Understanding the Pathophysiology of Intracranial Aneurysm: The ICAN Project.

BACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA. OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture. METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data. EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets. DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information.

Risk Stratification and Therapeutic Approach in Brugada Syndrome.

Brugada syndrome (BrS) is a clinical entity characterised by an incomplete right bundle branch block associated with an ST segment elevation in the right precordial leads and a risk of ventricular arrhythmia and sudden death in the absence of structural abnormalities. Patients with a personal history of sudden death have an annual arrhythmia risk of recurrence as high as 10 %. Similarly, the presence of syncope is consistently associated with an increased arrhythmic risk. This risk can be estimated at about 1.5 % per year. The risk is lower in asymptomatic patients. Regarding the relatively high rate of complication of Implantable cardioverter defibrillator (ICD) implantation, in most of the cases, asymptomatic patients with a Brugada syndrome revealed during ajmaline challenge do not need to be implanted. The situation is more complex in patients with a spontaneous type 1 aspect since the risk could be estimated to be around 0.8 % per year. For these patients, a careful evaluation of the arrhythmic risk using all the different tools available is mandatory.

Filamin-a-related myxomatous mitral valve dystrophy: genetic, echocardiographic and functional aspects.

Myxomatous dystrophy of the cardiac valves is a heterogeneous group of disorders, including syndromic diseases such as Marfan syndrome and isolated valvular diseases. Mitral valve prolapse, the most common form of this disease, is presumed to affect approximately 2% to 3% of the population and remains one of the most common causes of valvular surgery. During the past years, important effort has been made to better understand the pathophysiological basis of mitral valve prolapse. Autosomal-dominant transmission is the usual inheritance with reduced penetrance and variable expressivity. Three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32, but the underlying genetic defects are not currently known. An X-linked recessive form has been originally described by Monteleone and Fagan in 1969. Starting from one large French family and three smaller other families in which MVP was transmitted with an X-linked pattern, we have been able to identify three filamin A mutations p.Gly288Arg and p.Val711Asp and a 1,944-bp genomic deletion coding for exons 16 to 19. In this review, we describe the genetic, echocardiographic and functional aspects of the filamin-A-related myxomatous mitral valve dystrophy.