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BACKGROUND There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS). OBJECTIVES This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey. METHODS Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention. RESULTS A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001). CONCLUSIONS A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. (J Am Coll Cardiol 2021;78:2131-2143) (c) 2021 by the American College of Cardiology Foundation.

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%.

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%.

Background/Introduction Women with mechanical prosthetic heart valves are at greatest risk of developing complications.The main reason is that mechanical prosthetic heart valves require lifelong anticoagulation to reduce the high risk of associated thrombotic and hemorrhagic complications. Purpose The main goal of this study was to estimated risk factors and frequency of thrombotic and hemorrhagic complications during pregnancy, delivery and the postpartum period in women with prosthetic heart valves Methods According to retrospective cohort analyses in this study were included 70 patients with prosthetic heart valves who delivered in a specialized perinatal center from October 2010 to February 2020. All the patients were divided into two groups depending on prosthesis type: mechanical prostheses (44 deliveries in 44 patients), biological prostheses (22 deliveries in 19 patients). All patients were performed ECHO (Vivid 7, GE, USA). The average age were 30.7±5.2 years. The N-terminal brain natriuretic propeptide (NT-proBNP) concentration was determined by the quantitative electrochemiluminescence method using a Cobas E 411 analyzer (Roche, Switzerland). The activity of the anti –Xa factor was measured by chromogenic assays. Results In 9 (21.4%) pregnants with a mechanical valve prosthesis (MVP), prosthetic thrombosis was recorded until 2016. In 1 patient with mechanical valve prosthesis (2%) during pregnancy was complicated by an acute cerebral circulation disorder. Since 2016 there were monitored the activity of the anti –Xa factor. In 7 patients on the background of a change in anticoagulant therapy, pregnancy stopped in the early stages. Before pregnancy, 31.4% of the patients didn't have heart failure clinical manifestations, but in 12 (17.1%) patients during pregnancy had increase in NYHA Class maximum to NYHA Class III. The average NT-proBNP concentration was 912.3±1586.6 pg / ml. The frequency of the cesarean section in both groups was high: in patients with mechanical valve prosthesis in 78.5% and in the group of patients with biological valve prostheses in 68.1% of cases. There were not registered any new cases of prosthetic thrombosis after delivery, however, 9 patients had hemorrhagic complications in the early postpartum period, which required relaparotomy and blood transfusions. Regardless of frequent complications during pregnancy and in the postpartum period, no fatal outcomes have been reported. Conclusion The absence of mortality over the 9-years old observation and delivery in patients with valvular prostheses demonstrates the feasibility of monitoring and delivery of this category of patients in a specialized multidisciplinary medical center with experience in managing patients during pregnancy with valvular prostheses on anticoagulant therapy. Funding Acknowledgement Type of funding sources: None.

The mechanism of valve calcification, representing the main cause of aortic stenosis (AS) formation and progression still remains unclear. Currently, the role of the OPG/RANKL/RANK system is considered as one of important variants of valve calcification pathogenesis. In this study we have investigated the differences in the levels of OPG and sRANKL involved in the calcification processes in tissues of patients with severe AS. The study was performed on AS patients, on patients with aortic dilatation, and also on AS patients with aortic dilatation. Increased level of RANKL was found in AS patients and it was higher in valve than in aortic tissue. In patients with aortic dilatation the RANKL level negatively correlated with aortic dilatation. The results of this study confirm importance of the OPG/RANKL/RANK system for calcification in AS patients. Although patients of all groups had comparable values of OPG (including patients with aortic dilatation), increased RANKL level was found only in AS patients. This suggests involvement of some additional mechanisms influencing the increase of RANKL expression.

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.

