This study uses computer modeling to analyze beat-to-beat variations in action potential duration (APD) in cells modeling the long QT syndrome type 3 (LQT3). Simulations of wild-type cells showed stable APDs, while LQT3 mutant cells developed APD alternans over a narrow range of stimulation frequencies. APD alternans occurred when early afterdepolarizations (EADs) caused irregularities in the diastolic interval, leading to unstable APDs. Larger EADs in homozygous mutant cells caused APD alternans over a wider range of frequencies. This dynamical analysis helps explain rate-dependent arrhythmias in LQT3.
Harmonic Suppression of Shunt Hybrid Filter using LQR-PSO based IJECEIAES
In linear quadratic regulator (LQR), two different weighting matrices play an important role in presenting the performance of this controller. Instead of using classic common approach, which is trial and error method, this study proposes a particle swarm optimization (PSO) algorithm to track the best solution of the weighting matrices. The proposed algorithm is tested on shunt hybrid active power filter (APF) to mitigate the harmonic contents in voltage and current signals in a nonlinear load system. The modeling work of this proposed system is simulated using MATLAB/Simulink software. From the simulation, the obtained results proved that using PSO in tuning the LQR controller produce smoother nonlinear voltage and current signals. In fact, the amount of current to be injected into network can be reduced up to 95%. Besides, less time is consumed during searching the optimum weighting matrices using the proposed approach.
Calpain Inhibitors and Modulation of Ischaemia Reperfusion Induced Apoptosis ...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
The QRS changes during ischemia have historically been more difficult to parameterize
and have not come into clinical practice. This paper presented a new approach to analyze ischemia
by time parameter extraction of RS-Segment of the QRS complex. The proposed methodology
mainly focused on two prominent areas; first: detection of R and S points via Fast Fourier Transform
(FFT) based windowing & thresholding techniques with a sliding edge method. Second: calculating
the RS-Duration. The performances of the detection methods are validated and RS-Duration is
evaluated with the Fantasia database (Fantasia) for 20 healthy subjects & Long-Term ST Database
(LTSTDB) for 80 ischemic patients. The RS-Segment detection sensitivity (Se) and specificity (Sp)
are calculated 100% for Fantasia Database, whereas sensitivity (Se) is 91.6% and specificity (Sp) is
974% for LTSTDB.
Denoising of Radial Bioimpedance Signals using Adaptive Wavelet Packet Transf...iosrjce
In recent years, the accurate computer aided diagnosis of the cardiovascular diseases is gaining
momentum. In addition to accuracy, non-invasiveness of the measurement techniques has become the need of
the hour. Impedance cardiography is one such method which has become a synonym for indirect assessment of
monitoring the stroke volume, cardiac output and other hemodynamic parameters by monitoring the blood
volume changes of the body. Changes occurring in the blood volume within a certain body segment due to
various physiological processes are captured in terms of the impedance variations of that segment. But this
method is affected by electrical noise such as power line hum and motion and respiratory artifacts due to
movement of the subject while acquiring the bioimpedance signal. This can cause errors in the automatic
extraction of the characteristic points for estimation the hemodynamic parameters. This paper presents two
algorithms for baseline wander removal from the bioimpedance waveform obtained at the radial pulse of the left
hand, one based on wavelet packet decomposition and the other based on the Kalman filter. The impedance
signals have been acquired by using the peripheral pulse analyzer. The results for the wavelet packet decomposition are found to be better than that of the Kalman filter.
Harmonic Suppression of Shunt Hybrid Filter using LQR-PSO based IJECEIAES
In linear quadratic regulator (LQR), two different weighting matrices play an important role in presenting the performance of this controller. Instead of using classic common approach, which is trial and error method, this study proposes a particle swarm optimization (PSO) algorithm to track the best solution of the weighting matrices. The proposed algorithm is tested on shunt hybrid active power filter (APF) to mitigate the harmonic contents in voltage and current signals in a nonlinear load system. The modeling work of this proposed system is simulated using MATLAB/Simulink software. From the simulation, the obtained results proved that using PSO in tuning the LQR controller produce smoother nonlinear voltage and current signals. In fact, the amount of current to be injected into network can be reduced up to 95%. Besides, less time is consumed during searching the optimum weighting matrices using the proposed approach.
