Changes of Axial Resistance following Mechanical Strain Prevail Over Stretch-Activated Currents in the Modulation of Conduction Velocity in Cardiac Cell Strands

Abstract

Tissue deformation and stretch-activated currents (ISAC) exert a feedback on cardiac electrical function (mechano-electrical feedback). The effects of stretch on conduction velocity (CV) and their modulation by ISAC are still debated. We investigated the dependence of CV on passive tissue deformation and its modulation by ISAC in cultured cardiomyocyte strands and simulation studies.Strands of neonatal rat ventricular myocytes were cultured on deformable substrates. CV was measured optically under control conditions, upon 10% shortening and 10% lengthening. Simulations were conducted in fibers of ten Tusscher et al. model cells. A quadratic dependence of myoplasmic resistance on cell length was incorporated and gap junctional resistance (equal to myoplasmic resistance under control conditions) was assumed to be unaffected. ISAC was implemented as a constitutively active non-specific monovalent cation current with a nonlinear dependence on deformation.In cultured strands, CV decreased by 3.0% upon 10% shortening and increased by 3.9% upon 10% lengthening (n=25). In simulated fibers without ISAC, CV decreased by 5.1% and increased by 4.2% upon 10% shortening and 10% lengthening, respectively, in agreement with the experiments. When ISAC was incorporated at previously reported levels, it caused a slight resting membrane depolarization by ∼1 mV in undeformed fibers, but no major alteration of the CV behavior (4.8% decrease at 10% shortening; 3.9% increase at 10% lengthening). At large ISAC levels causing substantial membrane depolarization (≥5 mV) and inactivation of the Na+ current, the dependence of CV on tissue deformation was blunted or even inverted, with lengthening causing conduction slowing.Thus, during length changes of ±10%, axial tissue resistance and ISAC modulate conduction in opposite directions. However, at physiological ISAC levels, CV is primarily determined by axial tissue resistance.