Development Of Aortic Dilatation Research Articles

Prevalence and development of aortic dilation and dissection in women with Turner syndrome: a systematic review and meta-analysis

Objectives Women with Turner syndrome (TS) have an increased risk of aortic disease, reducing their life-expectancy. This study aimed to systematically review the prevalence of thoracic aortic dilatation, aortic dimensions and growth, and the incidence of aortic dissection in adult TS women. Methods A systematic literature search was conducted up to July 2022. Observational studies with an adult TS population were included, studies including children aged < 15 years old or a specific TS population were excluded. Results In total 21 studies were included. The pooled prevalence of ascending aortic dilatation was 23% (95%CI 19-26) at a mean pooled age of 29 years (95%CI 26-32), while the incidence of aortic dissection was 164 per 100.000 patient-years (95%CI 95-284). Three reporting studies showed aortic growth over time to be limited. Risk factors for aortic dilation or dissection were older age, bicuspid aortic valve, aortic coarctation and hypertension. Conclusion In adult women with TS, ascending aortic dilatation is common and the hazard of aortic dissection increased compared to the general population, whereas aortic growth is limited. Conventional risk markers do not explain all aortic dissection cases, therefore new imaging parameters and blood biomarkers are needed to improve prediction, allowing for patient-tailored follow-up and surgical decision making.

Preventive effect of beta-blockers in the development of aortic dilation in giant cell arteritis-related aortitis

ObjectivesTo analyze whether beta-blockers (BBs), in addition to conventional care, can decrease the risk of aortic dilation in giant-cell arteritis (GCA)-related aortitis. MethodsWe conducted in a single medical center retrospective study including 65 consecutive patients with GCA-related aortitis who all underwent aortic morphology control during follow-up. The impact of previous cardiovascular (CV) risk factors and/or events on BB prescription and on the risk for new aortic dilation was analyzed using a weighted (8-point maximum) score between 0 (i.e., 0/8 CV risk factors and events) and 1 (i.e., 8/8). ResultsAmong the 65 patients with GCA-related aortitis, 15 (23%) were taking BBs before GCA diagnosis and continued them thereafter. The vascular score was significantly higher in patients who received BBs (0.25 [0.125–0.625] vs. 0.125 [0–0.625] in patients without BBs, p < 0.0001). The median follow-up was 91 [25–163] months in GCA patients taking BBs and 61 [14–248] months in patients not taking BBs (p = 0.13). None of the patients taking BBs developed a new aortic dilation, whereas 15 (15/50; 30%) patients not taking BBs did (p = 0.01), as detected at a median time of 38 [6–120] months after the first imaging. Rates of other CV events during follow-up did not differ between the groups (p = 1). Conclusions: This study is the first to suggest that BBs in addition to conventional care in patients with GCA-related aortitis may help to prevent the risk of aortic dilation during follow-up. Larger-sized studies are required to confirm these results.

Association of immunological parameters with aortic dilatation in giant cell arteritis: a cross-sectional study

Aortic dilatation (AD) occurs in up to 30% of patients with giant cell arteritis (GCA). Reliable biomarkers for AD development, however, are still absent. The aim of this exploratory study was to evaluate whether immunological parameters are associated with the occurrence of AD in GCA. Cross-sectional study on 20 GCA patients with AD, 20 GCA patients without AD, and 20 non-GCA controls without AD measuring leukocytes, neutrophils, lymphocytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum amyloid A (SAA), interferon (IFN)-α, IFN-γ, IFN-γ-induced protein 10 (IP-10), interleukin (IL) 5, IL-8, IL-10, IL-17A, IL-18, IL-1 receptor antagonist, tumor necrosis factor (TNF)-α, platelet-derived growth factor (PDGF), L-selectin, P-selectin, and soluble intercellular adhesion molecule 1 (sICAM-1). AD was measured by aortic contrast-enhanced computed tomography and defined by enlargement of the aorta above population-based aortic diameters adjusted by age, gender, and body surface area. No significant differences were observed between GCA patients with AD and GCA patients without AD concerning levels of leukocytes, neutrophils, lymphocytes, CRP, ESR, SAA, IL-8, IL-18, PDGF, IP-10, selectins, and sICAM-1. Values of IFN-α, IFN-γ, IL-5, IL-10, IL-17A, IL-1 receptor antagonist, and TNF-α were all below the detection limits in more than 70% of subjects. Lymphocytes and CRP revealed positive correlations with the diameter of the thoracic descending aorta. Immunological parameters were not useful to conclude on the presence of AD in GCA. Further studies are required to test if CRP and lymphocytes may be useful to predict future development of AD in GCA.

