft replacement for dissecting aneurysm of the thoracoabdominal aorta in Marfan syndrome offers good early and long-term results. We believe total aortic replacement including the entire thoracoabdominal aorta and reconstruction of all visceral arteries should be recommended for selected patients with Marfan syndrome.

New therapeutic targets for ACE inhibitors and angiotensin receptor blockers

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) posses multiple beneficial effects such as cardioprotection, cerebroprotection, nephroprotection which provide opportunity to select the most suitable drug for the target vascular bed (e.g. coronary, or cerebral circulation). In some clinical settings, combined therapy ACE-I with ARB (double blockage of the renin-angiotensin-aldosteron system) may appear the most effective. These drugs (especially ARB) may successfully prevent atrial fibrillation and play a protective role in metabolic syndrome. Recently, it has been demonstrated that losartan is able to inhibit vasodilatation of the aorta in Marfan syndrome, which might prevent sudden death due to aorta rupture. An increasing role of ARB is most beneficial in hipotensive therapy (inhibition/regression of hypertension-related organ damage). With particular interest, results of the ONTARGET study are being awaited. This study is focused on the effect of double blockage (ramipril and telmisartan) on reduction of the occurrence of myocardial infarction, stroke, and heart failure.

Discrete Contributions of Elastic Fiber Components to Arterial Development and Mechanical Compliance

Even though elastin and fibrillin-1 are the major structural components of elastic fibers, mutations in elastin and fibrillin-1 lead to narrowing of large arteries in supravalvular aortic stenosis and dilation of the ascending aorta in Marfan syndrome, respectively. A genetic approach was therefore used here to distinguish the differential contributions of elastin and fibrillin-1 to arterial development and compliance. Key parameters of cardiovascular function were compared among adult mice haploinsufficient for elastin (Eln(+/-)), fibrillin-1 (Fbn1(+/-)), or both proteins (dHet). Physiological and morphological comparisons correlate elastin haploinsufficiency with increased blood pressure and vessel length and tortuosity in dHet mice, and fibrillin-1 haploinsufficiency with increased aortic diameter in the same mutant animals. Mechanical tests confirm that elastin and fibrillin-1 impart elastic recoil and tensile strength to the aortic wall, respectively. Additional ex vivo analyses demonstrate additive and overlapping contributions of elastin and fibrillin-1 to the material properties of vascular tissues. Lastly, light and electron microscopy evidence implicates fibrillin-1 in the hypertension-promoted remodeling of the elastin-deficient aorta. These results demonstrate that elastin and fibrillin-1 have both differential and complementary roles in arterial wall formation and function, and advance our knowledge of the structural determinants of vascular physiology and disease.

Treating the Thoracic Aorta in Marfan Syndrome: Surgery or TEVAR?

Marfan syndrome (MFS) is an inherited disorder of connective tissue that is historically associated with high mortality due to disorders of the cardiovascular system. Over the past 40 years, surgery to the aortic root and thoracoabdominal aorta has resulted in a significantly prolonged life expectancy. More recently, techniques for endovascular repair of the aortic complications of MFS have been described. In this article we review the relative merits of open and endovascular approaches to thoracic aortic complications in MFS, comparing outcomes from contemporary literature. A reasonably large body of evidence has developed concerning the surgical treatment of the aortic root, ascending thoracic aorta, and arch in MFS. It is clear from large series that pathology, such as acute type A dissections and aneurysmal dilatation, can be successfully repaired with low mortality. Recently published series, although reporting smaller numbers, have demonstrated that the same is true for open surgical replacement of descending thoracic and thoracoabdominal aortic aneurysms. The evidence for thoracic endovascular aortic repair in MFS is much more limited. Small series and registry or case reports describe a heterogeneous group of patients with only short-term follow-up. Outcomes of endovascular repair are mixed, with questionable longevity. Reoperation is, however, common in MFS, and minimally invasive techniques may provide a bridging role or alternative solution when revisiting the hostile surgical field.

