Molecular phenotyping and functional assessment of smooth muscle-like cells with pathogenic variants in aneurysm genes ACTA2, MYH11, SMAD3 and FBN1.

Aortic aneurysms (AAs) are pathological dilatations of the aorta. Pathogenic variants in genes encoding for proteins of the contractile machinery of vascular smooth muscle cells (VSMCs), genes encoding proteins of the transforming growth factor beta signaling pathway and extracellular matrix (ECM) homeostasis play a role in the weakening of the aortic wall. These variants affect the functioning of VSMC, the predominant cell type in the aorta. Many variants have unknown clinical significance, with unknown consequences on VSMC function and AA development. Our goal was to develop functional assays that show the effects of pathogenic variants in aneurysm-related genes. We used a previously developed fibroblast transdifferentiation protocol to induce VSMC-like cells, which are used for all assays. We compared transdifferentiated VSMC-like cells of patients with a pathogenic variant in genes encoding for components of VSMC contraction (ACTA2, MYH11), transforming growth factor beta (TGFß) signaling (SMAD3) and a dominant negative (DN) and two haploinsufficient variants in the ECM elastic laminae (FBN1) to those of healthy controls. The transdifferentiation efficiency, structural integrity of the cytoskeleton, TGFß signaling profile, migration velocity and maximum contraction were measured. Transdifferentiation efficiency was strongly reduced in SMAD3 and FBN1 DN patients. ACTA2 and FBN1 DN cells showed a decrease in SMAD2 phosphorylation. Migration velocity was impaired for ACTA2 and MYH11 cells. ACTA2 cells showed reduced contractility. In conclusion, these assays for showing effects of pathogenic variants may be promising tools to help reclassification of variants of unknown clinical significance in AA-related genes.

Epidemiology and management of aortic disease: aortic aneurysms and acute aortic syndromes.

The aorta is the 'greatest artery', through which oxygenated blood is delivered from the left ventricle to end organs with each cardiac cycle (200 million litres of blood transported in an average lifetime). The aorta can be affected by a wide spectrum of acute factors (such as cocaine use, weight lifting and trauma) and chronic acquired and/or genetic conditions (such as systemic arterial hypertension and phaeochromocytoma), which variously lead to increased aortic wall stress. The medial layer of the aorta can also be subject to abnormalities (such as Marfan syndrome, bicuspid aortic valve, inflammatory vasculitis, atherosclerosis and infections). Despite important advances in diagnostic and therapeutic interventions, data derived from registries and population-based studies highlight that the burden of aortic diseases remains high. Therefore, specific resources need to be allocated to design and implement preventive strategies (healthy lifestyles, modifications to cardiovascular risk factors, and educational and screening programmes) at individual and community levels. In this Review, we discuss the epidemiology, management and outcomes of the most common aortic diseases, namely, aortic aneurysms and acute aortic syndromes.

Patient-specific assessment of hemodynamics by computational fluid dynamics in patients with bicuspid aortopathy.

OBJECTIVE: Hemodynamics related to eccentric blood flow may factor into the development of bicuspid aortic valve aortopathy. We investigated wall shear stress distribution by means of magnetic resonance imaging-based computational fluid dynamics in patients with a bicuspid aortic valve. METHODS: Included were 12 patients with a bicuspid aortic valve (aortic stenosis, n = 11; root enlargement, n = 1). Three patients with a normal tricuspid aortic valve (arch aneurysm, n = 1; descending aortic aneurysm, n = 2) were included for comparison. The thoracic aorta geometry was reconstructed by means of 3-dimensional computed tomography angiography, and the bicuspid aortic valve orifice was modeled. Flow rates at the sinotubular junction and 3 aortic branches were measured at various time points by cine phase-contrast magnetic resonance imaging to define boundary conditions for computational fluid dynamics, and the flow was simulated. RESULTS: Bicuspid aortic valve cusp configurations were type 0 lateral (n = 4), type 0 anterior-posterior (n = 2), type 1 L-R (n = 4), and type 1 R-N (n = 2). Abnormal aortic helical flow was seen in the ascending aorta and transverse arch in all patients with bicuspid aortic valves and was right handed in 11 patients (91%). No such flow was seen in the patients with tricuspid aortic valves. The patients with bicuspid aortic valves were likely to have jet flow/wall impingement against the greater curvature of the proximal ascending aorta, resulting in remarkably increased wall shear stress around the impingement area. CONCLUSIONS: Computational fluid dynamics simulation is useful for precise evaluation of hemodynamics related to bicuspid aortic valve aortopathy. Such evaluation will advance our understanding of the disease pathophysiology and may facilitate molecular biological investigation.

