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Myocardial electrotonic coupling modulates repolarization heterogeneities in vivo: Implications for the assessment of pro-arrhythmic liabilities in vitro and in silico
354
Abstracts
showed regulation across all-time points for NPAA, whilst puromycin induced changes above 10× between days 14 and 28 for 28 genes. A panel of 68 urinary miRNAs associated with kidney injury, including miR-155, miR-21 and miR-30, is currently being assessed, aiming at increasing the robustness of region-specific molecular biomarker signatures. Overall, our findings confirm potential tubular, glomerular and collection duct specific molecular profiles of a more sub-acute nature than previously reported in pre-clinical studies. doi:10.1016/j.vascn.2016.02.062
0064 Myocardial electrotonic coupling modulates repolarization heterogeneities in vivo: Implications for the assessment of pro-arrhythmic liabilities in vitro and in silico Carlos del Rioa, Robert Hamlina,b, George Billmanb a
QTest Labs, Columbus, OH, USA The Ohio State University, Columbus, OH, USA
b
Passive electrical properties determining electrotonic cell-to-cell coupling in the myocardium can modulate repolarization disturbances/ heterogeneities; in short, poorly-coupled cells exert limited electrotonic influence(s) over their neighbors (i.e., lower space constant) facilitating induced/acquired heterogeneities, and therefore, pro-arrhythmic potential/behaviors. This study investigated, both in vivo and in silico, the effects of changes in myocardial electrotonic coupling on clinicallyrelevant indices of arrhythmic liabilities. Electrotonic coupling in vivo, both at rest and/or during acute ischemia in conscious dog, was modulated by interventions affecting autonomic balance/β-adrenoceptor (β-AR) signaling. At rest, acute ischemia induced marked electrotonic uncoupling but β-AR activation enhanced it; ischemic passive electrical derangements were blunted by vagal-nerve stimulation and complete/partial β-AR blockade but were enhanced by exercise. Overall, electrotonic derangements were well correlated with changes in the ratecorrected QT-interval (QTc, R2 = 0.89, P b 0.05) and/or the with duration (terminal-portion) of the T-wave (TPEc, R2 = 0.81, P b 0.05); these responses were well-modeled in silico by introducing (only) a spatially heterogeneous coupling resistance in a one dimensional structure of propagating cardiac action potentials following the Luo–Rudy formulation. Electrotonic uncoupling also predicted ischemic T-wave alternans (TWA, R2 = 0.82, P b 0.05), a known risk-marker for malignant arrhythmias in the clinic. Taken together, these data demonstrate that the degree of ventricular electrotonic uncoupling can explain, at least partially, pro-arrhythmic electrocardiographic changes reflective of myocardial repolarization abnormalities in vivo, and therefore, it must be considered when examining pro-arrhythmic liabilities in vitro and/or in silico. doi:10.1016/j.vascn.2016.02.063
0065 Recent cardiac ion channel data helped to better understand the QT prolongation/Torsades de Pointes risk of hydroxyzine (Atarax®), a first generation antihistamine Annie Delaunois, Aurore Colomar, Christopher Peters, Anne-Françoise Schlit, Jean-Pierre Valentin
Hydroxyzine (Atarax®) is a first generation antihistamine launched in 1955, before the implementation of the ICH S7b guidance. Since 2000, several publications showed that hydroxyzine was a potent hERG blocker, with IC50 values ranging between 0.16 and 0.62 μM, depending on the assay conditions. In contrast, dog telemetry studies showed no QT prolongation up to free plasma concentrations of 1.25 μM, equivalent to 100-fold the free plasma concentration in man at the therapeutic dose of 50 mg (0.01 μM). To better understand the risk of QT prolongation and Torsades de Pointes (TdP) and explore the potential role of other ion channels, we generated a full patch-clamp dataset including 8 different cardiac ion currents. We confirmed that hydroxyzine is a potent hERG inhibitor (IC50: 0.39 μM at nearly physiological temperature) but that it also inhibits the fast inactivated state of Nav1.5 channel (IC50: 0.32 μM) as well as the Cav1.2 channel (IC50: 8.6 μM). This multi-ion channel effect, with Nav1.5 and/or Cav1.2 inhibitory activities possibly mitigating hERG blockade, could partially explain the absence of QT prolongation observed with hydroxyzine in in vivo preclinical studies, and the relatively limited number of QT prolongation or TdP cases reported over more than 60 years of clinical use. Nevertheless, in order to better protect patients, additional risk minimization measures have been taken, such as reducing the highest recommended dose from 300 mg to 100 mg or avoid the use of this drug in the elderly and in patients with risk factors of arrhythmia. doi:10.1016/j.vascn.2016.02.064
