Altered excitation-contraction coupling in human chronic atrial fibrillation

This review focuses on the (mal)adaptive processes in atrial excitation-contraction coupling occurring in patients with chronic atrial fibrillation. Cellular remodeling includes shortening of the atrial action potential duration and effective refractory period, depressed intracellular Ca<sup>2+</sup> transient, and reduced myocyte contractility. Here we summarize the current knowledge of the ionic bases underlying these changes. Understanding the molecular mechanisms of excitation-contraction-coupling remodeling in the fibrillating human atria is important to identify new potential targets for AF therapy

Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely

Post-operative atrial fibrillation is influenced by beta-blocker therapy but not by pre-operative atrial cellular electrophysiology

We investigated whether post-cardiac surgery (CS) new-onset atrial fibrillation (AF) is predicted by pre-CS atrial cellular electrophysiology, and whether the antiarrhythmic effect of beta-blocker therapy may involve pre-CS pharmacological remodeling. Atrial myocytes were obtained from consenting patients in sinus rhythm, just prior to CS. Action potentials and ion currents were recorded using whole-cell patch-clamp technique. Post-CS AF occurred in 53 of 212 patients (25%). Those with post-CS AF were older than those without (67 ± 2 vs 62 ± 1 years, P = 0.005). In cells from patients with post-CS AF, the action potential duration at 50% and 90% repolarization, maximum upstroke velocity, and effective refractory period (ERP) were 13 ± 4 ms, 217 ± 16 ms, 185 ± 10 V/s, and 216 ± 14 ms, respectively (n = 30 cells, 11 patients). Peak L-type Ca2+ current, transient outward and inward rectifier K+ currents, and the sustained outward current were −5.0 ± 0.5, 12.9 ± 2.4, −4.1 ± 0.4, and 9.7 ± 1.0 pA/pF, respectively (13-62 cells, 7-19 patients). None of these values were significantly different in cells from patients without post-CS AF (P > 0.05 for each, 60-279 cells, 29-86 patients), confirmed by multiple and logistic regression. In patients treated >7 days with a beta-blocker pre-CS, the incidence of post-CS AF was lower than in non-beta-blocked patients (13% vs 27%, P = 0.038). Pre-CS beta-blockade was associated with a prolonged pre-CS atrial cellular ERP (P = 0.001), by a similar degree (∼20%) in those with and without post-CS AF. Conclusion: Pre-CS human atrial cellular electrophysiology does not predict post-CS AF. Chronic beta-blocker therapy is associated with a reduced incidence of post-CS AF, unrelated to a pre-CS ERP-prolonging effect of this treatment

The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation

<b>Objective:</b> To investigate changes in human atrial single cell functional electrophysiological properties associated with chronic atrial fibrillation (AF), and the contribution to these of accompanying ion current changes. <b>Methods:</b> The whole cell patch clamp technique was used to record action potentials, the effective refractory period (ERP) and ion currents, in the absence and presence of drugs, in enzymatically isolated myocytes from 11 patients with chronic (<6 months) AF and 39 patients in sinus rhythm. <b>Results:</b> Stimulation at high rates (up to 600 beats/min) markedly shortened late repolarisation and the ERP in cells from patients in sinus rhythm, and depolarised the maximum diastolic potential (MDP). Chronic AF was associated with a reduction in the ERP at physiological rate (from 203±16 to 104±15 ms, P<0.05), and marked attenuation in rate effects on the ERP and repolarisation. The abbreviated terminal phase of repolarisation prevented fast rate-induced depolarisation of the MDP in cells from patients with AF. The density of L-type Ca<sup>2+</sup> (<i>I</i><sub>CaL</sub>) and transient outward K<sup>+</sup> (<i>I</i><sub>TO</sub>) currents was significantly reduced in cells from patients with AF (by 60–65%), whilst the inward rectifier K<sup>+</sup> current (IK1) was increased, and the sustained outward current (<i>I</i><sub>KSUS</sub>) was unaltered. Superfusion of cells from patients in sinus rhythm with nifedipine (10 micromol/l) moderately shortened repolarisation, but had no effect on the ERP (228±12 vs. 225±11 ms). 4-Aminopyridine (2 mmol/l) markedly prolonged repolarisation and the ERP (by 35%, P<0.05). However, the combination of these drugs had no effect on late repolarisation or refractoriness. <b>Conclusion:</b> Chronic AF in humans is associated with attenuation in adaptation of the atrial single cell ERP and MDP to fast rates, which may not be explained fully by accompanying changes in <i>I</i><sub>CaL</sub> and <i>I</i><sub>TO</sub>