Comparative in vitro study examined the osteogenic potential of interstitial cells of aortic valve obtained from the patients with aortic stenosis and from control recipients of orthotopic heart transplantation with intact aortic valve. The osteogenic inductors augmented mineralization of aortic valve interstitial cells (AVIC) in patients with aortic stenosis in comparison with the control level. Native AVIC culture of aortic stenosis patients demonstrated overexpression of osteopontin gene (OPN) and underexpression of osteoprotegerin gene (OPG) in comparison with control levels. In both groups, AVIC differentiation was associated with overexpression of RUNX2 and SPRY1 genes. In AVIC of aortic stenosis patients, expression of BMP2 gene was significantly greater than the control level. The study revealed an enhanced sensitivity of AVIC to osteogenic inductors in aortic stenosis patients, which indicates probable implication of OPN, OPG, and BMP2 genes in pathogenesis of aortic valve calcification.

Osteogenic transformation as a result of cellular plasticity could be both beneficial, in the case of bone formation, and hazardous, in the case of vascular calcification. Mechanisms driving vascular calcification remain poorly understood, while calcification of the vessels is one of the leading causes of morbidity and mortality. In particular, calcification of the aortic valve is a serious complication requiring surgical intervention. The mechanisms behind aortic valve calcification and the origin of cells driving osteogenic transformation of the aortic valve remain questionable. A circulating stem cell theory supports the view that pathologic calcification could originate not only from valve cells, but also from other sources. The aim of this study was to estimate the osteogenic potential of adipose tissue-derived mesenchymal stem cells (MSCs) from people with calcification of the aortic valve versus MSCs from healthy people; further, to compare the capacity of osteogenic differentiation between MSCs and valve interstitial cells (VICs) from healthy donors and patients with severe calcification of the aortic valve. MSCs and VICs were isolated from either healthy donors or from patients with aortic valve calcification. The cells were immunophenotyped for conventional MSC markers by flow cytometry. Osteogenic differentiation was induced by addition of specific osteogenic inductors to the culture medium. Osteogenic differentiation was assessed by alizarin red staining and by estimation of RUNX2 expression by qPCR. The MSCs of healthy donors were capable of efficient osteogenic differentiation, while MSCs of the patients with aortic valve calcification were not capable of osteogenic differentiation. We conclude that there is no correlation between the capacity of adipose MSCs to osteogenically transform and calcification of the aortic valve. Most likely, peripheral MSCs of adipose origin could not be a source of aortic valve calcification.

Introduction. The large-scale studies on adult patients with congenital heart disease (CHD) demonstrated high prevalence of thrombocytopenia, especially in patients with Eisenmenger syndrome (sEis). The exact reasons for the decline of platelet count in adults with CHD are currently unknown. Objective: to determine the prevalence of thrombocytopenia in a representative group of adult patients with CHD and explore the possible causes of thrombocytopenia. Methods. A retrospective study of 17 pregnant women with CHD was carried out. All women were admitted for delivery to Federal Almazov North-West Medical Research Centre. Data are presented as median (25th, 75th percentile) and as M±σ for parametric variables. Results. The median age was 26 (21; 28) years. The average period of gestation at the time of admission was 31 (28; 34) weeks. 12 (70.6 %) patients had sEis. At the time of admission PAPsys was 88 (82; 98) mm Hg, SpO 2 - 92 (85; 95)%. In whole group the platelet count median was 105 (62; 164) 10 9 /L, while in 12 (71%) women platelet count was less than 150 10 9 /L. There was a significant difference between patients with sEis and women without right-to-left shunt in platelet count: 99 (73; 105) and 162 (138; 166) 10 9 /L, respectively, p

