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Heart rhythm: the official journal of the Heart Rhythm Society 09/2011; 9(2):230-1. · 4.56 Impact Factor
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ABSTRACT: Recently, we demonstrated that ajmaline caused ST segment elevation in the heart of an SCN5A mutation carrier by excitation failure in structurally discontinuous myocardium. In patients with Brugada syndrome, ST segment elevation is modulated by cardiac sodium (I(Na)), transient outward (I(to)), and L-type calcium currents (I(CaL)).
To establish experimentally whether excitation failure by current-to-load mismatch causes ST segment elevation and is modulated by I(to) and I(CaL).
In porcine epicardial shavings, isthmuses of 0.9, 1.1, or 1.3 mm in width were created parallel to the fiber orientation. Local activation was recorded electrically or optically (di-4-ANEPPS) simultaneously with a pseudo-electrocardiogram (ECG) before and after ajmaline application. Intra- and extracellular potentials and ECGs were simulated in a computer model of the heart and thorax before and after introduction of right ventricular structural discontinuities and during varying levels of I(Na), I(to), and I(CaL).
In epicardial shavings, conduction blocked after ajmaline in a frequency-dependent manner in all preparations with isthmuses ≤ 1.1 mm width. Total conduction block occurred in three of four preparations with isthmuses of 0.9 mm versus one of seven with isthmuses ≥ 1.1 mm (P<.05). Excitation failure resulted in ST segment elevation on the pseudo-ECG. In computer simulations, subepicardial structural discontinuities caused local activation delay and made the success of conduction sensitive to I(Na), I(to), and I(CaL). Reduction of I(to) and increase of I(CaL) resulted in a higher excitatory current, overcame subepicardial excitation failure, and reduced the ST segment elevation.
Excitation failure by current-to-load mismatch causes ST segment elevation and, like ST segment elevation in Brugada patients, is modulated by I(to) and I(CaL).
Heart rhythm: the official journal of the Heart Rhythm Society 01/2011; 8(1):111-8. · 4.56 Impact Factor
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ABSTRACT: Models of cardiac electrical activity cover a wide range of spatial scales, from the genesis of the ionic currents in individual cardiomyocytes to the generation of electrocardiograms on the torso. The level of detail that is appropriate and practicable depends on the problem investigated and the scope of the computations that are required. We briefly present three examples of modelling: the dynamics of the entrainment of a single cell, the impact of fibrosis on electrical propagation in a piece of tissue and the generation of ECG in human. In each case, the methods, results and limitations are discussed.
Medecine sciences: M/S 01/2010; 26(1):57-64. · 0.64 Impact Factor
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Mark G Hoogendijk, Mark Potse,
André C Linnenbank,
Arie O Verkerk,
Hester M den Ruijter,
Shirley C M van Amersfoorth,
Eva C Klaver,
Leander Beekman,
Connie R Bezzina,
Pieter G Postema,
Hanno L Tan,
Annette G Reimer,
Allard C van der Wal,
Arend D J Ten Harkel,
Michiel Dalinghaus,
Alain Vinet,
Arthur A M Wilde,
Jacques M T de Bakker,
Ruben Coronel
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ABSTRACT: The Brugada sign has been associated with mutations in SCN5A and with right ventricular structural abnormalities. Their role in the Brugada sign and the associated ventricular arrhythmias is unknown.
The purpose of this study was to delineate the role of structural abnormalities and sodium channel dysfunction in the Brugada sign.
Activation and repolarization characteristics of the explanted heart of a patient with a loss-of-function mutation in SCN5A (G752R) and dilated cardiomyopathy were determined after induction of right-sided ST-segment elevation by ajmaline. In addition, right ventricular structural discontinuities and sodium channel dysfunction were simulated in a computer model encompassing the heart and thorax.
