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D Escande

Publications and source records attributed to D Escande.

At least 19 recordsLinked to original sources
PubMed2006

[Sudden cardiac death: toward the identification of susceptibity genes].

Sudden cardiac death (SCD) remains a major health problem in developed countries with a rate of incidence close to 1/1000 inhabitants/year. In most cases (>80%), SCD occurs as the initial manifestation of a previously ignored cardiac disease, usually coronary artery disease. As a consequence, known risk factors for SCD overlap with those for coronary artery disease and thus are not contributive to identify individuals prone to SCD in the general population. Several clinical studies have demonstrated an increased risk for SCD if one family first-degree relative has experienced SCD, suggesting a genetically acquired susceptibility. Discovering the molecular determinant of this genetic susceptibility may demonstrate extreme value to stratify the risk in the community and to guide prevention. The present review analyses state-of-the-heart research conducted in this field and tentatively measure the distance to be covered before large-scale genetic tests are routinely available in clinical practice.

Death, Sudden, Cardiac↗
PubMed2003

Human Kv1.6 current displays a C-type-like inactivation when re-expressed in cos-7 cells.

The human Kv1.6K(+) channel was functionally re-expressed in COS-7 cells at different levels. Voltage-activated K(+) currents are recorded upon cell membrane depolarization independently of the level of Kv1.6 expression. The current acquires a fast inactivation when Kv1.6 expression is increased. Inactivation was not affected by divalent cations or by extracellular tetraethylammonium. We have characterized the inactivation properties in biophysical terms. The fraction of inactivated current and the kinetics of inactivation are increased as the cell becomes more depolarized. Inactivated current can be reactivated according to a bi-exponential function of time. Additional experiments indicate that Kv1.6 inactivation properties are close to those of a conventional C-type inactivation. This work suggests that the concentration of Kv1.6 channel in the cell membrane strongly modulates the kinetic properties of Kv1.6-induced K(+) current. The physiological implications of these modifications are discussed.

Adaptation, Physiological↗
PubMed2003

Phosphatidylinositol-4,5-bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K+ channels.

Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is a major signaling molecule implicated in the regulation of various ion transporters and channels. Here we show that PIP(2) and intracellular MgATP control the activity of the KCNQ1/KCNE1 potassium channel complex. In excised patch-clamp recordings, the KCNQ1/KCNE1 current decreased spontaneously with time. This rundown was markedly slowed by cytosolic application of PIP(2) and fully prevented by application of PIP(2) plus MgATP. PIP(2)-dependent rundown was accompanied by acceleration in the current deactivation kinetics, whereas the MgATP-dependent rundown was not. Cytosolic application of PIP(2) slowed deactivation kinetics and also shifted the voltage dependency of the channel activation toward negative potentials. Complex changes in the current characteristics induced by membrane PIP(2) was fully restituted by a model originally elaborated for ATP-regulated two transmembrane-domain potassium channels. The model is consistent with stabilization by PIP(2) of KCNQ1/KCNE1 channels in the open state. Our data suggest a striking functional homology between a six transmembrane-domain voltage-gated channel and a two transmembrane-domain ATP-gated channel.

Adenosine Triphosphate↗
PubMed2001

Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.

BACKGROUND: The SCN5A gene encoding the human cardiac sodium channel alpha subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease). METHODS AND RESULTS: In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na(+) current but normal protein trafficking. CONCLUSIONS: We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation.

Animals↗
PubMed2001

Genetic manipulation of cardiac K(+) channel function in mice: what have we learned, and where do we go from here?

