Angelo Livolsi

MR diagnosis of subdiaphragmatic anomalous pulmonary venous drainage in a newborn.

Our report describes a case of infradiaphragmatic total anomalous pulmonary venous return diagnosed by MR in a newborn with an interruption of the aortic arch with ventricular septum defect and anomalous pulmonary venous drainage. The severity of the congenital cardiopathy did not permit surgical treatment and the infant died soon after. Pathology confirmed the MR findings. Magnetic resonance not only complements echocardiography but also can be used for patients in intensive care and can in our case avoid angiography.

Cardiac Muscarinic Receptor Overexpression in Sudden Infant Death Syndrome

Background Sudden infant death syndrome (SIDS) remains the leading cause of death among infants less than 1 year of age. Disturbed expression of some neurotransmitters and their receptors has been shown in the central nervous system of SIDS victims but no biological abnormality of the peripheral vago-cardiac system has been demonstrated to date. The present study aimed to seek vago-cardiac abnormalities in SIDS victims. The cardiac level of expression of muscarinic receptors, as well as acetylcholinesterase enzyme activity were investigated. Methodology/Principal Findings Left ventricular samples and blood samples were obtained from autopsies of SIDS and children deceased from non cardiac causes. Binding experiments performed with [3H]NMS, a selective muscarinic ligand, in cardiac membrane preparations showed that the density of cardiac muscarinic receptors was increased as shown by a more than doubled Bmax value in SIDS (n = 9 SIDS versus 8 controls). On average, the erythrocyte acetylcholinesterase enzyme activity was also significantly increased (n = 9 SIDS versus 11 controls). Conclusions In the present study, it has been shown for the first time that cardiac muscarinic receptor overexpression is associated with SIDS. The increase of acetylcholinesterase enzyme activity appears as a possible regulatory mechanism.

Pre- and post-operative MRI study of an aneurysm of the right brachiocephalic artery with tracheal compression

Sir: Anomal ies of the aortic arch have an estimated incidence of 3% in the general populat ion and are usually asymptomatic. The rare symptomatic forms may be life-threatening due to lower airway compression necessitating early diagnosis and surgical management . Their diagnosis rests on the association of bar ium oeosophagography, tracheobronchoscopy, angiography, and more recently on cardiac MRI [1, 2]. Fig. 2, Pre-operative sagittal section: the brachiocephalic trunk (~) causes almost total obstruction of the trachea (T). The aorta (A) presents an aneurysm. B, right pulmonary artery; C, left atrium; D, right atrium

Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

Background Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity. Rabbits with marked vagal pauses following injection of phenylephrine were selected and crossed to obtain a vagal hyperreactive strain. The density of cardiac muscarinic receptors and acetylcholinesterase (AchE) gene expression were assessed. Blood markers of the observed cardiac abnormalities were also sought. Methodology/Principal Findings Cardiac muscarinic M2 and M3 receptors were overexpressed in hyperreactive rabbits compared to control animals (2.3-fold and 2.5-fold, respectively) and the severity of the phenylephrine-induced bradycardia was correlated with their densities. A similar overexpression of M2 receptors was observed in peripheral mononuclear white blood cells, suggesting that cardiac M2 receptor expression can be inferred with high confidence from measurements in blood cells. Sequencing of the coding fragment of the M2 receptor gene revealed a single nucleotide mutation in 83% of hyperreactive animals, possibly contributing for the transcript overexpression. Significant increases in AchE expression and activity were also assessed (AchE mRNA amplification ratio of 3.6 versus normal rabbits). This phenomenon might represent a compensatory consequence of muscarinic receptors overexpression. Alterations in M2 receptor and AchE expression occurred between the 5th and the 7th week of age, a critical period also characterized by a higher mortality rate of hyperreactive rabbits (52% in H rabbits versus 13% in normal rabbits) and preceeded the appearance of functional disorders. Conclusions/Significance The results suggest that cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas AchE hyperactivity appears as a compensatory consequence of it. Since similar vagal disorders were observed recently by us in SIDS, muscarinic receptor overexpression could become a marker of risk of vasovagal syncopes and SIDS.

Expression of Circulating Muscarinic Receptors in Infants With Severe Idiopathic Life-Threatening Events.

Expression of Circulating Muscarinic Receptors in Infants With Severe Idiopathic Life-Threatening Events About half of the apparent life-threatening events (ALTEs) that occur among infants remain unexplained and are called idiopathic.1 Yet there is no biomarker associated with idiopathic ALTEs. Although the connection between ALTEs and sudden infant death syndrome (SIDS) remains controversial, the cholinergic system has been investigated in the pathogenesis of both.2-4 We investigate the M2 muscarinic receptors’ expression in the blood samples of infants who experienced severe ALTEs.

First Model of Spontaneous Vagal Hyperreactivity and Its Mode of Genetic Transmission

Background—The main purpose of our study was to define an animal model of vagal hyperreactivity and its genetic transmission. Methods and Results—We first investigated the vagal reactivity with phenylephrine in conscious rabbits. Barosensitivity and the maximal bradycardic response were measured at the upper mean blood pressure plateau. Hyperreactive (H) animals were selected and crossbred with normal (N) ones. Results showed no significant difference between calculated barosensitivity values after the different doses of phenylephrine. In contrast, an increase of the values and a great dispersion appeared 1 to 5 beats after the end of the ramp. Marked pauses (6000 to 20 000 ms) were obtained with some rabbits, which were blocked by atropine. A significant excess of hyperreactive offspring was observed in H×H crossings compared with N×N ones (39.4% male and 42.3% female offspring versus 14.4% and 4.4%, respectively). Few female offspring were hyperreactive compared with males in N×H and N×N crossings (4.1% versus 23.4% and 4.4% versus 14.4%, respectively). Conclusions—This study describes the first model of spontaneous vagal pauses. The inheritance could be polygenic with a partial sex-limited character.