In the explanted heart, disappearance of local activation in unipolar electrograms at the basal right ventricular epicardium was followed by monophasic ST-segment elevation. The local origin of this phenomenon was confirmed by coaxial electrograms. Neither early repolarization nor late activation correlated with ST-segment elevation. At sites of local ST-segment elevation, the subepicardium was interspersed with adipose tissue and contained more fibrous tissue than either the left ventricle or control hearts. In computer simulations entailing right ventricular structural discontinuities, reduction of sodium channel conductance or size of the gaps between introduced barriers resulted in subepicardial excitation failure or delayed activation by current-to-load mismatch and in the Brugada sign on the ECG.
Right ventricular excitation failure and activation delay by current-to-load mismatch in the subepicardium can cause the Brugada sign. Therefore, current-to-load mismatch may underlie the ventricular arrhythmias in patients with the Brugada sign.
Heart rhythm: the official journal of the Heart Rhythm Society 10/2009; 7(2):238-48. · 4.56 Impact Factor
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ABSTRACT: Local unipolar electrograms (UEGs) permit assessment of local activation and repolarization times at multiple sites simultaneously. However, UEG-based indexes of local repolarization are still debated, in particular for positive T waves. Previous experimental and computer modeling studies have not been able to terminate the debate. In this study we validate a simple theoretical model of the UEG and use it to explain how repolarization statistics in the UEG relate to those in the action potential. The model reconstructs the UEG by taking the difference between an inverted local action potential and a position-independent remote signal. In normal tissue, this extremely simple model predicts T-wave morphology with surprising accuracy while explaining in a readily understandable way why the instant of repolarization is always related to the steepest upstroke of the UEG, both in positive and negative T waves, and why positive T waves are related to early repolarizing sites, whereas negative T waves are related to late repolarizing sites.
AJP Heart and Circulatory Physiology 06/2009; 297(2):H792-801. · 3.71 Impact Factor
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ABSTRACT: The boundary-element method (BEM) is widely used for electrocardiogram (ECG) simulation. Its major disadvantage is its perceived inability to deal with the anisotropic electric conductivity of the myocardial interstitium, which led researchers to represent only intracellular anisotropy or neglect anisotropy altogether. We computed ECGs with a BEM model based on dipole sources that accounted for a "compound" anisotropy ratio. The ECGs were compared with those computed by a finite-difference model, in which intracellular and interstitial anisotropy could be represented without compromise. For a given set of conductivities, we always found a compound anisotropy value that led to acceptable differences between BEM and finite-difference results. In contrast, a fully isotropic model produced unacceptably large differences. A model that accounted only for intracellular anisotropy showed intermediate performance. We conclude that using a compound anisotropy ratio allows BEM-based ECG models to more accurately represent both anisotropies.
Medical & Biological Engineering 04/2009; 47(7):719-29. · 1.76 Impact Factor
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Medical & Biological Engineering 02/2009; 47(3):241-3. · 1.76 Impact Factor
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ABSTRACT: Ischemic heart disease is associated with large mortality and morbidity. Understanding of the relations between coronary artery occlusion, geometry of the ischemic region, physiology of ischemia, and the resulting changes in electrocardiogram (ECG) leads and catheter signals is important to support diagnosis and treatment. Computer models play an important role in understanding ischemia, by linking experimental to clinical results. In this paper we argue that the observed transport of extracellular potassium should be represented in such models. We used a diffusion equation to describe the transport mechanism. This model reproduced the measured spatial distribution of potassium, and its temporal development. We discuss the role of potassium transport next to other aspects of ischemia: the mechanism of changes in action potential and ECG, cellular coupling, anisotropic bidomain tissue conductivity, and the geometry of the ischemic zone.