Mapping the Substrate of Atrial Fibrillation: Tools and Techniques

Atrial fibrillation (AF) is the most common cardiac arrhythmia that affects an estimated 33.5 million people worldwide. Despite its prevalence and economic burden, treatments remain relatively ineffective. Interventional treatments using catheter ablation have shown more success in cure rates than pharmacologic methods for AF. However, success rates diminish drastically in patients with more advanced forms of the disease. The focus of this research is to develop a mapping strategy to improve the success of ablation. To achieve this goal, I used a computational model of excitation in order to simulate atrial fibrillation and evaluate mapping strategies that could guide ablation. I first propose a substrate guided mapping strategy to allow patient-specific treatment rather than a one size fits all approach. Ablation guided by this method reduced AF episode durations compared to baseline durations and an equal amount of random ablation in computational simulations. Because the accuracy of electrogram mapping is dependent upon catheter-tissue contact, I then provide a method to identify the distance between the electrode recording sites and the tissue surface using only the electrogram signal. The algorithm was validated both in silico and in vivo. Finally, I develop a classification algorithm for the identification of activation patterns using simultaneous, multi-site electrode recordings to aid in the development of an appropriate ablation strategy during AF. These findings provide a framework for future mapping and ablation studies in humans and assist in the development of individualized ablation strategies for patients with higher disease burden

Patterns of Left Atrial Activation and Evaluation of Atrial Asynchrony in Patients with Atrial Fibrillation and Normal Controls: Factors beyond Left Atrial Dimensions

I. Extensive experimental and clinical data suggest that certain electrical and structural changes develop in the atria of patients with atrial fibrillation (AF). These alterations are commonly referred as atrial remodeling and are considered to play a crucial role in the self-perpetuation of this arrhythmia. a. A hallmark of LA structural remodeling is the LA dilatation which is a predictor for progression to chronic AF and therapeutic failure as well. However, AF is associated not only with LA enlargement but also with asymmetrical changes in the left atrial geometry. b. Furthermore, the electrical remodeling is characterized by slower and asynchronous inter- and intra-atrial conduction that also contributes to the maintenance of AF. Some studies suggested a role of the conduction block in the Bachmann’s bundle, connecting the right and left atrium, in the AF pathophysiology and LA remodeling. II. Echocardiography and especially the tissue Doppler method can provide additional insight into the nature of the LA remodeling, because it allows the characterization of the intrinsic LA velocities. a. Using pulsed-wave tissue Doppler (PW-TDI) is possible to measure the interval from the onset of the surface P wave to the A´ velocity at the lateral mitral annulus as a representation of the total interatrial conduction time (TACT). In number of studies, it was demonstrated that prolonged TACT was associated with new-onset AF, AF after open heart surgery, and AF recurrences after electrical cardioversion and catheter ablation. b. An important limitation of the previous studies is that TACT has never been validated by direct measurements of the true electrical conduction in the LA. Moreover, it was assumed that the activation of the lateral MA must be the latest LA activation site. III. In this study, we sought to evaluate the feasibility of the PW-TDI as a simple and quick method to evaluate the LA asynchrony. For the purpose, we measured the time intervals from the onset of P-wave to the A´ (P-A´) in PW-TDI at 4 different left atrial sites next to mitral annulus (septal, lateral, anterior and inferior) in patients referred for electrophysiological study and catheter ablation because of atrial fibrillation or other arrhythmias. a. The differences between the longest and shortest P-A´ (DLS-PA´), as well as the standard deviation (SD-4PA´) of all 4 values were calculated as indexes for LA asynchrony. Importantly, LA asynchrony in patients with AF was compared with a matched control group of patients without history of AF. b. Moreover, the TACT was validated by comparing it with the actual electrical activation of the left atrium measured directly in the coronary sinus. For this purpose, the intervals between the onset of the P-wave and the local LA activation at the distal electrode pair of a catheter inserted in the coronary sinus were measured. c. Having in mind the ovoid LA shape and asymmetrical changes in LA geometry observed in patients with AF, we hypothesized that the lateral mitral annulus may not always be the latest activation spot. Therefore, we sought to determine the latest LA activation site exhibiting the longest P-A´ interval, as well as to describe the sequence of LA activation in AF patients and non-AF controls. IV. One hundred and thirty patients with AF (AF group) and 70 patients without a history of AF (non-AF control group) were examined prospectively using PW-TDI. a. Both groups were matched for the baseline characteristics, including LA diameter. The P-A´ interval measured with PW-TDI at the lateral LA showed a strong, positive, linear correlation with the P-A activation at the distal poles of the CS catheter at the lateral MA: Pearson r=0.708; P=0.0001. b. Asynchrony in the AF group was more pronounced in comparison to the non-AF control group. Patients in the AF group had longer DLS-PA´ as compared to controls: 37±16 msec. vs. 28±13 msec.; P=0.0001, as well as bigger SD-4PA´: 17±7 msec. vs. 13±5 msec.; P=0.0001. c. Furthermore, distinct patterns of LA activation were observed. Most AF patients (86.5%) showed an upward LA activation with inferior LA breakthrough, whereas the non-AF controls exhibited mostly a downward LA activation (65.5%), spreading from LA roof downwards. d. ROC analysis revealed that P-A´ at anterior LA successfully discriminated patients with AF from the non-AF controls (AUC 0.85, P 55 msec. discriminated between AF patients and controls with 85% sensitivity; 81% specificity; positive predictive value of 0.898, and negative predictive value of 0.707. V. In conclusion, PW-TDI can be reliably used to assess the LA asynchrony. Patients with atrial fibrillation showed greater LA asynchrony in PW-TDI independently from the LA dimensions. For the first time, we described that LA activation showed 3 distinct patterns with the upward LA activation being the most frequently observed in patients with AF. Patients with AF demonstrated a prolonged P-A´ activation time at the anterior left atrium. P-A´ at anterior LA > 55 msec. discriminates between patients with AF and non-AF controls with high sensitivity and specificity. This method can be useful to identity patients at risk for occurrence of new-onset atrial fibrillation, as well as to assess the severity of the LA remodeling in order to improve the selection of patients for catheter ablation.:Table of Contents 1 Background 5 1.1 Mechanisms of initiation and perpetuation of atrial fibrillation 5 1.2 Left atrial remodeling in atrial fibrillation 7 1.3 Echocardiographic assessment of left atrial remodeling 8 1.4 Pathophysiology of interatrial conduction in atrial fibrillation 10 2 Objectives and methods 11 2.1 Study objectives 11 2.2 Methods 11 2.2.1 Echocardiography 13 2.2.2 Electrophysiological study 15 2.2.3 Statistical methods 16 3 Publication 17 4 Discussion 26 5 Limitations 30 6 Conclusion 31 7 Synopsis 32 8 References 36 9 Selbstständigkeitserklärung 47 10 Curriculum vitae and list of publications 48 11 Danksagung /Acknowledgments 5

