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Y Rudy

Publications and source records attributed to Y Rudy.

At least 19 recordsLinked to original sources
PubMed2001

Mechanistic insights into very slow conduction in branching cardiac tissue: a model study.

It is known that branching strands of cardiac tissue can form a substrate for very slow conduction. The branches slow conduction by acting as current loads drawing depolarizing current from the main strand ("pull" effect). It has been suggested that, upon depolarization of the branches, they become current sources reinjecting current back into the strand, thus enhancing propagation safety ("push" effect). It was the aim of this study to verify this hypothesis and to assess the contribution of the push effect to propagation velocity and safety. Conduction was investigated in strands of Luo-Rudy dynamic model cells that branch from either a single branch point or from multiple successive branch points. In single-branching strands, blocking the push effect by not allowing current to flow retrogradely from the branches into the strand did not significantly increase the branching-induced local propagation delay. However, in multiple branching strands, blocking the push effect resulted in a significant slowing of overall conduction velocity or even in conduction failure. Furthermore, for certain slow velocities, the safety factor for propagation was higher when slow conduction was caused by branching tissue geometry than by reduced excitability without branching. Therefore, these results confirm the proposed "pull and push" mechanism of slow, but nevertheless robust, conduction in branching structures. Slow conduction based on this mechanism could occur in the atrioventricular node, where multiple branching is structurally present. It could also support reentrant excitation in diseased myocardium where the substrate is structurally complex.

Animals↗
PubMed2001

Imaging dispersion of myocardial repolarization, I: comparison of body-surface and epicardial measures.

BACKGROUND: Body-surface ECG measures (QT dispersion [QTd], QRST integrals) have been used as indices of myocardial repolarization abnormalities with the goal of identifying patients at risk of fatal arrhythmias. The clinical utility of these measures has been questioned. We investigate the complex relationship between epicardial and body-surface potentials in the context of regionally abnormal myocardial repolarization. METHODS AND RESULTS: Epicardial potentials were recorded with a 224-electrode sock from an open-chest dog during control, regional epicardial warming, cooling, and adjacent warming and cooling to induce localized alterations in myocardial repolarization and regions of increased repolarization dispersion. Body-surface potentials were generated from these epicardial potentials in a human torso model. Epicardial estimates of repolarization (activation recovery intervals [ARIs] and QRST integrals) were evaluated for their ability to identify regions with increased repolarization dispersion. Body-surface QRST integrals and QTd in 12-lead ECG and 64-lead body-surface potential maps were evaluated for their ability to detect increased dispersion of myocardial repolarization. Epicardial ARI and QRST integral maps successfully located epicardial regions with increased dispersion of repolarization. The increased dispersion was not consistently reflected in the 12-lead or 64-lead ECG QTd or in the body-surface QRST integral maps. CONCLUSIONS: This study demonstrates the inadequacy of body-surface measures that are thought to reflect myocardial dispersion of repolarization. In contrast, measures based on epicardial electrograms (ARI or epicardial QRST integral maps) provide physiologically relevant information about myocardial repolarization and can locate regions of increased dispersion.

Animals↗
PubMed2001

Imaging dispersion of myocardial repolarization, II: noninvasive reconstruction of epicardial measures.

BACKGROUND: Dispersion of myocardial repolarization supports the development and maintenance of life-threatening arrhythmias. Current noninvasive approaches for detecting substrates with increased dispersion based on ECG measures (eg, QT dispersion) have shown limited success and inconsistencies. The companion article shows that, in contrast, epicardial potentials and derived measures reflect local dispersion of repolarization. Here, using a recently developed ECG imaging method, we evaluate the feasibility of noninvasive reconstruction of such epicardial measures from body-surface ECG data. METHODS AND RESULTS: Epicardial potentials were recorded with a 224-electrode sock from an open-chest dog during control, regional warming, cooling, and simultaneous adjacent warming and cooling to induce localized changes in myocardial repolarization and regions of increased dispersion. Body-surface potentials were generated from these epicardial potentials in a human torso model. Realistic geometric errors and measurement noise were added to the torso data, which were then used to noninvasively reconstruct epicardial measures of repolarization dispersion (activation recovery intervals [ARIs] and QRST integrals). Repolarization properties were accurately depicted by ECG imaging, including (1) shortened ARIs and increased QRST integrals over the warmed region, (2) prolonged ARIs and decreased QRST integrals over the cooled region, and (3) high gradients of ARIs and QRST integrals over the adjacent warmed and cooled regions. CONCLUSIONS: ECG imaging can reconstruct repolarization properties accurately and localize areas of increased dispersion of repolarization in the heart noninvasively. Its clinical significance lies in the possibility of noninvasive risk stratification and in guidance and evaluation of therapy.

