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Tobias Opthof - One of the best experts on this subject based on the ideXlab platform.
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Cardiac activation-Repolarization patterns and ion channel expression mapping in intact isolated normal human Hearts.
Heart rhythm, 2016Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, Leander Beekman, Jesús Álvarez-garcía, Cristian Munoz-guijosa, Ruben CoronelAbstract:Background The Repolarization pattern of the human Heart is unknown. Objective The purpose of this study was to perform a multisite analysis of the activation–Repolarization patterns and mRNA expression patterns of ion channel subunits in isolated human Hearts. Methods Hearts from 3 donors without reported cardiac disease were Langendorff perfused with the patient's own blood. A standard ECG was obtained before explantation. Up to 92 unipolar electrograms from 24 transmural needles were obtained during right atrial pacing. Local activation and Repolarization times and activation–recovery intervals (ARI) were measured. The mRNA levels of subunits of the channels carrying the transient outward current and slow and rapid components of the delayed rectifier current were determined by quantitative reverse transcriptase polymerase chain reaction at up to 63 sites. Results The Repolarization gradients in the 3 Hearts were different and occurred along all axes without midmural late Repolarization. A negative activation–Repolarization relationship occurred along the epicardium, but this relationship was positive in the whole Hearts. Coefficients of variation of mRNA levels (40%–80%) and of the Kv7.1 protein (alpha-subunit slow delayed rectifier channel) were larger than those of ARIs (7%–17%). The regional mRNA expression patterns were similar in the 3 Hearts, unlike the ARI profiles. The expression level of individual mRNAs and of Kv7.1 did not correlate with local ARIs at the same sites. Conclusion In the normal human Heart, Repolarization gradients encompass all axes, without late midmural Repolarization. Last activated areas do not repolarize first as previously assumed. Gradients of mRNAs of single ion channel subunits and of ARIs do not correlate.
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Repolarization mapping in relation to quantitative expression patterns of major ion channels in the isolated perfused healthy human Heart
European Heart Journal, 2013Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, J. Álvarez, C Muñoz, Ruben Coronel, Juan CincaAbstract:Background: The Repolarization pattern of the human Heart is important for the understanding of the normal T wave and its changes in disease. This pattern is largely unknown, let alone its relation with expression patterns of ion channels. We therefore studied explanted Hearts obtained from 7 donors free of structural cardiac disorders. Methods: Informed consent was obtained from the relatives of the deceased and the study was approved by the Ethical Review Board (Barcelona). Clinical data and an ECG were recorded before explantation. Hearts were perfused according to Langendorff with whole blood of the same donor. Up to 24 transmural needles (each 4 electrodes at 4 mm distance) were inserted in the left, septal and right ventricular myocardium and activation and Repolarization patterns were obtained during pacing from the right atrium at a cycle length of 700 msec. Transmural tissue samples were obtained from the locations of the needles, cut in three transmural portions and immediately stored in liquid nitrogen. mRNA levels of ion channel subunits KCND2, KCND3, KCNIP2, KCNQ1, KCNE1 and KCNE2 were determined (in duplicate) by real-time quantitative PCR and normalized to the housekeeping gene HPRT. Results: From 2 Hearts a complete set of electrophysiological and qPCR data were obtained. The ECG of both patients (a man of 66 and a woman of 73 years) was normal, and one had a biphasic T wave in the precordial leads. In both Hearts activation-recovery intervals (ARIs) were significantly longer in the left (LV) than in the right ventricle (RV). Nevertheless, in one Heart with the biphasic T wave Repolarization terminated simultaneously in RV and LV. In the other Heart Repolarization in the RV preceded that in the LV. No relevant transmural or apico-basal gradients in Repolarization were observed. However, in both Hearts prominent anterior to posterior gradients were present. Of the ion channels studied, mRNA expression levels of KCND2 and KCNE2 were very low, whereas KCNIP2 was highly expressed. Coefficients of variation of the selected mRNA levels was considerably larger than that of ARIs (50 vs. 10%). KCND3 mRNA was significantly higher in LV than RV in both Hearts. There were no relevant correlations between the density of any of the tested mRNAs and ARIs. Conclusion: We present the first Repolarization and expression maps of the normal human Heart. It shows that regional variability of expression is several folds higher than variability of ARIs. The distribution of Repolarization gradients is not directly related to patterns of mRNAs encoding major ion channel subunits.
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Is there a significant transmural gradient in Repolarization time in the intact Heart?: Repolarization Gradients in the Intact Heart.