Calpain Inhibitors and Modulation of Ischaemia Reperfusion Induced Apoptosis ...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
The QRS changes during ischemia have historically been more difficult to parameterize
and have not come into clinical practice. This paper presented a new approach to analyze ischemia
by time parameter extraction of RS-Segment of the QRS complex. The proposed methodology
mainly focused on two prominent areas; first: detection of R and S points via Fast Fourier Transform
(FFT) based windowing & thresholding techniques with a sliding edge method. Second: calculating
the RS-Duration. The performances of the detection methods are validated and RS-Duration is
evaluated with the Fantasia database (Fantasia) for 20 healthy subjects & Long-Term ST Database
(LTSTDB) for 80 ischemic patients. The RS-Segment detection sensitivity (Se) and specificity (Sp)
are calculated 100% for Fantasia Database, whereas sensitivity (Se) is 91.6% and specificity (Sp) is
974% for LTSTDB.
Denoising of Radial Bioimpedance Signals using Adaptive Wavelet Packet Transf...iosrjce
In recent years, the accurate computer aided diagnosis of the cardiovascular diseases is gaining
momentum. In addition to accuracy, non-invasiveness of the measurement techniques has become the need of
the hour. Impedance cardiography is one such method which has become a synonym for indirect assessment of
monitoring the stroke volume, cardiac output and other hemodynamic parameters by monitoring the blood
volume changes of the body. Changes occurring in the blood volume within a certain body segment due to
various physiological processes are captured in terms of the impedance variations of that segment. But this
method is affected by electrical noise such as power line hum and motion and respiratory artifacts due to
movement of the subject while acquiring the bioimpedance signal. This can cause errors in the automatic
extraction of the characteristic points for estimation the hemodynamic parameters. This paper presents two
algorithms for baseline wander removal from the bioimpedance waveform obtained at the radial pulse of the left
hand, one based on wavelet packet decomposition and the other based on the Kalman filter. The impedance
signals have been acquired by using the peripheral pulse analyzer. The results for the wavelet packet decomposition are found to be better than that of the Kalman filter.
IJRET : International Journal of Research in Engineering and Technology is an international peer reviewed, online journal published by eSAT Publishing House for the enhancement of research in various disciplines of Engineering and Technology. The aim and scope of the journal is to provide an academic medium and an important reference for the advancement and dissemination of research results that support high-level learning, teaching and research in the fields of Engineering and Technology. We bring together Scientists, Academician, Field Engineers, Scholars and Students of related fields of Engineering and Technology
IJRET : International Journal of Research in Engineering and Technology is an international peer reviewed, online journal published by eSAT Publishing House for the enhancement of research in various disciplines of Engineering and Technology. The aim and scope of the journal is to provide an academic medium and an important reference for the advancement and dissemination of research results that support high-level learning, teaching and research in the fields of Engineering and Technology. We bring together Scientists, Academician, Field Engineers, Scholars and Students of related fields of Engineering and Technology
International Journal of Computational Engineering Research (IJCER) is dedicated to protecting personal information and will make every reasonable effort to handle collected information appropriately. All information collected, as well as related requests, will be handled as carefully and efficiently as possible in accordance with IJCER standards for integrity and objectivity.
International Journal of Engineering Research and Development (IJERD)IJERD Editor
journal publishing, how to publish research paper, Call For research paper, international journal, publishing a paper, IJERD, journal of science and technology, how to get a research paper published, publishing a paper, publishing of journal, publishing of research paper, reserach and review articles, IJERD Journal, How to publish your research paper, publish research paper, open access engineering journal, Engineering journal, Mathemetics journal, Physics journal, Chemistry journal, Computer Engineering, Computer Science journal, how to submit your paper, peer reviw journal, indexed journal, reserach and review articles, engineering journal, www.ijerd.com, research journals,
yahoo journals, bing journals, International Journal of Engineering Research and Development, google journals, hard copy of journal
Hemodynamic Assessment Series by Transonic -- Part 1: PV Loop Case StudyInsideScientific
Session 3 of our PV Loop Webseries was a case study review in Pressure-Volume loops, sponsored by Transonic. Guest speakers, Dr. Craig Emter, Dr. Robert Hamlin, Dr. Timothy Hacker, and Dr. Filip Konecny discussed the role of PV loops in HFpEF, Drug-Discovery and Safety Testing, Right Ventricular PV Loops in Pulmonary HTN, and Medical Device Testing using LVADs as an example. The over riding topic linking all four of these short lectures was how PV loops work in concert with other techniques, permitting complete hemodynamic evaluation.
