Metabolic Determinants of the Progression of Aortic Stenosis (PROGRESSA)

• Progression of aortic valve calcification [ Time Frame: Patients will be followed every 2 years, up to 5 years ] [ Designated as safety issue: No ]
  Annualized progression rate of aortic valve calcium
• Progression of myocardial fibrosis and dysfunction [ Time Frame: PPatients will be followed every 2 years, up to 5 years ] [ Designated as safety issue: No ]
  Annualized progression rate of myocardial fibrosis and global longitudinal myocardial strain

• Progression of aortic calcification and stiffness [ Time Frame: Patients will be followed every 2 years, up to 5 years ] [ Designated as safety issue: No ]
  Annualized progression rate of calcification measured by computed tomography and aortic compliance measured (CT) by cardiac magnetic resonance (CMR) and Doppler-echocardiography
• Progression of coronary artery calcification [ Time Frame: Patients will be followed every 2 years, up to 5 years ] [ Designated as safety issue: No ]
  Annualized progression rate of coronary artery calcification measured by CT
• Progression of global hemodynamic load [ Time Frame: Patients will be followed every 1 year, up to 5 years ] [ Designated as safety issue: No ]
  Annualized progression rate of valvulo-arterial impedance measured by Doppler-echocardiography
• 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 ] [ Designated as safety issue: No ]
  Cardiovascular-related mortality; hospitalization for heart failure; surgical or transcatheter aortic valve replacement motivated by the development of symptoms or LV systolic dysfunction
• 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 ] [ Designated as safety issue: No ]
  Myocardial infarction; unstable angina; revascularization procedure
• All-cause mortality [ Time Frame: From date of baseline until the date of death from any cause assessed up to 5 years ] [ Designated as safety issue: No ]
  Death from any cause

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.

Cohort will be selected at primary care clinic

• Other: Doppler-echocardiography
• Radiation: Computed tomography
• Other: Magnetic resonance imaging
• Biological: Fasting blood sample

• Capoulade R, Clavel MA, Dumesnil JG, Chan KL, Teo KK, Tam JW, Côté N, Mathieu P, Després 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.
• Côté N, El Husseini D, Pépin 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.
• Audet A, Côté N, Couture C, Bossé Y, Després JP, Pibarot P, Mathieu P. Amyloid substance within stenotic aortic valves promotes mineralization. Histopathology. 2012 May 29;61(4):610-619. doi: 10.1111/j.1365-2559.2012.04265.x. [Epub ahead of print]
• 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.
• Shetty R, Girerd N, Côté N, Arsenault B, Després 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.
• Côté N, El Husseini D, Pépin A, Guauque-Olarte S, Ducharme V, Bouchard-Cannon P, Audet A, Fournier D, Gaudreault N, Derbali H, McKee MD, Simard C, Després JP, Pibarot P, Bossé 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.
• Côté N, Couture C, Pibarot P, Després 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.
• Gaudreault N, Ducharme V, Lamontagne M, Guauque-Olarte S, Mathieu P, Pibarot P, Bossé 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.
• Mohty D, Pibarot P, Côté N, Cartier A, Audet A, Després 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.
• Pagé A, Dumesnil JG, Clavel MA, Chan KL, Teo KK, Tam JW, Mathieu P, Després 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.
• Derbali H, Bossé Y, Côté N, Pibarot P, Audet A, Pépin A, Arsenault B, Couture C, Després 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.
• Bossé Y, Miqdad A, Fournier D, Pépin 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.
• Côté N, Pibarot P, Pépin A, Fournier D, Audet A, Arsenault B, Couture C, Poirier P, Després 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.
• Mohty D, Pibarot P, Després 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.
• Mathieu P, Després JP, Pibarot P. The 'valvulo-metabolic' risk in calcific aortic valve disease. Can J Cardiol. 2007 Oct;23 Suppl B:32B-39B. Review. Erratum in: Can J Cardiol. 2009 Mar;25(3):140.
• Mohty D, Pibarot P, Després JP, Côté 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. Epub 2007 Nov 1.
• Côté C, Pibarot P, Després 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. Epub 2007 Oct 11.
• Pibarot P, Dumesnil JG, Mathieu P. [New insight into the treatment of aortic stenosis]. Med Sci (Paris). 2007 Jan;23(1):81-7. French.
• Briand M, Lemieux I, Dumesnil JG, Mathieu P, Cartier A, Després 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. Epub 2006 May 15.
• Charest A, Pépin A, Shetty R, Côté 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. Epub 2006 May 18.
• 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. Epub 2006 Jan 31.
• 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.

Inclusion Criteria:

• Age >21 years
• Presence of aortic stenosis defined as peak aortic jet velocity ≥2.5 m/s

Exclusion Criteria:

• Symptomatic aortic stenosis
• Very severe aortic stenosis defined as an AVA≤0.6 cm2
• Left ventricular ejection fraction < 50%
• More than mild aortic or mitral regurgitation, or mitral stenosis
• Atrial fibrillation or flutter
• Pregnant or lactating women
• Contraindications to gadolinium-enhanced MRI

• Canadian Institutes of Health Research (CIHR)
• Heart and Stroke Foundation of Canada