Peculiar Clinical Presentation of Coxsackievirus B4 Infection: Neonatal Restrictive Cardiomyopathy

Introduction  Restrictive cardiomyopathy in fetuses and neonates is extremely rare and has a poor outcome. Its etiology in neonates is elusive: metabolic diseases (e.g., Gaucher, Hurler syndrome), neuromuscular disorders (e.g., muscular dystrophies, myofibrillar myopathies), or rare presentation of genetic syndromes (e.g., Coffin–Lowry syndrome) account for a minority of the cases, the majority remaining idiopathic. Case Study  We report the case of a 17-day-old male infant presenting cardiogenic shock following a restrictive dysfunction of the left ventricle. Postmortem investigations revealed coxsackievirus B4 myocarditis with histological lesions limited to the left heart. However, polymerase chain reaction (PCR) for coxsackievirus B4 was positive in the left as well as in the right ventricular samples. Conclusion  In conclusion, coxsackievirus myocarditis is a cause of restrictive cardiomyopathy, and its diagnosis should involve PCR screening as a more sensitive technique.

129 : Cardiac muscarinic receptor overexpression as a possible cause of vagal hyperreactivity

1 Which importance for P 450 Cytochromes in drug interactions? A study from the French PharmacoVigilance Database AC Danton, A Sommet, G Durrieu, H Bagheri and JL Montastruc Service de Pharmacologie, Faculté de Médecine, Toulouse, France Objective: Cytochromes (CYPs) are a superfamily of isoenzymes involved in drug metabolism. The main isoenzymes are CYP 1A2, 2C9, 2D6 and 3A4. However, their relative importance in clinically significant interactions remains unknown. The aim of the present study was to investigate in the French PharmacoVigilance Database (FPVD) the number and characteristics of drug-drug interactions possibly explained by involvement of CYPs. Methods: Spontaneous notifications of Adverse Drug Reactions (ADRs) recorded by Toulouse Midi-Pyrénées PharmacoVigilance Centre between 1st January and 31st August 2008 were extracted from the FPVD. For each observation, we recorded the main characteristics of patients (age, gender), involved drug(s) (name, pharmacological class and involved CYP) and induced ADRs (type, ‘seriousness’, evolution). Results: Between 1st January and 31st August 2008, 1205 ADRs were registered by Toulouse Midi-Pyrénées PharmacoVigilance Centre into the FPVD. They involved 683 women (56.6%). In 12 cases, patients were less than 1 year old and in 14 cases, age was not informed. For other observations, mean age was 55.8 (median value: 58.0) years. Among these ADRs, 410 (34%) were ‘serious’ (including 24 fatal outcomes), 356 involved only one drug and 730 did not involve any drug interaction. Finally, 119 reports (i.e. 9.9% of registered ADRs) involved one (or more) drug interaction related to CYPs. Among these 119 notifications, the most frequently involved CYP was 3A4/5 (n = 81), followed by 2C19 (n = 20), 2C9 (n = 16), 2D6 (n = 16) and 2E1 (n = 1). In 13 notifications, several CYPs were involved. Drugs more frequently involved in this kind of drug interaction were amiodarone (n = 21) followed by proton pump inhibitors (n = 11), meprobamate (n = 9), antiretrovirals (n = 9) and rifampicine (n = 6). There was no major difference in ‘seriousness’ or evolution of ADRs between CYP-related interactions and others. In 22 cases, ADRs were possibly due to CYP-related drug interaction (18.5% of CYP-related drug interactions). Conclusion: CYP-related drug interactions are found in around 10% of ADRs registered in the FPVD. The most frequently involved CYPs are 3A4/5 (68%) followed by 2C19 (17%). This CYP-involving interaction leads to clinically significant consequences (ADR) in almost one case out of five. These data underline the importance of CYPs not only in drug interactions but also in mechanisms of ADRs.

Anatomie cardiovasculaire et analyse segmentaire sequentielle en IRM

Resume L’imagerie des malformations congenitales cardio-vasculaires a beneficie ces dernieres annees de l’apport considerable des techniques d’imagerie en coupes avec en premiere ligne l’echocardiographie. L’IRM, en plus de son champ de vue large (sans interference osseuse ou aerique), de son excellente resolution spatiale, apporte une approche fonctionnelle originale sur les flux. Sa place, gagnee en deuxieme intention apres l’echocardiographie dans l’evaluation de ces anomalies, repond en premier lieu au souci legitime d’eviter chez l’enfant et l’adulte jeune, le recours a des techniques d’exploration invasives ou ionisantes. Son approche multiplanaire necessite cependant, comme pour toute technique « tomographique », une reconstruction mentale tridimensionnelle de l’anatomie cardio-vasculaire a partir d’une serie de coupes sequentielles de 3 a 10 mm d’epaisseur obtenue en temps differe. Il est donc important en premier lieu de bien connaitre les particularites de l’anatomie cardiaque normale dans les plans de coupes habituellement realises. Cette demarche permettra de proceder a une analyse segmentaire cardio-vasculaire qui repose sur l’identification des cavites cardiaques, des gros vaisseaux et de leur mode de connexion. Elle doit, comme en echocardiographie, proceder de facon systematique au niveau de chacun des trois compartiments cardiaques (atrial, ventriculaire et arteriel) qui, dans un cœur normal, sont connectes de facon concordante a droite (AD-> VD- > AP) ou a gauche (AG- > VG- > Ao). Dans les malformations congenitales, chacun des segments peut en effet occuper une situation anormale. Pour certaines d’entre elles, 1’IRM apparait indispensable pour completer le bilan echographique.