Background Aortic stenosis (AS) is the most common acquired valvular heart disease. Calcification of the aortic valve (AV) cusps is the main pathogenetic mechanism of AS formation, however triggering and progression mechanisms of it are not fully understood. Aortic valve interstitial cells (AVIC) are one of the main cell populations responsible for the AV structure and homeostasis. The aim of the study was to characterize the ability of AVIC to osteogenic differentiation using the model of the primary culture of AVIC of patients with aortic stenosis and assess the expression of genes involved in osteogenesis (RUNX2, BMPG2, SPRY1, SOX9, CTNNB1, POSTN, OPG and OPN). Materials and methods The study was carried out on primary human AVIC culture obtained by enzymatic dissociation of experimental valve specimens from patients with AS (n=15) and the control specimens from the orthotopic heart transplantation recipients (n=10). To assess the osteogenic potential of AVIC, the routine stem cell osteodifferentiation protocol based on the culture medium with addition of inductors (10 mM β-glycerophosphate, 0.1 μM dexamethasone, and 50 μg/ml ascorbic acid) was used. Calcium deposits were demonstrated by Alizarin Red staining. Analysis of the expression of osteogenic differentiation genes, such as RUNX2 (runtrelated transcription factor 2), BMP2 (bone morphogenetic protein 2), SPRY1 (Sprouty RTK signaling antagonist 1), SOX-9 (SRY-box9), CTNNB1 (β-catenin1), POSTN (periostin), OPG (osteoprotegerin), and OPN (osteopontin), was performed by real-time PCR. Results The inductors of osteogenic differentiation provoked greater mineralization of AVIC cultures derived from the patients with AS than that observed in control group (p=0.0003). The expression of RUNX2 and SPRY1 in non-differentiated cells was reduced compared with control cells in patients with bicuspid AV (p=0.02). After 21 days of the osteogenic induction, the expression of RUNX2 and SPRY1 increased in all three groups. At the same time, the expression of SPRY1 was lower in the group with bicuspid AV compared with tricuspid AV (p=0.007). The expression level of BMP2 did not differ between groups in unstimulated AVIC, however, it increased after osteogenic differentiation in the group of patients with tricuspid AV (p=0.017). OPN expression was higher in cells from tricuspid AV, while OPG expression was reduced in patients with both bicuspid and tricuspid AV (p Conclusions The osteogenic potential of AVIC is increased in patients with aortic stenosis. The gene expression profile of osteogenic differentiation differs in patients with a bicuspid and tricuspid aortic valve. Damage of protective mechanisms may be a potential mechanism for accelerated valve calcification mostly in patients with tricuspid aortic valve. Acknowledgement/Funding Russian Foundation for Basic Research, project 18-015-00016

Introduction Calcification is the key pathological process in aortic stenosis (AS) development. Circulating biomarkers and nuclear imaging methods could characterize the valvular calcification activity. Purpose To compare diagnostic values of serum fetiun A level and PET/CT with 18F NaF in assessment of aortic valve calcification. Methods 88 pts with asymptomatic AS were included: 39pts with tricuspid aortic valve (TAV) and 49 pts with bicuspid aortic valve (BAV). ECHO was performed at baseline and in 16.6±4.2 months. At start serum level of fetuin A was measured by ELlSA in all pts and PET/CT with 18F NaF was performed in 60 of these pts (29 TAV pts and 31 BAV pts). Maximum standardized uptake value (SUV) was measured within circular region of interest (ROI) of 3.52 square millimeters that was drawn around areas of maximal 18F-NaF uptake in the valve. Blood-pool activity was estimated using maximum SUV within the same ROI, which was drawn on the left atrium. Ratio between maximum tissue and background SUV (TBR) was calculated. CT calcium scoring was performed using dedicated software. Results Pts with TAV were significantly older then BAV pts (62.4±5.3 yrs vs 55.9±8.4 yrs, p=0.003). TAV and BAV groups were comparable in AS severity by ECHO (peak aortic jet velocity (Vmax): 3.1±0.6 m/s vs 3.1±0.7 m/s, p=0.72). Both groups did not differ in valvular calcification degree (Agatston score 1433.9±1327.9 vs 1617.7±1404.5, p=0.59) and 18F-NaF uptake level (TBR 1.6±0.3 vs 1.6±0.5, p=0.64). Agatston score and TBR max 18F NaF were associated with AS severity measured by Vmax (r=0.58; p Conclusions Despite comparable valve calcification activity measured by PET/CT with 18F NaF in TAV and BAV pts, decreased circulating fetuin A was observed only in BAV pts, that may be related to different underlying pathophysiological mechanisms. Low serum fetuin-A level was associated with progression of AS, particularly in BAV pts. Acknowledgement/Funding Grant of Russian Foundation for Basic Research No. 18-015-00016

