title: Structural heterogeneity promotes triggered activity, reflection and arrhythmogenesis in cardiomyocyte monolayers.
abstract: Patients with structural heart disease are predisposed to arrhythmias by incompletely understood mechanisms. We hypothesized that tissue expansions promote source-to-sink mismatch leading to early after-depolarizations (EADs) and reflection of impulses in monolayers of well-polarized neonatal rat ventricular cardiomyocytes.We traced electrical propagation optically in patterned monolayers consisting of two wide regions connected by a thin isthmus.Structural heterogeneities provided a substrate for EADs, retrograde propagation along the same pathway (reflection) and reentry initiation. Reflection always originated during the action potential (AP) plateau at the distal expansion. To determine whether increased sodium current(INa) would promote EADs, we employed adenoviral transfer of Nav1.5 (Ad-Nav1.5). Compared with uninfected and adenoviral expression of green fluorescent protein (Ad-GFP; viral control),Ad-Nav1.5 significantly increased Nav1.5 protein expression, peak and persistent INa density, A Pupstroke velocity, AP duration, conduction velocity and EAD incidence, as well as reflection incidence (29.2%, n =48 vs. uninfected, 9.4%, n =64; and Ad-GFP, 4.8%, n =21). Likewise,the persistent INa agonist veratridine (0.05–3 μM) prolonged the AP, leading to EADs and reflection. Reflection led to functional reentry distally and bigeminal and trigeminal rhythms proximally. Reflection was rare in the absence of structural heterogeneities.Computer simulations demonstrated the importance of persistent INa in triggering reflection and predicted that the gradient between the depolarizing cells at the distal expansion and the repolarizing cells within the isthmus enabled retrograde flow of depolarizing electrotonic current to trigger EADs and reflection. A combination of a substrate (structural heterogeneity) and a trigger (increased persistent INa and EADs) promotes reflection and arrhythmogenesis.
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48108, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Auerbach
authors.forename: Krzysztof R
authors.initials: KR
authors.lastname: Grzda
authors.forename: Philip B
authors.initials: PB
authors.lastname: Furspan
authors.forename: Priscila Y
authors.initials: PY
authors.lastname: Sato
authors.forename: Sergey
authors.initials: S
authors.lastname: Mironov
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000200:Action Potentials; D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D003198:Computer Simulation; D005822:Genetic Vectors; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D002120:Calcium Channel Agonists; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012964:Sodium