Regional left atrial voltage in patients with atrial fibrillation

BACKGROUND: Regional differences in fibrosis, particularly related to the posterior wall and septum, may be important in atrial fibrillation (AF). Using electroanatomic mapping, voltage can be used as a measure of fibrosis. OBJECTIVES: The purpose of this study was to determine if patients with AF have disproportionately lower voltage in the septal and posterior walls of the left atrium. METHODS: Sinus rhythm left atrial electroanatomic maps were used in serial patients presenting for left atrial ablation of AF (8-mm tip). Patients undergoing left atrial mapping for focal atrial tachycardia (AT) were used as a comparison group (4-mm tip). Animal experiments were performed to assess the influence of ablation catheter tip size on voltage amplitude. RESULTS: The posterior and septal walls exhibited the lowest voltages in both groups. Compared with the anterior wall, there was a 3.78-fold greater odds of finding a low-voltage point (<0.5 mV) in the septum (P <.001) and a 3.37-fold greater odds of finding a low-voltage point in the posterior wall (P <.001) in the AF patients; the proportion of low-voltage points by region were not significantly different in the AT group. In the animal model, the mean voltage obtained from an 8-mm ablation catheter was significantly higher (0.30 +/- 0.17 mV) than that obtained from the same points using a 4-mm catheter (0.22 +/- 0.17, P = .05). CONCLUSION: Regional differences in voltage are present in patients with atrial arrhythmias, with AF patients exhibiting significantly more low-voltage areas in the septum and posterior walls.     

Alcohol and vagal tone as triggers for paroxysmal atrial fibrillation

Alcohol and vagal activity may be important triggers for paroxysmal atrial fibrillation (PAF), but it remains unknown if these associations occur more often than would be expected by chance alone because of the lack of a comparator group in previous studies. We compared self-reported frequency of these triggers in patients with PAF to those with other supraventricular tachycardias (SVTs). Consecutive consenting patients presenting for electrophysiology procedures at a single university medical center underwent a structured interview regarding arrhythmia triggers. Two hundred twenty-three patients with a documented arrhythmia (133 with PAF and 90 with SVT) completed the survey. After multivariable adjustment, patients with PAF had a 4.42 greater odds (95% confidence interval [CI] 1.35 to 14.44) of reporting alcohol consumption (p = 0.014) and a 2.02 greater odds (95% CI 1.02 to 4.00) of reporting vagal activity (p = 0.044) as an arrhythmia trigger compared to patients with SVT. In patients with PAF, drinking primarily beer was associated with alcohol as a trigger (odds ratio [OR] 4.49, 95% CI 1.41 to 14.28, p = 0.011), whereas younger age (OR 0.68, 95% CI 0.49 to 0.95, p = 0.022) and a family history of AF (OR 5.73, 95% CI 1.21 to 27.23, p = 0.028) each were independently associated with having vagal activity provoke an episode. Patients with PAF and alcohol triggers were more likely to have vagal triggers (OR 10.32, 95% CI 1.05 to 101.42, p = 0.045). In conclusion, alcohol consumption and vagal activity elicit PAF significantly more often than SVT. Alcohol and vagal triggers often were found in the same patients with PAF, raising the possibility that alcohol may precipitate AF by vagal mechanisms.     

The perplexing complexity of cardiac arrhythmias: Beyond electrical remodeling

Cardiac arrhythmias continue to pose a major medical challenge and significant public health burden. Atrial fibrillation, the most prevalent arrhythmia, affects more than two million Americans annually and is associated with a twofold increase in mortality. In addition, more than 250,000 Americans each year suffer ventricular arrhythmias, often resulting in sudden cardiac death. Despite the high incidence and societal impact of cardiac arrhythmias, presently there are insufficient insights into the molecular mechanisms involved in arrhythmia generation, propagation, and/or maintenance or into the molecular determinants of disease risk, prognosis, and progression. In addition, present therapeutic strategies for arrhythmia abatement often are ineffective or require palliative device therapy after persistent changes in the electrical and conduction characteristics of the heart have occurred, changes that appear to increase the risk for arrhythmia progression. This article reviews our present understanding of the complexity of mechanisms that regulate cardiac membrane excitability and cardiac function and explores the role of derangements in these mechanisms that interact to induce arrhythmogenic substrates. Approaches are recommended for future investigations focused on providing new mechanistic insights and therapeutic interventions.     