In the mammalian myocardium, potassium (K(+)) channels control resting potentials, action potential waveforms, automaticity, and refractory periods and, in most cardiac cells, multiple types of K(+) channels that subserve these functions are expressed. Molecular cloning has revealed the presence of a large number of K(+) channel pore forming (alpha) and accessory (beta) subunits in the heart, and considerable progress has been made recently in defining the relationships between expressed K(+) channel subunits and functional cardiac K(+) channels. To date, more than 20 mouse models with altered K(+) channel expression/functioning have been generated using dominant-negative transgenic and targeted gene deletion approaches. In several instances, the genetic manipulation of K(+) channel subunit expression has revealed the role of specific K(+) channel subunit subfamilies or individual K(+) channel subunit genes in the generation of myocardial K(+) channels. In other cases, however, the phenotypic consequences have been unexpected. This review summarizes what has been learned from the in situ genetic manipulation of cardiac K(+) channel functioning in the mouse, discusses the limitations of the models developed to date, and explores the likely directions of future research.

Action Potentials↗
PubMed2001

Inactivating properties of recombinant ROMK2 channels expressed in mammalian cells.

Biophysical properties of ROMK2 channel were investigated at physiological temperature, after reexpression of the recombinant ROMK2 protein in a mammalian cell expression system (COS-7). We observed that ROMK2 induced an inwardly rectifying K(+) current whether polyvalent cations were present or not. Above +10 mV, ROMK2-induced current exhibited a voltage- and time-dependent decay, consistent with an inactivation process. Inactivation of ROMK2-induced current was also seen in inside out patch from ROMK2-expressing Xenopus oocyte. In COS-7 cells, inactivation was found to account for most of the inward rectification. Mg(2+) and spermine modulated rectification by accelerating inactivation kinetics independently of membrane potential. These results establish for the first time ROMK2 properties in a mammalian cell expression system.

Animals↗
PubMed2001

Beta(3)-adrenoceptors control Cl(-) conductance in rabbit nasal epithelium.

We have investigated the effects of beta(3)-adrenoceptor stimulation in vivo on nasal epithelium. We have recorded the transepithelial potential difference in New Zealand white rabbit nostrils. Superfusion of the nasal epithelial surface with a Cl(-)-free medium supplemented with amiloride, hyperpolarized the nasal potential difference. Isoprenaline produced a hyperpolarization of the nasal potential difference that was not prevented by nadolol, a potent beta(1)-/beta(2)-adrenoceptor antagonist, but was abolished by bupranolol, a nonselective beta(1-3)-adrenoceptor antagonist. SR 58611 ((RS)-N-[(25)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronapht-2-yl]-(2R)-2-(3-chlorophenyl)-2 hydroethanamine hydrochloride) and CGP 12177 (4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2-1), a preferential and a partial beta(3)-adrenoceptor agonists, respectively, also produced hyperpolarization of the nasal potential difference. SR 59230 (3-(2-ethylphenoxy)-1-[(1S)1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)-2-propanol oxalate), a selective beta(3)-adrenoceptor antagonist, abolished the effects of CGP 12177. We conclude that beta(3)-adrenoceptor stimulation resulted in modifications in the nasal potential difference. These findings strengthen the view that beta(3)-adrenoceptors are implicated in controlling water and salt transport in the normal respiratory epithelium.

Adrenergic beta-3 Receptor Agonists↗
PubMed2001

Mice disrupted for the KvLQT1 potassium channel regulator IsK gene accumulate mature T cells.

The IsK protein associates with KvLQT1 potassium channels to generate the slow component of the outward rectifying K(+) current involved in human cardiac repolarization. Mutations in either KCNE1 (encoding IsK) or KCNQ1 (encoding KvLQT1) genes have been associated with the long QT syndrome, a genetic disorder leading to prolonged cardiac repolarization and sudden death. We now report that the IsK protein is also involved in mature T cell homeostasis. In KCNE1 gene knockout mice, we observed a significant increase in the T cell compartment. Thymus and peripheral lymphoid organs of KCNE1-/- mice displayed a significant increase in mature T cells. The immunological phenotype of KCNE1-/- is age-dependent and only expressed in adult mice. Both IsK and KvLQT1 mRNA are expressed in murine thymus. Our data suggest that, in addition to its role in myocardial repolarization, the IsK-KvLQT1 tandem also plays a crucial role in T cell homeostasis.

