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Frequency analysis of atrial action potential alternans: a sensitive clinical index of individual propensity to atrial fibrillation.

ABSTRACT: Few clinical indices identify the propensity of patients to atrial fibrillation (AF) when not in AF. Repolarization alternans has been shown to indicate AF vulnerability, but is limited in its sensitivity to detect changes in action potential (AP) duration (APD), which may be subtle. We hypothesized that spectral analysis would be a more sensitive and robust marker of AP alternans and thus a better clinical index of individual propensity to AF than APD alternans.In 31 patients (12 persistent AF, 15 paroxysmal AF, 4 controls with no AF), we recorded left (n=27) and right (n=6) atrial monophasic APs during incremental pacing from cycle length 500 ms (120 beats per minute) to AF onset. Alternans was measured by APD and spectral analysis. At baseline pacing (median cycle length [1st, 3rd quartiles], 500 ms [500, 500]), APD alternans was detected in only 7 of 27 AF patients (no controls), whereas spectral AP alternans was detected in 18 of 27 AF patients (no controls; P=0.003); AP alternans was more prevalent in persistent than paroxysmal AF, and absent in controls (P=0.018 APD; P=0.042 spectral). Spectral AP alternans magnitude at baseline was highest in persistent AF, with modest rate-dependent amplification, followed by paroxysmal AF, with marked rate dependence, and undetectable in controls until just before induced AF.Spectral AP alternans near baseline rates can identify patients with, versus those without, clinical histories and pathophysiological substrates for AF. Future studies should examine whether the presence of spectral AP alternans during sinus rhythm may obviate the need to actually demonstrate AF, such as on ambulatory ECG monitoring.

SUBMITTER: Lalani GG

PROVIDER: S-EPMC3897260 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Frequency analysis of atrial action potential alternans: a sensitive clinical index of individual propensity to atrial fibrillation.

Lalani Gautam G GG Schricker Amir A AA Clopton Paul P Krummen David E DE Narayan Sanjiv M SM

Circulation. Arrhythmia and electrophysiology 20130831 5

<h4>Background</h4>Few clinical indices identify the propensity of patients to atrial fibrillation (AF) when not in AF. Repolarization alternans has been shown to indicate AF vulnerability, but is limited in its sensitivity to detect changes in action potential (AP) duration (APD), which may be subtle. We hypothesized that spectral analysis would be a more sensitive and robust marker of AP alternans and thus a better clinical index of individual propensity to AF than APD alternans.<h4>Methods an ...[more]

PMID: 23995250

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Project description:Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic APD alternans in patients with AF.

Project description:AimsHuman atrial electrophysiology exhibits high inter-subject variability in both sinus rhythm (SR) and chronic atrial fibrillation (cAF) patients. Variability is however rarely investigated in experimental and theoretical electrophysiological studies, thus hampering the understanding of its underlying causes but also its implications in explaining differences in the response to disease and treatment. In our study, we aim at investigating the ability of populations of human atrial cell models to capture the inter-subject variability in action potential (AP) recorded in 363 patients both under SR and cAF conditions.Methods and resultsHuman AP recordings in atrial trabeculae (n = 469) from SR and cAF patients were used to calibrate populations of computational SR and cAF atrial AP models. Three populations of over 2000 sampled models were generated, based on three different human atrial AP models. Experimental calibration selected populations of AP models yielding AP with morphology and duration in range with experimental recordings. Populations using the three original models can mimic variability in experimental AP in both SR and cAF, with median conductance values in SR for most ionic currents deviating less than 30% from their original peak values. All cAF populations show similar variations in G(K1), G(Kur) and G(to), consistent with AF-related remodeling as reported in experiments. In all SR and cAF model populations, inter-subject variability in I(K1) and I(NaK) underlies variability in APD90, variability in I(Kur), I(CaL) and I(NaK) modulates variability in APD50 and combined variability in Ito and I(Kur) determines variability in APD20. The large variability in human atrial AP triangulation is mostly determined by I(K1) and either I(NaK) or I(NaCa) depending on the model.ConclusionExperimentally-calibrated human atrial AP models populations mimic AP variability in SR and cAF patient recordings, and identify potential ionic determinants of inter-subject variability in human atrial AP duration and morphology in SR versus cAF.

Dataset Information

Frequency analysis of atrial action potential alternans: a sensitive clinical index of individual propensity to atrial fibrillation.

Publications

Frequency analysis of atrial action potential alternans: a sensitive clinical index of individual propensity to atrial fibrillation.

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