Hemodynamic Assessment in Bicuspid Aortic Valve Disease and Aortic Dilation: New Insights From Voxel-By-Voxel Analysis of Reverse Flow, Stasis, and Energetics

Objectives: Clinical management decisions surrounding ascending aorta (AAo) dilation in bicuspid aortic valve (BAV) disease benefit from personalized predictive tools. 4D-flow MRI may provide patient-specific markers reflective of BAV-associated aortopathy. This study aims to explore novel 4D-flow MRI parametric voxel-by-voxel forward flow, reverse flow, kinetic energy and stasis in BAV disease. We hypothesize that novel parametric voxel-by-voxel markers will be associated with aortic dilation and referral for surgery and can enhance our understanding of BAV hemodynamics beyond standard metrics.Methods: A total of 96 subjects (73 BAV patients, 23 healthy controls) underwent MRI scan. Healthy controls had no known cardiovascular disease. Patients were clinically referred for AAo dilation assessment. Indexed diameters were obtained by dividing the aortic diameter by the patient’s body surface area. Patients were followed for the occurrence of aortic surgery. 4D-flow analysis was performed by a single observer in five regions: left ventricular outflow tract (LVOT), AAo, arch, proximal descending aorta (PDAo), and distal descending aorta (DDAo). In each region peak velocity, kinetic energy (KE), forward flow (FF), reverse flow (RF), and stasis were measured on a voxel-by-voxel basis. T-tests (or non-parametric equivalent) compared flow parameters between cohorts. Univariate and multivariate analyses explored associations between diameter and parametric voxel-by-voxel parameters.Results: Compared to controls, BAV patients showed reduced stasis (p < 0.01) and increased RF and FF (p < 0.01) throughout the aorta, and KE remained similar. In the AAo, indexed diameter correlated with age (R = 0.326, p = 0.01), FF (R = −0.648, p < 0.001), RF (R = −0.441, p < 0.001), and stasis (R = −0.288, p < 0.05). In multivariate analysis, FF showed a significant inverse association with AAo indexed diameter, independent of age. During a median 179 ± 180 days of follow-up, 23 patients (32%) required aortic surgery. Compared to patients not requiring surgery, they showed increased KE and peak velocity in the proximal aorta (p < 0.01), accompanied by increased RF and reduced stasis throughout the entire aorta (p < 0.01).Conclusion: Novel voxel-by-voxel reverse flow and stasis were altered in BAV patients and are associated with aortic dilation and surgical treatment.

Evaluation of the Relationship between Para-aortic Adipose Tissue and Ascending Aortic Diameter using a New Method

Purpose: Para-aortic adipose tissue (PAT) is the local adipose tissue that externally surrounds the aorta. It contributes significantly to aortic atherosclerosis and enlargement. Studies conducted with computed tomography and magnetic resonance have shown that individuals with aortic aneurysm had more PAT than healthy individuals. In this study, we measured PAT for the first time using transthoracic echocardiography (TTE).The aim of this study is to investigate the possible relationship of TTE measured PAT with ascending aortic width.Methods: PAT was defined as the hypoechoic space in front of ascending aortic 2 cm above the sinotubular junction at the end of the systole. Patients were divided into 2 groups according to the presence of dilatation in the ascending aorta using Roman's classification (aortic size index, ASI). ASI of less than 21 was considered no aortic dilation and an ASI of 21mm/m2 or greater was considered to have aortic dilation.Results: A total of 321 unselected patients were divided into the ascending aortic dilatation (AAD) group (n=96) and the normal ascending aorta diameter group (n=225 patients). PAT was significantly higher in the AAD group compared with the non-ADD group (0.9 (0.48) vs. 0.7 (0.91) mm, p < 0.0001). Univariate and multivariate logistic regression analysis revealed that PAT (OR: 3.005, 95%CI (1.445–6.251)) were significantly associated with AAD.Conclusion: Our results showed an association between PAT measured by transthoracic echocardiography and ascending aorta width. PAT appears to be an important follow-up parameter in patients at risk of developing aortic aneurysm.

Age and Sex Dependency of Thoracic Aortopathy in a Mouse Model of Marfan Syndrome

Thoracic aortic aneurysm is one of the manifestations of Marfan syndrome (MFS) that is known to affect men more severely than women. However, the incidence of MFS is similar between men and women. The aim of this study is to show that during pathological aortic dilation, sex-dependent severity of thoracic aortopathy in a mouse model of Marfan syndrome translates into sex-dependent alterations in cells and matrix of the ascending aorta, consequently affecting aortic biomechanics. Fibrillin1 C1041G/+ were used as a mouse model of MFS. Ultrasound measurements from 3-12 months showed increased aortic diameter in Marfan aorta with larger percent increase in diameter for males compared to females. Immunohistochemistry showed decreased contractile smooth muscle cells in Marfan aortic wall compared to healthy aorta, which was accompanied by decreased contractility measured by wire myography. Elastin autofluorescence, second harmonic generation microscopy of collagen fibers and passive biomechanical assessments using myography showed more severe damage to elastin fibers, increased medial fibrosis, and increased stiffness of the aortic wall in MFS males but not females. Male and female heterozygotes showed increased expression of Sca-1-positive adventitial progenitor cells vs. controls at young ages. In agreement with clinical data, Marfan mice demonstrate sex-dependent severity of thoracic aortopathy. It was also shown that aging exacerbates the disease state especially for males. Our findings suggest that female mice are protected from progression of aortic dilation at early ages, leading to a lag in aneurysm growth.

