The role of atrial dilatation in the domestication of atrial fibrillation

Numerous clinical investigations as well as recent experimental studies have demonstrated that atrial fibrillation (AF) is a progressive arrhythmia. With time paroxysmal AF becomes persistent and the success rate of cardioversion of persistent AF declines. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to the increase in stability of the arrhythmia. However, ‘domestication of AF’ must also depend on other mechanisms since the persistence of AF continues to increase after electrical remodeling has been completed. During the first days of AF in the goat, electrical and contractile remodeling (loss of atrial contractility) followed exactly the same time course suggesting that they are due to the same underlying mechanism. Contractile remodeling not only enhances the risk of atrial thrombus formation, it also enhances atrial dilatation by increasing the compliance of the fibrillating atrium. In goats with chronic AV-block atrial dilatation increased the duration of artificially induced AF-episodes but did not change atrial refractoriness or the AF cycle length. When AF was maintained a couple of days in these animals, a shortening of the atrial refractory period did occur. However, the AF cycle length did not decrease. Long lasting episodes of AF with a long AF cycle length and a wide excitable gap suggest that in this model AF is mainly promoted by conduction disturbances. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electroanatomical substrate in dilated atria is characterized by increased non-uniform anisotropy and macroscopic slowing of conduction, promoting reentrant circuits in the atria. Prevention of electroanatomical remodeling by blockade of pathways activated by chronic atrial stretch therefore provides a promising strategy for future treatment of AF.     

Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation

Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR) also increases AF inducibility, but it is not clear whether the underlying mechanism is similar. Therefore, we have investigated atrial electrophysiology in a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical mapping and compared it with control dogs and with the canine RAP model (6-8 wk of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing at 100 beats/min). At followup, optical action potentials were recorded using a 16 x 16 photodiode array from 2 x 2-cm left atrial (LA) and right atrial (RA) areas in perfused preparations, with pacing electrodes around the field of view to study direction dependency of conduction. Action potential duration at 80% repolarization (APD(80)) was not different between control and MR but was reduced in RAP atria. Conduction velocities during normal pacing were not different between groups. However, the MR LA showed increased conduction heterogeneity during pacing at short cycle lengths and during premature extrastimuli, which frequently caused pronounced regional conduction slowing. Conduction in the MR LA during extrastimulation also displayed a marked dependence on propagation direction. These phenomena were not observed in the MR RA and in control and RAP atria. Thus both models form distinctly different AF substrates; in RAP dogs, the decrease in APD(80) may stabilize reentry. In MR dogs, regional LA conduction slowing and increased directional dependency, allowing unidirectional conduction block and preferential paths of conduction, may account for increased AF inducibility.     

Left atrial dilatation resulting from chronic mitral regurgitation decreases spatiotemporal organization of atrial fibrillation in left atrium

Atrial conduction properties have been shown to differ among animal atrial fibrillation (AF) models of rapid atrial pacing (RAP), chronic mitral regurgitation (MR), and control. We hypothesized that these conduction differences would continue with the onset of AF, which would affect AF spatiotemporal organization, resulting in model-specific characteristics of AF. With frequency domain analysis of electrograms acquired from high-density optical mapping, AF from the right (RA) and left (LA) atrium in animals with RAP and MR were compared with control animals. At follow-up, the hearts were excised and perfused, and optical action potentials were recorded from a 2 x 2-cm area each of the RA and LA free wall with a 16 x 16 photodiode array. AF was induced with extra stimuli, several 2.4-s AF episodes were recorded in each dog, and a fast Fourier transform was calculated. The dominant frequency (DF) was determined, and the organization (organization index, OI) was calculated as the ratio of the area under the dominant peak and its harmonics to the total area of the spectrum. All possible pairs of electrograms for each episode were cross-correlated. LA AF in the chronic MR model showed an increase in the highest DF, the number of DF domains, and in frequency gradient compared with AF in control or RAP models. In addition, there was a decrease in OI and in the correlation coefficients in the LA of the MR model. These results suggest that the AF substrate in the MR model may be different from that of control or RAP models.     