Background Nowadays, Pulmonary Hypertension (PH) is one of the most pressing issues in cardiovascular disease. Subsequently, pregnant women have a high degree of risk of morbidity and mortality and this poses a big challenge. Studies show that very often PH occurs due to congenital heart disease and for this reason, it is recommended to avoid pregnancy or to terminate the pregnancy at an early stage. Women who choose to remain pregnant should be treated at specialized PH centers with the experience of managing PH during and after pregnancy. Purpose The main purpose of this study was to estimate the survival of pregnant pts with PH depending on the severity of PH and etiology. Methods 8336 women during delivery on admission were screened from the period spanning January 2014 to December 2016. Of this number, 4268 (51%) the medical records of pregnant women with cardiovascular disease were retrospectively reviewed to identify patients with coexisting PH and pregnancies. Data on 98 (1.18%) pts with PH were identified and included in the study. All patients' PH severity was measured by Doppler echocardiography. Pulmonary artery systolic pressure value of 35 to 50 mm Hg, 51 to 70 mm Hg, or greater than 71 mm Hg measured by echocardiography corresponded to the mild, moderate, or severe PH, respectively. Demographics, characteristics of PH and pregnancy, management and outcomes were as well analyzed. Results 54 cases (55%) were classified into WHO group 1, 40 cases (41%) in group 2 (reason –left heart disease), 4 cases (4%) in group 4 (reason - pulmonary thromboembolism), and none in group 3 or 5. The systolic pulmonary artery pressure was Conclusion Our study shows that maternal mortality is associated with the severity of PH. Mortality in pregnant patients with pulmonary hypertension is still the most discussed problem in cardiology and obstetrics. It is necessary to diagnose this disease at an early stage, prevent pregnancy in pts with severe to moderate PH as much as possible, continue observation, adequately apply therapy in order to help curtail this problem.

Background Controversial results on maternal risk and fetal outcome have been reported in women with aortic stenosis (AS). Objectives The authors sought to investigate maternal and fetal outcomes in patients with AS in a large cohort. Methods The Registry on Pregnancy and Cardiac Disease (ROPAC) is a global, prospective observational registry of women with structural heart disease, providing a uniquely large study population. Data of women with moderate (peak gradient 36 to 63 mm Hg) and severe AS (peak gradient ≥64 mm Hg) were analyzed. Results Of 2,966 pregnancies in ROPAC, the authors identified 96 women who had at least moderate AS (34 with severe AS). No deaths were observed during pregnancy and in the first week after delivery. However, 20.8% of women were hospitalized for cardiac reasons during pregnancy. This was significantly more common in severe AS compared with moderate AS (35.3% vs. 12.9%; p = 0.02), and reached the highest rate (42.1%) in severe, symptomatic AS. Pregnancy was complicated by heart failure in 6.7% of asymptomatic and 26.3% of symptomatic patients, but could be managed medically, except for 1 patient who was symptomatic before pregnancy and underwent balloon valvotomy. Children of patients with severe AS had a significantly higher percentage of low birth weight (35.0% vs. 6.0%; p = 0.006). Conclusions Mortality in pregnant women with AS, including those with severe AS, appears to be close to zero in the current era. Symptomatic and severe AS does, however, carry a substantial risk of heart failure and is associated with high rates of hospitalization for cardiac reasons, although heart failure can nearly always be managed medically. The results highlight the importance of appropriate pre-conceptional patient evaluation and counseling.

OBJECTIVES: To describe the incidence, onset, predictors and outcome of ventricular tachyarrhythmia (VTA) in pregnant women with heart disease. BACKGROUND: VTA during pregnancy will cause maternal morbidity and even mortality and will have impact on fetal outcome. Insufficient data exist on the incidence and outcome of VTA in pregnancy. METHODS AND RESULTS: From January 2007 up to October 2013, 99 hospitals in 39 countries enrolled 2966 pregnancies in women with structural heart disease. Forty-two women (1.4%) developed clinically relevant VTA during pregnancy, which occurred mainly in the third trimester (48%). NYHA class >1 before pregnancy was an independent predictor for VTA. Heart failure during pregnancy was more common in women with VTA than in women without VTA (24% vs. 12%, p=0.03) and maternal mortality was respectively 2.4% and 0.3% (p=0.15). More women with VTA delivered by Cesarean section than women without VTA (68% vs. 47%, p=0.01). Neonatal death, preterm birth (

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.

