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International audience; Objective: The indication of percutaneous renal transluminal angioplasty (PTRA) in fibromuscular dysplasia (FMD) is mainly based on renal artery stenosis (RAS) due to atherosclerosis criteria, which are not specific to FMD. Consequently, the selection of patients who could benefit from this treatment and its effectiveness remain uncertain. The aims of this study were to: (1) report the effects of PTRA guided by trans-stenotic pressure measurements on hypertension 7 months after treatment; (2) assess the impact of pressure measurement to guide treatment efficacy in comparison to visual angiographic parameters; and (3) evaluate the reproducibility and accuracy of the stenosis measurement using a 4F catheter in comparison to a pressure guidewire.Methods: This prospective multi-centric study analyzed 24 patients with hypertension with RAS due to FMD that required PTRA. Clinical, duplex ultrasound, and angiographic indices were collected, and patients were followed up for 7 months (±1 month). Angiographic indices were measured twice both by a pressure guidewire and a 4F catheter. Assessment of procedural and clinical success of angioplasty was performed for all patients.Results: Twenty-three patients (96%) had procedural success (considered as a post-PTRA translesional systolic gradient ≤10 mmHg or reduced by at least 80%) with a significant decrease in the systolic gradient after angioplasty (26.50 mmHg; [interquartile range, 16.75-38.75] vs 0.00 [interquartile range, 0.00-2.00]; P < .01). Three patients (12%) had complications, including two renal artery dissections and one partial renal infarction. Twenty-one patients (88%) were clinical responders to angioplasty at follow-up. Visual stenosis assessment showed a poor correlation with systolic gradient measurement before and after PTRA (R from -0.05 to 0.41; P = 0.06-0.82). High correlations were found between pressure measurements made by a 4F catheter and guidewire (R from 0.64 to 0.89; P ≤ .003).Conclusions: In patients selected by clinical indicators and duplex ultrasound, reaching a translesional systolic gradient ≤10 mmHg or reduced by at least 80% after angioplasty, promotes a high success rate for PTRA in hypertension due to FMD RAS.Trial registration: ClinicalTrials.gov NCT02586870.

Objectives This study sought to assess the respective effects of aldosterone and blood pressure (BP) levels on myocardial fibrosis in humans. Background Experimentally, aldosterone promotes left ventricular (LV) hypertrophy, and interstitial myocardial fibrosis in the presence of high salt intake. Methods The study included 20 patients with primary aldosteronism (PA) (high aldosterone and high BP), 20 patients with essential hypertension (HTN) (average aldosterone and high BP), 20 patients with secondary aldosteronism due to Bartter/Gitelman (BG) syndrome (high aldosterone and normal BP), and 20 healthy subjects (HS) (normal aldosterone and normal BP). Participants in each group were of similar age and sex distributions, and asymptomatic. Cardiac magnetic resonance including cine and T1 mapping was performed blind to the study group to quantify global LV mass index, as well as intracellular mass index and extracellular mass index considered as a measure of myocardial fibrosis in vivo. Results Median plasma aldosterone concentration was as follows: PA = 709 pmol/l (interquartile range [IQR]: 430 to 918 pmol/l); HTN = 197 pmol/l (IQR: 121 to 345 pmol/l); BG = 297 pmol/l (IQR: 180 to 428 pmol/l); and HS = 105 pmol/l (IQR: 85 to 227 pmol/l). Systolic BP was as follows: PA = 147 ± 15 mm Hg; HTN = 133 ± 19 mm Hg; BG = 116 ± 9 mm Hg; and HS = 117 ± 12 mm Hg. LV end-diastolic volume showed underloading in BG and overloading in patients with PA (63 ± 13 ml/m2 vs. 82 ± 15 ml/m2; p Conclusions Only primary pathological aldosterone excess combined with high BP increased both extracellular myocardial matrix and intracellular mass. Secondary aldosterone excess with normal BP did not affect extracellular myocardial matrix. (Study of Myocardial Interstitial Fibrosis in Hyperaldosteronism; NCT02938910 ).

Summary Background Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. Methods In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18–75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT02649426 . Findings Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (−8·0 mm Hg [IQR –16·4 to 0·0] vs –3·0 mm Hg [–10·3 to 1·8]; median between-group difference –4·5 mm Hg [95% CI –8·5 to –0·3]; adjusted p=0·022); the median between-group difference was –5·8 mm Hg (95% CI –9·7 to –1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. Interpretation Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. Funding ReCor Medical.

Background: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment. Methods: Patients with a daytime ambulatory BP ≥135/85 mm Hg and Results: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group ( P =0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P =0.010 and 1.4±1.5 versus 2.0±1.8, P =0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (−18.1±12.2 versus −15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: −4.3 mm Hg, 95% confidence interval, −7.9 to −0.6, P =0.024). There were no major adverse events in either group through 6 months. Conclusions: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02649426.

