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1.
Artigo em Inglês | MEDLINE | ID: mdl-32561919

RESUMO

CONTEXT: Primary aldosteronism (PA) comprises unilateral (lateralized, LPA) and bilateral disease (BPA). The identification of LPA is important to recommend potentially curative adrenalectomy. Adrenal venous sampling (AVS) is considered the gold standard for PA subtyping, but the procedure is available in few referral centers. OBJECTIVE: To develop prediction models for subtype diagnosis of PA using patient clinical and biochemical characteristics. DESIGN, PATIENTS AND SETTING: Patients referred to a tertiary hypertension unit. Diagnostic algorithms were built and tested in a training (N=150) and in an internal validation cohort (N=65), respectively. The models were validated in an external independent cohort (N=118). MAIN OUTCOME MEASURE: Regression analyses and supervised machine learning algorithms were used to develop and validate two diagnostic models and a 20-point score to classify patients with PA according to subtype diagnosis. RESULTS: Six parameters were associated with a diagnosis of LPA (aldosterone at screening and after confirmatory testing, lowest potassium value, presence/absence of nodules, nodule diameter, and computed tomography results) and were included in the diagnostic models. Machine learning algorithms displayed high accuracy at training and internal validation (79.1% to 93%), whereas a 20-point score reached an AUC of 0.896, and a sensitivity/specificity of 91.7/79.3%. An integrated flow-chart correctly addressed 96.3% of patients to surgery and would have avoided AVS in 43.7% of patients. The external validation on an independent cohort confirmed a similar diagnostic performance. CONCLUSIONS: Diagnostic modelling techniques can be used for subtype diagnosis and guide surgical decision in patients with PA in centers where AVS is unavailable.

2.
J Clin Endocrinol Metab ; 105(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32303754

RESUMO

CONTEXT: The clinical spectrum and knowledge of the molecular mechanisms underlying primary aldosteronism (PA), the most frequent form of endocrine hypertension, has evolved over recent years. In accordance with the Endocrine Society guidelines and in light of the growing evidence showing adverse cardiovascular outcomes, it is expected that a progressively wider population of patients affected by hypertension will be screened for PA, including the elderly. EVIDENCE ACQUISITION: A systematic search of PubMed was undertaken for studies related to the renin-angiotensin-aldosterone system (RAAS), PA, and adrenal histopathology in the elderly population. EVIDENCE SYNTHESIS: Several studies showed an age-dependent decrease in the activity of RAAS, together with a progressive decrease of the aldosterone response to sodium intake, particularly after the sixth decade of life. The positive correlation between age and serum aldosterone during liberal sodium intake over serum aldosterone during sodium restriction is paralleled by histological changes in adrenal aldosterone synthase (CYP11B2) expression patterns. Immunohistochemical studies showed a progressive loss of the continuous expression of CYP11B2 in the adrenal zona glomerulosa with aging and a concomitant increase of aldosterone-producing cell clusters, which might be responsible for relatively autonomous aldosterone production. Additionally, following PA confirmation and subtype diagnosis, older age is correlated with a lower benefit after adrenalectomy for unilateral PA. CONCLUSIONS: Accumulating evidence suggests that RAAS physiology and regulation show age-related changes. Further studies may investigate to what extent these variations might affect the diagnostic workup of patients affected by PA.

4.
Horm Metab Res ; 52(6): 366-372, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32219799

RESUMO

The coexistence of aldosterone oversecretion and obstructive sleep apnea is frequently observed, especially in patients with resistant hypertension, obesity, and metabolic syndrome. Since aldosterone excess and sleep apnea are both independently associated with an increased risk of cardiovascular disease, to investigate whether their coexistence might be attributed to common predisposing conditions, such as metabolic disorders, or to an actual pathophysiological interconnection appears of great importance. Fluid overload and metabolic abnormalities relating to aldosterone oversecretion may be implicated in obstructive sleep apnea development. Nocturnal intermittent hypoxia may in turn exacerbate renin-angiotensin-aldosterone system activity, thus leading to hyperaldosteronism. Furthermore, fat tissue excess and adipocyte secretory products might predispose to both sleep apnea and aldosterone oversecretion in subjects with obesity. Consistent with these evidences, obstructive sleep apnea frequently affects patients with primary aldosteronism. Conversely, whether primary aldosteronism is more prevalent in individuals affected by obstructive sleep apnea compared to the general population remains controversial.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32147420