Animals↗
PubMed2001

Ionic charge conservation and long-term steady state in the Luo-Rudy dynamic cell model.

It has been postulated that cardiac cell models accounting for changes in intracellular ion concentrations violate a conservation principle, and, as a result, computed parameters (e.g., ion concentrations and transmembrane potential, V(m)) drift in time, never attaining steady state. To address this issue, models have been proposed that invoke the charge conservation principle to calculate V(m) from ion concentrations ("algebraic" method), rather than from transmembrane current ("differential" method). The aims of this study are to compare model behavior during prolonged periods of pacing using the algebraic and differential methods, and to address the issue of model drift. We pace the Luo-Rudy dynamic model of a cardiac ventricular cell and compare the time-dependent behavior of computed parameters using the algebraic and differential methods. When ions carried by the stimulus current are taken into account, the algebraic and differential methods yield identical results and neither shows drift in computed parameters. The present study establishes the proper pacing protocol for simulation studies of cellular behavior during long periods of rapid pacing. Such studies are essential for mechanistic understanding of arrhythmogenesis, since cells are subjected to rapid periodic stimulation during many arrhythmias.

Animals↗
PubMed2001

Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death.

BACKGROUND: A variety of mutations in HERG, the major subunit of the rapidly activating component of the cardiac delayed rectifier I(Kr), have been found to underlie the congenital Long-QT syndrome, LQT2. LQT2 may give rise to severe arrhythmogenic phenotypes leading to sudden cardiac death. OBJECTIVE: We attempt to elucidate the mechanisms by which heterogeneous LQT2 genotypes can lead to prolongation of the action potential duration (APD) and consequently the QT interval on the ECG. METHODS: We develop Markovian models of wild-type (WT) and mutant I(Kr) channels and incorporate these models into a comprehensive model of the cardiac ventricular cell. RESULTS: Using this virtual transgenic cell model, we describe the effects of HERG mutations on the cardiac ventricular action potential (AP) and provide insight into the mechanism by which each defect results in a net loss of repolarizing current and prolongation of APD. CONCLUSIONS: This study demonstrates which mutations can prolong APD sufficiently to generate early afterdepolarizations (EADs), which may trigger life-threatening arrhythmias. The severity of the phenotype is shown to depend on the specific kinetic changes and how they affect I(Kr) during the time course of the action potential. Clarifying how defects in HERG can lead to impaired cellular electrophysiology can improve our understanding of the link between channel structure and cellular function.

Action Potentials↗
PubMed2001

Noninvasive electrocardiogram imaging of substrate and intramural ventricular tachycardia in infarcted hearts.

OBJECTIVES: The goal of this study was to experimentally evaluate a novel noninvasive electrocardiographic imaging modality during intramural reentrant ventricular tachycardia (VT). BACKGROUND: Myocardial infarction and subsequent remodeling produce abnormal electrophysiologic substrates capable of initiating and maintaining reentrant arrhythmias. Existing noninvasive electrocardiographic methods cannot characterize abnormal electrophysiologic substrates in the heart or the details of associated arrhythmias. A noninvasive method with such capabilities is needed to identify patients at risk of arrhythmias and to guide and evaluate therapy. METHODS: A dog heart with a four-day-old infarction was suspended in a human shaped torso-tank. Measured body surface potentials were used to noninvasively compute epicardial potentials, electrograms and isochrones. Accuracy of reconstruction was evaluated by direct comparison to measured data. Reconstructions were performed during right atrial pacing and nine cycles of VT. RESULTS: Noninvasively reconstructed potential maps, electrograms and isochrones identified: 1) the location of electrophysiologically abnormal infarct substrate; 2) the epicardial activation sequences during the VTs; 3) the locations of epicardial breakthrough sites; and 4) electrophysiologic evidence for activation of the Purkinje system and septum during the reentrant beats. CONCLUSIONS: Electrocardiographic imaging can noninvasively reconstruct electrophysiologic information on the epicardium during VT with intramural reentry, provide information about the location of the intramural components of reentry and image abnormal electrophysiologic substrates associated with infarction.

Animals↗
PubMed2001

Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome.

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.

Adrenergic beta-Agonists↗
PubMed2001

Electrocardiographic imaging: I. Effect of torso inhomogeneities on body surface electrocardiographic potentials.

