No description available.

No description available.

An electrocardiogram (ECG) is a bioelectrical signal which records the heart's electrical activity versus time. It is an important diagnostic tool for assessing heart functions. The interpretation of ECG signal is an application of pattern recognition. The techniques used in this pattern recognition comprise: signal pre-processing, QRS detection, feature extraction and neural network for signal classification. In this project, signal processing and neural network toolbox will be used in Matlab environment. The processed signal source came from the Massachusetts Institute of Technology Beth Israel Hospital (MIT-BIH) arrhythmia database which was developed for research in cardiac electro-physiology.Five conditions of ECG waveform were selected from MIT-BIH database in this research. The ECG samples were processed and normalised to produce a set of features that can be used in different structures of neural network and subsequent recognition rates were recorded. Backpropagation algorithm will be considered for different structures of neural network and the performance in each case will be measured. This research is focused on finding the best neural network structure for ECG signal classification and a number of signal pre-processing and QRS detection algorithms were also tested. The feature extraction is based on an existing algorithm.The results of recognition rates are compared to find a better structure for ECG classification. Different ECG feature inputs were used in the experiments to compare and find a desirable features input for ECG classification. Among different structures, it was found that a three layer network structure with 25 inputs, 5 neurons in the output layer and 5 neurons in its hidden layers possessed the best performance with highest recognition rate of 91.8% for five cardiac conditions. The average accuracy rate for this kind of structure with different structures was 84.93%. It was also tested that 25 feature input is suitable for training and testing in ECG classification. Based on this result, the method of using important ECG features plus a suitable number of compressed ECG signals can dramatically decrease the complexity of the neural network structure, which can increase the testing speed and the accuracy rate of the network verification. It also gives further suggestions to plan the experiments for the future work.

