Analysis of Prevalence and Clinical Features of Aortic Stenosis in Patients with and without Bicuspid Aortic Valve Using Machine Learning Methods.

Aortic stenosis (AS) is the most commonly diagnosed valvular heart disease, and its prevalence increases with the aging of the general population. However, AS is often diagnosed at a severe stage, necessitating surgical treatment, due to its long asymptomatic period. The objective of this study was to analyze the frequency of AS in a population of cardiovascular patients using echocardiography (ECHO) and to identify clinical factors and features associated with these patient groups. We utilized machine learning methods to analyze 84,851 echocardiograms performed between 2010 and 2018 at the National Medical Research Center named after V.A. Almazov. The primary indications for ECHO were coronary artery disease (CAD) and hypertension (HP), accounting for 33.5% and 14.2% of the cases, respectively. The frequency of AS was found to be 13.26% among the patients (n = 11,252). Within our study, 1544 patients had a bicuspid aortic valve (BAV), while 83,316 patients had a tricuspid aortic valve (TAV). BAV patients were observed to be younger compared to TAV patients. AS was more prevalent in the BAV group (59%) compared to the TAV group (12%), with a p-value of <0.0001. By employing a machine learning algorithm, we randomly identified significant features present in AS patients, including age, hypertension (HP), aortic regurgitation (AR), ascending aortic dilatation (AscAD), and BAV. These findings could serve as additional indications for earlier observation and more frequent ECHO in specific patient groups for the earlier detection of developing AS.

Clinical features and pregnancy outcomes in women with aortopulmonary window defect: case series.

Background: Aortopulmonary window is a rare congenital heart defect that results in severe pulmonary arterial hypertension (PAH), Eisenmenger syndrome, and congestive heart failure in the first months of life. Pregnancy is absolutely contraindicated in the patients with this condition. Case summary: This paper describes two clinical cases of pregnancy in patients (28 and 20 years old) with aortopulmonary window defect, severe PAH, and Eisenmenger syndrome that ended in preterm delivery by caesarean section. One patient died in the postpartum period due to progression of right ventricular heart failure. The younger patient survived childbirth and the postpartum period; later, she continued therapy at the PAH centre. Discussion: We describe unusual cases of clinical features in pregnant women with aortopulmonary window defect. Due to the rare occurrence and low survival rate of patients with uncorrected aortopulmonary window defect, descriptions of clinical cases of this defect in adults are very rare. It is very important to note the necessity of observation of these patients in specialized centres by a multidisciplinary team of healthcare professionals, due to the high risk of cardiovascular, obstetric complications, and death.

Redo aortic valve-sparing root replacement for failing autograft after the Ross procedure: A case report.

INTRODUCTION AND IMPORTANCE: Late pulmonary autograft dilatation is observed in 10-20 % of patients after the Ross procedure, more often during the second decade of follow-up. Composite aortic root replacement with a valved conduit is the most common redo procedure. An aortic valve-sparing root replacement does not require lifelong anticoagulation and may significantly decrease the risk of complications, associated with a valve prosthesis. PRESENTATION OF THE CASE: We report a case of late pulmonary autograft dilatation developed after the Ross procedure. The annual transthoracic echocardiography after 20 years revealed severe dilatation of the pulmonary autograft, measuring 60 mm in diameter. The patient underwent a successful elective redo valve-sparing aortic root replacement (David I procedure). The aortic cross-clamp time was 144 min, and the CPB time was 181 min. The patient had an uneventful midterm postoperative course. CLINICAL DISCUSSION: Late pulmonary autograft failure after the Ross procedure is a relatively rare condition, leading to repeat operation. Late autograft failure can contribute to aortic regurgitation, heart failure, and death due to ascending aortic dissection and rupture. Several research groups reported good early and midterm results of redo valve-sparing root replacement in such cases. In a reoperative valve-sparing root replacement after the Ross procedure, the portion of the native aorta with the adjacent part of the autograft may complicate the aortic root proper sizing. CONCLUSION: Redo valve-sparing root replacement (David I procedure) is a viable option in pulmonary autograft dilatation with unaffected valve leaflets.

Application of Machine Learning Methods to Analyze Occurrence and Clinical Features of Ascending Aortic Dilatation in Patients with and without Bicuspid Aortic Valve.

