Development Of Aortic Stenosis Research Articles

Long-Term Outcomes After Transcatheter Aortic Valve Implantation in Patients With Chronic Inflammatory Disease.

Chronic inflammatory disease (CID) accelerates atherosclerosis and the development of aortic stenosis. Data on long-term outcomes after transcatheter aortic valve implantation (TAVI) in those patients are missing. The aim of this study was to investigate the clinical long-term outcomes of patients with and without autoimmune-related CID undergoing TAVI for the treatment of severe aortic stenosis. From a prospective registry, consecutive patients with TAVI were included. Baseline clinic and imaging data (echocardiographic and computed tomography) were analyzed. Long-term (up to 5 years) clinical and echocardiographic outcomes were studied. Of 1000 consecutive patients (mean age 81±6 years, 46% female), 107 (11%) had CID; the most frequent entities included polymyalgia rheumatica (31%) and rheumatoid arthritis (28%). Patients with CID were predominantly female (60% versus 44%, P=0.002) and more often had pulmonary disorders (21% versus 13%, P=0.046) and atrial fibrillation (32% versus 20%, P=0.003). The presence of CID was associated with a higher rate of postinterventional infection (5% versus 1%, P=0.007) and further emerged as a risk factor for rehospitalization for bleeding or infection (hazard ratio, 1.93 and 1.62, respectively). Premature valve degeneration, endocarditis, and all-cause mortality were not increased among patients with CID. This real-world analysis found that patients with CID undergoing TAVI were associated with a higher risk of postinterventional infectious complications and rehospitalization due to infection. However, valve durability and survival seem not to differ between patients with TAVI with versus without CID.

Clinical Use of Blood Flow Analysis through 4D-Flow Imaging in Aortic Valve Disease.

Bicuspid aortic valve (BAV), which affects 1% of the general population, results from the abnormal fusion of the cusps of the aortic valve. BAV can lead to the dilatation of the aorta, aortic coarctation, development of aortic stenosis (AS), and aortic regurgitation. Surgical intervention is usually recommended for patients with BAV and bicuspid aortopathy. This review aims to examine 4D-flow imaging as a tool in cardiac magnetic resonance imaging for assessing abnormal blood flow and its clinical application in BAV and AS. We present a historical clinical approach summarizing evidence of abnormal blood flow in aortic valve disease. We highlight how abnormal flow patterns can contribute to the development of aortic dilatation and novel flow-based biomarkers that can be used for a better understanding of the disease progression.

Subtotal Nephrectomy Associated with a High-Phosphate Diet in Rats Mimics the Development of Calcified Aortic Valve Disease Associated with Chronic Renal Failure

Introduction. This study addressed the hypothesis that subtotal nephrectomy associated with a high-phosphorus diet (5/6Nx + P) in rats represents a suitable animal model to mimic the cardiovascular consequences of chronic kidney disease (CKD) including calcified aortic valve disease (CAVD). Indeed, the latter contributes to the high morbidity and mortality of CKD patients and sorely lacks preclinical models for pathophysiological and pharmacological studies. Methods. Renal and cardiovascular function and structure were compared between sham-operated and 5/6 Nx rats + P 10 to 12 weeks after surgery. Results. As expected, 11 weeks after surgery, 5/6Nx + P rats developed CKD as demonstrated by their increase in plasma creatinine and urea nitrogen and decrease in glomerular filtration rate, estimated by using fluorescein-isothiocyanate-labelled sinistrin, anemia, polyuria, and polydipsia compared to sham-operated animals on a normal-phosphorus diet. At the vascular level, 5/6Nx + P rats had an increase in the calcium content of the aorta; a decrease in mesenteric artery dilatation in response to a stepwise increase in flow, illustrating the vascular dysfunction; and an increase in blood pressure. Moreover, immunohistology showed a marked deposition of hydroxyapatite crystals in the aortic valve of 5/6Nx + P rats. Echocardiography demonstrated that this was associated with a decrease in aortic valve cusp separation and an increase in aortic valve mean pressure gradient and in peak aortic valve velocity. Left-ventricular diastolic and systolic dysfunction as well as fibrosis were also present in 5/6Nx + P rats. Conclusion. This study demonstrates that 5/6Nx + P recapitulates the cardiovascular consequences observed in humans with CKD. In particular, the initiation of CAVD was shown, highlighting the interest of this animal model to study the mechanisms involved in the development of aortic stenosis and test new therapeutic strategies at an early stage of the disease.