Aortic dilation and growth in women with Turner syndrome

ObjectiveWomen with Turner syndrome (TS) are at increased risk of aortic dissection, which is a life-threatening event associated with aortic dilation. Knowledge on the development of aortic dilation over time...

A computational analysis of potential aortic dilation induced by the hemodynamic effects of bicuspid aortic valve phenotypes

Background and objectivesThe bicuspid aortic valve (BAV) is a major risk factor for the progression of aortic dilation (AD) because of the induced abnormal blood flow environment in aorta. The differences in the development of AD induced by BAV phenotypes remains unclear. Therefore, the objective of this study was to assess the potential locations of AD induced by different phenotypes of BAV. The different effects of opening orifice area and leaflet orientation on ascending aortic hemodynamics in Type-1 BAV was investigated by means of numerical simulation. MethodsFinite element dynamic analysis was performed on tricuspid aortic valve (TAV) and BAV models to simulate the motion of the leaflets and obtain the geometrical characteristics of AV at peak systole as a reference, which were used for aortic models. Then, four sets of aortic fluid models were designed according to the leaflet fusion types [TAV; BAV (left-right-coronary cusp fusion, LR; right-non-coronary cusp fusion, RN; left-non-coronary cusp fusion, LN)], and the computational fluid dynamics method was applied to compare the hemodynamic differences within the aorta at peak systole. ResultsThe maximum opening area of BAV was significantly reduced, resulting in alterations in aortic hemodynamics compared with TAV. The velocity streamlines were essentially parallel to the aortic wall in TAV. The average pressure and wall shear stress in aorta tend to be stable. In contrary, the eccentricity of BAV orifice jet resulted in high-velocity flow directed toward the ascending aorta (AA) wall and aortic arch for LR and LN; RN features an asymmetrical velocity distribution toward the outer bend of the middle AA, and eccentric flow tends to impact the distal AA. As the flow angle is associated with distinct flow impingement locations, different degrees of WSS and pressure concentration occur along the aortic wall from the AA to the aortic arch in three BAV types. ConclusionsThe BAV morphotype affects the aortic hemodynamics, and the abnormal blood flow associated with BAV may play a role in AD. The different BAV phenotypes determine the direction of blood flow jet and change the expression of dilation. LR is likely to cause dilation of the tubular AA; RN results in dilation of the middle AA to proximal aortic arch; and LN causes an increased incidence of the tubular AA and the proximal aortic arch.

Different patterns and specific outcomes of large-vessel involvements in giant cell arteritis

Large-vessel involvement (LVI) in giant cell arteritis (GCA) includes different clinical and imaging patterns that are rarely described separately at diagnosis and whose specific cardiovascular outcomes are unknown.We conducted a nationwide retrospective study and included GCA patients with LVI demonstrated on imaging at diagnosis between 2007 and 2017. We analyzed the prognosis of three different imaging patterns of LVI present at diagnosis, with some of them overlapping but with the first one present in all patients: 1) inflammation of the aorta and/or its branches; 2) dilation of the aorta; and 3) stenosis of the aortic branches. A control group of GCA patients without LVI was constituted.We included 183 patients with LVI and 105 controls without LVI. Altogether, among the 183 patients who all showed inflammation of the aorta and/or its main branches, concomitant aortic dilation and large-vessel stenosis were observed in 27 (15%) and 55 (30%) patients, respectively. During the follow-up period, new cardiovascular events occurred in 49% and 11% of LVI patients and controls, respectively (p < 0.0001). Inflammation of the aorta and/or its branches (HR: 3.42 [2.09–5.83], p < 0.0001) and large-artery stenosis (HR: 2.75 [1.80–4.15], p < 0.0001) were independent predictive factors of new cardiovascular events. Conversely, the use of an immunosuppressant besides corticosteroids was a protective factor against new cardiovascular events (HR: 0.44 [0.29–0.66], p < 0.0001) and the development of aortic dilation (HR: 0.43 [0.23–0.77], p = 0.005).This study suggests different forms of cardiovascular events according to the initial imaging pattern of LVI.

