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J Jalife

Publications and source records attributed to J Jalife.

At least 37 records · Page 2Linked to original sources
PubMed2000

Distribution of excitation frequencies on the epicardial and endocardial surfaces of fibrillating ventricular wall of the sheep heart.

Tissue heterogeneities may play an important role in the mechanism of ventricular tachycardia (VT) and fibrillation (VF) and can lead to a complex spatial distribution of excitation frequencies. Here we used optical mapping and Fourier analysis to determine the distribution of excitation frequencies in >20 000 sites of fibrillating ventricular tissue. Our objective was to use such a distribution as a tool to quantify the degree of organization during VF. Fourteen episodes of VT/VF were induced via rapid pacing in 9 isolated, coronary perfused, and superfused sheep ventricular slabs (3x3 cm(2)). A dual-camera video-imaging system was used for simultaneous optical recordings from the entire epi- and endocardial surfaces. The local frequencies of excitation were determined at each pixel and displayed as dominant frequency (DF) maps. A typical DF map consisted of several (8.2+/-3.6) discrete areas (domains) with a uniform DF within each domain. The DFs in adjacent domains were often in 1:2, 3:4, or 4:5 ratios, which was shown to be a result of an intermittent Wenckebach-like conduction block at the domain boundaries. The domain patterns were relatively stable and could persist from several seconds to several minutes. The complexity in the organization of the domains, the number of domains, and the dispersion of frequencies increased with the rate of the arrhythmia. Domain patterns on the epicardial and endocardial surfaces were not correlated. Sustained epicardial or endocardial reentry was observed in only 3 episodes. Observed frequency patterns during VT/VF suggest that the underlying mechanism may be a sustained intramural reentrant source interacting with tissue heterogeneities.

Animals↗
PubMed2000

Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart.

BACKGROUND: Atrial fibrillation (AF) has traditionally been described as aperiodic or random. Yet, ongoing sources of high-frequency periodic activity have recently been suggested to underlie AF in the sheep heart. Our objective was to use a combination of optical and bipolar electrode recordings to identify sites of periodic activity during AF and elucidate their mechanism. METHODS AND RESULTS: AF was induced by rapid pacing in the presence of 0.1 to 0.5 micromol/L acetylcholine in 7 Langendorff-perfused sheep hearts. We used simultaneous optical mapping of the right and left atria (RA and LA) and frequency sampling of optical and bipolar electrode recordings (including a roving electrode) to identify sites having the highest dominant frequency (DF). Rotors were identified from optical recordings, and their rotation period, core area, and perimeter were measured. In all, 35 AF episodes were analyzed. Mean LA and RA DFs were 14.7+/-3.8 and 10.3+/-2.1 Hz, respectively. Spatiotemporal periodicity was seen in the LA during all episodes. In 5 of 7 experiments, a single site having periodic activity at the highest DF was localized. The highest DF was most often (80%) localized to the posterior LA, near or at the pulmonary vein ostium. Rotors (n=14) were localized on the LA. The mean core perimeter and area were 10.4+/-2.8 mm and 3.8+/-2.8 mm(2), respectively. CONCLUSIONS: Frequency sampling allows rapid identification of discrete sites of high-frequency periodic activity during AF. Stable microreentrant sources are the most likely underlying mechanism of AF in this model.

Animals↗
PubMed2000

Dynamics of wavelets and their role in atrial fibrillation in the isolated sheep heart.

BACKGROUND: The multiple wavelet hypothesis is the most commonly accepted mechanism underlying atrial fibrillation (AF). However, high frequency periodic activity has recently been suggested to underlie atrial fibrillation in the isolated sheep heart. We hypothesized that in this model, multiple wavelets during AF are generated by fibrillatory conduction away from periodic sources and by themselves may not be essential for AF maintenance. METHODS AND RESULTS: We have used a new method of phase mapping that enables identification of phase singularities (PSs), which flank individual wavelets during sustained AF. The approach enabled characterization of the initiation, termination, and lifespan of wavelets formed as a result of wavebreaks, which are created by the interaction of wave fronts with functional and anatomical obstacles in their path. AF was induced in six Langendorff-perfused sheep hearts in the presence of acetylcholine. High resolution video imaging was utilized in the presence of a voltage sensitive dye; two-dimensional phase maps were constructed from optical recordings. The major results were as follows: (1) the critical inter-PS/wavelet distance for the formation of rotors was 4 mm, (2) the spatial distribution of wavelets/PSs was non-random. (3) the lifespan of PSs/wavelets was short; 98% of PSs/wavelets existed for < 1 rotation, and (4) the mean number of waves that entered our mapping field (15.7 +/- 1.6) exceeded the mean number of waves that exited it (9.7 +/- 1.5; P < 0.001). CONCLUSIONS: Our results strongly suggest that multiple wavelets may result from breakup of high frequency organized waves in the isolated Langendorff-perfused sheep heart, and as such are not a robust mechanism for the maintenance of AF in our model.

