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Biomedical subjects

Y Rudy

Publications and source records attributed to Y Rudy.

At least 19 recordsLinked to original sources
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↗
PubMed2000

Action potential propagation in inhomogeneous cardiac tissue: safety factor considerations and ionic mechanism.

Heterogeneity of myocardial structure and membrane excitability is accentuated by pathology and remodeling. In this study, a detailed model of the ventricular myocyte in a multicellular fiber was used to compute a location-dependent quantitative measure of conduction (safety factor, SF) and to determine the kinetics and contribution of sodium current (I(Na)) and L-type calcium current [I(Ca(L))] during conduction. We obtained the following results. 1) SF decreases sharply for propagation into regions of increased electrical load (tissue expansion, increased gap junction coupling, reduced excitability, hyperkalemia); it can be <1 locally (a value indicating conduction failure) and can recover beyond the transition region to resume propagation. 2) SF and propagation across inhomogeneities involve major contribution from I(Ca(L)). 3) Modulating I(Na) or I(Ca(L)) (by blocking agents or calcium overload) can cause unidirectional block in the inhomogeneous region. 4) Structural inhomogeneity causes local augmentation of I(Ca(L)) and suppression of I(Na) in a feedback fashion. 5) Propagation across regions of suppressed I(Na) is achieved via a I(Ca(L))-dependent mechanism. 6) Reduced intercellular coupling can effectively compensate for reduced SF caused by tissue expansion but not by reduced membrane excitability.

Action Potentials↗
PubMed2000

Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome.

Hereditary long QT syndrome (hLQTS) is a heterogeneous genetic disease characterized by prolonged QT interval in the electrocardiogram, recurrent syncope, and sudden cardiac death. Mutations in the cardiac potassium channel HERG (KCNH2) are the second most common form of hLQTS and reduce the delayed rectifier K(+) currents, thereby prolonging repolarization. We studied a novel COOH-terminal missense mutation, HERG R752W, which segregated with the disease in a family of 101 genotyped individuals. When the mutant cRNA was expressed in Xenopus oocytes it produced enhanced rather than reduced currents. Simulations using the Luo-Rudy model predicted minimal shortening rather than prolongation of the cardiac action potential. Consequently, a normal or shortened QT interval would be expected in contrast to the long QT observed clinically. This anomaly was resolved by our observation that the mutant protein was not delivered to the plasma membrane of mammalian cells but was retained intracellularly. We found that this trafficking defect was corrected at lower incubation temperatures and that functional channels were now delivered to the plasma membrane. However, trafficking could not be restored by chemical chaperones or E-4031, a specific blocker of HERG channels. Therefore, HERG R752W represents a new class of trafficking mutants in hLQTS. The occurrence of different classes of misprocessed channels suggests that a unified therapeutic approach for altering HERG trafficking will not be possible and that different treatment modalities will have to be matched to the different classes of trafficking mutants.

Action Potentials↗
PubMed2000

Dynamics of action potential head-tail interaction during reentry in cardiac tissue: ionic mechanisms.

In a sufficiently short reentry pathway, the excitation wave front (head) propagates into tissue that is partially refractory (tail) from the previous action potential (AP). We incorporate a detailed mathematical model of the ventricular myocyte into a one-dimensional closed pathway to investigate the effects of head-tail interaction and ion accumulation on the dynamics of reentry. The results were the following: 1) a high degree of head-tail interaction produces oscillations in several AP properties; 2) Ca(2+)-transient oscillations are in phase with AP duration oscillations and are often of greater magnitude; 3) as the wave front propagates around the pathway, AP properties undergo periodic spatial oscillations that produce complicated temporal oscillations at a single site; 4) depending on the degree of head-tail interaction, intracellular [Na(+)] accumulation during reentry either stabilizes or destabilizes reentry; and 5) elevated extracellular [K(+)] destabilizes reentry by prolonging the tail of postrepolarization refractoriness.

Action Potentials↗
PubMed1999

Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia.

Advances in genetics and molecular biology have provided an extensive body of information on the structure and function of the elementary building blocks of living systems. Genetic defects in membrane ion channels can disrupt the delicate balance of dynamic interactions between the ion channels and the cellular environment, leading to altered cell function. As ion-channel defects are typically studied in isolated expression systems, away from the cellular environment where they function physiologically, a connection between molecular findings and the physiology and pathophysiology of the cell is rarely established. Here we describe a single-channel-based Markovian modelling approach that bridges this gap. We achieve this by determining the cellular arrhythmogenic consequences of a mutation in the cardiac sodium channel that can lead to a clinical arrhythmogenic disorder (the long-QT syndrome) and sudden cardiac death.

Action Potentials↗
PubMed1999

Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study.

