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

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.

Poor adherence to medication and salt restriction as a barrier to reaching blood pressure control in patients with hypertension: Cross-sectional study from 12 sub-Saharan countries.

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

First International Consensus on the diagnosis and management of fibromuscular dysplasia.

This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD), which was commissioned by the working group 'Hypertension and the Kidney' of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.

First international consensus on the diagnosis and management of fibromuscular dysplasia.

This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD) which was commissioned by the Working Group 'Hypertension and the Kidney' of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.

Fibromuscular Dysplasia and Its Neurologic Manifestations: A Systematic Review.

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

Socioeconomic Status and Hypertension Control in Sub-Saharan Africa: The Multination EIGHT Study (Evaluation of Hypertension in Sub-Saharan Africa).

Systemic hypertension is a rapidly growing epidemic in Africa. The role of socioeconomic status on blood pressure control has not been well studied in this part of the world. We, therefore, aimed to quantify the association of socioeconomic status both at the individual and at the country level with blood pressure control in Sub-Saharan Africa. We conducted a cross-sectional survey in urban clinics of 12 countries, both low income and middle income, in Sub-Saharan Africa. Standardized blood pressure measures were made among the hypertensive patients attending the clinics. Blood pressure control was defined as blood pressure <140/90 mm Hg, and hypertension grades were defined according to the European Society of Cardiology guidelines. A total of 2198 hypertensive patients (58.4±11.8 years; 39.9% men) were included. Uncontrolled hypertension was present in 1692 patients (77.4%), including 1044 (47.7%) with ≥grade 2 hypertension. The proportion of uncontrolled hypertension progressively increased with decreasing level of patient individual wealth, respectively, 72.8%, 79.3%, and 81.8% (P for trend, <0.01). Stratified analysis shows that these differences of uncontrolled hypertension according to individual wealth index were observed in low-income countries (P for trend, 0.03) and not in middle-income countries (P for trend, 0.26). In low-income countries, the odds of uncontrolled hypertension increased 1.37-fold (odds ratio, 1.37 [0.99-1.90]) and 1.88-fold (odds ratio, 1.88 [1.10-3.21]) in patients with middle and low individual wealth as compared with high individual wealth. Similarly, the grade of hypertension increased progressively with decreasing level of individual patient wealth (P for trend, <0.01). Strategies for hypertension control in Sub-Saharan Africa should especially focus on people in the lowest individual wealth groups who also reside in low-income countries.

Sex differences in antihypertensive treatment in France among 17 856 patients in a tertiary hypertension unit.

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

Substandard drugs among five common antihypertensive generic medications: an analysis from 10 African countries.

OBJECTIVE: Hypertension results in more deaths than any other risk factor and has been on the rise in sub-Saharan Africa over the past few decades. Generic drugs have helped improve accessibility and affordability of antihypertensive therapy in developing countries. However, assessment of quality standards of these products is important. We performed a quality assessment of five commonly used antihypertensive generic drugs in 10 sub-Saharan African countries and studied the impact of price on quality. METHODS: Drug samples were prospectively collected using standardized methods between 2012 and 2014. We developed a validated reversed-phase liquid chromatography with tandem mass spectrometry method to accurately quantify the active ingredient in a certified public laboratory. Quality was defined based on the percentage ratio of measured to expected dosage of active ingredient. RESULTS: A total of 1185 samples were assessed, of which 70.0% were generic (n = 830). Among the generic drugs, the percentage of poor-quality drugs was 24.3% (n = 202/830). The percentage ratio of measured to expected dosage of active ingredient ranged from 49.2 to 111.3%; the majority (81.7%) of the poor-quality samples had insufficient quantity of the active ingredient. Moreover, poor quality was not associated with purchase price of the drug. CONCLUSION: In this study from 10 sub-Saharan African countries, nearly one-quarter of the available generic antihypertensive drugs were found to be of poor quality. Concerted measures to improve the quality of antihypertensive drugs could lead to major improvements in hypertension control with attendant reduction of its deleterious consequences in low-income and middle-income countries.

Cause of renal infarction: a retrospective analysis of 186 consecutive cases.