Acetylcholine↗
PubMed2000

Temporal organization of atrial activity and irregular ventricular rhythm during spontaneous atrial fibrillation: an in vivo study in the horse.

INTRODUCTION: Atrial fibrillation (AF) is common in healthy horses. We studied the temporal organization of AF to test the hypothesis that the arrhythmia is governed by a high degree of periodicity and therefore is not random in the horse. Further, we surmised that concealed conduction of AF impulses in the AV node results in an inverse relationship between AF frequency and ventricular frequency. METHODS AND RESULTS: Fast Fourier transform (FFT) analysis of atrial activity was done on signal-averaged ECGs (n = 11) and atrial electrograms (n = 3) of horses with AF at control (C), after quinidine sulfate (22 mg/kg by mouth every 2 hours) at 50% time to conversion (T50), and immediately before conversion (T90) to sinus rhythm. FFT always revealed a single dominant frequency peak. The mean dominant frequency decreased until conversion (C = 6.84 +/- 0.85 Hz, T50 = 4.87 +/- 1.5 Hz, T90 = 3.41 +/- 1.18 Hz; P < 0.001). Mean AA intervals (n = 500) gradually increased after quinidine. Mean RR intervals (n = 500), standard deviation of the mean (SDM), Poincaré plots, and serial autocorrelograms (SACs) of 500 RR intervals were measured at C and T90 to determine the ventricular response to AF and quinidine-induced changes in the variability of the ventricular response. Mean RR interval and SDM were reduced after quinidine (C = 1431 +/- 266 msec and 695 +/- 23 msec; T90 = 974 +/- 116 msec and 273 +/- 158 msec, respectively; P < 0.01). Poincaré plots and SAC at C and at T90 revealed a significant correlation of consecutive RR intervals typical of a system with a deterministic behavior. At T90, the variability of RR intervals was reduced and the overall periodicity of RR intervals was increased after quinidine administration. CONCLUSION: In the horse, AF is a complex arrhythmia characterized by a high degree of underlying periodicity. The inverse AA-to-RR interval relationship and reduced variability of RR intervals after quinidine suggest that the ventricular response during AF results from rate-dependent concealment of AF wavelets bombarding the AV node, which nevertheless results in a significant degree of short-term predictability of beat-to-beat changes in RR intervals.

Animals↗
PubMed2000

Spatially distributed dominant excitation frequencies reveal hidden organization in atrial fibrillation in the Langendorff-perfused sheep heart.

INTRODUCTION: Atrial fibrillation (AF) is characterized by complex wave propagation, yet periodic excitation suggesting a high degree of organization may be revealed during sustained AF. We provide a systematic quantification of the spatial distribution of dominant frequencies (DFs) of local excitation on the epicardium of the right atrial (RA) free wall and left atrial (LA) appendage of the isolated sheep heart during AF. The data reveal, for the first time, hidden organization, independent of the activation sequences or nature of electrograms. METHODS AND RESULTS: In 13 Langendorff-perfused sheep hearts, AF was induced in presence of 0.1 to 0.6 microM acetylcholine. Video movies (potentiometric dye di-4-ANEPPS) of the RA and LA (>30,000 and >20,000 pixels, respectively) were obtained at 120 frames/sec and a biatrial electrogram was recorded. Spectral analyses were performed on movies with DF maps constructed. During AF, the activity formed stable discrete domains with uniform DFs within each domain. Acceleration of AF increased the number of domains (R = 0.81, P < 0.0001) and the DF variance (R = 0.63, P < 0.001), indicating a decrease in organization. Also, the LA was faster and more homogeneous, with smaller number of DF domains, compared to the RA (P < 0.00001). CONCLUSION: In this model, AF is characterized by multiple domains with distinct DFs on the atrial epicardium. The decrease in domain area with increased rate suggests that AF results from high-frequency impulses that undergo spectral transformations. The LA is generally faster and more organized than the RA, suggesting that the sources for the impulses are localized to the LA.