Rationale and design of GISSI OUTLIERS VAR Study in bicuspid aortic valve patients: prospective longitudinal, multicenter study to investigate correlation between surgical, echo distinctive features, histologic and genetic findings in phenotypically homogeneous outlier cases.

BACKGROUND/OBJECTIVES: Bicuspid aortic valve (BAV) is the most common congenital heart disorder, affecting up to 2% of the population. Involvement of aortic root and ascending aorta (aneurysm or, eventually, dissection) is frequent in patients with pathologic or normal functioning BAV. Unfortunately, there are no well-known correlations between valvular and vascular diseases. In VAR protocol, with a new strategy of research, we analysemultiple aspects of BAV disease through correlation between surgical, echo, histologic and genetic findings in phenotypically homogeneous outlier cases. METHODS: VAR protocol is a prospective, longitudinal, multicenter study. It observes 4 homogeneous small groups of BAV surgical patients (15 patients each): isolated aortic regurgitation, isolated ascending aortic aneurysm, aortic regurgitation associated with aortic aneurysm, isolated aortic stenosis in older patients (>60years). Echo analysis is extended to first-degree relatives and, in case of BAV, genetic test is performed. Patients and relatives are enrolled in 10 cardiac surgery/cardiologic centers throughout Italy. CONCLUSIONS: The aim of the study is to identify predictors of favorable or unfavorable evolution of BAV in terms of valvular dysfunction and/or aortic aneurysm. Correlations between different features could help in identification of various BAV risk groups, rationalizing follow-up and treatment.

Incidence, Management, and Immediate- and Long-Term Outcomes After Iatrogenic Aortic Dissection During Diagnostic or Interventional Coronary Procedures.

BACKGROUND: Aortic dissection type A is a disease with high mortality. Iatrogenic aortic dissection after interventional procedures is infrequent, and prognostic data are scarce. Our objective was to analyze its incidence, patient profile, and long-term prognosis. METHODS AND RESULTS: Between 2000 and 2014, we retrospectively analyzed 74 patients with dissection of the ascending aorta. Clinical and procedural data were reviewed, and later, we performed a prospective clinical follow-up by telephone or in the office. The incidence of aortic dissection was 0.06%. Our patients, predominantly male (67.6%), had a mean age of 66.9±10.8 years. With multiple cardiovascular risk factors, the main reason for cardiac catheterization was an acute coronary syndrome (n=54). The complication was detected acutely in all, trying to engage the right coronary artery in 47 and the left main artery in 30 and after other maneuvers in 2, mostly complex therapeutic procedures (78.4%). A coronary artery was involved in 45 patients (60.8%). Thirty-five patients underwent an angioplasty and stent implantation; 3 had cardiac surgery; and 36 were managed conservatively. Two patients died of cardiogenic shock after the dissection. After a median follow-up of 51.2 months (range, 16.4-104.8 months), none of the remaining patients developed complications as a result of the dissection, progression, ischemia, pain, or dissection recurrence. CONCLUSIONS: Iatrogenic catheter dissection of the aorta is a rare complication that carries an excellent short- and long-term prognosis with the adoption of a conservative approach. When a coronary artery is involved as an entry point, it usually can be safely sealed with a stent with good long-term outcomes.

Impact of aortic aneurysm on hospitalizations in patients with marfan syndrome: a multi-institutional study.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder affecting 1 in 3,000 people. Cardiovascular involvement is a prominent feature of MFS, with aortic dissection and/or rupture being the leading cause of death. Advances in the medical and surgical care of patients with MFS have improved survival. Hospital resource utilization and outcomes have not been evaluated in a large population of patients with MFS. We sought to analyze pediatric hospital resource utilization and outcomes in patients with MFS. Nationally distributed data from 43 pediatric hospitals in the 2004-2011 Pediatric Health Information System database were used to identify patients admitted to the hospital with International Classification of Diseases-9th Revision codes for a diagnosis of MFS. Aortic aneurysm (AA) with or without dissection, length of stay (LOS), and hospital charges were determined. During the study period, there were 1,978 admissions in 1,228 patients with MFS. AA was present in 217 (11%) admissions in 188 (15%) patients (63% male). Mean age of patients with AA was 13.8 ± 5.9 years. Aortic dissection or rupture was present in 15 (7% with AA) admissions in 15 (8% with AA) patients (mean age 15.7 ± 5.2 years). Other cardiac diagnoses occurred more commonly in the AA cohort (p < 0.0001), regardless of the reason for admission. Cardiothoracic surgical procedures were performed in 116 AA admissions (53%). Mean LOS, hospital charges per admission, and charges per day were significantly higher in AA cohort compared to those without AA. In-hospital mortality for AA was 2%. The presence of AA in patients with MFS increases hospital resource utilization. Cardiothoracic surgeries are commonly performed in this cohort. Other cardiovascular diagnoses are more prevalent in patients with AA suggesting a more severe phenotype.