BACKGROUND: Renal infarction can cause abrupt and severe hypertension and less frequently renal failure. Renal infarction results from disruption of renal blood flow in the main ipsilateral renal artery or in a segmental branch. Underlying mechanism is either general, 'embolic' or 'thrombophilic', or local related to primary 'renal artery lesion'. It depends on various causes. In absence of an identified cause, renal infarction is classified as 'idiopathic'. Previous studies report a significant number of 'idiopathic' renal infarction. OBJECTIVE: The aim of this study was to analyze various renal infarction causes. METHODS: Between July 2000 and June 2015, 259 consecutive patients with renal infarction were admitted to our hospital center and retrospectively identified from weekly multidisciplinary round. Main clinical and biological characteristics were extracted from clinical data warehouse. Renal imaging was reviewed by two readers unaware of the diagnosis. RESULTS: Of 259 initially identified patients, 30 were excluded owing to a lack of imaging or clinical data and 43 because iatrogenic renal infarction. In the 186 studied patients, dissection was observed in 76 patients (40.8%) and occlusion in 75 (40.3%). Renal infarction mechanisms were 'renal artery lesion' (n = 151; 81.2%), 'embolic' (n = 17; 9.1%), 'thrombophilic' (n = 11; 5.9%) and 'idiopathic' (n = 7; 3.8%). Predominant renal artery lesions were atherosclerosis disease (n = 52; 34.4%) followed by dissecting hematoma (n = 35; 23.2%) and fibromuscular dysplasia (n = 29; 19.2%). Right and left kidneys were equally involved. CONCLUSION: Renal artery lesion is the most frequent cause of renal infarction. This result underlines the need for extensive arterial exploration to identify the renal infarction mechanism and, in case of renal artery lesion, the underlying vascular disease.

High Prevalence of Multiple Arterial Bed Lesions in Patients With Fibromuscular Dysplasia: The ARCADIA Registry (Assessment of Renal and Cervical Artery Dysplasia).

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

Fighting fake medicines: First quality evaluation of cardiac drugs in Africa.

BACKGROUND: The growing menace of poor quality and falsified drugs constitutes a major hazard, compromising healthcare and patient outcomes. Efforts to assess drug standards worldwide have almost exclusively focused on anti-microbial drugs; with no study to date on cardiovascular drugs. Our study aims to assess quality of seven routinely used cardiovascular medications (anticoagulants, antihypertensives and statins) in ten Sub-Saharan African countries. METHODS: Drugs were prospectively collected using standardized methods between 2012 and 2014 from licensed (random pharmacies) and unlicensed (street-markets) places of sale in Africa. We developed a validated reversed-phase liquid chromatography with tandem mass spectrometry method to accurately quantify the active ingredient in a certified public laboratory. Three quality categories were defined based on the ratio of the measured to the expected dosage of the active ingredient: A (good quality): 95% to 105%, B (low quality): 85 to 94.99% or 105.01 to 115%, C (very low quality): <85% or >115%. RESULTS: All expected medicines (n=3468 samples) were collected in Benin, Burkina-Faso, Congo-Brazzaville, the Democratic Republic of Congo, Guinea, Côte d'Ivoire, Mauritania, Niger, Togo and Senegal. Out of the 1530 samples randomly tested, poor quality (types B and C) was identified in 249 (16.3%) samples. The prevalence of poor quality was significantly increased in certain specific drugs (amlodipine 29% and captopril 26%), in generic versions (23%) and in drugs produced in Asia (35%). The proportion of poor quality reached 50% when drugs produced in Asia were sold in street-markets. CONCLUSION: In this first study assessing the quality of cardiovascular drugs in Africa, we found a significant proportion of poor quality drugs. This requires continued monitoring strategies.

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

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

Suppression of Aldosterone Secretion After Recumbent Saline Infusion Does Not Exclude Lateralized Primary Aldosteronism.

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

Adherence to Antihypertensive Treatment and the Blood Pressure-Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial.

