PDF file, 794KB, Supplementary figure S1. Gross MAX deletion analysis Supplementary figure S2. Immunohistochemical assessment. Supplementary figure S3. Pedigree of 3 families with affected relatives in more than one generation.

Background. - Sub-Saharan Africa is experiencing a rising burden of hypertension. Antihypertensive medications and diet are the cornerstone of effective hypertension control. Aims. - To assess adherence to medication and salt restriction in 12 sub-Saharan countries, and to study the relationship between adherence and blood pressure control in patients with hypertension. Methods. - We conducted a cross-sectional survey in urban clinics in twelve sub-Saharan countries. Data were collected on demographics, treatment and adequacy of blood pressure control in patients with hypertension attending the clinics. Adherence was assessed by questionnaires completed by the patients. Hypertension grades were defined according to European Society of Cardiology guidelines. Association between adherence and blood pressure control was investigated using multilevel logistic regression analysis, adjusting for age, sex and country. Results. - Among the 2198 patients, 77.4% had uncontrolled blood pressure, 34.0% were poorly adherent to salt restriction, 64.4% were poorly adherent to medication and 24.6% were poorly adherent to both. Poor adherence to salt restriction (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.03-1.72), medication (OR 1.56, 95% CI 1.25-1.93) or both (OR 1.91 1.39-2.66) was related to uncontrolled blood pressure. Moreover, poor adherence to both medication and salt restriction was related to a 1.52-fold (95% CI 1.04-2.22), 1.8-fold (95% CI 1.22-2.65) and 3.08-fold (95% CI 2.02-4.69) increased likelihood of hypertension grade 1, 2 and 3, respectively. Conclusions. - High levels of poor adherence to salt restriction and medication were noted in this urban sub-Saharan study; both were significantly associated with uncontrolled blood pressure, representing major opportunities for intervention to improve hypertension control in sub-Saharan Africa. (C) 2020 Elsevier Masson SAS. All rights reserved.

Importance Data on neurologic manifestations of fibromuscular dysplasia (FMD) are rare, and current knowledge remains limited. Objectives To present a comprehensive review of the epidemiologic characteristics, management, and prognosis of the neurologic manifestations associated with cerebrovascular FMD (ie, involving cervical or intracranial arteries) and to guide future research priorities. Evidence Review References were identified through searches of PubMed from inception to December 2017 using both the medical subject headings and text words. Additional sources were also identified by reviewing reference lists of relevant articles and through searches of the authors’ personal files. Selected articles described at least 1 clinical or radiologic feature and/or outcome of cerebrovascular FMD. Isolated case reports could be included if they described interesting or noteworthy manifestations of FMD. Findings A total of 84 relevant references were identified. Diagnosis of cerebrovascular FMD is based on the appearance of alternating arterial dilatation and constriction (“string of beads”) or of focal narrowing, with no sign of atherosclerotic or inflammatory lesions. Although the diagnosis is easily apparent on results of radiographic imaging, making a diagnosis can be challenging in children or individuals with atypical phenotypes, such as purely intracranial FMD and arterial diaphragm. Involvement of multiple arteries is common, and there is increased incidence of cervical artery dissection and intracranial aneurysms. A variant in the PHACTR1 gene has been associated with FMD as well as cervical artery dissection and migraine, although less than 5% of cases of FMD are familial. Headaches, mainly of the migraine type, are observed in up to 70% of patients with FMD. Cerebrovascular FMD is mostly asymptomatic, but the most frequent neurologic manifestations include transient ischemic attack and ischemic stroke, notably in the presence of associated cervical artery dissection. Other conditions associated with FMD include subarachnoid hemorrhage and, rarely, intracranial hemorrhage. Management relies on observational data and expert opinion. Antiplatelet therapy is considered reasonable to prevent thromboembolic complications. Endovascular therapy is typically restricted to cases with symptomatic stenosis despite optimal medical therapy or in those with rupture of an intracranial aneurysm. Conclusions and Relevance Longitudinal cohort studies of individuals of multiple ethnicities with biosampling are needed to better understand the risk factors, pathophysiological features, and outcomes of FMD. Patient advocacy groups could assist researchers in answering patient-centered questions regarding FMD.

Maurizio Castellano, Jacques W. Lenders, Pierre-Francois Plouin, Enrico Agabiti Rosei Clinica Medica and Molecular Medicine Laboratory, University of Brescia, Spedali Civili di Brescia, Brescia, Italy Department of Internal Medicine, Division of Vascular Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Hypertension unit, Hôpital Européen Georges Pompidou, Faculté de Médecine René Descartes Paris-5, Paris, France European Society of Hypertension Scientific Newsletter: Update on Hypertension Management 2010; 11: No. 43

