An investigation into therapies for atrial arrythmias using a biophysical model of the human atria (original) (raw)
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Animal models of arrhythmia: classic electrophysiology to genetically modified large animals
Nature Reviews Cardiology, 2019
Arrhythmias are an important health-care issue affecting millions of people worldwide 1-4. Various types of arrhythmias exist, ranging from less harmful, premature capture beats to sinoatrial or atrioventricular (AV) conduction block and from rare familial arrhythmia syndromes to the most common sustained arrhythmia, atrial fibrillation (AF). The overall prevalence of arrhythmias is approximately 3.4% (1.4% in individuals aged <18 years and 10.1% in individuals aged >75 years) 5. Arrhythmias are the main reason for sudden cardiac death (SCD), which accounts for 25% of all deaths 6-11 , and are associated with substantial morbidity, such as a fivefold increased risk of stroke in AF 9,12-15. Therapeutic strategy depends on the arrhythmia and can include drug therapy, catheter ablation, device implantation and treatment of concomitant diseases 12,16. Current treatment strategies have substantially improved survival but remain ineffective in many patients and are associated with numerous complications 17,18 and adverse effects 19. Therefore, today's largely symptomatic treatments have to be improved by innovative therapies that would ideally target causal proarrhythmic mechanisms 20. The pathophysiological basis of arrhythmias is complex and still incompletely understood, but similarities in the fundamental mechanisms between different forms of arrhythmias have been identified 21,22. In general, bradyarrhythmias or tachyarrhythmias occur because of primary or secondary alterations in important myocardial electrical properties, such as excitation or impulse formation, conduction and repolarization. In the heart, the sinus node acts as a pacemaker, generating electrical impulses. Other regions of the heart also have pacemaker activity but are physiologically suppressed by the sinus node. Altered ion channel expression or function can augment pacemaker function, a process called enhanced automaticity, leading to arrhythmias 23. Given that the sinus node is highly innervated by the autonomic nervous system, changes in the autonomic tone can also affect automaticity, leading to sinus tachycardia or bradycardia 24,25. Ca 2+ accumulation, for example, during atrial tachycardia or in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), results in multiple maladaptive changes, such as a subsequent Ca 2+ leak from the sarcoplasmic reticulum that causes a depolarizing current, leading to delayed afterdepolarizations. These alterations cause progressive depolarization of the cell and ectopic firing called triggered activity that
Cardiovascular Research, 2005
The complex pathophysiology of human arrhythmias has proven difficult to model. Direct correlations between the traditional arrhythmia mechanisms, including abnormal excitability, conduction, or repolarization and underlying molecular or cellular biology are poorly defined, as the primary etiologies of many human arrhythmias remain unknown. Since the causes of several arrhythmic syndromes have been identified, genetic models reproducing the mechanisms of these arrhythmias have become feasible. Initial murine modeling has revealed that in many cases the pathophysiology of the respective human disease is more complex than had been suspected. Insights from human genetic studies and animal models strongly suggest that the primary molecular defects may contribute at many stages in the causal chain leading to arrhythmia. The comprehensive analysis of each arrhythmia will require knowledge not only of the membrane effects of the primary defects, but also downstream intracellular signals, the developmental results of these perturbations, and the integration of compensatory responses and environmental factors. Precise modeling will require not only the mutation of specific residues in known disease genes, but also the systematic study of each of the many steps in arrhythmogenesis. Ultimately, such models will enable unbiased screens for disease mechanisms and novel therapies.
A Simulation Study of Alternans-Arrhythmia Based on Physiology of Invertebrate Heart
Alternans is an arrhythmia exhibiting alternating amplitude/interval from beat to beat on heartbeat recordings, such as the finger pulse. Alternans is well known since Traube's document in 1872 and is called harbinger of death, but the mechanisms for its generation is not fully defined and much work still remains. We studied this abnormal state of the heart, in animal models (electrophysiology) and with a numerical model (computer simulation). We focused our attention on a causal association between the pace-making cells and ventricular cells. We revealed that one of the main causalities in generating alternates was a potassium ionic abnormality. We discussed the concentration of ions in the extracellular space of the heart-tissue.
