Mexiletine-quinidine combination: Electrophysiologic correlates of a favorable antiarrhythmic interaction in humans

Combination therapy with mexiletine and quinidine has been shown to be more effective than either agent alone. The ability of mexiletine monotherapy, quinidine monotherapy and mexiletine-quinidine combination therapy to suppress inducible sustained ventricular tachycardia was related to drug-induced changes in ventricular refractoriness, conduction times and monophasic action potential duration recorded from both ventricles. Ventricular tachycardia could no longer be induced in 7 (35%) of the 20 patients studied with combination therapy. This was a significantly higher proportion of patients than that of the groups responding to either monotherapy (quinidine, 10%; mexiletine, 5%).Ventricular effective and functional refractory periods were measured when applying single (S2), double (S3) and triple (S4) extrastimuli. Quinidine monotherapy increased functional and effective refractory periods of both single and multiple extrastimuli. However, when comparing measurements made during mexiletine treatment with those at baseline, mexiletine monotherapy increased only the refractory periods of S4. The effective refractory period of S4 during mexiletine monotherapy (200 ± 20 ins) was significantly longer than at baseline (160 ± 21 ms). Similarly, when comparing measurements made during combination therapy with those during quinidine monotherapy, combination therapy significantly increased the refractory periods only of multiple extrastimuli. The effective refractory period of S4 during combination therapy (253 ± 26 ms) was significantly longer than that of quinidine monotherapy (223 ± 27 ms). The only other significant difference between combination therapy and monotherapy with either agent was a greater prolongation of conduction time to the left ventricular dyskinetic zone with combination therapy.Therefore, mexiletine-quinidine combination therapy is associated with additional prolongation of the refractory periods of multiple extrastimuli and with further prolongation of conduction into the dyskinetic zone of the left ventricle. These electrophysiologic effects may be markers of enhanced antiarrhythmic activity

The topology of U-duality (sub-)groups

We discuss the topology of the symmetry groups appearing in compactified (super-)gravity, and discuss two applications. First, we demonstrate that for 3 dimensional sigma models on a symmetric space G/H with G non-compact and H the maximal compact subgroup of G, the possibility of oxidation to a higher dimensional theory can immediately be deduced from the topology of H. Second, by comparing the actual symmetry groups appearing in maximal supergravities with the subgroups of SL(32,R) and Spin(32), we argue that these groups cannot serve as a local symmetry group for M-theory in a formulation of de Wit-Nicolai type.Comment: 18 pages, LaTeX, 1 figure, 2 table

Ketones Prevent Oxidative Impairment of Hippocampal Synaptic Integrity through K\u3csub\u3eATP\u3c/sub\u3e Channels

Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (KATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of KATP channel activation. Ketones dose-dependently reversed oxidative impairment of hippocampal synaptic integrity, neuronal viability, and bioenergetic capacity, and this action was mirrored by the KATP channel activator diazoxide. Inhibition of KATP channels reversed ketone-evoked hippocampal protection, and genetic ablation of the inwardly rectifying K+ channel subunit Kir6.2, a critical component of KATP channels, partially negated the synaptic protection afforded by ketones. This partial protection was completely reversed by co-application of the KATP blocker, 5-hydoxydecanoate (5HD). We conclude that, under conditions of oxidative injury, ketones induce synaptic protection in part through activation of KATP channels

A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources

KEY POINTS: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) capture patient-specific genotype-phenotype relationships, as well as cell-to-cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole-cell model of iPSC-CMs, composed of single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC-CMs This framework links molecular mechanisms to cellular-level outputs by revealing unique subsets of model parameters linked to known iPSC-CM phenotypes ABSTRACT: There is a profound need to develop a strategy for predicting patient-to-patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient-specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). A major strength of this approach is that iPSC-CMs contain donor genetic information and therefore capture patient-specific genotype-phenotype relationships. A cited detriment of iPSC-CMs is the cell-to-cell variability observed in electrical activity. We postulated, however, that cell-to-cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole-cell model of iPSC-CMs composed of simple model components comprising ion channel models with single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM data for all major ionic currents. By optimizing ionic current model parameters to multiple experimental datasets, we incorporate experimentally-observed variability in the ionic currents. The resulting population of cellular models predicts robust inter-subject variability in iPSC-CMs. This approach links molecular mechanisms to known cellular-level iPSC-CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyse the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacological interventions for studying the mechanisms of rare events, such as arrhythmia triggers.S

