Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis

Abstract

Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. This is of particularly dire clinical relevance, as calcific aortic valve disease can progress rapidly to aortic stenosis, heart failure, and eventually premature death. Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

“…High-throughput sequencing technology allows for large scale evaluation of genetic variants, gene expression and quantification of protein and small molecules within a tissue sample, yielding vast amounts of data ( 202 ). The application of this multi-omics approach has implicated many novel pathways in the development of CAVD ( 203 ). High throughput omics strategies also have the ability to reveal mechanisms behind previously observed observations in CAVD.…”

Purinergic Receptor P2Y2 Stimulation Averts Aortic Valve Interstitial Cell Calcification and Myofibroblastic Activation

“…Further studies are needed to better investigate the molecular pathway activated by 2ThioUTP and to prove its antifibrotic effects in vivo. In this regard, the multi-omics approaches implemented in the last few years to study the CAVS progression [ 11 , 17 , 29 ] could unveil if P2RY2 plays a crucial role in maintaining the aortic valve ECM homeostasis. We know that sex influences the development and progression of CAVS, in terms of both calcium and fibrotic tissue deposition, and the majority of patients enrolled for this study were men [ 30 ].…”

“…Despite the huge number of studies aimed at defining the molecular effectors of CAVS progression, they are not yet fully discovered. Several proteins have been identified as key regulators of ectopic calcification [ 6 , 17 , 18 ]. Of note, the activation of purinergic receptor P2Y2 (P2RY2) has been linked to calcium resorption [ 19 , 20 ] and to tissue fibrosis [ 21 ].…”

Profiling Genome-Wide DNA Methylation Patterns in Human Aortic and Mitral Valves

“…While there are several studies exploring the epigenetics of abnormal valves in the literature ( 57 , 73 , 74 ), they are not standardized and do not include methylation of normal valves. Previous studies have addressed how DNA methylation affects valvular disease processes.…”