Mechanotransduction mechanisms for intraventricular diastolic vortex forces and myocardial deformations: part 1

Abstract

Epigenetic mechanisms are fundamental in cardiac adaptations, remodeling, reverse remodeling, and disease. This two-article series proposes that variable forces associated with diastolic RV/LV rotatory intraventricular flows can exert physiologically and clinically important, albeit still unappreciated, epigenetic actions influencing functional and morphological cardiac adaptations and/or maladaptations. Taken in toto, the two-part survey formulates a new paradigm in which intraventricular diastolic filling vortex-associated forces play a fundamental epigenetic role, and examines how heart cells react to these forces. The objectives are to provide a perspective on vortical epigenetic effects, to introduce emerging ideas, and to suggest directions of multidisciplinary translational research. The main goal is to make pertinent biophysics and cytomechanical dynamic systems concepts accessible to interested translational and clinical cardiologists. I recognize that the diversity of the epigenetic problems can give rise to a diversity of approaches and multifaceted specialized research undertakings. Specificity may dominate the picture. However, I take a contrasting approach. Are there concepts that are central enough that they should be developed in some detail? Broadness competes with specificity. Would, however, this viewpoint allow for a more encompassing view that may otherwise be lost by generation of fragmented results? Part 1 serves as a general introduction, focusing on background concepts, on intracardiac vortex imaging methods, and on diastolic filling vortex-associated forces acting epigenetically on RV/LV endocardium and myocardium. Part 2 will describe pertinent available pluridisciplinary knowledge/research relating to mechanotransduction mechanisms for intraventricular diastolic vortex forces and myocardial deformations and to their epigenetic actions on myocardial and ventricular function and adaptations.

Figure 1

Top: A nucleosome is a section of DNA that is wrapped around a core of positively charged proteins called histones that bind the negatively charged DNA and aid in its packaging. Double-stranded DNA loops around 8 histones twice, forming the nucleosome, which is the building block of chromatin packaging. Chromatin forms chromosomes within the nucleus and exists in two forms: euchromatin, is less condensed and can be transcribed; heterochromatin, is highly condensed and is typically not transcribed. There are many ways that gene expression is controlled. Adding or removing chemical groups to or from histones can alter gene expression; acetylation and phosphorylation make the histones less positively charged because acetyl and phosphoryl groups are negative and their tight hold on DNA becomes looser. Conversely, extensive methylation of cytosine in DNA is correlated with reduced DNA transcription. Bottom: Endo- and myocardial shear and “squeeze” can impact myocardial and RV/LV morphomechanics by affecting chromatin structure and differential gene expression. See discussion in text.

Figure 2

a. Satisfying the viscous flow “no-slip” condition at a solid-fluid interface, the intraventricular ejection flow field streamlines are perpendicular to the contracting endocardial surface; consequently, there is no shear (tangential) endocardial stress during ejection. b. RV/LV diastolic flow patterns. Fortuitously, flow-governing fluid dynamic principles do not allow inflow to mirror outflow streamlines throughout the ensuing filling phase. During filling, there ensues flow separation and formation of a toroidal vortex that surrounds a central jet. Thus, laminar vortical shear and “squeeze” forces can come into existence. The incoming jet strikes the vicinity of the ventricular apex and is surrounded by the toroidal vortex whose main strength is within the outflow tract of each chamber. c. Rotation in the intraventricular blood stream naturally encourages a more or less vigorous scouring (tractive shear and torque) of the endocardium lining the RV/LV chamber and causes centrifugal “squeeze” forces to come into existence; see discussion in text and Figure 3. P, pressure: acts perpendicularly; WS, wall shear: acts tangentially on the endocardial surface. (Adapted, in part, from Pasipoularides et al. [12], by kind permission of the American Physiological Society.)

Figure 3

Top: Rotational large-scale vortical motion in the intraventricular flow field can generate a more or less vigorous scouring (tractive shear and torque) of the endocardium lining the chamber. Bottom: Under the action of centripetal and centrifugal forces associated with RV/LV rotatory diastolic flow, the endocardium and other wall components get deformed, akin to a ball squeezed between one’s palms. This dynamic interplay and its disturbances are likely to have intriguing epigenetic actions affecting cardiac function, adaptations, and abnormalities acting concurrently with the vortex-induced shear (Top), as summarized in the Middle. Middle: Myocardial cells (endocardium, myocytes, and fibroblasts) can move, change shape, and switch genes on and off in response to changes in hydrodynamic shear and “squeeze” (see discussion in text). They sense their physical 3D Bernardian “environment,” including variable diastolic vortical shear and “squeeze” forces, by transducing mechanical deformations and forces into differentiated transcription and translation signals, which can adjust cellular and extracellular tissue and organ structure. Mechanosensitive controls modulate myocyte shape and intracellular architecture, and processes as diverse as concentric and eccentric hypertrophy, remodeling and apoptosis, involved in cardiac homeostasis and adaptations, and also in maladaptive responses and disease.