AIMS: Since December 2015, the European/International Fibromuscular Dysplasia (FMD) Registry enrolled 1022 patients from 22 countries. We present their characteristics according to disease subtype, age and gender, as well as predictors of widespread disease, aneurysms and dissections. METHODS AND RESULTS: All patients diagnosed with FMD (string-of-beads or focal stenosis in at least one vascular bed) based on CTA, MRA and/or catheter-based angiography were eligible.Patients were predominantly women (82%) and Caucasians (88%). Age at diagnosis was 46±16 years (12% ≥65yo), 86% were hypertensive, 72% had multifocal and 57% multivessel FMD. Compared to patients with multifocal FMD, patients with focal FMD were younger, more often men, had less often multivessel FMD but more revascularizations. Compared to women with FMD, men were younger, had more often focal FMD and arterial dissections. Compared to younger patients with FMD, patients ≥65yo had more often multifocal FMD, lower eGFR and more atherosclerotic lesions. Independent predictors of multivessel FMD were age at FMD diagnosis, stroke, multifocal subtype, presence of aneurysm or dissection and family history of FMD. Predictors of aneurysms were multivessel and multifocal FMD. Predictors of dissections were age at FMD diagnosis, male gender, stroke and multivessel FMD. CONCLUSIONS: The European/International FMD Registry allowed large-scale characterization of distinct profiles of patients with FMD and, more importantly, identification of a unique set of independent predictors of widespread disease, aneurysms and dissections, paving the way for targeted screening, management and follow-up of FMD. TRANSLATIONAL PERSPECTIVE: Fibromuscular dysplasia (FMD) is nowadays considered as a systemic arterial disease, warranting brain-to-pelvis vascular imaging in all patients. However, most current evidence is derived from a limited number of expert centres. Furthermore, one size may not fit all. Based on analysis of the first thousand patients enrolled in the European/International FMD registry (46 centres; 22 countries) we characterized distinct patient profiles according to FMD subtype, age and gender and identified predictors of widespread disease, aneurysms and dissections, paving the way for individualized management and follow-up. Further studies will allow refining patient characterization according to ethnicity, genetic profile and imaging biomarkers.

We aimed to compare the characteristics of the patients with renal infarction related to nontrauma renal artery dissection (RAD) with versus without an underlying vascular disease and report long-term renal and vascular outcomes, as well as new-onset renal and extra-RADs. Data from 72 consecutive patients with RAD referred to our Hypertension Unit between 2000 and 2015 were analyzed. Radiological data, including a systematic brain-to-pelvis computed tomography angiography, were independently reviewed. Three main causes of RAD were identified at the initial work-up: fibromuscular dysplasia (n=16); dissecting or aneurysmal multisite arterial disease (n=21) not linked to any known vascular disease; and isolated RAD (n=24) without any other arterial lesion. At diagnosis, patients (median age 46 [interquartile range, 40–53] years, 70.5% males, 26.2% preexisting hypertension, 65.6% smokers) had a median blood pressure of 138 (125–152)/87 (78–97) mm Hg. Estimated glomerular filtration rate was 81 (66–95) mL/min per 1.73 m 2 and 18% had renal impairment. Patients were treated with antiplatelet drugs (65.6%), anticoagulant (3.3%). A total of 11.5% underwent angioplasty. No clinical or biological difference was observed between the 3 groups. After 51 (19–92) months follow-up, blood pressure was reduced by 13 (0–29)/9 (3–18) mm Hg; 11.5% of patients had estimated glomerular filtration rate 2 . RAD evolved toward healing (67.2%), aneurysmal dilation (24.6%), or stenosis (8.2%). New-onset RAD was as frequent in dissecting or aneurysmal multisite arterial disease (23.8%) than in fibromuscular dysplasia (25%) group, whereas de novo extrarenal dissection was 6-fold more frequent in dissecting or aneurysmal multisite arterial disease (38.1%) than in fibromuscular dysplasia (6.3%) group. No new event occurred in patients with an initial diagnosis of isolated RAD. Initial diagnostic accuracy using thorough systematic exhaustive explorations of arterial sites helps to stratify the risk of new-onset dissection and adapt monitoring accordingly.

Fibromuscular dysplasia (FMD) is an arteriopathy that presents clinically by hypertension and stroke, mostly in early middle-aged women. We report results from the first genome-wide association meta-analysis of FMD including 1962 FMD cases and 7100 controls. We confirmedPHACTR1and identified three new loci (LRP1, ATP2B1, andLIMA1)associated with FMD. Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). FMD associated variants were located in arterial-specific enhancers active in vascular smooth muscle cells and fibroblasts. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. Cross-trait linkage disequilibrium analyses identified positive genetic correlations with blood pressure, migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independent from the genetics of blood pressure.