Aortic aneurysm (AA) rapture is one of the leading causes of death worldwide. Unfortunately, the diagnosis of AA is often verified after the onset of complications, in most cases after aortic rupture. The aim of this study was to evaluate the frequency of ascending aortic aneurysm (AscAA) and aortic dilatation (AD) in patients with cardiovascular diseases undergoing echocardiography, and to identify the main risk factors depending on the morphology of the aortic valve. We processed 84,851 echocardiographic (ECHO) records of 13,050 patients with aortic dilatation (AD) in the Almazov National Medical Research Centre from 2010 to 2018, using machine learning methodologies. Despite a high prevalence of AD, the main reason for the performed ECHO was coronary artery disease (CAD) and hypertension (HP) in 33.5% and 14.2% of the patient groups, respectively. The prevalence of ascending AD (>40 mm) was 15.4% (13,050 patients; 78.3% (10,212 patients) in men and 21.7% (2838 patients) in women). Only 1.6% (n = 212) of the 13,050 patients with AD knew about AD before undergoing ECHO in our center. Among all the patients who underwent ECHO, we identified 1544 (1.8%) with bicuspid aortic valve (BAV) and 635 with BAV had AD (only 4.8% of all AD patients). According to the results of the random forest feature importance analysis, we identified the eight main factors of AD: age, male sex, vmax aortic valve (AV), aortic stenosis (AS), blood pressure, aortic regurgitation (AR), diabetes mellitus, and heart failure (HF). The known factors of AD-like HP, CAD, hyperlipidemia, BAV, and obesity, were also AD risk factors, but were not as important. Our study showed a high frequency of AscAA and dilation. Standard risk factors of AscAA such as HP, hyperlipidemia, or obesity are significantly more common in patients with AD, but the main factors in the formation of AD are age, male sex, vmax AV, blood pressure, AS, AR, HF, and diabetes mellitus. In males with BAV, AD incidence did not differ significantly, but the presence of congenital heart disease was one of the 12 main risk factors for the formation of AD and association with more significant aortic dilatation in AscAA groups.

Dynamic Aortic Aneurism Risk Factors.

According to different systematic reviews incidence of thoracic aortic aneurysms (TAA) in the general population is increasing in frequency ranging from 5 to 10.4 per 100000 patients. However, only few studies have illustrated the role of different risk factors in the onset and progression of ascending aortic dilatation. Currently, noninvasive imaging techniques are used to assess the progression rate of aortic and aortic valve disease. Transthoracic (TT) Echocardiographic examination routinely includes evaluation of the aorta It is the most available screening method for diagnosis of proximal aortic dilatation. Since the predominant area of dilation is the proximal aorta, TT-echo is often sufficient for screening. We retrospectively analyzed the ECHO database with 78499 echocardiographic records in the Almazov National Medical Research Centre to identify patients with aneurysm. Detailed information including demographic characteristics, ECHO results and comorbidities were extracted from outpatient clinic and from hospital charts related to hospitalizations occurring within a year before index echocardiography was performed. Comorbid diseases were similarly extracted from outpatient clinic and/or hospital admissions. The classifier showed an AUC-ROC for predicting of aneurism detection after a repeated ECHO at 82%.

Notch signaling in the pathogenesis of thoracic aortic aneurysms: A bridge between embryonic and adult states.

Aneurysms of the thoracic aorta are a "silent killer" with no evident clinical signs until the fatal outcome. Molecular and genetic bases of thoracic aortic aneurysms mainly include transforming growth factor beta signaling, smooth muscle contractile units and metabolism genes, and extracellular matrix genes. In recent studies, a role of Notch signaling, among other pathways, has emerged in disease pathogenesis. Notch is a highly conserved signaling pathway that regulates the development and differentiation of many types of tissues and influences major cellular processes such as cell proliferation, differentiation and apoptosis. Mutations in several Notch signaling components have been associated with a number of heart defects, demonstrating an essential role of Notch signaling both in cardiovascular system development and its maintenance during postnatal life. This review discusses the role of Notch signaling in the pathogenesis of thoracic aortic aneurysms considering development and maintenance of the aortic root and how developmental regulations by Notch signaling may influence thoracic aortic aneurysms.