Circulation. Arrhythmia and electrophysiology, 2009Co-Authors: Tobias Opthof, Ruben Coronel, Michiel J. JanseAbstract:In 1880, Burdon-Sanderson and Page recorded the ECG of the frog simultaneously with monophasic action potentials from the base and the apex of the left ventricle (LV).1 Part of the ventricular muscle was injured with a hot wire, and monophasic action potentials were recorded as the potential difference between the injured region and an uninjured area. The ECG was recorded with a capillary electrometer, a slow, but reliable instrument. They noted that Repolarization occurred earlier at the base than at the apex.1 Warming the base resulted in a shortening of the basal action potential, leading to a deeper, more negative, and longer T wave in the ECG. Comparable findings were reported by Bayliss and Starling2 and by Mines.3 Noble and Cohen4 have reviewed the early literature on the T wave. Response by Patel et al p 89 Thus, around the turn of the 19th century, the concept that the T wave is caused by apicobasal gradients in Repolarization was well established. However, nowadays, the notion that transmural differences in Repolarization form the basis for the genesis of the T wave has been gaining a wide acceptance. In modern textbooks, there are diagrams depicting action potentials at the endocardium and the epicardium, where Repolarization occurs earlier at the epicardium.5,6 To quote Mirvis and Goldberger7: “… action potential durations are longest near the endocardium and shortest near the epicardium, which produces a transmural gradient in recovery periods. Differences in action potential durations are greater than differences in activation times, so recovery is completed near the epicardium before it is completed near the endocardium.” Because of this, according to Garibyan and Lilly8: “… in the normal Heart, the forces of depolarization and Repolarization are usually oriented in the same direction on the ECG …
Ruben Coronel - One of the best experts on this subject based on the ideXlab platform.
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Cardiac activation-Repolarization patterns and ion channel expression mapping in intact isolated normal human Hearts.
Heart rhythm, 2016Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, Leander Beekman, Jesús Álvarez-garcía, Cristian Munoz-guijosa, Ruben CoronelAbstract:Background The Repolarization pattern of the human Heart is unknown. Objective The purpose of this study was to perform a multisite analysis of the activation–Repolarization patterns and mRNA expression patterns of ion channel subunits in isolated human Hearts. Methods Hearts from 3 donors without reported cardiac disease were Langendorff perfused with the patient's own blood. A standard ECG was obtained before explantation. Up to 92 unipolar electrograms from 24 transmural needles were obtained during right atrial pacing. Local activation and Repolarization times and activation–recovery intervals (ARI) were measured. The mRNA levels of subunits of the channels carrying the transient outward current and slow and rapid components of the delayed rectifier current were determined by quantitative reverse transcriptase polymerase chain reaction at up to 63 sites. Results The Repolarization gradients in the 3 Hearts were different and occurred along all axes without midmural late Repolarization. A negative activation–Repolarization relationship occurred along the epicardium, but this relationship was positive in the whole Hearts. Coefficients of variation of mRNA levels (40%–80%) and of the Kv7.1 protein (alpha-subunit slow delayed rectifier channel) were larger than those of ARIs (7%–17%). The regional mRNA expression patterns were similar in the 3 Hearts, unlike the ARI profiles. The expression level of individual mRNAs and of Kv7.1 did not correlate with local ARIs at the same sites. Conclusion In the normal human Heart, Repolarization gradients encompass all axes, without late midmural Repolarization. Last activated areas do not repolarize first as previously assumed. Gradients of mRNAs of single ion channel subunits and of ARIs do not correlate.