4D flow CMR in assessment of valve-related ascending aortic disease.

Blood flow imaging with 3-dimensional time-resolved, phase-contrast cardiac magnetic resonance (4-dimensional [4D] Flow) is an innovative and visually appealing method for studying cardiovascular disease that allows quantification of important secondary vascular parameters including wall shear stress. The hypothesis of this pilot study is that 4D Flow will become a powerful tool for characterizing the relationship of aortic valve-related flow dynamics, especially with bicuspid aortic valve (BAV), and progression of ascending aortic (AsAo) dilation. We identified 46 patients previously studied with 4D Flow: tricuspid aortic valve patients without valvular disease (n = 20), and BAV patients with either normal flow (n = 7) or eccentric systolic jets resulting in abnormal right-handed helical AsAo flow (n = 19). The subgroup of patients with BAV and eccentric systolic AsAo blood flow was found to have significantly and asymmetrically elevated wall shear stress. This increased hemodynamic burden may place them at risk for AsAo aneurysm.

Balloon expandable stent implantation for native and recurrent coarctation of the aorta--prospective computed tomography assessment of stent integrity, aneurysm formation and stenosis relief.

BACKGROUND: Stenting for aortic coarctation is known to be effective in the medium term. Aneurysm formation following stent implantation is a recognised complication. However, data regarding aortic wall injury and stent integrity following stent placement are sparse. OBJECTIVES: We report comprehensive clinical, echocardiographic and prospective CT follow-up data following stenting for aortic coarctation from a single centre. Methods Full data analysis of all patients undergoing balloon expandable stent implantation and follow-up procedures in a single tertiary congenital cardiac unit. RESULTS: Between October 2002 and April 2008, we performed 102 coarctation stent procedures on 88 patients. Median age was 20.6 years (range 8.5-65) and median weight 65 kg (range 34-101). 94 stents (26 covered) were implanted. 12 procedures were re-dilatations. Stenting resulted in a reduction of the gradient across the site of coarctation, from a median of 20 mm Hg to 4 mm Hg. There were no procedure-related deaths. Four patients had immediate complications (one requiring emergency surgery). During median follow-up of 34.5 months (range 4.2-72.8), two patients had late complications requiring additional stent procedures. Follow-up CT data are available in 84 patients with MRI in one patient (96.5%). Only one patient developed a procedure-related aortic aneurysm. All stent fractures (n=7) occurred with a single stent design. CONCLUSIONS: Stenting for aortic coarctation and re-coarctation is effective with low immediate complication rates. CT is useful in the longer term for assessment of stent integrity and post-procedural aneurysm formation. Overall incidence of post-procedural aneurysm is rare and stent fractures were not seen with newer generation stents.

Pregnancy in Marfan syndrome: maternal and fetal risk and recommendations for patient assessment and management.

Pregnancy in women with the Marfan syndrome (MFS) is associated with the potential for a catastrophic and even fatal acute aortic dissection and the risk of having a child who will inherit the syndrome. The approach to pregnancy in patients with MFS is therefore challenging and deserves special considerations. This article presents an extensive review of available clinical information and provides recommendations for the management of patients with MFS during pregnancy.

Aorta and aortic valve morphologies predisposing to aortic dissection. An in vivo assessment with transoesophageal echocardiography.

