Publications by authors named "Aurélien Lorthioir"

24 Publications

  • Page 1 of 1

Renal Outcome and New-Onset Renal and Extrarenal Dissections in Patients With Nontrauma Renal Artery Dissection Associated With Renal Infarction.

Hypertension 2021 May 10:HYPERTENSIONAHA12016540. Epub 2021 May 10.

Hypertension Unit, AP-HP, Hôpital Européen Georges Pompidou, Paris, France. (A.-L.F., G.B., A.L., M.A., L.A.).

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 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 <60 mL/min per 1.73 m. 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.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16540DOI Listing
May 2021

Aldosterone-Related Myocardial Extracellular Matrix Expansion in Hypertension in Humans: A Proof-of-Concept Study by Cardiac Magnetic Resonance.

JACC Cardiovasc Imaging 2020 10 16;13(10):2149-2159. Epub 2020 Sep 16.

Department of Radiology, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Hypertension, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Biological & Statistic, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France; Paris Cardiovascular Research Center, French Institute of Health and Medical Research, Paris, France. Electronic address:

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/m vs. 82 ± 15 ml/m; p < 0.0001). Intracellular mass index increased with BP across groups (BG: 36 [IQR: 29 to 41]; HS: 40 [IQR: 36 to 46]; HTN: 51 [IQR: 42 to 54]; PA: 50 [IQR: 46 to 67]; p < 0.0001). Extracellular mass index was similar in BG, HS, and HTN (16 [IQR: 12 to 20]; 15 [IQR: 11 to 18]; and 14 [IQR: 12 to 17], respectively) but 30% higher in PA (21 [IQR: 18 to 29]; p < 0.0001) remaining significant after adjustment for mean BP.

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).
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http://dx.doi.org/10.1016/j.jcmg.2020.06.026DOI Listing
October 2020

Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia.

Cardiovasc Res 2021 Mar;117(4):1154-1165

Department of Radiology, Assistance-publique-hôpitaux de Paris, Hopital Européen Georges Pompidou, F-75015 Paris, France.

Aims: 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. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.

Methods And Results: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro.

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 signalling in non-atherosclerotic stenosis and dissection.
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http://dx.doi.org/10.1093/cvr/cvaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983006PMC
March 2021

The European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI)-clinical phenotypes and their predictors based on a cohort of 1000 patients.

Cardiovasc Res 2021 Feb;117(3):950-959

Shanghai Institute of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

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 computed tomography angiography, magnetic resonance angiography, and/or catheter-based angiography were eligible. Patients were predominantly women (82%) and Caucasians (88%). Age at diagnosis was 46 ± 16 years (12% ≥65 years old), 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 ≥65 years old had more often multifocal FMD, lower estimated glomerular filtration rate 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.
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http://dx.doi.org/10.1093/cvr/cvaa102DOI Listing
February 2021

[What is resistant hypertension and how to diagnose it?]

Rev Prat 2019 Dec;69(10):1099-1103

Service d'hypertension artérielle, Hôpital européen Georges-Pompidou, AP-HP, université de Paris, Paris, France.

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.
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December 2019

[Which methods of blood pressure measurement should you choose?]

Rev Prat 2019 Dec;69(10):1076-1079

Service d'hypertension artérielle, hôpital européen Georges-Pompidou, AP-HP, Paris, France.

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.
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December 2019

Clinic Versus Ambulatory Blood Pressure in Resistant Hypertension: Impact of Antihypertensive Medication Nonadherence: A Post Hoc Analysis the DENERHTN Study.

Hypertension 2019 11 23;74(5):1096-1103. Epub 2019 Sep 23.

From the INSERM, Centre d'Investigations Cliniques- Plurithématique 1418, Paris, France (I.H., H.P., M.A.).