WHAT IS RESISTANT HYPERTENSION AND HOW TO DIAGNOSE IT?. High blood pressure is one of the leading factors influencing the cardiovascular risk. Despite current knowledge on the management of hypertension and the numerous antihypertensive drugs available, hypertension remains insufficiently controlled and part of these « uncontrolled » patients meet the definition of resistant hypertension. Resistant hypertension is defined by the failure to achieve blood pressure target (office blood pressure smaller than 140/90 mm Hg) despite appropriate treatment with optimal doses of three antihypertensive drugs, ideally a combination of a renin angiotensin system blocker, a calcium channel blocker and a diuretic. Pseudoresistance should be excluded by using 24 h ambulatory blood pressure or home blood pressure measurements. The management of resistant hypertension includes the identification of lifestyle factors such as obesity, excessive alcohol and dietary sodium intake, volume overload, drug-induced hypertension and the screening of secondary forms of hypertension. The treatment associates lifestyle changes, reinforcement of adherence to treatment, discontinuation of interfering substances, association of antihypertensive drugs on top of the initial triple therapy, especially aldosterone antagonists (spironolactone) as fourth line treatment. Follow-up should be based on home blood pressure.QU’EST-CE QUE L’HYPERTENSION ARTÉRIELLE RÉSISTANTE ET COMMENT L’OBJECTIVER ?. L’hypertension artérielle est l’un des principaux facteurs de risque cardiovasculaire. En dépit des nombreuses recommandations des sociétés savantes et du nombre important de classes d’antihypertenseurs disponibles, l’hypertension artérielle demeure insuffisamment contrôlée, et parmi les patients non contrôlés certains ont une hypertension résistante. L’hypertension artérielle résistante est caractérisée par la non-atteinte de la cible tensionnelle (mesure clinique plus petit que 140/90 mmHg) malgré une trithérapie à doses optimales comportant idéalement un bloqueur du système rénine-angiotensine, un antagoniste des canaux calciques et un diurétique thiazidique ou apparenté. On doit s’assurer de la réalité du niveau tensionnel (par mesure ambulatoire de la pression artérielle ou par automesure à domicile), de la bonne observance du traitement, de l’absence de prise de médicaments ou toxiques vasoactifs, de l’absence de cause méconnue. On doit aussi identifier les facteurs favorisant comme l’obésité, l’inactivité physique et la consommation excessive d’alcool et de sel. La conduite à tenir associe un renforcement des règles hygiéno-diététiques strictes, l’arrêt des substances hypertensives ou interférant avec l’efficacité des traitements antihypertenseurs, et l’ajout de différentes classes d’antihypertenseurs en sus de la trithérapie de base, en particulier la spironolactone à faible dose en quatrième ligne. Le suivi s’appuiera sur l’automesure à domicile.

Which methods of blood pressure measurement should you choose? Blood pressure measurement in the doctor's office is the standard method for detecting hypertension. It must be confirmed by measures performed outside the office by home blood pressure monitoring or by ambulatory blood pressure monitoring. All methods of blood pressure measurement require compliance with standardized rules. Home blood pressure monitoring is widely available and cheap, and patients use it even without any medical supervision. It is a useful method for detecting white coat hypertension and masked hypertension and for adapting treatments. After teaching the method to the patient, home blood pressure monitoring allows him to be involved in his care, which can help improve adherence to treatment.Quelles méthodes de mesure de la pression artérielle choisir ? La mesure de la pression artérielle au cabinet du médecin est la méthode classique pour dépister l’hypertension. Elle doit être confirmée par des mesures réalisées en dehors du cabinet par automesure tensionnelle ou par mesure ambulatoire de la pression artérielle. Toutes les méthodes de mesure de la pression artérielle nécessitent le respect de règles standardisées. L’automesure tensionnelle est facilement disponible et peu coûteuse, et les patients l’utilisent même en dehors de tout encadrement médical. C’est une méthode utile pour dépister l’hypertension « blouse blanche » et l’hypertension masquée et pour adapter les traitements. Après un enseignement de la méthode au patient, l’automesure lui permet de devenir acteur de sa prise en charge, ce qui peut améliorer son observance des traitements.

Background: Cervical artery dissection (CeAD) is one of the most frequent manifestations of fibromuscular dysplasia (FMD). However, the risk factors for CeAD are unknown. We investigated factors associated with CeAD in the ARCADIA (Assessment of Renal and Cervical Artery Dysplasia) registry and performed a pooled analysis of published and unpublished data. Methods: Patients included were women and men ≥18 years, diagnosed with renal, cervical, or intracranial artery FMD, prospectively recruited at 16 university hospitals in France and Belgium. Diagnosis of CeAD was established by stroke specialists in each participating center, according to standard diagnostic criteria. Associations between CeAD and potential determinants were assessed by calculations of crude and adjusted odds ratios. Results: Among 469 patients (415 women) with FMD, 68 (14.5%) had CeAD. CeAD patients were younger, more likely to be men and to have a history of migraine, and less likely to have a history of hypertension, than non-CeAD patients. In the multivariate analysis, male sex (OR=2.75 ; CI95% 1.39-5.46), history of migraine (OR=1.93 ; 1.08-3.44), age >50 years (OR=0.41 ; 0.23-0.74), history of hypertension (OR=0.35 ; 0.19-0.63), and the number of vascular beds involved by FMD >=3 (OR=2.46 ; 1.13-5.35) remained significantly associated with CeAD. We collected data from 2 published studies and unpublished data from the US and the European Registries. There was no overlap between studies. In a pooled analysis (289 CeAD in 1933 patients), male sex was significantly associated with CeAD (pooled OR=2.04 ; 1.41-2.95, I2=0%, Figure). Conclusion: In patients with FMD, male sex and multisite involvement are associated with of CeAD, in addition to other previous known risk factors.

