<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01679431</url>
  </required_header>
  <id_info>
    <org_study_id>MOP-114997</org_study_id>
    <nct_id>NCT01679431</nct_id>
  </id_info>
  <brief_title>Metabolic Determinants of the Progression of Aortic Stenosis</brief_title>
  <acronym>PROGRESSA</acronym>
  <official_title>Metabolic Determinants of the Progression of Aortic Stenosis - PROGRESSA Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Laval University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Heart and Stroke Foundation of Canada</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Laval University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Calcific aortic stenosis (AS) has become the most common cardiac disease after coronary&#xD;
      artery disease and hypertension. Unfortunately no medical therapies have been proven to&#xD;
      decrease either the progression of valve stenosis or the resulting adverse effects on&#xD;
      myocardial remodeling and function. In light of the studies performed in PROGRESSA, it&#xD;
      becomes obvious that: i) AS is a complex and actively regulated process that involves the&#xD;
      interaction of several pathways including lipid infiltration and retention, chronic&#xD;
      inflammation, osteogenic activation, and active mineralization within the valvular tissues;&#xD;
      ii) AS is not a disease strictly limited to the aortic valve but rather a systemic disease&#xD;
      that often involves calcification and stiffening of the aorta and impairment of LV function&#xD;
      as a consequence of pressure overload. Our findings suggest that the dysmetabolic milieu&#xD;
      linked to visceral obesity may accelerate the deterioration of the structure and function not&#xD;
      only of the aortic valve but also of the aorta and of the left ventricle. These findings open&#xD;
      new avenues of research and provide strong impetus for the elaboration of prospective studies&#xD;
      focusing on the &quot;valvulo-metabolic risk&quot; in AS.&#xD;
&#xD;
      The general hypotheses are: The metabolic abnormalities linked to visceral obesity accelerate&#xD;
      (1) the progression of valvular calcification and stenosis, aortic calcification and&#xD;
      stiffness; (2) the progression of myocardial fibrosis and dysfunction.&#xD;
&#xD;
      The general objectives of the study are to elucidate the mechanisms implicated in the&#xD;
      pathogenesis of AS and to identify the metabolic factors that determine the progression of:&#xD;
      i) aortic valve calcification and stenosis; ii) myocardial fibrosis and dysfunction; and iii)&#xD;
      clinical outcomes.&#xD;
&#xD;
      This study will contribute to identifying the key metabolic determinants of AS progression&#xD;
      and will pave the way for the future development of non surgical therapies for this disease.&#xD;
      The results of this study would provide strong support to the realization of randomized trial&#xD;
      to test the efficacy of lifestyle modification program or new pharmacological treatment&#xD;
      aiming at the reduction of visceral fat and associated metabolic abnormalities in the AS&#xD;
      population. Furthermore, this study will contribute to the identification of novel blood and&#xD;
      imaging biomarkers of faster disease progression, which will help to optimize risk&#xD;
      stratification and timing of AVR in the AS population.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The hypotheses are: (1) The metabolic abnormalities linked to visceral obesity increase: i)&#xD;
      the progression of aortic valve calcification and stenosis, of aortic calcification and&#xD;
      stiffness, and thereby of the global hemodynamic load imposed on the LV; ii) the progression&#xD;
      of myocardial hypertrophy, fibrosis, and dysfunction, iii) the loss in bone mineral density,&#xD;
      and iv) the occurrence of adverse events in patients with AS. (2) Specifically, insulin&#xD;
      resistance, the small, dense LDL and HDL phenotypes, enhanced oxidative stress &amp; inflammatory&#xD;
      state, and activation of the RAS act synergistically to: i) promote infiltration, retention,&#xD;
      and modification of lipids within the valvular and arterial tissues, ii) enhance the&#xD;
      inflammatory and osteoblastic response to oxidized lipids, iii) activate apoptosis of VICs&#xD;
      and apoptosis-mediated calcification of the aortic valve and aorta, iv) promote osteoclastic&#xD;
      activity and demineralization within the bone tissues (calcification paradox) (Figs. 1&amp;6).&#xD;
      These mechanisms predominate in the middle-aged patients, whereas imbalance in nuclear&#xD;
      coregulators, alteration of adipokine system, dysregulation of mineral metabolism, and loss&#xD;
      calcification inhibitors are the main contributing mechanisms in the elderly (Figs. 1,5,6).&#xD;
      The contribution of visceral obesity to disease progression is more important in the patients&#xD;
      with mildly or moderately calcified valves than in those with heavily calcified valves. In&#xD;
      the latter, further progression of calcification and stenosis is predominantly influenced&#xD;
      dysregulation of mineral metabolism. (3) The alteration of the myocardial energetic&#xD;
      substrates and of the protein synthesis/degradation balance associated with visceral obesity&#xD;
      and insulin resistance amplify the development of myocardial hypertrophy and fibrosis in&#xD;
      response to pressure overload and accelerates the progression to myocardial dysfunction&#xD;
      (Figs. 7&amp;8). The adverse LV remodelling and fibrosis resulting from the synergistic effects&#xD;
      of pressure overload and dysmetabolism predispose to the occurrence of paradoxical low flow&#xD;
      AS and cardiac events.&#xD;
&#xD;
      The general objectives of the study are to elucidate the mechanisms implicated in the&#xD;
      pathogenesis of AS and to identify the metabolic factors that determine the progression of:&#xD;
      i) aortic valve calcification and stenosis; ii) aorta calcification and stiffness, iii)&#xD;
      myocardial remodeling, fibrosis and dysfunction; and iv) clinical outcomes in the AS&#xD;
      population.&#xD;
&#xD;
      The specific aims of the study are:&#xD;
&#xD;
        1. To obtain and analyze: i) the metabolic profile, ii) the progression of aortic valve,&#xD;
           aorta, and coronary artery calcification measured by CT, iii) the hemodynamic&#xD;
