Calcific Aortic Valve Disease: Part 2—Morphomechanical Abnormalities, Gene Reexpression, and Gender Effects on Ventricular Hypertrophy and Its Reversibility

Abstract

In part 1, we considered cytomolecular mechanisms underlying calcific aortic valve disease (CAVD), hemodynamics, and adaptive feedbacks controlling pathological left ventricular hypertrophy provoked by ensuing aortic valvular stenosis (AVS). In part 2, we survey diverse signal transduction pathways that precede cellular/molecular mechanisms controlling hypertrophic gene expression by activation of specific transcription factors that induce sarcomere replication in-parallel. Such signaling pathways represent potential targets for therapeutic intervention and prevention of decompensation/failure. Hypertrophy provoking signals, in the form of dynamic stresses and ligand/effector molecules that bind to specific receptors to initiate the hypertrophy, are transcribed across the sarcolemma by several second messengers. They comprise intricate feedback mechanisms involving gene network cascades, specific signaling molecules encompassing G protein-coupled receptors and mechanotransducers, and myocardial stresses. Future multidisciplinary studies will characterize the adaptive/maladaptive nature of the AVS-induced hypertrophy, its gender- and individual patient-dependent peculiarities, and its response to surgical/medical interventions. They will herald more effective, precision medicine treatments.

Genomic translational research: Paving the way to individualized cardiac functional analyses and personalized cardiology

“…For instance, cholesterol-independent beneficial pleiotropic effects of statins have to do with improving or restoring endothelial function, attenuating vascular and myocardial adverse remodeling, decreasing oxidative stress and vascular inflammation, enhancing the stability of atherosclerotic plaques, and inhibiting the thrombogenic response [62,63]. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules [35,36,129]. …”

Know Me! Unraveling the Riddle of Calcific Aortic Valve Disease by Bioinformatics

“…Rheumatic heart valve disease, erstwhile significant cause of aortic stenosis (AS), is nowadays rare in industrialized countries. Calcific aortic valve disease (CAVD) is expressed in old-age as ectopic mineralization (calcification) and fibrosis of the tri-leaflet aortic valve, and it is commonly described as age-related degenerative or dystrophic calcific AS (Pasipoularides 2010; Pasipoularides et al 2016a, b). Some 2% of the population have congenitally bicuspid aortic valves, which are much more likely to calcify than tricuspid ones, and about one-half of these will develop CAVD.…”

“…In 1904, the eminent German physiologist-pathologist Johann Georg Mönckeberg (1877–1925), first described CAVD in Virchows Archiv , as a passive process associated with rheumatic fever or aging (Mönckeberg 1904). The recognition that CAVD arises from active cellular mechanisms involving genetic epigenetic and environmental interactions implies that the causative processes might be investigated and targeted to treat medically (Pasipoularides 2016a, b). This is the motivation for the application of a number of emerging genomic bioinformatics approaches to the analysis and characterization of key genes involved in the initiation and progression of CAVD, several of which are utilized in the trailblazing Article by Liu et al (2017), in this issue of The Tohoku Journal of Experimental Medicine , which opens doors to CAVD not envisioned by most medical investigators just a short time ago.…”

“…CAVD had formerly been considered as a passive and non-modifiable wear-and-tear disease process that comes along with advancing age (see epigraph ). However, considerable evidence has now accumulated from molecular studies supporting a cell-mediated, active disease process involving risk factors and histopathophysiological features (endothelial cell and macrophage activation, proteolytic activity, and osteogenesis in inflamed valves) that characterize atherosclerosis (Rajamannan et al 2011; Yutzey et al 2014; Pasipoularides 2016a, b). …”

Aortic stenosis: diagnosis and management

“…Eventually myocardial ischaemia occurs as the hypertrophied myocardium is less compliant with increased oxygen demands that cannot be met. [8][9][10] How do patients present?…”