Clinic-ambulatory blood pressure (BP) difference is influenced by patients- and device-related factors and inadequate clinic-BP measurement. We investigated whether nonadherence to antihypertensive medications may also influence this difference in a post hoc analysis of the DENERHTN trial (Renal Denervation for Hypertension). We pooled the data of 77 out of 106 evaluable patients with apparent resistant hypertension who received a standardized antihypertensive treatment and had both ambulatory BP and drug-screening results available at baseline after 1 month of standardized triple therapy and at 6 months on a median of 5 antihypertensive drugs. After drug assay samplings on study visits, patients took their antihypertensive treatment under supervision immediately after the start of the ambulatory BP recording, and supine clinic BP was measured 24 hours post-dosing; both allowed to calculate the clinic minus daytime ambulatory systolic BP (SBP) difference (clinic-SBP-day-SBP). A total of 29 (37.7%) were found nonadherent to medications at baseline and 38 (49.4%) at 6 months. At baseline, the mean clinic-SBP-day-SBP difference in the nonadherent group was 12.7 mm Hg (95% CI, 7.8-17.7 mm Hg, <0.001). In contrast, clinic SBP was almost identical to day-SBP in the adherent group (clinic-SBP-day-SBP difference, 0.1 mm Hg; 95% CI, -3.3 to 3.5 mm Hg; =0.947). Similar observations were made at 6 months. Using receiver operating characteristics curves, we found that a 6 mm Hg cutoff of clinic-SBP-day-SBP difference had 67% sensitivity and 69% specificity to predict nonadherence to the triple therapy at baseline. In conclusion, a large clinic-SBP-day-SBP difference may help discriminating between adherence and nonadherence to treatment in patients with resistant hypertension. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01570777.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13520DOI Listing
November 2019

Resistant Hypertension and Atherosclerotic Renal Artery Stenosis: Effects of Angioplasty on Ambulatory Blood Pressure. A Retrospective Uncontrolled Single-Center Study.

Hypertension 2019 12 28;74(6):1516-1523. Epub 2019 Oct 28.

Hypertension Unit, AP-HP, Hôpital Européen Georges-Pompidou, 75015, Paris, France (A.L., G.B., N.D., M.A., L.A.).

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 (<0.001 for both), and the number of antihypertensive treatments decreased to 3.6±1.4 (=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, ≤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.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13393DOI Listing
December 2019

Cortisol and Aldosterone Responses to Hypoglycemia and Na Depletion in Women With Non-Classic 21-Hydroxylase Deficiency.

J Clin Endocrinol Metab 2020 01;105(1)

Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre, France.

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® <2 ng/mL. Each participant underwent sequentially an insulin tolerance test to evaluate cortisol secretion and a sodium depletion test, obtained by oral administration of 40 mg of furosemide under low sodium diet (<20 mmol during 24 hours), to evaluate renin and aldosterone secretion.

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.
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http://dx.doi.org/10.1210/clinem/dgz005DOI Listing
January 2020

[Spironolactone in resistant essential hypertension].

Presse Med 2019 Dec 28;48(12):1431-1438. Epub 2019 Aug 28.

AP-HP, hôpital européen Georges-Pompidou, hypertension unit, 20, rue Leblanc, 75015 Paris, France; Paris-Descartes university, faculty of medicine, 75006 Paris, France.

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<30mL/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.
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http://dx.doi.org/10.1016/j.lpm.2019.07.027DOI Listing
December 2019

[Malignant hypertension: A bright future].

Presse Med 2019 Dec 27;48(12):1439-1444. Epub 2019 Aug 27.

CHU de Bordeaux, hôpital Saint-André, 1, rue Jean-Burguet, 33000 Bordeaux, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lpm.2019.07.007DOI Listing
December 2019

Adrenal adaptation in potassium-depleted men: role of progesterone?

Nephrol Dial Transplant 2020 11;35(11):1901-1908

Sorbonne Université, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.

Background: In 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.

Methods: Twelve 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.

Results: The 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.

Conclusion: The 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.
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http://dx.doi.org/10.1093/ndt/gfz135DOI Listing
November 2020

Deep Vascular Phenotyping in Patients With Renal Multifocal Fibromuscular Dysplasia.

Hypertension 2019 02;73(2):371-378

APHP, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (H.K., A.L., M.F., X.J., S.L., P.B., M.A.).

Arterial fibromuscular dysplasia is a nonatherosclerotic, noninflammatory vascular disease, whose pathophysiology is still unknown. We performed deep image-based vascular phenotyping of nonaffected arteries to look for systemic vascular alterations in fibromuscular dysplasia. This single center cross-sectional study included 50 patients with multifocal renal fibromuscular dysplasia, 50 hypertensive patients, and 50 healthy controls, matched for age, sex, and ethnicity; hypertensive patients were matched also for blood pressure. Brachial artery endothelium-dependent and endothelium-independent dilation were studied by echotracking. Aortic stiffness was assessed by carotid-to-femoral pulse wave velocity. We quantified the presence of supernumerary acoustic interfaces within the common carotid wall by the triple signal (TS) score. We plotted the Young incremental elastic modulus/stress curves for common carotid artery, derived from echotracking and tonometry. Patients with fibromuscular dysplasia had impaired endothelium-independent dilation (adjusted P=0.002), smaller brachial artery diameter but comparable endothelium-dependent dilation and aortic stiffness. The prevalence of TS score >6 was 56%, 40%, 24% in patients with fibromuscular dysplasia, hypertensives, and controls, respectively ( P=0.005). Fibromuscular dysplasia remained significantly associated with TS in the multiple regression model ( P=0.022). Impaired endothelium-dependent dilation was present only in patients with fibromuscular dysplasia, TS score >6 ( P=0.047). Incremental elastic modulus was higher for a given wall stress (80 kPa) in the presence of a TS score >6, especially in fibromuscular dysplasia. In conclusion, nonclinically affected large- and medium-sized arteries in patients with multifocal renal fibromuscular dysplasia exhibit a cluster of diffuse alterations in smooth muscle cell function, arterial geometry, wall characteristics, and mechanical properties. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01935752.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12189DOI Listing
February 2019

