Gi Alpha 1-mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

Circulation. Aug, 2007  |  Pubmed ID: 17646583

Cardiac hypertrophy is a major risk factor for arrhythmias and sudden cardiac death. However, the underlying signaling mechanisms involved in the induction of arrhythmia and electrophysiological remodeling in cardiac hypertrophy are unclear.

Quantitative Panoramic Imaging of Epicardial Electrical Activity

Annals of Biomedical Engineering. Oct, 2008  |  Pubmed ID: 18654852

Fluorescent imaging with voltage- and/or calcium-sensitive dyes has revolutionized cardiac physiology research. Here we present improved panoramic imaging for optically mapping electrical activity from the entire epicardium of the Langendorff-perfused rabbit heart. Combined with reconstruction of the 3D heart surface, the functional data can be conveniently visualized on the realistic heart geometry. Methods to quantify the panoramic data set are introduced by first describing a simple approach to mesh the heart in regular grid form. The regular grid mesh provides substrate for easy translation of previously available non-linear dynamics methods for 2D array data. It also simplifies the unwrapping of curved three-dimensional surface to 2D surface for global epicardial visualization of the functional data. The translated quantification methods include activation maps (isochrones), phase maps, phase singularity, and electric stimulus-induced virtual electrode polarization (VEP) maps. We also adapt a method to calculate the conduction velocities on the global epicardial surface by taking the curvature of the heart surface into account.

Panoramic Imaging Reveals Basic Mechanisms of Induction and Termination of Ventricular Tachycardia in Rabbit Heart with Chronic Infarction: Implications for Low-voltage Cardioversion

Heart Rhythm : the Official Journal of the Heart Rhythm Society. Jan, 2009  |  Pubmed ID: 18996057

Sudden cardiac death due to arrhythmia in the settings of chronic myocardial infarction (MI) is an important clinical problem. Arrhythmic risk post-MI continues indefinitely even if heart failure and acute ischemia are not present due to the anatomic substrate of the scar and border zone (BZ) tissue.

Multiple Monophasic Shocks Improve Electrotherapy of Ventricular Tachycardia in a Rabbit Model of Chronic Infarction

Heart Rhythm : the Official Journal of the Heart Rhythm Society. Jul, 2009  |  Pubmed ID: 19560090

We previously showed that the cardioversion threshold (CVT) for ventricular tachycardia (VT) is phase dependent when a single monophasic shock (1MP) is used.

Enhanced Susceptibility to Alternans in a Rabbit Model of Chronic Myocardial Infarction

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2009  |  Pubmed ID: 19964643

The aim of this study is to examine how structural discontinuity and functional remodeling changes the susceptibility to alternans of action potential duration (APD) in a rabbit model of chronic myocardial infarction (MI). Optical mapping experiments using voltage-sensitive dyes were performed in 14 rabbit hearts. We found that (1) APD alternans starts at a significantly slower pacing rate in hearts with MI (n = 7) than in normal hearts (n = 7), with the original sites of alternans of APD located in the infarct region and infarct adjacent regions. (2) Alternans of activation cycle length (CL) precedes the occurrence of spatially discordant alternans of APD, with the regions of activation CL alternans located in the infarct adjacent regions. Based on these results, we conclude that susceptibility to alternans are significantly enhanced in this rabbit model of chronic MI, and the enhancement is strongly correlated to structural and functional heterogeneity imposed by the infarction.

Transmural Dispersion of Repolarization in Failing and Nonfailing Human Ventricle

Circulation Research. Mar, 2010  |  Pubmed ID: 20093630

Transmural dispersion of repolarization has been shown to play a role in the genesis of ventricular tachycardia and fibrillation in different animal models of heart failure (HF). Heterogeneous changes of repolarization within the midmyocardial population of ventricular cells have been considered an important contributor to the HF phenotype. However, there is limited electrophysiological data from the human heart.