Case Study 1: Integrating Coronary Vascular & Myocardial Function in Mini-swine with Heart Failure (an aortic banding model of HFpEF) -- Dr. Craig Emter
Case Study 2: What are the properties of this compound? (reviewing the value and need for PV loops in drug-discovery and safety testing in pharmaceutical research labs) -- Dr. Robert Hamlin
Case Study 3: The Utility of Right Ventricular PV Loops (a mouse model of Pulmonary Arterial Hypertension that transitions from compensatory RV remodeling to right heart failure) Dr. Timothy Hacker
Case Study 4: Synergy of Pressure-Volume Technology with Left Ventricular Assisted Devices (why PV loops are valuable when conducting LVAD testing in both pre and post operation situations)
TOWARDS TEMPERATURE-INSENSITIVE NANOSCALE CMOS CIRCUITS WITH ADAPTIVELY REGUL...VLSICS Design
In this paper, we show that the temperature-induced performance drop seen in nanoscale CMOS circuitscan be tackled by powering the circuits with adaptively regulated voltage power supplies. Essentially, when temperature rises, the supply voltage will be bumped up to offset otherwise performance degradation. To avoid thermal over-drift as chip temperature exceeds its operation range, a voltage limiteris integrated into the proposed power supply to cap the supply voltage. Using this proposed adaptive voltage source to power individual CMOS logic gates and/or subsystems will free the chips from using expensive high-precision temperature sensors for thermal management and performance tuning. Experiments on various benchmark circuits, which are implemented with a 45nm CMOS technology, have confirmed that the circuit delay variation can be reduced to 15%~30% over a wide temperature range (0℃ to 90℃), a sharp contrast to the large delay variations(50%~75%)observed in most IC designs where a constant power supply is employed.
A combined skewed ring oscillator by different type of delay stages is presented. This paper aims to drive a high stable and relatively high frequency but still use a full transistor circuit for ring oscillator with combined delay stages and skewed connections. First we propose two types of common inverters then calculate their delay time and analysis their dependence of delay time to variation of power supply voltage. The simulation results verify that delay time of these two CMOS inverters show opposite behaviour versus power supply changing. So a combined structure can obtain more appropriate frequency stability versus power supply noise. Also in order to increase oscillation frequency we have used the negative skewed delay
connections. The simulation results using HSPICE for 0.18 µm CMOS shows a good agreement with analysis results. In addition in this paper the mathematical justification for improved functioning of this combined skewed ring oscillator has been proved. This justification shows appropriate agreement with the
simulation results. From mathematical point of view the proposed ring oscillator has better frequency stability in comparison with other types of ring oscillators. In fact, the oscillation frequency sensitivity to supply voltage noise is reduced considerably.