Medical & Biological Engineering & Computing 01/2008; 45(12):1187-99. · 1.88 Impact Factor
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22nd Annual International Symposium on High Performance Computing Systems and Applications (HPCS 2008), June 9-11, 2008, Québec City, Canada; 01/2008
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ABSTRACT: The dynamics of reentry is studied in a one-dimensional loop of model cardiac cells with discrete intercellular gap junction resistance (R). Each cell is represented by a continuous cable with ionic current given by a modified Beeler-Reuter formulation. For R below a limiting value, propagation is found to change from period-1 to quasiperiodic (QP) at a critical loop length (L(crit)) that decreases with R. Quasiperiodic reentry exists from L(crit) to a minimum length (L(min)), which also shortens with R. The decrease of L(crit) (R) is not a simple scaling, but the bifurcation can still be predicted from the slope of the restitution curve giving the duration of the action potential as a function of the diastolic interval. However, the shape of the restitution curve changes with R. An increase of R does not seem to increase the number of possible QP solutions since, as in the continuous cable, only two QP modes of propagation were found despite an extensive search through alternative initial conditions.
Physical Review E 09/2007; 76(2 Pt 1):021928. · 2.26 Impact Factor
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ABSTRACT: Propagation of depolarisation and repolarisation in myocardium results from an interplay of membrane potential, transmembrane current, and intercellular current. This process can be represented mathematically with a reaction-diffusion (RD) equation. Solving RD equations for a whole heart requires a supercomputer. Therefore, earlier models used predefined action potential (AP) shapes and fixed propagation velocities. We discuss why RD models are important when T waves are studied.
We simulated propagating AP with an RD model of the human heart, which included heterogeneity of membrane properties. Computed activation times served as input to a model that used predefined AP, and to a "hybrid model" that computed AP only during repolarisation. The hybrid model was tested with different spatial resolutions. Electrocardiograms (ECGs) were computed with all three models.
Computed QRS complexes were practically identical in all models. T waves in the fixed-AP model had 20 to 40% larger amplitudes in leads V1-V3. The hybrid model produced the same T waves as the RD model at 0.25-mm resolution, but underestimated T-wave amplitude at lower resolutions.
Fixed AP waveforms in a forward ECG model lead to exaggerated T waves. Hybrid models require the same high spatial resolution as RD models.
Anadolu kardiyoloji dergisi: AKD = the Anatolian journal of cardiology 08/2007; 7 Suppl 1:123-4. · 0.44 Impact Factor
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ABSTRACT: The instant of maximum slope (Tup) of the T wave in the unipolar electrogram is a well-established measure of repolarisation time (TR). Nevertheless, recent observations on positive T waves have caused a renewed debate. The purpose of this study was to elucidate the mechanism that leads to positive and negative T waves and to investigate which electrogram feature best predicts TR.
We simulated propagating action potentials (AP) and electrograms with a bidomain reaction-diffusion model of the human heart including heterogeneous ion-channel properties. To explain positive T waves we compared results with those of a much simpler model, which predicts T waves from local and remote AP.
Repolarisation time was defined as the instant of steepest downstroke of the AP. T wave polarity was mostly determined by TR. Positive T waves occurred at early-repolarising sites. Correlation between Tup and TR was >0.99, in both negative and positive T waves. T wave area and peak value also correlated highly with TR.
The polarity of the T wave is primarily determined by TR. Positive T waves occur at early-repolarising sites. Local TR is best estimated by Tup, also in positive T waves.
Anadolu kardiyoloji dergisi: AKD = the Anatolian journal of cardiology 08/2007; 7 Suppl 1:164-7. · 0.44 Impact Factor
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ABSTRACT: The electrocardiogram (ECG) obtained during stress testing often shows a typical pattern of primary ST depression. A similar pattern can occur in unstable angina. Current textbooks consider ST depression as a direct result of partial occlusion of a coronary artery. However, animal models could not reproduce this phenomenon. An alternative explanation for ST depression specific to stress testing involves global subendocardial ischemia. In this study, we evaluated both explanations with a realistic mathematical model of the human heart.
The ECG was simulated with an anisotropic reaction-diffusion model of the human heart and an inhomogeneous boundary-element model of the human torso.