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Repolarization mapping in relation to quantitative expression patterns of major ion channels in the isolated perfused healthy human Heart
European Heart Journal, 2013Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, J. Álvarez, C Muñoz, Ruben Coronel, Juan CincaAbstract:Background: The Repolarization pattern of the human Heart is important for the understanding of the normal T wave and its changes in disease. This pattern is largely unknown, let alone its relation with expression patterns of ion channels. We therefore studied explanted Hearts obtained from 7 donors free of structural cardiac disorders. Methods: Informed consent was obtained from the relatives of the deceased and the study was approved by the Ethical Review Board (Barcelona). Clinical data and an ECG were recorded before explantation. Hearts were perfused according to Langendorff with whole blood of the same donor. Up to 24 transmural needles (each 4 electrodes at 4 mm distance) were inserted in the left, septal and right ventricular myocardium and activation and Repolarization patterns were obtained during pacing from the right atrium at a cycle length of 700 msec. Transmural tissue samples were obtained from the locations of the needles, cut in three transmural portions and immediately stored in liquid nitrogen. mRNA levels of ion channel subunits KCND2, KCND3, KCNIP2, KCNQ1, KCNE1 and KCNE2 were determined (in duplicate) by real-time quantitative PCR and normalized to the housekeeping gene HPRT. Results: From 2 Hearts a complete set of electrophysiological and qPCR data were obtained. The ECG of both patients (a man of 66 and a woman of 73 years) was normal, and one had a biphasic T wave in the precordial leads. In both Hearts activation-recovery intervals (ARIs) were significantly longer in the left (LV) than in the right ventricle (RV). Nevertheless, in one Heart with the biphasic T wave Repolarization terminated simultaneously in RV and LV. In the other Heart Repolarization in the RV preceded that in the LV. No relevant transmural or apico-basal gradients in Repolarization were observed. However, in both Hearts prominent anterior to posterior gradients were present. Of the ion channels studied, mRNA expression levels of KCND2 and KCNE2 were very low, whereas KCNIP2 was highly expressed. Coefficients of variation of the selected mRNA levels was considerably larger than that of ARIs (50 vs. 10%). KCND3 mRNA was significantly higher in LV than RV in both Hearts. There were no relevant correlations between the density of any of the tested mRNAs and ARIs. Conclusion: We present the first Repolarization and expression maps of the normal human Heart. It shows that regional variability of expression is several folds higher than variability of ARIs. The distribution of Repolarization gradients is not directly related to patterns of mRNAs encoding major ion channel subunits.
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Is there a significant transmural gradient in Repolarization time in the intact Heart?: Repolarization Gradients in the Intact Heart.
Circulation. Arrhythmia and electrophysiology, 2009Co-Authors: Tobias Opthof, Ruben Coronel, Michiel J. JanseAbstract:In 1880, Burdon-Sanderson and Page recorded the ECG of the frog simultaneously with monophasic action potentials from the base and the apex of the left ventricle (LV).1 Part of the ventricular muscle was injured with a hot wire, and monophasic action potentials were recorded as the potential difference between the injured region and an uninjured area. The ECG was recorded with a capillary electrometer, a slow, but reliable instrument. They noted that Repolarization occurred earlier at the base than at the apex.1 Warming the base resulted in a shortening of the basal action potential, leading to a deeper, more negative, and longer T wave in the ECG. Comparable findings were reported by Bayliss and Starling2 and by Mines.3 Noble and Cohen4 have reviewed the early literature on the T wave. Response by Patel et al p 89 Thus, around the turn of the 19th century, the concept that the T wave is caused by apicobasal gradients in Repolarization was well established. However, nowadays, the notion that transmural differences in Repolarization form the basis for the genesis of the T wave has been gaining a wide acceptance. In modern textbooks, there are diagrams depicting action potentials at the endocardium and the epicardium, where Repolarization occurs earlier at the epicardium.5,6 To quote Mirvis and Goldberger7: “… action potential durations are longest near the endocardium and shortest near the epicardium, which produces a transmural gradient in recovery periods. Differences in action potential durations are greater than differences in activation times, so recovery is completed near the epicardium before it is completed near the endocardium.” Because of this, according to Garibyan and Lilly8: “… in the normal Heart, the forces of depolarization and Repolarization are usually oriented in the same direction on the ECG …
Tinatin I. Brelidze - One of the best experts on this subject based on the ideXlab platform.
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Increased Smooth Muscle Kv11.1 Channel Expression in Pulmonary Hypertension and Protective Role of Kv11.1 Channel Blocker Dofetilide
The American journal of pathology, 2019Co-Authors: Nataliia V. Shults, Vladyslava Rybka, Yuichiro J. Suzuki, Tinatin I. BrelidzeAbstract:Kv11.1 potassium channels are essential for Heart Repolarization. Prescription medication that blocks Kv11.1 channels lengthens the ventricular action potential and causes cardiac arrhythmias. Surprisingly little is known about the Kv11.1 channel expression and function in the lung tissue. Here we report that Kv11.1 channels were abundantly expressed in the large pulmonary arteries (PAs) of healthy lung tissues from humans and rats. Kv11.1 channel expression was increased in the lungs of humans affected by chronic obstructive pulmonary disease-associated pulmonary hypertension and in the lungs of rats with pulmonary arterial hypertension (PAH). In healthy lung tissues from humans and rats, Kv11.1 channels were confined to the large PAs. In humans with chronic obstructive pulmonary disease-associated pulmonary hypertension and in rats with PAH, Kv11.1 channels were expressed in both the large and small PAs. The increase in Kv11.1 channel expression closely followed the time-course of the development of pulmonary vascular remodeling in PAH rats. Treatment of PAH rats with dofetilide, an Kv11.1 channel blocker approved by the US Food and Drug Administration for use in the treatment of arrythmia, inhibited PAH-associated pulmonary vascular remodeling. Taken together, the findings from this study uncovered a novel role of Kv11.1 channels in lung function and their potential as new drug targets in the treatment of pulmonary hypertension. The protective effect of dofetilide raises the possibility of repurposing this antiarrhythmic drug for the treatment of patients with pulmonary hypertension.