Animals↗
PubMed2000

Ventricular fibrillation: mechanisms of initiation and maintenance.

Ventricular fibrillation (VF) is the major immediate cause of sudden cardiac death. Traditionally, VF has been defined as turbulent cardiac electrical activity, which implies a large amount of irregularity in the electrical waves that underlie ventricular excitation. During VF, the heart rate is too high (> 550 excitations/minute) to allow adequate pumping of blood. In the electrocardiogram (ECG), ventricular complexes that are ever-changing in frequency, contour, and amplitude characterize VF. This article reviews prevailing theories for the initiation and maintenance of VF, as well as its spatio-temporal organization. Particular attention is given to recent experiments and computer simulations suggesting that VF may be explained in terms of highly periodic three-dimensional rotors that activate the ventricles at exceedingly high frequency. Such rotors may show at least two different behaviors: (a) At one extreme, they may drift throughout the heart at high speeds producing beat-to-beat changes in the activation sequence. (b) At the other extreme, rotors may be relatively stationary, activating the ventricles at such high frequencies that the wave fronts emanating from them breakup at varying distances, resulting in complex spatio-temporal patterns of fibrillatory conduction. In either case, the recorded ECG patterns are indistinguishable from VF. The data discussed have paved the way for a better understanding of the mechanisms of VF in the normal, as well as the diseased, human heart.

Animals↗
PubMed1999

Reentry and fibrillation in the mouse heart. A challenge to the critical mass hypothesis.

The idea that fibrillation is only possible in hearts exceeding a critical size was introduced by W. Garrey >80 years ago and has since been generally accepted. In ventricular tissue, this critical size was originally estimated to be 400 mm(2). Recent estimates suggest that the critical size required for sustained reentry is approximately 100 to 200 mm(2), whereas 6 times this area is required for ventricular fibrillation. According to these estimates, fibrillation is not possible in the mouse heart, where the ventricular surface area is approximately 100 mm(2). To test whether sustained ventricular fibrillation could be induced in such an area, we used a high-speed video imaging system and a voltage-sensitive dye to quantify electrical activity on the epicardial surface of the Langendorff-perfused adult mouse heart. In 6 hearts, measurements during ventricular pacing at a basic cycle length (BCL) of 120 ms yielded maximum and minimum conduction velocities (CV(max) and CV(min)) of 0.63+/-0.04 and 0.38+/-0.02 mm/ms, respectively. At a BCL of 80 ms, CV(max) and CV(min) changed to 0.55+/-0.03 and 0. 34+/-0.02 mm/ms. Action potential durations (APDs), measured at 70% repolarization at those pacing frequencies were found to be 44.5+/-2. 9 and 40.4+/-2.6 ms, respectively. The wavelengths (CVxAPD) were calculated to be 28.6+/-3.4 mm in the CV(max) direction and 16.8+/-1. 5 mm in the CV(min) direction at BCL 120 ms. Wavelengths were significantly reduced (P<0.05) at BCL 80 ms (CV(max), 22.2+/-1.8 mm; CV(min), 13.7+/-0.9 mm). In 5 hearts, stationary vortex-like reentry organized by single rotors (4 of 5 hearts) or by pairs of rotors (1 of 5 hearts) was induced by burst pacing. In the ECG, the activity manifested as sustained monomorphic tachycardia. Detailed analysis showed that the local CVs were reduced in the vicinity of the rotor center, which allowed the reentry to take place within a smaller area than was calculated from wavelength measurements during pacing. In 4 of 7 hearts, burst pacing resulted in a polymorphic ECG pattern indistinguishable from ventricular fibrillation. These data challenge the critical mass hypothesis by demonstrating that ventricular tissue with an area as small as 100 mm(2) is capable of undergoing sustained fibrillatory activity.

Action Potentials↗
PubMed1999

[Electrophysiology of the atrioventricular node during atrial fibrillation. I. Ventricular rhythm].