A variety of drugs prolong cardiac repolarization (manifested as QT prolongation on ECG), although the major example are the so-called class III antiarrhythmics. However, antiarrhythmic drugs which prolong cardiac repolarization are not harmless, as they may also be proarrhythmic, inducing a potentially fatal arrhythmia known as torsade de pointes (TdP). Recently, it has become apparent that a wide variety of non-antiarrhythmic agents may also, as an entirely undesired side-effect, provoke TdP. TdP is also characteristic of the congenital long QT syndrome, one form of which is caused by mutations in the HERG gene which encodes the major repolarizing potassium channel, IKr. Furthermore, HERG appears to be the main molecular target for drugs which cause QT prolongation. This thesis investigates the cellular mechanism for QT prolongation, proarrhythmia and sudden death associated with several commonly prescribed non-antiarrhythmic drugs. Specifically, we studied the effects of an antimalarial agent, halofantrine, and five psychoactive agents, thioridazine, chlorpromazine, clozapine, amitriptyline and mianserin on the HERG channel. A better understanding of the way these drugs interact with HERG could facilitate the development of safer drugs. We used the whole-cell voltage clamp technique to study currents produced by stable transfection of HERG into Chinese hamster ovary cells (CHO-K1). Our HERG-transfected cells possessed a potassium channel with biophysical properties similar to HERG-transfected cells previously reported (e.g. Xenopus oocytes, human embryonic kidney cells 293) and also to human IKr. HERG currents were potently inhibited by E-4031, a defining pharmacological signature of IKr. Therefore, these cells provide an appropriate model for the study of this important current in isolation. Halofantrine is a widely used antimalarial agent which has been associated with QT prolongation, TdP and sudden death. Halofantrine blocked HERG tail currents potently with an IC50 of 196.9 nM. Channel inhibition was time-, voltage- and use-dependent. Halofantrine did not alter channel activation or deactivation kinetics but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid-activation potential of steady state inactivation. Block increased with increasing depolarizing pulse duration and was enhanced by pulses that render channels inactivated. This is the first report of HERG channel blockade by halofantrine and is the likely cellular mechanism for its proarrhythmic potential. Our data indicate preferential binding of halofantrine to the open and inactivated channel states. Cardiovascular mortality in psychiatric patients is high. Reports of sudden unexplained death in those taking antipsychotic drugs have raised concerns that part of this excess may be due to drug-induced arrhythmias. We found that thioridazine and chlorpromazine blocked HERG channels (IC50 1.07 ????M and 1.47????M respectively) at clinically relevant concentrations and this is likely the cellular mechanism for their ability to prolong QT interval and induce TdP. To date, HERG block by chlorpromazine has not been reported and the state dependence of channel blockade by these phenothiazines has not been studied. Our results indicate that both drugs preferentially bind to closed HERG channels on the basis that block was not time-, voltage- or use-dependent, did not alter channel activation or deactivation kinetics and was unaffected by the depolarizing pulse duration. Clozapine is the prototype of the newer atypical antipsychotic drugs and is more efficacious and better tolerated than the traditional agents. Serious cardiotoxicity have occurred in clozapine-treated patients including sudden death. We found that clozapine produced a tonic block on HERG channels indicating preferential binding to the closed channel state. The IC50 for block was 2.62 ????M. This is close to the therapeutic concentration of the drug (0.6 to 2 ????M) and concentrations above 10 ????M have been reported during overdoses. Although there have been no specific reports of QT prolongation or TdP in clozapine-treated patients, our data raises the possibility of proarrhythmia as another potential explanation for sudden death during clozapine treatment. Amitriptyline, a commonly prescribed tricyclic antidepressant, can induce a variety of cardiac rhythm disturbances. Most reports have attributed these effects to its Na+ channel blocking ability. We found that amitriptyline blocked HERG channels with an IC50 of 10 ????M. Such high concentrations can be achieved during overdoses. Thus HERG channel blockade likely underlies amitriptyline????s QT-prolonging effect. Channel inhibition by amitriptyline exhibited positive voltage- and use-dependence and increased progressively with further prolongation of depolarization during an envelope of tails protocol, indicating preferential binding to an activated (open/inactivated) state of the channel. In contrast to the tricyclics, the tetracyclic antidepressant, mianserin, is much safer and only very rarely associated with cardiac complications. HERG channel blockade by mianserin was the least potent among the 5 psychoactive drugs we studied, with an IC50 of 14.78 ????M, which is 30- to 40-fold higher than therapeutic plasma concentrations of the drug. This probably, in part, accounts for the lack of reports of QT prolongation or TdP with mianserin. Mianserin displayed preferential affinity for an activated state of HERG channels on the basis of voltage-dependent block, a hyperpolarizing shift in the voltage of half-maximal activation and an increase in block at low external potassium concentration. Our results show that HERG block is a common feature of many non-cardiac drugs and that this underlies their potential for QT prolongation and TdP. Although the proarrhythmic risk varies according to potency of HERG block (e.g. mianserin is a weak blocker and does not induce TdP), other factors such as drug metabolism, protein binding and myocardial concentrations are also important since the risk of proarrhythmia during clinical use differ significantly even among the more potent HERG blockers. The preferential binding of these drugs to different channel states together with their diverse chemical structures suggest the presence of multiple distinct binding sites for drugs on HERG channels. There is increasing awareness that many non-antiarrhythmic drugs can prolong the QT interval and provoke TdP. Cardiac safety is now a major issue in new drug development. Our model of HERG K+ channels stably expressed in a mammalian cell line (CHO-K1) provides a useful tool for screening, at the preclinical stage, the proarrhythmic potential of novel drugs intended for human use.