481 Association Of Inflammation And Lipoprotein(a) With The Burden Of Aortic Valve Calcification

Introduction: Lipoprotein(a) [Lp(a)] and inflammation are important risk factors for aortic valve calcification (AVC), the underlying process in the development of aortic stenosis. A strong interaction between Lp(a) and inflammation has been observed for atherosclerotic cardiovascular disease (ASCVD), but it is uncertain whether this interaction exists for AVC.

TRPM4 in radiation-induced aortic valve remodeling

Thoracic radiation therapy may lead to unexpected cardiac remodelling, and up to 12% of patients treated with radiotherapy for breast cancer develop valvular dysfunction including regurgitation and stenosis. This phenomenon can affect both aortic and mitral valves and involve fibrosis and calcification. It is suspected that irradiation modify Ca2+ handling as well as fibroblast activity or development, but molecular determinants remain unknown. The monovalent non-selective cation channel TRPM4 is known to be involved in calcium handling since it modulates driving force for Ca2 + -entry and produced cell depolarization potentiating voltage-gated Ca2+ channels opening. It also participates in human atrial fibroblast transition to myofibroblast, a phenomenon with similarities to those observed during aortic valve stenosis. This channel exhibits a high expression in cardiac tissue and is involved in cardiac remodeling. Our aim was to evaluate the participation of TRPM4 in radiation-induced valvular damages. In order to achieve this aim we developed a model of 4 months Trpm4+/+ and Trpm4-/- mouse submitted to 10 Gy irradiation at the aortic valve. Cardiac parameters were evaluated by echography measurements at 5 months post-irradiation. At that time, mice were euthanized and hearts collected for histological assessments. In control conditions Trpm4-/- mice exhibited a left ventricular hypertrophy compared to Trpm4+/+, as previously reported in this model, but maximal velocity of aortic jet (Vmax) was similar in Trpm4+/+ and Trpm4-/- mice. Five month after irradiation, Trpm4+/+ mice developed a significant 30% increase in Vmax as well as an increase in maximal and mean pressure gradient, while no significant variation was detected in Trpm4-/- animals. Trpm4+/+ irradiated mice have shown a significant 48% increase of the surface of aortic valve leaflets compare to Trpm4+/+ control mice while no significant variation were observed in Trpm4-/- animals. These results indicate that TRPM4 promote radiation-induced valvular remodelling. Thus TRPM4 might be regarded as a target to prevent cardiac side effects in chest radiotherapy and might be involved in aortic stenosis development. This work was supported by a grant ANR-16-RHUS-0003 and conducted as part of the FHU CARNAVAL project.

Prioritization of Candidate Biomarkers for Degenerative Aortic Stenosis through a Systems Biology-Based In-Silico Approach.

Degenerative aortic stenosis is the most common valve disease in the elderly and is usually confirmed at an advanced stage when the only treatment is surgery. This work is focused on the study of previously defined biomarkers through systems biology and artificial neuronal networks to understand their potential role within aortic stenosis. The goal was generating a molecular panel of biomarkers to ensure an accurate diagnosis, risk stratification, and follow-up of aortic stenosis patients. We used in silico studies to combine and re-analyze the results of our previous studies and, with information from multiple databases, established a mathematical model. After this, we prioritized two proteins related to endoplasmic reticulum stress, thrombospondin-1 and endoplasmin, which have not been previously validated as markers for aortic stenosis, and analyzed them in a cell model and in plasma from human subjects. Large-scale bioinformatics tools allow us to extract the most significant results after using high throughput analytical techniques. Our results could help to prevent the development of aortic stenosis and open the possibility of a future strategy based on more specific therapies.

The Influence of Coronary Artery Disease in the Development of Aortic Stenosis and the Importance of the Albumin Redox State.

