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Loss of flow responsive Tie1 results in Impaired Aortic valve remodeling.

ABSTRACT: The mechanisms regulating endothelial cell response to hemodynamic forces required for heart valve development, especially valve remodeling, remain elusive. Tie1, an endothelial specific receptor tyrosine kinase, is up-regulated by oscillating shear stress and is required for lymphatic valve development. In this study, we demonstrate that valvular endothelial Tie1 is differentially expressed in a dynamic pattern predicted by disturbed flow during valve remodeling. Following valvular endocardial specific deletion of Tie1 in mice, we observed enlarged aortic valve leaflets, decreased valve stiffness and valvular insufficiency. Valve abnormalities were only detected in late gestation and early postnatal mutant animals and worsened with age. The mutant mice developed perturbed extracellular matrix (ECM) deposition and remodeling characterized by increased glycosaminoglycan and decreased collagen content, as well as increased valve interstitial cell expression of Sox9, a transcription factor essential for normal ECM maturation during heart valve development. This study provides the first evidence that Tie1 is involved in modulation of late valve remodeling and suggests that an important Tie1-Sox9 signaling axis exists through which disturbed flows are converted by endocardial cells to paracrine Sox9 signals to modulate normal matrix remodeling of the aortic valve.

SUBMITTER: Qu X

PROVIDER: S-EPMC8269330 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.

Project description:AimsMyxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/?-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/?-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined.Methods and resultsTo investigate the role of Wnt/?-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/?-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/?-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/?-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/?-catenin signalling in the development of MVD.ConclusionsAltogether, these data indicate that Axin2 limits Wnt/?-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/?-catenin signalling resulting from loss of Axin2 leads to progressive MVD.

| S-EPMC5220675 | biostudies-literature

On the Significance of Systolic Flow Waveform on Aortic Valve Energy Loss.

Project description:This study aims to quantitatively and qualitatively assess energy dissipation in the aortic valve as a function of systolic aortic flow waveform representing pathologies where flow time-to-peak is delayed. A bioprosthetic valve was tested in the aortic position of a left-heart simulator under physiological pressure and flow conditions. The flow loop piston pump was programmed to generate three different flow waveforms each with a different peak time annotated as early peak (EP) with a rapid acceleration, mid peak (MP) and late peak (LP) with a rapid deceleration. Energy dissipation was calculated from flow and pressure measurements while sinus vorticity dynamics were evaluated using time-resolved planar particle image velocimetry. Average pressure gradients during systole are found 30.2 ± 0.19, 30.7 ± 0.25 and 32.9 ± 0.29 mmHg and average dissipation over systole is found 0.95 ± 0.026, 1.05 ± 0.034 and 1.25 ± 0.043 W for EP, MP and LP respectively. As systole's acceleration phase is slower, sinus vortices are more likely to form, necessitating more energy exchange from shear layers inducing more viscous dissipation. EP found in healthy individuals is superior in terms of reducing energy dissipation and increasing aortic valve efficiency. In the context of possible left ventricular dysfunction and aortic stenosis, this means that delayed time-to-peak in the aortic flow waveform seen is not compensatory.

| S-EPMC6249097 | biostudies-literature

Aortic sinus flow stasis likely in valve-in-valve transcatheter aortic valve implantation.

Project description:OBJECTIVE:Valve-in-valve procedures using transcatheter aortic valves are increasingly performed to treat degenerated bioprosthetic surgical aortic valves because they are less invasive than redo aortic valve replacement. The objective of this study is to quantify the changes in aortic sinus blood flow dynamics before and after a valve-in-valve procedure to gain insight into mechanisms for clinical and subclinical thrombosis of leaflets. METHODS:A detailed description of the sinus hemodynamics for valve-in-valve implantation was performed in vitro. A Medtronic Hancock II (Medtronic Inc, Minneapolis, Minn) porcine bioprosthesis was modeled as a surgical aortic valve, and Medtronic CoreValve and Edwards Sapien (Edwards Lifesciences, Irvine, Calif) valves were used as the transcatheter aortic valves. High-resolution particle image velocimetry was used to compare the flow patterns from these 2 valves within both the left coronary and noncoronary sinuses in vitro. RESULTS:Velocity and vorticity within the surgical valve sinuses reached peak values of 0.7 m/s and 1000 s-1, with a 70% decrease in peak fluid shear stress near the aortic side of the leaflet in the noncoronary sinus. With the introduction of transcatheter aortic valves, peak velocity and vorticity were reduced to approximately 0.4 m/s and 550 s-1 and 0.58 m/s and 653 s-1 without coronary flow and 0.60 m/s and 631 s-1 and 0.81 m/s and 669 s-1 with coronary flow for the CoreValve and Sapien valve-in-valve implantations, respectively. Peak shear stress was approximately 38% higher along the aortic side of the coronary versus noncoronary transcatheter aortic valve leaflet. CONCLUSIONS:Decreased flow and shear stress in valve-in-valve procedures indicate a higher risk of leaflet thrombosis secondary to flow stasis, perhaps more so in the noncoronary sinus.

| S-EPMC5479725 | biostudies-literature

Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment-Impact on Aortic Valve Remodeling.