BACKGROUND: The DENERHTN trial (Renal Denervation for Hypertension) confirmed the blood pressure-lowering efficacy of renal denervation added to a standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months. We report the influence of adherence to antihypertensive treatment on blood pressure control. METHODS: One hundred six patients with hypertension resistant to 4 weeks of treatment with indapamide 1.5 mg/d, ramipril 10 mg/d (or irbesartan 300 mg/d), and amlodipine 10 mg/d were randomly assigned to renal denervation plus standardized stepped-care antihypertensive treatment, or the same antihypertensive treatment alone. For standardized stepped-care antihypertensive treatment, spironolactone 25 mg/d, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d were sequentially added at monthly visits if home blood pressure was ≥135/85 mm Hg after randomization. We assessed adherence to antihypertensive treatment at 6 months by drug screening in urine/plasma samples from 85 patients. RESULTS: The numbers of fully adherent (20/40 versus 21/45), partially nonadherent (13/40 versus 20/45), or completely nonadherent patients (7/40 versus 4/45) to antihypertensive treatment were not different in the renal denervation and the control groups, respectively (P=0.3605). The difference in the change in daytime ambulatory systolic blood pressure from baseline to 6 months between the 2 groups was -6.7 mm Hg (P=0.0461) in fully adherent and -7.8 mm Hg (P=0.0996) in nonadherent (partially nonadherent plus completely nonadherent) patients. The between-patient variability of daytime ambulatory systolic blood pressure was greater for nonadherent than for fully adherent patients. CONCLUSIONS: In the DENERHTN trial, the prevalence of nonadherence to antihypertensive drugs at 6 months was high (≈50%) but not different in the renal denervation and control groups. Regardless of adherence to treatment, renal denervation plus standardized stepped-care antihypertensive treatment resulted in a greater decrease in blood pressure than standardized stepped-care antihypertensive treatment alone. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01570777.

SFE/SFHTA/AFCE primary aldosteronism consensus: Introduction and handbook.

The French Endocrinology Society (SFE) French Hypertension Society (SFHTA) and Francophone Endocrine Surgery Association (AFCE) have drawn up recommendations for the management of primary aldosteronism (PA), based on an analysis of the literature by 27 experts in 7 work-groups. PA is suspected in case of hypertension associated with one of the following characteristics: severity, resistance, associated hypokalemia, disproportionate target organ lesions, or adrenal incidentaloma with hypertension or hypokalemia. Diagnosis is founded on aldosterone/renin ratio (ARR) measured under standardized conditions. Diagnostic thresholds are expressed according to the measurement units employed. Diagnosis is established for suprathreshold ARR associated with aldosterone concentrations >550pmol/L (200pg/mL) on 2 measurements, and rejected for aldosterone concentration<240pmol/L (90pg/mL) and/or subthreshold ARR. The diagnostic threshold applied is different if certain medication cannot be interrupted. In intermediate situations, dynamic testing is performed. Genetic forms of PA are screened for in young subjects and/or in case of familial history. The patient should be informed of the results expected from medical and surgical treatment of PA before exploration for lateralization is proposed. Lateralization is explored by adrenal vein sampling (AVS), except in patients under 35 years of age with unilateral adenoma on imaging. If PA proves to be lateralized, unilateral adrenalectomy may be performed, with adaptation of medical treatment pre- and postoperatively. If PA is non-lateralized or the patient refuses surgery, spironolactone is administered as first-line treatment, replaced by amiloride, eplerenone or calcium-channel blockers if insufficiently effective or poorly tolerated.

MANAGEMENT OF ENDOCRINE DISEASE: Recurrence or new tumors after complete resection of pheochromocytomas and paragangliomas: a systematic review and meta-analysis.

