Empana, Jean‐Philippe

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid arteries. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed ∼26K common variants (MAF>0.05) using an exome-chip array. We followed up 13 loci (P<10-4) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined Ncases=512, Ncontrols=669) confirmed this association, with an overall OR of 1.39, (P=7.4х10e-10 , All Ncases=1154, All Ncontrols=3895). The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure (P=0.0009), increased intima media thickness (P=0.001) and wall cross-sectional area (P=0.003) of carotids assessed by echotracking in 3800 population-based individuals. The correlation of genotypes with the expression of PHACTR1 in primary cultured human fibroblasts showed higher expression in FMD risk allele carriers, compared to non carriers (N=57, P=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (P=0.003) indicating impaired vascular development. In conclusion, we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

Introduction: Conflicting results exist regarding the impact of gender on survival after Sudden Cardiac Arrest (SCA). Hypothesis: Assess association between female gender and survival after SCA Methods: An electronic search of Embase, Ovid MEDLINE In-Process & Non-Indexed Citations and EBM Reviews - Cochrane Register of Controlled Trials, EBM Reviews - Cochrane Database of Systematic Reviews and Google was conducted (January 1948 to January 2014) for studies of any study design and language, examining the gender effect on survival at hospital discharge after a SCA. Two independent reviewers selected studies and extracted data. The inter-rater agreements kappa were measured at the first and second selection steps. Moreover, the pooled OR and 95% CI, concerning women vs. men survival at hospital discharge after an OHCA were calculated with a random effect model. Subgroups analyses were performed, according to the cardiac origin of OHCAs and according to the study quality. Study quality criteria were based on the New Castle Ottawa Scale. Results: After a detailed screening of 556 citations, 12 studies were identified involving 404 621 patients. The inter-rater agreements kappa was high for the 2 study selection steps (0.91 and 1). In most studies, women were older and had less favorable baseline characteristics including a lower prevalence of witnessed-OHCA, OHCA in a public location, bystander cardio-pulmonary resuscitation and shockable rhythms compared to men. However and after adjustment for these differences, women were more likely to survive at hospital discharge (N=12; OR: 1.11 [1.02-1.21]; p=0.013). This result remains in studies analyzing OHCA of presumed cardiac origin (N=7; OR: 1.17 [1.03-1.34]; p=0.017) and in studies of high quality (N=7; OR: 1.11 [1.02-1.21]; p=0.017). Conclusion: Despite less favorable baseline characteristics, women are more likely to survive at hospital discharge after an OHCA. Further studies are needed to explain this paradox.