Enlightening the Association between Bicuspid Aortic Valve and Aortopathy.

Bicuspid aortic valve (BAV) patients have an increased incidence of developing aortic dilation. Despite its importance, the pathogenesis of aortopathy in BAV is still largely undetermined. Nowadays, intense focus falls both on BAV morphology and progression of valvular dysfunction and on the development of aortic dilation. However, less is known about the relationship between aortic valve morphology and aortic dilation. A better understanding of the molecular pathways involved in the homeostasis of the aortic wall, including the extracellular matrix, the plasticity of the vascular smooth cells, TGFβ signaling, and epigenetic dysregulation, is key to enlighten the mechanisms underpinning BAV-aortopathy development and progression. To date, there are two main theories on this subject, i.e., the genetic and the hemodynamic theory, with an ongoing debate over the pathogenesis of BAV-aortopathy. Furthermore, the lack of early detection biomarkers leads to challenges in the management of patients affected by BAV-aortopathy. Here, we critically review the current knowledge on the driving mechanisms of BAV-aortopathy together with the current clinical management and lack of available biomarkers allowing for early detection and better treatment optimization.

Impaired aortic distensibility and elevated central blood pressure in Turner Syndrome: a cardiovascular magnetic resonance study

BackgroundWomen with Turner Syndrome have an increased risk for aortic dissection. Arterial stiffening is a risk factor for aortic dilatation and dissection. Here we investigate if arterial stiffening can be observed in Turner Syndrome patients and is an initial step in the development of aortic dilatation and subsequent dissection.MethodsFifty-seven women with Turner Syndrome (48 years [29–66]) and thirty-six age- and sex-matched controls (49 years [26–68]) were included. Distensibility, blood pressure, carotid-femoral pulse wave velocity (PWV), the augmentation index (Aix) and central blood pressure were determined using cardiovascular magnetic resonance, a 24-h blood pressure measurement and applanation tonometry. Aortic distensibility was determined at three locations: ascending aorta, transverse aortic arch, and descending aorta.ResultsMean aortic distensibility in the descending aorta was significantly lower in Turner Syndrome compared to healthy controls (P = 0.02), however, this was due to a much lower distensibility among Turner Syndrome with coarctation, while Turner Syndrome without coarctation had similar distensibility as controls. Both the mean heart rate adjusted Aix (31.4% vs. 24.4%; P = 0.02) and central diastolic blood pressure (78.8 mmHg vs. 73.7 mmHg; P = 0.02) were higher in Turner Syndrome compared to controls, and these indices correlated significantly with ambulatory night-time diastolic blood pressure. The presence of aortic coarctation (r = − 0.44, P = 0.005) and a higher central systolic blood pressure (r = − 0.34, P = 0.03), age and presence of diabetes were inversely correlated with aortic distensibility in TS.ConclusionAortic wall function in the descending aorta is impaired in Turner Syndrome with lower distensibility among those with coarctation of the aorta, and among all Turner Syndrome higher Aix, and elevated central diastolic blood pressure when compared to sex- and age-matched controls.Trial registrationThe study was registered at ClinicalTrials.gov (#NCT01678274) on September 3, 2012.

Influence of the Sievers type and valvular functional impairment in bicuspid associated aortopathy in a prospective series