Predisposing factors for aortic dissection are well known from necropsy series. To evaluate the frequency of aortic and aortic valve disease in aortic dissection in vivo, 139 patients with acute aortic dissection (96 men, 43 women, mean age 60.5 +/- 15.7 years) were studied by transoesophageal echocardiography (TEE) using 3.5 and 5.0 MHz transducers. Left ventricular hypertrophy by TEE, defined as an end-diastolic wall thickness of the left ventricular septal wall over 1.5 cm, was found in 42 (67.7%) of 62 patients with type I, in 10 (58.8%) of 17 patients with type II and in 46 (76.7%) of 60 patients with type III dissection. The mean value for the aortic root diameter was 3.2 +/- 1.3 cm.m-2 in type I dissection and 2.8 +/- 0.9 cm.m-2(ns) in type II dissection. In the patient group with type III dissection this diameter was significantly smaller (1.8 +/- 0.9 cm.m-2; P < 0.001). Thickening of aortic valve leaflets was demonstrated in six (9.7%) of 62 patients with aortic dissection type I (two of them with mild aortic stenosis), in two (11.8%) of 17 patients with aortic dissection type II and in 15 (25.0%) of 60 patients with aortic dissection type III. A bicuspid aortic valve was diagnosed in five (6.3%) of 79 patients with aortic dissection types I and II and in one (1.7%) of 60 patients with type III dissection. By colour coded Doppler echocardiography, aortic regurgitation was found in 46 (74.2%) of 62 patients with type I, 13 (76.5%) of 17 patients with type II and 23 (38.3%) of 60 patients with type III dissection.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic dissection after aortic valve replacement: incidence and consequences for strategy.

From 1986 to 1994, 10 patients were observed to have developed an acute aortic dissection at some stage after an aortic valve replacement (AVR). Study of the characteristics of these patients showed that all patients had an aortic diameter of 50 mm or more (range 50 to 80 mm, mean 64 mm), and 70% suffered from systemic hypertension. Subsequently, the echocardiographic database, containing data from 33,105 studies in 21,484 patients, was searched for cases of AVR in which an accurate aortic dimension could be measured. Of 524 patients who had undergone AVR, an accurate aortic diameter was recorded in 419. Thirty-seven patients had an aortic size greater than 50 mm. All acute dissections occurred in this group of patients. The incidence of acute dissections among patients with significant aortic dilatation following AVR was 27%, whereas the overall incidence of acute dissection after AVR is 0.6%. Although there was a preponderance of tilting disc mechanical valves in the dissecting patients, the type of valve implanted does not seem to be of any importance. From these observations, we conclude that implantation of a valved conduit is indicated even in the presence of mild annuloaortic ectasia (aortic size = 50 mm). Patients who have had an AVR and show an enlarging aortic diameter exceeding 50 mm should have an elective reoperation at an early stage, especially when systemic hypertension is present.

Assessment of the role of pancreatic proteases in human abdominal aortic aneurysms and occlusive disease.

Previous studies on the pathogenesis of abdominal aortic aneurysms have shown both elastase-like activity in the aortic wall and a decreased elastin content. The present study, using specific radioimmunoassays for pancreatic elastase 2 (IRE2) and cationic trypsin(ogen) (IRCT), investigates the concentrations of these proteases which are known to circulate in blood, in abdominal aortic aneurysms. Aortic specimens were obtained from 32 patients with aneurysms and 21 patients with atherosclerotic occlusive disease. Aortic tissue, obtained at autopsy from young adults, served as controls. Elastase-like activity was 300% and 800% higher, respectively, in aortic homogenates from aneurysms in comparison to occlusive disease and control aortic tissue. This was associated with 1.4-fold higher level of IRE2 and 2.7-fold higher levels of IRCT as compared to occlusive disease. Although there was no significant difference in the aortic collagen concentration among all 3 groups, the elastin content of aneurysmal aorta was 85% and 74% lower, respectively, in comparison to control and occlusive aorta. The results of this investigation demonstrate the presence of pancreatic elastase 2 and cationic trypsin(ogen) in abdominal aortic aneurysmal tissue and suggest that circulating pancreatic proteases contribute to the pathophysiology of aneurysms of the infrarenal aorta.

Nuclear magnetic resonance imaging in the assessment of unusual abdominal aortic aneurysms.

Ultrasound and computed tomography (CT) have become primary methods of evaluating patients with abdominal aortic aneurysms. Arteriography may be necessary for further assessment. We have recently investigated two patients with complicated abdominal aortic aneurysms, one patient with Marfan's syndrome and the other with Behcet's disease. The initial diagnosis in both cases was made by ultrasound, but CT was inconclusive and aortography was contraindicated in both patients. Nuclear magnetic resonance (NMR) imaging was performed to see if further information could be obtained. This technique was useful in both cases, with elegant demonstration of the anatomy.