title: Effect of anisotropy on ventricular vulnerability to unidirectional block and reentry by single premature stimulation during normal sinus rhythm in rat heart.
abstract: Single high-intensity premature stimuli when applied to the ventricles during ventricular drive of an ectopic site, as in Winfree's "pinwheel experiment," usually induce reentry arrhythmias in the normal heart, while single low-intensity stimuli barely do. Yet ventricular arrhythmia vulnerability during normal sinus rhythm remains largely unexplored. With a view to define the role of anisotropy on ventricular vulnerability to unidirectional conduction block and reentry, we revisited the pinwheel experiment with reduced constraints in the in situ rat heart. New features included single premature stimulation during normal sinus rhythm, stimulation and unipolar potential mapping from the same high-resolution epicardial electrode array, and progressive increase in stimulation strength and prematurity from diastolic threshold until arrhythmia induction. Measurements were performed with 1-ms cathodal stimuli at multiple test sites (n= 26) in seven rats. Stimulus-induced virtual electrode polarization during sinus beat recovery phase influenced premature ventricular responses. Specifically, gradual increase in stimulus strength and prematurity progressively induced make, break, and graded-response stimulation mechanisms. Hence unidirectional conduction block occurred as follows:1) along fiber direction, on right and left ventricular free walls (n= 23), initiating figure-eight reentry (n= 17) and tachycardia (n= 12), and2) across fiber direction, on lower interventricular septum (n= 3), initiating spiral wave reentry (n= 2) and tachycardia (n= 1). Critical time window (55.1 ± 4.7 ms, 68.2 ± 6.0 ms) and stimulus strength lower limit (4.9 ± 0.6 mA) defined vulnerability to reentry. A novel finding of this study was that ventricular tachycardia evolves and is maintained by episodes of scroll-like wave and focal activation couplets. We also found that single low-intensity premature stimuli can induce repetitive ventricular response (n= 13) characterized by focal activations.NEW & NOTEWORTHYWe performed ventricular cathodal point stimulation during sinus rhythm by progressively increasing stimulus strength and prematurity. Virtual electrode polarization and recovery gradient progressively induced make, break, and graded-response stimulation mechanisms. Unidirectional conduction block occurred along or across fiber direction, initiating figure-eight or spiral wave reentry, respectively, and tachycardia sustained by scroll wave and focal activations.
authors.affiliation: Department of Life Sciences, Università degli Studi, Parma, Italy.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Università degli Studi, Parma, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Life Sciences, Università degli Studi, Parma, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Buccarello
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: P R
authors.initials: PR
authors.lastname: Ershler
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: R L
authors.initials: RL
authors.lastname: Lux
authors.affiliation: Azienda Unità Sanitaria Locale, Unit of Cardiology, Parma, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Callegari
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences, Unit of Pathology, Università degli Studi, Parma, Italy.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Università degli Studi, Parma, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Corradi
authors.affiliation: Department of Life Sciences, Università degli Studi, Parma, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Carnevali
authors.affiliation: Department of Life Sciences, Università degli Studi, Parma, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sgoifo
authors.affiliation: CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Università degli Studi, Parma, Italy.|Humanitas Clinical and Research Center, Rozzano (Milan), Italy; and.
authors.forename: M
authors.initials: M
authors.lastname: Miragoli
authors.affiliation: Department of Life Sciences, Università degli Studi, Parma, Italy.|Cardiac Stem Cell Interdepartmental Center "CISTAC," Università degli Studi, Parma, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Musso
authors.affiliation: Department of Life Sciences, Università degli Studi, Parma, Italy; emilio.macchi@unipr.it.|CERT, Center of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, Università degli Studi, Parma, Italy.|Cardiac Stem Cell Interdepartmental Center "CISTAC," Università degli Studi, Parma, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Macchi
mesh_terms: D000818:Animals; D016880:Anisotropy; D001146:Arrhythmia, Sinus; D004558:Electric Stimulation; D004566:Electrodes; D056149:Epicardial Mapping; D006327:Heart Block / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects; D006346:Heart Septum / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology*; D051381:Rats; D012032:Refractory Period, Electrophysiological; D013615:Tachycardia, Sinoatrial Nodal Reentry / Q000503:physiopathology; D017180:Tachycardia, Ventricular / Q000503:physiopathology; D016277:Ventricular Function, Left
keywords: arrhythmia vulnerability; myocardial anisotropy; pinwheel experiment; single premature stimulation during sinus rhythm; unidirectional conduction block and reentry