Metabolic Determinants of the Progression of Aortic Stenosis
Metabolic Determinants of the Progression of Aortic Stenosis
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.
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