Angiogenesis and Fibrosis in Aortic Stenosis

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POLESTAR Trial – An International Multi-center Early Discharge TAVI Program REPRISE EDGE 29 mm EU Study The CONFIDENCE Registry Interest of Cardiac Computed Tomography to Optimize and Improve the Procedure of TAVI Transapical Implantation of the Medtronic Engager Transcatheter Aortic Valve Implantation System – The Engager European Pivotal Trial Post-Market Follow-up of the CENTERA Transcatheter Heart Valve System SecOnd-generation seLf-expandable Versus Balloon-expandable Valves and gEneral Versus Local Anesthesia in TAVI Balloon Aortic Valvuloplasty During Surgical Aortic Valve Replacement The PROTEMBO SF Trial Adjuvant Radiation in Aortic Valvuloplasty – ARAVA Value of Oral Phytate (InsP6) in the Prevention of Progression of the Cardiovascular Calcifications Supra-Annular vs. Annular ValvEs for Small Annuli Heart Leaflet Technologies Valve Study A Study to Evaluate the Neuro-embolic Consequences of TAVR Femoral vs Radial Approach and MRI Evaluation of Strokes Mortality Post-TAVI and Correlation With Haemodynamic Parameters. 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Coupling Modification Evaluated by PRAM During TAVI Procedure CoreValve Advance International Post Market Study HLT transfemOral Replacement of aortIc Valve Via transcatherteriZatiON SWISS TAVI Registry CoreValve™ Evolut R™ FORWARD Study Transfemoral Replacement of Aortic Valve With HLT MeriDIAN Valve Early Feasibility Trial Follow-up After TAVR Without Systematic Intensive Care Unit Admission ACURATE NEO/TF Transcatheter Heart Valves and Non-inferiority Versus Medtronic CoreValve Systems CoreValve™ Evolut R™ 34 mm System Registry (CoreValve34) Inflammation and Thrombosis in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement (TAVR) ACURATE TA™ Valve Implantation Registry: SAVI 2 Colibri Transcatheter Aortic Heart Valve System Study HLT Meridian Valve CE Mark Trial Transfemoral Replacement of Aortic Valve With HLT MeriDIAN Valve Feasibility Trial CANADA Assessment of Arrhythmias in Patients Undergoing Transcatheter Aortic Valve Implantation Using a Small Insertable Cardiac Monitoring Device Reactive Oxygen Species Following Aortic Valve Replacement Biological Factors Associated With Subclinical Valvular Thrombosis Hemodynamic Comparison of Tissue Aortic Valves Volume Challenge Added to DSE in the Diagnosis of Severe LFLGAS Impact of Perioperative Treatment With Intravenous Glutamine on Myocardial Protection in Cardiac Surgery Patients With Aortic Stenosis The Effects of High Spinal Anesthesia on Heart Function, Stress Response and Pain Control in Aortic Valve Surgery A Clinical Trial of Transcatheter Aortic Valves in Dialysis Patients (Japan) Erythropoietin + Iron Therapy for Anemic Patients Undergoing Aortic Valve Replacement A Study Evaluating the Effects of Ataciguat (HMR1766) on Aortic Valve Calcification Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study Prehabilitation to Improve Functional and Clinical Outcomes in Patients With Aortic Stenosis Evaluation of Transcatheter Aortic Valve Replacement Compared to SurveilLance for Patients With AsYmptomatic Severe Aortic Stenosis Phono- and Electrocardiogram Assisted Detection of Valvular Disease The Medtronic TAVR 2.0 US Clinical Study PREVAIL-J – Transfemoral & Transapical Placement of Aortic Balloon Expandable Transcatheter Valves Trial (Japan) Regression of Myocardial Fibrosis After Aortic Valve Replacement Transcatheter Aortic Valve Replacement Versu Surgical Aortix Valve Replacement for Treating Elderly Patients With Severe Aortic Stenosis and Small Aortic Annuli: A Prospective Randomized Study The VIVA Trial ACURATE Neo™ AS Aortic Bioprosthesis for Implantation Using the ACURATE neoTM AS TF Transfemoral Delivery System in Patients With Severe Aortic Stenosis THE ALIGN-AS TRIAL: JenaValve Pericardial TAVR Aortic Stenosis Study Prognostic Impact of Myocardial Longitudinal Strain in Asymptomatic Aortic Stenosis: a Meta-Analysis Severe Aortic Valve Stenosis and Concomitant Coronary Artery Disease in Patients Undergoing TAVI Treatment of Aortic Stenosis in Brazil: Cost-Utility Analysis of TAVI vs SAVR Clinical Evaluation of MDT-2111 in Subjects With Small Aortic Annuli and Symptomatic Severe Aortic Stenosis Valvuloplasty Scoring Balloon Catheter First-in-Man Study Effect of Angiotensin II Receptor Blockers (ARB) on Left Ventricular Reverse Remodelling After Aortic Valve Replacement in Severe Valvular Aortic Stenosis Surgical Treatment of Aortic Stenosis With a Next Generation Surgical Aortic Valve Registry to Evaluate the Impact of a Valve Coordinator on Aortic Stenosis / TAVI Outcome – (German Pilot) Quality of Care in AS IMPULSE Study Biomarkers in Aortic Stenosis – B.A.S.S. 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Effect of vItamin K2 on Calciummetabolism on 18F-NaF PET/MRI Endothelial Progenitors in Aortic Stenosis: Association With Aortic Stenosis Progression and Severity Outcomes of Transcatheter Aortic Valve Implantation in Oncology Patients With Severe Aortic Stenosis Evaluation of BAV in Different Hemodynamic Entities of Severe AS Intravenous Iron Supplement for Iron Deficiency in Patients With Severe Aortic Stenosis The SAPIEN 3 Ultra System in Intermediate Risk Patients With Symptomatic Severe Aortic Stenosis Clinical Value of Stress Echocardiography in Moderate Aortic Stenosis CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement Outcomes of Transcatheter Aortic Valve Implantation in Management of Severe Symptomatic Aortic Stenosis Safety and Efficacy of Lotus Valve For TAVI In Patients With Severe Aortic Stenosis In Chinese Population Rehabilitation in Aortic Stenosis Patients Aortic Stenosis Evaluated Via Modern Ballistocardiography and Seismocardiography Study of Platelet Activation by Severe Aortic Stenosis and Its Correction by Transcatheter Aortic Valve Implantation Sizing-sTrategy of Bicuspid AoRtic Valve Stenosis With Transcatheter Self-expandable Valve The Plasma Serotonin and Aortic Stenosis: a Pilot Study. 