Data on neurologic manifestations of fibromuscular dysplasia (FMD) are rare, and current knowledge remains limited.To present a comprehensive review of the epidemiologic characteristics, management, and prognosis of the neurologic manifestations associated with cerebrovascular FMD (ie, involving cervical or intracranial arteries) and to guide future research priorities.References were identified through searches of PubMed from inception to December 2017 using both the medical subject headings and text words. Additional sources were also identified by reviewing reference lists of relevant articles and through searches of the authors' personal files. Selected articles described at least 1 clinical or radiologic feature and/or outcome of cerebrovascular FMD. Isolated case reports could be included if they described interesting or noteworthy manifestations of FMD.A total of 84 relevant references were identified. Diagnosis of cerebrovascular FMD is based on the appearance of alternating arterial dilatation and constriction ("string of beads") or of focal narrowing, with no sign of atherosclerotic or inflammatory lesions. Although the diagnosis is easily apparent on results of radiographic imaging, making a diagnosis can be challenging in children or individuals with atypical phenotypes, such as purely intracranial FMD and arterial diaphragm. Involvement of multiple arteries is common, and there is increased incidence of cervical artery dissection and intracranial aneurysms. A variant in the PHACTR1 gene has been associated with FMD as well as cervical artery dissection and migraine, although less than 5% of cases of FMD are familial. Headaches, mainly of the migraine type, are observed in up to 70% of patients with FMD. Cerebrovascular FMD is mostly asymptomatic, but the most frequent neurologic manifestations include transient ischemic attack and ischemic stroke, notably in the presence of associated cervical artery dissection. Other conditions associated with FMD include subarachnoid hemorrhage and, rarely, intracranial hemorrhage. Management relies on observational data and expert opinion. Antiplatelet therapy is considered reasonable to prevent thromboembolic complications. Endovascular therapy is typically restricted to cases with symptomatic stenosis despite optimal medical therapy or in those with rupture of an intracranial aneurysm.Longitudinal cohort studies of individuals of multiple ethnicities with biosampling are needed to better understand the risk factors, pathophysiological features, and outcomes of FMD. Patient advocacy groups could assist researchers in answering patient-centered questions regarding FMD.

Out-of-hospital sudden cardiac arrest remains a major public health issue, with more than 40000 new cases occurring in France every year. Overall, less than 10% will eventually survive. The first minutes are essential, and a more systematic effective cardiopulmonary resuscitation, combining cardiac massage and early defibrillation, should allow much higher survival rates. An ambitious and well-coordinated program, based on an adequate education of the general population since childhood, is mandatory to substantially improve outcomes. In the present report, the French National Medical Academy suggests a strategy, based on four essential measures, for a better public education to life-saving techniques.

Background:Sex differences in antihypertensive treatment have often been highlighted, but whether there is truly a difference or whether this difference is mediated by confounding factors has yet to be deciphered.Patients and methods:We performed a cross-sectional study on the first consultation in the Georges Pompidou Hospital Tertiary Hypertension Unit between July 2000 and June 2015 to explore sex differences in both patient and treatment characteristics over this period.Results:A total of 17856 patients were included. We observed in both women and men an increase in blood pressure control over time despite having more comorbidities. In conjunction, there was an increasing number of treated patients and treatments per patient. The treatments previously selected by the referring physicians strongly differed by sex: women were more frequently treated with loop diuretics [odds ratio (OR)=1.2 (95% confidence interval (CI): 1.05-1.37)], thiazide diuretics [OR=1.13 (95% CI: 1.03-1.23)], aldosterone-receptor blockers [OR=1.41 (95% CI: 1.24-1.61)], and beta blockers [OR=1.53 (95% CI: 1.41-1.66)] but less frequently with angiotensin-converting enzyme inhibitors [OR=0.77 (95% CI: 0.70-0.84)], angiotensin II-receptor blockers [OR=0.93 (95% CI: 0.86-1.0)], and calcium channel blockers [OR=0.72 (95% CI: 0.67-0.78)] than men after adjusting for various patient-related confounding factors.Conclusion:Blood pressure control has greatly improved over the last 15 years in both men and women. Although the treatment choice remained strongly dependent on sex, this is not justified by a sex-related difference in cardiovascular benefit from antihypertensive treatment.

Introduction: Systemic hypertension is a rapidly growing epidemic in Sub-Saharan Africa. Adequacy of blood pressure(BP) control and the factors influencing it, especially the role of socio-economic status(SES) have not been well studied in this part of the world. Hypothesis: We therefore aimed to quantify the association of SES both at the individual and at the country level with BP control in Sub-Saharan Africa. Methods: We conducted a cross-sectional survey in urban clinics of twelve countries, both low-income and middle-income, in Sub-Saharan Africa. Data were collected on demographics, treatment and standardized BP measures were made among the hypertensive patients attending the clinics. BP control was defined as BPu003c140/90 mmHg and hypertension grades were defined according to European Society of Cardiology guidelines. Country income was retrieved from the World Bank database and patient’s individual wealth status was documented by the treating physician. The separate association between SES (both cou...