Heart rate detection using hilbert transformeSAT Journals
Abstract The electrocardiogram (ECG) is a well known method that can be used to measure Heart Rate Variability (HRV). This paper describes a procedure for processing electrocardiogram signals (ECG) to detect Heart Rate Variability (HRV). In recent years, there have been wide-ranging studies on Heart rate variability in ECG signals and analysis of Respiratory Sinus Arrhythmia (RSA). Normally the Heart rate variability is studied based on cycle length variability, heart period variability, RR variability and RR interval tachogram. The HRV provides information about the sympathetic-parasympathetic autonomic stability and consequently about the risk of unpredicted cardiac death. The heart beats in ECG signal are detected by detecting R-Peaks in ECG signals and used to determine useful information about the various cardiac abnormalities. The temporal locations of the R-wave are identified as the locations of the QRS complexes. In the presence of poor signal-to-noise ratios or pathological signals and wrong placement of ECG electrodes, the QRS complex may be missed or falsely detected and may lead to poor results in calculating heart beat in turn inter-beat intervals. We have studied the effects of number of common elements of QRS detection methods using MIT/BIH arrhythmia database and devised a simple and effective method. In this method, first the ECG signal is preprocessed using band-pass filter; later the Hilbert Transform is applied on filtered ECG signal to enhance the presence of QRS complexes, to detect R-Peaks by setting a threshold and finally the RR-intervals are calculated to determine Heart Rate. We have implemented our method using MATLAB on ECG signal which is obtained from MIT/BIH arrhythmia database. Our MATLAB implementation results in the detection of QRS complexes in ECG signal, locate the R-Peaks, computes Heart Rate (HR) by calculating RR-internal and plotting of HR signal to show the information about HRV. Index Terms: ECG, QRS complex, R-Peaks, HRV, Heart Rate signal, RSA, Hilbert Transform, Arrhythmia, MIT/BIH, MATLAB and Lynn’s filters
TOWARDS TEMPERATURE-INSENSITIVE NANOSCALE CMOS CIRCUITS WITH ADAPTIVELY REGUL...VLSICS Design
In this paper, we show that the temperature-induced performance drop seen in nanoscale CMOS circuitscan be tackled by powering the circuits with adaptively regulated voltage power supplies. Essentially, when temperature rises, the supply voltage will be bumped up to offset otherwise performance degradation. To avoid thermal over-drift as chip temperature exceeds its operation range, a voltage limiteris integrated into the proposed power supply to cap the supply voltage. Using this proposed adaptive voltage source to power individual CMOS logic gates and/or subsystems will free the chips from using expensive high-precision temperature sensors for thermal management and performance tuning. Experiments on various benchmark circuits, which are implemented with a 45nm CMOS technology, have confirmed that the circuit delay variation can be reduced to 15%~30% over a wide temperature range (0℃ to 90℃), a sharp contrast to the large delay variations(50%~75%)observed in most IC designs where a
constant power supply is employed.
Design of the Pulse Oximetry Measurement Circuit and Its Sensing System Based...IOSRJEEE
The pulse oximetry circuit and its sensing system is designed based on the standard CMOS technology of 0.18um. The reflection oxygen sensor is used to collect the pulse oximeter signal of human body, then the collected physiological signals are processed by the data processing circuit The data processing circuit is composed of two parts: the amplifying circuit and the band-pass filter circuit, and the pulse oximeter data processed by the data processing circuit is written into the tag through the SPI communication The RFID reader read the data in the RFID tag through wireless communication, and display the data . The experimental results show that the maximum error is ±1%. The maximum error of the pulse is ±1.9%. The stability and feasibility of pulse blood oxygen sensing system is demonstrated in this paper and it will have a good application prospect in the direction of wearable medical wisdom research
Learning Objectives:
Describe the consequences of hyper- and hypovolemia for surgical and critically ill patients.
Develop a fluid management strategy for individual patients
IJRET : International Journal of Research in Engineering and Technology is an international peer reviewed, online journal published by eSAT Publishing House for the enhancement of research in various disciplines of Engineering and Technology. The aim and scope of the journal is to provide an academic medium and an important reference for the advancement and dissemination of research results that support high-level learning, teaching and research in the fields of Engineering and Technology. We bring together Scientists, Academician, Field Engineers, Scholars and Students of related fields of Engineering and Technology
IJRET : International Journal of Research in Engineering and Technology is an international peer reviewed, online journal published by eSAT Publishing House for the enhancement of research in various disciplines of Engineering and Technology. The aim and scope of the journal is to provide an academic medium and an important reference for the advancement and dissemination of research results that support high-level learning, teaching and research in the fields of Engineering and Technology. We bring together Scientists, Academician, Field Engineers, Scholars and Students of related fields of Engineering and Technology
International Journal of Computational Engineering Research (IJCER) is dedicated to protecting personal information and will make every reasonable effort to handle collected information appropriately. All information collected, as well as related requests, will be handled as carefully and efficiently as possible in accordance with IJCER standards for integrity and objectivity.
