18F-FDG PET/CT: bicuspid aortic valve patients’ underestimated ally. A systematic review

The aortic arch and its branches form during the third week of embryogenesis, which involves a complex process. Abnormalities of the arch branching pattern arise by persistence of segments of arches that normally disappear or the disappearance of segments of arches that normally remain, or both [1]. The most common human aortic arch branching pattern has the innominate artery, the left common carotid artery and the left subclavian artery all as separate branches (Fig. 1). The most common variant branching pattern involves the left common carotid artery arising in a common origin with the innominate artery (Fig. 2), and the next most common the similar left common carotid artery originating from the innominate artery itself (Fig. 3). A true bovine arch involves a single common brachiocephalic trunk arising from the arch which then splits into the right subclavian artery, a bicarotid trunk and a left subclavian artery (Fig. 4), and is actually extremely uncommon in humans [2]. Originally the variations of t...

The bicuspid aortic valve and its relation to aortic dilation

Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (<4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.

Introduction: Bicuspid Aortic Valve (BAV) is associated with premature valve and vascular complications. Thirty to 50% of BAV patients require surgery for valve diseases and/or ascending aorta (AA) dilatation. Increasing studies suggest that the measure of AA diameter, as criteria for aortic surgery, is an imperfect predictor of dissection and rupture. Therefore there is a need to identify reliable markers of dysfunctional AA to guide the decision for surgery. Recently, Advanced glycation end products (AGEs), such as HMGB-1 and S100A12, and their binding to the Receptor for AGE (RAGE) have been associated to mechanisms of valve and vascular degeneration. We previously demonstrated that BAV patients have higher plasma levels of the soluble form of RAGE (sRAGE) when compared with tricuspid aortic valve (TAV) patients. We also showed that the AA of BAV patients with higher circulating sRAGE is characterized by severe elastin degradation and matrix disorganization when compared to those with lower sRAGE. Hypothesis: We hypothesized that the level of circulating sRAGE may be related to the expression of AGEs and RAGE in the AA. Methods: HMGB-1 and S100A12 plasma values were measured by ELISA in BAV (N=20) and TAV (N=20) patients previously tested for sRAGE. Logistic regression and multivariate analysis were performed. AA tissue from BAV patients with sRAGE concentration ranging from 491 pg/mL to 5978 pg/mL were tested for the expression of RAGE, HMGB-1 and S100A12 by immunohistochemistry and Western blotting. Results: RAGE expression linearly increased in the AA of BAV patients with higher plasma sRAGE (R2=0.5). RAGE and sRAGE levels correlate with the expression of HMGB-1. S100A12 was minimally detected and restricted to inflammatory infiltrates in both BAV and TAV patients with AA dilatation. Plasma level of S100A12 and HMGB-1 were not significantly different in BAV patients when compared to TAV and did not correlate with sRAGE concentration. Conclusions: These results suggest that HMGB1-mediated RAGE activation in the AA of BAV patients may be responsible for tissue degeneration and increased sRAGE release in the bloodstream. The interaction AGE-RAGE in the AA of BAV patients may help in evaluating the risk for rapid AA degeneration independently of dilation.

The prevalence of coronary artery disease (CAD) in bicuspid aortic valve (BAV) patients is a debatable topic. Several studies have indicated that BAV patients have a lower prevalence of CAD compared with patients with a tricuspid aortic valve (TAV), but the effects of age and gender have not always been considered. This systematic review provides an overview of articles which report on CAD in BAV and TAV patients. Searches were executed in April 2021 and January 2022 according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines in three online databases: Medline, Embase, and Scopus. Screening and data extraction was done by two investigators separately. Primary and secondary outcomes were compared between BAV and TAV patients; a fixed effects model was used for correcting on confounders. Literature search yielded 1,529 articles with 44 being eligible for inclusion. BAV patients were younger (56.4 ± 8.3 years) than TAV patients (64 ± 10.3 years, p < 0.001). All CAD risk factors and CAD were more prevalent in TAV patients. No significant difference remained after correcting for age and gender as confounders. BAV patients have a lower prevalence of CAD and CAD risk factors compared with TAV patients. However, when the age differences between both groups are considered in the analyses, a similar prevalence of both CAD and CAD risk factors is found.