18F-NaF Uptake and Aortic Stenosis Progression Cardiovascular Rehabilitation in Patients With Severe Aortic Stenosis Submitted to Valvar Correction Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study Clinical Outcome of Patients With Low-gradient Severe Aortic Stenosis Ultrasonic Markers for Myocardial Fibrosis and Prognosis in Aortic Stenosis Fetal Intervention for Aortic Stenosis and Evolving Hypoplastic Left Heart Syndrome The PARTNER 3 – Trial – The Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis Ventricular Remodeling In Patients With Aortic Stenosis Assessed Echocardiography Podocan and Wnt Pathway in Left Ventricular Remodeling of Aortic Stenosis Preoperative Assessment of Aortic Valve Stenosis and Coronary Artery Disease Statin Therapy in Asymptomatic Aortic Stenosis Validation of the “TASQ” in Patients Undergoing SAVR or TF-TAVI Analysis and Comparative Evaluation of Aortic Calcium by Computed Tomography and Histopathology in Patients With Aortic Stenosis Improving Echo Measurements in the Diagnosis of Aortic Stenosis accuRate Evaluation of Benefit With Optimal Medical Treatment With or With-Out Transcatheter Valve Repair of PARADOXical Low Flow Low Gradient Aortic Stenosis – REBOOT-PARADOX Aortic Stenosis: Determinants and Prognostic Value of Preoperative Left Ventricular Remodeling After Valvular Replacement Randomized Study for the Optimal Treatment of Symptomatic Patients With Low Gradient Severe Aortic Valve Stenosis and Preserved Left Ventricular Ejection Fraction Microvascular Dysfunction in Aortic Stenosis Percutaneous Aortic 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Surgery in Patients With Native Aortic Valve Stenosis Measurement of Myocardial Stiffness Using Elastometry in Patients With Aortic Stenosis Study to Improve Outcomes in Aortic Stenosis Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study) Severe Aortic Stenosis in Patients Referred for Valve Surgery Frailty and Mortality in Older Old With Severe Aortic Stenosis Myocardial Efficiency of the Left Ventricle in Asymptomatic Patients With Aortic Valve Stenosis – a Prognostic Marker and a Target for Intervention? PCSK9 Inhibitors in the Progression of Aortic Stenosis Early Surgery Versus Conventional Treatment in Very Severe Aortic Stenosis Randomized Study to Evaluate the Efficacy of Fluvastatin on Inflammatory Markers in Patients With Aortic Stenosis. A Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aortic Stenosis: The CHOICE Trial Angiogenesis and Fibrosis in Aortic Stenosis Acquired Von Willebrand Syndrome in Severe Aortic Stenosis Effect of Bisoprolol on Progression of Aortic Stenosis Use of Cardiac-MRI to Predict Results for People With Severe Aortic Stenosis Effects of Rosuvastatin on Aortic Stenosis Progression Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (PULSE AS) Valvosoft First-In-Man Study in Severe Symptomatic Aortic Stenosis Assessment of Myocardial Tissue Damage in Aortic Stenosis Genetics of Aortic Stenosis: From Family Forms to the Common Forms ACURATE Neo™ Aortic Bioprosthesis for Implantation Using the ACURATE TA™ LP Transapical Delivery System in Patients With Severe Aortic Stenosis ACURATE Neo™ TA Delivery System in Patient With Severe Aortic Stenosis Genetic of Aortic Valve Stenosis – Clinical and Therapeutic Implications The Role of Myocardial Fibrosis in Patients With Aortic Stenosis Morbidity and Mortality Due to Deferral of Aortic Valve Replacement in Patients With Severe Aortic Stenosis Serum Biomarkers for Aortic Valve Stenosis Aortic Stenosis: Determinants of Progression, Severity and Left Ventricular Remodeling Aortic Stenosis in Elderly : Determinant of Progression Biological Variation of Cardiac Biomarkers in Aortic Valve Stenosis GPx Activity in Subjects With Aortic Stenosis Undergoing TAVR Low Flow Low Gradient Aortic Stenosis Relevance of the (re)Search for a Contractile Reserve Vivio AS (Aortic Stenosis) Algorithm Optimization Study Risk Prediction in Aortic Stenosis Acute Haemodynamic Effects of Treatment With Angiotensin Converting Enzyme (ACE)-Inhibitors in Patients With Symptomatic Aortic Stenosis Utility of Exercise-induced N-terminal (NT) Pro-brain Natriuretic Peptide Levels in Predicting Prognosis in Asymptomatic Aortic Stenosis Heart Failure and Aortic Stenosis Transcriptome Valvular Aortic Stenosis: Study of Myocardiac Fibrosis by Magnetic Resonance Imagery Vivio AS (Aortic Stenosis) Detection Study Cardiac MRI for Severe Aortic Stenosis Metabolic Determinants of the Progression of Aortic Stenosis Impact of a Patient Decision Aid for Treatment of Aortic Stenosis Early Detection of Aortic Stenosis in the Community During Flu Vaccination Correlation of Auscultatory Severity of Aortic Stenosis With Trans Thoracic Echocardiography The Effect of Lipitor on Aortic Stenosis