Francisco J. Noriega - One of the best experts on this subject based on the ideXlab platform.
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Cardiac activation-Repolarization patterns and ion channel expression mapping in intact isolated normal human Hearts.
Heart rhythm, 2016Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, Leander Beekman, Jesús Álvarez-garcía, Cristian Munoz-guijosa, Ruben CoronelAbstract:Background The Repolarization pattern of the human Heart is unknown. Objective The purpose of this study was to perform a multisite analysis of the activation–Repolarization patterns and mRNA expression patterns of ion channel subunits in isolated human Hearts. Methods Hearts from 3 donors without reported cardiac disease were Langendorff perfused with the patient's own blood. A standard ECG was obtained before explantation. Up to 92 unipolar electrograms from 24 transmural needles were obtained during right atrial pacing. Local activation and Repolarization times and activation–recovery intervals (ARI) were measured. The mRNA levels of subunits of the channels carrying the transient outward current and slow and rapid components of the delayed rectifier current were determined by quantitative reverse transcriptase polymerase chain reaction at up to 63 sites. Results The Repolarization gradients in the 3 Hearts were different and occurred along all axes without midmural late Repolarization. A negative activation–Repolarization relationship occurred along the epicardium, but this relationship was positive in the whole Hearts. Coefficients of variation of mRNA levels (40%–80%) and of the Kv7.1 protein (alpha-subunit slow delayed rectifier channel) were larger than those of ARIs (7%–17%). The regional mRNA expression patterns were similar in the 3 Hearts, unlike the ARI profiles. The expression level of individual mRNAs and of Kv7.1 did not correlate with local ARIs at the same sites. Conclusion In the normal human Heart, Repolarization gradients encompass all axes, without late midmural Repolarization. Last activated areas do not repolarize first as previously assumed. Gradients of mRNAs of single ion channel subunits and of ARIs do not correlate.
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Repolarization mapping in relation to quantitative expression patterns of major ion channels in the isolated perfused healthy human Heart
European Heart Journal, 2013Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, J. Álvarez, C Muñoz, Ruben Coronel, Juan CincaAbstract:Background: The Repolarization pattern of the human Heart is important for the understanding of the normal T wave and its changes in disease. This pattern is largely unknown, let alone its relation with expression patterns of ion channels. We therefore studied explanted Hearts obtained from 7 donors free of structural cardiac disorders. Methods: Informed consent was obtained from the relatives of the deceased and the study was approved by the Ethical Review Board (Barcelona). Clinical data and an ECG were recorded before explantation. Hearts were perfused according to Langendorff with whole blood of the same donor. Up to 24 transmural needles (each 4 electrodes at 4 mm distance) were inserted in the left, septal and right ventricular myocardium and activation and Repolarization patterns were obtained during pacing from the right atrium at a cycle length of 700 msec. Transmural tissue samples were obtained from the locations of the needles, cut in three transmural portions and immediately stored in liquid nitrogen. mRNA levels of ion channel subunits KCND2, KCND3, KCNIP2, KCNQ1, KCNE1 and KCNE2 were determined (in duplicate) by real-time quantitative PCR and normalized to the housekeeping gene HPRT. Results: From 2 Hearts a complete set of electrophysiological and qPCR data were obtained. The ECG of both patients (a man of 66 and a woman of 73 years) was normal, and one had a biphasic T wave in the precordial leads. In both Hearts activation-recovery intervals (ARIs) were significantly longer in the left (LV) than in the right ventricle (RV). Nevertheless, in one Heart with the biphasic T wave Repolarization terminated simultaneously in RV and LV. In the other Heart Repolarization in the RV preceded that in the LV. No relevant transmural or apico-basal gradients in Repolarization were observed. However, in both Hearts prominent anterior to posterior gradients were present. Of the ion channels studied, mRNA expression levels of KCND2 and KCNE2 were very low, whereas KCNIP2 was highly expressed. Coefficients of variation of the selected mRNA levels was considerably larger than that of ARIs (50 vs. 10%). KCND3 mRNA was significantly higher in LV than RV in both Hearts. There were no relevant correlations between the density of any of the tested mRNAs and ARIs. Conclusion: We present the first Repolarization and expression maps of the normal human Heart. It shows that regional variability of expression is several folds higher than variability of ARIs. The distribution of Repolarization gradients is not directly related to patterns of mRNAs encoding major ion channel subunits.