International Journal of Engineering Research and Development (IJERD)IJERD Editor
journal publishing, how to publish research paper, Call For research paper, international journal, publishing a paper, IJERD, journal of science and technology, how to get a research paper published, publishing a paper, publishing of journal, publishing of research paper, reserach and review articles, IJERD Journal, How to publish your research paper, publish research paper, open access engineering journal, Engineering journal, Mathemetics journal, Physics journal, Chemistry journal, Computer Engineering, Computer Science journal, how to submit your paper, peer reviw journal, indexed journal, reserach and review articles, engineering journal, www.ijerd.com, research journals,
yahoo journals, bing journals, International Journal of Engineering Research and Development, google journals, hard copy of journal
Hemodynamic Assessment Series by Transonic -- Part 1: PV Loop Case StudyInsideScientific
Session 3 of our PV Loop Webseries was a case study review in Pressure-Volume loops, sponsored by Transonic. Guest speakers, Dr. Craig Emter, Dr. Robert Hamlin, Dr. Timothy Hacker, and Dr. Filip Konecny discussed the role of PV loops in HFpEF, Drug-Discovery and Safety Testing, Right Ventricular PV Loops in Pulmonary HTN, and Medical Device Testing using LVADs as an example. The over riding topic linking all four of these short lectures was how PV loops work in concert with other techniques, permitting complete hemodynamic evaluation.
Case Study 1: Integrating Coronary Vascular & Myocardial Function in Mini-swine with Heart Failure (an aortic banding model of HFpEF) -- Dr. Craig Emter
Case Study 2: What are the properties of this compound? (reviewing the value and need for PV loops in drug-discovery and safety testing in pharmaceutical research labs) -- Dr. Robert Hamlin
Case Study 3: The Utility of Right Ventricular PV Loops (a mouse model of Pulmonary Arterial Hypertension that transitions from compensatory RV remodeling to right heart failure) Dr. Timothy Hacker
Case Study 4: Synergy of Pressure-Volume Technology with Left Ventricular Assisted Devices (why PV loops are valuable when conducting LVAD testing in both pre and post operation situations)
TOWARDS TEMPERATURE-INSENSITIVE NANOSCALE CMOS CIRCUITS WITH ADAPTIVELY REGUL...VLSICS Design
In this paper, we show that the temperature-induced performance drop seen in nanoscale CMOS circuitscan be tackled by powering the circuits with adaptively regulated voltage power supplies. Essentially, when temperature rises, the supply voltage will be bumped up to offset otherwise performance degradation. To avoid thermal over-drift as chip temperature exceeds its operation range, a voltage limiteris integrated into the proposed power supply to cap the supply voltage. Using this proposed adaptive voltage source to power individual CMOS logic gates and/or subsystems will free the chips from using expensive high-precision temperature sensors for thermal management and performance tuning. Experiments on various benchmark circuits, which are implemented with a 45nm CMOS technology, have confirmed that the circuit delay variation can be reduced to 15%~30% over a wide temperature range (0℃ to 90℃), a sharp contrast to the large delay variations(50%~75%)observed in most IC designs where a constant power supply is employed.
A combined skewed ring oscillator by different type of delay stages is presented. This paper aims to drive a high stable and relatively high frequency but still use a full transistor circuit for ring oscillator with combined delay stages and skewed connections. First we propose two types of common inverters then calculate their delay time and analysis their dependence of delay time to variation of power supply voltage. The simulation results verify that delay time of these two CMOS inverters show opposite behaviour versus power supply changing. So a combined structure can obtain more appropriate frequency stability versus power supply noise. Also in order to increase oscillation frequency we have used the negative skewed delay
connections. The simulation results using HSPICE for 0.18 µm CMOS shows a good agreement with analysis results. In addition in this paper the mathematical justification for improved functioning of this combined skewed ring oscillator has been proved. This justification shows appropriate agreement with the
simulation results. From mathematical point of view the proposed ring oscillator has better frequency stability in comparison with other types of ring oscillators. In fact, the oscillation frequency sensitivity to supply voltage noise is reduced considerably.