Brain Injury After Transcatheter Replacement of Bicuspid Versus Tricuspid Aortic Valves

Background Thoracic aortic aneurysm (TAA) is a pathological widening of the aorta, due to degeneration of extracellular matrix (ECM) and loss of smooth muscle cells (SMCs). Bicuspid aortic valve (BAV) is a congenital disorder present in 1-2 % of the population which makes TAA associated with BAV a common complication. Previously we showed that aortas isolated from BAV and normal tricuspid aortic valve (TAV) patients are different both at gene and protein levels. Particularly, differences in the TGFβ pathway seem to be crucial players in aneurysm development, affecting matrix remodeling and wound healing. Since SMCs and myofibroblasts are the critical cells responsible for these activities, we evaluated different properties of the cells focusing on fibronectin (FN) and its spliced versions, a target gene of TGFβ. Interestingly, extra domain A of FN (EDA) was previously described for its roles in vascular morphogenesis, as well as in processes like migration and proliferation. Methods and results Biopsies from the thoracic aorta and Aortic valves were collected during Elective Aortic Valve Replacement Surgery. mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=46) and BAV (n=77). Expression of EDA was found increased only in dilated aortas from TAV patients but not in BAV patients. Primary SMCs were isolated with the explant outgrowth technique from aortas of BAV and TAV patients (n=15). Myofibroblasts were isolated by collagenase digestion from BAV and TAV valves (n=30). Cells were cultured and treated with TGFβ at a concentration of 20 ng/ml for 6h. TGFβ treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in SMCs from TAV patients but not in cells derived from BAV patients. We have not observed clear differences in SMC proliferation and migration. Myofibrolasts analysis is ongoing. Conclusions So far, our results suggest that despite a decreased EDA-fibronectin expression in BAV cells, the phenotype of SMCs isolated from BAV and TAV patients in culture does not differ. However, impaired TGFβ signaling that may result in the increased susceptibility of BAV patients to develop TAA could be due to effects on other cell types.

ObjectivesPatients with bicuspid aortic valve disease requiring surgical aortic valve replacement are often younger and want to avoid lifelong anticoagulation. A multicentre single-arm non-randomized study, the COMMENCE trial, studied outcomes of RESILIA tissue aortic valves in bicuspid aortic valve patients through 7 years of follow-up.MethodsOf 672 patients who underwent surgical replacement of native aortic valves, 214 had bicuspid and 458 had tricuspid aortic valves. Propensity score analyses with inverse probability of treatment weighting were utilized to minimize bias due to measured confounders. Linear mixed-effect models compared longitudinal changes in haemodynamic parameters.ResultsPatients with bicuspid were significantly younger than those with tricuspid aortic valves—mean age of bicuspid: 59.8 (12.4) vs tricuspid: 70.2 (9.5) years; P < .001; 39/214 (18%) bicuspid aortic valve patients were <50 years old. There was no evidence of structural valve deterioration in any bicuspid aortic valve patients over 7 years of follow-up. At 7 years, there was no significant difference between bicuspid and tricuspid aortic valve patients in propensity score- and age-adjusted survival (91.9% vs 88.1%, respectively; P = .35), stroke, or reoperation. Among bicuspid aortic valve patients <65 years of age, there was no significant difference in prosthetic valve effective orifice areas and mean gradients between 3 months and 7 years postoperatively.ConclusionsPatients with bicuspid aortic valves had excellent outcomes with RESILIA tissue valves at 7 years with no evidence of structural valve deterioration. These results suggest a durable alternative for carefully selected younger patients wishing to avoid anticoagulation.Clinical Trial Registration NumberNCT01757665.

Circulating endothelial microparticles are elevated in bicuspid aortic valve disease and related to aortic dilation

Background and Aims: The mechanisms underlying bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) ascending aortic aneurysm are still unknown. We sought to identify predictors of aortopathy in BAV and TAV patients, respectively, and determine the genetic contribution to the valve phenotype. Methods: This study included BAV (n=545) and TAV (n=496) patients with aortic valve disease and/or ascending aorta dilatation but devoid of coronary artery disease. We applied machine learning algorithms and classic logistic regression models using multiple variable selection methodologies to predict individuals of high risk of aneurysm. Analyses included comprehensive multidimensional data (i.e., valve morphology, plasma analyses, genetic- and clinical data, family history of cardiovascular diseases, prevalent diseases, demographic, lifestyle and medication). The genetic impact on phenotype was estimated in a genome-wide complex trait analysis using a variance components model. Results: BAV patients were younger (60.4±12.3 years) than TAV patients (70.2±9.5 years), and had a higher frequency of aortic dilatation (45.1% and 29% for BAV and TAV, respectively. P&lt;0.001). The unadjusted aneurysm prediction model showed a mean AUC of 0.8 for TAV patients, with absence of aortic stenosis (AS) being the main predictor, followed by diabetes and hsCRP. Using the same clinical measures in our prediction model for BAV patients resulted in a AUC of only 0.6 which cannot be considered a good predictor of aortic dilatation. Instead, genetic estimation showed higher genetic impact on BAV patients for both ascending aortic dimensions (sinotubular junction, sinus valsalva and aortic root) (genetic impact of 0.8 and 0.3 on BAV and TAV, respectively) and plasma profiles of 455 proteins (BAV: 0.8 vs. TAV: 0.3, for both dimensions and protein levels). Conclusions: The predictive classifier of TAV patients is clinically relevant and potentially offers important implications for better targeting TAV individual at high risk of developing aneurysm. Cardiovascular risk profiles appear to be more predictive of aortopathy than valve morphology and genetic data in TAV patients, whereas in BAV patients, the genetic contribution exceeds environmental factors.