Calcific aortic valve and coronary artery diseases are related cardiovascular pathologies in which common processes lead to the calcification of the corresponding affected tissue. Among the mechanisms involved in calcification, the oxidative stress that drives the oxidation of sulfur-containing amino acids such ascysteines is of particular interest. However, there are important differences between calcific aortic valve disease and coronary artery disease, particularly in terms of the reactive oxygen substances and enzymes involved. To evaluate what effect coronary artery disease has on aortic valves, we analyzed valve tissue from patients with severe calcific aortic stenosis with and without coronary artery disease. Proteins and peptides with oxidized cysteines sites were quantified, leading to the identification of 16 proteins with different levels of expression between the two conditions studied, as well as differences in the redox state of the tissue. We also identified two specific sites of cysteine oxidation in albumin that have not been described previously. These results provide evidence that coronary artery disease affects valve calcification, modifying the molecular profile of aortic valve tissue. In addition, the redox proteome is also altered when these conditions coincide, notably affecting human serum albumin.

The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications.

Despite the elucidation of the pathways behind the development of aortic stenosis (AS), there remains no effective medical treatment to slow or reverse its progress. Instead, the gold standard of care in severe or symptomatic AS is replacement of the aortic valve. Oxidative stress is implicated, both directly as well as indirectly, in lipid infiltration, inflammation and fibro-calcification, all of which are key processes underlying the pathophysiology of degenerative AS. This culminates in the breakdown of the extracellular matrix, differentiation of the valvular interstitial cells into an osteogenic phenotype, and finally, calcium deposition as well as thickening of the aortic valve. Oxidative stress is thus a promising and potential therapeutic target for the treatment of AS. Several studies focusing on the mitigation of oxidative stress in the context of AS have shown some success in animal and in vitro models, however similar benefits have yet to be seen in clinical trials. Statin therapy, once thought to be the key to the treatment of AS, has yielded disappointing results, however newer lipid lowering therapies may hold some promise. Other potential therapies, such as manipulation of microRNAs, blockade of the renin-angiotensin-aldosterone system and the use of dipeptidylpeptidase-4 inhibitors will also be reviewed.

Circulating metabolome does not predict development of aortic stenosis

Abstract Background Calcific aortic valve disease (CAVD) is the most common valvular heart disease in Western world. CAVD is ranging from mild aortic valve sclerosis to severe obstructive aortic stenosis (AS). The development of AS has been associated with several risk factors including age, sex and hypertension. However, there is limited knowledge about factors that predict the development of aortic stenosis. Purpose We investigated if the circulating metabolite profile can predict the development of aortic stenosis in Finnish males. Methods We did a non-targeted LC-MS metabolomics analysis to baseline (1984–1989) serum samples from a prospective population-based Kuopio Ischemic Heart Disease risk factor study (KIHD) cohort of 2682 random Finnish males aged from 42 to 60 years. During the follow-up (until year 2020), 53 subjects developed either moderate (peak flow gradient 36–64mmHg or mean flow gradient 20–40mmHg) or severe aortic valvular stenosis (peak flow gradient over 64mmHg or mean gradient over 40mmHg). The AS patients were collected from the KIHD database using appropriate ICD-10 -codes for aortic valvular disease (from baseline to the end of the year 2017) and the diagnosis was checked manually using hospital medical records of the individuals. Results The AS patients seemed to have altered lipid metabolism and possibly altered composition of gut microbiota, since several acylcarnitines (e.g. octanoylcarnitine [Cohen's d=−0.40], decanoylcarnitine [d=−0.43], layroylcarnitine [d=−0.41], and oleoylcarnitine [d=−0.40]), and branched chain amino acids (BCAA, e.g. leucine [d=0.39], and isoleucine [d=0.49]) had p-values below 0.05. However, after correction for multiple testing, there were no significant differences between the cases and controls. Conclusions The present preliminary results, in need of verification with a larger set of samples, suggest that subjects, who will later develop AS might have reduced levels of acylcarnitines and increased levels of BCAA when compared to matched controls. However, these changes do not have large effects sizes and are likely not good candidates for biomarkers to predict future diagnosis of AS. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Finnish Cultural Foundation, The Finnish Foundation for Cardiovascular Research.

Association between Serum Phosphate Levels and the Development of Aortic Stenosis in Patients Undergoing Hemodialysis.

We aimed to investigate the factors associated with the development of aortic stenosis (AS) in patients undergoing hemodialysis (HD), and to elucidate the prognosis of HD patients with AS. Patients on HD that had also undergone echocardiography at Nagasaki Renal Center between July 2011 and June 2012 were included. Patients with AS at the time of inclusion were excluded. The diagnosis of AS was based on an annual routine or additional echocardiography. The patients were followed up until June 2021. The association between patient background and AS was also evaluated. Of the 302 patients (mean age, 67.4 ± 13.3 years; male, 58%; median dialysis history, 4.7 years), 60 developed AS and 10 underwent aortic valve replacement. A Cox proportional hazards model revealed that age (hazard ratio (HR), 1.07; 95% confidential interval (CI), 1.04–1.10; p < 0.001) and serum phosphate levels (HR, 1.40; 95%CI, 1.16–1.67, p < 0.001) were independent risk factors for developing AS. Incidentally, there was no significant mortality difference between patients with AS and those without (p = 0.53). Serum phosphate levels are a risk factor for developing AS and should be controlled. Annual echocardiography may contribute to the early detection of AS and improves the prognosis of patients undergoing HD.

INCREASED PREVALENCE AND HIGHER 1-YEAR MORTALITY OF PATIENT HOSPITALIZED FOR AORTIC STENOSIS WITH COMORBID CHRONIC KIDNEY DISEASE IN THE PROVINCE OF QUEBEC, CANADA

Abstract Objective: Development of aortic stenosis is associated with valvular calcifications which are highly prevalent in chronic kidney disease (CKD). The objective of this study was to evaluate the temporal trends in the prevalence and 1-year mortality of patients hospitalized for aortic stenosis according to comorbid CKD status in the province of Quebec, between 2000–2017. Design and method: Using the Quebec Integrated Chronic Disease Surveillance System, we identified patients aged 20 years and older with incident aortic stenosis using International Classification of Diseases diagnostic codes versions 9 and 10, in the hospital discharge database. We subsequently combined hospital discharges and physician billing claims databases to identify patients with comorbid CKD in the two years prior to aortic stenosis’ diagnosis. Three subgroups of CKD were considered: 1) non-CKD, 2) pre-dialysis and 3) dialysis. The distribution of the 2016–2017 aortic stenosis population was used for age-standardization of prevalence, 1-year all-cause and cardiovascular mortality. Results: We included 108 780 patients with incident aortic stenosis (females: 51.8%; mean age (±SD): 76.4 ± 11.7; comorbid CKD status: 80 768 non-CKD; 26 809 pre-dialysis; 1 203 dialysis). During the study period, the age-standardized prevalence of non-CKD patients decreased by 14% (80.72% [95% CI 77.56–83.99] to 69.56% [95% CI 67.23–71.94]; Figure 1). Inversely, the age-standardized prevalence of pre-dialysis and dialysis patients increased by 58% (18.52% [95% CI 16.93–20.21] to 29.33% [95% CI 27.82–30.91]) and 46% (0.76% [95% CI 0.51–1.11] to 1.11% [95% CI 0.84–1.44]), respectively. Age-standardized 1-year all-cause and cardiovascular mortality decreased over time but remained higher in patients with comorbid CKD. In 2015–2016, age-standardized relative risk of 1-year all-cause mortality was significantly higher in pre-dialysis (RR = 1.56 [95% CI 1.44, 1.69]) and dialysis (RR = 2.04 [95% CI 1.62–2.61]) than in non-CKD patients. Age-standardized relative risk of 1-year cardiovascular mortality was also significantly higher in pre-dialysis (RR = 1.83 [95% CI 1.66–2.03]) and dialysis (RR = 2.28 [95% CI 1.68–3.09]) than in non-CKD patients. Conclusions: Prevalence of patients with incident aortic stenosis and comorbid CKD increased between 2000–2017. 1-year all-cause and cardiovascular mortality improved over time but remain higher in aortic stenosis patients with comorbid CKD.