Postextrasystolic U Wave Augmentation, a New Marker of Increased Arrhythmic Risk in Patients Without the Long QT Syndrome

Objectives. We attempted to determine the correlation between the presence of postextrasystolic changes in the STU segment and a history of sustained ventricular arrhythmias.

Background. Postextrasystolic U wave augmentation (a marked increment in U wave amplitude after premature ventricular complexes [PVCs]) is an adverse prognostic sign in the “pause-dependent long QT syndrome.” However, the prevalence of postextrasystolic changes in patients without the long QT syndrome is unknown.

Methods. We compared the configuration of the STU segment of the postextrasystolic beat (the sinus beat after a PVC) with the STU configuration during sinus rhythm in three patient groups: 1) 41 patients with spontaneous ventricular tachycardia/fibrillation (VT/VF) (VT/VF group), 2) 63 patients with heart disease and high grade ventricular arrhythmias (control group), and 3) 29 patients with high grade ventricular arrhythmias but no heart disease (reference group).

Results. Postextrasystolic T wave changes did not correlate with a history of ventricular tachyarrhythmias. However, postextrasystolic U wave changes were more common among the patients with VT/VF than among control subjects (39% vs. 8.7%, p < 0.001). By logistic multiple regression analysis, a low left ventricular ejection fraction (p < 0.001) and postextrasystolic U wave changes (p < 0.005) were independent predictors of ventricular tachyarrhythmias.

Conclusions. Postextrasystolic T wave changes are common and lack predictive value. Postextrasystolic U wave changes may be a specific marker of a tendency to the development of spontaneous ventricular arrhythmias. Prospective studies should be performed to confirm this association.

(J Am Coll Cardiol 1996;28:1746–52)>     

Cardiac conduction is required to preserve cardiac chamber morphology

Electrical cardiac forces have been previously hypothesized to play a significant role in cardiac morphogenesis and remodeling. In response to electrical forces, cultured cardiomyocytes rearrange their cytoskeletal structure and modify their gene expression profile. To translate such in vitro data to the intact heart, we used a collection of zebrafish cardiac mutants and transgenics to investigate whether cardiac conduction could influence in vivo cardiac morphogenesis independent of contractile forces. We show that the cardiac mutant dco^s226 develops heart failure and interrupted cardiac morphogenesis following uncoordinated ventricular contraction. Using in vivo optical mapping/calcium imaging, we determined that the dco cardiac phenotype was primarily due to aberrant ventricular conduction. Because cardiac contraction and intracardiac hemodynamic forces can also influence cardiac development, we further analyzed the dco phenotype in noncontractile hearts and observed that disorganized ventricular conduction could affect cardiomyocyte morphology and subsequent heart morphogenesis in the absence of contraction or flow. By positional cloning, we found that dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart formation or function. Detailed analysis of the mouse Cx46 mutant revealed the presence of cardiac conduction defects frequently associated with human heart failure. Overall, these in vivo studies indicate that cardiac electrical forces are required to preserve cardiac chamber morphology and may act as a key epigenetic factor in cardiac remodeling.     

Atrial Fibrillation: What are the Targets for Intervention?

Atrial fibrillation (AF) is a difficult and growing problem in the population. While medical therapy controls symptoms in many patients, a proportion of individuals with this common arrhythmia cannot be optimally managed with drugs alone. However, truly curative therapy for AF has always been one of the holy grails of electrophysiology. The surgical maze procedure was the first to offer permanent maintenance of sinus rhythm in patients with AF but subjected the patient to open heart surgery; a catheter-based translation of the maze procedure served as proof of concept that a catheterization technique could be used to treat AF. Subsequent experience has narrowed the electrophysiologist's attention to ablation of triggers of AF, most often residing in the pulmonary veins, rather than requiring more extensive ablation lines to control the arrhythmia. The following discussion deals with the development and current status of techniques for catheter ablation of atrial fibrillation, focusing on determination of appropriate target sites for ablation.     