Background Non-classic 21-hydroxylase deficiency is usually diagnosed in post-pubertal women because of androgen excess. Indication of systematic steroid replacement therapy is controversial because the risk of acute adrenal insufficiency is unknown. In order to specify this risk we evaluated the cortisol and aldosterone secretions in response to appropriate pharmacologic challenges. Methods In this prospective case–control non-inferiority study we investigated 20 women with non-classic 21-hydroxylase deficiency carrying biallelic CYP21A2 mutations and with serum 17-hydroxyprogesterone (17OHP) >10 ng/mL after stimulation with Synacthen® (tetracosactrin) and 20 age- and body mass index-matched healthy women with 17OHP after Synacthen® Findings The peak serum cortisol concentration after insulin hypoglycemia was lower in patients than in controls (mean difference –47 ng/mL, 90% CI, –66, P = 0.0026). A peak serum cortisol above a cutoff value of 170 ng/mL was obtained in all controls but only in 55% of patients (P = 0.0039). Twenty-four hours after sodium depletion, blood pressure, plasma sodium, potassium, and serum aldosterone concentrations were comparable between the two groups, but patients had higher stimulated renin concentrations than controls (P = 0.0044). Interpretation Patients with non-classic 21-hydroxylase deficiency frequently display partial cortisol insufficiency and compensated defect in aldosterone secretion. Their clinical management should systematically include assessment of adrenal functions.

Drug-induced hypertension is often underestimated. Several drugs prescribed for conditions other than hypertension as well as some herbal remedies, over-the-counter drugs, or recreational drug use (cocaine, anabolic steroids, etc.) can increase blood pressure or blunt the blood pressure-lowering effect of antihypertensive treatments. Some drugs induce sodium retention associated with extracellular volume expansion. Others directly or indirectly activate the sympathetic nervous system, act directly on arterial smooth muscle tone, or have no clear mechanism of action. Other drugs may directly or indirectly interfere with the pharmacokinetic and/or pharmacodynamic profile of the antihypertensive drugs and thus can reverse their blood pressure-lowering effect. Careful evaluation of the drugs taken by patients for conditions other than cardiovascular diseases, through the completion of a standardized questionnaire or the use of drug–drug interaction-checking websites, can help to identify drug-related hypertension.

Introduction Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, affecting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity. Objective We aim at identifying genetic causes of FMD to better understand its mechanism and relation with other vasculopathies. Methods We report results from the first genome-wide association meta-analysis of six studies including 1962 FMD cases and 7100 controls. We integrated genetic association with arterial gene expression using transcriptome-wide association analysis. To identify FMD associated variants located in regulatory elements, we determined open chromatin regions in artery-derived primary cells using ATAC-Seq and estimated heritability and genetic correlation of FMD with other vascular traits and diseases using LD Score regression. Results We found an estimate of SNP-based heritability compatible with a polygenic feature for FMD and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). We found that FMD associated variants were located in arterial-specific regulatory elements. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We found significant genetic overlap between FMD and blood pressure, although hypertension was not confounding the genetic association with FMD. We also report an important genetic overlap with migraine, intracranial aneurysm, coronary artery disease and LDL cholesterol. Conclusion We identified several loci related to vascular contraction, suggesting that altered vascular tonicity may play a role in the pathogenesis of FMD. We find that FMD is genetically close to several vascular diseases where vascular integrity is impaired.