Background: Sex differences in antihypertensive treatment have often been highlighted, but whether there is truly a difference or whether this difference is mediated by confounding factors has yet to be deciphered. Patients and methods: We performed a cross-sectional study on the first consultation in the Georges Pompidou Hospital Tertiary Hypertension Unit between July 2000 and June 2015 to explore sex differences in both patient and treatment characteristics over this period. Results: A total of 17 856 patients were included. We observed in both women and men an increase in blood pressure control over time despite having more comorbidities. In conjunction, there was an increasing number of treated patients and treatments per patient. The treatments previously selected by the referring physicians strongly differed by sex: women were more frequently treated with loop diuretics [odds ratio (OR) = 1.2 (95% confidence interval (CI): 1.05–1.37)], thiazide diuretics [OR = 1.13 (95% CI: 1.03–1.23)], aldosterone-receptor blockers [OR = 1.41 (95% CI: 1.24–1.61)], and beta blockers [OR = 1.53 (95% CI: 1.41–1.66)] but less frequently with angiotensin-converting enzyme inhibitors [OR = 0.77 (95% CI: 0.70–0.84)], angiotensin II-receptor blockers [OR = 0.93 (95% CI: 0.86–1.0)], and calcium channel blockers [OR = 0.72 (95% CI: 0.67–0.78)] than men after adjusting for various patient-related confounding factors. Conclusion: Blood pressure control has greatly improved over the last 15 years in both men and women. Although the treatment choice remained strongly dependent on sex, this is not justified by a sex-related difference in cardiovascular benefit from antihypertensive treatment.

Objective: The pioneering works of French and United States research teams have changed our conception of Fibromuscular Dysplasia (FMD) from a rare cause of renal artery stenosis in young women to a more frequent, often systemic vascular disease, which can be diagnosed at all ages, both in men and women. We report here the main characteristics of the first 609 patients enrolled in the European/International FMD registry endorsed by the ESH. Design and method: The current analysis was performed in 609 patients enrolled from November 2015 to January 2018 in 30 centres from 17 countries also including 3 extra-European countries (Argentina, Japan and Tunisia). Results: Enrolled patients were predominantly women (83%) and Caucasians (88%). Age at diagnosis was 45.8 ± 15.8 years, 74% of patients were hypertensive, 72% had a multifocal FMD and 31% multivessel FMD. Family history of FMD was reported in 2.7% of cases. Compared to patients with multifocal FMD, patients with focal FMD were younger (39.2 ± 15.9 vs. 48.4 ± 14.9 years, p = 0.003), more often male (26% vs. 13%, p = 0.0002), had less often multivessel FMD (12% vs. 39%, p = 0.0001) and more frequent revascularization interventions (70% vs. 50%, p = 0.01). Compared to patients with single-vessel FMD, patients with multivessel FMD were older (49.5 ± 14.2 vs. 44.1 ± 16.1 years, p = 0.03), had lower eGFR (84.2 ± 28.1 vs. 94.4 ± 40.6 mL/min, p = 0.0005) and were more frequently of the multifocal subtype (89% vs. 64%, p = 0.00001). Notably, the proportion of arterial dissections was higher in men than in women (12% vs. 2%, p = 0.01). Conclusions: The main findings of the European/International FMD registry are in line with those of the French-Belgian ARCADIA study and the United States registry, with the exception of a lower proportion of multivessel FMD, which probably reflects a lack of systematic vascular exploration in some centres. In the near future, the European/International FMD registry will make possible further comparisons between old and young, incident and prevalent patients, and/or patients from different ethnicities or regions of the world. Accumulation of follow-up data may also provide insights on predictive factors of progression/complication.

Introduction: Systemic hypertension is a rapidly growing epidemic in Sub-Saharan Africa. Adequacy of blood pressure(BP) control and the factors influencing it, especially the role of socio-economic status(SES) have not been well studied in this part of the world. Hypothesis: We therefore aimed to quantify the association of SES both at the individual and at the country level with BP control in Sub-Saharan Africa. Methods: We conducted a cross-sectional survey in urban clinics of twelve countries, both low-income and middle-income, in Sub-Saharan Africa. Data were collected on demographics, treatment and standardized BP measures were made among the hypertensive patients attending the clinics. BP control was defined as BP<140/90 mmHg and hypertension grades were defined according to European Society of Cardiology guidelines. Country income was retrieved from the World Bank database and patient’s individual wealth status was documented by the treating physician. The separate association between SES (both country-level income and individual patient wealth) and BP control was investigated using Generalized Linear Mixed-Effects Models adjusted on sex and age. Results: A total of 2198 hypertensive patients (58.4±11.8years; 39.9% male) were included, of whom 1017(46.3%) were from low-income and 1181(53.7%) from middle-income countries. Individual wealth level was low, mid and high in 376(17.6%), 1053(49.2%) and 713(33.3%) patients respectively. Uncontrolled hypertension was present in 1692 patients(77.4%) including 1044(47.7%) with ≥grade 2 hypertension. The proportion of uncontrolled hypertension progressively increased with decreasing level of patient individual wealth, respectively 72.8%, 79.3% and 81.8%(p for trend<0.01). Stratified analysis shows that these differences of uncontrolled hypertension according to individual wealth index were observed in low-income countries(p for trend=0.03) and not in middle-income countries(p for trend=0.26). In low-income countries the odds of uncontrolled hypertension increased 1.37 fold(OR=1.37 [0.99-1.90]) and 1.88 fold(OR=1.88 [1.10-3.21]) in patients with middle and low individual wealth as compared to high individual wealth. Similarly, the grade of hypertension increased progressively with decreasing level of individual patient wealth(p for trend <0.01). Conclusions: Low individual wealth was significantly associated with poor hypertension control, especially in low-income countries. Strategies for hypertension control in Sub-Saharan Africa should especially focus on people in the lowest individual wealth groups who also reside in low-income countries.