           progression of valve stenosis by Doppler-echocardiography, iv) the progression of&#xD;
           myocardial remodeling, fibrosis, and dysfunction by MRI, v) the change in bone mineral&#xD;
           density by DXA, vi) the occurrence of clinical outcomes (AVR or death), and vii) the&#xD;
           valvular tissues explanted at the time of AVR in a series of 280 patients with AS.&#xD;
&#xD;
        2. To perform histo-pathologic and genetic/protein expression analyses of valve tissues to&#xD;
           document the lipid infiltration /retention/modification and the inflammatory and&#xD;
           osteoblastic activities within the metabolic abnormalities, age, valve phenotype, and&#xD;
           bone mineral density.&#xD;
&#xD;
        3. To study the relationship between the cardio-metabolic determinants: i) traditional&#xD;
           cardiovascular risk factors (hypercholesterolemia, hypertension, smoking), ii) amount of&#xD;
           visceral fat and metabolic abnormalities associated with visceral obesity and the&#xD;
           outcome variables: i) progression of aortic valve calcification and stenosis, aorta&#xD;
           calcification and stiffening, bone mineral loss, and myocardial remodelling, fibrosis&#xD;
           and dysfunction, ii) occurrence of adverse outcomes, iii) lipid infiltration/ retention/&#xD;
           modification, inflammatory/osteoblastic activities in the valve&#xD;
&#xD;
        4. To determine if the impact of these cardio-metabolic determinants on disease progression&#xD;
           differ according to age, gender, BAV phenotype, and degree of aortic valve calcification&#xD;
           at baseline.&#xD;
&#xD;
        5. To examine the relationship between aortic valve/aorta/coronary (i.e. ectopic)&#xD;
           calcification and bone mineral density and determine the impact of cardio-metabolic and&#xD;
           mineral metabolism factors on this relationship.&#xD;
&#xD;
        6. To examine the respective contribution of aortic valve calcification/stenosis, aorta&#xD;
           calcification /stiffness, coronary calcification, bone density, and myocardial fibrosis&#xD;
           to the occurrence of clinical outcomes in this AS cohort.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>April 2005</start_date>
  <completion_date type="Anticipated">January 2024</completion_date>
  <primary_completion_date type="Anticipated">January 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Progression of aortic valve stenosis</measure>
    <time_frame>Patients will be followed every 1 year, up to 5 years</time_frame>
    <description>Annualized progression rate of aortic stenosis hemodynamic severity calculate as the difference between peak aortic jet velocity, transvalvular gradients, and aortic valve area measured at baseline and those measured at the last follow-up divided by the time between the first and last examinations.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression of aortic valve calcification</measure>
    <time_frame>Patients will be followed every 2 years, up to 5 years</time_frame>
    <description>Annualized progression rate of aortic valve calcium</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression of myocardial fibrosis and dysfunction</measure>
    <time_frame>PPatients will be followed every 2 years, up to 5 years</time_frame>
    <description>Annualized progression rate of myocardial fibrosis and global longitudinal myocardial strain</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Progression of aortic calcification and stiffness</measure>
    <time_frame>Patients will be followed every 2 years, up to 5 years</time_frame>
    <description>Annualized progression rate of calcification measured by computed tomography and aortic compliance measured (CT) by cardiac magnetic resonance (CMR) and Doppler-echocardiography</description>
  </other_outcome>
  <other_outcome>
    <measure>Progression of coronary artery calcification</measure>
    <time_frame>Patients will be followed every 2 years, up to 5 years</time_frame>
    <description>Annualized progression rate of coronary artery calcification measured by CT</description>
  </other_outcome>
  <other_outcome>
    <measure>Progression of global hemodynamic load</measure>
    <time_frame>Patients will be followed every 1 year, up to 5 years</time_frame>
    <description>Annualized progression rate of valvulo-arterial impedance measured by Doppler-echocardiography</description>
  </other_outcome>
  <other_outcome>
    <measure>Aortic stenosis related events</measure>
    <time_frame>From date of baseline until the date of first documented aortic stenosis related events (as defined on description box), assessed up to 5 years</time_frame>
    <description>Cardiovascular-related mortality; hospitalization for heart failure; surgical or transcatheter aortic valve replacement motivated by the development of symptoms or LV systolic dysfunction</description>
  </other_outcome>
  <other_outcome>
    <measure>Ischemic cardiovascular events</measure>
    <time_frame>From date of baseline until the date of first documented ischemic cardiovascular events (as defined on description box), assessed up to 5 years</time_frame>
    <description>Myocardial infarction; unstable angina; revascularization procedure</description>
  </other_outcome>
  <other_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>From date of baseline until the date of death from any cause assessed up to 5 years</time_frame>
    <description>Death from any cause</description>
  </other_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">250</enrollment>
  <condition>Aortic Valve Stenosis</condition>
  <arm_group>
    <arm_group_label>Patients with aortic stenosis</arm_group_label>
    <description>Patients have every year: 1) an assessment of cardiometabolic risk profile with measure of body mass index, waist circumference and fasting blood sample and 2) a comprehensive Doppler-echocardiography exam.&#xD;
Computed tomography and magnetic resonance imaging are performed every 2 years.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Doppler-echocardiography</intervention_name>
    <arm_group_label>Patients with aortic stenosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Computed tomography</intervention_name>
    <arm_group_label>Patients with aortic stenosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Magnetic resonance imaging</intervention_name>