A variety of drugs prolong cardiac repolarization (manifested as QT prolongation on ECG), although the major example are the so-called class III antiarrhythmics. However, antiarrhythmic drugs which prolong cardiac repolarization are not harmless, as they may also be proarrhythmic, inducing a potentially fatal arrhythmia known as torsade de pointes (TdP). Recently, it has become apparent that a wide variety of non-antiarrhythmic agents may also, as an entirely undesired side-effect, provoke TdP. TdP is also characteristic of the congenital long QT syndrome, one form of which is caused by mutations in the HERG gene which encodes the major repolarizing potassium channel, IKr. Furthermore, HERG appears to be the main molecular target for drugs which cause QT prolongation. This thesis investigates the cellular mechanism for QT prolongation, proarrhythmia and sudden death associated with several commonly prescribed non-antiarrhythmic drugs. Specifically, we studied the effects of an antimalarial agent, halofantrine, and five psychoactive agents, thioridazine, chlorpromazine, clozapine, amitriptyline and mianserin on the HERG channel. A better understanding of the way these drugs interact with HERG could facilitate the development of safer drugs. We used the whole-cell voltage clamp technique to study currents produced by stable transfection of HERG into Chinese hamster ovary cells (CHO-K1). Our HERG-transfected cells possessed a potassium channel with biophysical properties similar to HERG-transfected cells previously reported (e.g. Xenopus oocytes, human embryonic kidney cells 293) and also to human IKr. HERG currents were potently inhibited by E-4031, a defining pharmacological signature of IKr. Therefore, these cells provide an appropriate model for the study of this important current in isolation. Halofantrine is a widely used antimalarial agent which has been associated with QT prolongation, TdP and sudden death. Halofantrine blocked HERG tail currents potently with an IC50 of 196.9 nM. Channel inhibition was time-, voltage- and use-dependent. Halofantrine did not alter channel activation or deactivation kinetics but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid-activation potential of steady state inactivation. Block increased with increasing depolarizing pulse duration and was enhanced by pulses that render channels inactivated. This is the first report of HERG channel blockade by halofantrine and is the likely cellular mechanism for its proarrhythmic potential. Our data indicate preferential binding of halofantrine to the open and inactivated channel states. Cardiovascular mortality in psychiatric patients is high. Reports of sudden unexplained death in those taking antipsychotic drugs have raised concerns that part of this excess may be due to drug-induced arrhythmias. We found that thioridazine and chlorpromazine blocked HERG channels (IC50 1.07 ????M and 1.47????M respectively) at clinically relevant concentrations and this is likely the cellular mechanism for their ability to prolong QT interval and induce TdP. To date, HERG block by chlorpromazine has not been reported and the state dependence of channel blockade by these phenothiazines has not been studied. Our results indicate that both drugs preferentially bind to closed HERG channels on the basis that block was not time-, voltage- or use-dependent, did not alter channel activation or deactivation kinetics and was unaffected by the depolarizing pulse duration. Clozapine is the prototype of the newer atypical antipsychotic drugs and is more efficacious and better tolerated than the traditional agents. Serious cardiotoxicity have occurred in clozapine-treated patients including sudden death. We found that clozapine produced a tonic block on HERG channels indicating preferential binding to the closed channel state. The IC50 for block was 2.62 ????M. This is close to the therapeutic concentration of the drug (0.6 to 2 ????M) and concentrations above 10 ????M have been reported during overdoses. Although there have been no specific reports of QT prolongation or TdP in clozapine-treated patients, our data raises the possibility of proarrhythmia as another potential explanation for sudden death during clozapine treatment. Amitriptyline, a commonly prescribed tricyclic antidepressant, can induce a variety of cardiac rhythm disturbances. Most reports have attributed these effects to its Na+ channel blocking ability. We found that amitriptyline blocked HERG channels with an IC50 of 10 ????M. Such high concentrations can be achieved during overdoses. Thus HERG channel blockade likely underlies amitriptyline????s QT-prolonging effect. Channel inhibition by amitriptyline exhibited positive voltage- and use-dependence and increased progressively with further prolongation of depolarization during an envelope of tails protocol, indicating preferential binding to an activated (open/inactivated) state of the channel. In contrast to the tricyclics, the tetracyclic antidepressant, mianserin, is much safer and only very rarely associated with cardiac complications. HERG channel blockade by mianserin was the least potent among the 5 psychoactive drugs we studied, with an IC50 of 14.78 ????M, which is 30- to 40-fold higher than therapeutic plasma concentrations of the drug. This probably, in part, accounts for the lack of reports of QT prolongation or TdP with mianserin. Mianserin displayed preferential affinity for an activated state of HERG channels on the basis of voltage-dependent block, a hyperpolarizing shift in the voltage of half-maximal activation and an increase in block at low external potassium concentration. Our results show that HERG block is a common feature of many non-cardiac drugs and that this underlies their potential for QT prolongation and TdP. Although the proarrhythmic risk varies according to potency of HERG block (e.g. mianserin is a weak blocker and does not induce TdP), other factors such as drug metabolism, protein binding and myocardial concentrations are also important since the risk of proarrhythmia during clinical use differ significantly even among the more potent HERG blockers. The preferential binding of these drugs to different channel states together with their diverse chemical structures suggest the presence of multiple distinct binding sites for drugs on HERG channels. There is increasing awareness that many non-antiarrhythmic drugs can prolong the QT interval and provoke TdP. Cardiac safety is now a major issue in new drug development. Our model of HERG K+ channels stably expressed in a mammalian cell line (CHO-K1) provides a useful tool for screening, at the preclinical stage, the proarrhythmic potential of novel drugs intended for human use.