Brief Title

Angiogenesis and Fibrosis in Aortic Stenosis

Official Title

The Identification of In Vivo Angiogenesis and Fibrosis in Aortic Stenosis Using Positron Emission Tomography

Brief Summary

      Angiogenesis and fibrosis lie at the heart of a number of fundamental processes responsible
      for cardiovascular disease. In this proposal, the investigators intend to build upon a highly
      successful programme of studies exploring the cardiovascular applications of positron
      emission tomography. Specifically, the investigators will explore the potential role of a
      novel radiotracer, 18F-fluciclatide, which is a highly selective ligand for the αvβ3 and αvβ5
      integrin receptors that are up regulated during angiogenesis, and tissue fibrosis and
      remodelling. This tracer has been successfully used to assess angiogenesis in metastatic
      tumours and its uptake is suppressed by anti-angiogenic therapies. The investigators here
      propose to describe the pattern of uptake of 18F-fluciclatide in cardiovascular diseases,
      specifically aortic stenosis and aortic atherosclerosis. The investigators will correlate
      18F-fluciclatide uptake with in vivo measures of angiogenesis and fibrosis as well as ex vivo
      histological characterisation of tissue. If successful, this novel radiotracer could provide
      an extremely important non-invasive method of assessing in vivo angiogenesis, plaque
      vulnerability, and tissue remodelling as well as potential applications in developing stem
      cell therapies.
    