Quinidine pharmacodynamics in patients with arrhythmia: Effects of left ventricular function

Objectives.This study was undertaken to determine whether quinidine pharmacodynamics are altered in the presence of left ventricular dysfunction.Background.Left ventricular function is an independent predictor of antiarrhythmic drug efficacy. However, the effects of left ventricular dysfunction on the pharmacodynamics of antiarrhythmic drugs have not been studied extensively.Methods.Signal-averaged electrocardiograms were obtained and quinidine plasma concentrations measured during 24-h quinidine washout in 22 patients.Results.Linear quinidine concentration-effect relations were observed for QRS and QT intervals corrected for heart rate. The slopes of the concentration-effect relation describing changes in the corrected QT (QTc) interval were significantly higher in the group with left ventricular ejection fraction ≥0.35 ([mean ±SD] 29.5 ± 11.2 ms/μg per ml) than in the group with a low left ventricular ejection fraction (15.7 ± 9.7 ms/μg per ml, p = 0.001). The QRS concentration-effect relations were not different in the two groups. A significant linear correlation was observed between the slopes of the concentration-effect relations describing changes in QTc intervals and left ventricular ejection fraction (r = 0.7, p < 0.001). Nineteen patients with inducible ventricular tachycardia underwent serial electrophysiologic studies for evaluation of quinidine efficacy. Ventricular tachycardia could not be induced during quinidine therapy in eight patients. The slopes of the quinidine concentration-effect relations for QTc intervals were significantly higher in quinidine responders than in nonresponders (p < 0.05).Conclusions.The effects of quinidine on ventricular repolarization are linearly related to left ventricular ejection fraction. Quinidine concentration-effect relations describing ventricular repolarization are associated with antiarrhythmic efficacy in patients with ventricular tachycardia

Electrophysiologic actions of high plasma concentrations of propranolol in human subjects

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (> 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 ± 17 ng/ml) and at high concentrations (472 ± 68 ng/ml). Significant (p < 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p < 0.05). At high concentrations, there was significant (p < 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period.In summary, the concentration-response relations for atrioventricular conductivity and sinus node automat-icity were flat above concentrations of 150 ng/ml. On the other hand, the durations of the monophasic action potential and the QTc interval shortened at high concentrations. It is concluded that propranolol, in addition to blocking beta-receptors, produces other beta-receptor independent electrophysiologic effects in human beings

Palaeomagnetism of the Ordovician dolerites of the Crozon Peninsula (France)

In order to obtain a Lower Palaeozoic pole for the Armorican Massif and to test the origin of the Ibero-Armorican arc, the Ordovician dolerites of the Crozon peninsula have been palaeomagnetically studied. The samples show a multicomponent magnetization which has been revealed by AF and thermal demagnetization and thoroughly investigated with rock magnetic experiments, polished section examinations and K/Ar dating. Four groups of directions have been recognized, often superimposed on each other in an individual sample. One component (D) has always the lowest blocking temperatures and coercivities and is considered to be of viscous origin, acquired recently in situ or in the laboratory during storage. Two components (A and B) are interpreted to be of secondary origin and to correspond to the observed K/Ar age distribution between 300 and 190 Myr. These ages represent the time interval between two regional thermo-tectonic events, associated with the Hercynian orogeny and the intrusion of dykes related to the early opening of the Central Atlantic Ocean and the Bay of Biscay. A fourth component (C) could be of Ordovician or younger Palaeozoic age; it is not clear whether the age of the magnetization is pre- or post-folding, but a pre-folding age would yield a direction of magnetization similar to Ordovician results from the Iberian peninsula. The latter interpretation suggests a fairly high palaeolatitude, which is in agreement with a glacio-marine postulated for sediments overlying the dolerite sills.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73214/1/j.1365-246X.1983.tb03785.x.pd