Fibromuscular dysplasia (FMD) commonly affects the renal and cervical arteries but has been described to affect other vascular beds as well. The prevalence of and clinical characteristics associated with multisite FMD (string-of-beds or focal stenoses affecting at least 2 vascular beds) are not known. In the prospective ARCADIA registry (Assessment of Renal and Cervical Artery Dysplasia), symptomatic patients with renal artery (RA) FMD underwent tomographic- or magnetic resonance-angiography from the aortic arch to the intracranial arteries and those with cervical FMD from the diaphragm to the pelvis. Of 469 patients (84.0% women), 225 (48.0%) had multisite FMD. In addition, 86 of 244 patients with single-site disease had dissections or aneurisms affecting other vascular beds, totaling 311 patients (66.3%) with lesions in >1 vascular bed. Among patients with a cerebrovascular presentation, the prevalence of RA lesions was higher in patients with than in those without hypertension (odds ratio, 3.4; 95% confidence interval, 1.99–6.15). Among patients with a renal presentation, the prevalence of cervical lesions was higher in patients with bilateral than in those with unilateral RA lesions (odds ratio, 1.9; 95% confidence interval, 0.99–3.57). In conclusion, FMD is a systemic arterial disease. At least 2 vascular beds were affected by dysplastic stenoses in 48.0% of cases and by dysplastic stenoses, aneurysms, and dissections in 66.1% of cases. RA imaging should be proposed to hypertensive patients with a cerebrovascular presentation. Cervical artery imaging should be considered in patients with a renal presentation and bilateral RA lesions. Clinical Trial Registration— URL: www.Clinicaltrials.gov . Unique identifier: NCT02884141.

Guidelines recommend suppression tests such as the saline infusion test (SIT) to ascertain the diagnosis of primary aldosteronism (PA) in patients with a high aldosterone:renin ratio. However, suppression tests have only been evaluated in small retrospective series, and some experts consider that they are not helpful for the diagnosis of PA. In this study, we evaluated whether low post-SIT aldosterone concentrations do exclude lateralized PA. Between February 2009 and December 2013, 199 patients diagnosed with PA on the basis of 2 elevated aldosterone:renin ratio results and a high basal plasma or urinary aldosterone level or high post-SIT aldosterone level had a selective adrenal venous sampling. We used a selectivity index of 2 and a lateralization index of 4 to interpret the adrenal venous sampling results. Baseline characteristics of the patients were the following (percent or median): men 63%, 48 years old, office blood pressure 142/88 mm Hg, serum potassium 3.4 mmol/L, aldosterone:renin ratio 113 pmol/mU, plasma aldosterone concentration 588 pmol/L. The proportion of patients with lateralized adrenal venous sampling was 12 of 41 (29%) among those with post-SIT aldosterone <139 pmol/L (5 ng/dL) and 38 of 104 (37%) among those with post-SIT aldosterone <277 pmol/L (10 ng/dL). Post-SIT aldosterone levels were not associated with the blood pressure outcome of adrenalectomy. A low post-SIT aldosterone level cannot rule out lateralized PA, even with a low threshold (139 pmol/L). Adrenal venous sampling should be considered for patients who are eligible for surgery with elevated basal aldosterone levels even if they have low aldosterone concentrations after recumbent saline suppression testing.

Fibromuscular dysplasia, a non-atherosclerotic and non-inflammatory disease of medium size arteries, commonly affects the renal and carotid arteries ( the latter are dealt with in another article). It is more frequent in women from third to fifth decade and the genetic origin of the disease is proven in some cases. Once considered rare, for there are numerous asymptomatic cases, its prevalence in currently estimated around one percent. There are two distinct types of fibromuscular dysplasia." multi-focal (four out of five cases) and focal dysplasia. The most frequent presentation is hypertension in relation with renal artery involvement, which is amenable to percutaneous angioplasty. Fibromuscular dysplasia of digestive and iliac arteries is rare and usually asymptomatic. Patients with spontaneous coronary acute dissection commonly have dysplastic lesions affecting non-coronary arteries. Data from the ARCADIA registry show that the majority of patients with the condition have multisite fibromuscular dysplasia, i.e. lesions affecting two or more vascular beds.