Bicuspid aortic valve (BAV) is associated with high incidence of ascending aortic aneurysm. In BAV sporadic form, changes in outflow's hemodynamic secondary to the valvular morphotype are said to play a prominent role in the aortic dilatation. We aimed at comparing the different ascending aorta segment diameters according to the morphotype and the function of the BAV. We evaluated 174 patients with sporadic BAV by transthoracic echocardiography. The valvular function was defined as either Aortic Insufficiency (AI) if Grade ≥ 2 and aortic Stenosis (AS) if mean gradient > 20 mmHg. Aortic diameters were measured at the Valsalva sinus, tubular ascending aorta and at the aortic arch. Kruskal-Wallis, Mann–Whitney and Spearman tests were used for comparisons. Among the non-operated patients, Sievers’ morphotype was type 1LR for 63%, type 1NR for 18%, and other types counted for 19%. The Valsalva sinus diameter did not differ according to the Sievers’ type ( P = 0.78). The type 1LR type compared to the type1NR appeared to have a wider tubular aorta, but not significantly (42.3 ± 8.5 vs. 36.4 ± 7.3 mm; P = 0.06). Aortic valve function was distributed as follows: AI: 39%, AS: 20%, Both: 9%, Normal: 32%. Comparison of the different valve dysfunctions revealed a difference at the Valsalva ( P < 10–4) and the tubular aorta ( P = 0.001) but not at the aortic arch level ( P = 0.62). AI was highly associated with an increase of the aortic diameters of any segment, excepting for the arch. In addition, aortic diameters increased with age in case of AI (Valsalva: r = 0.28; P = 0.02; Tubular aorta: r = 0.27; P = 0.02) and not in case of AS ( r = –0.06; P = 0.73 and r = –0.03; P = 0.84). Our results showed the tremendous role of AI in the aortic dilation of all segments except the arch. However no influence of BAV morphotype was noticed on aortic diameters. Our results give rise to the relatively limited influence of the valvular morphology in the development of aortic dilation.

Systolic flow displacement using 3D magnetic resonance imaging in an experimental model of ascending aorta aneurysm: impact of rheological factors.

The impact of systolic flow displacement on the development and progression of ascending aorta dilatation in aortic valve disease is a matter of controversy. Our objective was to study the association between rheological stimuli and development of aortic dilatation in a large animal model of supravalvular aortic stenosis and eccentric flow. Twenty-four pigs weighing 10-14 kg were randomly allocated (ratio 2:1) to either restrictive ascending aortic banding or sham operation. Aortic diameter and systolic flow displacement were assessed by three-dimensional phase-contrast magnetic resonance imaging at 6 and 18 weeks after surgery. Twenty pigs (n = 14, banded vs n = 6, sham) completed full imaging protocol and were included in the analysis. After the last follow-up, a subset of 14 animals was sacrificed for histological analysis. All banded animals developed significant progressive aortic dilatation both at 6 and 18 weeks, compared with sham-operated pigs: 34.3 ± 4.8 vs 21.4 ± 2.7 mm at 6 weeks (P < 0.001); and 50.0 ± 8.4 vs 38.0 ± 8.3 mm at 18 weeks (P = 0.002). The peak gradient at 6 weeks showed a trend to positively correlate with aortic diameter at 18 weeks (R = 0.50, P = 0.06), whereas the systolic flow displacement at 6 weeks correlated better with aortic diameter at 18 weeks (R = 0.59, P = 0.02). The aortic wall thickness was significantly decreased in the anterior aortic section in banded, compared with sham-operated, pigs (1.5 ± 0.4 vs 2.0 ± 0.1 mm, respectively; P = 0.03). In addition, banded pigs showed a higher degree of cystic medial necrosis and elastin fibre fragmentation, compared with sham-operated animals. In this preclinical model of supravalvular aortic stenosis and eccentric flow, we found that systolic flow displacement at earlier stages is positively correlated with the degree of aortic dilatation during follow-up as assessed by three-dimensional phase-contrast magnetic resonance imaging. If our findings are confirmed in further studies, this imaging parameter might be useful to identify those subjects with aortic valve disease who are at risk of developing aortic dilatation at a later stage.

FRI0477 Outcome of Large-Vessel Involvement in GIANT Cell Arteritis after 1-Year of Glucocorticoid Treatment: Prospective Study Using Computed Tompography Angiography

BackgroundIn a previous study, computed tomography angiography (CTA) disclosed signs of large-vessel vasculitis (LVV) in 67.5% of giant cell arteritis (GCA) patients at the time of diagnosis. Moreover, 15% of...