Abstract 2608: Alterations In Biomechnical Properties of Ascending Aorta in Marfan Syndrome by Real-time 2-D Ultrasound Speckle Tracking Imaging

Background : Thoracic aortic aneurysm and dissection (TAAD) is the leading cause of death in patients with Marfan syndrome (MFS) and other aortic disease (AD). The natural history of AD aries significantly. The size of the aorta alone does not always predict the risks of complications, such as catastrophic TAAD. Objectives : We sought to develop an ultrasound technique to quantitatively measure deformation of the ascending aorta (Ao) using a real-time 2-D ultrasound speckle tracking imaging (USTI) technique to investigate: alterations in biomechanical properties of AAo in MFS, and early and sensitive markers for TAAD for MFS. Methods: A total of 40 patients (MFS: n=18, age=11.4 ± 6.2 years, versus Control: n = 22, age=10.2 ± 4.3, p = 0.46) were prospectively enrolled. Real-time 2-D echocardiography was performed. The dimension of the AAo root (at the level of aortic annulus, sinus of Valsalva (SOV), sino-tubular junction and ascending aorta) was tracked and measured continuously in the cardiac cycle to derive the maximal and minimal systolic and diastolic dimensions using USTI (Philips Medical Systems). These measurements were used to yield dimensions, strain (deformation), strain rate (rate of deformation), distensibility, stiffness index and elastic modulus. Results: The results were summarized in Table 1 . Compared with controls, the MFS group had significantly enlarged dimension of the AAo root (P&lt;0.0001). In addition, the biomechanical properties were significantly altered, suggestive of reduced deformation, distensibility, elasticity and increased stiffness of the AAo root. Conclusions: This study demonstrated the feasibility of quantitative measurement of the biomechanical properties of the AAo in MFS using USTI. We have also shown significant deterioration of the biomechanical properties in MFS. Table 1. Biomechanical properties of AAO in MFS

Mechanical and Pharmacological Approaches to Investigate the Pathogenesis of Marfan Syndrome in the Abdominal Aorta

Background: Occurrence of disease complications in the abdominal aorta in Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1, is relatively rare. We hypothesized that Marfan syndrome could affect the structure, vasomotor function and mechanical property of the abdominal aorta. Methods and Results: Abdominal aorta from mice at 3, 6, 9 and 12 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1^C1039G/+, Marfan mice, n = 50), were compared with those from age-matched control littermates (n = 50). Marfan abdominal aorta demonstrated pronounced elastic fiber degradation and disorganization, concomitant with an increased aortic stiffness during aging. In the isometric force measurement, vasoconstriction in response to membrane depolarization or phenylephrine stimulation was similar in both Marfan and control abdominal aorta. However, Marfan abdominal aorta was less sensitive to the inhibition of the phenylephrine-induced contraction by indomethacin and SQ-29548, during which the release of thromboxane A₂ was one half of that of the controls. Nevertheless, the protein expression of cyclooxygenase-1 and cyclooxygenase-2 detected by Western immunoblotting was not different between the 2 strains. Conclusions: We demonstrated that Marfan syndrome affected abdominal aorta with respect to matrix elastic fiber organization, aortic stiffness and release of thromboxane A₂.

Imbalanced synthesis of cyclooxygenase‐derived thromboxane A2 and prostacyclin compromises vasomotor function of the thoracic aorta in Marfan syndrome

Thoracic aortic dissection is a life-threatening complication of Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1. We have demonstrated that nitric oxide-mediated endothelial-dependent relaxation is impaired in the thoracic aorta in Marfan syndrome. In the present study, we determined whether the cyclooxygenase (COX)-pathway is involved in the compromised aortic vasomotor function. Thoracic aortae from mice at 3, 6 and 9 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 (C1039G/+), 'Marfan', n=35), were compared with those from age-matched controls (n=35). Isometric force measurement revealed that preincubation with indomethacin, a non-specific COX inhibitor, but not valeryl salicylate, a specific COX-1 inhibitor, improved the phenylephrine-induced contractions (at 6 months, EC(50) and E(max) were increased 4.5-fold and by 45%, respectively) in Marfan aortae. Sensitivity to acetylcholine-induced relaxation was improved 10-fold. Blockade of the thromboxane-endoperoxide receptor by SQ-29548 did not affect phenylephrine-mediated contractions in Marfan aortae, although they did respond to the thromboxane analogue, U46619. From 6 months on, phenylephrine-induced secretion of prostacyclin and thromboxane A(2) in Marfan aortae was 200% and 40%, respectively, of those in controls. Reduced COX-1 expression was detected in Marfan aortae at 3 and 9 months, whilst COX-2 expression was increased from 3 months on. The compromised vasomotor function in Marfan thoracic aortae is associated with an imbalanced synthesis of thromboxane A(2) and prostacyclin resulting from the differential protein expression of COX-1 and COX-2.