Objective: Renal infarction (RI) is a rare disease (0.004% of patients admitted to emergency units), due to a disruption of renal blood flow of the main ipsilateral renal artery (RA) or of one of its segmental branches due to either a local in-situ or a general mechanism. The local mechanism includes RA occlusion, dissection, aneurysm or stenosis which 1) may lead to in-situ RA thrombosis or renal emboli and 2) can be due to various etiologies including atherosclerosis disease (ASD), fibromuscular dysplasia (FMD), dissecting hematoma (DH), extension of an aortic dissection (AoD) to the RA, miscellaneous arterial disease (AD), iatrogenic post-RA catheterization/surgery complication (IC) or post-renal trauma complication (T). The general mechanism includes thromboembolic disease (TED) due to arrhythmia, aortic thromboembolism, or a hypercoagulable state. The aim of this study is to analyze the various RI causes. Design and method: Patients with RI admitted consecutively to our tertiary hospital center between 07/2000 and 06/2015 were retrospectively identified from the weekly reports of our multidisciplinary rounds. Main clinical and biological characteristics of the patients were extracted from our clinical data warehouse. All identified patients had renal CT-angiogram (CTA) which was reviewed by two readers blind to the first radiological report to confirm RI diagnosis and assess its underlying mechanism/etiology. In case of discrepancy between the independent CTA reading and the initial CTA or multidisciplinary meeting report (n = 41), the final diagnosis was made by a vascular radiologist on a third independent reading. Results: We identified a total of 278 patients of whom 49 were excluded and the 229 remaining had confirmed RI. The 2 most frequent mechanisms of RI were RA occlusions (48%) and dissections (36%) (table). RA occlusions were mainly due to ASD. RA dissections mainly related to DH (43%) and FMD (20%). 19% of RI were due to a complication of an endovascular or surgical procedure.Conclusions: In this large case series, RI was predominantly due to in-situ mechanisms mainly related to RA occlusion or dissection. RA occlusions were more frequently associated with ASD whereas RA dissections were mainly related to DH and FMD.