GATA5 and Endothelial Nitric Oxide Synthase Expression in the Ascending Aorta Is Related to Aortic Size and Valve Morphology

The pathogenesis of aortic dilatation in patients with congenital aortic valve anomalies is poorly understood. Recent studies suggest that alterations of gene expression may be related to ascending aortic aneurysm formation in these patients. Knockout of endothelial nitric oxide synthase (eNOS) and GATA5 is associated with bicuspid aortic valves in mice. To study the role of eNOS and GATA5 in human congenital aortic valve disease and aortic dilatation, we investigated their gene expression in aortic tissue from patients with unicuspid, bicuspid, and tricuspid aortic valves. Samples from 84 patients (33 tricuspid, 32bicuspid, and 19 unicuspid) were harvested intraoperatively from the ascending aorta. GATA5 and eNOS expression was determined by real-time polymerase chain reaction. GATA5 and eNOS expression in the aortic wall from patients with unicuspid aortic valves (GATA5: mean [M], 2.14; standard deviation [SD], 1.72; eNOS: M, 3.40; SD, 3.83) was significantly higher than in tricuspid aortic valves (GATA5: M, 1.12; SD, 0.80; eNOS: M, 1.00; SD, 0.74; each p < 0.05). Patients with bicuspid aortic valves (GATA5: M, 1.29, SD, 1.33; eNOS: M, 1.66; SD, 1.31) had a significantly higher eNOS expression than patients with tricuspid aortic valves (p < 0.05). The expression levels of eNOS and GATA5 correlated positively with each other and negatively with the ascending aortic diameter. Our data suggest that GATA5, possibly through upregulation of eNOS, plays a role in the development of aortic dilatation in patients with unicuspid and bicuspid aortic valves. The differential gene expression in patients with unicuspid compared with bicuspid aortic valves suggests that the pathogenesis of both aortic valve anomalies may be different.

Wall shear stress and flow patterns in the ascending aorta in patients with bicuspid aortic valves differ significantly from tricuspid aortic valves: a prospective study

We compared flow and wall shear stress (WSS) patterns in the ascending aorta of individuals with either bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV) using four-dimensional cardiovascular magnetic resonance (4D-CMR). BAV are known to be associated with dilation and dissection of the ascending aorta. However, the cause of vessel disease in patients with BAVs is unknown. Inborn connective tissue disease and also dilation secondary to increased WSS because of altered blood flow patterns in the ascending aorta are discussed as causes for dilation of the aorta. WSS can be estimated non-invasively by 4D-CMR. Eighteen, otherwise, healthy individuals with functionally normal BAVs were compared prospectively with an age- and sex-matched control group of healthy individuals with TAV. Blood flow data were obtained by 4D-CMR visualization and WSS was calculated with specific software tools. Eighty-five per cent of the individuals with BAVs showed a high-grade helical flow pattern in the ascending aorta compared with 6% of the individuals with TAV. WSS in the ascending aorta was significantly altered in individuals with BAVs compared with TAV. WSS and flow patterns in the ascending aorta in patients with BAVs without concomitant valve or vessel disease are significantly different compared with TAV. The significantly higher shear forces may have an impact on the development of aortic dilation in patients with BAVs.

4-dimensional flow patterns in the ascending aorta differ strongly between bicuspid and tricuspid aortic valves

Objectives: Bicuspid aortic valves (BAV) and their associated complications often require both replacement of the aortic valve and the ascending aorta (AAo). The etiology of aortic wall disease, however, is unknown. It is controversial if either a genetic tissue defect or vessel disease secondary to altered blood flow is the underlying reason. This study compared flow patterns in the AAo of BAV patients to individuals with tricuspid aortic valve (TAV) using four-dimensional cardiovascular magnetic resonance (4D-CMR). Methods: Eighteen subjects with normally functioning BAV, without stenosis, regurgitation or aortic dilation were compared with 18 age and sex matched volunteers with TAV. 4D blood flow data of the AAo were obtained by CMR (spatial resolution=2.1×1.7×2.5mm3, temporal resolution=39.2ms). Derived 4D flow animations were then evaluated by three independent and blinded observers. Results: Abnormal helical flow in the AAo was seen in 85% of the BAV group (figure 1). In TAV altered flow was only found in 6%. Comparison of 4D flow patterns revealed a significant difference between BAV and TAV (p=0.0004). Conclusions: Patients with BAV but no concomitant valve disease have significantly different 4D flow patterns compared to patients with TAV. This altered flow may lead to increased stress upon the wall and thereby heavily impact the development of aortic dilation in BAV. These findings suggest that connective tissue defects may only be a secondary finding in these patients and aortic root replacement should not generally be performed.

