Electrotonic Myofibroblast-to-Myocyte Coupling Increases Propensity to Reentrant Arrhythmias in Two-Dimensional Cardiac Monolayers

Abstract

In pathological conditions such as ischemic cardiomyopathy and heart failure, differentiation of fibroblasts into myofibroblasts may result in myocyte-fibroblast electrical coupling via gap junctions. We hypothesized that myofibroblast proliferation and increased heterocellular coupling significantly alter two-dimensional cardiac wave propagation and reentry dynamics. Co-cultures of myocytes and myofibroblasts from neonatal rat ventricles were optically mapped using a voltage-sensitive dye during pacing and sustained reentry. The myofibroblast/myocyte ratio was changed systematically, and junctional coupling of the myofibroblasts was reduced or increased using silencing RNAi or adenoviral overexpression of Cx43, respectively. Numerical simulations in two-dimensional models were used to quantify the effects of heterocellular coupling on conduction velocity (CV) and reentry dynamics. In both simulations and experiments, reentry frequency and CV diminished with larger myofibroblast/myocyte area ratios; complexity of propagation increased, resulting in wave fractionation and reentry multiplication. The relationship between CV and coupling was biphasic: an initial decrease in CV was followed by an increase as heterocellular coupling increased. Low heterocellular coupling resulted in fragmented and wavy wavefronts; at high coupling wavefronts became smoother. Heterocellular coupling alters conduction velocity, reentry stability, and complexity of wave propagation. The results provide novel insight into the mechanisms whereby electrical myocyte-myofibroblast interactions modify wave propagation and the propensity to reentrant arrhythmias.

Clinical and Pathological Impact of Tissue Fibrosis on Lethal Arrhythmic Events in Hypertrophic Cardiomyopathy Patients With Impaired Systolic Function

“…In a coculture model, increased myofibroblast/myocyte area decreased conduction velocity and degenerated a spiral re-entry into multiple waves, like a VF. 24 Thus, increased myocardial fibrosis and disarray in HCM usually decreases excitation propagation, leading to a conduction delay or block, a substrate of re-entrant arrhythmias. SAECG can noninvasively evaluate a delayed potential as a substrate of ventricular arrhythmias in several diseases, although a previous study suggested that SAECG was not always useful for identifying HCM patients with VT or SCD.…”

Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study

“…In this way, the fibroblast proliferation changed the form of the re-entry. In addition, because of the presence of the fibroblasts, the CV slowed (Miragoli et al, 2006;Zlochiver et al, 2008), which contributed to stabilization of the spiral wave. This further illustrates that fibroblast proliferation aggravated the cardiac condition.…”

“…Therefore, the functional roles of the fibroblasts in cardiac electrical and mechanical activities have attracted increasing interest, and have been explored in experimental studies (Miragoli et al, 2007;Zlochiver et al, 2008) and computational models (MacCannell et al, 2007;Tanaka et al, 2007;Jacquemet and Henriquez, 2008;Zlochiver et al, 2008;Sachse et al, 2009). Both experimental and computational studies (Miragoli et al, 2006;Jacquemet and Henriquez, 2008;Zlochiver et al, 2008) have illustrated that non-monotonic changes in conduction velocity (CV) are caused by increasing the fibroblast population. ten Tusscher and Panfilov (2007) showed that CV decreased from 0.7 to 0.3 m/s as the percentage of fibroblast proliferous cells rose from 0 to 40% in two-dimensional (2D) tissue.…”

Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

“…By co-culturing neonatal cardiomyocytes and fibroblasts at different fibroblast infiltration ratios, Zlochiver et al reported that the electrical interaction between myocytes and fibroblasts determines rotor dynamics by altering the conduction velocity and wavefront complexity [16]. In vitro models also allowed the evaluation of the effects of mechanical stretch on the calcium dynamics and the mechanisms of initiation of AF in a model of HL-1 cells (i.e.…”