An electrocardiogram (ECG) is a bioelectrical signal which records the heart's electrical activity versus time. It is an important diagnostic tool for assessing heart functions. The interpretation of ECG signal is an application of pattern recognition. The techniques used in this pattern recognition comprise: signal pre-processing, QRS detection, feature extraction and neural network for signal classification. In this project, signal processing and neural network toolbox will be used in Matlab environment. The processed signal source came from the Massachusetts Institute of Technology Beth Israel Hospital (MIT-BIH) arrhythmia database which was developed for research in cardiac electro-physiology.Five conditions of ECG waveform were selected from MIT-BIH database in this research. The ECG samples were processed and normalised to produce a set of features that can be used in different structures of neural network and subsequent recognition rates were recorded. Backpropagation algorithm will be considered for different structures of neural network and the performance in each case will be measured. This research is focused on finding the best neural network structure for ECG signal classification and a number of signal pre-processing and QRS detection algorithms were also tested. The feature extraction is based on an existing algorithm.The results of recognition rates are compared to find a better structure for ECG classification. Different ECG feature inputs were used in the experiments to compare and find a desirable features input for ECG classification. Among different structures, it was found that a three layer network structure with 25 inputs, 5 neurons in the output layer and 5 neurons in its hidden layers possessed the best performance with highest recognition rate of 91.8% for five cardiac conditions. The average accuracy rate for this kind of structure with different structures was 84.93%. It was also tested that 25 feature input is suitable for training and testing in ECG classification. Based on this result, the method of using important ECG features plus a suitable number of compressed ECG signals can dramatically decrease the complexity of the neural network structure, which can increase the testing speed and the accuracy rate of the network verification. It also gives further suggestions to plan the experiments for the future work.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Thesis (M. D.)--University of New South Wales, 2002. / Also available online.

It was believed that a study of athletes under the stress of competition would present a somewhat different challenge than would the same tests held under laboratory conditions. The belief was that actual competition would produce a far greater emotional and physiological stress than could be produced in an artificial setting. For this reason then, nineteen highly trained and healthy, teen-age swimmers of championship calibre were selected for study before and after sprint swimming competition. One swimmer was studied a second time, two years after the first testing, making a total of twenty sets of observations. The subjects were studied before the exercise to determine their resting blood pressures and pulse rates and to record their resting electrocardiograms. The swimming races were, for the most part, held in regularly scheduled meets and were distances of one-hundred and ten yards. Four observations were made following official time trials of similar swimming-events. The study was to-be concerned with the changes and recovery of the electrocardiograms, pulse rates and blood pressures following the races. In reviewing the literature, no similar study could be found that employed the use of serial electrocardiograms that would present a view of the recovery of the heart during a selected time interval immediately following actual competition. Therefore, this study concerned itself with a thirty minute recovery period beginning three minutes after the race. Each subject, then, had electrocardiograms taken at: three, six, nine, twelve, fifteen, twenty, twenty-five and thirty minute intervals following the "all-out" sprint. Blood pressure readings were also taken at regular intervals and the pulse rate was automatically recorded by the electrocardiograph. The results of these measurements indicated individual variations in blood pressure and pulse rate. However, general trends were observed in the measurements of the P-R interval, the ST segment and the T wave. The P-R interval, in twelve of the twenty cases, was prolonged. ST depression was seen in eight cases. The T wave was lowered considerably in all of the cases, with T inversion in nine of the athletes. Eighteen of the twenty observations showed one or all of the following major variations: PR prolongation, T inversion, ST depression. These three changes of the electrocardiogram, if: of sufficient degree, are taken as evidence of cardiac disease according to medical tests. Several studies of athletes observed after exercise have also pointed out that PR prolongation, T wave inversion and ST depression are to be taken as pathological variations. In the present study, these variations were not present in the resting recordings of any of the subjects. These variations did appear, however, at different times throughout the thirty minute recovery period. The deflections of concern, for the most part, had returned to normal by the end of the test. This evidence might then suggest that such variation, in healthy, young athletes, appearing after strenuous competition, would be indicative of functional adjustment of the myocardium to this situation of physical and emotional stress. / Education, Faculty of / Curriculum and Pedagogy (EDCP), Department of / Graduate

No description available.