Urokinase-type plasminogen activator deficiency in bone marrow-derived cells augments rupture of angiotensin II-induced abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) are associated with fragmentation of extracellular matrix during development of aortic dilation and rupture. Therefore, it is important to identify specific protease systems involved in extracellular matrix degradation during AAA formation. The present study determined the contribution of the urokinase system to AAA formation and rupture. Angiotensin II (Ang II)-induced AAAs were associated with increased aortic abundance of both urokinase-type plasminogen activator receptor (uPAR) and urokinase-type plasminogen activator (uPA) proteins. However, this increased presence was unrelated to AAA formation because deficiencies of either uPAR or uPA had no effect on either the incidence or size of Ang II-induced AAAs in both normolipidemic mice and low-density lipoprotein receptor-/- mice fed a saturated fat-enriched diet. Although uPA deficiency did not affect development of AAAs, there was an effect of increasing mortality rate from AAA rupture in hypercholesterolemic mice. Bone marrow transplantation demonstrated that enhanced aneurysmal rupture was attributable to deficiency of uPA in leukocytes. uPA deficiency led to an increased propensity for impaired resolution of the thrombotic material within the aneurysmal tissue. Neither uPAR nor uPA deficiency had any effect on Ang II-induced atherosclerosis in low-density lipoprotein receptor-/- mice. The uPA-uPAR axis has no effect on the formation of Ang II-induced AAAs, but uPA deficiency promotes aneurysmal rupture.

Visualization of flow in the ascending aorta: bicuspid aortic valves compared to tricuspid aortic valves

Bicuspid aortic valves (BAV) are frequently associated with dilation of the ascending aorta (AAo). Two opposing hypotheses advocate either an inborn connective tissue defect or dilation secondary to altered blood flow in the AAo. This study was initiated to evaluate flow patterns in the AAo of BAV patients compared to those in persons with tricuspid aortic valve (TAV) using four-dimensional cardiovascular magnetic resonance (CMR). 18 healthy individuals with normally functioning BAV were compared with an age and sex matched control group with tricuspid aortic valve (TAV). Classification of flow alterations was performed by three blinded observers concerning their intensity. Flow patterns in the matched pairs were significantly different (p=0.0004). This altered flow may have an important impact on the development of aortic dilation in patients with BAV. The connective tissue defect may only be a secondary finding in these patients.

RETRACTED: A role for plasma transforming growth factor-β and matrix metalloproteinases in aortic aneurysm surveillance in Marfan syndrome?

We have previously shown that the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced aortic diameter by 3-7mm in Marfan syndrome (MFS) patients. Excessive signalling by the transforming growth factor-beta (TGF-beta) has been implicated in the development of aortic dilatation. We hypothesised that reduction in aortic diameter would correlate with reduction in plasma TGF-beta and matrix metalloproteinase (MMP) levels. 17 MFS patients (aged 33+/-5 (mean+/-SD)) on standard beta-blocker therapy were randomised to also receive perindopril (n=10) or placebo (n=7) for 24 weeks in a double blind study. Aortic root diameters were assessed at four sites via transthoracic echocardiography. Venous blood samples were analysed for latent and active TGF-beta, MMP-2 and MMP-3 levels. Perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (by 1.2-3mm/m(2), p<0.001). In addition, compared to placebo perindopril significantly reduced latent TGF-beta levels by 14.0+/-4.5ng/ml (p=0.01), active TGF-beta levels by 4+/-1ng/ml (p=0.02), MMP-2 levels by 22+/-6ng/ml (p<0.001), and MMP-3 levels by 5+/-1ng/ml (p<0.001). There were moderately strong correlations between the pre/post intervention change in aortic diameters and the change in both latent (r=0.49-0.76, p=0.001-0.04) and active TGF-beta (r=0.59-0.73, p=0.002-0.02), MMP-2 (r=0.63-0.75, p=0.001-0.007), and MMP-3 plasma levels (r=0.81-0.83, p<0.0001). Plasma TGF-beta, MMP-2 and MMP-3 should be further explored in longitudinal trials as potential prognostic indicators of progression of aortic dilatation and response to therapy in MFS.

