Johan Petrini

Unraveling divergent gene expression profiles in bicuspid and tricuspid aortic valve patients with thoracic aortic dilatation: the ASAP study.

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.

Bicuspid aortic valve leaflet morphology in relation to aortic root morphology: a study of 300 patients undergoing open-heart surgery §

OBJECTIVE There is an ongoing discussion regarding the mechanism of aortic dilatation in bicuspid aortic valve (BAV) disease, that is, is this a hemodynamic effect or related to an inborn weakness of the aortic wall? This study evaluated the possibility of BAV morphology being related to ascending aorta morphology as such a correlation would strengthen the idea that hemodynamic alterations cause the dilatation of the aorta. METHODS The morphology of the ascending aorta of 300 patients admitted for aortic valve and/or ascending aorta disease was evaluated by echocardiography and related to the surgeons inspection of the aortic valve. RESULTS A tricuspid aortic valve (TAV), BAV, or unicuspid aortic valve (UAV) was present in 130, 160, and 10 patients, respectively. Ascending aortic aneurysm was more common in patients with BAV compared with TAV (36% and 12%, respectively; p < 0.001), while ectasia of the aorta was similarly common (8% in both groups). Aortic stenosis or regurgitation was equally distributed in TAV and BAV patients with normal aortas (p=0.82). When the aorta was dilated, aortic stenosis was predominantly associated with BAV (BAV 56%, TAV 4%; p < 0.001), while aortic regurgitation was more common in TAV (TAV 81%, BAV 29%; p<0.001). In BAV patients, fusion of the right- and left coronary cusp was predominant (74%) followed by right- and non-coronary cusp fusion (14%) and true BAV (fusion of the right- and left coronary cusp without remnant raphe; 11%) (p < 0.001). The relative distribution of ascending aortic aneurysm or ectasia was similar in all morphologically different BAV (p = 0.95). CONCLUSIONS In our study population, >50% of the patients admitted for surgery had a bicuspid valve. Aortic aneurysm was more common in BAV than in TAV patients. Aortic stenosis and aortic regurgitation were equally common in TAV and BAV with normal aortic dimensions, while aortic regurgitation was predominant in TAV with dilated aortas and aortic stenosis in BAV with dilated aortas. Dilatation of the aorta was similarly distributed regardless of BAV leaflet morphology. These findings support the idea of an intrinsic mechanisms underlying dilatation of the aorta in BAV patients.

Impaired Splicing of Fibronectin Is Associated With Thoracic Aortic Aneurysm Formation in Patients With Bicuspid Aortic Valve

Objective—Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients. Methods and Results—The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (&rgr;=0.58) but not in BAV (&rgr;=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-&bgr; treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-&bgr; signaling pathway may explain the impaired EDA inclusion in BAV patients. Conclusion—Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.

The feasibility of velocity vector imaging by transesophageal echocardiography for assessment of elastic properties of the descending aorta in aortic valve disease.

BACKGROUND Velocity vector imaging (VVI) is a novel two-dimensional speckle-based imaging technique for evaluation of tissue deformation. The aim of this study was to determine the feasibility and variability of VVI for the assessment of aortic strain, distensibility, and stiffness in patients with aortic valve disease. METHOD Eighty-five patients (mean age 66 +/- 11 years) with aortic stenosis (AS) or aortic regurgitation (AR) were examined in the operating room before the operation using transesophageal echocardiography (TEE). The two-dimensional short-axis images and M-mode recordings of the descending aorta were acquired simultaneously with the invasive blood pressure measurement in the radial artery. The TEE images were analyzed off-line using VVI software. RESULTS In comparison with patients with AS, patients with AR displayed significantly higher circumferential strain (7.6% +/- 4.5% vs. 3.7% +/- 1.9%, P < .001) and distensibility (27.1 +/- 12.8 kPa(-1)10(-3) vs. 17.2 +/- 7.2 kPa(-1)10(-3), P < .001) by VVI and distensibility (32.8 +/- 16.7 kPa(-1)10(-3) vs. 21.7 +/- 10.6 kPa(-1)10(-3), P < .004) by M-mode. Stiffness was higher in AS than AR, as measured by VVI (13.3 +/- 6.0 vs. 10.5 +/- 6.0, P < .01) and M-mode (11.2 +/- 6.1 vs. 10.4 +/- 9.1, P < .048). The correlations between VVI and M-mode distensibility (r = 0.84) and stiffness (r = 0.84) were both highly significant (P < .0001). The VVI strain measurements showed low inter- and intraobserver variability with intraclass correlations greater than 0.95 and coefficients of variation less than 10%. CONCLUSION VVI-derived strain, distensibility, and stiffness differ significantly between AR and AS and correlate strongly with the corresponding M-mode-derived parameters. VVI is a feasible method for the assessment of the elastic properties of the descending aorta with low variability and has the advantage of incorporating the entire aortic wall circumference in the analysis, consequently accounting for local variations in the elastic properties of the aorta.