    <arm_group_label>Patients with aortic stenosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fasting blood sample</intervention_name>
    <arm_group_label>Patients with aortic stenosis</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Fasting blood sample (serum, lithium-heparin, EDTA) and white cells - Tissue (explanted&#xD;
      aortic valves)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Cohort will be selected at primary care clinic&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;21 years&#xD;
&#xD;
          -  Presence of aortic stenosis defined as peak aortic jet velocity ≥2.5 m/s&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Symptomatic aortic stenosis&#xD;
&#xD;
          -  Very severe aortic stenosis defined as an AVA≤0.6 cm2&#xD;
&#xD;
          -  Left ventricular ejection fraction &lt; 50%&#xD;
&#xD;
          -  More than mild aortic or mitral regurgitation, or mitral stenosis&#xD;
&#xD;
          -  Atrial fibrillation or flutter&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Contraindications to gadolinium-enhanced MRI&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philippe Pibarot, PhD, DVM</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut universitaire de cardiologie et de pneumologie de Québec, University Laval</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Philippe Pibarot, PhD, DVM</last_name>
    <phone>418-656-8711</phone>
    <phone_ext>5938</phone_ext>
    <email>Philippe.Pibarot@med.ulaval.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Romain Capoulade, MSc</last_name>
    <phone>418-656-8711</phone>
    <phone_ext>3845</phone_ext>
    <email>Romain.Capoulade@criucpq.ulaval.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Institut Universitaire de Cardiologie et de Pneumologie de Québec</name>
      <address>
        <city>Québec</city>
        <zip>G1V4G5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Philippe Pibarot, PhD</last_name>
      <phone>418-656-8711</phone>
      <phone_ext>5938</phone_ext>
      <email>Philippe.Pibarot@med.ulaval.ca</email>
    </contact>
    <contact_backup>
      <last_name>Romain Capoulade, MSc</last_name>
      <phone>418-656-8711</phone>
      <phone_ext>3845</phone_ext>
      <email>Romain.Capoulade@criucpq.ulaval.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Phillipe Pibarot, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Capoulade R, Clavel MA, Dumesnil JG, Chan KL, Teo KK, Tam JW, Cote N, Mathieu P, Despres JP, Pibarot P; ASTRONOMER Investigators. Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy. J Am Coll Cardiol. 2012 Jul 17;60(3):216-23. doi: 10.1016/j.jacc.2012.03.052.</citation>
    <PMID>22789885</PMID>
  </reference>
  <reference>
    <citation>Cote N, El Husseini D, Pepin A, Bouvet C, Gilbert LA, Audet A, Fournier D, Pibarot P, Moreau P, Mathieu P. Inhibition of ectonucleotidase with ARL67156 prevents the development of calcific aortic valve disease in warfarin-treated rats. Eur J Pharmacol. 2012 Aug 15;689(1-3):139-46. doi: 10.1016/j.ejphar.2012.05.016. Epub 2012 May 31.</citation>
    <PMID>22659116</PMID>
  </reference>
  <reference>
    <citation>Audet A, Cote N, Couture C, Bosse Y, Despres JP, Pibarot P, Mathieu P. Amyloid substance within stenotic aortic valves promotes mineralization. Histopathology. 2012 Oct;61(4):610-9. doi: 10.1111/j.1365-2559.2012.04265.x.</citation>
    <PMID>22642224</PMID>
  </reference>
  <reference>
    <citation>Carter S, Miard S, Roy-Bellavance C, Boivin L, Li Z, Pibarot P, Mathieu P, Picard F. Sirt1 inhibits resistin expression in aortic stenosis. PLoS One. 2012;7(4):e35110. doi: 10.1371/journal.pone.0035110. Epub 2012 Apr 6.</citation>
    <PMID>22493735</PMID>
  </reference>
  <reference>
    <citation>Shetty R, Girerd N, Cote N, Arsenault B, Despres JP, Pibarot P, Mathieu P. Elevated proportion of small, dense low-density lipoprotein particles and lower adiponectin blood levels predict early structural valve degeneration of bioprostheses. Cardiology. 2012;121(1):20-6. doi: 10.1159/000336170. Epub 2012 Feb 25.</citation>
    <PMID>22378142</PMID>
  </reference>
  <reference>
    <citation>Cote N, El Husseini D, Pepin A, Guauque-Olarte S, Ducharme V, Bouchard-Cannon P, Audet A, Fournier D, Gaudreault N, Derbali H, McKee MD, Simard C, Despres JP, Pibarot P, Bosse Y, Mathieu P. ATP acts as a survival signal and prevents the mineralization of aortic valve. J Mol Cell Cardiol. 2012 May;52(5):1191-202. doi: 10.1016/j.yjmcc.2012.02.003. Epub 2012 Feb 16.</citation>
    <PMID>22366713</PMID>
  </reference>
  <reference>
    <citation>Cote N, Couture C, Pibarot P, Despres JP, Mathieu P. Angiotensin receptor blockers are associated with a lower remodelling score of stenotic aortic valves. Eur J Clin Invest. 2011 Nov;41(11):1172-9. doi: 10.1111/j.1365-2362.2011.02522.x.</citation>
    <PMID>21988540</PMID>
  </reference>
  <reference>
    <citation>Gaudreault N, Ducharme V, Lamontagne M, Guauque-Olarte S, Mathieu P, Pibarot P, Bosse Y. Replication of genetic association studies in aortic stenosis in adults. Am J Cardiol. 2011 Nov 1;108(9):1305-10. doi: 10.1016/j.amjcard.2011.06.050. Epub 2011 Aug 18.</citation>
    <PMID>21855833</PMID>
  </reference>
  <reference>
    <citation>Mohty D, Pibarot P, Cote N, Cartier A, Audet A, Despres JP, Mathieu P. Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis. Cardiology. 2011;118(2):140-6. doi: 10.1159/000327588. Epub 2011 May 19.</citation>
    <PMID>21597293</PMID>
  </reference>
  <reference>
    <citation>Page A, Dumesnil JG, Clavel MA, Chan KL, Teo KK, Tam JW, Mathieu P, Despres JP, Pibarot P; ASTRONOMER Investigators. Metabolic syndrome is associated with more pronounced impairment of left ventricle geometry and function in patients with calcific aortic stenosis: a substudy of the ASTRONOMER (Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin). J Am Coll Cardiol. 2010 Apr 27;55(17):1867-74. doi: 10.1016/j.jacc.2009.11.083.</citation>
    <PMID>20413039</PMID>
  </reference>
  <reference>
    <citation>Derbali H, Bosse Y, Cote N, Pibarot P, Audet A, Pepin A, Arsenault B, Couture C, Despres JP, Mathieu P. Increased biglycan in aortic valve stenosis leads to the overexpression of phospholipid transfer protein via Toll-like receptor 2. Am J Pathol. 2010 Jun;176(6):2638-45. doi: 10.2353/ajpath.2010.090541. Epub 2010 Apr 9.</citation>
    <PMID>20382708</PMID>
  </reference>
  <reference>
    <citation>Bosse Y, Miqdad A, Fournier D, Pepin A, Pibarot P, Mathieu P. Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves. Circ Cardiovasc Genet. 2009 Oct;2(5):489-98. doi: 10.1161/CIRCGENETICS.108.820795. Epub 2009 Jul 8.</citation>