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.

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/β-catenin pathways was estimated by qPCR; WNT/β-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/β-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.

Aims Calcific aortic valve disease is the most common heart valve disease in the Western world. Bicuspid and tricuspid aortic valve calcifications are traditionally considered together although the dynamics of the disease progression is different between the two groups of patients. Notch signaling is critical for bicuspid valve development and NOTCH1 mutations are associated with bicuspid valve and calcification. We hypothesized that Notch-dependent mechanisms of valve mineralization might be different in the two groups. Methods and results We used aortic valve interstitial cells and valve endothelial cells from patients with calcific aortic stenosis with bicuspid or tricuspid aortic valve. Expression of Notch-related genes in valve interstitial cells by qPCR was different between bicuspid and tricuspid groups. Discriminant analysis of gene expression pattern in the interstitial cells revealed that the cells from calcified bicuspid valves formed a separate group from calcified tricuspid and control cells. Interstitial cells from bicuspid calcified valves demonstrated significantly higher sensitivity to stimuli at early stages of induced proosteogenic differentiation and were significantly more sensitive to the activation of proosteogenic OPN, ALP and POSTIN expression by Notch activation. Notch-activated endothelial-to-mesenchymal transition and the corresponding expression of HEY1 and SLUG were also more prominent in bicuspid valve derived endothelial cells compared to the cells from calcified tricuspid and healthy valves. Conclusion Early signaling events including Notch-dependent mechanisms that are responsible for the initiation of aortic valve calcification are different between the patients with bicuspid and tricuspid aortic valves.

Objective: Aortic valve (AV) calcification is the major cause of aortic stenosis viewed as severe heart failure. Calcification was earlier believed to be a passive degenerative process, however it ...

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.

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.

The level of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1α) in human blood plasma was investigated. Samples of healthy individuals (n=34) and patients with cardiovascular diseases (n=110), including aortic aneurysm (n=69), aortic stenosis (n=25) and patients without aortic pathologies were analyzed. In patients the PGC1α concentration was higher than that in healthy persons, and tended to decrease with age. Elevated concentrations of lactic acid, total homocysteine and asymmetric dimethylarginine in the blood of patients suggested a parallel development of endothelial and secondary mitochondrial dysfunction. However, concentrations of lactic and pyruvic acids exceeding reference limit were associated with the decrease in the PGC1α level.Vpervye provedeno issledovanie urovnia belka PGC1a (1a-koaktivatora gamma-retseptora, aktiviruiushchego proliferatsiiu peroksisom) v plazme krovi. Issledovany obraztsy zdorovykh lits (n=34) i patsientov s serdechno- sosudistymi zabolevaniiami (n=110), v tom chisle s anevrizmoĭ aorty (n=69), s aortal'nym stenozom (n=25) i bez patologii aorty. V gruppe patsientov kontsentratsiia PGC1a byla vyshe, chem u zdorovykh lits, i imela tendentsiiu k snizheniiu s vozrastom. Povyshennye kontsentratsii molochnoĭ kisloty, obshchego gomotsisteina i asimmetrichnogo dimetilarginina v krovi patsientov svidetel'stvovali o parallel'nom narastanii éndotelial'noĭ i vtorichnoĭ mitokhondrial'noĭ disfunktsiĭ. Na fone kontsentratsiĭ molochnoĭ i pirovinogradnoĭ kislot vyshe referentnykh znacheniĭ obnaruzheno snizhenie kontsentratsii PGC1a.

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.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.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.

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.