Aging↗
PubMed2001

Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: Phenotypic characterisation.

OBJECTIVES: The KCNQ1 gene encodes the KvLQT1 potassium channel, which generates in the human heart the slow component of the cardiac delayed rectifier current, I(Ks). Mutations in KCNQ1 are the most frequent cause of the congenital long QT syndrome. We have previously cloned a cardiac KCNQ1 human isoform, which exerts a strong dominant-negative effect on KvLQT1 channels. We took advantage of this dominant-negative isoform to engineer an in vivo model of KvLQT1 disruption, obtained by overexpressing the dominant-negative subunit under the control of the alpha-myosin heavy chain promoter. RESULTS: Three different transgenic lines demonstrated a phenotype with increasing severity. Functional suppression of KvLQT1 in transgenic mice led to a markedly prolonged QT interval associated with sinus node dysfunction. Transgenic mice also demonstrated atrio-ventricular block leading to occasional Wenckebach phenomenon. The atrio-ventricular block was associated with prolonged AH but normal HV interval in His recordings. Prolonged QT interval correlated with prolonged action potential duration and with reduced K(+) current density in patch-clamp experiments. RNase protection assay revealed remodeling of K(+) channel expression in transgenic mice. CONCLUSIONS: Our transgenic mouse model suggests a role for KvLQT1 channels not only in the mouse cardiac repolarisation but also in the sinus node automaticity and in the propagation of the impulse through the AV node.

Action Potentials↗
PubMed2001

Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part II: Pharmacological profile.

OBJECTIVE: The acquired long QT syndrome results most often from the action of I(Kr) blocking-drugs on cardiac repolarization. We have evaluated a transgenic (TG) mouse (FVB) overexpressing a dominant-negative KvLQT1 isoform, as an in vivo screening model for I(Kr) blocking drugs. RESULTS: In TG mice, six-lead ECGs demonstrated sinus bradycardia, atrioventricular block, and QTc prolongation. Various drugs were injected intraperitoneally after blockade of the autonomic nervous system and serial ECGs were recorded. The end of the initial rapid phase of the T wave corrected for heart rate using a formula for mouse heart (QTrc), was used as a surrogate for the QT interval. Dofetilide, a specific I(Kr) blocker, did not prolong the QTrc interval either in TG or in wild-type (WT) mice but dose-dependently lengthened the sinus period in TG mice but not in WT mice. Other I(Kr) blockers including E 4031, haloperidol, sultopride, astemizole, cisapride and terikalant behaved similarly to dofetilide. Tedisamil, a blocker of the transient outward current, dose-dependently prolonged the QTrc in WT mice but not in TG mice and also reduced the sinus rhythm in both WT and TG mice. Lidocaine dose-dependently shortened the QTrc interval in TG mice and also lengthened the P wave duration. Nicardipine dose-dependently shortened QTrc and also produced sinus arrest in both WT and TG mice. CONCLUSIONS: We conclude that KvLQT1-invalidated TG mice discriminates in vivo drugs that blocks I(Kr) from drugs that block the transient outward current, the sodium current or the calcium current.

Animals↗
PubMed2001

Divergent expression of delayed rectifier K(+) channel subunits during mouse heart development.

The repolarization phase of the cardiac action potential is dependent on transmembrane K(+) currents. The slow (I(Ks)) and fast (I(Kr)) components of the delayed-rectifier cardiac K(+) current are generated by pore-forming alpha subunits KCNQ1 and KCNH2, respectively, in association with regulatory beta-subunit KCNE1, KCNE2 and perphaps KCNE3. In the present study we have investigated the distribution of transcripts encoding these five potassium channel-forming subunits during mouse heart development as well as the protein distribution of KCNQ1 and KCNH2. KCNQ1 and KCNH2 mRNAs (and protein) are first expressed at embryonic day (E) 9.5, showing comparable levels of expression within the atrial and ventricular myocardium during the embryonic and fetal stages. In contrast, the beta-subunits display a more dynamic pattern of expression during development. KCNE1 expression is first observed at E9.5 throughout the entire myocardium and progressively is confined to the ventricular myocardium. With further development (E16.5), KCNE1 expression is mainly confined to the compact ventricular myocardium. KCNE2 is first expressed at E9.5 and it is restricted already to the atrial myocardium. KCNE3 is first expressed at E8.5 throughout the myocardium and with further development, it becomes restricted to the atrial myocardium. The fact that alpha subunits are homogeneously distributed within the myocardium, whereas the beta subunits display a regionalized expression profile during cardiac development, suggest that differences in the slow and fast component of the delayed-rectifier cardiac K(+) currents between the atrial and the ventricular cardiomyocytes are mainly determined by differential beta-subunit distribution.

Animals↗
PubMed2001

Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype.

AIMS: In families with the long QT syndrome penetrance may be low: up to 70% of gene carriers may have a normal QTc interval. These patients require therapy, similar to that in those with longer QTc intervals, but identifying them, using molecular analysis, is difficult to apply on a large scale. A large French family affected by the long QT1 syndrome was followed-up over a 25-year period. In adult males but not in females, the QTc interval normalized after puberty. We aimed to find clinical criteria, based on ambulatory ECG recordings so that we could improve diagnosis in affected members with a normal QTc. METHODS AND RESULTS: Linkage analysis and direct sequencing were an indicator of the long QT1 gene in our family. Reverse transcription-polymerase chain reaction analysis demonstrated abnormal transcripts in lymphocytes from silent gene carriers. The functional profile of mutated protein isoforms was investigated using the patch-clamp technique. Dynamic analysis of ventricular depolarization was conducted using Holter recordings in patients, and in sex- and age-matched controls. Circadian variations of the QTc interval and the QT/RR relationship were assessed. Sensitivity, specificity, and predictive values were evaluated for proposed clinical criteria. We found that dynamic analysis of the QT interval permitted individual diagnosis in mutation carriers even when the QTc interval was normal (adult males). CONCLUSION: Dynamic analysis of the QT interval is of diagnostic value in the long QT1 syndrome in patients with a normal phenotype. Clinical implications include improvement in screening and patient management.

Adolescent↗
PubMed2001

Differential expression of KvLQT1 and its regulator IsK in mouse epithelia.

KCNQ1 is the human gene responsible in most cases for the long QT syndrome, a genetic disorder characterized by anomalies in cardiac repolarization leading to arrhythmias and sudden death. KCNQ1 encodes a pore-forming K+ channel subunit termed KvLQT1 which, in association with its regulatory beta-subunit IsK (also called minK), produces the slow component of the delayed-rectifier cardiac K+ current. We used in situ hybridization to localize KvLQT1 and IsK mRNAs in various tissues from adult mice. We showed that KvLQT1 mRNA expression is widely distributed in epithelial tissues, in the absence (small intestine, lung, liver, thymus) or presence (kidney, stomach, exocrine pancreas) of its regulator IsK. In the kidney and the stomach, however, the expression patterns of KvLQT1 and IsK do not coincide. In many tissues, in situ data obtained with the IsK probe coincide with beta-galactosidase expression in IsK-deficient mice in which the bacterial lacZ gene has been substituted for the IsK coding region. Because expression of KvLQT1 in the presence or absence of its regulator generates a K+ current with different biophysical characteristics, the role of KvLQT1 in epithelial cells may vary depending on the expression of its regulator IsK. The high level of KvLQT1 expression in epithelial tissues is consistent with its potential role in K+ secretion and recycling, in maintaining the resting potential, and in regulating Cl- secretion and/or Na+ absorption.

Animals↗
PubMed2001

AKAP proteins anchor cAMP-dependent protein kinase to KvLQT1/IsK channel complex.

In cardiac myocytes, the slow component of the delayed rectifier K(+) current (I(Ks)) is regulated by cAMP. Elevated cAMP increases I(Ks) amplitude, slows its deactivation kinetics, and shifts its activation curve. At the molecular level, I(Ks) channels are composed of KvLQT1/IsK complexes. In a variety of mammalian heterologous expression systems maintained at physiological temperature, we explored cAMP regulation of recombinant KvLQT1/IsK complexes. In these systems, KvLQT1/IsK complexes were totally insensitive to cAMP regulation. cAMP regulation was not restored by coexpression with the dominant negative isoform of KvLQT1 or with the cystic fibrosis transmembrane regulator. In contrast, coexpression of the neuronal A kinase anchoring protein (AKAP)79, a fragment of a cardiac AKAP (mAKAP), or cardiac AKAP15/18 restored cAMP regulation of KvLQT1/IsK complexes inasmuch as cAMP stimulation increased the I(Ks) amplitude, increased its deactivation time constant, and negatively shifted its activation curve. However, in cells expressing an AKAP, the effects of cAMP stimulation on the I(Ks) amplitude remained modest compared with those previously reported in cardiac myocytes. The effects of cAMP stimulation were fully prevented by including the Ht31 peptide (a global disruptor of protein kinase A anchoring) in the intracellular medium. We concluded that cAMP regulation of I(Ks) requires protein kinase A anchoring by AKAPs, which therefore participate with the channel protein complex underlying I(Ks).

3T3 Cells↗
PubMed2001

Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel.

Agonists of the serotonin 5-hydroxytryptamine 4 (5-HT4) receptor are widely used to activate motility in the gastrointestinal tract. Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects. Cisapride is a potent blocker of human ether-à-gogo (HERG) K(+) channels and prolongs the cardiac action potential in a reverse use dependence manner. We compared the effects of four different 5-HT4 receptor agonists (cisapride, prucalopride, renzapride and mosapride) on cloned HERG channels with the objective to evaluate and compare their proarrhythmic potential. K(+) currents from HERG-transfected COS-7 cells were recorded under physiological conditions using the whole cell configuration of the patch-clamp technique. Short (500 ms) depolarizing prepulses were used and following deactivating HERG currents were measured. Cisapride inhibited the HERG channels in a concentration-dependent manner with an IC(50) of 2.4 10(-7) M. The IC(50) value for prucalopride to block HERG (5.7 10(-6) M) was 20-fold higher than that of cisapride. Renzapride was slightly more potent than prucalopride (IC(50) = 1.8 10(-6) M). Mosapride produced no significant effects on the recombinant HERG current. The voltage dependence of HERG block was also investigated. The block mediated by cisapride or renzapride was voltage-dependent whereas that produced by prucalopride was not. We conclude that the rank order of potency of 5-HT4 agonists to block HERG is cisapride > renzapride > prucalopride > mosapride. We also conclude that 5-HT4 agonists devoid of side effects on the HERG current such as mosapride can be found as a safe alternative to cisapride.

Animals↗
PubMed2000

Pharmacogenetics of cardiac K(+) channels.

A number of commonly prescribed drugs belonging to various therapeutic classes (antiarrhythmic, antibiotic, antifungal, antihistamine, antipsychotic, prokinetic drugs...) possess, in common, the adverse property to prolong cardiac repolarization [prolonged QT interval duration on surface electrocardiogram (ECG)], exposing patients to a risk of torsade-de-pointes arrhythmias, syncope, and sudden death. Arrhythmias related to drug-induced QT prolongation do not occur in every patient treated with these drugs but most likely occur in a subset of susceptible patients. These patients have a high risk of recurrence of arrhythmias upon exposure to any of the other drugs that broaden the QT interval. It is currently suspected (though not yet proven) that susceptible individuals carry a silent mutation in one of the genes responsible for the congenital long QT syndrome. Indeed, it appears more and more clear that a large proportion of congenital long QT syndrome gene carriers, have a normal QT interval and a normal phenotype and therefore, remain undiagnosed. Therefore, a much larger than previously thought proportion of the general population may be affected by asymptomatic mutations in cardiac ion channel encoding genes. No routine technology is currently available in identifying these patients preventively.

Animals↗