The effect of renal artery angioplasty on blood pressure in patients with true resistant hypertension and atherosclerotic renal artery stenosis has not been fully investigated due to the exclusion of these patients from most trials. In this study, we assessed the benefits of renal angioplasty on daytime ambulatory blood pressure (dABP) in this subgroup of patients. Medical records of our hypertension department were retrospectively analyzed from 2000 to 2016. Seventy-two patients were identified with resistant hypertension (dABP >135 or 85 mm Hg despite at least 3 antihypertensive drugs, including a diuretic) and atherosclerotic renal artery stenosis treated by angioplasty. Atherosclerotic renal artery stenosis was unilateral in 57 patients and bilateral in 15 patients. The mean age of the patients was 67.8±11.2 years; dABP was 157±16/82±10 mm Hg despite 4.0±1.0 antihypertensive treatments; estimated glomerular filtration rate was 52 (41–63) mL/min. After renal angioplasty, dABPM decreased by 14.0±17.3/6.4±8.7 mm Hg ( P P =0.002) with no significant change in estimated glomerular filtration rate. A high baseline systolic dABP and a low body mass index were independent predictors of systolic dABP changes. The decrease in dABP was confirmed in a subgroup of patients at one and 3 years of follow-up (N=31 and N=18 respectively, P ≤0.001 for systolic and diastolic blood pressure at both visits). In this retrospective uncontrolled single-center study, angioplasty in patients with atherosclerotic renal artery stenosis and with true resistant hypertension significantly decreased dABP, reducing the need for antihypertensive treatment with no change in estimated glomerular filtration rate.

BackgroundIn rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy.MethodsTwelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test.ResultsThe potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin.ConclusionThe increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.

Resistant hypertension is defined as uncontrolled blood pressure (BP) despite three antihypertensive agents including a diuretic (thiazide diuretic if renal function is normal or loop diuretic in case of chronic kidney disease with eGFR30mL/min), a renin-angiotensin system blocker (ARB or ACEI) and a calcium channel blocker, at optimal doses. Resistance must be confirmed by out-of-office measurements (ambulatory blood pressure monitoring or home blood pressure monitoring) and patients should be asked about treatment compliance and excessive salt or alcohol intake. If the diagnosis of resistant hypertension is confirmed, the patient should be referred to a hypertension specialist to screen for secondary causes of hypertension as they are frequent in this context. If essential resistant hypertension is confirmed, the mineralocorticoid receptor antagonist, spironolactone, should be added (25 to 50mg daily). In the event of a contraindication to spironolactone, or if adverse effects occur, a beta-blocker, an alpha-blocker, or a centrally acting antihypertensive drug should be prescribed.

International audience; Resistant hypertension is defined as uncontrolled blood pressure (BP) despite three antihypertensive agents including a diuretic (thiazide diuretic if renal function is normal or loop diuretic in case of chronic kidney disease with eGFR

L’hypertension artérielle (HTA) maligne n’a pas disparu, elle a été oubliée. Son incidence augmente à nouveau. Elle assombrit considérablement le pronostic de jeunes patients (35 à 55 ans en moyenne). Il existe probablement des facteurs de prédisposition, plusieurs hypothèses sont à l’étude. De nouveaux critères diagnostiques et de nouvelles options thérapeutiques ont été proposés, ils devront être validés. Devant ces enjeux importants pour les patients, le premier registre prospectif multicentrique sur cette pathologie va être mis en place en France en Septembre 2019. [Malignant hypertension: A bright future] Malignant hypertension has not disappeared, it has been forgotten. Its incidence is increasing again. It considerably worsens the prognosis of young patients (35 to 55 years old on average). There might be susceptibility factors, several hypotheses are under study. New diagnostic criteria and therapeutic options have been proposed and will have to be validated. Faced with these important challenges for patients, the first prospective multicentric register on this pathology will be set up in France in September 2019.

Malignant hypertension (MHT) still exists, leading young people to a poor prognosis. Yet, we lack clear guidelines, mainly because data are scarce. We initiated the first MHT multicentric network to assess these issues. We built a 28 centers network so far, aiming for 40–50 French centers end 2020, and European participation in 2021. We prospectively recruit patients with severe hypertension (> 180/110) and severe hypertensive retinopathy (common definition) or 3-target organ damage among heart, kidney, brain and thrombotic microangiopathy (MOD HTN definition). We hope to recruit 500 patients in 5 years, with a 5 years follow up. We currently collect clinical and examination data, aiming for building a biobank and a target organ damage corelab to entirely reconsider the disease. During the first 6 months, we recruited as planned 58 patients, 41% were male, 49.1 ± 15 years old. Half of them were not known hypertensive, and one third presented a secondary hypertension. Non-observance was reported in 25% of patients as a trigger. Mean blood pressure was 219 ± 29//119 ± 20 mmHg. Patient care pathway was very different according to initial symptoms, target organ damage and centers: hypertension, neurology, nephrology, cardiology, internal medicine, intensive care unit and emergency department. Target organ damage was respectively 70%, 33%, 25% and 25% for kidney, heart, brain and thrombotic microangiopathy, mostly improving during follow up. Most of patients (70%) benefited from intravenous antihypertensive treatment and saline infusion. Length of stay was on average 8 days. Malignant Hypertension clearly didn’t disappear, but was diluted between the different specialities and forgotten. This most severe presentation has to be considered once again to better manage our patients. The unique HAMA network should make it possible to gather high-quality data to improve our knowledge and rediscover the disease.