Multiscale Imaging of the Human Heart: Building the Foundation for Human Systems Physiology and Translational Medicine

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2010  |  Pubmed ID: 21095821

The development of human cardiovascular systems physiology is inhibited by the lack of multiscale functional physiological data, which represents human heart physiology at the molecular, cellular, tissue, organ, and system levels. We have developed an experimental approach to study explanted human hearts in vitro at multiple physiological scales with a wide array of imaging modalities. This approach has already yielded data indicating significant differences between animal models of diseases and actual human heart disease. Our data provides a quantitative foundation for multiscale physiological models of the cardiovascular system and will allow improvement in translation of medical technology and pharmacology from animal models to therapy.

Transmural Heterogeneity and Remodeling of Ventricular Excitation-contraction Coupling in Human Heart Failure

Circulation. May, 2011  |  Pubmed ID: 21502574

Excitation-contraction (EC) coupling is altered in end-stage heart failure. However, spatial heterogeneity of this remodeling has not been established at the tissue level in failing human heart. The objective of this article was to study functional remodeling of excitation-contraction coupling and calcium handling in failing and nonfailing human hearts.

Spatiotemporal Control of Heart Rate in a Rabbit Heart

Journal of Electrocardiology. Nov-Dec, 2011  |  Pubmed ID: 21937057

Sinoatrial node is responsible for the origin of the wave of excitation, which spreads throughout the heart and orchestrates cardiac contraction via calcium-mediated excitation-contraction coupling. P wave represents the spread of excitation in the atria. It is well known that the autonomic nervous system controls the heart rate by dynamically altering both cellular ionic fluxes and the anatomical location of the leading pacemaker. In this study, we used isolated rabbit right atria and mathematical model of the pacemaker region of the rabbit heart. Application of isoproterenol resulted in dose-dependent acceleration of the heart rate and superior shift of the leading pacemaker. In the mathematical model, such behavior could be reproduced by a gradient of expression in β1-adrenergic receptors along the superior-inferior axis. Application of acetylcholine resulted in preferentially inferior shift of pacemaker and slowing of the heart rate. The mathematical model reproduced this behavior with imposing a gradient of expression of acetylcholine-sensitive potassium channel. We conclude that anatomical shift of the leading pacemaker in the rabbit heart could be achieved through gradient of expression of β1-adrenergic receptors and I(K,ACh).

The Role of Dynamic Instability and Wavelength in Arrhythmia Maintenance As Revealed by Panoramic Imaging with Blebbistatin Vs. 2,3-butanedione Monoxime

American Journal of Physiology. Heart and Circulatory Physiology. Jan, 2012  |  Pubmed ID: 22037192

Unlike other excitation-contraction uncouplers, blebbistatin has few electrophysiological side effects and has gained increasing acceptance as an excitation-contraction uncoupler in optical mapping experiments. However, the possible role of blebbistatin in ventricular arrhythmia has hitherto been unknown. Furthermore, experiments with blebbistatin and 2,3-butanedione monoxime (BDM) offer an opportunity to assess the contribution of dynamic instability and wavelength of impulse propagation to the induction and maintenance of ventricular arrhythmia. Recordings of monophasic action potentials were used to assess effects of blebbistatin in Langendorff-perfused rabbit hearts (n = 5). Additionally, panoramic optical mapping experiments were conducted in rabbit hearts (n = 7) that were sequentially perfused with BDM, then washed out, and subsequently perfused with blebbistatin. The susceptibility to arrhythmia was investigated using a shock-on-T protocol. We found that 1) application of blebbistatin did not change action potential duration (APD) restitution; 2) in contrast to blebbistatin, BDM flattened APD restitution curve and reduced the wavelength; and 3) incidence of sustained arrhythmia was much lower under blebbistatin than under BDM (2/123 vs. 23/99). While arrhythmias under BDM were able to stabilize, the arrhythmias under blebbistatin were unstable and terminated spontaneously. In conclusion, the lower susceptibility to arrhythmia under blebbistatin than under BDM indicates that blebbistatin has less effects on arrhythmia dynamics. A steep restitution slope under blebbistatin is associated with higher dynamic instability, manifested by the higher incidence of not only wave breaks but also wave extinctions. This relatively high dynamic instability leads to the self-termination of arrhythmia because of the sufficiently long wavelength under blebbistatin.

Shock-induced Focal Arrhythmias: Not Driven by Calcium?

Heart Rhythm : the Official Journal of the Heart Rhythm Society. Jan, 2012  |  Pubmed ID: 22079556