Heart rate detection using hilbert transformeSAT Journals
Abstract The electrocardiogram (ECG) is a well known method that can be used to measure Heart Rate Variability (HRV). This paper describes a procedure for processing electrocardiogram signals (ECG) to detect Heart Rate Variability (HRV). In recent years, there have been wide-ranging studies on Heart rate variability in ECG signals and analysis of Respiratory Sinus Arrhythmia (RSA). Normally the Heart rate variability is studied based on cycle length variability, heart period variability, RR variability and RR interval tachogram. The HRV provides information about the sympathetic-parasympathetic autonomic stability and consequently about the risk of unpredicted cardiac death. The heart beats in ECG signal are detected by detecting R-Peaks in ECG signals and used to determine useful information about the various cardiac abnormalities. The temporal locations of the R-wave are identified as the locations of the QRS complexes. In the presence of poor signal-to-noise ratios or pathological signals and wrong placement of ECG electrodes, the QRS complex may be missed or falsely detected and may lead to poor results in calculating heart beat in turn inter-beat intervals. We have studied the effects of number of common elements of QRS detection methods using MIT/BIH arrhythmia database and devised a simple and effective method. In this method, first the ECG signal is preprocessed using band-pass filter; later the Hilbert Transform is applied on filtered ECG signal to enhance the presence of QRS complexes, to detect R-Peaks by setting a threshold and finally the RR-intervals are calculated to determine Heart Rate. We have implemented our method using MATLAB on ECG signal which is obtained from MIT/BIH arrhythmia database. Our MATLAB implementation results in the detection of QRS complexes in ECG signal, locate the R-Peaks, computes Heart Rate (HR) by calculating RR-internal and plotting of HR signal to show the information about HRV. Index Terms: ECG, QRS complex, R-Peaks, HRV, Heart Rate signal, RSA, Hilbert Transform, Arrhythmia, MIT/BIH, MATLAB and Lynn’s filters
TOWARDS TEMPERATURE-INSENSITIVE NANOSCALE CMOS CIRCUITS WITH ADAPTIVELY REGUL...VLSICS Design
In this paper, we show that the temperature-induced performance drop seen in nanoscale CMOS circuitscan be tackled by powering the circuits with adaptively regulated voltage power supplies. Essentially, when temperature rises, the supply voltage will be bumped up to offset otherwise performance degradation. To avoid thermal over-drift as chip temperature exceeds its operation range, a voltage limiteris integrated into the proposed power supply to cap the supply voltage. Using this proposed adaptive voltage source to power individual CMOS logic gates and/or subsystems will free the chips from using expensive high-precision temperature sensors for thermal management and performance tuning. Experiments on various benchmark circuits, which are implemented with a 45nm CMOS technology, have confirmed that the circuit delay variation can be reduced to 15%~30% over a wide temperature range (0℃ to 90℃), a sharp contrast to the large delay variations(50%~75%)observed in most IC designs where a
constant power supply is employed.
Design of the Pulse Oximetry Measurement Circuit and Its Sensing System Based...IOSRJEEE
The pulse oximetry circuit and its sensing system is designed based on the standard CMOS technology of 0.18um. The reflection oxygen sensor is used to collect the pulse oximeter signal of human body, then the collected physiological signals are processed by the data processing circuit The data processing circuit is composed of two parts: the amplifying circuit and the band-pass filter circuit, and the pulse oximeter data processed by the data processing circuit is written into the tag through the SPI communication The RFID reader read the data in the RFID tag through wireless communication, and display the data . The experimental results show that the maximum error is ±1%. The maximum error of the pulse is ±1.9%. The stability and feasibility of pulse blood oxygen sensing system is demonstrated in this paper and it will have a good application prospect in the direction of wearable medical wisdom research
Learning Objectives:
Describe the consequences of hyper- and hypovolemia for surgical and critically ill patients.
Develop a fluid management strategy for individual patients
2. (Na+), potassium (K+), and calcium (Ca2+) ions. All the
ionic currents, except for the fast sodium current (INa), are
formulated according to the Hodgkin-Huxley formalism. A
detailed description of each current can be found in the
original paper [11].