Objectives: The purpose of this study was to evaluate potential mechanisms promoting ascending aorta aneurysm (AAA) development in the pts with different pathology. Design and methods: Aortic tissue samples were collected during operation from 50 pts with AAA: 16 pts with atherosclerosis (AS) (mean age 60.1±1.6 yrs; 1.5:1, ratio m:f), 22 pts with bicuspid aortic valves (BAV) (mean age 55.7±1.9 yrs; 1.6:1, ratio m:f) and 12 pts with tricuspid valves (TAV) (mean age 50.4±4.3 yrs; 1.7:1, ratio m:f). Tissue samples were collected from 17 pts without aortic pathology (mean age 56.5±3.5 yrs). Matrix metalloproteinase (MMP) -2,-9 activities were assessed in aortic tissue homogenates by substrate-specific zymographic analysis. The relative abundances of latent MMP-2,9, collagen I, elastin and fibrillin were determined by quantitative immunoblotting techniques. Arterial stiffness was assessed by SphygmoCor device (Australia) using indirect carotid-femoral distance. The normal value of pulse wave velocity (PWV) was considered below 10 m/s. Results: There were no significant differences in thoracic aorta diameter between the groups (65.4±13.3 mm in AS, vs 58.0±4.8 mm in BAV vs 64.1±12.9 mm in TAV). Latent MMP2 was increased in all AAA groups compared with controls (BAV, TAV and AS p=0.003, p=0.029, p=0.007, respectively). But latent MMP9 was higher only in BAV group (p=0.04). Aortic dilatation in pts with BAV was associated with increased active MMP-9 level (r=0.66, p=0.037). There was increased the collagen/elastin ratio in all pts with AAA, but significant only in BAV (3.2±2.3) compared with controls (1.1±0.5, p=0.018). An increase of collagen content was correlated with active MMP9 level in pts with AS (r=0.559, p=0.037), whereas change of collagen/elastin ratio in pts with BAV was associated with increased latent MMP2 (r=0.608, p=0.02). Tendency to increase of latent and active MMP9 level was related with increase of index augmentation in all groups. Conclusions: Composition of the extracellular matrix determines the MMP activity and plays an important role in the pathogenesis of AAA. More significant changes in the composition of the extracellular matrix proteins may explain the rapid increase in the aorta diameter in pts with BAV. Arterial stiffness can be used as a marker for noninvasive monitoring of patients with aortic dilatation.

Objective To evaluate outcomes of aortic valve-sparing operations in patients with aortic root aneurysms (ARA) combined with aortic insufficiency (AI) Methods Since March 2006, in our clinic 264 patients with ascending aortic aneurysms were operated on. 140 patients had ARA combined with aortic valve (AV) disease. 50 patients underwent aortic valve-sparing surgery. We performed 49 Tirone David I (TD-I) and 1 Yacoub procedures. Additional procedures were hemiarch repair (n = 1), mitral valve repair (n = 9) and CABG (n = 6). We assessed hospital and long-term results of aortic valve-sparing operations. Results Total hospital (30-day) mortality was 4% (n = 2). 2(4%) patients required reoperation due to post-operative bleeding. Echocardiography showed none or trivial AI in 38%, mild AI in 54% and moderate AI in 8%. We revealed positive correlation between residual AI and size of aortic annulus, previous AI grade, and size of aortic prosthesis (optimal result in linear aortic graft size 3–5 mm exceeding aortic annulus size). Follow-up was 60% completed. Late mortality was 2% (1 patient). Echocardiography revealed none or trivial AI in 53%, mild AI in 20%, moderate AI in 17% and severe AI in 10% (3 patients). One patient required reoperation 3 years after TD-I operation, the AV replacement with mechanical prosthesis was performed. Another two patients with severe AI are under close surveillance due to normal LV size and NYHA class 1–2. We revealed positive correlation between late AI and residual AI grade, and aortic leaflets coaptation point (optimal result in cases with location of coaptation point at the aortic annulus level or 1–2 mm upper). Conclusions TD-1 aortic valve-sparing reimplantation is optimal method of treatment in patients with ARA, AI and unaltered AV leaflets. Concordance of linear aortic graft size 3–5 mm exceeding aortic annulus and positioning of AV leaflets coaptation point at the level of aortic annulus or 1–2 mm upper are precursors of good result of valve-sparing operation.