Detailed Description

      Integrins

      Integrins are a group of molecules responsible for intercellular adhesion and signalling.
      They comprise a superfamily of heterodimeric receptors that are composed of 18 different α
      and β subunits. In combination, they can generate 24 different receptor subtypes with a range
      of physiological and pathophysiological functions. The αvβ3 receptor is an integrin that is
      found at low levels on mature endothelial cells but is markedly up regulated on endothelial
      cells of actively growing blood vessels. It was previously known as the vitronectin receptor
      although it was subsequently found to bind many other ligands including fibrinogen,
      fibronectin, laminin, thrombospondin, von Willebrand factor, and certain collagen subtypes.
      These features are also seen with the αvβ5 integrin receptor, with both receptors recognising
      the arginine-glycine-aspartate (RGD) motif present on these ligands.

      1.1.2 Role of αvβ3 and αvβ5 Integrins in Cardiovascular Disease

      The expression of αvβ3 and αvβ5 receptors is up regulated in a number of diseased states and
      this has been particularly well characterised in the angiogenesis associated with tumour
      growth and metastases. However, there are many potential roles for this integrin pathway in
      cardiovascular disease including myocardial infarction, atherosclerosis, restenosis, aortic
      stenosis and aneurysm disease that have been relatively unexplored.

      1.1.2.1 Aortic Stenosis

      Aortic stenosis is characterized by extensive valvular thickening due to accumulation of
      fibrous tissue and remodeling of the extracellular matrix. In all three layers of the valve,
      abundant fibroblast-like cells are found and are commonly referred to as valvular
      interstitial cells. A sub-population of these cells become activated by the inflammatory
      activity within the valve and differentiate into myofibroblasts. Whilst fibroblasts control
      the synthesis of collagen in the normal valve, myofibroblasts are responsible for the
      accelerated fibrosis observed within stenotic valves. In addition, matrix metalloproteinases
      are secreted by myofibroblasts and inflammatory cells, and have an important and complex role
      in the restructuring of the valve leaflet matrix. As already indicated, activation and
      differentiation of fibroblasts into myofibroblasts are dependent on αvβ3 and αvβ5 receptor
      expression. In addition, mirroring the situation in carotid atherosclerosis, patients with
      severe aortic stenosis have a high incidence (78%) of intraleaflet haemorrhage and this is
      associated with angiogenesis and more rapid disease progression.

      Histopathological studies have confirmed fibrosis to be an integral part of the left
      ventricular hypertrophic process in aortic stenosis. Myofibroblasts infiltrate the myocardium
      and secrete extracellular matrix proteins including collagen types I and III. Areas of
      fibrosis are observed to co-localize with areas of myocyte apoptosis and it has been
      suggested that fibrosis occurs as a form of scarring after myocyte death and injury. As with
      fibrosis in the valve, the renin-angiotensin system, transforming growth factor-beta and an
      imbalance in matrix metalloproteinase and their tissue inhibitor activity have all been
      implicated in this process. A mid-wall pattern of fibrosis has been observed in the
      myocardium of up to 38% of patients with moderate or severe aortic stenosis and has been
      associated with a more advanced hypertrophic response. Importantly, there is also an 8-fold
      increase in mortality associated with mid-wall fibrosis.

      1.1.2.2 Atherosclerosis and Restenosis

      The development of atherosclerosis is due to a complex interplay of oxidised lipid,
      inflammatory cell infiltration, and smooth muscle cell migration in the arterial wall. Once
      established, atherosclerotic plaques may progress and rupture leading to the clinical
      presentations of acute myocardial infarction and stroke. Features associated with plaque
      rupture include a thin fibrous cap, lipid-rich pool and intraplaque haemorrhage. Indeed,
      plaque rupture is particularly associated with plaque neovascularisation and
      vascular-endothelial growth factor expression suggesting that instability may be induced by
      angiogenesis. Thus, up regulation of αvβ3 and αvβ5 receptors may represent a novel marker of,
      and potential therapeutic target for, plaque vulnerability.