Limited subendocardial ischemic zones caused small ST depression in ECG leads not overlying the ischemic region. An ischemic zone of 50% transmural extent covering the entire left ventricular subendocardium caused an ST-depression pattern similar to that observed during stress test.
In contrast to regional subendocardial ischemia, global subendocardial ischemia can explain ST depression in our model.
Anadolu kardiyoloji dergisi: AKD = the Anatolian journal of cardiology 08/2007; 7 Suppl 1:145-7. · 0.44 Impact Factor
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ABSTRACT: Dynamics of reentry are studied in a one dimensional loop of model cardiac cells with discrete intercellular gap junction resistance ($R$). Each cell is represented by a continuous cable with ionic current given by a modified Beeler-Reuter formulation. For $R$ below a limiting value, propagation is found to change from period-1 to quasi-periodic ($QP$) at a critical loop length ($L_{crit}$) that decreases with $R$. Quasi-periodic reentry exists from $L_{crit}$ to a minimum length ($L_{min}$) that is also shortening with $R$. The decrease of $L_{crit}(R)$ is not a simple scaling, but the bifurcation can still be predicted from the slope of the restitution curve giving the duration of the action potential as a function of the diastolic interval. However, the shape of the restitution curve changes with $R$. Comment: 6 pages, 7 figures
03/2007;
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ABSTRACT: Myocardial ischemia causes ST segment elevation or depression in electrocardiograms and epicardial leads. ST depression in epicardium overlying the ischemic zone indicates that the ischemia is nontransmural. However, nontransmural ischemia does not always cause ST depression. Especially in animal models, ST depression is hard to reproduce.
The purpose of this study was to determine the circumstances in which ST depression could be expected.
We studied ischemia in a large-scale computer model of the human heart. A realistic representation of the ischemia-induced changes in resting membrane potential was used, which was based on diffusion of extracellular potassium. Ischemia diameter, transmural extent, and tissue conductivity were varied.
Our simulations confirm earlier work showing that partial-thickness ischemia, like full-thickness ischemia, typically causes ST elevation in an anisotropic model of the ventricles. However, we identified three situations in which ST depression can occur in overlying leads. The first is a reduced anisotropy ratio of the intracellular conductivity, which may result from hypertrophy and gap-junctional remodeling, circumstances that are likely to accompany ischemia. Second, an increase of the extracellular anisotropy has the same effect. Third, ST depression was found, independent of the anisotropy ratios, in very large and thin ischemic regions, resembling those that may occur in left-main or multivessel disease.
Both tissue remodeling and geometric factors can explain ST depression in overlying epicardial leads. We note at the same time that ST elevation is found in most circumstances, while depression occurs as a reciprocal effect, even in partial-thickness ischemia.
Heart Rhythm 03/2007; 4(2):200-6. · 4.10 Impact Factor
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ABSTRACT: Myocardial ischemia leads to an efflux of potassium ions from affected cells. The resulting depolarization of the resting membrane is one of the main features of ischemic myocardium. It has been shown experimentally that a part of the surplus interstitial potassium is transported out of the ischemic zone, even if no coronary blood flow is present in the affected area. We propose to model this transport mechanism mathematically with a diffusion equation. This model explains the measured spatial profiles of extracellular potential and potassium concentration. In addition, it allows a quantitative prediction of the transmembrane current that flows as a result of ischemia-induced depolarization. This current is thought to play a role in arrhythmogenicity, which is an important cause of mortality in acute myocardial infarction. Our model predicts that this current reaches its maximum exactly on the border of the hypoxic area. An important depolarizing current would be present just within the border, where hypoxia is accompanied by a resting membrane potential that is only slightly elevated, due to coupling with the adjacent normal tissue. Still, in the presence of potassium transport the predicted current density is not large enough to explain ectopic activation on the lateral border of the ischemia. This suggests that activation is more likely to occur at the endocardium, where the potassium gradient is steeper.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2007; 2007:6331-4.