CD73 Rather Than CD39 Is Mainly Involved in Controlling Purinergic Signaling in Calcified Aortic Valve Disease.

The study aimed to compare composition of peripheral blood T-cell subsets and assess their surface expression of CD39 and CD73 ectonucleotidases in patients with severe and moderate aortic stenosis (AS) as well as to evaluate involvement of T-cell-mediated immune processes in valve calcification. The study was performed with 38 patients suffering from severe calcified aortic stenosis (SAS), 33 patients with MAS, and 30 apparently healthy volunteers (HVs). The relative distribution and percentage of T-cell subsets expressing CD39 and CD73 were evaluated by flow cytometry. T helper (Th) and cytotoxic T-cell subsets (Tcyt) were identified by using CD3, CD4, and CD8 antibodies. Regulatory T cells (Tregs) were characterized by the expression of CD3, CD4, and high IL-2R alpha chain (CD25high) levels. CD45R0 and CD62L were used to assess differentiation stage of Th, Tcyt, and Treg subsets. It was found that MAS and SAS patients differed in terms of relative distribution of Tcyt and absolute number of Treg. Moreover, the absolute number of Tcyt and terminally differentiated CD45RA-positive effector T-cells (TEMRA) subset was significantly higher in SAS vs. MAS patients and HVs. However, the absolute and relative number of naïve Th and the absolute number of Treg were significantly higher in MAS vs. SAS patients; the relative number of naïve Tregs was significantly (p < 0.01) decreased in SAS patients. It was shown that CD73 expression was significantly higher in SAS vs. MAS patients noted in all EM, CM, TEMRA, and naïve Th cell subsets. However, only the latter were significantly increased (p = 0.003) in patients compared with HVs. SAS vs. MAS patients were noted to have significantly higher percentage of CD73+ EM Tcyt (p = 0.006) and CD73+ CM Tcyt (p = 0.002). The expression of CD73 in patients significantly differed in all three Treg populations such as EM (p = 0.049), CM (p = 0.044), and naïve (p < 0.001). No significant differences in CD39 expression level was found in MAS and SAS patients compared with the HV group. Overall, the data obtained demonstrated that purinergic signaling was involved in the pathogenesis of aortic stenosis and calcification potentially acting via various cell types, wherein among enzymes, degrading extracellular ATP CD73 rather than CD39 played a prominent role.

Notch, BMP and WNT/ß-catenin network is impaired in endothelial cells of the patients with thoracic aortic aneurysm.

Cellular and molecular mechanisms of thoracic aortic aneurysm are still not clear and therapeutic approaches are mostly absent. The role of endothelial cells in aortic wall integrity is emerging from recent studies. Although Notch pathway ensures endothelial development and integrity, and NOTCH1 mutations have been associated with thoracic aortic aneurysms, the role of this pathway in aneurysm remains elusive. The purpose of the present work was to study functions of Notch genes in endothelial cells of patients with sporadic thoracic aortic aneurysm. Aortic endothelial cells were isolated from aortic tissue of patients with thoracic aortic aneurysm and healthy donors. Gene expression of Notch and related BMP and WNT/ß-catenin pathways was estimated by qPCR; WNT/ß-catenin signaling was studied by TCF-luciferase reporter. To study the stress-response the cells were subjected to laminar shear stress and the expression of corresponding genes was estimated by qPCR. Analyses of mRNA expression of Notch genes, Notch target genes and Notch related pathways showed that endothelial cells of aneurysm patients have dysregulated Notch/BMP/WNT pathways compared to donor cells. Activity of Wnt pathway was significantly elevated in endothelial cells of the patients. Cells from patients had attenuated activation of DLL4, SNAIL1, DKK1 and BMP2 in response to shear stress. In conclusion endothelial cells of the patients with thoracic aortic aneurysm have dysregulated Notch, BMP and WNT/ß-catenin related signaling. Shear stress-response and cross-talk between Notch and Wnt pathways that normally ensures aortic integrity and resistance of endothelial cells to stress is impaired in aneurysmal patients.

Mechanisms of Smooth Muscle Cell Differentiation Are Distinctly Altered in Thoracic Aortic Aneurysms Associated with Bicuspid or Tricuspid Aortic Valves.