Energetic metabolism during acute stretch-related atrial fibrillation

Background and methods Perturbations in energetic metabolism and impaired atrial contractility may play an important role in the pathogenesis of atrial fibrillation (AF). Besides, atrial stretch is commonly associated with AF. However, the atrial energetics of stretch-related AF are poorly understood. Here, we measured indicators of energy metabolism during acute stretch-related AF. PCr, adenine nucleotides, and derivatives concentrations as well as the activity of the F₀F₁-ATPase and Na,K-ATPase were obtained after 1 h of stretch and/or AF in isolated rabbit hearts and compared to control hearts without stretch and AF. Results After 1 h of stretch-related AF, the total adenine nucleotides’ pool was significantly lower (42.2 ± 2.6 vs. 63.7 ± 8.3 μmol/g protein in control group, P < 0.05) and the PCr/ATP ratio significantly higher (2.3 ± 0.3 vs. 1.1 ± 0.1 in control group P < 0.05), because of ATP, ADP, and AMP decrease and PCr increase. The sum of high-energy phosphate compounds did not change. There were no significant differences in F₀F₁-ATPase nor Na,K-ATPase activity between the groups. Conclusions Results show that in this experimental model, acute stretch-related AF induces specific modifications of atrial myocytes energetics that may play a pivotal role in the perpetuation of the arrhythmia.     

Non-linear coupling of atrial activation processes during atrial fibrillation in humans

The activation patterns underlying the electrical activity of the heart during atrial fibrillation (AF) are not entirely random. The aim of this study was to assess the local organization of the activation processes during AF by estimating the non-linear coupling between activation sequences (ASs) in two atrial sites. To quantitatively estimate the degree of non-linear coupling we extracted two indices based on a multivariate embedding procedure and on the estimation of the correlation dimension (CD) and correlation entropy (CE), termed independence of complexity and of independence of predictability, respectively. We analysed AS in two atrial sites in 30 informed subjects during chronic AF of type I, II and III (Wells' classification), ten 6-s-long episodes of each type. Surrogates were used to reject the hypothesis that the time series were generated by linear stochastic dynamics. We estimated CD and CE according to the coarse-grained approach, which leads to a fixed high value for the embedding dimension in all the analysed ASs, and a typical value for the distance between the two ASs in the phase space. Various degrees of organization, ranging from completely synchronized to fully de-coupled signals, were observed: significant degrees of non-linear coupling were found in segments belonging in types I and II AF, whereas type III electrograms always turned out to be weakly coupled. This finding links the morphology of single electrograms to the synchronization between pairs of closely spaced electrograms. Our bivariate approach suggests that the measurement of organization during AF should be based on the estimation of the non-linear coupling between two sites. This approach appears to be more reliable and sensitive than non-linear analysis of single electrograms or linear analysis of their coupling.     

Rates of hemorrhage during warfarin therapy for atrial fibrillation

Background:

Although warfarin has been extensively studied in clinical trials, little is known about rates of hemorrhage attributable to its use in routine clinical practice. Our objective was to examine incident hemorrhagic events in a large population-based cohort of patients with atrial fibrillation who were starting treatment with warfarin.

Methods:

We conducted a population-based cohort study involving residents of Ontario (age ≥ 66 yr) with atrial fibrillation who started taking warfarin between Apr. 1, 1997, and Mar. 31, 2008. We defined a major hemorrhage as any visit to hospital for hemorrage. We determined crude rates of hemorrhage during warfarin treatment, overall and stratified by CHADS₂ score (congestive heart failure, hypertension, age ≥ 75 yr, diabetes mellitus and prior stroke, transient ischemic attack or thromboembolism).

Results:

We included 125 195 patients with atrial fibrillation who started treatment with warfarin during the study period. Overall, the rate of hemorrhage was 3.8% (95% confidence interval [CI] 3.8%–3.9%) per person-year. The risk of major hemorrhage was highest during the first 30 days of treatment. During this period, rates of hemorrhage were 11.8% (95% CI 11.1%–12.5%) per person-year in all patients and 16.7% (95% CI 14.3%–19.4%) per person-year among patients with a CHADS₂ scores of 4 or greater. Over the 5-year follow-up, 10 840 patients (8.7%) visited the hospital for hemorrhage; of these patients, 1963 (18.1%) died in hospital or within 7 days of being discharged.