    <PMID>20031625</PMID>
  </reference>
  <reference>
    <citation>Cote N, Pibarot P, Pepin A, Fournier D, Audet A, Arsenault B, Couture C, Poirier P, Despres JP, Mathieu P. Oxidized low-density lipoprotein, angiotensin II and increased waist cirumference are associated with valve inflammation in prehypertensive patients with aortic stenosis. Int J Cardiol. 2010 Dec 3;145(3):444-9. doi: 10.1016/j.ijcard.2009.05.054. Epub 2009 Jun 13.</citation>
    <PMID>19525020</PMID>
  </reference>
  <reference>
    <citation>Mohty D, Pibarot P, Despres JP, Cartier A, Arsenault B, Picard F, Mathieu P. Age-related differences in the pathogenesis of calcific aortic stenosis: the potential role of resistin. Int J Cardiol. 2010 Jul 9;142(2):126-32. doi: 10.1016/j.ijcard.2008.12.068. Epub 2009 Jan 21.</citation>
    <PMID>19162347</PMID>
  </reference>
  <reference>
    <citation>Mathieu P, Despres JP, Pibarot P. The 'valvulo-metabolic' risk in calcific aortic valve disease. Can J Cardiol. 2007 Oct;23 Suppl B(Suppl B):32B-39B. doi: 10.1016/s0828-282x(07)71008-5. Erratum In: Can J Cardiol. 2009 Mar;25(3):140.</citation>
    <PMID>17932585</PMID>
  </reference>
  <reference>
    <citation>Mohty D, Pibarot P, Despres JP, Cote C, Arsenault B, Cartier A, Cosnay P, Couture C, Mathieu P. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):187-93. doi: 10.1161/ATVBAHA.107.154989. Epub 2007 Nov 1.</citation>
    <PMID>17975118</PMID>
  </reference>
  <reference>
    <citation>Cote C, Pibarot P, Despres JP, Mohty D, Cartier A, Arsenault BJ, Couture C, Mathieu P. Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis. Heart. 2008 Sep;94(9):1175-80. doi: 10.1136/hrt.2007.125740. Epub 2007 Oct 11.</citation>
    <PMID>17932090</PMID>
  </reference>
  <reference>
    <citation>Pibarot P, Dumesnil JG, Mathieu P. [New insight into the treatment of aortic stenosis]. Med Sci (Paris). 2007 Jan;23(1):81-7. doi: 10.1051/medsci/200723181. French.</citation>
    <PMID>17212936</PMID>
  </reference>
  <reference>
    <citation>Briand M, Lemieux I, Dumesnil JG, Mathieu P, Cartier A, Despres JP, Arsenault M, Couet J, Pibarot P. Metabolic syndrome negatively influences disease progression and prognosis in aortic stenosis. J Am Coll Cardiol. 2006 Jun 6;47(11):2229-36. doi: 10.1016/j.jacc.2005.12.073. Epub 2006 May 15.</citation>
    <PMID>16750688</PMID>
  </reference>
  <reference>
    <citation>Charest A, Pepin A, Shetty R, Cote C, Voisine P, Dagenais F, Pibarot P, Mathieu P. Distribution of SPARC during neovascularisation of degenerative aortic stenosis. Heart. 2006 Dec;92(12):1844-9. doi: 10.1136/hrt.2005.086595. Epub 2006 May 18.</citation>
    <PMID>16709694</PMID>
  </reference>
  <reference>
    <citation>Shetty R, Pepin A, Charest A, Perron J, Doyle D, Voisine P, Dagenais F, Pibarot P, Mathieu P. Expression of bone-regulatory proteins in human valve allografts. Heart. 2006 Sep;92(9):1303-8. doi: 10.1136/hrt.2005.075903. Epub 2006 Jan 31.</citation>
    <PMID>16449517</PMID>
  </reference>
  <reference>
    <citation>Briand M, Dumesnil JG, Kadem L, Tongue AG, Rieu R, Garcia D, Pibarot P. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. J Am Coll Cardiol. 2005 Jul 19;46(2):291-8. doi: 10.1016/j.jacc.2004.10.081.</citation>
    <PMID>16022957</PMID>
  </reference>
  <reference>
    <citation>Tastet L, Capoulade R, Shen M, Clavel MA, Cote N, Mathieu P, Arsenault M, Bedard E, Tremblay A, Samson M, Bosse Y, Dumesnil JG, Arsenault BJ, Beaudoin J, Bernier M, Despres JP, Pibarot P. ApoB/ApoA-I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study. J Am Heart Assoc. 2018 Feb 10;7(4):e007980. doi: 10.1161/JAHA.117.007980.</citation>
    <PMID>29440006</PMID>
  </reference>
  <reference>
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  </reference>
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    <PMID>24161325</PMID>
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  <verification_date>September 2021</verification_date>
  <study_first_submitted>August 24, 2012</study_first_submitted>
  <study_first_submitted_qc>August 31, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 6, 2012</study_first_posted>
  <last_update_submitted>September 20, 2021</last_update_submitted>
  <last_update_submitted_qc>September 20, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 21, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Laval University</investigator_affiliation>
    <investigator_full_name>Philippe Pibarot</investigator_full_name>
    <investigator_title>Doctor</investigator_title>
  </responsible_party>
  <keyword>Aortic Stenosis</keyword>
  <keyword>Obesity, Abdominal</keyword>
  <keyword>Metabolic Syndrome X</keyword>
  <keyword>Insulin Resistance</keyword>
  <keyword>Echocardiography, Doppler</keyword>
  <keyword>Multidetector Computed Tomography</keyword>
  <keyword>Magnetic Resonance Imaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aortic Valve Stenosis</mesh_term>
    <mesh_term>Constriction, Pathologic</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01679431
org study id: MOP-114997
nct id: NCT01679431
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Calcific aortic stenosis (AS) has become the most common cardiac disease after coronary
      artery disease and hypertension. Unfortunately no medical therapies have been proven to
      decrease either the progression of valve stenosis or the resulting adverse effects on
      myocardial remodeling and function. In light of the studies performed in PROGRESSA, it
      becomes obvious that: i) AS is a complex and actively regulated process that involves the
      interaction of several pathways including lipid infiltration and retention, chronic
      inflammation, osteogenic activation, and active mineralization within the valvular tissues;
      ii) AS is not a disease strictly limited to the aortic valve but rather a systemic disease
      that often involves calcification and stiffening of the aorta and impairment of LV function
      as a consequence of pressure overload. Our findings suggest that the dysmetabolic milieu
      linked to visceral obesity may accelerate the deterioration of the structure and function not
      only of the aortic valve but also of the aorta and of the left ventricle. These findings open
      new avenues of research and provide strong impetus for the elaboration of prospective studies
      focusing on the "valvulo-metabolic risk" in AS.