Atrial fibrillation (AF) occurs in 0.9% of the population, in 6% of persons over 65 and in 10% of persons over 80. It is an important independent risk factor for thromboembolism, especially cerebral infarctions. The functions of the atrioventricular (AV) node are: (a) optimal adjustment of the time between the contractions of atria and ventricles; (b) protection of the ventricles against excessively high frequencies of atrial tachycardia; (c) a pacemaker function in case of atrial arrest. AF is an irregular, disorganized electrical activity of the atria. On the ECG, P waves are absent and the baseline shows wavelets constantly changing in shape, duration, amplitude and direction. Development and existence of AF are correlated with a sufficiently large number of myocardial cells and a sufficient degree of difference between the electrical properties of the myocardial cells. In the absence of an AV conduction block, the resulting ventricular rhythm is completely irregular. The constant irregularity of the ventricular rhythm is independent of ventricular frequency and independent of cardiac and other characteristics of the patient. Electrical stimulation of the right ventricle leads to complete AV block.

Adult↗
PubMed1999

[Electrophysiology of the atrioventricular node during atrial fibrillation. II. The influence of atrial impulses].

An atrial impulse that is not conducted to the ventricle may slow down the conduction of the next atrial impulse. A ventricular extrasystole may also affect the conduction through the AV node. This phenomenon is called 'concealed conduction'. At least three mechanisms are possible to explain concealed conduction, but neither weakening of the impulse as the conduction proceeds nor electrotonic modulation of the pacemaker function of the AV node is in accordance with the observed constant irregularity of atrial fibrillation. The most probable mechanism to explain the ventricular rhythm during atrial fibrillation is the electrotonic change (inhibition) by atrial impulses of the conduction properties of the AV node.

Adult↗
PubMed1999

Proton and zinc effects on HERG currents.

The proton and Zn2+ effects on the human ether-a-go-go related gene (HERG) channels were studied after expression in Xenopus oocytes and stable transfection in the mammalian L929 cell line. Experiments were carried out using the two-electrode voltage clamp at room temperature (oocytes) or the whole-cell patch clamp technique at 35 degrees C (L929 cells). In oocytes, during moderate extracellular acidification (pHo = 6.4), current activation was not shifted on the voltage axis, the time course of current activation was unchanged, but tail current deactivation was dramatically accelerated. At pHo < 6.4, in addition to accelerating deactivation, the time course of activation was slower and the midpoint voltage of current activation was shifted to more positive values. Protons and Zn2+ accelerated the kinetics of deactivation with apparent Kd values about one order of magnitude lower than for tail current inhibition. For protons, the Kd values for the effect on tail current amplitude versus kinetics were, respectively, 1.8 microM (pKa = 5.8) and 0.1 microM (pKa = 7.0). In the presence of Zn2+, the corresponding Kd values were, respectively, 1.2 mM and 169 microM. In L929 cells, acidification to pHo = 6.4 did not shift the midpoint voltage of current activation and had no effect on the time course of current activation. Furthermore, the onset and recovery of inactivation were not affected. However, the acidification significantly accelerated tail current deactivation. We conclude that protons and Zn2+ directly interact with HERG channels and that the interaction results, preferentially, in the regulation of channel deactivation mechanism.

Animals↗
PubMed1999

Spatial and temporal organization in ventricular fibrillation.

Ventricular fibrillation (VF) is the leading heart rhythm alteration that results in sudden cardiac death, yet the detailed mechanisms of the arrhythmia remain elusive. Fibrillation has been defined as "turbulent" cardiac electrical activity, which conjures up the idea of totally random and disorganized activation of the ventricles. I review theoretical concepts and recently published results based on a newly developed algorithm, "two-dimensional phase mapping," which demonstrates that VF is not random and may be analyzed quantitatively. The approach is based on video imaging of voltage-sensitive dye fluorescence to record transmembrane potential simultaneously from 20,000 sites on the epicardial surface of rabbit and sheep ventricles. During VF, activity shows a strong periodic component centered near approximately 500 beats/min. Phase maps reveal that VF depends on the organization of electrical waves around a small number of "phase singularities" that have relatively short lifespans and form as a result of interactions of wavefronts with obstacles in their paths. Overall, the evidence demonstrates that there is a high degree of temporal and spatial organization in cardiac fibrillation. The results may pave the way for a better understanding of the mechanisms of VF in normal, as well as in diseased, hearts.

