Comments on "A model for human ventricular tissue".
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Action Potentials↗
Biomedical subjects
Yoram Rudy
Publications and source records attributed to Yoram Rudy.
Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model.
BACKGROUND: Computational biology is a powerful tool for elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. A novel theoretical model of the canine ventricular epicardial action potential and calcium cycling was developed and used to investigate ionic mechanisms underlying Ca2+ transient (CaT) and action potential duration (APD) rate dependence. METHODS AND RESULTS: The Ca2+/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca2+-release formulation, Ca2+ subspace, dynamic chloride handling, and formulations for major ion currents based on canine ventricular data. Decreasing pacing cycle length from 8000 to 300 ms shortened APD primarily because of I(Ca(L)) reduction, with additional contributions from I(to1), I(NaK), and late I(Na). CaT amplitude increased as cycle length decreased from 8000 to 500 ms. This positive rate-dependent property depended on CaMKII activity. CONCLUSIONS: CaMKII is an important determinant of the rate dependence of CaT but not of APD, which depends on ion-channel kinetics. The model of CaMKII regulation may serve as a paradigm for modeling effects of other regulatory pathways on cell function.
4-Aminopyridine↗
Conductive bridges in cardiac tissue: a beneficial role or an arrhythmogenic substrate?
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Action Potentials↗
Noninvasive electrocardiographic imaging for cardiac electrophysiology and arrhythmia.
Over 7 million people worldwide die annually from erratic heart rhythms (cardiac arrhythmias), and many more are disabled. Yet there is no imaging modality to identify patients at risk, provide accurate diagnosis and guide therapy. Standard diagnostic techniques such as the electrocardiogram (ECG) provide only low-resolution projections of cardiac electrical activity on the body surface. Here we demonstrate the successful application in humans of a new imaging modality called electrocardiographic imaging (ECGI), which noninvasively images cardiac electrical activity in the heart. In ECGI, a multielectrode vest records 224 body-surface electrocardiograms; electrical potentials, electrograms and isochrones are then reconstructed on the heart's surface using geometrical information from computed tomography (CT) and a mathematical algorithm. We provide examples of ECGI application during atrial and ventricular activation and ventricular repolarization in (i) normal heart (ii) heart with a conduction disorder (right bundle branch block) (iii) focal activation initiated by right or left ventricular pacing, and (iv) atrial flutter.
Arrhythmias, Cardiac↗
Genetic defects, ionic currents and electrocardiographic alterations.
Most experimental data on the kinetic properties of cardiac ion channels and their modification by genetic defects have been obtained in expression systems (e.g., Xenopus oocyte), away from the cellular environment where these channels function to generate the cardiac action potential. In this article, we describe the use of computational biology (computer simulations) in integrating such information on single ion channels into models of the functioning cardiac cell. We use this approach to mechanistically relate molecular processes to whole-cell electrophysiological function and its manifestation in electrocardiographic waveforms. Examples are provided from the congenital long QT syndrome and the Brugada syndrome.
Action Potentials↗
Basic mechanisms of cardiac impulse propagation and associated arrhythmias.
Propagation of excitation in the heart involves action potential (AP) generation by cardiac cells and its propagation in the multicellular tissue. AP conduction is the outcome of complex interactions between cellular electrical activity, electrical cell-to-cell communication, and the cardiac tissue structure. As shown in this review, strong interactions occur among these determinants of electrical impulse propagation. A special form of conduction that underlies many cardiac arrhythmias involves circulating excitation. In this situation, the curvature of the propagating excitation wavefront and the interaction of the wavefront with the repolarization tail of the preceding wave are additional important determinants of impulse propagation. This review attempts to synthesize results from computer simulations and experimental preparations to define mechanisms and biophysical principles that govern normal and abnormal conduction in the heart.
Action Potentials↗
From genetics to cellular function using computational biology.