Background Fibromuscular Dysplasia (FMD) and Spontaneous Coronary Artery Dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. Objectives We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. Methods We analyzed 29 exomes that included familial and sporadic FMD. Follow-up was conducted by targeted or Sanger sequencing (1,071 FMD and 365 SCAD patients) or lookups in exome (264 FMD) or genome sequences (488 SCAD), all independent and unrelated. We used TRAPD burden test to test for enrichment in patients compared to gnomAD controls. The biological effects of variants on receptor signaling and protein expression were characterized using transient overexpression in human cells. Results We identified one rare loss-of-function variant (LoF) (MAFgnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor (hIP) gene (PTGIR), a key player in vascular remodeling. Follow-up in > 1,300 FMD patients revealed four additional LoF allele carriers and a putative enrichment in FMD (PTRAPD = 8 × 10-4), in addition to several rare missense variants. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P) to severely impair hIP function in vitro. Genetic analyses of PTGIR in SCAD revealed one patient who carries Q163X, one with L67P and one carrying a rare splicing mutation (c.768 + 1C > G), but not a significant enrichment (PTRAPD = 0.12) in SCAD. Conclusions Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection.

Rationale and Aim: This study is aimed at identifying possible patterns of vascular wall disarray and remodeling in radial arteries of patients with fibromuscular dysplasia (FMD), by means of ultrahigh frequency ultrasound (UHFUS). Methods: UHFUS scans of the radial arteries and of 30 FMD patients and 30 healthy controls were obtained by VevoMD (70 MHz probe, FUJIFILM, VisualSonics, Toronto, Canada). 10 end-diastolic frames for each subject were analyzed. 74 radiomic features and 4 engineered parameters were extracted: intima-media thickness (IMT) and adventitia thickness (AT), an adjunctive acoustic interface for each layer (IMT and AT triple signal). The extracted parameters were used to train classification models, using Support Vector Machine Linear (SVM), K-Nearest Neighbors (KNN), Logistic Regression, Linear Discriminant Analysis (LDA). The models were then tested on an independent validation population (38 FMD patients and 28 healthy subjects). Results: IMT (185 ± 46 vs 168 ± 37, p =) and AT (104 ± 34 vs 96 ± 35, p = 0.004) were significantly higher in FMD than in controls. IMT and AT triple signal were also more frequent in FMD than in control images (p < for both). The most accurate classification models were LDA (sensitivity = 0.67, specificity = 0.76, accuracy = 0.71, AUC = 0.71) and Logistic Regression (sensitivity = 0.71, specificity = 0.72, accuracy = 0.71, AUC = 0.71). The models showed and accuracy of about 70% when tested on the validation population. Conclusions: Wall ultrastructure of radial arteries of FMD patients is extensively altered: IMT and AT are thickened and the first and/or second layer of the arterial wall is splitted, showing a triple signal feature. Radiomic descriptors combined with engineered parameters allow to distinguish between radial images from FMD patients and controls with a 70% accuracy.

See related article, pp 381–390 Despite current knowledge on the management of hypertension and the availability of multiple potent antihypertensive drugs, hypertension remains poorly controlled worldwide, and its prevalence is increasing because of the aging of populations and the obesity epidemic.1 Part of the patients have resistant hypertension (RHTN) to at least a triple antihypertensive therapy including a diuretic.2 Aging, male gender, black ethnicity, blood pressure (BP) at detection of hypertension, as well as obesity, diabetes mellitus, a Framingham 10-year coronary risk >20%, chronic kidney disease, and the presence of target organ damage are significantly associated with RHTN.2 In addition, obstructive sleep apnea (OSA) often associated with hypertension particularly in obese patients, is about almost 4× more frequent in patients with RHTN.2 Its pathophysiology includes sympathetic overdrive, aldosterone excess3 as well as possible fluid retention and its nocturnal rostral redistribution from the legs, where it may narrow the upper airway and increase its collapsibility, predisposing to OSA during sleep.4 The treatment strategy in RHTN is based on antihypertensive drug escalation, including aldosterone antagonists as fourth line treatment,5 …

The role of vasopressin (AVP) in the pathophysiology of primary aldosteronism (PA) remains unclear.The primary aim of this study was to investigate AVP secretion in PA by measuring the plasma concentration of copeptin (PCop), the C-terminal portion of provasopressin. The secondary aim was to assess renal sensitivity to AVP.This was a cross-sectional study in a tertiary-care hospital.We recruited 115 patients with PA, 48 patients with essential hypertension (EH), and 108 normotensive healthy subjects (HS). Blood was sampled for biochemical and hormonal evaluations in fasting condition after 1-h rest in supine position. Osmolality was determined in 24-h urine. PCop was determined by immunoassay.The main outcome measure was adjusted difference in PCop between groups.After adjustment for sex, body mass index, systolic blood pressure, natremia, and kalemia, PCop was significantly higher in patients with PA than in HS (geometric mean ratio, 1.61; 95% confidence interval [CI], 1.26-2.06; P.0001) and patients with EH (1.40; 95% CI, 1.08-1.82; P = .0070) PCop was positively correlated with natremia (P = .0094). Urine osmolality was significantly lower in patients with PA than in HS (0.82; 95% CI, 0.74-0.92; P = .0002) and 24-h urinary output was significantly higher in patients with PA than in HS (1.32; 95% CI, 1.11-1.56; P = .0005). The relationship between urine osmolality and PCop was shifted downward in patients with PA but was similar in patients with EH and HS, indicating peripheral resistance to AVP.PCop increases in patients with PA in response to an increase in natremia and a renal resistance phenomenon, indicating that AVP release is chronically stimulated in PA.