A unique method by which to quantitate synchrony with equilibrium radionuclide angiography

Background

Cardiac resynchronization therapy (CRT) improves symptoms and the survival rate in patients with advanced heart failure by improving synchrony. However, CRT is not always successful, is costly, and is applied without individualization. There is no specific measure of synchrony. The goal of this study was to analyze new quantitative parameters of synchrony and compare them with established measures.

Methods and Results

Equilibrium radionuclide angiography, phase angle (Ø), and amplitude quantitate regional contraction timing and magnitude and are the basis for new synchrony (S) and entropy (E) parameters. S is the vector sum of all amplitudes based on the angular distribution of Ø divided by the scalar sum of the length of all vectors. Complete S equals 1, and its absence equals 0. E measures the disorder in the region of interest, is 1 with random contraction and 0 with full synchrony, and differentiates among differing contraction patterns. Left ventricular S and E were measured in 22 normal equilibrium radionuclide angiography studies, where regions of interest were drawn from the left ventricle, left atrium, and background to analyze model ventricles with normal wall motion (N), ventricles with aneurysm (An), ventricles with severe diffuse dysfunction (Diff), and ventricles with severe regional dysfunction (Reg). The new S and E parameters were highly reproducible and well differentiated among N, An, Diff, and Reg, which were not separated by SD Ø (SD of ventricular phase), which has gained popularity as a measure of synchrony.

Conclusion

Unique scintigraphic parameters for the evaluation of ventricular synchrony were derived, and their added value was determine compared with established measures.Indications for pacemaker therapy now include the treatment of severe congestive heart failure (CHF). Atrial triggered biventricular pacemakers reduce CHF symptoms¹ and prolong life² in patients with cardiomyopathy, severe CHF, left ventricular (LV) ejection fraction (EF) lower than 35%, and QRS greater than 120 milliseconds. Such pacing, or cardiac resynchronization therapy (CRT), seeks to reduce the heterogeneity and increase the synchrony of ventricular activation, conduction, and contraction. CRT has improved hemodynamics, increased exercise tolerance, reduced symptoms and the need for hospitalization,^1,32 reversed ventricular remodeling, and^4,5 reduced the all-cause mortality rate² in CHF. However, CRT is costly, fails to improve symptoms or activity level in more than 30% of patients,^2,3,6 and is applied blindly without individualization or consideration of lead placement sight.⁷A variety of echocardiographic methods have sought to measure synchrony and its serial changes with CRT.^4,8-16 A recent study presented evidence of the poor reproducibility of several widely applied echocardiographic measurements by which to determine ventricular synchrony.¹⁷ Magnetic resonance imaging has excellent resolution of regional wall motion and has been applied to assess ventricular synchrony and its response to pacing therapy.¹⁸ However, these methods are complex and are not well established or widely available, and magnetic resonance imaging has not been widely applied after pacing. An accurate and reproducible method is needed by which to objectively measure regional ventricular synchrony.¹⁹Phase image analysis, a functional method based on the first Fourier harmonic fit of the gated blood pool time versus radioactivity curve, generates the parameters of amplitude (A), which parallels the extent of regional ventricular contraction or stroke volume, and phase angle (Ø), which represents the timing of regional contraction. It was applied early with demonstrated reproducibility²⁰ to show the linkage between electrical and mechanical dyssynchrony21 and to characterize the contraction pattern in heart failure and its alteration with CRT.^22,23 The SD of ventricular Ø, applied as a marker of synchrony, has been shown to demonstrate the beneficial effects of biventricular pacing,²⁴ and its strong prognostic value has been shown in patients with congestive cardiomyopathy and CHF, superior to LVEF.²⁵ The SD Ø may not be optimal for synchrony evaluation.We sought improved, more sensitive parameters to better differentiate synchrony among the spectrum of possible patterns of dyssynergy. We derived, initially evaluated, and here present new synchrony (S) and entropy (E) parameters, based on the phase method, to quantitate regional and global ventricular synchrony and applied them in simulation and clinical protocols.

     

Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.