Cellular and molecular mechanisms of thoracic aortic aneurysm are not clear and therapeutic approaches are mostly absent. Thoracic aortic aneurysm is associated with defective differentiation of smooth muscle cells (SMC) of aortic wall. Bicuspid aortic valve (BAV) comparing to tricuspid aortic valve (TAV) significantly predisposes to a risk of thoracic aortic aneurysms. It has been suggested recently that BAV-associated aortopathies represent a separate pathology comparing to TAV-associated dilations. The only proven candidate gene that has been associated with BAV remains NOTCH1. In this study we tested the hypothesis that Notch-dependent and related TGF-ß and BMP differentiation pathways are differently altered in aortic SMC of BAV- vs. TAV-associated aortic aneurysms. SMC were isolated from aortic tissues of the patients with BAV- or TAV-associated aortic aneurysms and from healthy donors used as controls. Gene expression was verified by qPCR and Western blotting. For TGF-ß induced differentiation SMC were treated with the medium containing TGF-ß1. To induce proosteogenic signaling we cultured SMC in the presence of specific osteogenic factors. Notch-dependent differentiation was induced via lentiviral transduction of SMC with activated Notch1 domain. MYOCD expression, a master gene of SMC differentiation, was down regulated in SMC of both BAV and TAV patients. Discriminant analysis of gene expression patterns included a set of contractile genes specific for SMC, Notch-related genes and proosteogenic genes and revealed that control cells form a separate cluster from both BAV and TAV group, while BAV- and TAV-derived SMC are partially distinct with some overlapping. In differentiation experiments TGF-ß caused similar patterns of target gene expression for BAV- and TAV derived cells while the induction was higher in the diseased cells than in control ones. Osteogenic induction caused significant change in RUNX2 expression exclusively in BAV group. Notch activation induced significant ACTA2 expression also exclusively in BAV group. We show that Notch acts synergistically with proosteogenic factors to induce ACTA2 transcription and osteogenic differentiation. In conclusion we have found differences in responsiveness of SMC to Notch and to proosteogenic induction between BAV- and TAV-associated aortic aneurysms.

NOTCH1 Mutations in Aortic Stenosis: Association with Osteoprotegerin/RANK/RANKL.

Background. The NOTCH pathway is known to be important in the pathogenesis of calcific aortic valve disease, possibly through regulators of osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and its ligand (RANKL) system. The purpose of the present study was to search for possible associations between NOTCH1 gene mutations and circulating levels of OPG and soluble RANKL (sRANKL) in patients with aortic stenosis (AS). Methods. The study was performed on 61 patients with AS including 31 with bicuspid and 30 with tricuspid aortic valves. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Serum OPG and sRANKL levels were assessed. Results. In total, 6 genetic variants of the NOTCH1 gene including two new mutations were identified in the study group. In an age- and arterial hypertension-adjusted multivariable regression analysis, the serum OPG levels and the OPG/sRANKL ratio were correlated with NOTCH1 missense variants. All studied missense variants in NOTCH1 gene were found in Ca(2+)-binding EGF motif of the NOTCH extracellular domain bound to Delta-like 4. Conclusion. Our results suggest that the OPG/RANKL/RANK system might be directly influenced by genetic variants of NOTCH1 in aortic valve calcification.

Global cardiac risk assessment in the Registry Of Pregnancy And Cardiac disease: results of a registry from the European Society of Cardiology.

AIMS: To validate the modified World Health Organization (mWHO) risk classification in advanced and emerging countries, and to identify additional risk factors for cardiac events during pregnancy. METHODS AND RESULTS: The ongoing prospective worldwide Registry Of Pregnancy And Cardiac disease (ROPAC) included 2742 pregnant women (mean age ± standard deviation, 29.2 ± 5.5 years) with established cardiac disease: 1827 from advanced countries and 915 from emerging countries. In patients from advanced countries, congenital heart disease was the most prevalent diagnosis (70%) while in emerging countries valvular heart disease was more common (55%). A cardiac event occurred in 566 patients (20.6%) during pregnancy: 234 (12.8%) in advanced countries and 332 (36.3%) in emerging countries. The mWHO classification had a moderate performance to discriminate between women with and without cardiac events (c-statistic 0.711 and 95% confidence interval (CI) 0.686-0.735). However, its performance in advanced countries (0.726) was better than in emerging countries (0.633). The best performance was found in patients with acquired heart disease from developed countries (0.712). Pre-pregnancy signs of heart failure and, in advanced countries, atrial fibrillation and no previous cardiac intervention added prognostic value to the mWHO classification, with a c-statistic of 0.751 (95% CI 0.715-0.786) in advanced countries and of 0.724 (95% CI 0.691-0.758) in emerging countries. CONCLUSION: The mWHO risk classification is a useful tool for predicting cardiac events during pregnancy in women with established cardiac disease in advanced countries, but seems less effective in emerging countries. Data on pre-pregnancy cardiac condition including signs of heart failure and atrial fibrillation, may help to improve preconception counselling in advanced and emerging countries.

Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms.

Thoracic aortic aneurysm develops as a result of complex series of events that alter the cellular structure and the composition of the extracellular matrix of the aortic wall. The purpose of the present work was to study the cellular functions of endothelial and smooth muscle cells from the patients with aneurysms of the thoracic aorta. We studied endothelial and smooth muscle cells from aneurysms in patients with bicuspid aortic valve and with tricuspid aortic valve. The expression of key markers of endothelial (CD31, vWF, and VE-cadherin) and smooth muscle (SMA, SM22α, calponin, and vimentin) cells as well extracellular matrix and MMP activity was studied as well as and apoptosis and cell proliferation. Expression of functional markers of endothelial and smooth muscle cells was reduced in patient cells. Cellular proliferation, migration, and synthesis of extracellular matrix proteins are attenuated in the cells of the patients. We show for the first time that aortic endothelial cell phenotype is changed in the thoracic aortic aneurysms compared to normal aortic wall. In conclusion both endothelial and smooth muscle cells from aneurysms of the ascending aorta have downregulated specific cellular markers and altered functional properties, such as growth rate, apoptosis induction, and extracellular matrix synthesis.

Notch-dependent EMT is attenuated in patients with aortic aneurysm and bicuspid aortic valve.

Bicuspid aortic valve is the most common congenital heart malformation and the reasons for the aortopathies associated with bicuspid aortic valve remain unclear. NOTCH1 mutations are associated with bicuspid aortic valve and have been found in individuals with various left ventricular outflow tract abnormalities. Notch is a key signaling during cardiac valve formation that promotes the endothelial-to-mesenchymal transition. We address the role of Notch signaling in human aortic endothelial cells from patients with bicuspid aortic valve and aortic aneurysm. Aortic endothelial cells were isolated from tissue fragments of bicuspid aortic valve-associated thoracic aortic aneurysm patients and from healthy donors. Endothelial-to-mesenchymal transition was induced by activation of Notch signaling. Effectiveness of the transition was estimated by loss of endothelial and gain of mesenchymal markers by immunocytochemistry and qPCR. We show that aortic endothelial cells from the patients with aortic aneurysm and bicuspid aortic valve have down regulated Notch signaling and fail to activate Notch-dependent endothelial-to-mesenchymal transition in response to its stimulation by different Notch ligands. Our findings support the idea that bicuspid aortic valve and associated aortic aneurysm is associated with dysregulation of the entire Notch signaling pathway independently on the specific gene mutation.

Asymmetric Dimethylarginine in Patients with Ascending Aortic Aneurysms.

BACKGROUND: Ascending thoracic aortic aneurysm (aTAA) is a heterogeneous group of disorders that involve impaired endothelial function. The nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) serves as an endothelial dysfunction marker. Thus, we investigated ADMA levels in patients with aTAA. METHODS: Eighty-six patients with aTAA and 18 healthy individuals were enrolled. All patients underwent echocardiography. Plasma ADMA levels were measured using high-performance liquid chromatography. RESULTS: ADMA levels were higher in aTAA patients than in control patients (p = 0.034). According to the multivariable regression model, higher ADMA levels were associated with ascending aortic diameter (p = 0.017), smoking (p = 0.016), and log-transformed estimated glomerular filtration rate (eGFR, p = 0.005). CONCLUSION: This pilot study demonstrates an association of ADMA with ascending aortic dilatation; however, further studies are needed to investigate whether increased ADMA levels underlie aTAA development.