Mechanotransduction Mechanisms for Intraventricular Diastolic Vortex Forces and Myocardial Deformations: Part 2

Abstract

Epigenetic mechanisms are fundamental in cardiac adaptations, remodeling, reverse remodeling, and disease. A primary goal of translational cardiovascular research is recognizing whether disease related changes in phenotype can be averted by eliminating or reducing the effects of environmental epigenetic risks. There may be significant medical benefits in using gene-by-environment interaction knowledge to prevent or reverse organ abnormalities and disease. This survey proposes that “environmental” forces associated with diastolic RV/LV rotatory flows exert important, albeit still unappreciated, epigenetic actions influencing functional and morphological cardiac adaptations. Mechanisms analogous to Murray's law of hydrodynamic shear-induced endothelial cell modulation of vascular geometry are likely to link diastolic vortex-associated shear, torque and “squeeze” forces to RV/LV adaptations. The time has come to explore a new paradigm in which such forces play a fundamental epigenetic role, and to work out how heart cells react to them. Findings are considered from various disciplines, imaging modalities, computational fluid dynamics, molecular cell biology and cytomechanics. Examined are, among others, structural dynamics of myocardial cells (endocardium, cardiomyocytes, and fibroblasts), cytoskeleton, nucleoskeleton, and extracellular matrix, mechanotransduction and signaling, and mechanical epigenetic influences on genetic expression. To help integrate and focus relevant pluridisciplinary research, rotatory RV/LV filling flow is placed within a working context that has a cytomechanics perspective. This new frontier in contemporary cardiac research should uncover versatile mechanistic insights linking filling vortex patterns and attendant forces to variable expressions of gene regulation in RV/LV myocardium. In due course, it should reveal intrinsic homeostatic arrangements that support ventricular myocardial function and adaptability.

3D imaging in CUBIC-cleared mouse heart tissue: going deeper

“…Heart diseases are often accompanied by structural changes in the vascular network and/or the myocardium that may result in impaired contractility or relaxation of the ventricles and eventually lead to heart failure [1,2]. Despite advancements in the field, our understanding of the adult heart structure and its remodeling following disease is still limited by the inability to provide three-dimensional (3D) images of the myocardium at cellular resolution.…”

Calcific Aortic Valve Disease: Part 1—Molecular Pathogenetic Aspects, Hemodynamics, and Adaptive Feedbacks

“…Intriguingly, endothelial phenotype is determined by a combination of intrinsic programmed gene expression and local epigenetic or environmental extrinsic factors [4, 5, 13]. Mechanical stresses on the cusps in conjunction with atherosclerotic risk factors can induce endothelial dysfunction/leakage with buildup of lipids and minerals, which provoke inflammation and actuate valvular myofibroblasts and/or circulating pluripotent mesenchymal cells resulting in their osteoblastic metaplasia/transdifferentiation [14]; these processes provoke ECM alterations and neovascularization [15].…”

“…The aortopathy of BAVD is attended by cystic medial degeneration, variations in signaling pathways and matrix metalloproteinase activity and by apoptosis [4, 5], thus putting the patient with BAV at increased risk for aortic aneurysm and dissection—such complications can cause problems during and after aortic valve replacement. Combining the various new tools for discovery, as developed in subsequent Sections of this Survey, promises to yield burgeoning insights into the genomic underpinnings of BAV and CAVD.…”

“…Mechanotransduction contributes to cardiac function by initiating time-related adaptive myocardial cell and ECM morphomechanical adjustments [4, 5, 13]. As is true of other homeostatic mechanisms, mechanotransduction can be viewed as a feedback control loop initiator with vital clinical relevance, considering that it transduces forces into sarcomerogenesis (cf.…”

“…The AV leaflets are made up of specialized valvular endothelial and interstitial cells akin to fibroblasts and an extracellular matrix (ECM) that contains collagen, elastin and glycosaminoglycans. Valve cells and the extracellular microenvironment are dynamic and reciprocally regulated; interstitial cells interact with their microenvironment directly via integrins, with biochemical signals through receptors, and with adjacent cells via cadherins [4, 5]. The valvular endothelium is an important regulator of (patho) physiological processes, including atherogenesis [6, 7].…”