Novel pharmacological targets for calcific aortic valve disease: Prevention and treatments

Abstract

Calcific aortic valve disease (CAVD) is the most common valvular disorder in the elderly, with the incidence of 3% in general population of Western countries. The initial phase of CAVD is characterized by leaflet thickening and possible spotty calcification (i.e. aortic valve sclerosis (AVSc)), while advanced stages have leaflets structure degeneration (i.e. aortic valve stenosis (AS)). The pathological cellular and molecular mechanisms, involved in CAVD, are extracellular matrix degradation, aberrant matrix deposition, fibrosis, mineralization, inflammation, lipid accumulation, and neo-angiogenesis. CAVD clinical risk shares considerable overlap with those of atherosclerosis and they include hypertension, smoking habits, and hyperlipidemia. Unfortunately, surgical aortic valve replacement and transcatheter aortic valve implantation are the only available treatments when the disease become severe and symptoms occur. Indeed, no approved pharmacological approach is available for CAVD patients. In this review, we describe the current literature evidence on possible future therapeutic targets for this debilitating and fatal disease such as PCSK9, P2Y2 receptor, cadherin 11, and DDP-4.

Introduction

Calcific aortic valve disease (CAVD) is an active and multifactorial pathological process that starts with the alteration of leaflet cellular mechanisms, leading to matrix remodeling and subsequently to calcification with hemodynamic obstruction [1,2]. Aortic valve sclerosis (AVSc) is the earliest manifestation of CAVD, characterized by focal thickening with or without the presence of calcium and with no significant hemodynamic changes [3]. In the general population, 30% of individuals over 65 years of age are affected by AVSc [4]. Due to extracellular matrix degradation, aberrant matrix deposition, fibrosis, inflammatory cell infiltration, lipid accumulation, and neo-angiogenesis of the valve tissue [1], AVSc progresses to aortic valve stenosis (AS), the end-stage of the disease (Fig. 1). However, AVSc patients have a low progression rate (2% every year) to symptomatic AS [5]. Indeed, AS prevalence is ∼3% in people older than 65 years of age, while it reaches almost 8% in people older than 75 years of age [6,7]. Thus, in the elderly, AS is the most common manifestation of cardiac valve disease, in Western countries [8]. Notably, people with congenital bicuspid aortic valve have the fastest progression of CAVD [9]. In bicuspid aortic valves, the elevated mechanical stress stimulates the acceleration of fibrosis and calcification of the leaflets [10].

The classic triad of symptoms of severe AS are heart failure, syncope, and angina. Once these symptoms occur, surgical aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI) are the only available strategies to treat the patients affected by this debilitating and fatal disease [11]. Hence, the aim of the present review is to analyse the current evidence regarding existing and future pharmacological therapeutic targets for CAVD (Table 1, Table 2).