B. Markovian Model of the INa
The gating behavior of the sodium channel is repre-
sented as a continuos-time Markov model. This Markovian
representation of the INa is integrated into the single cell
model, yielding a computer model that simulates the ∆KPQ
mutation associated with the LQT3 syndrome (see [9] for
more details). The ∆KPQ-LQT3 model accounts for both
WT and ∆KPQ channels, so the total output macroscopic
sodium current can be expressed as
INa = α ·INa−MT +(1−α)·INa−WT (2)
where INa−MT is the current produced by MT channels,
INa−WT the current produced by WT channels, and α is
the penetrance index, i.e. the proportion of WT and MT
channels, in such a way that:
• α = 0 represents a WT cell;
• α = 0.5 represents a heterozygous cell;
• α = 1 represents a homozygous MT cell.
The accuracy of this model has been thoroughly tested and
validated according to experimental data [6]–[9].
C. Simulation conditions
All simulations were performed on a desktop PC (3GHz,
2GB RAM), using C/C++. The integration time step was
taken to be ∆t = 0.005 ms. The APD is defined as the
interval between the AP upstroke and the repolarization
potential of −70 mV, which is approximately the APD at
90% repolarization.
D. Stimulation protocol
In this paper, beat-to-beat APD variations are characterized
by using a long-term stimulation protocol. Starting from an
initial Basic Cycle Length (BCL) B0, both WT and ∆KPQ
cells are paced at decreasing BCLs (B). For each cycle
length B, cells are stimulated for 60 seconds. After that, B
is decreased in ∆ ms, so Bnew = Bold − ∆. The protocol is
repeated until the minimum value of B for which an APD
can be elicited for each given stimulus is attained. By means
of this protocol, the temporal evolution of the APD can be
obtained (Fig. 1). This is a useful representation, since it
shows how the APD accommodates [12] in response to step
decrements in B. Abrupt changes in the APD result at time
instants where decrements in B take place (vertical dotted
lines). Then, as time goes by, the APD slowly reaches the
steady-state, until another stimulation rate is used.
III. RESULTS
A. Stimulation protocol of the WT
Fig. 1 illustrates the results of applying the stimulation
protocol to a WT cell. As the value of B was changed, the
0 50 100 150 200 250 300 350 400 450
100
120
140
160
180
200
220
240
260
280
300
time (s)
APD(ms)
B0
= 1000 B = 900 B = 800 B = 700 B = 600 B = 500 B = 400 B = 300
Fig. 1. Stimulation protocol for a WT cell. From a starting value
of B0 = 1000 ms, cycle length was decreased until B = 300 ms, with
∆ = 100 ms. For each B, the APD slowly reaches the steady-state (APD
accommodation). Even if the APD seems not to reach a steady-state, longer
stimulation periods -i.e. 120 s- has been studied showing that effectively it
does.
WT cell responded in a stable 1:1 manner. This response
pattern corresponds to a normal behavior, in which APD
variations from one beat to the other are negligible (for the
same B).
B. Stimulation protocol of the MT
A very different behavior results when applying the stim-
ulation protocol to a ∆KPQ MT cell. The APD accommoda-
tion of a heterozygous cell (α = 0.5) is plotted in Fig. 2 (a).
As shown, for B = 800 and 700 ms, the APD does not
have a steady-state, rather it alternates between a discrete
set of values. Thus, the APD oscillates from one of these
values to the other on a beat-to-beat basis. An example of
the beat-to-beat variation of the AP can be seen in Fig. 2 (b).
Unstable EADs disrupt the balance between the APD and the
preceding diastolic interval (DI). In consequence, the APD
never reaches a steady state, giving rise to APD alternans.
Pacing cycle intervals B, for which no EADs (B = 600 to 300
ms), or stable EADs (B = 1000 and 900 ms) are present, do
not show APD alternans (Fig. 3).
In a homozygous ∆KPQ cell (α = 1.0), APD alternans
arises over a wider range of stimulation intervals when
compared to a heterozygous cell (Fig. 4 (a)). In this case,
there are no stable states until the 1:1 response returns at
B = 300 ms. It is also remarkable that the AP shows large
EADs, thus indicating that the larger the EADs, the more
unstable the APD.
We have found that the results presented above are not
dependent on the values of B0 and ∆. Test values of B0 ranged
between B0 ±200 ms of the original value (i.e B0 = 1000 for
heterozygous cell). ∆ has been changed from small values
(∆ = 10 ms), to larger values (∆ = 500 ms). Simultaneous
variations of both B0 and ∆ also yielded similar results.