This article illustrates how computational biology (computer modeling) can be used to link genetic mutations to their cellular phenotypes. Examples are provided from ion channel defects that are associated with hereditary cardiac arrhythmias--that is, the long QT and Brugada syndromes. State-specific Markov models of wild-type and mutant channels are formulated and introduced into a computer model of the ventricular cardiac cell. Simulations are conducted to study the rate-dependent alterations in action potential properties caused by the mutations. Results provide insights into the cellular mechanisms of QT-interval prolongation on the ECG in the long QT syndrome and of ST-segment elevation in the right precordial leads in the Brugada syndrome.
Computational Biology↗
Comments on: "Role of individual ionic current systems in ventricular cells hypothesized by a model study" by Matsuoka S, Sarai N, Kuratomi S, Ono K, and Noma A. Jpn J Physiol 53: 105-123, 2003.
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Impulse propagation in synthetic strands of neonatal cardiac myocytes with genetically reduced levels of connexin43.
Connexin43 (Cx43) is a major determinant of the electrical properties of the myocardium. Closure of gap junctions causes rapid slowing of propagation velocity (theta), but the precise effect of a reduction in Cx43 levels due to genetic manipulation has only partially been clarified. In this study, morphological and electrical properties of synthetic strands of cultured neonatal ventricular myocytes from Cx43+/+ (wild type, WT) and Cx+/- (heterozygote, HZ) mice were compared. Quantitative immunofluorescence analysis of Cx43 demonstrated a 43% reduction of Cx43 expression in the HZ versus WT mice. Cell dimensions, connectivity, and alignment were independent of genotype. Measurement of electrical properties by microelectrodes and optical mapping showed no differences in action potential amplitude or minimum diastolic potential between WT and HZ. However, maximal upstroke velocity of the transmembrane action potential, dV/dtmax, was increased and action potential duration was reduced in HZ versus WT. theta was similar in the two genotypes. Computer simulation of propagation and dV/dtmax showed a relatively small dependence of theta on gap junction coupling, thus explaining the lack of observed differences in theta between WT and HZ. Importantly, the simulations suggested that the difference in dV/dtmax is due to an upregulation of INa in HZ versus WT. Thus, heterozygote-null mutation of Cx43 produces a complex electrical phenotype in synthetic strands that is characterized by both changes in ion channel function and cell-to-cell coupling. The lack of changes in theta in this tissue is explained by the dominating role of myoplasmic resistance and the compensatory increase of dV/dtmax.
Action Potentials↗
Mechanism of pacemaking in I(K1)-downregulated myocytes.
Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, I(K1), in guinea pig ventricular cells. We simulated these cells by adjusting I(K1) conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% I(K1) suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, I(NaCa), which depends on the intracellular calcium concentration [Ca2+]i. This [Ca2+]i dependence suggests responsiveness (increase in rate) to beta-adrenergic stimulation (betaAS), as observed experimentally. Simulations of betaAS demonstrate such responsiveness, which depends on I(NaCa) expression. However, a simultaneous betaAS-mediated increase in the slow delayed rectifier, I(Ks), limits betaAS sensitivity.
Action Potentials↗
Heart-surface reconstruction and ECG electrodes localization using fluoroscopy, epipolar geometry and stereovision: application to noninvasive imaging of cardiac electrical activity.
To date there is no imaging modality for cardiac arrhythmias which remain the leading cause of sudden death in the United States (> 300000/yr.). Electrocardiographic imaging (ECGI), a noninvasive modality that images cardiac arrhythmias from body surface potentials, requires the geometrical relationship between the heart surface and the positions of body surface ECG electrodes. A photographic method was validated in a mannequin and used to determine the three-dimensional coordinates of body surface ECG electrodes to within 1 mm of their actual positions. Since fluoroscopy is available in the cardiac electrophysiology (EP) laboratory where diagnosis and treatment of cardiac arrhythmias is conducted, a fluoroscopic method to determine the heart surface geometry was developed based on projective geometry, epipolar geometry, point reconstruction, b-spline interpolation and visualization. Fluoroscopy-reconstructed hearts in a phantom and a human subject were validated using high-resolution computed tomography (CT) imaging. The mean absolute distance error for the fluoroscopy-reconstructed heart relative to the CT heart was 4 mm (phantom) and 10 mm (human). In the human, ECGI images of normal cardiac electrical activity on the fluoroscopy-reconstructed heart showed close correlation with those obtained on the CT heart. Results demonstrate the feasibility of this approach for clinical noninvasive imaging of cardiac arrhythmias in the interventional EP laboratory.