      The general hypotheses are: The metabolic abnormalities linked to visceral obesity accelerate
      (1) the progression of valvular calcification and stenosis, aortic calcification and
      stiffness; (2) the progression of myocardial fibrosis and dysfunction.

      The general objectives of the study are to elucidate the mechanisms implicated in the
      pathogenesis of AS and to identify the metabolic factors that determine the progression of:
      i) aortic valve calcification and stenosis; ii) myocardial fibrosis and dysfunction; and iii)
      clinical outcomes.

      This study will contribute to identifying the key metabolic determinants of AS progression
      and will pave the way for the future development of non surgical therapies for this disease.
      The results of this study would provide strong support to the realization of randomized trial
      to test the efficacy of lifestyle modification program or new pharmacological treatment
      aiming at the reduction of visceral fat and associated metabolic abnormalities in the AS
      population. Furthermore, this study will contribute to the identification of novel blood and
      imaging biomarkers of faster disease progression, which will help to optimize risk
      stratification and timing of AVR in the AS population.
The hypotheses are: (1) The metabolic abnormalities linked to visceral obesity increase: i)
      the progression of aortic valve calcification and stenosis, of aortic calcification and
      stiffness, and thereby of the global hemodynamic load imposed on the LV; ii) the progression
      of myocardial hypertrophy, fibrosis, and dysfunction, iii) the loss in bone mineral density,
      and iv) the occurrence of adverse events in patients with AS. (2) Specifically, insulin
      resistance, the small, dense LDL and HDL phenotypes, enhanced oxidative stress & inflammatory
      state, and activation of the RAS act synergistically to: i) promote infiltration, retention,
      and modification of lipids within the valvular and arterial tissues, ii) enhance the
      inflammatory and osteoblastic response to oxidized lipids, iii) activate apoptosis of VICs
      and apoptosis-mediated calcification of the aortic valve and aorta, iv) promote osteoclastic
      activity and demineralization within the bone tissues (calcification paradox) (Figs. 1&6).
      These mechanisms predominate in the middle-aged patients, whereas imbalance in nuclear
      coregulators, alteration of adipokine system, dysregulation of mineral metabolism, and loss
      calcification inhibitors are the main contributing mechanisms in the elderly (Figs. 1,5,6).
      The contribution of visceral obesity to disease progression is more important in the patients
      with mildly or moderately calcified valves than in those with heavily calcified valves. In
      the latter, further progression of calcification and stenosis is predominantly influenced
      dysregulation of mineral metabolism. (3) The alteration of the myocardial energetic
      substrates and of the protein synthesis/degradation balance associated with visceral obesity
      and insulin resistance amplify the development of myocardial hypertrophy and fibrosis in
      response to pressure overload and accelerates the progression to myocardial dysfunction
      (Figs. 7&8). The adverse LV remodelling and fibrosis resulting from the synergistic effects
      of pressure overload and dysmetabolism predispose to the occurrence of paradoxical low flow
      AS and cardiac events.

      The general objectives of the study are to elucidate the mechanisms implicated in the
      pathogenesis of AS and to identify the metabolic factors that determine the progression of:
      i) aortic valve calcification and stenosis; ii) aorta calcification and stiffness, iii)
      myocardial remodeling, fibrosis and dysfunction; and iv) clinical outcomes in the AS
      population.

      The specific aims of the study are:

        1. To obtain and analyze: i) the metabolic profile, ii) the progression of aortic valve,
           aorta, and coronary artery calcification measured by CT, iii) the hemodynamic
           progression of valve stenosis by Doppler-echocardiography, iv) the progression of
           myocardial remodeling, fibrosis, and dysfunction by MRI, v) the change in bone mineral
           density by DXA, vi) the occurrence of clinical outcomes (AVR or death), and vii) the
           valvular tissues explanted at the time of AVR in a series of 280 patients with AS.

        2. To perform histo-pathologic and genetic/protein expression analyses of valve tissues to
           document the lipid infiltration /retention/modification and the inflammatory and
           osteoblastic activities within the metabolic abnormalities, age, valve phenotype, and
           bone mineral density.

        3. To study the relationship between the cardio-metabolic determinants: i) traditional
           cardiovascular risk factors (hypercholesterolemia, hypertension, smoking), ii) amount of
           visceral fat and metabolic abnormalities associated with visceral obesity and the
           outcome variables: i) progression of aortic valve calcification and stenosis, aorta
           calcification and stiffening, bone mineral loss, and myocardial remodelling, fibrosis
           and dysfunction, ii) occurrence of adverse outcomes, iii) lipid infiltration/ retention/
           modification, inflammatory/osteoblastic activities in the valve

        4. To determine if the impact of these cardio-metabolic determinants on disease progression
           differ according to age, gender, BAV phenotype, and degree of aortic valve calcification
           at baseline.

        5. To examine the relationship between aortic valve/aorta/coronary (i.e. ectopic)
           calcification and bone mineral density and determine the impact of cardio-metabolic and
           mineral metabolism factors on this relationship.

        6. To examine the respective contribution of aortic valve calcification/stenosis, aorta
           calcification /stiffness, coronary calcification, bone density, and myocardial fibrosis
           to the occurrence of clinical outcomes in this AS cohort.
observational model: Cohort
time perspective: Prospective
measure: Progression of aortic valve stenosis
time frame: Patients will be followed every 1 year, up to 5 years
description: Annualized progression rate of aortic stenosis hemodynamic severity calculate as the difference between peak aortic jet velocity, transvalvular gradients, and aortic valve area measured at baseline and those measured at the last follow-up divided by the time between the first and last examinations.