INTRODUCTION: Body surface potential maps (BSPMs) and conventional ECG reflect electrical sources generated by cardiac excitation and repolarization and noninvasively provide important diagnostic information about the electrical state of the heart. Because the heart is located within the torso volume conductor, body surface potentials also reflect the effects of torso inhomogeneities, which include blood, lungs, bone, muscle, fat, and fluid. It is necessary to characterize and understand these effects in order to interpret BSPM and ECG in terms of cardiac activity without "contamination" from the inhomogeneous volume conductor. METHODS AND RESULTS: Actual measured epicardial and body surface potentials were obtained during normal sinus rhythm and for different pacing protocols from a Langendorff-perfused dog heart suspended in a human-shaped torso tank. Accurate geometry of the torso inhomogeneities was digitized from the Visual Human Project and appropriately introduced into a computer model of the tank setup. The geometry and electrical properties of the volume conductor could be varied. Both homogeneous and inhomogeneous torsos have major smoothing effects on BSPM, which is of very low resolution compared with its corresponding epicardial potential pattern. Relative to a homogeneous torso, the inhomogeneities have only a minor effect on BSPM patterns. They augment potential magnitudes depending on the pattern of epicardial activation. Variations of geometry and electrical properties within the normal physiologic range have minimal effects. CONCLUSION: Effects of torso inhomogeneities on 12-lead ECGs are minimal, and the associated ECG changes fall within the range of normal interindividual variations.

Algorithms↗
PubMed2001

Electrocardiographic imaging: II. Effect of torso inhomogeneities on noninvasive reconstruction of epicardial potentials, electrograms, and isochrones.

INTRODUCTION: Noninvasive electrocardiographic imaging (ECGI) involves inverse reconstruction of epicardial potentials, electrograms (EGMs), and isochrones from body surface potential maps (BSPMs). The heart lies in a volume conductor that includes lungs, blood, bone, muscle, and fluid. We investigate the effects of these torso inhomogeneities on reconstructed epicardial potentials, EGMs, and isochrones to address the issue of whether they should be included in clinical ECGI methodology. METHODS AND RESULTS: Potential data were obtained for different pacing protocols from a dog heart suspended in a human-shaped torso tank. Accurate geometry of torso inhomogeneities was digitized from the Visual Human Project and appropriately introduced into a computer model of the torso. Three models were used: accurate inhomogeneous torso, homogeneous torso, and a torso with stylized lungs (to generate an approximate model). The inhomogeneous model was used to compute BSPMs from the measured epicardial potentials. These BSPMs were the starting point for inverse computations in the different torso models. Epicardial potential maps, EGMs, and isochrones were computed. The homogeneous model produced slightly less accurate epicardial potential reconstructions than the inhomogeneous model and stylized lung model, but epicardial potential patterns, EGMs, isochrones, and locations of pacing sites were reconstructed with comparable accuracy when torso inhomogeneities were ignored. CONCLUSION: The results demonstrate that, in the clinical application, it is not necessary to include torso inhomogeneities for noninvasive reconstructions of epicardial potentials, EGMs, and activation sequences.

Animals↗
PubMed2001

The ionic mechanisms of conduction in cardiac tissue.

Computer simulations are used to characterize conduction of the cardiac action potential under the following conditions: 1. Acute myocardial ischemia, 2. Reduced membrane excitability, 3. Reduced intercellular coupling, and 4. Propagation through inhomogeneous tissue structures.

Action Potentials↗
PubMed2000

A noninvasive imaging modality for cardiac arrhythmias.

BACKGROUND: The last decade witnessed an explosion of information regarding the genetic, molecular, and mechanistic basis of heart disease. Translating this information into clinical practice requires the development of novel functional imaging modalities for diagnosis, localization, and guided intervention. A noninvasive modality for imaging cardiac arrhythmias is not yet available. Present electrocardiographic methods cannot precisely localize a ventricular tachycardia (VT) or its key reentrant circuit components. Recently, we developed a noninvasive electrocardiographic imaging modality (ECGI) that can reconstruct epicardial electrophysiological information from body surface potentials. Here, we extend its application to image reentrant arrhythmias. METHODS AND RESULTS: Epicardial potentials were recorded during VT with a 490 electrode sock during an open chest procedure in 2 dogs with 4-day-old myocardial infarctions. Body surface potentials were generated from these epicardial potentials in a human torso model. Realistic geometry errors and measurement noise were added to the torso data, which were then used to noninvasively reconstruct epicardial isochrones, electrograms, and potentials with excellent accuracy. ECGI reconstructed the reentry pathway and its key components, including (1) the central common pathway, (2) the VT exit site, (3) lines of block, and (4) regions of slow and fast conduction. This allowed for detailed characterization of the reentrant circuit morphology. CONCLUSIONS: ECGI can noninvasively image arrhythmic activation on the epicardium during VT to identify and localize key components of the arrhythmogenic pathway that can be effective targets for antiarrhythmic intervention.