Rob F. Wiegerinck - One of the best experts on this subject based on the ideXlab platform.
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Cardiac activation-Repolarization patterns and ion channel expression mapping in intact isolated normal human Hearts.
Heart rhythm, 2016Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, Leander Beekman, Jesús Álvarez-garcía, Cristian Munoz-guijosa, Ruben CoronelAbstract:Background The Repolarization pattern of the human Heart is unknown. Objective The purpose of this study was to perform a multisite analysis of the activation–Repolarization patterns and mRNA expression patterns of ion channel subunits in isolated human Hearts. Methods Hearts from 3 donors without reported cardiac disease were Langendorff perfused with the patient's own blood. A standard ECG was obtained before explantation. Up to 92 unipolar electrograms from 24 transmural needles were obtained during right atrial pacing. Local activation and Repolarization times and activation–recovery intervals (ARI) were measured. The mRNA levels of subunits of the channels carrying the transient outward current and slow and rapid components of the delayed rectifier current were determined by quantitative reverse transcriptase polymerase chain reaction at up to 63 sites. Results The Repolarization gradients in the 3 Hearts were different and occurred along all axes without midmural late Repolarization. A negative activation–Repolarization relationship occurred along the epicardium, but this relationship was positive in the whole Hearts. Coefficients of variation of mRNA levels (40%–80%) and of the Kv7.1 protein (alpha-subunit slow delayed rectifier channel) were larger than those of ARIs (7%–17%). The regional mRNA expression patterns were similar in the 3 Hearts, unlike the ARI profiles. The expression level of individual mRNAs and of Kv7.1 did not correlate with local ARIs at the same sites. Conclusion In the normal human Heart, Repolarization gradients encompass all axes, without late midmural Repolarization. Last activated areas do not repolarize first as previously assumed. Gradients of mRNAs of single ion channel subunits and of ARIs do not correlate.
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Repolarization mapping in relation to quantitative expression patterns of major ion channels in the isolated perfused healthy human Heart
European Heart Journal, 2013Co-Authors: Tobias Opthof, Francisco J. Noriega, Rob F. Wiegerinck, A. Tasiam, Carol Ann Remme, Esther Jorge, J. Álvarez, C Muñoz, Ruben Coronel, Juan CincaAbstract:Background: The Repolarization pattern of the human Heart is important for the understanding of the normal T wave and its changes in disease. This pattern is largely unknown, let alone its relation with expression patterns of ion channels. We therefore studied explanted Hearts obtained from 7 donors free of structural cardiac disorders. Methods: Informed consent was obtained from the relatives of the deceased and the study was approved by the Ethical Review Board (Barcelona). Clinical data and an ECG were recorded before explantation. Hearts were perfused according to Langendorff with whole blood of the same donor. Up to 24 transmural needles (each 4 electrodes at 4 mm distance) were inserted in the left, septal and right ventricular myocardium and activation and Repolarization patterns were obtained during pacing from the right atrium at a cycle length of 700 msec. Transmural tissue samples were obtained from the locations of the needles, cut in three transmural portions and immediately stored in liquid nitrogen. mRNA levels of ion channel subunits KCND2, KCND3, KCNIP2, KCNQ1, KCNE1 and KCNE2 were determined (in duplicate) by real-time quantitative PCR and normalized to the housekeeping gene HPRT. Results: From 2 Hearts a complete set of electrophysiological and qPCR data were obtained. The ECG of both patients (a man of 66 and a woman of 73 years) was normal, and one had a biphasic T wave in the precordial leads. In both Hearts activation-recovery intervals (ARIs) were significantly longer in the left (LV) than in the right ventricle (RV). Nevertheless, in one Heart with the biphasic T wave Repolarization terminated simultaneously in RV and LV. In the other Heart Repolarization in the RV preceded that in the LV. No relevant transmural or apico-basal gradients in Repolarization were observed. However, in both Hearts prominent anterior to posterior gradients were present. Of the ion channels studied, mRNA expression levels of KCND2 and KCNE2 were very low, whereas KCNIP2 was highly expressed. Coefficients of variation of the selected mRNA levels was considerably larger than that of ARIs (50 vs. 10%). KCND3 mRNA was significantly higher in LV than RV in both Hearts. There were no relevant correlations between the density of any of the tested mRNAs and ARIs. Conclusion: We present the first Repolarization and expression maps of the normal human Heart. It shows that regional variability of expression is several folds higher than variability of ARIs. The distribution of Repolarization gradients is not directly related to patterns of mRNAs encoding major ion channel subunits.
