A comprehensive study of calcific aortic stenosis: from rabbit to human samples.

L Mourino-Alvarez,R Rincon,M G Barderas,M Martin-Lorenzo,A S Maroto,F Vivanco,T Martin-Rojas,N Corbacho-Alonso,F De La Cuesta,L R Padial,G Alvarez-Llamas,M Baldan-Martin,L F Lopez-Almodovar,T Sastre-Oliva

doi:10.1242/dmm.033423

Abstract

ABSTRACTThe global incidence of calcific aortic stenosis (CAS) is increasing owing, in part, to a growing elderly population. The condition poses a great challenge to public health, because of the multiple comorbidities of these older patients. Using a rabbit model of CAS, we sought to characterize protein alterations associated with calcified valve tissue that can be ultimately measured in plasma as non-invasive biomarkers of CAS. Aortic valves from healthy and mild stenotic rabbits were analyzed by two-dimensional difference gel electrophoresis, and selected reaction monitoring was used to directly measure the differentially expressed proteins in plasma from the same rabbits to corroborate their potential as diagnostic indicators. Similar analyses were performed in plasma from human subjects, to examine the suitability of these diagnostic indicators for transfer to the clinical setting. Eight proteins were found to be differentially expressed in CAS tissue, but only three were also altered in plasma samples from rabbits and humans: transitional endoplasmic reticulum ATPase, tropomyosin α-1 chain and L-lactate dehydrogenase B chain. Results of receiver operating characteristic curves showed the discriminative power of the scores, which increased when the three proteins were analyzed as a panel. Our study shows that a molecular panel comprising three proteins related to osteoblastic differentiation could have utility as a serum CAS indicator and/or therapeutic target.

Highlights

Aortic stenosis is defined as a narrowing of the aortic valve (AV), which results in reduced blood flow to the body and in compromised heart function (Rajamannan et al, 2011)
This is especially important in the setting of Calcific aortic stenosis (CAS) given the etiology of the disease: at advanced ages, CAS is usually accompanied by other comorbidities such as hypertension or diabetes
The increase in the transvalvular gradient confirmed the development of CAS in the pathological group, which was concomitant with a significant increase in cholesterol, characteristics that have been previously described in patients with CAS (Kamath and Rai, 2008; Akat et al, 2010)

Summary

Introduction

Aortic stenosis is defined as a narrowing of the aortic valve (AV), which results in reduced blood flow to the body and in compromised heart function (Rajamannan et al, 2011). Calcific aortic stenosis (CAS), the most common etiology of aortic stenosis. Matrix remodeling and active bone formation occurs, leading to calcification (Otto, 2006). CAS has a prolonged asymptomatic period defined as aortic sclerosis, during which time calcification of the valve begins to occur, but with no elevation of the transvalvular gradient. Once symptoms develop, CAS is rapidly fatal as there is no effective pharmacologic treatment (Dweck et al, 2012). Efforts have been directed at controlling CAS progression and towards better understanding the molecular mechanisms of CAS to provide potential indicators at early stages of the disease

Methods

Results

Conclusion