HomeHypertensionVol. 68, No. 4Revisiting Fibromuscular Dysplasia Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBRevisiting Fibromuscular DysplasiaRationale of the European Fibromuscular Dysplasia Initiative Alexandre Persu, Patricia Van der Niepen, Emmanuel Touzé, Sofie Gevaert, Elena Berra, Pamela Mace, Pierre-François Plouin and Xavier Jeunemaitreon behalf of the Working Group "Hypertension and the Kidney" of the European Society of Hypertension and the European Fibromuscular Dysplasia Initiative Alexandre PersuAlexandre Persu From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). , Patricia Van der NiepenPatricia Van der Niepen From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). , Emmanuel TouzéEmmanuel Touzé From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). , Sofie GevaertSofie Gevaert From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). , Elena BerraElena Berra From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). , Pamela MacePamela Mace From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). , Pierre-François PlouinPierre-François Plouin From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). and Xavier JeunemaitreXavier Jeunemaitre From the Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P., E.B.), and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. (A.P.); Department of Internal Medicine, Division of Nephrology and Hypertension, Universitair Ziekenhuis Brussel (Vrije Universiteit Brussel, VUB), Brussel, Belgium, (P.V.D.N.); Normandie Université, UNICAEN, Inserm U919, CHU Côte de Nacre, Caen, 14000 France (E.T.); Department of Cardiology, Ghent University Hospital, Ghent, Belgium (S.G.); Department of Medical Sciences, Internal Medicine and Hypertension Division, AOU Città della Salute e della Scienza, Turin, Italy (E.B.); Fibromuscular Dysplasia Society of America, Rocky River, OH (P.M.); Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (P.-F.P.); Université Paris-Descartes, Paris Sorbonne Cité, F-75006 Paris, France (P.-F.P.); and Université Paris-Descartes, Paris Sorbonne Cité; AP-HP, Department of Genetics, Hôpital Europeen Georges Pompidou; INSERM, UMR-S 970, PARCC, Paris, France (X.J.). and on behalf of the Working Group "Hypertension and the Kidney" of the European Society of Hypertension and the European Fibromuscular Dysplasia Initiative Originally published8 Aug 2016https://doi.org/10.1161/HYPERTENSIONAHA.116.07543Hypertension. 2016;68:832–839is corrected byCorrectionOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2016: Previous Version 1 IntroductionFibromuscular dysplasia (FMD) has been defined as an idiopathic, segmental, nonatherosclerotic, and noninflammatory disease of the musculature of arterial walls, leading to stenosis of small- and medium-sized arteries.1,2 Furthermore, to confirm the diagnosis of FMD, arterial diseases of monogenic origin, inflammatory arterial diseases, and the use of arterial vasoconstrictors have to be excluded. Renal FMD may lead to renovascular hypertension, less frequently renal artery dissection, renal infarction, and aneurysm rupture.1 Cervico-cephalic FMD can result in ischemic or hemorrhagic stroke, cervical artery dissection, and may be also associated with intracerebral aneurysms and risk of subarachnoid hemorrhage.3 In some patients, the diagnosis of FMD can lead to invasive procedures, such as percutaneous angioplasty, reconstructive surgery, or intracranial aneurysm clipping. Thus, both the disease and its treatment can lead to significant morbidity and mortality.1The French4–6 and the US7–10 registries have led to a reappraisal of the frequency, demographic characteristics, classification, pathophysiology, and management of FMD. The face of the disease is evolving from a rare disease of renal arteries accounting for a minority of cases of secondary hypertension in young women to a "systemic" vascular disease affecting renal and also cervico-cephalic, coronary, and iliac arteries1,11 (Table 1). In various cohorts, despite incomplete exploration, mostly driven by symptoms and clinical complaints, FMD of ≥2 vascular beds was consistently found in >30% of cases.1,7,12,13 The French ARCADIA (Assessment of Renal and Cervical Artery Dysplasia) registry, which required a standardized vascular work-up in all patients, will soon provide a more precise estimate of the frequency of diffuse FMD. Besides female sex and repeated mechanical trauma because of increased kidney mobility,14 recent works suggest a contribution of smoking6 in progression of the disease, as well as a genetic susceptibility.15,16 High-resolution cardiac echo-tracking,17 mechanistic,18 biochemical, and genetic studies15,16 will soon lead to a better understanding and classification of the disease. Furthermore, registries should help to identify characteristics of patients likely to develop extensive, progressive, or complicated forms of FMD.Table 1. Five Things All Physicians Should Know About Fibromuscular Dysplasia (FMD)Data from kidney donor studies suggest that the prevalence of FMD has been substantially underestimated.In current cohorts, the mean age at diagnosis of FMD is >50 y.FMD is more frequent in young to middle-aged women, but may be also diagnosed in men, and at all ages of life, from infancy to the elderly old.FMD is a systemic disease with frequent involvement of multiple vascular beds, including but not limited to renal and cervico-cephalic arteries.FMD can be associated with spontaneous coronary artery dissection (SCAD).FMD has a hereditary component, and the first susceptibility genes are currently being identified.Progresses in the understanding of the disease and research perspectives have been extensively reviewed on the occasion of the First National Meeting on Fibromuscular Dysplasia, endorsed by the European Society of Hypertension, which took place in Brussels on December 12, 2015, (http://www.saintluc.be/professionnels/agenda/2015/2015-12-12-fibromuscular-dysplasia.pdf), and summarized for an expert audience on the occasion of the 10th International Workshop on Structure and Function of the Vascular System (Paris, February 4–6, 2016). This short review covers the highlights of these meetings and provides the rationale for the European FMD initiative (see list of centers currently involved in the online-only Data Supplement).Renal FMDRenal FMD has been for long considered a rare disease with an estimated prevalence of ≈0.02–0.08%.2 However, recent data suggest that FMD is much more common. A meta-analysis based on kidney donor data found renal FMD in 4% of the potential kidney donor population.19,20 Along the same lines, in the CORAL trial (Cardiovascular Outcomes in Renal Atherosclerotic Lesions), where FMD was an exclusion criteria, the prevalence of FMD was 5.8%.20 Three main histopathologic types of renal FMD have been described according to the arterial wall involved, that is, intimal FMD (5%), medial FMD (>85%), and perimedial FMD (10%).21 However, nowadays, as few cases of FMD require surgery, and pathological documentation is lacking, this classification has become largely obsolete. Based on pathological–angiographic correlations, Kincaid proposed 3 types of renal artery FMD: multifocal (string-of-beads appearance), unifocal (solitary stenosis <1 