Modeling atrial arrhythmias : impact on clinical diagnosis and therapies

Atrial arrhythmias are the most frequent sustained rhythm disorders in humans and often lead to severe complications such as heart failure and stroke. Despite the important insights provided by animal models into the mechanisms of atrial arrhythmias, direct translation of experimental findings to new therapies in patients has not been straightforward. With the advances in computer technology, large-scale electroanatomical computer models of the atria that integrate information from the molecular to organ scale have reached a level of sophistication that they can be used to interpret the outcome of experimental and clinical studies and aid in the rational design of therapies. This paper reviews the state-of-the-art of computer models of the electrical dynamics of the atria and discusses the evolving role of simulation in assisting the clinical diagnosis and treatment of atrial arrhythmias

Management of patients with atrial fibrillation: different therapeutic options and role of electrophysiology-guided approaches.

At present the approach to atrial fibrillation treatment is based on the electrophysiological patterns of atrial fibrillation (on the basis of multiple intra-atrial recordings or sophisticated new mapping techniques) only in a restricted minority of patients, those who are candidate to ablation of the substrate and/or of the triggers. Atrial fibrillation has a broad spectrum of clinical presentations and a heterogeneous electrophysiological pattern. The treatment of this arrhythmia, both with drugs and non pharmacological treatments, has been based, classically, on empirical basis and on a clinically-guided staged-approach. The limitations of pharmacological treatment led in recent years to the development of a wide spectrum of non pharmacological treatments. This implies a change in the approach to atrial fibrillation and the need to identify potentially ideal candidates to complex and expensive treatments. In this view it is currently under investigation the possibility to identify potential responders to a definitive treatment or a combination of treatments (both pharmacological and non-pharmacological) on the basis of the electrophysiological pattern

Atrial remodeling in permanent atrial fibrillation : Mechanisms and pharmacological implications

Atrial fibrillation (AF), the most prevalent rhythm disorder in clinical practice, is currently significantly contributing to morbidity and mortality of the ageing population. In the past decades, a tremendous amount of research resulted in valuable insights into AF pathophysiology, with a primary focus on atrial remodeling. Defined as a persistent change in atrial function and structure, remodeling has the intrinsic properties to enhance the probability of focal (ectopic) and/or re-entrant pursuits, thus supporting AF persistence. The hallmark of structural remodeling is represented by atrial fibrosis, a multifactorial process involving an interaction between neurohormonal and cellular mediators. This paper provides a brief summary of the recent knowledge with respect to electrical and structural remodeling and novel insights into the pathogenesis of atrial fibrosis. Since current drug options for AF treatment are far from being optimal we also discuss the therapeutic principles and current alternatives for counteracting atrial fibrosis, and thus preventing arrhythmia recurrence