Algorithms↗
PubMed1999

Spiral drift and core properties.

We consider the drift of a stable, nonmeandering rotating spiral wave in a singly diffusive FitzHugh-Nagumo medium with generic reaction functions; the drift is assumed to be caused by a weak time-independent diffusivity gradient or convection term in the fast-variable equation. We address, to first order in the perturbation, the standard problem whose statement reads, "Given the unperturbed solution, as well as the model's parameters, predict the speed and direction of the drift in terms of the strength and direction of the perturbation." Our main results are as follows: First, we establish a mathematical equivalence between true gradients and convective perturbations; second, a variety of numerical examples, taken from computer simulations, are presented as a reference base for testing drift theories; and third, we propose a semiempirical solution to the drift problem, requiring only two quantities to be measured off the unperturbed spiral, namely, its period of rotation and the value of the fast variable at its center; good agreement with numerical simulations is found for moderately sparse spirals.

Biophysical Phenomena↗
PubMed1999

Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping.

INTRODUCTION: Gap junction channels are important determinants of conduction in the heart and may play a central role in the development of lethal cardiac arrhythmias. The recent development of a Cx43-deficient mouse has raised fundamental questions about the role of specific connexin isoforms in intercellular communication in the heart. Although a homozygous null mutation of the Cx43 gene (Cx43-/-) is lethal, the heterozygous (Cx43+/-) animals survive to adulthood. Reports on the cardiac electrophysiologic phenotype of the Cx43+/- mice are contradictory. Thus, the effects of a null mutation of a single Cx43 allele require reevaluation. METHODS AND RESULTS: High-resolution video mapping techniques were used to study propagation in hearts from Cx43+/- and littermate control (Cx43+/+) mice. Local conduction velocities (CVs) and conduction patterns were quantitatively measured by determining conduction vectors. We undertook the characterization of ECG parameters and epicardial CVs of normal and Cx43+/- mouse hearts. ECG measurements obtained from 12 Cx43+/+ and 6 Cx43+/- age matched mice did not show differences in any parameter, including QRS duration (14.5 +/- 0.9 and 15.7 +/- 2.3 msec for Cx43+/+ and Cx43+/-, respectively). In addition, using a sensitive method of detecting changes in local CV, video images of epicardial wave propagation revealed similar activation patterns and velocities in both groups of mice. CONCLUSION: A sensitive method that accurately measures local CVs throughout the ventricles revealed no changes in Cx43+/- mice, which is consistent with the demonstration that ECG parameter values in the heterozygous mice are the same as those in wild-type mice.

Animals↗
PubMed1999

Connexins and impulse propagation in the mouse heart.

Gap junction channels are essential for normal cardiac impulse propagation. Three gap junction proteins, known as connexins, are expressed in the heart: Cx40, Cx43, and Cx45. Each of these proteins forms channels with unique biophysical and electrophysiologic properties, as well as spatial distribution of expression throughout the heart. However, the specific functional role of the individual connexins in normal and abnormal propagation is unknown. The availability of genetically engineered mouse models, together with new developments in optical mapping technology, makes it possible to integrate knowledge about molecular mechanisms of intercellular communication and its regulation with our growing understanding of the microscopic and global dynamics of electrical impulse propagation during normal and abnormal cardiac rhythms. This article reviews knowledge on the mechanisms of cardiac impulse propagation, with particular focus on the role of cardiac connexins in electrical communication between cells. It summarizes results of recent studies on the electrophysiologic consequences of defects in the functional expression of specific gap junction channels in mice lacking either the Cx43 or Cx40 gene. It also reviews data obtained in a transgenic mouse model in which cell loss and remodeling of gap junction distribution leads to increased susceptibility to arrhythmias and sudden cardiac death. Overall, the results demonstrate that these are potentially powerful strategies for studying fundamental mechanisms of cardiac electrical activity and for testing the hypothesis that certain cardiac arrhythmias involve gap junction or other membrane channel dysfunction. These new approaches, which permit one to manipulate electrical wave propagation at the molecular level, should provide new insight into the detailed mechanisms of initiation, maintenance, and termination of cardiac arrhythmias, and may lead to more effective means to treat arrhythmias and prevent sudden cardiac death.