measure: Progression of aortic valve calcification
time frame: Patients will be followed every 2 years, up to 5 years
description: Annualized progression rate of aortic valve calcium
measure: Progression of myocardial fibrosis and dysfunction
time frame: PPatients will be followed every 2 years, up to 5 years
description: Annualized progression rate of myocardial fibrosis and global longitudinal myocardial strain
measure: Progression of aortic calcification and stiffness
time frame: Patients will be followed every 2 years, up to 5 years
description: Annualized progression rate of calcification measured by computed tomography and aortic compliance measured (CT) by cardiac magnetic resonance (CMR) and Doppler-echocardiography
measure: Progression of coronary artery calcification
time frame: Patients will be followed every 2 years, up to 5 years
description: Annualized progression rate of coronary artery calcification measured by CT
measure: Progression of global hemodynamic load
time frame: Patients will be followed every 1 year, up to 5 years
description: Annualized progression rate of valvulo-arterial impedance measured by Doppler-echocardiography
measure: Aortic stenosis related events
time frame: From date of baseline until the date of first documented aortic stenosis related events (as defined on description box), assessed up to 5 years
description: Cardiovascular-related mortality; hospitalization for heart failure; surgical or transcatheter aortic valve replacement motivated by the development of symptoms or LV systolic dysfunction
measure: Ischemic cardiovascular events
time frame: From date of baseline until the date of first documented ischemic cardiovascular events (as defined on description box), assessed up to 5 years
description: Myocardial infarction; unstable angina; revascularization procedure
measure: All-cause mortality
time frame: From date of baseline until the date of death from any cause assessed up to 5 years
description: Death from any cause
arm group label: Patients with aortic stenosis
description: Patients have every year: 1) an assessment of cardiometabolic risk profile with measure of body mass index, waist circumference and fasting blood sample and 2) a comprehensive Doppler-echocardiography exam.
Computed tomography and magnetic resonance imaging are performed every 2 years.
intervention type: Diagnostic Test
intervention name: Doppler-echocardiography
arm group label: Patients with aortic stenosis
intervention type: Radiation
intervention name: Computed tomography
arm group label: Patients with aortic stenosis
intervention type: Other
intervention name: Magnetic resonance imaging
arm group label: Patients with aortic stenosis
intervention type: Biological
intervention name: Fasting blood sample
arm group label: Patients with aortic stenosis
Fasting blood sample (serum, lithium-heparin, EDTA) and white cells - Tissue (explanted
      aortic valves)
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Philippe Pibarot, PhD, DVM
role: Principal Investigator
affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, University Laval
last name: Philippe Pibarot, PhD, DVM
phone: 418-656-8711
phone ext: 5938
email: Philippe.Pibarot@med.ulaval.ca
last name: Romain Capoulade, MSc
phone: 418-656-8711
phone ext: 3845
email: Romain.Capoulade@criucpq.ulaval.ca
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Canada
citation: Capoulade R, Clavel MA, Dumesnil JG, Chan KL, Teo KK, Tam JW, Cote N, Mathieu P, Despres JP, Pibarot P; ASTRONOMER Investigators. Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy. J Am Coll Cardiol. 2012 Jul 17;60(3):216-23. doi: 10.1016/j.jacc.2012.03.052.
PMID: 22789885
citation: Cote N, El Husseini D, Pepin A, Bouvet C, Gilbert LA, Audet A, Fournier D, Pibarot P, Moreau P, Mathieu P. Inhibition of ectonucleotidase with ARL67156 prevents the development of calcific aortic valve disease in warfarin-treated rats. Eur J Pharmacol. 2012 Aug 15;689(1-3):139-46. doi: 10.1016/j.ejphar.2012.05.016. Epub 2012 May 31.
PMID: 22659116
citation: Audet A, Cote N, Couture C, Bosse Y, Despres JP, Pibarot P, Mathieu P. Amyloid substance within stenotic aortic valves promotes mineralization. Histopathology. 2012 Oct;61(4):610-9. doi: 10.1111/j.1365-2559.2012.04265.x.
PMID: 22642224
citation: Carter S, Miard S, Roy-Bellavance C, Boivin L, Li Z, Pibarot P, Mathieu P, Picard F. Sirt1 inhibits resistin expression in aortic stenosis. PLoS One. 2012;7(4):e35110. doi: 10.1371/journal.pone.0035110. Epub 2012 Apr 6.
PMID: 22493735
citation: Shetty R, Girerd N, Cote N, Arsenault B, Despres JP, Pibarot P, Mathieu P. Elevated proportion of small, dense low-density lipoprotein particles and lower adiponectin blood levels predict early structural valve degeneration of bioprostheses. Cardiology. 2012;121(1):20-6. doi: 10.1159/000336170. Epub 2012 Feb 25.
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citation: Cote N, Couture C, Pibarot P, Despres JP, Mathieu P. Angiotensin receptor blockers are associated with a lower remodelling score of stenotic aortic valves. Eur J Clin Invest. 2011 Nov;41(11):1172-9. doi: 10.1111/j.1365-2362.2011.02522.x.
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citation: Gaudreault N, Ducharme V, Lamontagne M, Guauque-Olarte S, Mathieu P, Pibarot P, Bosse Y. Replication of genetic association studies in aortic stenosis in adults. Am J Cardiol. 2011 Nov 1;108(9):1305-10. doi: 10.1016/j.amjcard.2011.06.050. Epub 2011 Aug 18.
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citation: Mohty D, Pibarot P, Cote N, Cartier A, Audet A, Despres JP, Mathieu P. Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis. Cardiology. 2011;118(2):140-6. doi: 10.1159/000327588. Epub 2011 May 19.
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citation: Page A, Dumesnil JG, Clavel MA, Chan KL, Teo KK, Tam JW, Mathieu P, Despres JP, Pibarot P; ASTRONOMER Investigators. Metabolic syndrome is associated with more pronounced impairment of left ventricle geometry and function in patients with calcific aortic stenosis: a substudy of the ASTRONOMER (Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin). J Am Coll Cardiol. 2010 Apr 27;55(17):1867-74. doi: 10.1016/j.jacc.2009.11.083.
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citation: Bosse Y, Miqdad A, Fournier D, Pepin A, Pibarot P, Mathieu P. Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves. Circ Cardiovasc Genet. 2009 Oct;2(5):489-98. doi: 10.1161/CIRCGENETICS.108.820795. Epub 2009 Jul 8.
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citation: Cote N, Pibarot P, Pepin A, Fournier D, Audet A, Arsenault B, Couture C, Poirier P, Despres JP, Mathieu P. Oxidized low-density lipoprotein, angiotensin II and increased waist cirumference are associated with valve inflammation in prehypertensive patients with aortic stenosis. Int J Cardiol. 2010 Dec 3;145(3):444-9. doi: 10.1016/j.ijcard.2009.05.054. Epub 2009 Jun 13.
