Stretch modulation of cardiac contractility: importance of myocyte calcium during the slow force response

Abstract

The mechanical response of the heart to myocardial stretch has been understood since the work of muscle physiologists more than 100 years ago, whereby an increase in ventricular chamber filling during diastole increases the subsequent force of contraction. The stretch-induced increase in contraction is biphasic. There is an abrupt increase in the force that coincides with the stretch (the rapid response), which is then followed by a slower response that develops over several minutes (the slow force response, or SFR). The SFR is associated with a progressive increase in the magnitude of the Ca²⁺ transient, the event that initiates myocyte cross-bridge cycling and force development. However, the mechanisms underlying the stretch-dependent increase in the Ca²⁺ transient are still debated. This review outlines recent literature on the SFR and summarizes the different stretch-activated Ca²⁺ entry pathways. The SFR might result from a combination of several different cellular mechanisms initiated in response to activation of different cellular stretch sensors.

Keywords: Autocrine/paracrine response; Calcium influx; Cardiac stretch; G-coupled protein receptors; Slow force response; Stretch-activated channels.

Fig. 1

Representative slow force response from a rat trabecula. Panel A shows stress before, during (solid bar), and after a step increase in muscle length. Panel B shows individual Ca²⁺ transients (340/380 fura-2 ratio, LHS) and twitches (stress, RHS) immediately after stretch (i) and following 200 s of stretch (ii) for the time points indicated by arrows in panel A

Fig. 2

Model of steady-state Ca²⁺ cycling. With each cardiac cycle movement of Ca²⁺ takes place between four separate compartments. These are: (i) the external compartment which represents the extracellular fluid surrounding the myocytes; (ii) the myocyte cytosol; (iii) the internal Ca²⁺ store or sarcoplasmic reticulum (SR); and (iv) the intracellular buffers (which include the mitochondria). During steady state conditions, equal amounts of Ca²⁺ move between the compartments. The width of the red arrows shows the relative amount of Ca²⁺ movement during each cardiac cycle, with the thick arrows representing 70–90% of the Ca²⁺, depending on the species, and the dashed arrows representing less than 2% of total Ca²⁺