Interpretation:

In this large cohort of older patients with atrial fibrillation, we found that rates of hemorrhage are highest within the first 30 days of warfarin therapy. These rates are considerably higher than the rates of 1%–3% reported in randomized controlled trials of warfarin therapy. Our study provides timely estimates of warfarin-related adverse events that may be useful to clinicians, patients and policy-makers as new options for treatment become available.Atrial fibrillation is a major risk factor for stroke and systemic embolism, and strong evidence supports the use of the anticoagulant warfarin to reduce this risk.^1–3 However, warfarin has a narrow therapeutic range and requires regular monitoring of the international normalized ratio to optimize its effectiveness and minimize the risk of hemorrhage.^4,5 Although rates of major hemorrhage reported in trials of warfarin therapy typically range between 1% and 3% per person-year,^6–11 observational studies suggest that rates may be considerably higher when warfarin is prescribed outside of a clinical trial setting,^12–15 approaching 7% per person-year in some studies.^13–15 The different safety profiles derived from clinical trials and observational data may reflect the careful selection of patients, precise definitions of bleeding and close monitoring in the trial setting. Furthermore, although a few observational studies suggest that hemorrhage rates are higher than generally appreciated, these studies involve small numbers of patients who received care in specialized settings.^14–16 Consequently, the generalizability of their results to general practice may be limited.More information regarding hemorrhage rates during warfarin therapy is particularly important in light of the recent introduction of new oral anticoagulant agents such as dabigatran, rivaroxaban and apixaban, which may be associated with different outcome profiles.^17–19 There are currently no large studies offering real-world, population-based estimates of hemorrhage rates among patients taking warfarin, which are needed for future comparisons with new anticoagulant agents once they are widely used in routine clinical practice.²⁰We sought to describe the risk of incident hemorrhage in a large population-based cohort of patients with atrial fibrillation who had recently started warfarin therapy.     

Expression of AMIDASE1 (AMI1) is suppressed during the first two days after germination

The regulation of cellular auxin levels is a critical factor in determining plant growth and architecture, as indole-3-acetic acid (IAA) gradients along the plant axis and local IAA maxima are known to initiate numerous plant growth responses. The regulation of auxin homeostasis is mediated in part by transport, conjugation and deconjugation, as well as by de novo biosynthesis. However, the pathways of IAA biosynthesis are yet not entirely characterized at the molecular and biochemical level. It is suggested that several biosynthetic routes for the formation of IAA have evolved. One such pathway proceeds via the intermediate indole-3-acetamide (IAM), which is converted into IAA by the activity of specific IAM hydrolases, such as Arabidopsis AMIDASE1 (AMI1). In this article we present evidence to support the argument that AMI1-dependent IAA synthesis is likely not to be used during the first two days of seedling development.Key words: Arabidopsis thaliana, auxin biosynthesis, AMIDASE1, indole-3-acetic acid, indole-3-acetamide, LEAFY COTYLEDON1, seed developmentAuxins are versatile plant hormones that play diverse roles in regulating many aspects of plant growth and development.¹ To enable auxins to develop their activity, a tight spatiotemporal control of cellular indole-3-acetic acid (IAA) contents is absolutely necessary since it is well-documented that auxin action is dose dependent, and that high IAA levels can have inhibitory effects on plant growth.² To achieve this goal, plants have evolved a set of different mechanisms to control cellular hormone levels. On the one hand, plants possess several pathways that contribute to the de novo synthesis of IAA. This multiplicity of biosynthetic routes presumably facilitates fine-tuning of the IAA production. On the other hand, plants are equipped with a variety of enzymes that are used to conjugate free auxin to either sugars, amino acids or peptides and small proteins, respectively, or on the contrary, that act as IAA-conjugate hydrolases, releasing free IAA from corresponding conjugates. IAA-conjugates serve as a physiologically inactive storage form of IAA from which the active hormone can be quickly released on demand. Alternatively, conjugation of IAA can mark the first step of IAA catabolism. In general, conjugation and deconjugation of free IAA are ways to positively or negatively affect active hormone levels, which adds another level of complexity to the system. Additionally, IAA can be transported from cell to cell in a polar manner, which is dependent on the action of several transport proteins. All together, these means are used to form auxin gradients and local maxima that are essential to initiate plant growth processes, such as root or leaf primordia formation.³     