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ABSTRACT: As a measure of local repolarization time (T(R)), the instant of maximum slope (T(up)) of the T wave in the local unipolar electrogram is commonly used. Measurement of T(up) can be difficult, especially in positive T waves. These difficulties have led some researchers to propose the instant of maximum downslope (T(down)) as a marker of T(R) when the T wave is positive. To improve understanding of T-wave parameters, we simulated electrograms with a bidomain model of the human heart. To test T-wave parameters, we compared them to T(R) determined from the local membrane potential. We propose a simple model of the electrogram, which we validated by comparison to the bidomain model. With the simple model, it is straightforward to show that the sign of the T wave is almost uniquely determined by T(R). We then used the bidomain model to simulate the effects of a variety of pathologies and technical difficulties, which the simple model could not account for. Generally, T(up) was a much better estimate for T(R) than T(down). Regional fibrosis could attenuate local electrogram components and reduce accuracy of T(up) as a marker for T(R). In fibrotic tissue, T(down) was not related to T(R) at all. This investigation of electrogram slopes required the simulation of extracellular potentials with about 100 times more precision than needed for simulation of visually acceptable waveforms alone. This requirement is more difficult to meet in larger models, but it was actually possible for a human-heart model with 60 million nodes. By sacrificing some spatial resolutions, we kept the computational requirements within acceptable limits for multiple simulations.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2007; 2007:6644-7.
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ABSTRACT: A bidomain reaction-diffusion model of the human heart was developed, and potentials resulting from normal depolarization and repolarization were compared with results from a compatible monodomain model. Comparisons were made for an empty isolated heart and for a heart with fluid-filled ventricles. Both sinus rhythm and ectopic activation were simulated. The bidomain model took 2 days on 32 processors to simulate a complete cardiac cycle. Differences between monodomain and bidomain results were extremely small, even for the extracellular potentials, which in case of the monodomain model were computed with a high-resolution forward model. Propagation of activation was 2% faster in the bidomain model than in the monodomain model. Electrograms computed with monodomain and bidomain models were visually indistinguishable. We conclude that, in the absence of applied currents, propagating action potentials on the scale of a human heart can be studied with a monodomain model.
IEEE Transactions on Biomedical Engineering 01/2007; 53(12 Pt 1):2425-35. · 2.28 Impact Factor
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ABSTRACT: A bidomain reaction-diffusion model of the human heart was developed and potentials resulting from normal depolarization and repolarization were compared with results from a compatible monodomain model. Comparisons were made for an empty isolated heart and for a heart with fluid-filled ventricles. Both sinus rhythm and ectopic activation were simulated. The model took 2 days on 32 processors to simulate a complete cardiac cycle. Differences between monodomain and bidomain results were very small, even for the extracellular potentials which, for the monodomain model, were computed with a high-resolution forward model. Electrograms computed with monodomain and bidomain models were visually indistinguishable. We conclude that, in the absence of applied currents, propagating action potentials on the scale of a human heart can be studied with a monodomain model.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:3895-8.
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ABSTRACT: ST-segment depression in epicardial electrograms can be a "reciprocal" effect of remote myocardial ischemia (MI), and can also be due to local partial-thickness or "subendocardial" MI. Experimental studies have shown either ST elevation or depression in leads overlying a subendocardial ischemic region. Those reporting elevation have shown depression over the lateral borders of the ischemia. Simulation studies with anisotropic models have explained the ST-elevation results. Presently, while experimentalists may have difficulty understanding the ST elevation, most model studies fail to explain ST depression in overlying leads during partial-thickness ischemia. We have simulated partial-thickness ischemia in a 3-dimensional model of the human heart. Our results show that the conductivity of the intracavitary blood, geometry of the ischemic region, and bidomain anisotropy ratios can all have a decisive influence on the sign of the ST deviation. We hypothesize that ST depression in leads overlying an ischemic zone is due to subendocardial ischemia in tissue where a redistribution of gap junctions has taken place.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:3899-902.