Animals↗
PubMed2000

Cellular arrhythmogenic effects of congenital and acquired long-QT syndrome in the heterogeneous myocardium.

BACKGROUND: Certain alterations by mutations or drugs of the potassium currents I(Ks) and I(Kr) and the sodium current I(Na) give rise to several types of the long-QT syndrome. I(Ks) is heterogeneously distributed across the ventricular wall. METHODS AND RESULTS: We investigated the effects of reducing I(Ks) or I(Kr) or enhancing late I(Na) (to simulate the 3 forms of long-QT syndrome) on action potential duration (APD) in the context of I(Ks) heterogeneity. We introduced I(Ks) heterogeneity in the Luo-Rudy dynamic cell model to simulate epicardial, endocardial, and midmyocardial (M) cells. Results demonstrated higher susceptibility of M cells to the development of arrhythmogenic early afterdepolarizations (EADs) in isolated cells and poorly coupled tissue. An important observation is that I(Kr) block or late I(Na) acts to increase APD differences between the cell types, whereas I(Ks) block minimizes such differences. Also, for normal transverse coupling, EADs develop in the endocardial region rather than in the M region as the result of strong electrotonic interaction. CONCLUSIONS: I(Ks) heterogeneity and intercellular coupling strongly influence EAD development during interventions or disorders that prolong APD. M cells in isolation or in poorly coupled tissue are more susceptible to EAD development than epicardial or endocardial cells. In well-coupled myocardium, EAD formation in the subendocardium can be the source of focal arrhythmias or provide the trigger for reentrant excitation. The efficacy of I(Ks) block in minimizing APD dispersion could have important implications for antiarrhythmic therapy.

Action Potentials↗
PubMed2000

Noninvasive ECG imaging of electrophysiologically abnormal substrates in infarcted hearts : A model study.

BACKGROUND: Myocardial infarction and subsequent remodeling create substrates with altered electrophysiological (EP) properties that are highly arrhythmogenic. Existing ECG methods cannot always detect the existence of such substrates nor provide any detailed information about their EP characteristics. A noninvasive method with such capabilities is greatly needed for identifying patients at risk of arrhythmias and for guidance and evaluation of therapy. Recently, we developed a noninvasive ECG imaging modality that can reconstruct epicardial EP information from body surface potentials. We extended its application to hearts with structural disease and examined its ability to detect and characterize abnormal EP substrates. METHODS AND RESULTS: Epicardial potentials were recorded with a 490-electrode sock from an open-chest dog. Recordings were obtained from a normal heart and from the same heart 2 hours after left anterior descending coronary artery occlusion and ethanol injection to create an infarct. Body surface potentials were generated from these epicardial potentials in a human torso model. Realistic geometry errors and measurement noise were added to the torso data, which were then used to noninvasively reconstruct epicardial potentials and electrograms (EGMs), with excellent accuracy. EP characteristics associated with the infarct substrate were reconstructed, including (1) a negative region over the infarct, (2) EGMs with large predominant negative deflections (eg, Q-wave EGMs), (3) Q-wave EGMs with superimposed RS deflections reflecting local activation of surviving myocardium within the infarct border zone, (4) reduced magnitudes of EGM negative derivatives, and (5) negative QRS integrals of EGMs over the infarct. CONCLUSIONS: ECG imaging can noninvasively detect and map abnormal EP substrates associated with infarction and structural heart disease.

Animals↗
PubMed2000

Determinants of excitability in cardiac myocytes: mechanistic investigation of memory effect.

UNLABELLED: The excitability of a cardiac cell depends upon many factors, including the rate and duration of pacing. Furthermore, cell excitability and its variability underlie many electrophysiological phenomena in the heart. In this study, we used a detailed mathematical model of the ventricular myocyte to investigate the determinants of excitability and gain insight into the mechanism by which excitability depends on the rate and duration of pacing (the memory effect). RESULTS: i) The primary determinant of excitability depends upon the duration (T) of the stimulus. ii) For a short T, excitability is determined by the difference between the threshold membrane potential and the resting membrane potential. iii) For a long T, excitability is determined by the resting membrane resistance, R(m). iv) In the case of long T, pacing induced changes in [Na(+)](i) and [Ca(2+)](i) over time affect R(m) and excitability by shifting the current-voltage (IV) curve in the vertical direction and are responsible for the memory effect. CONCLUSIONS: The results have important implications during an arrhythmia, where a cardiac cell may be subjected to rapid repetitive excitation for an extended period of time. Effective anti-arrhythmic strategies may be developed to exploit the R(m) dependence of excitability for a long T.

