This contribution is being co-published in the following journals: Journal of Hypertension and Vascular Medicine. There will be minor differences in the version published in Vascular Medicine due to copy-editing differences.

Girls and women with Turner syndrome face a lifelong struggle with both congenital heart disease and acquired cardiovascular conditions. Bicuspid aortic valve is common, and many have left-sided heart obstructive disease of varying severity, from hypoplastic left-sided heart syndrome to minimal aortic stenosis or coarctation of the aorta. Significant enlargement of the thoracic aorta may progress to catastrophic aortic dissection and rupture. It is becoming increasingly apparent that a variety of other cardiovascular conditions, including early-onset hypertension, ischemic heart disease, and stroke, are the major factors reducing the life span of those with Turner syndrome. The presentations and management of cardiovascular conditions in Turner syndrome differ significantly from the general population. Therefore, an international working group reviewed the available evidence regarding the diagnosis and treatment of cardiovascular diseases in Turner syndrome. It is recognized that the suggestions for clinical practice stated here are only the beginning of a process that must also involve the establishment of quality indicators, structures and processes for implementation, and outcome studies.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development.We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

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