ABC of atrial fibrillation. Antithrombotic treatment for atrial fibrillation.

Antithrombotic prophylaxis with long term warfarin or aspirin reduces thromboembolic risk in atrial fibrillation. Identification, risk assessment, and regular review of all patients with atrial fibrillation should be routine in general and hospital practice. Risk stratification is easily performed on clinical grounds--echocardiography may refine it.     

Spatial correlation analysis of atrial activation patterns during sustained atrial fibrillation in conscious goats

In this study we applied both linear and nonlinear spatial correlation measures to characterize epicardial activation patterns of sustained atrial fibrillation in instrumented conscious goats. It was investigated if nonlinearity was involved in the spatial coupling of atrial regions and to what extent fibrillation was organized in the experimental model of sustained atrial fibrillation (AF) in instrumented goats. Data were collected in five goats during experiments to convert AF by continuous infusion of cibenzoline. Spatial organization during AF was quantified with the linear spatial cross correlation function and the nonlinear spatial cross redundancy which was calculated using the Grassberger-Procaccia correlation integral. Two different types of correlation were evaluated to distinguish simultaneous interaction from non-simultaneous interaction, for instance resulting from propagation of fibrillation waves. The nonlinear association length and the linear correlation length were estimated along the principal axes of iso-correlation contours in two-dimensional correlation maps of the nonlinear spatial redundancy and the linear spatial correlation function, respectively. To quantitatively assess the degree of nonlinearity, the association length was also estimated from the linearized spatial redundancy using multivariate surrogate data. The differences between the nonlinear and linearized association lengths indicated that a nonlinear component in the spatial organization of AF predominantly existed in the right atrium. The degree of organization characterized by association length along the short principal axis was higher in the right atrium (15 +/- 7 mm) than in the left atrium (8 +/- 4 mm). The spatial extension of coherent atrial patches was estimated from a surface of association equal to the area spanned by the principal axes of iso-correlation contours from the redundancy, including the effects from non-simultaneous interaction. Interpreting this area as the spatial domain of a fibrillation wavelet, the results suggest that the mapped region was activated on average by two wavelets in the left atrium and by one wavelet in the right atrium. Therefore, the activation pattern of sustained AF in goats was relatively organized, consistent with type II of AF. It is suggested that the surface of association is a measure of the number of independent wavelets present in the atria during sustained AF, and that larger association lengths result from fewer and larger reentrant circuits.     

Effect of atrial dilatation on the tendency of atrial arrhythmias

The arrhythmogenic effect of atrial dilatation was studied by electrophysiological investigations carried out on 24 dogs. Atrial distension was evoked by increasing the pressure in the right atrium (12 to 14 mm Hg) or by the balloon dilatation of the left atrium. Programmed electrical stimulation of the heart was used for the electrophysiological investigations. In addition to the superficial ECG leads also atrial and ventricular epicardial electrograms were obtained for the ECG recording. Acute atrial dilatation led to shortening of the atrial refractory period, whereas neither impulse conduction of the heart, nor pacemaker activity of the sinus node exhibited any alteration. Atrial dilatation resulted in pathological atrial irritability, and early or frequent atrial stimulation caused atrial tachycardia of shorter (non sustained) or longer (sustained) duration. Repetitive atrial extrasystoles in response to early stimuli could also frequently be observed during atrial dilatation. The obtained results indicate that atrial dilatation is arrhythmogenic and may lead to the development of atrial tachycardia.