Animals↗
PubMed2000

Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study.

Sodium overload of cardiac cells can accompany various pathologies and induce fatal cardiac arrhythmias. We investigate effects of elevated intracellular sodium on the cardiac action potential (AP) and on intracellular calcium using the Luo-Rudy model of a mammalian ventricular myocyte. The results are: 1) During rapid pacing, AP duration (APD) shortens in two phases, a rapid phase without Na(+) accumulation and a slower phase that depends on [Na(+)](i). 2) The rapid APD shortening is due to incomplete deactivation (accumulation) of I(Ks). 3) The slow phase is due to increased repolarizing currents I(NaK) and reverse-mode I(NaCa), secondary to elevated [Na(+)](i). 4) Na(+)-overload slows the rate of AP depolarization, allowing time for greater I(Ca(L)) activation; it also enhances reverse-mode I(NaCa). The resulting increased Ca(2+) influx triggers a greater [Ca(2+)](i) transient. 5) Reverse-mode I(NaCa) alone can trigger Ca(2+) release in a voltage and [Na(+)](i)-dependent manner. 6) During I(NaK) block, Na(+) and Ca(2+) accumulate and APD shortens due to enhanced reverse-mode I(NaCa); contribution of I(K(Na)) to APD shortening is negligible. By slowing AP depolarization (hence velocity) and shortening APD, Na(+)-overload acts to enhance inducibility of reentrant arrhythmias. Shortened APD with elevated [Ca(2+)](i) (secondary to Na(+)-overload) also predisposes the myocardium to arrhythmogenic delayed afterdepolarizations.

Action Potentials↗
PubMed2000

Electrophysiologic endocardial mapping from a noncontact nonexpandable catheter: a validation study of a geometry-based concept.

INTRODUCTION: The need for high-resolution simultaneous mapping of cardiac excitation and arrhythmias on a beat-by-beat basis is widely recognized. Here we validate a noncontact mapping approach that combines a spiral catheter design with mathematical reconstruction to generate potential maps, electrograms, and activation maps (isochrones) on the entire left ventricular endocardial surface during a single beat. The approach is applicable to any heart chamber. METHODS AND RESULTS: The catheter is 3 mm (9 French) in diameter and carries 96 electrodes. Reconstruction accuracy is evaluated through direct comparison with endocardial data measured with 95 needle electrodes. Results show that endocardial potentials, electrograms, and isochrones are reconstructed with good accuracy during pacing from single or multiple sites (simulating ectopic activity). Pacing sites can be located to within 5 mm of their actual position, and intersite distances of 17 mm can be resolved during dual pacing. The reconstructed potential pattern reflects the intramural depth of pacing. The reconstructions are robust in the presence of geometric errors, and the accuracy is minimally reduced when only 62 catheter electrodes are used (32 are sufficient for pacing site localization). CONCLUSION: The study demonstrates that simultaneous endocardial mapping can be accomplished during a single beat from a spiral-shaped noncontact catheter with good accuracy.

Animals↗
PubMed2000

From genome to physiome: integrative models of cardiac excitation.

The last decade has generated extensive information on the genetic and molecular basis of disease. A major challenge remains the integration of this information into the physiological environment of the functioning cell and tissue. This article illustrates the use of computational biology in meeting this challenge in the context of cardiac excitation and arrhythmia. (1) Genetics to Cell Function: Mutations that alter the kinetics of the cardiac sodium channel, INa, give rise to a congenital form of the long QT syndrome that can lead to sudden death. Using a computer modelof the cardiac cell, we simulated the effects of the mutations on the action potential, demonstrating its prolongation at slowrate and the develop-rate and the development of arrhythmogenic early afterdepolarizations due to reactivation of L-type Ca channels, ICa(L) [Clancy and Rudy, Nature (London) 400:566, 1999]. (2) Multicellular Tissue: Slow conduction is an important property of propagation arrhythmias (reentry). Very slow conduction is supported by reduced intercellular coupling through gap junctions. Using a multicellular fiber model, we have shown that slow conduction is very stable and, in contrast to normal conduction which depends solely on INa, requires a major contribution from ICa(L) (Shaw and Rudy, Circ. Res. 81:727, 1997).

Action Potentials↗