641
Authorized licensed use limited to: Univ Rey Juan Carlos. Downloaded on June 10, 2009 at 04:02 from IEEE Xplore. Restrictions apply.
3. 0 50 100 150 200 250 300 350 400 450
50
100
150
200
250
300
350
400
time (s)
APD(ms) B = 800 B = 700
B0
= 1000
173 174 175 176 177 178 179 180
−80
−60
−40
−20
0
20
40
time (s)
V(mv)
(a) (b)
Fig. 2. Stimulation protocol applied to a heterozygous cell. (a) APD accommodation; simulations parameters are the same as for the WT (B0 = 1000 ms,
∆ = 100 ms). (b) A sequence of APs exhibiting APD alternans. This behavior corresponds to APs measured at B = 800 ms.
112 113 114 115 116 117 118 119 120
−80
−60
−40
−20
0
20
40
time (s)
V(mv)
295 296 297 298 299 300
−80
−60
−40
−20
0
20
40
time (s)
V(mv)
(a) (b)
Fig. 3. Sequences of APs of a heterozygous cell measured at different time instants. (a) Before APD alternans occur (B = 900 ms). (b) After APD
alternans take place (B = 600 ms).
IV. DISCUSSION
In the present study, we have analyzed the dynamic behav-
ior of both WT and ∆KPQ cells, using a Markovian computer
model of the ∆KPQ-LQT3 syndrome subjected to a long-
term stimulation protocol. A picture of the time evolution
of the APD identified APD alternans in MT cells over a
narrow range of stimulation frequencies. This result may
help to explain why patients with ∆KPQ mutation are likely
to develop arrhythmias within different heart rate ranges
compared with normals or other types of LQT syndrome [1].
More interestingly, APD alternans is also linked to T waves
alternans [13], an ECG phenomenon associated with LQT
syndrome that has been proposed as an important harbinger
for ventricular arrhythmia [14]. On the other hand, presence
of EADs is not a sufficient condition to generate alternans,
as for very low stimulation intervals (i.e. B > 900 ms for a
heterozygous cell) APs with stable EADs do not show APD
alternans. However, in a narrow band of stimulation intervals,
EADs generated in MT cells induce irregularities in the DI,
leading to beat-to-beat irregularities in the APD. Further, as it
was shown when comparing heterozygous and homozygous
MT cells, large EADs produces irregularities (alternans) at
the APD in wider range of stimulation frequencies.
V. CONCLUSIONS AND FUTURE WORK
Our simulations demonstrate that a dynamical analysis
at the cellular level based on computer simulations is an
useful approach to link molecular defects to mechanisms
of rate dependent arrhythmias. We have also shown that
potential mechanisms of LQT3 arrhythmias can not be
attributed exclusively to EADs or APD alternans, but to a
contribution of both factors. Future research should study
the dynamic dependence between EADs and APD alternans.
Extensions of the cellular model proposed here, to one-
dimensional and two-dimensional ventricular tissue models,
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4. 0 100 200 300 400 500 600
100
200
300
400
500
600
700
time (s)
APD(ms)
B
0
= 1200 B = 1000 B = 300
171 172 173 174 175 176 177 178 179 180
−80
−60
−40
−20
0
20
40
time (s)
V(mv)
(a) (b)
Fig. 4. Stimulation protocol applied to a homozygous MT cell. (a) APD accommodation, simulations were carried out for B0 = 1200 ms and ∆ = 100
ms. (b) A sequence of APs exhibiting APD alternans. This behavior corresponds to APs measured at B = 1000 ms.
would allow us to analyze further the mechanism of cardiac
arrhythmia in terms of both EADs and spatially discordant
APD alternans [15]. Finally, the predictions of this theoretical
analysis based on computer simulations are readily testable
in experiments using cardiac cells that express the ∆KPQ
and other mutations that are relevant to the LQT syndrome.
VI. ACKNOWLEDGMENTS
We thank Drs. Colleen E. Clancy and Zheng I. Zhu
for providing source code used in this study and for kind
technical support.
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