0066 Off-target cardiac Na-channel inhibition in preclinical and clinical development—A case study Mark Deurincka, Ingrid Pruimbooma, Haisong Jub, Berengere Dumotiera, Martin Traeberta a
Novartis Institutes of Biomedical Research, Basel, Switzerland Novartis Institutes of Biomedical Research, East Hanover, NJ, USA
b
A candidate drug for gastrointestinal indications demonstrated cardiac Na-channel inhibition in preclinical assays. Moderate inhibition of hNav1.5 (IC50 of 15 μM) contributed to attenuated conduction in the isolated rabbit heart and QRS widening in arterially perfused rabbit left ventricular wedge preparations. Invasive and noninvasive dog telemetry studies revealed dosedependent but transient cardiovascular effects, such as a minor decrease in arterial blood pressure, as well as widening of the PR and QRS interval, without direct effects on QTc intervals. Decreased heart rate and first degree atrioventricular block were noted at higher dose levels. Standard ECGs collected in 2- and 4-week toxicology studies revealed similar ECG findings. Magnitude and time of occurrence of these effects correlated well with systemic plasma Tmax and Cmax values. No effects on body temperature were noted. Telemetered male Wistar rats showed increases in left ventricular systolic pressure and decreases in heart rate. At higher doses, increased systemic arterial blood pressure and pulse pressure were observed. A single ascending dose study in healthy volunteers revealed moderate and transient, but significant PR and QRS widening at the highest dose of 800 mg/day. At this and lower dose levels, pharmacodynamic activity was confirmed by functional gastrointestinal effects. This data set shows consistent off-target cardiac sodium channel inhibition with good translation from in vitro to animals and humans at therapeutic exposure and above. Additional effects on blood pressure and heart rate were considered to be related to a possible pharmacological off-target effect on the autonomic nervous system. doi:10.1016/j.vascn.2016.02.065
UCB Biopharma sprl, Braine-l'Alleud, Belgium
Abstracts
showed regulation across all-time points for NPAA, whilst puromycin induced changes above 10× between days 14 and 28 for 28 genes. A panel of 68 urinary miRNAs associated with kidney injury, including miR-155, miR-21 and miR-30, is currently being assessed, aiming at increasing the robustness of region-specific molecular biomarker signatures. Overall, our findings confirm potential tubular, glomerular and collection duct specific molecular profiles of a more sub-acute nature than previously reported in pre-clinical studies. doi:10.1016/j.vascn.2016.02.062
0064 Myocardial electrotonic coupling modulates repolarization heterogeneities in vivo: Implications for the assessment of pro-arrhythmic liabilities in vitro and in silico Carlos del Rioa, Robert Hamlina,b, George Billmanb a
QTest Labs, Columbus, OH, USA The Ohio State University, Columbus, OH, USA
b
Passive electrical properties determining electrotonic cell-to-cell coupling in the myocardium can modulate repolarization disturbances/ heterogeneities; in short, poorly-coupled cells exert limited electrotonic influence(s) over their neighbors (i.e., lower space constant) facilitating induced/acquired heterogeneities, and therefore, pro-arrhythmic potential/behaviors. This study investigated, both in vivo and in silico, the effects of changes in myocardial electrotonic coupling on clinicallyrelevant indices of arrhythmic liabilities. Electrotonic coupling in vivo, both at rest and/or during acute ischemia in conscious dog, was modulated by interventions affecting autonomic balance/β-adrenoceptor (β-AR) signaling. At rest, acute ischemia induced marked electrotonic uncoupling but β-AR activation enhanced it; ischemic passive electrical derangements were blunted by vagal-nerve stimulation and complete/partial β-AR blockade but were enhanced by exercise. Overall, electrotonic derangements were well correlated with changes in the ratecorrected QT-interval (QTc, R2 = 0.89, P b 0.05) and/or the with duration (terminal-portion) of the T-wave (TPEc, R2 = 0.81, P b 0.05); these responses were well-modeled in silico by introducing (only) a spatially heterogeneous coupling resistance in a one dimensional structure of propagating cardiac action potentials following the Luo–Rudy formulation. Electrotonic uncoupling also predicted ischemic T-wave alternans (TWA, R2 = 0.82, P b 0.05), a known risk-marker for malignant arrhythmias in the clinic. Taken together, these data demonstrate that the degree of ventricular electrotonic uncoupling can explain, at least partially, pro-arrhythmic electrocardiographic changes reflective of myocardial repolarization abnormalities in vivo, and therefore, it must be considered when examining pro-arrhythmic liabilities in vitro and/or in silico. doi:10.1016/j.vascn.2016.02.063