Inducible Prmt1 ablation in adult vascular smooth muscle leads to contractile dysfunction and aortic dissection

Vascular smooth muscle cells (VSMCs) have remarkable plasticity in response to diverse environmental cues. Although these cells are versatile, chronic stress can trigger VSMC dysfunction, which ultimately leads to vascular diseases such as aortic aneurysm and atherosclerosis. Protein arginine methyltransferase 1 (Prmt1) is a major enzyme catalyzing asymmetric arginine dimethylation of proteins that are sources of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Although a potential role of Prmt1 in vascular pathogenesis has been proposed, its role in vascular function has yet to be clarified. Here, we investigated the role and underlying mechanism of Prmt1 in vascular smooth muscle contractility and function. The expression of PRMT1 and contractile-related genes was significantly decreased in the aortas of elderly humans and patients with aortic aneurysms. Mice with VSMC-specific Prmt1 ablation (smKO) exhibited partial lethality, low blood pressure and aortic dilation. The Prmt1-ablated aortas showed aortic dissection with elastic fiber degeneration and cell death. Ex vivo and in vitro analyses indicated that Prmt1 ablation significantly decreased the contractility of the aorta and traction forces of VSMCs. Prmt1 ablation downregulated the expression of contractile genes such as myocardin while upregulating the expression of synthetic genes, thus causing the contractile to synthetic phenotypic switch of VSMCs. In addition, mechanistic studies demonstrated that Prmt1 directly regulates myocardin gene activation by modulating epigenetic histone modifications in the myocardin promoter region. Thus, our study demonstrates that VSMC Prmt1 is essential for vascular homeostasis and that its ablation causes aortic dilation/dissection through impaired myocardin expression.

Pregnancy in women with bicuspid aortic valve

Background Aortic dissection during pregnancy is uncommon, however, the risk of aortic dissection is increased if there is underlying aortopathy. Bicuspid aortic valve (BAV) is common in the general population and is associated with the presence of an aortic aneurysm, but this condition is mostly asymptomatic and ignored in women of childbearing age. Data on pregnancy in patients with BAV are scarce, and guidelines on this topic are based on the consensus opinion of experts. The risk of occurrence of aortic dissection as a function of aortic diameter during pregnancy remains poorly known in women with BAV. Purpose To investigate demographic and echocardiographic characteristics and aortic events associated with pregnancy in women with BAV and to estimate ascending aortic diameter at the time of pregnancy. Methods We performed a retrospective study using data from our tertiary centre. All women seen at our centre between 1996 and 2020 with BAV, at least 1 pregnancy, and no genetic syndrome were included. We have collected data from echocardiograms performed in and out of our centre and aortic events. Assuming from the literature an annual aortic dilation rate of 0.2 mm at the sinus of Valsalva and 0.4 mm at the tubular ascending aorta, we estimated ascending aortic size and Z-score at the time of pregnancy. Results We identified 47 women with BAV with occurrence of 103 pregnancies. The median age of BAV diagnosis was 43 years. The aorta was measured at a median of 13.3 years since the last delivery. At BAV diagnosis, the median largest ascending aortic diameter was 44mm, and the median Z-score was +4.3. Ascending aortic diameter was ≥40mm in 37/47 (79%) and Z-score ≥2 in 44/47 (94%). No aortic dissection was observed during pregnancy and postpartum in all 103 pregnancies. At the time of pregnancy, the estimated median diameter of the ascending aorta was 37mm and the estimated median Z-score was +3.3. The largest aortic diameter during pregnancy was estimated to be ≥40mm in 36/103 pregnancies, ≥45mm in 13/103, and ≥50mm in 1/103; Z-score was estimated to be ≥2 in 81/103 and ≥4 in 40/103. Type A aortic dissection occurred in 1 woman, 13 years after pregnancy, and type B aortic dissection in 1 woman, 14 years after pregnancy. Planned surgery was performed in 8 women at a median of 17.5 years after the last pregnancy: 1 isolated aortic valve replacement and 7 prophylactic aortic surgeries associated with aortic valve surgery. Conclusions In our population of women with BAV, pregnancy is not associated with the occurrence of aortic dissection even though, when estimating aortic diameter at the time of pregnancy, the rate of aortic dilation was high (Z-score ≥2 in 81/103 pregnancies). Prospective studies of a large population of women with BAV are needed to assess the risk of aortic complication during pregnancy according to aortic diameter. FUNDunding Acknowledgement Type of funding sources: None.