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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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.

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

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• Audet A, Côté N, Couture C, Bossé Y, Després 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.
• 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.
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• 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.
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• 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.
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• Shen M, Tastet L, Capoulade R, Larose É, Bédard É, 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.

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