cm in length), and tubular (stenosis at least 1 cm in length) FMD.22 As the 2 last categories differ only by the length of the diseased segment, Savard et al have proposed to group them under the generic term "unifocal."4Hypertension of variable severity is the most common clinical presentation of FMD. Occasionally, an epigastric or flank bruit at physical examination can also lead to the diagnosis. Flank pain may be a manifestation of renal artery dissection or aneurysm. FMD-associated arterial aneurysms at any location have been reported in 17% (33% in renal artery) and dissections in 19.7% (22% in renal artery) of patients in the US registry.7 Renal insufficiency is uncommon and often due to renal artery dissection and renal infarction. Progression to end-stage renal disease is very rare.The diagnosis of renal FMD can be made by using noninvasive imaging studies, including duplex ultrasonography, and angiography by computed tomography or magnetic resonance. However, the gold standard remains catheter-based angiography.23 In equivocal cases, intravascular ultrasound and pressure measurements can help to assess the hemodynamic significance of a stenosis and the anatomic success after percutaneous intervention.1The treatment of patients with renal FMD may include medical therapy with surveillance, endovascular therapy (angioplasty without stenting), or surgery. The decision depends on the nature and location of vascular lesions (stenosis/dissection/aneurysm), the presence and severity of symptoms, prior vascular events related to FMD, and comorbid conditions.1 Medical therapy includes antihypertensive drugs, preferably blockers of the renin–angiotensin system, treatment of other cardiovascular risk factors, and antiplatelet or antithrombotic drugs after angioplasty or in case of renal artery dissection or thrombosis. Hypertension cure after revascularization varies between 30% and 50%. The younger the patient, the more recent the hypertension, the higher the cure rate. The rate of success is also higher in unifocal than in multifocal forms.1,24 Indefinite, yearly follow-up of blood pressure, kidney function, and kidney length appears appropriate.1,25Cerebrovascular FMDFMD of the carotid and vertebral arteries has long been considered less frequent than renal FMD, but recent observational studies and registries3,7 suggest that the prevalence of both entities may be similar. Furthermore, renal and cervical FMD frequently coexist, with a prevalence of 65% of carotid FMD lesions in patients with renal FMD according to the US registry.7 Though interventional treatment is only seldom required, detection of cervical FMD has implications for the patients as it may help to improve primary and secondary prevention of cerebrovascular events and lead to the diagnosis of FMD of renal or other vascular beds.1 The main circumstances of diagnosis of cervico-cephalic FMD include incidental diagnosis, screening in patients with renal FMD, pulsatile tinnitus, cervical artery dissection, cerebral ischemia, subarachnoid hemorrhage, unruptured intracranial aneurysm, and rarely arterio-venous fistula or Moyamoya syndrome.3 Another symptom frequently associated with cerebrovascular FMD in the US FMD registry7 is headache (60% of patients, with 32% reporting classical migraines). This finding is in agreement with previous reports, also discussed by Olin et al.7 However, in the absence of demonstrated causal link between both entities, the association of migraine with cervico-cephalic FMD may partly reflect an exploration bias as up to 25% of females experience migraines during their life,26 which may lead to cerebrovascular imaging and incidental finding of FMD lesions. FMD of supra-aortic trunks has been also associated with the presence of arterial tortuosities.27 In the US FMD registry,7 ischemic stroke was reported in ≈10% of patients and transient ischemic attack in ≈20%. Ischemic symptoms are due either to a thromboembolic mechanism or to hemodynamic compromise of the distal circulation. FMD is also associated with first ever, multiple and recurrent cervical artery dissection.3 Coexistence with atherosclerotic lesions is common, especially in cases diagnosed after 50 years.In contrast with cervical FMD, intracranial FMD is very rare and usually corresponds to an extension of the extracranial disease. However, the prevalence of the disease may be underestimated as diagnosis of minor form or unifocal forms of FMD is challenging. Moreover, intracranial aneurysms, sometimes multiple, are common (≈6%) in FMD patients.28 While the classification of FMD in multifocal and unifocal forms4 also applies to cervical FMD, an atypical form of FMD characterized by the presence of a diaphragm at the origin of the internal carotid (bulb) has been described in young patients of African descent with stroke.29 So far, all pathologically confirmed cases were intimal FMD.29 Whether this subtype corresponds to the same disease as "classical" unifocal or multifocal FMD is still unclear, notably because it has no equivalent in the renal territory.The natural history of cervical and intracranial FMD is unknown. Old series of patients with cervical FMD found rates of recurrent stroke/transient ischemic attack in the range of 0% to 5%, but populations are heterogeneous.3 FMD seems to increase the risk of recurrent cervical dissection,30,31 but no data exist on intracranial aneurysms.Carotid duplex is often used as diagnostic test for internal carotid FMD and is a primary tool for surveillance of carotid FMD lesions. Nevertheless, as cervical FMD is often distal, in a substantial proportion of cases, diseased vessel segments may be overlooked by ultrasounds. Furthermore, carotid duplex does not allow detection of associated cerebral aneurysms. Accordingly, the European FMD consensus has recommended magnetic resonance angiography or preferably computed tomographic (CT)angiography as the first-line screening test for cerebrovascular FMD, especially in patients with renal artery FMD.1In most cases, treatment of cervico-cephalic FMD is conservative, including antithrombotic drugs in patients with cerebral ischemia and control of cardiovascular risk factors (especially smoking). In the absence of specific evidence, the management of FMD-related aneurysms—including endovascular or surgical treatment—does not differ from that of aneurysms of other origin. Rarely, severe stenotic cervical FMD lesions with ischemic or hemodynamic manifestations (pulsatile tinnitus) may require angioplasty stenting.3Spontaneous Coronary Artery Dissection and FMDWhile multifocal FMD lesions of the coronary arteries appear to be exceptional,32 recent works suggest the existence of a tight link between FMD and another rare vascular disease, spontaneous coronary artery dissection (SCAD). SCAD is caused by dissection or hematoma formation within the vessel media, causing luminal compression and obstruction. The diagnosis of SCAD should be considered in case of acute coronary event occurring in young or middle-aged women with few cardiovascular risk factors. Notably, the age at diagnosis of SCAD is similar to that of FMD—in the range of 50 years—while the female prevalence is even higher (>90%).33 Intense physical and psychological stress, including