BACKGROUND: A growing body of evidence suggests that heterogeneity of ion channel expression and electrophysiological characteristics is an important property of the ventricular myocardium. The 2 components of the delayed rectifier potassium current, IKr (rapid) and IKs (slow), play a dominant role in the repolarization of the action potential and are important determinants of its duration. METHODS AND RESULTS: In this report, the effects of heterogeneities of IKr and IKs on action potential duration (APD) and its rate dependence (adaptation) are studied with the use of the LRd model of a mammalian ventricular cell. Results demonstrate the importance of IKs density variations in heterogeneity of repolarization. Cells with reduced IKs (eg, mid-myocardial M cells) display long APD and steep dependence of APD on rate. Mechanistically, accumulation of IKs activation and increased sodium calcium exchange current, INaCa, secondary to Na+ accumulation at a fast rate underlie the steep APD-rate relation of these cells. When cells are electrotonically coupled in a multicellular fiber through resistive gap junction, APD differences are reduced. The results demonstrate strong dependence of APD heterogeneity on the degree of intercellular coupling even in the normal physiological range. Highly reduced coupling maximizes APD heterogeneity. CONCLUSIONS: Heterogeneity of IKs:IKr density strongly influences APD and its rate dependence. However, in the intact myocardium, the degree of gap-junction coupling may be an important factor that determines the manifestation of APD heterogeneity and dispersion of repolarization. The clinical significance of this study is in the context of repolarization abnormalities and associated arrhythmias (eg, long QT syndrome and torsade de pointes).

Action Potentials↗
PubMed1999

Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II.

Genetic approaches have succeeded in defining the molecular basis of an increasing array of heart diseases, such as hypertrophic cardiomyopathy and the long-QT syndromes, associated with serious arrhythmias. Importantly, the way in which this new knowledge can be applied to managing patients and to the development of syndrome-specific antiarrhythmic strategies is evolving rapidly because of these recent advances. In addition, the extent to which new knowledge represents a purely research tool versus the extent to which it can be applied clinically is also evolving. The present article represents a consensus report of a meeting of the European Working Group on Arrhythmias. The current state of the art of the molecular and genetic basis of inherited arrhythmias is first reviewed, followed by practical advice on the role of genetic testing in these and other syndromes and the way in which new findings have influenced current understanding of the molecular and biophysical basis of arrhythmogenesis.

Arrhythmias, Cardiac↗
PubMed1999

Pause induced early afterdepolarizations in the long QT syndrome: a simulation study.

OBJECTIVE: The long QT syndrome (LQTS) is characterized by prolonged repolarization and propensity to syncope and sudden death due to polymorphic ventricular tachycardias such as torsade de pointes (TdP). The exact mechanism of TdP is unclear, but pause-induced early afterdepolarizations (EADs) have been implicated in its initiation. In this study we investigate the mechanism of pause-induced EADs following pacing at clinically relevant rates and characterize the sensitivity of different cell types (epicardial, midmyocardial, and endocardial) to EAD development. METHODS: Simulations were conducted using the Luo-Rudy (LRd) model of the mamalian ventricular action potential (AP). Three cell types--epicardial, midmyocardial (M), and enocardial--are represented by altering the channel density of the slow delayed rectifier current, IKs. LQTS is modelled by enhanced late sodium current (LQT3), or reduced density of functional channels that conduct IKr (LQT2) and IKs (LQT1). The cell is paced 40 times at a constant Basic Cycle Length (BCL) of 500 ms. Following a 1500 ms pause, an additional single stimulus is applied. RESULTS: Our results demonstrate that pause-induced EADs develop preferentially in M cells under conditions of prolonged repolarization. These EADs develop at plateau potentials ('plateau EADs'). Mechanistic investigation shows that prolongation of the plateau phase of the post-pause AP due to a smaller delayed rectifier potassium current, IKs' and enhancement of the sodium-calcium exchange current, INaCa, allows for the reactivation of the L-type calcium current, ICa(L), which depolarizes the membrane to generate the EAD. CONCLUSIONS: APD is a very important determinant of arrhythmogenesis and its prolongation, either due to acquired or congenital LQTS, can result in the appearance of EADs. The formation of pause-induced EADs preferentially in M cells suggests a possible role for these cells in the generation of arrhythmias that are associated with abnormalities of repolarization (e.g., TdP). The ionic mechanism of pause-induced EADs involves reactivation of the L-type calcium current during the prolonged plateau of the post-pause AP.

Action Potentials↗
PubMed1999

An interactive graphical system for automated mapping and display of cardiac rhythms.

Electrical cardiac mapping has been used to study the mechanisms of cardiac arrhythmias, to assist in clinical diagnosis of rhythm disorders, to guide interventional procedures, or to evaluate the effects of antiarrhythmic drugs. Manual determination of local activation times, the first step in constructing activation maps, is a time-consuming process that precludes the possibility of on-line interactive mapping during an electrophysiologic experiment or a clinical procedure. This report describes an interactive graphic user interface application that (1) automatically determines the activation sequences with good accuracy, (2) displays graphical presentations of activation maps within seconds, and (3) allows manual interactive adjustments. Five automated activation time detection algorithms, one for bipolar electrograms and four for unipolar electrograms, were evaluated and compared. High-density canine recordings were used to evaluate the accuracy of the system. Data included normal atrial activation (sinus rhythm) and abnormal reentrant atrial activation (atrial flutter).

Algorithms↗