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citation: Mathieu P, Despres JP, Pibarot P. The 'valvulo-metabolic' risk in calcific aortic valve disease. Can J Cardiol. 2007 Oct;23 Suppl B(Suppl B):32B-39B. doi: 10.1016/s0828-282x(07)71008-5. Erratum In: Can J Cardiol. 2009 Mar;25(3):140.
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citation: Mohty D, Pibarot P, Despres JP, Cote C, Arsenault B, Cartier A, Cosnay P, Couture C, Mathieu P. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):187-93. doi: 10.1161/ATVBAHA.107.154989. Epub 2007 Nov 1.
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citation: Cote C, Pibarot P, Despres JP, Mohty D, Cartier A, Arsenault BJ, Couture C, Mathieu P. Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis. Heart. 2008 Sep;94(9):1175-80. doi: 10.1136/hrt.2007.125740. Epub 2007 Oct 11.
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citation: Briand M, Lemieux I, Dumesnil JG, Mathieu P, Cartier A, Despres JP, Arsenault M, Couet J, Pibarot P. Metabolic syndrome negatively influences disease progression and prognosis in aortic stenosis. J Am Coll Cardiol. 2006 Jun 6;47(11):2229-36. doi: 10.1016/j.jacc.2005.12.073. Epub 2006 May 15.
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citation: Charest A, Pepin A, Shetty R, Cote C, Voisine P, Dagenais F, Pibarot P, Mathieu P. Distribution of SPARC during neovascularisation of degenerative aortic stenosis. Heart. 2006 Dec;92(12):1844-9. doi: 10.1136/hrt.2005.086595. Epub 2006 May 18.
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citation: Shetty R, Pepin A, Charest A, Perron J, Doyle D, Voisine P, Dagenais F, Pibarot P, Mathieu P. Expression of bone-regulatory proteins in human valve allografts. Heart. 2006 Sep;92(9):1303-8. doi: 10.1136/hrt.2005.075903. Epub 2006 Jan 31.
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citation: Briand M, Dumesnil JG, Kadem L, Tongue AG, Rieu R, Garcia D, Pibarot P. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. J Am Coll Cardiol. 2005 Jul 19;46(2):291-8. doi: 10.1016/j.jacc.2004.10.081.
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citation: Capoulade R, Larose E, Mathieu P, Clavel MA, Dahou A, Arsenault M, Bedard E, Larue-Grondin S, Le Ven F, Dumesnil JG, Despres JP, Pibarot P. Visceral adiposity and left ventricular mass and function in patients with aortic stenosis: the PROGRESSA study. Can J Cardiol. 2014 Sep;30(9):1080-7. doi: 10.1016/j.cjca.2014.02.007. Epub 2014 Feb 19.
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citation: Capoulade R, Mahmut A, Tastet L, Arsenault M, Bedard E, Dumesnil JG, Despres JP, Larose E, Arsenault BJ, Bosse Y, Mathieu P, Pibarot P. Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis: the PROGRESSA study. JACC Cardiovasc Imaging. 2015 Jan;8(1):26-33. doi: 10.1016/j.jcmg.2014.09.016. Epub 2014 Nov 1.
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citation: Carter S, Capoulade R, Arsenault M, Bedard E, Dumesnil JG, Mathieu P, Pibarot P, Picard F. Relationship Between Insulin-Like Growth Factor Binding Protein-2 and Left Ventricular Stroke Volume in Patients With Aortic Stenosis. Can J Cardiol. 2015 Dec;31(12):1447-54. doi: 10.1016/j.cjca.2015.04.024. Epub 2015 Apr 30.
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citation: Shen M, Tastet L, Capoulade R, Larose E, Bedard E, Arsenault M, Chetaille P, Dumesnil JG, Mathieu P, Clavel MA, Pibarot P. Effect of age and aortic valve anatomy on calcification and haemodynamic severity of aortic stenosis. Heart. 2017 Jan 1;103(1):32-39. doi: 10.1136/heartjnl-2016-309665. Epub 2016 Aug 8.
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citation: Cote N, Mahmut A, Bosse Y, Couture C, Page S, Trahan S, Boulanger MC, Fournier D, Pibarot P, Mathieu P. Inflammation is associated with the remodeling of calcific aortic valve disease. Inflammation. 2013 Jun;36(3):573-81. doi: 10.1007/s10753-012-9579-6.
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citation: El Husseini D, Boulanger MC, Fournier D, Mahmut A, Bosse Y, Pibarot P, Mathieu P. High expression of the Pi-transporter SLC20A1/Pit1 in calcific aortic valve disease promotes mineralization through regulation of Akt-1. PLoS One. 2013;8(1):e53393. doi: 10.1371/journal.pone.0053393. Epub 2013 Jan 4.
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citation: Mahmut A, Boulanger MC, Fournier D, Couture C, Trahan S, Page S, Arsenault B, Despres JP, Pibarot P, Mathieu P. Lipoprotein lipase in aortic valve stenosis is associated with lipid retention and remodelling. Eur J Clin Invest. 2013 Jun;43(6):570-8. doi: 10.1111/eci.12081. Epub 2013 Apr 1.
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citation: Ducharme V, Guauque-Olarte S, Gaudreault N, Pibarot P, Mathieu P, Bosse Y. NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. J Heart Valve Dis. 2013 Mar;22(2):142-9.
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citation: Cote N, Mahmut A, Fournier D, Boulanger MC, Couture C, Despres JP, Trahan S, Bosse Y, Page S, Pibarot P, Mathieu P. Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease. Pathobiology. 2014;81(1):15-24. doi: 10.1159/000350896. Epub 2013 Aug 21.
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citation: Garcia J, Capoulade R, Le Ven F, Gaillard E, Kadem L, Pibarot P, Larose E. Discrepancies between cardiovascular magnetic resonance and Doppler echocardiography in the measurement of transvalvular gradient in aortic stenosis: the effect of flow vorticity. J Cardiovasc Magn Reson. 2013 Sep 20;15(1):84. doi: 10.1186/1532-429X-15-84.
