Calcific aortic stenosis: omics-based target discovery and therapy development

Abstract

Calcific aortic valve disease (CAVD) resulting in aortic stenosis (AS) is the most common form of valvular heart disease, affecting 2% of those over age 65. Those who develop symptomatic severe AS have an average further lifespan of <2 years without valve replacement, and three-quarters of these patients will develop heart failure, undergo valve replacement, or die within 5 years. There are no approved pharmaceutical therapies for AS, due primarily to a limited understanding of the molecular mechanisms that direct CAVD progression in the complex haemodynamic environment. Here, advances in efforts to understand the pathogenesis of CAVD and to identify putative drug targets derived from recent multi-omics studies [including (epi)genomics, transcriptomics, proteomics, and metabolomics] of blood and valvular tissues are reviewed. The recent explosion of single-cell omics-based studies in CAVD and the pathobiological and potential drug discovery insights gained from the application of omics to this disease area are a primary focus. Lastly, the translation of knowledge gained in valvular pathobiology into clinical therapies is addressed, with a particular emphasis on treatment regimens that consider sex-specific, renal, and lipid-mediated contributors to CAVD, and ongoing Phase I/II/III trials aimed at the prevention/treatment of AS are described.

Keywords: Aortic stenosis; Calcific aortic valve disease; Clinical trials; Omics; Target discovery; Translational research.

Graphical abstract

Calcific aortic valve disease (CAVD) results from a complex physiological microenvironment and multifaceted interplay amongst a number of putative initiators and drivers of disease. Multi-omics enables a holistic assessment of molecular drivers of CAVD via quantitation of the (epi)genome, transcriptome, proteome, and metabolome at both a bulk and single-cell level. Integration of multiple omics modalities facilitates the identification of novel, subtle, or cross-layer molecules and interactions. Target prioritization via systems biology precedes drug development and eventual pharmaceutical alternatives to surgical aortic valve replacement or transcatheter aortic valve replacement.

Figure 1

Natural progression of calcific aortic valve disease. Prior to the onset of symptoms or impairment of cardiac function, initial activation of resident valvular interstitial cells and valvular endothelial cells towards a myofibrogenic lineage by a combination of cardiometabolic, genetic, renal, and congenital risk factors leads to an intermediate disease stage marked by sclerotic valve leaflet thickening. Subsequently, in a small proportion of patients with valvular sclerosis (∼2% yearly), still largely unknown mechanisms drive valve cell osteogenesis and result in leaflet mineralization which reduces valve opening, increases left ventricular afterload, and induces cardiac hypertrophy. Left untreated, these patients typically progress rapidly to heart failure: within 5 years of developing symptomatic aortic stenosis, ∼75% will require aortic valve replacement or die

Figure 2

Multi-omics drug discovery pipeline in calcific aortic valve disease. Depending on study goals (e.g. mechanisms of pathogenesis, cell type-specific targets, biomarker discovery), multi-omic screening studies can be performed on valvular cells, tissues, plasma/serum, blood-/tissue-derived extracellular vesicles, and other relevant sample types. Quantification of differential molecular abundances between experimental groups of interest, integration of insights from multiple omics modalities, and unbiased target prioritization via network analysis derives target lists for follow-up translational studies. Validation of top targets can occur via well-established in silico, in vitro, or in vivo disease models that recapitulate specific aspects of calcific aortic valve disease pathogenesis relevant to the target’s putative mechanism of action. High-throughput screening of pre-existing small molecule libraries, engineering of targeted biologics, and other drug development approaches lead to pre-clinical and clinical trials to assess safety and efficacy. Iteration and optimization using samples derived from pre-clinical models and Phase I/II/III studies in humans may add further insight into (non-)responding sub-groups, off-target effects, mechanisms of action, and label extension/expansion.

Figure 3

Disease mechanisms, drug targets, and pharmaceutical therapies for aortic stenosis. A clear causal role for low-density lipoprotein cholesterol in aortic stenosis has driven extensive trials of lipid-lowering therapies including statins, proprotein convertase subtilisin/kexin type 9 inhibitors, and lipoprotein(a) inhibitors. Sodium–glucose cotransporter-2 inhibitors and angiotensin II receptor blockers appear to reduce mortality in aortic stenosis via mitigation of heart failure and normalization of blood pressure, though inhibition of the renin–angiotensin system by angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors may prevent monocyte activation and/or pro-inflammatory macrophage-derived signalling. Other therapeutic efforts have also targeted the inflammatory impact of these cells and signalling pathways on resident valvular interstitial cells and valvular endothelial cells, and include inhibition of dipeptidyl peptidase 4, peroxisome proliferator-activated receptor gamma activation, colchicine, denosumab (receptor activator of nuclear factor kappa beta ligand inhibition), and glucagon-like peptide 1 receptor agonists. Notably, pharmacological modulation dipeptidyl peptidase 4 and glucagon-like peptide 1 may also directly regulate valvular interstitial cell myofibrogenesis and osteogenesis. Drug targets implicated in pathological valvular interstitial cell differentiation also include cadherin 11 (blocked by the monoclonal antibody SYN0012) and soluble guanylate cyclase (activated by Ataciguat). Other therapeutics aim to directly target calcification by impairing hydroxyapatite mineral formation (inositol-based SNF472 and INS-3001) or by stabilizing common constituents of amyloidosis (Tafamidis) that may be contained in extracellular vesicles released from osteogenic valvular interstitial cells. Novel omics-derived pharmaceutical targets that remain to be tested in clinical trials include Sortilin (driver of valvular interstitial cell myofibro/osteogenesis), major facilitator superfamily domain containing 5 [lipoprotein(a) receptor], Apolipoprotein C-III, annexin A1/A5 (extracellular vesicle cargo/tethering), amyloid precursor protein, monoamine oxidase A, and aortic valve calcification-associated PIWI-interacting RNA