Bicuspid aortic valve (BAV) patients with aortic stenosis (AS) are known to develop dilatation of the ascending aorta at a younger age, but the morphology of the aorta in these patients is yet to be investigated. Thus, in this study, we aim to evaluate the aortic morphology of BAV patients with severe AS using thin-slice electrocardiogram (ECG) -gated computed tomography (CT) and identify the possible contributing effect of age.In this retrospective study, 122 BAV and 154 tricuspid aortic valve (TAV) patients who received aortic valve replacement for severe AS were assessed by thin-slice ECG-gated CT and three-dimensional reconstruction. The morphology of the ascending aorta was also evaluated among BAV patients aged < 70 (n = 72) and ≥ 70 (n = 50) years old. As per our findings, BAV patients with severe AS had significantly greater diameter (P < 0.01), elongation (P < 0.01), and tortuosity (P = 0.03) of the ascending aorta; minimum aortic arch angle (P < 0.01); and significantly lower calcified plaque (P < 0.01) compared with those of TAV patients even after adjusting for background. Multiple regression analysis showed that standardized partial regression coefficients (β) of dilatation (0.5) and elongation (0.35) were higher among other measurements of aortic morphology for BAV patients. BAV patients with severe AS aged ≥ 70 years had significantly greater diameter (42.0 [37.2-46.1] mm versus 40.4 [35.2-44.2] mm, P = 0.049) and elongation (133.8 [123.5-147.3] mm versus 127.0 [111.0-140.0] mm, P = 0.01) of the ascending aorta than those aged < 70 years.BAV patients with severe AS were determined to have greater dilatation and elongation of the ascending aorta. Moreover, BAV patients older than 70 years had greater diameter and elongation of the ascending aorta.

Introduction A lower prevalence of coronary artery disease (CAD) was previously reported among bicuspid aortic valve (BAV) patients compared with tricuspid aortic valve (TAV) patients undergoing surgical aortic valve replacement. Unknown is the prevalence of CAD among BAV patients undergoing transcatheter aortic valve implantation (TAVI). Methods Consecutive BAV patients undergoing cardiac computed tomography angiography (CCTA) before TAVI were included. Studies with insufficient imaging quality were excluded. Forty-nine patients with history of prior percutaneous coronary intervention or coronary artery bypass graft surgery were also excluded. Coronary artery stenosis was categorized as ≤50% or &amp;gt;50% luminal diameter stenosis. Results One hundred and fourteen consecutive BAV patients were enrolled (age 72±10.4 years, 64% males). BAV type 1A was the most common type (62%), followed by BAV type 0 (18%) and type 1C (10%). Cardiovascular risk factors were frequent: 23% (26) had history of diabetes mellitus, 45% (51) had dyslipidemia, 56% (64) had hypertension, and 25% (29) were current or past smokers. No correlation was found between calcium scoring of the aortic valve (3664.49±1671.01 Agatston Units) and calcium scoring of the coronary arteries (410.51±546.59 Agatston Units), correlation coefficient 0.43 (p=0.68). Obstructive coronary artery stenosis (&amp;gt;50% luminal diameter stenosis) was observed among the minority (16%) of BAV patients. A single vessel disease was found in 7% of BAV patients, two vessels disease in 5% and triple vessels disease in 4%. Three BAV patients had a single vessel chronic total occlusion. Conclusion Among patients with BAV referred for TAVI, CCTA showed a low prevalence of obstructive coronary artery disease. The absence of correlation between aortic valve and coronary artery calcium scoring suggests the possibility of two heterogeneous aspects of the complex BAV disease. Funding Acknowledgement Type of funding sources: None.