A nonsmoking 46-year-old male was referred to our hypertension excellence center at the Hospital Georges Pompidou in Paris because of hypertension associated with hypokalemia. His past medical history listed asthma treated by inhaled corticosteroid therapy, corneal transplant, and prostatic adenoma. He had neither been diagnosed with diabetes mellitus nor lipid disorder. His body mass index was 24.7 kg/m2. No family history of cardiovascular disease was known. Hypertension was diagnosed incidentally in 2011 at the age of 43 when he consulted his physician for a sport certification. Maximum systolic blood pressure was 190 mm Hg, blood test at that time revealed hypokalemia, with a minimum potassium level of 3 mmol/L. At the time of his first consultation at our department, the patient was already being treated with amlodipine and perindopril once a day. In addition, he received corticoid inhalation for asthma and an α-blocker (tamsulosin) for his prostate adenoma. The patient complained of headaches and dizziness. Diurnal ambulatory blood pressure was very high, 167/112 mm Hg. Blood potassium level was 2.9 mmol/L with inappropriate urinary excretion of potassium (93 mmol/d). Fasting plasma glucose was 5.7 mmol/L, and low-density lipoprotein cholesterol was 3.88 mmol/L. The patient was diagnosed with grade 3 hypertension and hypokalemia. Secondary causes of hypertension were explored, and treatment was modified accordingly. Amlodipine and perindopril administration was terminated, and urapidil was prescribed. Despite oral potassium supplements of 9 g/d, potassium levels remained at 3.0 mmol/L. Estimated glomerular filtration rate was 88 mL min−1 1.73 m−2, and urinary potassium excretion remained elevated (51 mmol/d). Renin and aldosterone …

L’interpretation de l’etat acidobasique peut se faire par deux approches : classique, centree sur le bicarbonate, ou moderne ou approche de Stewart, dans laquelle le bicarbonate est considere comme une variable dependante. L’analyse classique repose sur l’interpretation simultanee de la bicarbonatemie et de la PCO2. Le base excess (BE) permet de quantifier la part metabolique d’un desordre acidobasique. Le trou anionique plasmatique (TAP, corrige par l’albuminemie) vise a detecter la presence d’anions indoses. L’approche dite moderne de Stewart repose sur quatre grands principes de la physique-chimie : l’equilibre de dissociation de l’eau, la loi de dissociation des acides faibles, l’electroneutralite et la conservation de la masse. Elle identifie trois variables independantes : la difference des ions forts (SID), la concentration totale d’acide faible et la pression partielle de dioxyde de carbone (PCO2). Les ions forts sont les ions totalement dissocies au pH plasmatique: acides forts (Cl-et lactate, pKa 12). Le SID est physiologiquement de 40 mEq/l, ce qui correspond aux anions des acides faibles totaux. Ils sont quantifies par la somme de l’albuminate, des phosphates et des bicarbonates, etroitement correlee au BE de l’approche classique. Stewart definit un strong ion gap (SIG) equivalent au TAP moins la bicarbonatemie. On parle ainsi d’acidose a SID diminue et de SIG normal a la place d’acidose hyperchloremique a TAP normal. Cette revue tente de demontrer comment ces deux approches regardent a travers des prismes differents les memes phenomenes complexes d’equilibration entre les tampons.

The frequency of the diagnosed causes of secondary hypertension is only known from hospital-based records, which probably overestimate the true prevalence. Excluding oral contraceptive users and cases with renal failure, their overall frequency was estimated at 1 percent in the eighties, 5 percent in the nineties, and 9 percent in recent years. This increase in frequency was mostly due to an increased number of diagnosed cases of endocrine hypertension. The diagnosis of endocrine hypertension is not synonymous with the diagnosis of a surgically correctable form of hypertension. Indeed, hypertension is surgically curable in a minority of patients, mostly in patients with aldosterone-secreting adenomas or with pheochromocytomas or functional paragangliomas. The presentation, screening, diagnosis and therapeutic management of endocrine hypertension are discussed in the present issue.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic non-inflammatory arterial disease of unknown origin. We previously showed the presence of triple signal (TS) at ultrasound within common carotid artery (CCA) wall. We aimed at coupling TS presence with microconstituents of the vessel wall. We included 50 patients with multifocal FMD, 50 essential hypertensive (HT) patients and 50 healthy subjects (HS) matched for age, sex, ethnicity and BP (HT and FMD). TS score from the right and left CCA were assessed from 15-MHz echotracking system coupled with aplanation tonometry. 14 microconstituents of the CCA, representing geometry, perivascular tethering, and wall material coefficients were derived from fitting of the pressure-diameter curve. In multivariate analysis, age, hypercholesterolemia and IMT were significantly associated with TS, explaining 9.5% of its variance. TS was more frequent in FMD than HS (49% vs 16%, p