Ubiquitin-specific protease as the underlying gene biomarker for aortic stenosis

BackgroundAortic stenosis is a common heart valvular disease whose pathological processes include an inflammatory reaction and lipid accumulation. However, its detailed pathogenesis is yet to be completely elucidated. Therefore, it is of great significance to further explore the molecular mechanisms of aortic stenosis.MethodsFour datasets were downloaded from the Gene Expression Omnibus (GEO) database. Firstly, the differently expressed genes (DEGs) were screened between control and aortic stenosis samples. Secondly, weighted gene co-expression network analysis (WGCNA) was performed to find the highly relevant gene modules. Enrichment analysis and protein-protein interaction (PPI) networking were also performed, then Cytoscape was used to identify hub genes. Finally, the six participants (3 control participants and 3 patients with aortic stenosis) were recruited at the Tianjin Chest Hospital. In order to verify the expression level of USP14, several molecular experiments were performed, including hematoxylin-eosin (HE) staining, immunohistochemistry, immunofluorescence technology, real time-quantitative polymerase chain reaction (RT-qPCR), and western blotting.ResultsA total of 9636 DEGs were found between the control and aortic stenosis samples. The DEGs were mainly enriched in the autophagy-animal, cellular lipid catabolic process, apoptosis, and glycoside metabolic process categories. Eleven hub genes were identified via four different algorithms. Following verification of the patient samples, Ubiquitin-specific protease 14 (USP14) was found to be displayed at higher levels in the aortic stenosis samples.ConclusionUSP14 might be involved in the occurrence and development of aortic stenosis, so it would be a molecular target for early diagnosis and specific treatment of aortic stenosis. There is a significant association between the high expression of USP14 and aortic stenosis, indicating that this gene may be a genetic risk factor for aortic stenosis.

Prevalence and risk factors of aortic stenosis and aortic sclerosis: a 21-year follow-up of middle-aged men

Introduction. There is limited knowledge about factors associated with the development of aortic stenosis. This study aimed to examine the prevalence of aortic sclerosis or stenosis in 71-years-old men and determine which risk factors at 50 years of age predict the development of aortic sclerosis or aortic stenosis. Methods. A random sample of Swedish men from the general population, born in 1943 (n = 798) were followed for 21 years. Data on clinical characteristics and laboratory values were collected in 1993. An echocardiography was performed in 2014. We used logistic regression to examine the association between baseline data and the outcome. Results. Echocardiography was performed in 535 men, and aortic sclerosis or aortic stenosis was diagnosed in 27 (5.0%). 14 persons developed aortic stenosis (2.6%). Among men with aortic sclerosis or aortic stenosis, 29.6% were obese. In multivariable stepwise regression model, body mass index (odds ratio per unit increase 1.23 (95% CI 1.10–1.38; p = .0003)) and hypercholesterolemia, combined with high sensitive C-reactive protein (odds ratio versus all other 2.66 (1.18–6.00; p = .019)) were significantly associated with increased risk of developing aortic sclerosis or aortic stenosis. Body mass index was the only factor significantly associated with a higher risk of developing aortic stenosis. Conclusion. The prevalence of either aortic sclerosis or aortic stenosis was 5% and of aortic stenosis 2.6%. Obesity and hypercholesterolemia combined with elevated high sensitive C-reactive protein at the age of 50 predicted the development of degenerative aortic sclerosis or stenosis, whilst only obesity was correlated with the occurrence of aortic stenosis.

Warfarin calcifies human aortic valve interstitial cells at high-phosphate conditions via pregnane X receptor.

Warfarin, a vitamin K antagonist, is the most common anticoagulant used to prevent thromboembolisms associated with atrial fibrillation or following valvular surgery. Although several studies have revealed that long-term warfarin use accelerates aortic valve calcification and the development of aortic stenosis (AS), the detailed mechanism for this phenomenon remains unclear. Therefore, our aim was twofold: to establish the conditions for warfarin-induced calcification of human aortic valve interstitial cells (HAVICs) using high-inorganic phosphate (Pi) conditions and to investigate the underlying mechanism. We prepared and cultured HAVICs from aortic valves affected by calcific aortic valve stenosis (AS group) and aortic valves affected by aortic regurgitation but without any signs of calcification (non-AS group). Under Pi concentrations of 3.2mM, warfarin significantly increased the calcification and alkaline phosphatase (ALP) activity of AS but not non-AS group HAVICs. Furthermore, gene expression of bone morphogenetic protein 2 (BMP2), a calcigenic marker, was significantly increased following 7 days of warfarin treatment. Warfarin-induced calcification of AS group HAVICs at 3.2mM Pi was significantly inhibited by dorsomorphin, a Smad inhibitor, and the pregnane X receptor (PXR) inhibitors, ketoconazole and coumestrol, but was unaffected by SN-50, an NF-κB inhibitor. Warfarin was also able to increase BMP2 gene expression at a physiological Pi concentration (1.0mM). Furthermore, excess BMP2 (30ng/mL) facilitated warfarin-induced ALP upregulation and HAVIC calcification, an effect which was significantly reduced in the presence of coumestrol. Together, our results suggest that warfarin accelerates calcification of HAVICs from AS patients via the PXR-BMP2-ALP pathway.