Basal lamina structural alterations in human asymmetric aneurismatic aorta

Basal lamina (BL) is a crucial mechanical and functional component of blood vessels, constituting a sensor of extracellular microenvironment for endothelial cells and pericytes. Recently, an abnormality in the process of matrix microfibrillar component remodeling has been advocated as a mechanism involved in the development of aortic dilation. We focused our attention on BL composition and organization and studied some of the main components of the Extracellular Matrix such as Tenascin, Laminins, Fibronectin, type I, III and IV Collagens. We used surgical fragments from 27 patients, submitted to operation because of aortic root aneurysm and 5 normal aortic wall specimens from heart donors without any evidence for aneurysmal or atherosclerotic diseases of the aorta. Two samples of aortic wall were harvested from each patient, proximal to the sinotubular junction at the aortic convexity and concavity. Each specimen was processed both for immunohistochemical examination and molecular biology study. We compared the convexity of each aortic sample with the concavity of the same vessel, and both of them with the control samples. The synthesis of mRNA and the levels of each protein were assessed, respectively, by RT-PCR and Western Blot analysis. Immunohistochemistry elucidated the organization of BL, whose composition was revealed by molecular biology. All pathological samples showed a wall thinner than normal ones. Basal lamina of the aortic wall evidentiated important changes in the tridimensional arrangement of its major components which lost their regular arrangement in pathological specimens. Collagen I, Laminin alpha2 chain and Fibronectin amounts decreased in pathological samples, while type IV Collagen and Tenascin synthesis increased. Consistently with the common macroscopic observation that ascending aorta dilations tend to expand asymmetrically, with prevalent involvement of the vessel convexity and relative sparing of the concavity, Collagen type IV is more evident in the concavity and Tenascin in the convexity.

Abstract 2958: Perindopril Reduces Large Artery Stiffness and Left Ventricular Outflow Tract Diameter in Patients with Marfan syndrome

Introduction: Aortic stiffness is elevated in Marfan syndrome (MFS) contributing to aortic dilatation and rupture, the major cause of premature death in this population. Excessive signalling by the transforming growth factor-β(TGFβ) plays a crucial role in the development of aortic dilatation. Hypothesis: Given the known beneficial effects of angiotensin converting enzyme (ACE) inhibitors on arterial stiffness, we hypothesised that perindopril therapy would reduce aortic stiffness and attenuate aortic dilatation in MFS patients, possibly through effects on TGFβ signalling. Methods: 17 MFS patients (aged 33 ± 5) on standard β-blocker therapy were randomised to also receive perindopril (8mg od, n=10) or placebo (n=7) for 24 weeks in a double blind study. Indices of arterial stiffness were assessed globally via systemic arterial compliance (SAC) and augmentation index (AIx), and regionally via central (PWVc) and peripheral (PWVp) pulse wave velocity. Left ventricular outflow tract (LVOT) diameter was assessed via a transthoracic echocardiogram. Venous blood samples were analysed for latent and active TGFβ levels using ELISA. Results: Perindopril reduced arterial stiffness as indicated by increased SAC (perindopril 62 ± 11% vs placebo -4.30 ± 1%, p&lt;0.0001), reduced AIx (perindopril -23.50 ± 3% vs placebo 3 ± 1%, p&lt;0.0001), reduced PWVc (perindopril -21 ± 2% vs placebo 5 ± 2%, p&lt;0.0001) and PWVp (perindopril -20 ± 2% vs placebo 2 ± 1%, p&lt;0.0001). In addition, perindopril significantly reduced LVOT diameter (perindopril -2.8 ± 0.4mm vs placebo 1.1 ± 0.3mm, p&lt;0.0001). While perindopril marginally reduced mean arterial blood pressure (perindopril -1.3 ± 0.2mmHg vs placebo 0.2 ± 0.5mmHg, p=0.004), importantly, the observed changes in both stiffness (p=0.001– 0.006) and LVOT diameter (p&lt;0.001) remained significant when mean blood pressure was included as a covariate. Finally, perindopril reduced latent TGFβ levels by -14.0 ± 4.5ng/ml when compared to placebo (2.0 ± 2.3ng/ml, p=0.01), and active TGFβ levels by -4 ± 1ng/ml (placebo 3 ± 1 ng/ml, p=0.02). Conclusions: In conclusion, ACE inhibition reduces aortic stiffness and LVOT diameter in MFS patients possibly through attenuation of TGFβsignalling, and may potentially protect against aortic rupture.