      1.1.3 Fluciclatide

      Fluciclatide is a RGD-containing cyclic peptide that has recently been developed as an
      18F-radiotracer to detect tumour angiogenesis by positron emission tomography. It is highly
      selective for the αvβ3 and αvβ5 receptors with affinities (EC50) of 11.1 and 0.1 nM
      respectively with minimal cross reactivity with the αIIbβ3 receptor (EC50 281 nM).
      Pre-clinical tumour work has demonstrated that 18F-fluciclatide is taken up by glioblastomas
      and that this is suppressed by the anti-angiogenic tyrosine kinase inhibitor, sunitinib,
      confirming the specificity of fluciclatide for areas of angiogenesis. It has been assessed in
      phase I clinical trials and found to be safe and well tolerated.

      1.1.4 Aims

      To date, there have been many preclinical studies examining the application of radiotracers
      targeting the αvβ3 and αvβ5 integrin receptors. The clinical application of these tracers has
      been largely limited to oncology as a method of assessing angiogenesis within tumours. Here
      we wish to explore the role of the αvβ3 and αvβ5 receptor radiotracer, 18F-fluciclatide, to
      assess angiogenesis and fibrosis in patients with aortic stenosis as a measure of both
      valvular and myocardial fibrosis. This patient group will have co-existent aortic atheroma
      and this will provide us with an opportunistic assessment of tracer uptake in
      atherosclerosis. We feel it is important to assess a range of cardiovascular conditions to
      determine whether αvβ3 and αvβ5 integrin receptor expression is particular to certain disease
      processes. If successful, these preliminary data will permit the more detailed exploration of
      specific disease areas and novel therapeutic interventions. At present, fluciclatide is not
      licensed or approved for clinical use and is being used here as an Investigational Agent to
      explore the pathophysiology of aortic stenosis.

      1.2 ORIGINAL HYPOTHESES

      We hypothesise that 18F-fluciclatide can identify the expression of the αvβ3 and αvβ5
      integrin receptors in vivo in man in two major cardiovascular disease areas: aortic
      atherosclerosis and aortic stenosis. Specifically, we hypothesise that 18F-fluciclatide will:

        1. Be taken up into aortic atherosclerotic plaque.

        2. Show demonstrable uptake in the aortic valve and myocardium of patients with aortic
           stenosis that will correlate with the degree of active angiogenesis and fibrosis.

      6.1 ANGIOGENESIS AND FIBROSIS IN AORTIC STENOSIS

      Aortic stenosis is associated with substantial left ventricular hypertrophy and consequent
      myocardial fibrosis with the latter predicting prognosis. Left ventricular hypertrophy and
      associated fibrosis is also a major risk factor for adverse cardiovascular events in a number
      of other conditions including essential hypertension. Cardiac magnetic resonance imaging is
      the gold-standard method of assessing for the presence of myocardial fibrosis but it does not
      necessarily indicate the on going activity of the fibrotic process. In this study, we will
      assess the uptake of 18F-fluciclatide in patients with aortic stenosis as a model of pressure
      overload left ventricular hypertrophy. We will also seize the opportunity to determine
      whether there is any uptake of 18F-fluciclatide in the aortic valve given that this has been
      shown to have areas of fibrosis and angiogenesis.

      All study patients and healthy volunteers will undergo blood sampling, echocardiogram,
      positron emission and computed tomography scans with 18F-fluciclatide as well as cardiac
      magnetic resonance imaging with assessment of gadolinium late enhancement. Following
      injection of 18F-fluciclatide, patients will be monitored using our standard clinical
      approach, including observation of haemodynamic parameters, and this will continue throughout
      their study visit until departure. In patients undergoing aortic valve replacement surgery,
      aortic valve tissue will be retained and a 3-mm tru-cut biopsy of left ventricular myocardium
      obtained with which to compare the findings from the scans.

      Healthy volunteer patients will not undergo repeat assessment. After a period of one to two
      years from their initial scan, patients with Aortic Stenosis will return for repeat blood
      sampling, cardiac magnetic resonance imaging with assessment of late gadolinium enhancement
      and echocardiogram. Those patients who have undergone an aortic valve replacement will
      undergo repeat positron emission and computed tomography scans with 18F-fluciclatide six
      months after their operation, prior to their second cardiac MRI scan.

