Stretch-Activated Potassium Channels in the Human Heart: Pathophysiologic and Clinical Significance

Origins of Mechanical Stimuli

The heart functions in a highly dynamic mechanical environment and is continuously generating and exposed to a complex set of mechanical stimuli. These stimuli have three different origins: extracorporeal, intracorporeal/extracardiac, and intracardiac ( Fig. 14.1 ).

Mechanical influences that reach the heart from outside the body range from gravity-mediated changes in venous return during posture changes to anything impacting the chest.

Extracardiac in situ influences, such as breathing-associated pressure gradients and fluxes (e.g . , air in the lungs, blood in large vessels linking chest and abdomen), skeletal muscle contractions (e.g., during coughing or straining), and altered hemodynamic demand (e.g., during physical activity, at high altitude, or in pregnancy), are examples of stimuli capable of changing the in situ mechanical environment of the heart.

Mechanical cues from the heart itself can be divided into two categories: active and passive mechanics. Active forces, generated by muscle cells, involve structural alterations from nano to macro scales, involving proteins, membranous nanodomains, cells, extracellular matrix (ECM), tissue, and the whole organ. Myocytes are the principal source of active force, driving rhythmic cardiac contractions, although they are not the only cells able to contract. Smooth muscle cells and nonmyocytes such as fibroblasts are also known to contract actively, even if at orders of magnitude lower force and speed. Fibroblasts represent a nonnegligible part of the myocardial cell population, estimated to account from 20% to over 50% of the nonmyocyte population, depending on the tools used, and as chief producers of the ECM they also alter passive mechanics of cardiac tissue.

Indeed, active contraction can be impaired by mechanical properties of the tissue. These are determined in part by the ECM, which can be extensively remodeled in the course of disease. Tissue remodeling can lead to major changes in passive mechanical properties over time and/or space. After myocardial infarction (MI), for example, myocardial stiffness is initially decreased (down to a few kilopascals), but upon formation and maturation of postinfarct scar tissue, stiffness can rise to values of 50 to 100 kPa, well exceeding the stiffness of healthy tissue in the range of 5 to 10 kPa. This alters the workings of the myocardium. Pathologically soft ventricular tissue areas can bulge (paradoxical segment lengthening) during contraction of surrounding healthy myocardium, generating areas of increased stress and strain. Stiff fibrotic tissue produces less force (because of the decreased number of cardiomyocytes and the stiffened ECM, which is suspected to change myocyte contractility).

Pathologic tissue remodeling also alters force distribution, resulting in local regions of high stretch that are thought to trigger arrhythmias. Importantly, fibroblasts are not the only cell type that should be considered in the context of tissue remodeling: Immune cells, including macrophages, are also major players where mechanosensors are proposed to have important functions.

Force, Stress, Strain: Quite a Stretch

The forces present in the heart can be tensile, compressive, and shear inducing. These forces produce stresses ([force per unit of area], same unit as pressure) as illustrated in Fig. 14.1 .

Stress , if high enough, leads to deformation. The amount of deformation an object experiences, compared with its original size and shape, defines the strain (dimensionless). This parameter is, in most cases, the most easily accessible (both in experiments and by medical imaging), and it allows one to track mechanical input to a number of pathways initiated by mechanosensors.

Based on these definitions, the distinction between force, stress, and strain is clear.

In practice, the matter is much less trivial. Because of the heart’s complex histoanatomy, ventricular force generation gives rise to regionally and temporally varying shortening, thickening, sliding, bending, and twisting. Passive and active forces, as well as stresses and strains, coexist and are highly heterogeneous. In fact, it would be reasonable to suggest that no two cells in the heart undergo exactly the same mechanical cycle, that these cell-specific mechanical dynamics change with external hemodynamic demand, and that this high degree of cellular (force-length) heterogeneity is prerequired for externally homogeneous (pressure-volume) work, as expertly explained by Katz and Katz. Adding to the complexity, while deformations can often be tracked and quantified, there are no tools as of yet to report intramural forces (they can only be approximated, based on generally incomplete characterization of passive mechanics and ensemble properties such as intracavity pressure generated).

It is understandable therefore that the wording used to refer to mechanical stimuli tends to be vague and that it does not usually refer to actual physical parameters, including the phenomena activating mechanosensors. This chapter uses the term stretch , unless in contexts where stresses or strains at play can be characterized or quantified.

Mechanically Modulated Channels

Like other phenomenologic classifications, mechanosensitive ion channel categories are not absolute, and there is overlap with other ion channel nomenclatures. Several mechanosensitive ion channels are primarily voltage and/or ligand sensitive, while MEC effects arise from mechanical modulation of channel activity, localization, or expression.

Mechanically Gated Channels

The open probability of mechanically gated ion channels is primarily modulated by mechanical stimuli, such as stretch (for SAC) or cell volume changes (volume-activated channels [VAC]). The mammalian heart contains both SAC and VAC.

SAC respond within milliseconds to mechanical stimuli, ^, whereas VAC tend to show significant lag times (up to minutes) between the onset of cell volume changes and ion channel response. VAC are understood to be important contributors to cardiac electrophysiology in chronic disease settings, such as (post-)ischemic cell swelling and hypertrophy (where VAC are constitutionally active). For comprehensive reviews of VAC, see Okada et al. and Strange et al . ^, In the context of electrophysiologic responses to beat-by-beat changes in the mechanical environment, however, SAC are implied as a key mechanism underlying MEC.

The existence of SAC was first reported in 1984 by Guharay and Sachs in embryonic chick skeletal myocytes. SAC activity, initially considered by many as an artifact because of the difficulty of combining electrical recordings with membrane stretch, was quickly corroborated in other model systems, from bacteria to mammalian cardiomyocytes.

The SAC family includes SAC _NS and SAC _K . The ion selectivity profiles of these channels determine their transmembrane current reversal potential, which is halfway between activation potential (AP) plateau and resting potential for SAC _NS (usually between 0 mV and –25 mV) and close to the K ⁺ equilibrium potential for SAC _K (about –95 mV in cardiomyocytes).

SAC _NS include Piezo and transient receptor potential (TRP) channels. Piezo1 and Piezo2 were shown to be involved in a number of physiologic and pathophysiologic processes in several organs, including the heart (for Piezo1). Members of the vast TRP family are involved in mechano-transduction processes, and a number of them are expressed in the myocardium, but their direct stretch activation remains controversial.

Given their depolarizing effect on resting cardiomyocytes, SAC _NS have been implicated in mechanically triggered excitation and arrhythmogenesis. They have been comprehensively reviewed in the recent past and in previous editions of this textbook. Therefore the remainder of this chapter focuses on SAC _K .

Plasmalemmal SACK