RESUMEN
Determining optimal treatment strategies for complex arrhythmogenesis in AF is confounded by the lack of consensus regarding the mechanisms causing AF. Studies report different mechanisms for AF, ranging from hierarchical drivers to anarchical multiple activation wavelets. Differences in the assessment of AF mechanisms are likely due to AF being recorded across diverse models using different investigational tools, spatial scales and clinical populations. The authors review different AF mechanisms, including anatomical and functional re-entry, hierarchical drivers and anarchical multiple wavelets. They then describe different cardiac mapping techniques and analysis tools, including activation mapping, phase mapping and fibrosis identification. They explain and review different data challenges, including differences between recording devices in spatial and temporal resolutions, spatial coverage and recording surface, and report clinical outcomes using different data modalities. They suggest future research directions for investigating the mechanisms underlying human AF.
RESUMEN
Cardiac electrical alternans is a period-2 dynamical behavior with alternating long and short action potential durations (APD) that often precedes dangerous arrhythmias associated with cardiac arrest. Despite the importance of alternans, many current ordinary differential equations models of cardiac electrophysiology do not produce alternans, thereby limiting the use of these models for studying the mechanisms that underlie this condition. Because delay differential equations (DDEs) commonly induce complex dynamics in other biological systems, we investigate whether incorporating DDEs can lead to alternans development in cardiac models by studying the Fox et al. canine ventricular action potential model. After suppressing the alternans in the original model, we show that alternans can be obtained by introducing DDEs in the model gating variables, and we quantitatively compare the DDE-induced alternans with the alternans present in the original model. We analyze the behavior of the voltage, currents, and gating variables of the model to study the effects of the delays and to determine how alternans develops in that setting, and we discuss the mathematical and physiological implications of our findings. In future work, we aim to apply our approach to induce alternans in models that do not naturally exhibit such dynamics.
Asunto(s)
Potenciales de Acción/fisiología , Electrofisiología , Corazón/fisiología , Modelos Neurológicos , Animales , Canales de Calcio Tipo L/metabolismo , Perros , Activación del Canal Iónico/fisiología , Modelos Biológicos , Factores de TiempoRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) importantly contributes to the occurrence of atrial fibrillation (AF) in humans, but the mechanisms are poorly understood. Experimental research has provided insights into AF promotion by acute OSA episodes. However, patients with OSA usually have frequent nocturnal episodes for some time before manifesting AF. OBJECTIVES: The goal of this study was to test the hypothesis that repetitive OSA causes cardiac remodeling that predisposes to AF. METHODS: We mimicked OSA by using a mechanical ventilator and closing the airway at end-expiration with a 3-way stopcock (OSA rats). Matched control groups included rats with the ventilator stopped but airway left open (open airway rats) and continuously ventilated rats (sham rats). OSA rats were exposed to 20 consecutive 2-min cycles of 40 s of apnea/80 s of ventilation per day, 5 days per week for 4 weeks. RESULTS: OSA significantly increased the duration of AF from (median [interquartile range]) 2.6 s [1.9 s to 8.9 s] (shams) and 16 s [1.8 s to 93 s] (open airway) to 49s [34 s to 444 s]. AF inducibility increased to 56% (9 of 16) of OSA rats; this is up from 15% (2 of 13) and 13% (2 of 15) in open airway and sham rats, respectively (p < 0.05). OSA rats exhibited substantial atrial conduction slowing on optical mapping, along with connexin-43 down-regulation on both quantitative immunofluorescence (expression reduced by 58% vs sham rats) and Western blot (reduced by 38%), as well as increased atrial fibrous tissue content (by 71%). OSA also caused left ventricular hypertrophy, dilation, and diastolic dysfunction and enhanced AF inducibility during superimposed acute OSA episodes to 82.4% of rats. CONCLUSIONS: Chronically repeated OSA episodes cause AF-promoting cardiac remodeling, with conduction abnormalities related to connexin dysregulation and fibrosis playing a prominent role. This novel animal model provides mechanistic insights into an important clinical problem and may be useful for further exploration of underlying mechanisms and therapeutic approaches.
Asunto(s)
Fibrilación Atrial/fisiopatología , Remodelación Atrial/fisiología , Apnea Obstructiva del Sueño/fisiopatología , Animales , Conexina 43/metabolismo , Diástole , Modelos Animales de Enfermedad , Ecocardiografía , Electrofisiología , Atrios Cardíacos/fisiopatología , Masculino , Microscopía Confocal , Microscopía Fluorescente , Ratas , Ratas Sprague-Dawley , Respiración Artificial , Factores de TiempoRESUMEN
RATIONALE: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current (I(to)) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I(to) and that its overexpression might specifically alter PF I(to) properties and repolarization. OBJECTIVE: To assess the potential role of DPP6 in PF I(to). METHODS AND RESULTS: Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I(to) had similar density, but PF I(to) differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I(to) density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K(+)-channel interacting ß-subunit K(+)-channel interacting protein type-2, essential for normal expression of I(to) in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I(to); I(to) amplitude was greatly enhanced by coexpression with K(+)-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K(+)-channel interacting protein type-2 failed to alter I(to) compared with Kv4.3/K(+)-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I(to) composition) greatly enhanced I(to) compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I(to) enhancement can greatly accelerate PF repolarization. CONCLUSIONS: These results point to a previously unknown central role of DPP6 in PF I(to), with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.