Resistant Hypertension and Obstructive Sleep Apnea: Is There a Specific Indication for Endovascular Renal Denervation?

Hypertension 2018 08 25;72(2):281-282. Epub 2018 Jun 25.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, F-75015 Paris, France (M.A., L.A., A.L.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11368DOI Listing
August 2018

Case of Primary Aldosteronism With Discordant Hormonal and Computed Tomographic Findings.

Hypertension 2017 04 13;69(4):529-535. Epub 2017 Feb 13.

From the University Paris Descartes, AP-HP, Hypertension Unit, Hospital European Georges Pompidou, France (L.A., A.-L.F., M.B., A.L.); Hypertension Unit, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Israel (Y.S.); Clinica dell'Ipertensione, Department of Medicine, DIMED, University Hospital, Padova, Italy (G.P.R.); Physiology Department, DHU FIRE, Bichat Hospital, AP-HP, Inserm, University Paris Diderot, Sorbonne Paris Cité, France (E.V.P.); Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (A.F.D., R.M.T.); Division of Internal Medicine and Hypertension Unit, Department of Medical Science, University of Turin, Italy (P.M.); and University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (N.D.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08751DOI Listing
April 2017

Deciphering the Role of Vasopressin in Primary Aldosteronism.

J Clin Endocrinol Metab 2015 Sep 10;100(9):3297-303. Epub 2015 Jul 10.

Department of Internal Medicine (L.N.), Centro Hospitalar São João, 4200-319 Porto, Portugal; Center for Health Technology and Services Research, Faculty of Medicine (L.N.), University of Porto, 4099-002 Porto, Portugal; Université Paris Descartes, Faculté de Médecine (A.B., A.L., V.Z., S.B., L.A., P.-F.P., J.M., M.A.), Sorbonne Paris Cité F-75006 Paris, France; Assistance Publique Hôpitaux de Paris (A.B., E.C., A.L. V.Z., M.A.), Hôpital Européen Georges Pompidou, Centre d'Investigation Clinique, F-75015 Paris, France; INSERM, CIC 1418 (A.B., D.B., M.A.), F-75015 Paris, France; Laboratoire de Biomathématiques, Faculté de Pharmacie (E.C.), Université Paris Descartes, Sorbonne Paris Cité, F-75005 Paris, INSERM, UMR 1144 (E.C.), F-75015 Paris, France; and Département de Physiologie-Explorations Fonctionnelles (S.B.), and Unité d'Hypertension Artérielle (L.A., G.B., P.-F.P., M.A.), Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 75015 Paris, France.

Context: The role of vasopressin (AVP) in the pathophysiology of primary aldosteronism (PA) remains unclear.

Objectives: 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.

Design And Setting: This was a cross-sectional study in a tertiary-care hospital.

Protocol: 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.

Main Outcome Measure: The main outcome measure was adjusted difference in PCop between groups.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1210/JC.2015-2007DOI Listing
September 2015

Outcomes of drug-based and surgical treatments for primary aldosteronism.

Adv Chronic Kidney Dis 2015 May;22(3):196-203

Department of Internal Medicine, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France; Faculty of Medicine, Sorbonne Universités, UPMC Univ Paris 06, Paris, France; LIMICS, INSERM, UMR_S1142, Paris, France; Clinical Investigation Centre 9201, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; Clinical Investigation Centre 9201, INSERM, Paris, France; Faculty of Medicine, Université Paris-Descartes, Paris, France; Department of Visceral Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; and the Hypertension Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.

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.
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http://dx.doi.org/10.1053/j.ackd.2014.10.003DOI Listing
May 2015

The authors reply.

Kidney Int 2015 Apr;87(4):857

Department of Pharmacology & INSERM U1096, Rouen University Hospital, Rouen, France.