The shape of human atrial action potential accounts for different frequency-related changes in vitro
International Journal of Cardiology, 1996
We aimed at investigating frequency-related changes of human atria1 action potential (AP) in vitro to see whether baseline AP shape might account for different responses to increasing stimulation rates. Human right atria1 trabeculae (n=48) obtained from adult (n=38, mean age 59 ? 8, range 45-72 years) consecutive patients (~30% of those operated upon by a single surgeon; 1.26 preparations per patient, range l-2) were superfused in an organ bath with oxygenated (0, content 16 ml/l) and modified (NaHCO, 25.7 mmol/l) Tyrode's solution at 31°C. Baseline electrophysiology (pacing: 1 ms duration, 2-4 mA current intensity) at cycle length (CL) of 1000 ms was recorded in 90% (43 out of 48) of the preparations. The frequency-related protocol (CL from 1600 to 300 ms) was, however, undertaken in 23 (48%) preparations because 20 (42%) became pacing unresponsive immediately after baseline recordings. No statistical differences were seen when baseline electrophysiological parameters (mean 5 SD) were grouped according to late pacing responsiveness (n=43 vs. n=23): respectively, resting membrane potential (RMP) was -74 ? 6 vs. -75 ? 4 mV, maximal upstroke velocity (Vmax) 172 -C 60 vs. 173 ? 39 V/s, AP amplitude (APA) 89 2 11 vs. 91 5 8 mVand AP durations were at 30% (APD30%) 10 t 13 vs. 13 +-18 ms, 50% (APDSO%) 45 -C 79 vs. 62 ? 91 ms and 90% (APD90%) 383 i-103 vs. 407 t 108 ms. To classify baseline AP shape, two criteria were adopted: criterion 1 ("objective"), based on APA (cut-off 90 mV) and APD90% (cut-off 500 ms) computed values and criterion 2 ("visual") derived from the literature. These criteria enabled us to differentiate three AP shape types: type 1 (spike and dome), type 3 (no dome) and type 4 (extremely prolonged). At baseline, the two criteria diagnosed different proportions of AP shape types. There were, however, no intra-type statistical differences among electrophysiological parameters. By criterion 1, analysis of variance (ANOVA) showed significant inter-type differences of RMP,Vmax, APA, APDSO and 90% and by criterion 2 of APA, APD30, 50 and 90%, respectively. To facilitate comparisons with previous published data, criterion 2 was selected to analyse frequency-related changes of AP shape types. At low stimulation rate, ANOVA for repeated measures (with Greenhouse-Geisser g correction) showed inter-type differences for APD30, 50 and 90% (P=O.OOOOS). RMP, Vmax, APA and APD90% were overall frequency-related (P=O.OOOOS). Inter-type frequency-related differences were however seen only for APDBO%. Human atria1 AP durations (30, 50 and 90%) enable differentiation among AP shape types (1, 3 and 4). By a standardized use-dependent protocol overall RMP, Vmax, APA and APD90% are frequency-related. AP shape accounts for frequency-related changes of APD90% only. A type 4 AP shape with much prolonged AP duration had a flat frequency dependence. At high stimulation rates, adult type 1 and 3 AP shapes are indistinguishable. Use-dependent and pharmacological investigations in human atria1 myocytes need to take AP shape into account.
European Journal of Pharmaceutical Sciences, 2012
Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmann's bundle and pectinate myocytes are characterised by action potentials, ionic currents and action potential duration (APD) restitution. The principal effect of the ion channel remodelling of persistent atrial fibrillation (AF), and a mutation producing familial AF, was APD shortening at all rates. Electrical alternans was abolished by the modelled action of Dronedarone. AF induced gap junctional remodelling slows propagation velocity at all rates. Re-entrant spiral waves in 2-D models are characterised by their frequency, wavelength, meander and stability. For homogenous models of normal tissue, spiral waves self-terminate, due to meander to inexcitable boundaries, and by dissipation of excitation. AF electrical remodelling in these homogenous models led to persistence of spiral waves, and AF fibrotic remodelling to their breakdown into fibrillatory activity. An anatomical model of the atria was partially validated by the activation times of normal sinus rhythm. The use of tissue geometry from clinical MRI, and tissue anisotropy from ex vivo diffusion tensor magnetic resonance imaging is outlined. In the homogenous model of normal atria, a single scroll breaks down onto spatio-temporal irregularity (electrical fibrillation) that is self-terminating; while in the AF remodelled atria the fibrillatory activity is persistent. The persistence of electrical AF can be dissected in the model in terms of ion channel and intercellular coupling processes, that can be modified pharmacologically; the effects of anatomy, that can be modified by ablation; and the permanent effects of fibrosis, that need to be prevented.