Project description:Type 2 diabetes mellitus (T2D) is one of the prominent risk factors for the development and progression of calcific aortic valve disease. Nevertheless, little is known about molecular mechanisms of how T2D affects aortic valve (AV) remodeling. In this study, the influence of hyperinsulinemia and hyperglycemia on degenerative processes in valvular tissue is analyzed in intact AV exposed to an either static or dynamic 3D environment, respectively. The complex native dynamic environment of AV is simulated using a software-governed bioreactor system with controlled pulsatile flow. Dynamic cultivation resulted in significantly stronger fibrosis in AV tissue compared to static cultivation, while hyperinsulinemia and hyperglycemia had no impact on fibrosis. The expression of key differentiation markers and proteoglycans were altered by diabetic conditions in an environment-dependent manner. Furthermore, hyperinsulinemia and hyperglycemia affect insulin-signaling pathways. Western blot analysis showed increased phosphorylation level of protein kinase B (AKT) after acute insulin stimulation, which was lost in AV under hyperinsulinemia, indicating acquired insulin resistance of the AV tissue in response to elevated insulin levels. These data underline a complex interplay of diabetic conditions on one hand and biomechanical 3D environment on the other hand that possesses an impact on AV tissue remodeling.

| S-EPMC8268732 | biostudies-literature

Cerebral Blood Flow in Patients with Severe Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation.

Project description:BackgroundTranscatheter aortic valve implantation (TAVI) is a minimally invasive, life-saving treatment for patients with severe aortic valve stenosis that improves quality of life. We examined cardiac output and cerebral blood flow in patients undergoing TAVI to test the hypothesis that improved cardiac output after TAVI is associated with an increase in cerebral blood flow.DesignProspective cohort study.SettingEuropean high-volume tertiary multidisciplinary cardiac care.ParticipantsThirty-one patients (78.3 ± 4.6 years; 61% female) with severe symptomatic aortic valve stenosis.MeasurementsNoninvasive prospective assessment of cardiac output (L/min) by inert gas rebreathing and cerebral blood flow of the total gray matter (mL/100 g per min) using arterial spin labeling magnetic resonance imaging in resting state less than 24 hours before TAVI and at 3-month follow-up. Cerebral blood flow change was defined as the difference relative to baseline.ResultsOn average, cardiac output in patients with severe aortic valve stenosis increased from 4.0 ± 1.1 to 5.4 ± 2.4 L/min after TAVI (P = .003). The increase in cerebral blood flow after TAVI strongly varied between patients (7% ± 24%; P = .41) and related to the increase in cardiac output, with an 8.2% (standard error = 2.3%; P = .003) increase in cerebral blood flow per every additional liter of cardiac output following the TAVI procedure.ConclusionFollowing TAVI, there was an association of increase in cardiac output with increase in cerebral blood flow. These findings encourage future larger studies to determine the influence of TAVI on cerebral blood flow and cognitive function.

| S-EPMC7894507 | biostudies-literature

GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve.

Project description:BACKGROUND:Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined. METHODS:Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells. RESULTS:Gata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice. CONCLUSIONS:The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.

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Stretch responsive miRNAs in human aortic valve interstitial cells

Project description:miRNA-Sequencing was performed on human aortic valve interestitial cells (AVICs) exposed to 14% stretch at 1 hz or static conditions for 24h.

2015-01-09 | GSE49558 | GEO

Stretch responsive miRNAs in human aortic valve interstitial cells

Project description:miRNA-Sequencing was performed on human aortic valve interestitial cells (AVICs) exposed to 14% stretch at 1 hz or static conditions for 24h. Six static control and six samples exposed to cyclic stretch 14% for 24h

2015-01-09 | E-GEOD-49558 | biostudies-arrayexpress

Loss of sarcolipin results in atrial remodeling

Project description:Sarcolipin (SLN) is a key regulator of SERCA pump in atria. To determine the role of SLN in atrial Ca2+ homeostasis, we have generated a SLN null (sln-/-) mouse model. Ablation of SLN results in increased SR Ca2+ load and Ca2+ transients in atria. Further, loss of SLN results in electrophysiological and strcutural remodeling of atria. The SLN knockout and C57/BL6 wildtype mice (each n=3) were selected for RNA extraction. The cRNA probes were hybridized to Affymetrix gene array.

2010-11-01 | E-GEOD-23403 | biostudies-arrayexpress

Transvalvular Flow Rate Determines Prognostic Value of Aortic Valve Area in Aortic Stenosis.

Project description:BackgroundAortic valve area (AVA) ≤1.0 cm2 is a defining characteristic of severe aortic stenosis (AS). AVA can be underestimated at low transvalvular flow rate. Yet, the impact of flow rate on prognostic value of AVA ≤1.0 cm2 is unknown and is not incorporated into AS assessment.ObjectivesThis study aimed to evaluate the effect of flow rate on prognostic value of AVA in AS.MethodsIn total, 1,131 patients with moderate or severe AS and complete clinical follow-up were included as part of a longitudinal database. The effect of flow rate (ratio of stroke volume to ejection time) on prognostic value of AVA ≤1.0 cm2 for time to death was evaluated, adjusting for confounders. Sensitivity analysis was performed to identify the optimal cutoff for prognostic threshold of AVA. The findings were validated in a separate external longitudinal cohort of 939 patients.ResultsFlow rate had a significant effect on prognostic value of AVA. AVA ≤1.0 cm2 was not prognostic for mortality (p = 0.15) if AVA was measured at flow rates below median (≤242 ml/s). In contrast, AVA ≤1.0 cm2 was highly prognostic for mortality (p = 0.003) if AVA was measured at flow rates above median (>242 ml/s). Findings were irrespective of multivariable adjustment for age, sex, and surgical/transcatheter aortic valve replacement (as time-dependent covariates); comorbidities; medications; and echocardiographic features. AVA ≤1.0 cm2 was also not an independent predictor of mortality below median flow rate in the validation cohort. The optimal flow rate cutoff for prognostic threshold was 210 ml/s.ConclusionsTransvalvular flow rate determines prognostic value of AVA in AS. AVA measured at low flow rate is not a good prognostic marker and therefore not a good diagnostic marker for truly severe AS. Flow rate assessment should be incorporated into clinical diagnosis, classification, and prognosis of AS.

| S-EPMC8087111 | biostudies-literature