Elastic Properties of the Descending Aorta in Patients with a Bicuspid or Tricuspid Aortic Valve and Aortic Valvular Disease

BACKGROUND The aim of this study was to explore possible differences in aortic strain, distensibility, and stiffness in the descending thoracic aorta between patients with bicuspid aortic valves (BAVs) and those with tricuspid aortic valves (TAVs) in relation to type of aortic valve disease and known cardiovascular risk factors. METHODS Transesophageal echocardiography was used to examine 288 patients (mean age, 64 ± 13 years) in the operating room before surgery. The transesophageal echocardiographic images were analyzed offline using Velocity Vector Imaging software. One hundred forty patients had isolated severe aortic stenosis (AS) (89 of those with BAVs, 51 of those with TAVs), and 52 patients had isolated severe aortic regurgitation (AR) (24 of those with BAVs, 28 of those with TAVs). RESULTS In patients with AS, stiffness in the descending aorta was 10 (range, 7.3-16) in those with BAVs and 13 (range, 11-18) in those with TAVs (P < .001). Distensibility was 19 kPa(-1) 10(-3) (range, 13-27 kPa(-1) 10(-3)) in patients with BAVs and 15 kPa(-1) 10(-3) (range, 11-19 kPa(-1) 10(-3)) in those with TAVs (P < .01). In patients with AR, stiffness was 6.9 (range, 5.5-7.8) in those with BAVs and 8.0 (range, 6.6-11) in those with TAVs (P < .05). After correction for age, dimension of the ascending aorta, cholesterol, and stroke volume in a multivariate regression model, BAV was associated with lower strain and distensibility of the descending aorta in the AR group and higher distensibility in the AS group, whereas stiffness was no longer related to aortic valve morphology in either of the two groups. CONCLUSIONS The presence of BAVs in patients with severe AR is associated with lower strain and distensibility, suggesting that impairment of the elastic aortic properties may extend to the descending aorta. In patients with AS, BAVs correlate weakly with higher distensibility.

Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves

Individuals with a bicuspid aortic valve (BAV) are at significantly higher risk of developing aortic complications than individuals with tricuspid aortic valves (TAV) and defective signaling during the embryonic development and/or life time exposure to abnormal hemodynamic have been proposed as underlying factors. However, an explanation for the molecular mechanisms of aortopathy in BAV has not yet been provided. We combined proteomics, RNA analyses, immunohistochemistry, and electron microscopy to identify molecular differences in samples of non-dilated ascending aortas from BAV (N = 62) and TAV (N = 54) patients. Proteomic analysis was also performed for dilated aortas (N = 6 BAV and N = 5 TAV) to gain further insight into the aortopathy of BAV. Our results collectively showed the molecular signature of an endothelial/epithelial-mesenchymal (EndMT/EMT) transition-like process, associated with instability of intimal cell junctions and activation of RHOA pathway in the intima and media layers of ascending aorta in BAV patients. We propose that an improper regulation of EndMT/EMT during the spatiotemporally related embryogenesis of semilunar valves and ascending aorta in BAV individuals may result in aortic immaturity and instability prior to dilation. Exasperation of EndMT/EMT state in post embryonic life and/or exposure to non-physiological hemodynamic could lead to the aneurysm of ascending aorta in BAV individuals.

Aortic valve type and calcification as assessed by transthoracic and transoesophageal echocardiography.

Aortic valve calcification (AVC) may predict poor outcome. Bicuspid aortic valve (BAV) leads to several haemodynamic changes accelerating the progress of aortic valve (AV) disease.

Real‐time imaging required for optimal echocardiographic assessment of aortic valve calcification

Aortic valve calcification (AVC), even without haemodynamic significance, may be prognostically import as an expression of generalized atherosclerosis, but techniques for echocardiographic assessment are essentially unexplored.

Circumferential strain by velocity vector imaging and speckle-tracking echocardiography: validation against sonomicrometry in an aortic phantom

Evaluation of arterial deformation and mechanics using strain analysis on ultrasound greyscale images has gained increasing scientific interest. The aim of this study was to validate in vitro measurements of circumferential strain by velocity vector imaging (VVI) and speckle‐tracking echocardiography (STE) against sonomicrometry as a reference method.

Intima-media thickness of the descending aorta in patients with bicuspid aortic valve

Objective A bicuspid aortic valve (BAV) is associated with accelerated aortic valve disease (AVD) and abnormalities in aortic elasticity. We investigated the intima-media thickness of the descending aorta (AoIMT) in patients with AVD with or without an ascending aortic aneurysm (AscAA), in relation to BAV versus tricuspid aortic valve (TAV) phenotype, type of valve disease, cardiovascular risk factors, and single-nucleotide polymorphisms (SNPs) with a known association with carotid IMT. Methods and results 368 patients (210 with BAV, 158 with TAV,); mean age 64 ± 13 years) were examined using transesophageal echocardiography (TEE) before valvular and/or aortic surgery. No patient had a coronary disease (CAD). The AoIMT was measured on short-axis TEE images of the descending aorta using a semi-automated edge-detection technique. AoIMT was univariately (P < 0.05) related to age, blood pressure, smoking, creatinine, highly sensitive C-reactive protein, HDL, valve hemodynamics and BAV. In the TAV subgroup it was also associated with the rs200991 SNP. Using multivariate regression analysis, age was the main determinant for AoIMT (P < 0.001), followed by male gender (P = 0.02), BAV was no longer a significant predictor of AoIMT. AoIMT was still related to the rs200991 SNP in TAV (P = 0.034), and to creatinine in BAV (P = 0.019), when other variables were accounted for. Conclusions Intima-media thickness of the descending aorta is not affected by aortic valve morphology (BAV/TAV); age is the main determinant of AoIMT. Genetic markers (SNPs) known to influence IMT in the carotid artery seem to correlate to IMT in the descending aorta only in patients with TAV.