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citation: Mahmut A, Boulanger MC, El Husseini D, Fournier D, Bouchareb R, Despres JP, Pibarot P, Bosse Y, Mathieu P. Elevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease: implications for valve mineralization. J Am Coll Cardiol. 2014 Feb 11;63(5):460-9. doi: 10.1016/j.jacc.2013.05.105. Epub 2013 Oct 23.
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citation: Mahmut A, Mahjoub H, Boulanger MC, Fournier D, Despres JP, Pibarot P, Mathieu P. Lp-PLA2 is associated with structural valve degeneration of bioprostheses. Eur J Clin Invest. 2014 Feb;44(2):136-45. doi: 10.1111/eci.12199. Epub 2013 Nov 28.
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citation: Bouchareb R, Boulanger MC, Fournier D, Pibarot P, Messaddeq Y, Mathieu P. Mechanical strain induces the production of spheroid mineralized microparticles in the aortic valve through a RhoA/ROCK-dependent mechanism. J Mol Cell Cardiol. 2014 Feb;67:49-59. doi: 10.1016/j.yjmcc.2013.12.009. Epub 2013 Dec 22.
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citation: El Husseini D, Boulanger MC, Mahmut A, Bouchareb R, Laflamme MH, Fournier D, Pibarot P, Bosse Y, Mathieu P. P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease. J Mol Cell Cardiol. 2014 Jul;72:146-56. doi: 10.1016/j.yjmcc.2014.02.014. Epub 2014 Mar 11.
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citation: Capoulade R, Magne J, Dulgheru R, Hachicha Z, Dumesnil JG, O'Connor K, Arsenault M, Bergeron S, Pierard LA, Lancellotti P, Pibarot P. Prognostic value of plasma B-type natriuretic peptide levels after exercise in patients with severe asymptomatic aortic stenosis. Heart. 2014 Oct;100(20):1606-12. doi: 10.1136/heartjnl-2014-305729.
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citation: Capoulade R, Cote N, Mathieu P, Chan KL, Clavel MA, Dumesnil JG, Teo KK, Tam JW, Fournier D, Despres JP, Pibarot P; ASTRONOMER Investigators. Circulating levels of matrix gla protein and progression of aortic stenosis: a substudy of the Aortic Stenosis Progression Observation: Measuring Effects of rosuvastatin (ASTRONOMER) trial. Can J Cardiol. 2014 Sep;30(9):1088-95. doi: 10.1016/j.cjca.2014.03.025. Epub 2014 Mar 24.
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citation: Dargis N, Lamontagne M, Gaudreault N, Sbarra L, Henry C, Pibarot P, Mathieu P, Bosse Y. Identification of Gender-Specific Genetic Variants in Patients With Bicuspid Aortic Valve. Am J Cardiol. 2016 Feb 1;117(3):420-6. doi: 10.1016/j.amjcard.2015.10.058. Epub 2015 Nov 19.
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citation: Mahmut A, Mahjoub H, Boulanger MC, Dahou A, Bouchareb R, Capoulade R, Arsenault BJ, Larose E, Bosse Y, Pibarot P, Mathieu P. Circulating Lp-PLA2 is associated with high valvuloarterial impedance and low arterial compliance in patients with aortic valve bioprostheses. Clin Chim Acta. 2016 Apr 1;455:20-5. doi: 10.1016/j.cca.2016.01.014. Epub 2016 Jan 18.
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citation: Capoulade R, Le Ven F, Clavel MA, Dumesnil JG, Dahou A, Thebault C, Arsenault M, O'Connor K, Bedard E, Beaudoin J, Senechal M, Bernier M, Pibarot P. Echocardiographic predictors of outcomes in adults with aortic stenosis. Heart. 2016 Jun 15;102(12):934-42. doi: 10.1136/heartjnl-2015-308742. Epub 2016 Apr 5.
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citation: Hadji F, Boulanger MC, Guay SP, Gaudreault N, Amellah S, Mkannez G, Bouchareb R, Marchand JT, Nsaibia MJ, Guauque-Olarte S, Pibarot P, Bouchard L, Bosse Y, Mathieu P. Altered DNA Methylation of Long Noncoding RNA H19 in Calcific Aortic Valve Disease Promotes Mineralization by Silencing NOTCH1. Circulation. 2016 Dec 6;134(23):1848-1862. doi: 10.1161/CIRCULATIONAHA.116.023116. Epub 2016 Oct 27.
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citation: Tastet L, Enriquez-Sarano M, Capoulade R, Malouf J, Araoz PA, Shen M, Michelena HI, Larose E, Arsenault M, Bedard E, Pibarot P, Clavel MA. Impact of Aortic Valve Calcification and Sex on Hemodynamic Progression and Clinical Outcomes in AS. J Am Coll Cardiol. 2017 Apr 25;69(16):2096-2098. doi: 10.1016/j.jacc.2017.02.037. No abstract available.
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citation: Nsaibia MJ, Boulanger MC, Bouchareb R, Mkannez G, Le Quang K, Hadji F, Argaud D, Dahou A, Bosse Y, Koschinsky ML, Pibarot P, Arsenault BJ, Marette A, Mathieu P. OxLDL-derived lysophosphatidic acid promotes the progression of aortic valve stenosis through a LPAR1-RhoA-NF-kappaB pathway. Cardiovasc Res. 2017 Sep 1;113(11):1351-1363. doi: 10.1093/cvr/cvx089.
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citation: Shen M, Tastet L, Bergler-Klein J, Pibarot P, Clavel MA. Blood, tissue and imaging biomarkers in calcific aortic valve stenosis: past, present and future. Curr Opin Cardiol. 2018 Mar;33(2):125-133. doi: 10.1097/HCO.0000000000000487.
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citation: Theriault S, Gaudreault N, Lamontagne M, Rosa M, Boulanger MC, Messika-Zeitoun D, Clavel MA, Capoulade R, Dagenais F, Pibarot P, Mathieu P, Bosse Y. A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis. Nat Commun. 2018 Mar 7;9(1):988. doi: 10.1038/s41467-018-03260-6.
PMID: 29511167
responsible party type: Principal Investigator
investigator affiliation: Laval University
investigator full name: Philippe Pibarot
investigator title: Doctor
mesh term: Aortic Valve Stenosis
mesh term: Constriction, Pathologic