Animals↗
PubMed1998

Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart.

BACKGROUND: Ventricular fibrillation (VF) leads to global ischemia of the heart. After 1 to 2 minutes of onset, the VF rate decreases and appears more organized. The objectives of this study were to determine the effects of no-flow global ischemia on nonlinear wave dynamics and establish the mechanism of ischemia-induced slowing of the VF rate. METHODS AND RESULTS: Activation patterns of VF in the Langendorff-perfused rabbit heart were studied with the use of 2 protocols: (1) 15 minutes of no-flow global ischemia followed by reperfusion (n=7) and (2) decreased excitability induced by perfusion with 5 micromol/L of tetrodotoxin (TTX) followed by washout (n=3). Video imaging ( approximately 7500 pixels per frame; 240 frames per second) with a voltage-sensitive dye, ECG, and signal processing (fast Fourier transform) were used for analysis. The dominant frequency of VF decreased from 13.5+/-1.3 during control to 9.3+/-1.4 Hz at 5 minutes of global ischemia (P<0.02). The dominant frequency decreased from 13.9+/-1.1 during control to 7.0+/-0.3 Hz at 2 minutes of TTX infusion (P<0.001). The rotation period of rotors on the epicardial surface (n=27) strongly correlated with the inverse dominant frequency of the corresponding episode of VF (R2=0. 93). The core area, measured for 27 transiently appearing rotors, was 5.3+/-0.7 mm2 during control. A remarkable increase in core area was observed both during global ischemia (13.6+/-1.7 mm2; P<0.001) and TTX perfusion (16.8+/-3.6 mm2; P<0.001). Density of wave fronts decreased during both global ischemia (P<0.002) and TTX perfusion (P<0.002) compared with control. CONCLUSIONS: This study suggests that rotating spiral waves are most likely the underlying mechanism of VF and contribute to its frequency content. Ischemia-induced decrease in the VF rate results from an increase in the rotation period of spiral waves that occurs secondary to an increase in their core area. Remarkably, similar findings in the TTX protocol suggest that reduced excitability during ischemia is an important underlying mechanism for the changes seen.

Animals↗
PubMed1998

Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart.

BACKGROUND: The activation patterns that underlie the irregular electrical activity during atrial fibrillation (AF) have traditionally been described as disorganized or random. Recent studies, based predominantly on statistical methods, have provided evidence that AF is spatially organized. The objective of this study was to demonstrate the presence of spatial and temporal periodicity during AF. METHODS AND RESULTS: We used a combination of high-resolution video imaging, ECG recordings, and spectral analysis to identify sequential wave fronts with temporal periodicity and similar spatial patterns of propagation during 20 episodes of AF in 6 Langendorff-perfused sheep hearts. Spectral analysis of AF demonstrated multiple narrow-band peaks with a single dominant peak in all cases (mean, 9.4+/-2.6 Hz; cycle length, 112+/-26 ms). Evidence of spatiotemporal periodicity was found in 12 of 20 optical recordings of the right atrium (RA) and in all (n=19) recordings of the left atrium (LA). The cycle length of spatiotemporal periodic waves correlated with the dominant frequency of their respective optical pseudo-ECGs (LA: R2=0.99, slope=0.94 [95% CI, 0.88 to 0.99]; RA: R2=0.97, slope=0.92 [95% CI, 0.80 to 1.03]). The dominant frequency of the LA pseudo-ECG alone correlated with the global bipolar atrial EG (R2=0.76, slope=0.75 [95% CI, 0.52 to 0.99]). In specific examples, sources of periodic activity were seen as rotors in the epicardial sheet or as periodic breakthroughs that most likely represented transmural pectinate muscle reentry. However, in the majority of cases, periodic waves were seen to enter the mapping area from the edge of the field of view. CONCLUSIONS: Reentry in anatomically or functionally determined circuits forms the basis of spatiotemporal periodic activity during AF. The cycle length of sources in the LA determines the dominant peak in the frequency spectra in this experimental model of AF.

Animals↗
PubMed1998

Conditional lineage ablation to model human diseases.

Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.

Action Potentials↗