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.

Eligibility Criteria:
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