Algorithms↗
Noninvasive electrocardiographic imaging (ECGI): application of the generalized minimal residual (GMRes) method.
Electrocardiographic imaging (ECGI) is a developing imaging modality for cardiac electrophysiology and arrhythmias. It reconstructs epicardial potentials, electrograms, and isochrones from electrocardiographic body-surface potentials noninvasively. Current ECGI methodology employs Tikhonov regularization, which imposes constraints on the reconstructed potentials or their derivatives. This approach can sometimes reduce spatial resolution by smoothing the solution. Accuracy depends on a priori knowledge of solution characteristics and determination of an optimal regularization parameter. These properties led us to implement an independent, iterative approach for ECGI--the generalized minimal residual (GMRes) method--which does not apply constraints. GMRes was applied to experimental data during activation/repolarization of normal and infarcted hearts. GMRes reconstructions were compared to Tikhonov reconstructions and to measured "gold standards" in isolated hearts. Overall, the accuracy of GMRes solutions was similar to Tikhonov regularization. However, in certain cases GMRes recovered localized potential features (e.g., multiple potential minima), which were lost in the Tikhonov solution. Simultaneous use of these two complementary methods in clinical ECGI will ensure reliability and maximal extraction of diagnostic information in the absence of a priori information about a patient's condition.
Action Potentials↗
Localization of sodium channels in intercalated disks modulates cardiac conduction.
It is well known that the sodium current (I(Na)) and the degree of gap-junctional electrical coupling are the key determinants of action potential (AP) conduction in cardiac tissue. Immunohistochemical studies have shown that sodium channels (NaChs) are preferentially located in intercalated disks (IDs). Using dual immunocytochemical staining, we confirmed the colocalization of NaChs with connexin43 in cultures of neonatal rat ventricular myocytes. In mathematical simulations of conduction using the Luo-Rudy dynamic model of the ventricular AP, we assessed the hypothesis that conduction could be modulated by the preferential localization of NaChs in IDs. Localization of I(Na) at the ID caused a large negative potential in the intercellular cleft, which influenced conduction in two opposing ways, depending on the degree of electrical coupling: (1) for normal and moderately reduced coupling, the negative cleft potential led to a large overshoot of the transmembrane potential resulting in a decreased driving force for I(Na) itself (self-attenuation), which slowed conduction; (2) for greatly reduced coupling (<10%), the negative cleft potential induced by I(Na) in the prejunctional membrane led to suprathreshold depolarization of the postjunctional membrane, which facilitated and accelerated conduction. When cleft potential effects were not incorporated, conduction was not significantly affected by the ID localization of I(Na). By enhancing conduction through the establishment of cleft potentials, the localization of NaChs in IDs might protect the myocardium from conduction block, very slow conduction, and microreentry under conditions of greatly reduced coupling. Conversely, by supporting moderately slow conduction, this mechanism could also promote arrhythmias.
Animals↗
Ionic current basis of electrocardiographic waveforms: a model study.