Influence of Aortic Dilation on the Regional Aortic Stiffness of Bicuspid Aortic Valve Assessed by 4-Dimensional Flow Cardiac Magnetic Resonance: Comparison With Marfan Syndrome and Degenerative Aortic Aneurysm

Background Silent cerebral ischemic lesions (SCILs) is a common magnetic resonance imaging (MRI) finding in severe aortic stenosis patients post - transcatheter aortic valve replacement (TAVR). We evaluated the association between SCILs and cognitive alterations in patients with bicuspid aortic valve (BAV) versus tricuspid aortic valve (TAV) post-TAVR. Methods This study enrolled 100 consecutive TAVR (45 with BAV and 55 TAV). DW-MRI and neurocognitive evaluation (MoCA score) were performed at baseline, discharge, and 1- and 12-month post-discharge. Results Ninety-two out of the 100 patients (92%) exhibited cognitive dysfunction at baseline. Post-TAVR, overall cognitive function significantly improved, the average MOCA score increased from 18.69±6.74 to 22.18±6.30. During the 1-year follow-up, 54 patients demonstrated improved cognitive function, and the number of patients with moderate-to-severe cognitive dysfunction (MoCA score &amp;lt; 18) significantly decreased from 32 to 16. Prevalence of SCILs was 14% and 72% at baseline and discharge, respectively. New SCILs were observed in 60 patients at discharge, distributed across all vascular territories, averaging 4 lesions with a total volume of 215.4±195.4mm3. Although no significant correlation existed between total volume of new SCILs and cognitive changes post-TAVR (R=-0.133, p=0.206), patients with SCILs still displayed significant cognitive improvement (MoCA score from 18.4±6.6 to 22.0±7.1), whereas patients who developed large SCILs (lesion diameter &amp;gt;9) showed less improvement compared to those with small or median SCILs (number of patients who had cognitive improvement: 32 vs. 52, p&amp;lt;0.05). Cognitive function improvement post-TAVR did not significantly differ between BAV and TAV patients, MoCA scores were comparable (BAV group, n=45, from 18.63±6.68 to 21.88±6.80 vs. TAV group, n=55, from 18.73±6.81 to 22.42±5.80; p&amp;gt;0.05). DW-MRI revealed more new SCILs in BAV patients post-TAVR compare to TAV patients (235 lesions vs. 150 lesions, respectively). In BAV patients, SCILs primarily manifested in small and medium sizes (224 lesions), despite more severe calcification (valvular calcium volume 956.5±644.0 mm vs. 634.4±508.0 mm3; p=0.028). The number of large lesions was similar in the two groups (11 in BAV group and 10 in TAV group). Conclusion TAVR demonstrates positive effects on improving cognitive function in aortic stenosis patients, despite common occurrence of SCILs in both BAV and TAV patients. Cognitive function post-TAVR was comparable between BAV and TAV patients. The cognitive improvement from TAVR may be less impacted by small- and medium-sized SCILs, while severe SCILs might impede or diminish the cognitive benefits of TAVR.table

BackgroundPostoperative atrial fibrillation (PoAF) is one of the most common complications after cardiac surgery. Patients with a congenital bicuspid aortic valve (BAV) often require aortic valve surgery at a younger age than those with a tricuspid aortic valve (TAV). Previous research showed that the pre-existing atrial substrate plays a critical role in development of PoAF. However, the exact differences in pre-existing substrates between BAV and TAV in the pathophysiology of PoAF are still unknown.PurposeTo investigate differences in pre-existing substrates in BAV and TAV patients and development of early, (≤5 days after surgery) de novo PoAF.MethodsAdult patients without a history of atrial fibrillation with either a BAV (N=49) or TAV (N=53) who underwent valve and/ or aortic surgery were included in this study. Intraoperative high-density epicardial mapping of the atria was performed during sinus rhythm to investigate unipolar potential voltages, conduction velocity (CV) and conduction block (CB).ResultsBAV patients were significantly younger than TAV patients (58 years vs. 68 years p=<0.001). Early de novo PoAF occurred in 20 (41%) BAV patients and 20 (38%) TAV patients. Among patients who developed PoAF, baseline characteristics showed no significant differences. Analysis of the whole atrium showed no significant differences in the median potential voltage (4.7 mV versus 4.4 mV, p=0.923), low voltage areas (7.1% versus 8.2%, p=0.865), CV (93.0 cm/s versus 93.8 cm/s, p=0.730) and CB prevalences (1.8 % versus 2.3 %, p=0.705) between the BAV PoAF and TAV PoAF group. (Figure 1) Furthermore, no significant regional differences were found in the electrophysiological parameters of the right atrium, Bachman’s bundle, left atrium and pulmonary veins between BAV and TAV patients who developed early de novo PoAF.ConclusionsThere were no differences in pre-existing atrial substrate in both BAV and TAV patients who developed early de novo PoAF. This could indicate that the risk of PoAF in these patients might be dependent on other peri- or postoperative factors.