0065 Recent cardiac ion channel data helped to better understand the QT prolongation/Torsades de Pointes risk of hydroxyzine (Atarax®), a first generation antihistamine Annie Delaunois, Aurore Colomar, Christopher Peters, Anne-Françoise Schlit, Jean-Pierre Valentin
Hydroxyzine (Atarax®) is a first generation antihistamine launched in 1955, before the implementation of the ICH S7b guidance. Since 2000, several publications showed that hydroxyzine was a potent hERG blocker, with IC50 values ranging between 0.16 and 0.62 μM, depending on the assay conditions. In contrast, dog telemetry studies showed no QT prolongation up to free plasma concentrations of 1.25 μM, equivalent to 100-fold the free plasma concentration in man at the therapeutic dose of 50 mg (0.01 μM). To better understand the risk of QT prolongation and Torsades de Pointes (TdP) and explore the potential role of other ion channels, we generated a full patch-clamp dataset including 8 different cardiac ion currents. We confirmed that hydroxyzine is a potent hERG inhibitor (IC50: 0.39 μM at nearly physiological temperature) but that it also inhibits the fast inactivated state of Nav1.5 channel (IC50: 0.32 μM) as well as the Cav1.2 channel (IC50: 8.6 μM). This multi-ion channel effect, with Nav1.5 and/or Cav1.2 inhibitory activities possibly mitigating hERG blockade, could partially explain the absence of QT prolongation observed with hydroxyzine in in vivo preclinical studies, and the relatively limited number of QT prolongation or TdP cases reported over more than 60 years of clinical use. Nevertheless, in order to better protect patients, additional risk minimization measures have been taken, such as reducing the highest recommended dose from 300 mg to 100 mg or avoid the use of this drug in the elderly and in patients with risk factors of arrhythmia. doi:10.1016/j.vascn.2016.02.064
0066 Off-target cardiac Na-channel inhibition in preclinical and clinical development—A case study Mark Deurincka, Ingrid Pruimbooma, Haisong Jub, Berengere Dumotiera, Martin Traeberta a
Novartis Institutes of Biomedical Research, Basel, Switzerland Novartis Institutes of Biomedical Research, East Hanover, NJ, USA
b
A candidate drug for gastrointestinal indications demonstrated cardiac Na-channel inhibition in preclinical assays. Moderate inhibition of hNav1.5 (IC50 of 15 μM) contributed to attenuated conduction in the isolated rabbit heart and QRS widening in arterially perfused rabbit left ventricular wedge preparations. Invasive and noninvasive dog telemetry studies revealed dosedependent but transient cardiovascular effects, such as a minor decrease in arterial blood pressure, as well as widening of the PR and QRS interval, without direct effects on QTc intervals. Decreased heart rate and first degree atrioventricular block were noted at higher dose levels. Standard ECGs collected in 2- and 4-week toxicology studies revealed similar ECG findings. Magnitude and time of occurrence of these effects correlated well with systemic plasma Tmax and Cmax values. No effects on body temperature were noted. Telemetered male Wistar rats showed increases in left ventricular systolic pressure and decreases in heart rate. At higher doses, increased systemic arterial blood pressure and pulse pressure were observed. A single ascending dose study in healthy volunteers revealed moderate and transient, but significant PR and QRS widening at the highest dose of 800 mg/day. At this and lower dose levels, pharmacodynamic activity was confirmed by functional gastrointestinal effects. This data set shows consistent off-target cardiac sodium channel inhibition with good translation from in vitro to animals and humans at therapeutic exposure and above. Additional effects on blood pressure and heart rate were considered to be related to a possible pharmacological off-target effect on the autonomic nervous system. doi:10.1016/j.vascn.2016.02.065
UCB Biopharma sprl, Braine-l'Alleud, Belgium