OBJECTIVES: To systematically review the incidence and factors associated with recurrences or new tumors after apparent complete resection of pheochromocytoma or thoraco-abdomino-pelvic paraganglioma. DESIGN: A systematic review and meta-analysis of published literature was performed. METHODS: Pubmed and Embase from 1980 to 2012 were searched for studies published in English on patients with non-metastatic pheochromocytoma or thoraco-abdomino-pelvic paraganglioma, complete tumor resection, postoperative follow-up exceeding 1 month, and recurrence or new tumor documented by pathology, hormonal dosages, or imaging tests. Incidence rates of new events after curative surgery were calculated for each study that had sufficient information and pooled using random-effect meta-analysis. RESULTS: In total, 38 studies were selected from 3518 references, of which 36 reported retrospective cohorts from the USA, Europe, and Asia. Patient follow-up was neither standardized nor exhaustive in the included studies. A clear description of patient retrieval methods was available for nine studies and the follow-up protocol and patient flow for four studies. Only two studies used multivariable methods to assess potential predictors of postoperative events.The overall rate of recurrent disease from 34 studies was 0.98 events/100 person-years (95% confidence interval 0.71, 1.25). Syndromic diseases and paragangliomas were consistently associated with a higher risk of a new event in individual studies and in meta-regression analysis. CONCLUSIONS: The risk of recurrent disease after complete resection of pheochromocytoma may be lower than that previously estimated, corresponding to five events for 100 patients followed up for 5 years after complete resection. Risk stratification is required to tailor the follow-up protocol after complete resection of a pheochromocytoma or paraganglioma. Large multicenter studies are needed to this end.

SFE/SFHTA/AFCE consensus on primary aldosteronism, part 4: Subtype diagnosis.

To establish the cause of primary aldosteronism (PA), it is essential to distinguish unilateral from bilateral adrenal aldosterone secretion, as adrenalectomy improves aldosterone secretion and controls hypertension and hypokalemia only in the former. Except in the rare cases of type 1 or 3 familial hyperaldosteronism, which can be diagnosed genetically and are not candidates for surgery, lateralized aldosterone secretion is diagnosed on adrenal CT or MRI and adrenal venous sampling. Postural stimulation tests and (131)I-norcholesterol scintigraphy have poor diagnostic value and (11)C-metomidate PET is not yet available. We recommend that adrenal CT or MRI be performed in all cases of PA. Imaging may exceptionally identify adrenocortical carcinoma, for which the surgical objectives are carcinologic, and otherwise shows either normal or hyperplastic adrenals or unilateral adenoma. Imaging alone carries a risk of false positives in patients over 35 years of age (non-aldosterone-secreting adenoma) and false negatives in all patients (unilateral hyperplasia). We suggest that all candidates for surgery over 35 years of age undergo adrenal venous sampling, simultaneously in both adrenal veins, without ACTH stimulation, to confirm the unilateral form of the hypersecretion. Sampling results should be confirmed on adrenal vein cortisol assay showing a concentration at least double that found in peripheral veins. Aldosterone secretion should be considered lateralized when aldosterone/cortisol ratio on the dominant side is at least 4-fold higher than contralaterally.

[Fibromuscular dysplasia of renal arteries]. / Dysplasie fibromusculaire des artères rénales.

Fibromuscular dysplasia is non-atherosclerotic, non-inflammatory disease of the medium caliber arteries causing segmental stenosis, and sometimes aneurysm and/or dissection. Renal involvement is either asymptomatic or revealed by hypertension, rarely acute complications (renal infarction/hemorrhage). Cross-sectional imaging or angiography differentiates multifocal fibromuscular dysplasia (pearl necklace appearance) and focal fibromuscular dysplasia (tubular stenosis). Several differential diagnoses are to be mentioned. Carotid and vertebral involvement are possible. Smoking cessation must be encouraged. Selected patients benefit from renal revascularization. The best indications are recent or resistant hypertension, and progressive renal atrophy. Angioplasty without stent revascularization is the technique of choice in purely stenotic forms.

Building a Semantic Interoperability Framework for Care and Research in Fibromuscular Dysplasia.

UNLABELLED: Identifying patients with Fibromuscular Dysplasia (FMD) at the international level will have considerable value for understanding the epidemiology, clinical manifestations and susceptible genes in this arterial disease, but also for identifying eligible patients in clinical trials or cohorts. We present a two-step methodology to create a general semantic interoperability framework allowing access and comparison of distributed data over various nations, languages, formats and databases. METHODS: The first step is to develop a pivot multidimensional model based on a core dataset to harmonize existing heterogeneous data sources. The second step is to align the model to additional data, semantically related to FMD and collected currently in various registries. We present the results of the first step that has been fully completed with the validation and implementation of the model in a dedicated information system (SIR-FMD). We discuss the current achievements for step 2 and the extensibility of the methodology in the context of other rare diseases.