Association Between Cardiovascular Risk Factors and Aortic Stenosis: The CANHEART Aortic Stenosis Study

BackgroundFew longitudinal studies have delineated the association between traditional cardiovascular risk factors and development of aortic stenosis (AS). ObjectivesThe authors examined the association between traditional cardiovascular risk factors and incident severe AS in a large, unselected elderly population. MethodsThis observational cohort study used multiple linked health care population-based databases of individuals older than 65 years on April 1, 2002, without prior valvular disease, coronary artery disease, heart failure, cardiac arrhythmia, cerebrovascular disease, congenital heart disease, or admissions with cardiac symptoms. The relationship between hypertension (HTN), diabetes, dyslipidemia, and incident severe AS requiring hospitalization or surgical or interventional treatment was examined. ResultsAmong 1.12 million individuals followed for a median of 13 years, 20,995 subjects developed severe AS. Overall absolute incidence was 144 per 100,000 person-years (169 and 127 per 100,000 person-years in men and women, respectively). In cause-specific hazard models, HTN (adjusted hazard ratio [HR]: 1.71; 95% confidence interval [CI]: 1.66 to 1.76), diabetes (HR: 1.49; 95% CI: 1.44 to 1.54), and dyslipidemia (HR: 1.17; 95% CI: 1.14 to 1.21) were all significantly associated with increased risk of developing severe AS (all p < 0.001). There was a positive dose-response relationship between the number and duration of cardiac risk factors and risk of AS. In the Fine-Gray model, all 3 risk factors were independently associated with a higher incidence of AS. The population-attributable risk of AS associated with 3 cardiac risk factors was 34.4% (95% CI: 32.8 to 36.0). ConclusionsHTN, diabetes, and dyslipidemia have independent and dose-response associations with incident AS in an unselected population of older individuals, and together accounted for approximately one-third of the incidence of severe AS.

The year in cardiology 2016: valvular heart disease.

A large number of studies addressing various aspects of the diagnosis and treatment of valvular heart disease (VHD) have been published since the ESC Annual congress in 2015. As expected in this era of rapidly evolving therapeutic modalities and technologies, many scientific contributions are related to the expanded role of percutaneous interventions. New data are now available, consolidating the validity of the transcatheter approach in a variety of subsets of patients and therefore offering new strategies and perspectives in management. The most relevant articles have been selected for this review. It is well known that ageing of the population is associated with a higher prevalence of VHD. A large-scale echocardiographic screening involving 2500 individuals aged > 65 years was conducted to detect undiagnosed VHD ( Figure 1 ).1 Clinically significant (moderate or severe) undiagnosed VHD was identified in 6.4%. In addition, 4.9% of the cohort had pre-existing VHD (a total prevalence of 11.3%). Projecting these findings using population data, the prevalence of clinically significant VHD is estimated to double before 2050. The unique data of this study confirm the scale of the emerging epidemic of VHD, with widespread implications for clinicians and healthcare resources. In this scenario of predominantly elderly people affected by significant VHD, percutaneous modalities of treatment are expected to play a major role. Figure 1 UK population projections of diagnosed and undiagnosed significant valvular heart disease. The OxValve Population Cohort Study. Diagnosed estimates are based on the number excluded from participation in the present study due to a prior diagnosis of valvular heart disease. Undiagnosed estimates are based on the number with newly diagnosed significant valvular heart disease in OxVALVE-PCS. Reproduced with permission from D’Arcy JL et al .1 The mechanisms responsible for aortic valve calcification and development of aortic stenosis (AS) have been explored, and an association between valvular …

ITRAQ proteomic analysis of extracellular matrix remodeling in aortic valve disease.