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http://dx.doi.org/10.1038/ki.2014.421DOI Listing
April 2015

Progress in primary aldosteronism. Mineralocorticoid antagonist treatment for aldosterone-producing adenoma.

Eur J Endocrinol 2015 Mar 14;172(3):R125-9. Epub 2014 Oct 14.

Hypertension UnitClinical Investigation CenterAssistance Publique-Hopitaux de Paris and University Paris-Descartes, Hopital Europeen G Pompidou, 20 Rue Leblanc, 75015 Paris, France

Mineralocorticoid receptor antagonists have been used in patients with aldosterone-producing adenomas (APAs) as a test designed to predict the blood pressure (BP) outcome of surgery. They are commonly used in patients undergoing adrenalectomy to reduce BP and increase plasma potassium levels during the preoperative period. A small number of studies have compared the effects of surgery and mineralocorticoid antagonists either on BP, on serum potassium levels, or on the incidence of cardiovascular and renal outcomes in patients with primary aldosteronism with or without an APA; these studies found no difference between the two therapeutic options. Mineralocorticoid receptor antagonists can be used as a maintenance treatment for patients with APAs, who are judged to be poor operative risks or who do not want to undergo surgery.
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http://dx.doi.org/10.1530/EJE-14-0585DOI Listing
March 2015

Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans.

Kidney Int 2015 Feb 16;87(2):465-72. Epub 2014 Jul 16.

1] Department of Pharmacology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France [4] Centre d'Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, Rouen, France.

Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD.
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http://dx.doi.org/10.1038/ki.2014.241DOI Listing
February 2015

[Presentations and management of adrenal hypertension].

Presse Med 2014 Apr 23;43(4 Pt 1):420-7. Epub 2014 Feb 23.

Université Paris Descartes, Sorbonne Paris Cité, Assistance publique-Hôpitaux de Paris, hôpital européen Georges-Pompidou, unité d'hypertension artérielle, 75908 Paris cedex 15, France.

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.
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http://dx.doi.org/10.1016/j.lpm.2013.06.032DOI Listing
April 2014

New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension.

J Renin Angiotensin Aldosterone Syst 2013 Dec 12;14(4):285-9. Epub 2013 Nov 12.

1Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France.

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.
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http://dx.doi.org/10.1177/1470320313513408DOI Listing
December 2013

Can we use mineralocorticoid receptor blockade in diabetic patients with resistant hypertension? Yes we can! But it may be a double-edged sword.

J Hypertens 2013 Oct;31(10):1948-51

aAssistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit bUniversité Paris-Descartes cINSERM, Clinical Investigation Centre 9201, Paris, France.

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http://dx.doi.org/10.1097/HJH.0b013e328364bcdfDOI Listing
October 2013

Diabetic CVD--soluble epoxide hydrolase as a target.

Cardiovasc Hematol Agents Med Chem 2012 Sep;10(3):212-22

Department of Pharmacology, Rouen University Hospital, Rouen, France.

The incidence of cardiovascular diseases remains high in diabetic patients despite the optimization of blood glucose control and the therapeutic management of risk factors. One emerging promising pharmacological approach that may help to prevent the development of diabetic cardiovascular complications is to improve endothelial function through the restoration of the bioavailability of epoxyeicosatrienoic acids (EETs). EETs are crucial eicosanoid signaling molecules synthesized by cytochrome P450 epoxygenases in the vascular endothelium and in pancreatic islets. EETs promote vasodilatation and display attractive anti-inflammatory and anti-aggregating actions together with potent effects on insulin release and sensitivity. In animal models of insulin-resistance and diabetes, a decrease in EET availability has been reported, and is a deleterious mechanism that probably contributes to multiple metabolic, cardiovascular and renal disorders in this setting. Moreover, increasing experimental evidence suggest that the use of soluble epoxide hydrolase (sEH) inhibitors, which prevent EET degradation, is a promising pharmacological approach to prevent endothelial dysfunction and to protect against target organ damage in metabolic diseases. This review presents evidence that the EET pathway is disturbed from the early stages of metabolic diseases, and analyzes the potential contribution of EETs impairment to the progression of cardiovascular diseases associated with diabetes. Pathophysiological and therapeutic perspectives are thereafter discussed, including the necessity to demonstrate the role of EET pathway alterations in endothelial dysfunction associated with diabetes in human, and the interest of sEH inhibitors to prevent the development of diabetic cardiovascular complications, with the expected result of improving patients' health.
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http://dx.doi.org/10.2174/187152512802651042DOI Listing
September 2012