Body surface electrocardiograms and electrograms recorded from the surfaces of the heart are the basis for diagnosis and treatment of cardiac electrophysiological disorders and arrhythmias. Given recent advances in understanding the molecular mechanisms of arrhythmia, it is important to relate these electrocardiographic waveforms to cellular electrophysiological processes. This modeling study establishes the following principles: (1) voltage gradients created by heterogeneities of the slow-delayed rectifier (I(Ks)) and transient outward (I(to)) potassium current inscribe the T wave and J wave, respectively; T-wave polarity and width are strongly influenced by the degree of intercellular coupling through gap-junctions. (2) Changes in [K+]o modulate the T wave through their effect on the rapid-delayed rectifier, I(Kr). (3) Alterations of I(Ks), I(Kr), and I(Na) (fast sodium current) in long-QT syndrome (LQT1, LQT2, and LQT3, respectively) are reflected in characteristic QT-interval and T-wave changes; LQT1 prolongs QT without widening the T wave. (4) Accelerated inactivation of I(Na) on the background of large epicardial I(to) results in ST elevation (Brugada phenotype) that reflects the degree of severity. (5) Activation of the ATP-sensitive potassium current, I(K(ATP)), is sufficient to cause ST elevation during acute ischemia. These principles provide a mechanistic cellular basis for interpretation of electrocardiographic waveforms.
Action Potentials↗
Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.
BACKGROUND: Complex physiological interactions determine the functional consequences of gene abnormalities and make mechanistic interpretation of phenotypes extremely difficult. A recent example is a single mutation in the C terminus of the cardiac Na(+) channel, 1795insD. The mutation causes two distinct clinical syndromes, long QT (LQT) and Brugada, leading to life-threatening cardiac arrhythmias. Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced Na(+) channel function, and Brugada with reduced function. METHODS AND RESULTS: Using a computational approach, we demonstrate that the 1795insD mutation exerts variable effects depending on the myocardial substrate. We develop Markov models of the wild-type and 1795insD cardiac Na(+) channels. By incorporating the models into a virtual transgenic cell, we elucidate the mechanism by which 1795insD differentially disrupts cellular electrical behavior in epicardial and midmyocardial cell types. We provide a cellular mechanistic basis for the ECG abnormalities observed in patients carrying the 1795insD gene mutation. CONCLUSIONS: We demonstrate that the 1795insD mutation can cause both LQT and Brugada syndromes through interaction with the heterogeneous myocardium in a rate-dependent manner. The results highlight the complexity and multiplicity of genotype-phenotype relationships, and the usefulness of computational approaches in establishing a mechanistic link between genetic defects and functional abnormalities.
Action Potentials↗
Endocardial mapping of electrophysiologically abnormal substrates and cardiac arrhythmias using a noncontact nonexpandable catheter.
INTRODUCTION: In previous studies, we established methodology for reconstructing endocardial potential maps, electrograms, and isochrones from a noncontact intracavitary catheter during a single beat. Recently, we evaluated this approach using a 9-French (3-mm) spiral catheter in a normal heart preparation. Here we extend the approach to hearts with structural disease and examine its ability to detect and characterize abnormal electrophysiologic (EP) substrates and to map ventricular arrhythmias on a beat-by-beat basis. METHODS AND RESULTS: Reconstruction of endocardial potentials from cavity potentials measured with 82 electrodes mounted on a 9-French spiral catheter was performed in an isolated canine left ventricle (LV). Endocardial potentials were recorded with 91 intramural needles, providing a gold standard for evaluating the noncontact reconstruction. Studies were performed in a normal LV (control) and the same LV 3 hours after left anterior descending coronary artery occlusion and ethanol injection to create an infarct. Abnormal EP characteristics over the infarct were faithfully reconstructed, including (1) low potentials and electrogram derivatives; (2) fractionated electrograms; (3) small deflections on electrograms reflecting local activation; and (4) slow discontinuous conduction transverse to fibers. During arrhythmia, beat-to-beat dynamic shifts of initiation site and activation pattern were captured by the reconstruction. CONCLUSION: Noncontact, nonexpendable catheter mapping can locate and characterize abnormal EP substrates and can capture the endocardial sequence of an arrhythmia during a single beat.
Animals↗