Degenerative aortic stenosis (AS) is the most common worldwide cause of valve replacement. The aortic valve is a thin, complex, layered connective tissue with compartmentalized extracellular matrix (ECM) produced by specialized cell types, which directs blood flow in one direction through the heart. There is evidence suggesting remodeling of such ECM during aortic stenosis development. Thus, a better characterization of the role of ECM proteins in this disease would increase our understanding of the underlying molecular mechanisms. Aortic valve samples were collected from 18 patients which underwent aortic valve replacement (50% males, mean age of 74 years) and 18 normal control valves were obtained from necropsies (40% males, mean age of 69 years). The proteome of the samples was analyzed by 2D-LC MS/MS iTRAQ methodology. The results showed an altered expression of 13 ECM proteins of which 3 (biglycan, periostin, prolargin) were validated by Western blotting and/or SRM analyses. These findings are substantiated by our previous results demonstrating differential ECM protein expression. The present study has demonstrated a differential ECM protein pattern in individuals with AS, therefore supporting previous evidence of a dynamic ECM remodeling in human aortic valves during AS development.

Epidermal Growth Factor Signalling Promotes Pancreatic Beta-Cell Proliferation In Response to Nutrient Excess tn Rats Through MTOR And FOXM1

s / Can J Diabetes 37 (2013) S6eS11 S8 showed systolicddiastolic dysfunctions and a development of aortic stenosis in IGF-II mice compared to WT mice. Gene expression was consistent with LV hypertrophy revealed by up-regulation of ANP, BNP, b-MHC mRNA in IGF-II mice. Osteogenic gene expression (Runx2, SPP1, BGLAP) was significantly increased in aorta of IGF-II mice. After 2 months of treatment, 2thio-UTP injected IGF-II mice showed a reduction of peak aortic jet velocity (Vpeak [ 6.6%]) and pressure gradient (PG [ 12.5%]) compared to baseline (p<0.05). In contrast, saline-injected IGF-II mice showed an augmentation of Vpeak (+7.4%) and LV PG (+17.1%) during the same period. Conclusion: These results indicate for the first time that 2thio-UTP induces regression of calcific aortic stenosis and associated LV dysfunction in this new model of obese diabetic animals.

Secreted Wnt Modulators in Symptomatic Aortic Stenosis

BackgroundValve calcification and inflammation play key roles in the development of aortic stenosis (AS). The Wnt pathways have been linked to inflammation, bone metabolism, angiogenesis, and heart valve formation. We hypothesized that soluble Wnt modulators may be dysregulated in symptomatic AS.Methods and ResultsWe measured circulating levels (n=136) and aortic valve tissue expression (n=16) of the secreted Wnt modulators secreted frizzled related protein-3, dickkopf-1 (DKK-1), and Wnt inhibitory factor-1 (WIF-1) by enzyme immunoassay, immunostaining, and RT-PCR in patients with symptomatic, severe AS and investigated associations with echocardiographic parameters of AS and cardiac function. Finally, we assessed the prognostic value of these Wnt modulators in relation to all-cause mortality (n=35) during long-term follow-up (median 4.6 years; survivors, 4.8 years; nonsurvivors, 1.9 years) in these patients. Our main findings were: (1) serum levels of all Wnt modulators were markedly elevated in patients with symptomatic AS (mean increase 231% to 278%, P<0.001), (2) all Wnt modulators were present in calcified aortic valves but correlated poorly with systemic levels or degree of AS, (3) some modulators (ie, WIF-1) were associated with the degree of myocardial function and valvular calcification, (4) all Wnt modulators, and DKK-1 in particular, predicted long-term mortality in these patients also after adjusting for conventional predictors including NT-proBNP.ConclusionsTogether, these in vivo data support the involvement of Wnt signaling in the development of AS and suggest that circulating Wnt modulators should be further investigated as risk markers in larger AS populations, including patients with asymptomatic disease.

Role of 5-lipoxygenase pathway in the pathophysiology of the aortic stenosis

Evaluation of: Nagy E, Andersson DC, Caidahl K et al. Upregulation of the 5-lipoxygenase pathway in human aortic valves correlates with severity of stenosis and leads to leukotriene-induced effects on valvular myofibroblasts. Circulation DOI: 10.1161/CIRCULATIONAHA.110.966846 (2011) (Epub ahead of print).Understanding the exact pathophysiological mechanism of degenerative aortic stenosis is important in order to develop new treatment modalities and prevent progression of the disease. Recently, most of the inflammatory markers in association with aortic stenosis have been described. The authors of the paper under evaluation investigate the effects of the 5-lipoxygenase pathway on aortic valve stenosis and correlation with severity of stenosis. In this article, we suggest that the 5-lipoxygenase pathway is one of the possible factors in the development of aortic stenosis.