      Blood samples will be assessed using standard clinical biochemical and haematological
      profiles such as full blood count and urea and electrolytes. In addition, markers of cardiac
      ischaemia, fibrosis and angiogenesis will be assessed. Additional serum, plasma and DNA will
      be stored at -80 degrees Celsius for future potential analyses.

      6.1.2 Study Interpretation

      We anticipate that myocardial uptake of 18F-fluciclatide will be increased in patients with
      aortic stenosis and left ventricular hypertrophy. We expect the degree of myocardial uptake
      to correlate with cardiac magnetic resonance imaging assessment of fibrosis as well as the
      histological measures of fibrosis and αvβ3 and αvβ5 integrin receptor expression. We expect
      the degree of myocardial uptake to predict cardiac magnetic resonance imaging assessment of
      fibrosis following a period of one to two years. In exploratory analyses, we will also take
      the opportunity to assess the extent of 18F-fluciclatide uptake within the aortic valve
      itself, and if successful, correlate this with histological measures of angiogenesis and
      fibrosis.

      6.2 ANGIOGENESIS IN AORTIC ATHEROSCLEROSIS

      Patients with aortic stenosis will have a high prevalence of concomitant aortic
      atherosclerosis. In Dr Dweck's Fellowship, we were able to exploit this association and
      undertake secondary analyses of 18F-sodium fluoride uptake in aortic and coronary
      atherosclerosis. This generated some highly innovative findings that informed our
      understanding of atherosclerosis and the role of calcification.

      6.2.1 Study Schedule

      We will use the datasets obtained from the patients above to explore the uptake of
      18F-fluciclatide within the thoracic aorta. Atherosclerosis will be identified using computed
      tomography and magnetic resonance images obtained of the thorax at the time of the study
      scans. No additional image acquisition will be required. This will provide pilot data to
      inform subsequent dedicated studies focused on acutely inflamed atherosclerotic plaques, such
      as patients with recent transient ischaemic attacks or strokes attributable to carotid
      disease.
    


Study Type

Observational


Primary Outcome

The mean and maximum standardised uptake values (SUV) of fluciclatide for the myocardium and its correlation with the severity of aortic stenosis determined echocardiographically.

Secondary Outcome

 The mean and maximum standardised uptake values (SUV) of fluciclatide in the aortic valve in patients with aortic stenosis

Condition

Aortic Stenosis

Intervention

Cardiac MRI scan

Study Arms / Comparison Groups

 Healthy Volunteers
Description:  10 patients with normal echocardiogram studies and no history of ischaemic heart disease.
Patients to recieve CT-PET with fluciclatide, cardiac MRI scan, CT-coronary angiogram and echocardiogram.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

21

Start Date

April 2013

Completion Date

August 2015

Primary Completion Date

August 2015

Eligibility Criteria

        Inclusion Criteria

          -  asymptomatic mild (peak valve velocity of 2-5-3.0 m/s; n=10), moderate (peak valve
             velocity of 3.0-4.0 m/s; n=10) or severe aortic stenosis (peak valve velocity of >4.0
             m/s; n=10) and 10 patients with severe aortic stenosis proceeding to aortic valve
             replacement.

          -  Healthy control subjects (n=10) will have no past medical history of ischaemic heart
             disease or valvular heart disease and have a structurally normal heart on
             echocardiography.

        Exclusion Criteria:

          -  Atrial fibrillation

          -  Hepatic failure (Childs-Pugh grade B or C)

          -  Renal failure (estimated glomerular filtration rate <25 mL/min)

          -  Women of child-bearing potential

          -  Contraindication to magnetic resonance imaging

          -  Inability to undergo scanning

          -  Ochronosis and those with any form of collagen-vascular disease.
      

Gender

All

Ages

40 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

David E Newby, MBChB PhD, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT01837160

Organization ID

2012/R/CAR/23

Secondary IDs

FS/12/84/29814

Responsible Party

Sponsor

Study Sponsor

University of Edinburgh


Study Sponsor

David E Newby, MBChB PhD, Study Director, University of Edinburgh


Verification Date

March 2015