The Genetic Regulation of Aortic Valve Development and Calcific Disease

Abstract

Heart valves are dynamic, highly organized structures required for unidirectional blood flow through the heart. Over an average lifetime, the valve leaflets or cusps open and close over a billion times, however in over 5 million Americans, leaflet function fails due to biomechanical insufficiency in response to wear-and-tear or pathological stimulus. Calcific aortic valve disease (CAVD) is the most common valve pathology and leads to stiffening of the cusp and narrowing of the aortic orifice leading to stenosis and insufficiency. At the cellular level, CAVD is characterized by valve endothelial cell dysfunction and osteoblast-like differentiation of valve interstitial cells. These processes are associated with dysregulation of several molecular pathways important for valve development including Notch, Sox9, Tgfβ, Bmp, Wnt, as well as additional epigenetic regulators. In this review, we discuss the multifactorial mechanisms that contribute to CAVD pathogenesis and the potential of targeting these for the development of novel, alternative therapeutics beyond surgical intervention.

Increased Expression of miR-146a in Valvular Tissue From Patients With Aortic Valve Stenosis

“…Despite limitations of the present study (analysis of a single miRNA in a cohort comprising only patients with aortic valve stenosis, not subjects without this pathology), to our knowledge we present the first report plausibly implicating miR-146a in aortic valve stenosis. A spectrum of miRNAs, but not including miR-146a, has been recently found to be deregulated in patients with aortic stenosis [reviewed by Menon and Lincoln (6)]; miR-146a has also not been noted in microarray expression study combined with bioinformatics analyses (26), nor in a recent report by Duan et al (27). In this context, it is desirable to conduct studies of miRNA-146a expression in extended cohorts including specimen from patients without valvular disease.…”

“…e.g., by Pasipoularides (3) and Cho et al (4)], genetic and namely epigenetic mechanism have been recently nominated to play a role in aortic stenosis pathogenesis (5). In general, as reviewed by Menon and Lincoln (6) or Kishore and Petrek (7), epigenetic mechanisms exert their regulatory effects via processes of methylation, histone modification, and also activities of small non-coding RNAs—miRNAs.…”

Characterization of genomic regulation profiles in human mitral valve whole tissue to annotate genetic risk loci for mitral valve prolapse

“…The sentinel SNPs from loci associated with p-value < 10 −5 were used as reference for MVP-associated SNPs. We included in the analysis SNPs in high LD (r 2 < 0.7) in European samples from 1000 Genomes. To use homogenous peak sets and mitigate the difference in signal-to-noise ratio between samples, 500bp windows centered on peak summits were used for this analysis.…”

“…These cells communicate via paracrine signaling, and altered or damaged signaling within the VECs can lead to pathological changes in underlying VICs. 1,2,3 VICs are relatively quiescent non-contractile fibroblast-like cells that contribute to homeostasis of extracellular matrix (ECM) 4 . During valve development or under mechanical stress, VICs change phenotype and become activated myofibroblast-like cells that produce matrix metalloproteinases and inflammatory cytokines, which increase matrix production and remodel the ECM.…”

Fiber Scaffold Patterning for Mending Hearts: 3D Organization Bringing the Next Step

“…[ 8 ] For cardiac valves specifically, mechanical and bioprosthetic valve replacements are the current standard of care for advanced CAVD. [ 9 ] However, mechanical valves suffer from risk of thrombosis and bleeding, and patients require lifelong anti-coagulation therapy. [ 10 ] Bioprosthetic valves, typically obtained from bovine or porcine donors, do not suffer from thrombosis risks, but these can suffer from infection, inflammation, or calcification.…”