Cardiac Conduction through Engineered Tissue

Abstract

In children, interruption of cardiac atrioventricular (AV) electrical conduction can result from congenital defects, surgical interventions, and maternal autoimmune diseases during pregnancy. Complete AV conduction block is typically treated by implanting an electronic pacemaker device, although long-term pacing therapy in pediatric patients has significant complications. As a first step toward developing a substitute treatment, we implanted engineered tissue constructs in rat hearts to create an alternative AV conduction pathway. We found that skeletal muscle-

Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics

“…In contrast, the lack of measured electrical activity in the central scar (where VSFP2.3 expression was high) may be explained by the distance from AP-generating cells at the scar border (10 −3 -m domain), whereas nonmyocyte-mediated AP propagation terminates in the 10 −4 -m region in cell culture (14). Longer-distance AP propagation may be possible if passive conduction via nonmyocytes reaches AP-generating cells (acting as "repeater stations") in tissue containing a mix of both cell types, as documented for engineered tissue strands (12,13). Postinfarction scars, for example, tend to contain interspersed groups of surviving myocytes; this finding is less common in postablation scars (including our cryoinjured hearts).…”

“…Heterocellular electrotonic coupling that links groups of surviving myocytes could also explain conduction of electrical excitation into postinfarct (11) and cryoinjury scar tissue (7). It would also appear to be a key determinant of the success of engineered heterocellular tissue grafts, implanted to patch up cardiac conduction [e.g., to fix atrioventricular block (12,13)]. Additionally, effects of nonmyocytes on myocyte electrophysiology and AP propagation in fibrotic tissue may be arrhythmogenic by contributing to reentrant pathways and by altering excitability, repolarization, and conduction in heart muscle (30).…”

“…Possible functionality of connexin-based junctions was indicated in rabbit atrium, where dye diffusion between heterotypic cell types has been reported (6), and in mouse ventricle, where fibroblast-specific conditional connexin 43 knockout reduced transmission of injected current from healthy to scarred tissue (7). A number of clinical observations, such as transscar electrical conduction after atrial ablation (8) or surgical repair of congenital heart defects (9) and transplantation (10), in addition to experimental findings of electrical conduction into postinfarct (11) and cryoinjury (7) scars and along implanted tissue grafts (12,13) would be in keeping with a (passive) contribution by nonmyocytes to cardiac AP conduction. Functional heterocellular electrotonic coupling thus far has been shown conclusively in vitro only [where it is aided by phenotype conversion and connexin overexpression of cultured fibroblasts (14)(15)(16)(17)].…”

Regenerative therapies in electrophysiology and pacing

“…The need to reestablish normal cardiac activation in the setting of sinus rhythm and complete heart block has also led investigators to engineer bypass tracts such that sinus impulses can gain access to the ventricles [44]. However this work is still in its infancy relative to biological pacemaking.…”

An improved in vivo method for atrioventricular node ablation via thoracotomy

“…While such devices have revolutionized patient survival and quality of life, their use implies a number of associated issues, including limited device lifetime, active patient awareness in strong magnetic fields, gradual reduction in lead conductivity due to wear or scar formation on the electrode, and, for the pediatric population, the inability of an artificial device to grow with the child. Future treatments, such as tissue-engineered biodegradable scaffolds, could successfully address these issues, through biointegration into the existing tissue (2).…”