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Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart.

ABSTRACT: Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fibroblast-specific protein-1 driven conditional Cx43 knock-out mice (Cx43fsp1KO). Electrical coupling between the scar and uninjured myocardium was demonstrated by injecting current into the myocardium and recording depolarization in the scar through optical mapping. Coupling was significantly reduced in Cx43fsp1KO hearts. Voltage signals were recorded using microelectrodes from control scars but no signals were obtained from Cx43fsp1KO hearts. Recordings showed significantly decreased amplitude, depolarized resting membrane potential, increased duration and reduced upstroke velocity compared to surrounding myocytes, suggesting that the non-excitable cells in the scar closely follow myocyte action potentials. These results were further validated by mathematical simulations. Optical mapping demonstrated that current delivered within the scar could induce activation of the surrounding myocardium. These data demonstrate non-myocytes in the scar are electrically coupled to myocytes, and coupling depends on Cx43 expression.

SUBMITTER: Mahoney VM

PROVIDER: S-EPMC4886689 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart.

Mahoney Vanessa M VM Mezzano Valeria V Mirams Gary R GR Maass Karen K Li Zhen Z Cerrone Marina M Vasquez Carolina C Bapat Aneesh A Delmar Mario M Morley Gregory E GE

Scientific reports 20160531

Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fib ...[more]

PMID: 27244564

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Project description:A cable model that includes polarization-induced capacitive current is derived for modeling the solitonic conduction of electrotonic potentials in neuronal branchlets with microstructure containing endoplasmic membranes. A solution of the nonlinear cable equation modified for fissured intracellular medium with a source term representing charge 'soakage' is used to show how intracellular capacitive effects of bound electrical charges within mitochondrial membranes can influence electrotonic signals expressed as solitary waves. The elastic collision resulting from a head-on collision of two solitary waves results in localized and non-dispersing electrical solitons created by the nonlinearity of the source term. It has been shown that solitons in neurons with mitochondrial membrane and quasi-electrostatic interactions of charges held by the microstructure (i.e., charge 'soakage') have a slower velocity of propagation compared with solitons in neurons with microstructure, but without endoplasmic membranes. When the equilibrium potential is a small deviation from rest, the nonohmic conductance acts as a leaky channel and the solitons are small compared when the equilibrium potential is large and the outer mitochondrial membrane acts as an amplifier, boosting the amplitude of the endogenously generated solitons. These findings demonstrate a functional role of quasi-electrostatic interactions of bound electrical charges held by microstructure for sustaining solitons with robust self-regulation in their amplitude through changes in the mitochondrial membrane equilibrium potential. The implication of our results indicate that a phenomenological description of ionic current can be successfully modeled with displacement current in Maxwell's equations as a conduction process involving quasi-electrostatic interactions without the inclusion of diffusive current. This is the first study in which solitonic conduction of electrotonic potentials are generated by polarization-induced capacitive current in microstructure and nonohmic mitochondrial membrane current.

Project description:IntroductionConduction system pacing (CSP), in the form of His bundle pacing (HBP) or left bundle branch pacing (LBBP), is emerging as a valuable cardiac resynchronization therapy (CRT) delivery method. However, patient selection and therapy personalization for CSP delivery remain poorly characterized. We aim to compare pacing-induced electrical synchrony during CRT, HBP, LBBP, HBP with left ventricular (LV) epicardial lead (His-optimized CRT [HOT-CRT]), and LBBP with LV epicardial lead (LBBP-optimized CRT [LOT-CRT]) in patients with different conduction disease presentations using computational modeling.MethodsWe simulated ventricular activation on 24 four-chamber heart geometries, including His-Purkinje systems with proximal left bundle branch block (LBBB). We simulated septal scar, LV lateral wall scar, and mild and severe myocardium and LV His-Purkinje system conduction disease by decreasing the conduction velocity (CV) down to 70% and 35% of the healthy CV. Electrical synchrony was measured by the shortest interval to activate 90% of the ventricles (90% of biventricular activation time [BIVAT-90]).ResultsSevere LV His-Purkinje conduction disease favored CRT (BIVAT-90: HBP 101.5 ± 7.8 ms vs. CRT 93.0 ± 8.9 ms, p < .05), with additional electrical synchrony induced by HOT-CRT (87.6 ± 6.7 ms, p < .05) and LOT-CRT (73.9 ± 7.6 ms, p < .05). Patients with slow myocardium CV benefit more from CSP compared to CRT (BIVAT-90: CRT 134.5 ± 24.1 ms; HBP 97.1 ± 9.9 ms, p < .01; LBBP: 101.5 ± 10.7 ms, p < .01). Septal but not lateral wall scar made CSP ineffective, while CRT was able to resynchronize the ventricles in the presence of septal scar (BIVAT-90: baseline 119.1 ± 10.8 ms vs. CRT 85.1 ± 14.9 ms, p < .01).ConclusionSevere LV His-Purkinje conduction disease attenuates the benefits of CSP, with additional improvements achieved with HOT-CRT and LOT-CRT. Septal but not lateral wall scars make CSP ineffective.

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Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart.

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Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart.

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