Biomechanics of cardiac electromechanical coupling and mechanoelectric feedback

Abstract

Cardiac mechanical contraction is triggered by electrical activation via an intracellular calcium-dependent process known as excitation-contraction coupling. Dysregulation of cardiac myocyte intracellular calcium handling is a common feature of heart failure. At the organ scale, electrical dyssynchrony leads to mechanical alterations and exacerbates pump dysfunction in heart failure. A reverse coupling between cardiac mechanics and electrophysiology is also well established. It is commonly referred as cardiac mechanoelectric feedback and thought to be an important contributor to the increased risk of arrhythmia during pathological conditions that alter regional cardiac wall mechanics, including heart failure. At the cellular scale, most investigations of myocyte mechanoelectric feedback have focused on the roles of stretch-activated ion channels, though mechanisms that are independent of ionic currents have also been described. Here we review excitation-contraction coupling and mechanoelectric feedback at the cellular and organ scales, and we identify the need for new multicellular tissue-scale model systems and experiments that can help us to obtain a better understanding of how interactions between electrophysiological and mechanical processes at the cell scale affect ventricular electromechanical interactions at the organ scale in the normal and diseased heart.

Fig. 1

The relationship between excitation–contraction coupling and MEF from the scale of the myocyte to the whole heart

Fig. 2

The first step in the initiation of contraction begins with an influx of sodium ions, which depolarizes the membrane and opens the voltage-gated L-type calcium channels. This causes an influx of calcium into the cell, some of which binds to ryanodine receptors (RyR) located on surface of the sarcoplasmic reticulum (SR), which allows for a large scale release of calcium from inside the SR; a process referred to as calcium induced calcium release. There is then an abundance of free calcium in the cell that can bind to troponin (Tn), in particular troponin-C. This binding causes tropomyosin (Tm) to shift, exposing the myosin binding site on actin. Once the myosin head binds to actin, force is generated. At the end of the crossbridge cycle, calcium is released from troponin-C and is then either pumped out of the cell by the sodium-calcium exchanger (NCX) or resequestered into the SR via the sarcoplasmic reticulum calcium ATPase (SERCA) pump. Resulting changes in the mechanical context of the cell can alter the dynamics of conduction of electrical excitation throughout the tissue and the duration of cell action potential, by modulating channels, junctions, and cell capacitances and resistances; thus feeding back between cardiac mechanics and electrophysiology.

Fig. 3

Combined apparatus for biaxial stretch of micropatterned neonatal cardiomyocytes and optical mapping of cell membrane potential permits study of conduction through multicellular preparations. (a) Diagram of optical mapping and micropatterned stretch equipment; (b) representative map of electrical activation, spatial scale 2 mm; (c) example stretch experiment result, showing that conduction in the longitudinal and transverse directions of the micropatterned cell culture slows with biaxial stretch, scale 2 mm; and (d) Example activation map in a transgenic mouse model of arrhythmia associated with mechanoelectric junctions, in collaboration with Dr. Farah Sheikh, UCSD.

Fig. 4

Layout of a computer-controlled system designed for measuring cardiac muscle mechanics. The system is capable of measuring force, calcium transients, sarcomere length (in trabeculae), muscle length, and local muscle strain. The high-speed servomotor performs very precise stretches.

Fig. 5

(a) Measured strain in a mouse papillary muscle due to a 20% prestretch with a timing in relation to activation (vertical line) that is similar to (b) measured strain in the late activated region of a ventricularly paced dog heart