childbirth delivery, are well-known triggers, but appear to be less frequent than initially reported.33 More recently, a frequent association between SCAD and FMD of extracoronary vessels has been demonstrated in several single-center patient series, with prevalence varying from 52% to 86%.33–37 The largest and best explored series included 168 patients with SCAD, of which 72% had FMD of the renal, iliac, or cerebrovascular arteries.33 In an earlier series of 50 patients published by the same group, lesions of ≥2 noncoronary vascular beds were found in 42% of patients.35 Finally, in another series of 115 patients, 9/40 patients who underwent brain imaging had intracerebral aneurysms.36 SCAD has been also associated with connective tissue disorders and inflammatory vascular diseases.36,37 The diagnosis can be established during a coronary angiogram in presence of contrast dye staining of arterial wall with multiple radiolucent lumen (SCAD type 1). However, in many cases, this typical aspect is missing. More often, SCAD may be suspected in presence of smooth narrowing or tortuosity or coronary arteries (type 2) or even mimic atherosclerosis, with focal or tubular stenosis (type 3).38 The diagnosis of SCAD type 2 and even more so type 3 is difficult, but can be ascertained by intravascular ultrasound or optical coherence tomography showing the presence of hematoma or double lumen.39While SCAD accounts for <0.5% of unselected acute coronary events40 in women aged <50 years, the prevalence of SCAD was estimated to 5.7% in our retrospective monocentric cases series (n=336),41 8.7% in a large French database, including 11 605 patients (10.8% in case of ST-segment–elevation myocardial infarction),40 and up to 24% in an expert, highly focused Canadian center.42 While the high prevalence of SCAD in the latter may partly reflect a referral bias, it is clear that SCAD is frequently overlooked due to poor awareness, lack of standardized diagnostic criteria, and absence of optical coherence tomography or intravascular ultrasound. Still, the diagnosis of SCAD is of clinical relevance. Indeed, in contrast with atherosclerosis-related coronary events, management is usually conservative, in view of the high probability of spontaneous healing (>50%) and poor results of percutaneous coronary intervention and coronary artery bypass grafting.33 Furthermore, as mentioned higher, SCAD may indicate the existence of an underlying vascular disease, usually FMD, and lead to detection of abnormalities of other vascular beds.1 Whether SCAD results from coronary FMD lesions or reflects the presence of an underlying vascular abnormality common to both entities and whether the noncoronary FMD lesions documented in patients with SCAD have the same pathophysiology as "classical" FMD remain to be clarified.Genetics of FMDThe presence of FMD in siblings and twins has been reported as early as the years '60 to '70 of the last century.43–46 More recently, familial cases of the related SCAD entity have also been documented.47 In 1980, based on interviews of relatives of 20 index patients with FMD, Rushton suggested an autosomal dominant inheritance of the trait.48 However, in the absence of vascular imaging in family members, the reliability of these findings is questionable. In a French cohort of 100 index patients, angiographically documented FMD was diagnosed in at least another relative in 11% of cases.49 Along the same lines, the prevalence of self-reported FMD in relatives was 7.3% (26/354) in the US registry.7 In 2015, Kiando et al performed the first whole exome study in 7 pedigrees, each of them including at least 2 relatives with demonstrated FMD.15 Unfortunately, none of the 3971 genes screened showed variation in >3 of the 7 pedigrees under scrutiny, suggesting genetic heterogeneity of the trait.15Another pitfall of familial studies is the risk of misclassifying young relatives of FMD patients without overt FMD lesions as unaffected, while they may in fact harbor the trait, thereby decreasing statistical power to identify susceptibility genes. This difficulty may be partly overcome by the identification of subclinical lesions using high-resolution echographic analysis of the common carotid vascular wall. In the study conducted by Boutouyrie et al,17 carotid arteries of controls were typically characterized by a double signal corresponding to the blood–intima and media–adventitia interfaces, whereas in FMD patients, an additional interface was often observed, leading to a "triple signal" pattern, either continuous or discontinuous. In other cases, the blood intima interface itself was discontinuous ("dotted" aspect).17,50 These abnormalities were incorporated in a score, with the continuous signal corresponding to the highest score (2–7). A score >3 was associated with a sensitivity of 73% and a specificity of 81% for the diagnosis of FMD.17 Notably, in first-degree relatives of patients with FMD (6 families, 47 relatives), the score was slightly lower than that in index cases (4.17 versus 4.61; P=0.01), but much higher than in unrelated controls (2.52; P<10–5).50 Furthermore, segregation analysis was consistent with autosomal dominant inheritance of the trait.50 Admittedly, however, these findings need further investigation and replication in other cohorts. The triple signal aspect is also found—though less frequently—in some patients with essential hypertension and may be a marker of vascular hypertrophy rather than a hallmark of FMD per se. Still, there is no doubt that the technical advances made in noninvasive arterial imaging should provide further insights into the pathophysiology of FMD, help to correctly classify relatives of FMD patients without overt FMD lesions, and may serve as a surrogate marker in intrafamilial studies.As far as we know, the clinical,49 radiological, and histological characteristics of rare familial cases of FMD and of the more common apparently sporadic presentation do not differ. Furthermore, similar scores were found by echotracking in sporadic and familial forms of FMD.50 Finally, autosomal dominant transmission of echographic subclinical abnormalities50 suggests that the prevalence of inherited forms may be underestimated due to low penetrance. Accordingly, it may be postulated that there is a continuum between both forms and that, alongside with environmental factors, genetic factors may also contribute to the pathogenesis of apparently sporadic FMD. Earlier case–control studies failed to show an association between FMD and variants of genes coding for components of the renin–angiotensin system51 and extracellular matrix,52 including α-1 antitrypsin.53 However, a large association study looking for enrichment in gene variants in patients with sporadic FMD compared with controls disclosed a significant association between multifocal FMD and 3 genes coding for muscle proteins (OBSCN, DYNC2H1, and MYLK), one of them (MYLK) also involved in familial thoracic aortic dissection, and a fourth one associated with susceptibility to Moyamoya disease (RNF213).15 Finally, the first genome wide association study performed in the field has identified a locus on chromosome 6, associated both with FMD and with vascular phenotypes, such as intima–media thickness or arterial