Background: Fibromuscular dysplasia (FMD) is a rare idiopathic, non-atherosclerotic non-inflammatory vascular disease. This work represents the first study of the pathophysiology of FMD. We investigated the relationships between circulating biomarkers and the non-invasive vascular parameters. Methods: We included 50 patients with FMD, 50 essential hypertensive patients (HT) and 50 healthy subjects (NT) matched for age, sex, ethnicity and blood pressure. We determined circulating levels of total microparticles (MPs) (annexinV+MPs), endothelial MPs (CD144+MPs, CD62E+MPs and CD31+CD41-MPs) and SMC-MPs by flow cytometry analysis. We measured forearm endothelial function by post-ischemic flow dependent vasodilation. Shear stress was estimated using the formula of Weaver (1–3). Aortic stiffness was assessed by measuring carotid-femoral pulse wave velocity. Triple signal score was assessed from 15-MHz echotracking system. Results: There are no significant differences between rates of total MPs, endothelial MPs (CD144+MPs, CD62E+MPs and CD31+CD41-MPs) and SMC-MPs between 3 groups (with p-value 0.38 0.52 0.65 0.17 and 0.25 respectively). Endothelial MPs were not correlated with the endothelial dysfunction, nor with the shear stress, whether in FMD, NT or HT. We observed a strong negative correlation between aortic stiffness and nitroglycerin-mediated dilation in the group NT, HT and whole population (r= −0.43, p= 0.001 r= −0.29, p= 0.03 r = −0.35, p

Background: Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory vascular disease involving medium-sized muscular arteries, whose pathophysiology is still unknown. Objectives: We aimed at identifying systemic vascular alterations in usually non-affected arteries of patients with multifocal renal FMD by a deep imaging-based phenotyping. Methods: This cross-sectional study included FMD patients (n = 50, 84% hypertensives), age-, sex and BP-matched patients with primary hypertension (PH, n = 50) and healthy normotensive subjects (HS, n = 50). Brachial artery (BA) endothelium-dependent flow-mediated dilation (EDD) and endothelium-independent vasodilation (EID) were studied. Aortic stiffness was assessed by carotid-to-femoral pulse wave velocity (PWV). We quantified abnormal echographic patterns in the common carotid wall by the triple signal score. Common carotid Young’s incremental elastic modulus (Einc)/stress curves were also plotted. Results: FMD patients had impaired EID compared to PH and HS (p = 0.008, after adjustment for confounders p = 0.002), smaller BA diameter but comparable EDD and PWV. The prevalence of triple signal score >6 was 56%, 40%, 24% in FMD, PH and HS respectively (p = 0.005). FMD, but not PH, was significantly associated with triple signal (beta = 0.143, p = 0.022, r2 = 0.058). Impaired EDD was only present in FMD patients with triple signal score>6 (p for interaction=0.047). For a given stress value of 80 kPa, Einc was higher in the presence of a triple signal score >6, especially in FMD patients. Conclusions: Non-affected musculo-elastic and muscular arteries in patients with multifocal renal FMD exhibit a cluster of functional and structural abnormalities, while elastic arteries are preserved. Triple signal in FMD may identify a distinct vascular phenotype.

International audience; Treatments for primary aldosteronism (PA) aim to correct or prevent the deleterious consequences of hyperaldosteronism: hypertension, hypokalemia, and direct target organ damage. Patients with unilateral PA considered fit for surgery can undergo laparoscopic adrenalectomy, which significantly decreases blood pressure (BP) and medications in most cases and cures hypertension in about 40%. Mineralocorticoid receptor antagonists (MRA) are used to treat patients with bilateral PA and those with unilateral PA if surgery is not possible or not desired. Spironolactone is more potent than eplerenone, but high doses are poorly tolerated in men. MRA can be replaced or complemented with epithelial sodium channel blockers, such as amiloride. Thiazide diuretics and calcium channel blockers are used when the first-line drugs are insufficient to control BP. Dietary sodium restriction should be implemented in all cases because the deleterious consequences of hyperaldosteronism are dependent on salt loading. Several studies comparing the results of surgery and MRA have reported no differences in terms of BP, serum potassium concentration, or cardiovascular and kidney outcomes, although the benefits of treatment tend to be observed sooner with surgery. Patients with PA display relative glomerular hyperfiltration, which is reversed by specific treatment, revealing CKD in 30% of patients. However, further kidney damage is lessened by the treatment of PA.

There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension.