[Clinical case of the month. Inaugural myocardial infarction from a congenital coronary-cardiac fistula]. / Le cas clinique du mois. Infarctus myocardique inaugural sur une fistule coronaro-cardiaque congénitale.

We report a case of a 47-year-old woman with a typical clinical pain, a ST elevation in lateral EKG leads and an increase of the CPK-MB enzymes serum level suggesting the diagnosis of an acute lateral myocardial infarction. The emergency coronary arteriography did not showed any coronary artery lesions but a coronary artery fistula from the left main coronary artery to a terminal thrombosed aneurysmal dilatation located between the left atrium and the right pulmonary artery. Through this case report, authors will discuss aetiology, physiopathology, clinical presentation and treatment of coronary artery fistulae.

[Long QT syndrome: from clinical discovery to molecular etiopathogenesis]. / Le syndrome du QT long: de la découverte clinique à l'étiopathogénie moléculaire.

Before the era of Molecular Biology the etiopathogenic mechanism of the long QT Syndrome (LQTS) was hypothetized to be an inhomogeneity in the innervation of the myocardium by the sympathetic system resulting in abnormal myocardial repolarisation, prolongation of the QT interval and various rhythm disorders. The progress of Molecular Biology has led to abandon this hypothesis; it is now agreed that the etiopathology of the various forms of the LQTS and of the arrythmias which are associated with it lies in the presence of mutations localized on genes coding either for cardio-specific ionic channels or for proteins which modulate the activity of these ionic channels. Thus, the alterations, direct or indirect, of these cardio-specific ionic channels lead to a delayed repolarization of myocardial cells which manifest itself on the electrocardiogram by a prolongation of the QT interval. This delayed repolarization of myocardial cells would induce a reactivation of myocardial ionic channels of the L-Ca++ type which leads to the development of secondary late depolarization which represent the underlying cellular mechanisms for "torsade de pointes". This hypothesis is experimentally reinforced by the observation both in animals and in men of a prolongation of the QT interval as well as aspecific tachyarrythmias after pharmacologic blockade of myocardial potassium channels. Therefore the long QT syndromes probably find their origin in genetic abnormalities of the electro-ionic system of the heart whereas the mechanical function and the autonomic innervation appear to be entirely normal.

Pulsatile secretion of gonadotropin-releasing hormone by rat hypothalamic explants without cell bodies of GnRH neurons [corrected].

Gonadotropin-releasing hormone (GnRH) is typically secreted in a pulsatile manner. It is still unclear whether pulsatility depends on a GnRH pulse generator residing in the GnRH neurons or in other neurons. Since the cell bodies of GnRH neurons are located rostrally to the optic chiasm and the majority of GnRH terminals in the median eminence of the rat hypothalamus, we have compared GnRH secretion from individual preoptic, retrochiasmatic and median eminence explants using a static incubation system. GnRH is released from the three different types of explant in response to depolarization with veratridine or glutamate receptor stimulation using the agonist N-methyl-D-aspartate. Only the retrochiasmatic explants, however, show a characteristic pulsatile secretion of GnRH. The mean (+/- SD) interpulse interval is respectively 37 +/- 5, 25 +/- 4 and 12 +/- 1 min when the fractions are collected at 7.5-, 5.0- and 2.5-min intervals. The immunocytochemically stained GnRH cell bodies are normally distributed in the preoptic explants (n = 212-420) while only 3 GnRH cell bodies can be visualized in 7 retrochiasmatic explants. Semi-quantitative RT-PCR shows that GnRH mRNA is present in the retrochiasmatic explant in a ratio of about 1:600 relative to the preoptic explant. We conclude that pulsatile GnRH secretion occurs in the virtual absence of GnRH cell bodies but does not occur from GnRH terminals in the isolated median eminence. These data further indicate that a mechanism of GnRH pulsatility is located in the retrochiasmatic hypothalamus and involves neurons different from the GnRH neurons.

Duality of glutamatergic and GABAergic control of pulsatile GnRH secretion by rat hypothalamic explants: I. Effects of antisense oligodeoxynucleotides using explants including or excluding the preoptic area.

Using antisense oligodeoxynucleotides we aimed to study the role of N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors in the mechanism of Gonadotrophin-releasing hormone (GnRH) secretion in vitro. Since GnRH cell bodies are located in the rat preoptic hypothalamus while most GnRH terminals are in the retrochiasmatic hypothalamus, we compared the effects of oligodeoxynucleotides on explants of the whole (preoptic area included) or retrochiasmatic hypothalamus. When GnRH secretion is evoked by muscimol and NMDA, a time-related reduction of GnRH secretion is caused by antisense oligodeoxynucleotides for the beta subunit of the GABAA receptor and the NR2A subunit of the NMDA receptor, respectively. After 6-7 h, binding studies of tritiated ligands show a decrease in GABA- and NMDA-receptor expression. While these antisense effects are observed using whole explants, no such effects are seen using retrochiasmatic explants, indicating that the facilitatory GABAA and NMDA receptors are encoded in the preoptic area. Using several missense oligodeoxynucleotides or antisense for the NR2B and NR2C subunits of the NMDA receptor, the muscimol- and NMDA-evoked release of GnRH is not affected. When spontaneous pulsatile GnRH secretion is studied, the NR2A antisense oligodeoxynucleotides cause an increase of the interpulse interval. This increase is seen using whole but not retrochiasmatic explants. In contrast, the GABAA and NR2C antisense oligodeoxynucleotides result in a reduction of GnRH interpulse interval. Such a reduction is seen using whole as well as retrochiasmatic explants, indicating that the GABAA and NMDA receptors which mediate inhibition of GnRH pulsatility are encoded in the retrochiasmatic hypothalamus. We conclude that NMDA receptors (NR2A subunit) encoded in the preoptic hypothalamus mediate a facilitatory effect on GnRH pulsatility while GABAA and NMDA (NR2C subunit) receptors encoded in the retrochiasmatic hypothalamus mediate an inhibition of GnRH pulsatility. Pulsatile GnRH secretion is affected differently than the agonist-evoked release of GnRH suggesting that the GnRH secretory neurons and the GnRH pulse generator consist of different cellular entities.

Duality of glutamatergic and GABAergic control of pulsatile GnRH secretion by rat hypothalamic explants: II. Reduced NR2C- and GABAA-receptor-mediated inhibition at initiation of sexual maturation.

N-methyl-D-aspartate (NMDA) receptors and gamma-aminobutyric acid (GABA) receptors are involved in the mechanism of pulsatile gonadotrophin-releasing hormone (GnRH) secretion. The aim of this study was to elucidate the role of those receptors in the acceleration of pulsatile GnRH secretion seen at onset of puberty. Using hypothalamic explants from prepubertal (15 days), early pubertal (25 days) and adult (50 days) male rats, we studied the effects of pharmacological antagonists and antisense oligodeoxynucleotides on GnRH release evoked by NMDA and GABA receptor agonists as well as the interval between spontaneous GnRH secretory pulses. At the three studied ages, the muscimol-evoked release of GnRh is similarly inhibited by the GABAA receptor antagonist bicuculline. In contrast, the frequency of pulsatility is stimulated by bicuculline as indicated by a reduction of the mean GnRh interpulse interval from 60 to 40 min and such an effect is seen at 15 days only. The GnRH interpulse interval is also reduced by GABAA receptor antisense oligodeoxynucleotides at 15 days while no effects are seen at 25 days. At the three studied ages, the NMDA-evoked release of GnRH and the GnRh interpulse interval are similarly inhibited by 100 or 500 microM of the NMDA receptor antagonist 7-chlorokynurenic acid (7CK). These effects are consistent with the increase of GnRH interpulse interval caused by NR2A antisense oligodeoxynucleotides at 15 days (86 vs 64 min in controls) as well as 25 days (44 vs 36 min). A low (5 microM) concentration of 7CK does not result in any effect except a reduction of GnRH interpulse interval which is seen at 15 days only. A similar reduction of GnRh interpulse interval is obtained using NR2C antisense oligodeoxynucleotides at 15 days (50 vs 64 min in controls) while no effects are seen at 25 days (35 vs 36 min). At 25 days, muscimol can prevent the developmental increase in frequency of pulsatile GnRH secretion. In summary, pulsatile GnRH secretion by the prepubertal hypothalamus characteristically involves an inhibition mediated through GABAA receptors and the NR2C subunit of NMDA receptors. Based on these data, we propose a model for the mechanism of the onset of puberty which involves the disappearance or inactivation of GABAergic neurons located in the retrochiasmatic hypothalamus and expressing the NR2C subtype of NMDA receptors.