RESUMO

Low-renin hypertension (LRH) is a frequent condition in patients with arterial hypertension, accounting for 30% of patients. Monogenic forms can cause LRH in a minority of cases. However, in the large majority of patients, LRH is caused by the combined effects of congenital and acquired factors, comprising dietary habits. Several genetic variants have been proposed as co-factors in the pathogenesis of LRH with normal-low serum aldosterone. Emerging evidences support the hypothesis that a large proportion of LRH with normal-high serum aldosterone is associated with subclinical primary aldosteronism (PA). The recent identification of aldosterone-producing cell clusters (APCCs) as the possible cause of subclinical PA, further supported the concept of a continuous spectrum of autonomous aldosterone secretion, from subclinical forms towards overt PA. In this review we describe the main aspects of LRH, focusing on molecular basis, clinical risk profile and patients' management.

6.
Hypertension ; 75(4): 1025-1033, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32114853

RESUMO

Primary aldosteronism (PA) was considered a rare disorder almost always associated with hypokalemia. The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype. Many studies have reported the prevalence of hypokalemia in patients with PA; conversely, the prevalence of PA in patients with hypokalemia is unknown. In this retrospective observational study, we define the prevalence of hypokalemia in referred patients with hypertension and the prevalence of PA in patients with hypokalemia and hypertension. Hypokalemia was present in 15.8% of 5100 patients with hypertension, whereas 76.9% were normokalemic, and 7.3% hyperkalemic. The prevalence of PA in patients with hypokalemia was 28.1% and increased with decreasing potassium concentrations up to 88.5% of patients with spontaneous hypokalemia and potassium concentrations <2.5 mmol/L. A multivariate regression analysis demonstrated the association of hypokalemia with the occurrence of cardiovascular events independent of PA diagnosis. An association of PA with the occurrence of cardiovascular events and target organ damage independent of hypokalemia was also demonstrated. In conclusion, our results confirm that PA is a frequent cause of secondary hypertension in patients with hypokalemia, and the presence of hypertension and spontaneous hypokalemia are strong indications for PA diagnosis. Finally, we show that PA and hypokalemia are associated with an increased risk of cardiovascular events.

7.
Horm Cancer ; 11(1): 52-62, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32002807

RESUMO

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a high prevalence among patients with resistant hypertension. Despite the recent discovery of somatic variants in aldosterone-producing adenoma (APA)-associated PA, causes for PA due to bilateral aldosterone production (bilateral hyperaldosteronism; BHA) remain unknown. Herein, we identified rare gene variants in ATP2B4, in a cohort of patients with BHA. ATP2B4 belongs to the same family of Ca-ATPases as ATP2B3, which is involved in the pathogenesis of APA. Endogenous ATP2B4 expression was characterized in adrenal tissue, and the gene variants were functionally analyzed for effects on aldosterone synthase (CYP11B2) expression, steroid production in basal and agonist-stimulated conditions, and for changes in biophysical properties of channel properties. Knockdown of ATP2B4 in HAC15 exhibited reduced angiotensin II stimulation in one of four shRNA clones. Stable HAC15 cell lines with doxycycline (dox) - inducible wild-type and variant forms of ATP2B4 - were generated, and dox-induced upregulation of ATP2B4 mRNA and protein was confirmed. However, ATP2B4 variants did not alter basal or agonist-stimulated CYP11B2 expression. Whole-cell recordings in HAC15 cells indicated robust endogenous ATP2B4 conductance in native cells but reduced conductance with overexpressed WT and variant ATP2B4. The previously defined PA-causing ATP2B3 variant served as a positive control and exhibited elevated CYP11B2 mRNA. In conclusion, while this study did not confirm a pathogenic role for ATP2B4 variants in BHA, we describe the sequencing analysis for familial and sporadic BHA and outline a template for the thorough in vitro characterization of gene variants.

8.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789380

RESUMO

CONTEXT: Aldosterone-producing adrenocortical adenomas (APAs) are mainly composed of clear (lipid rich) and compact (eosinophilic) tumor cells. The detailed association between these histological features and somatic mutations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) in APAs is unknown. OBJECTIVE: To examine the association between histological features and individual genotypes in APAs. METHODS: Examination of 39 APAs subjected to targeted next-generation sequencing (11 KCNJ5, 10 ATP1A1, 10 ATP2B3, and 8 CACNA1D) and quantitative morphological and immunohistochemical (CYP11B2 and CYP17A1) analyses using digital imaging software. RESULTS: KCNJ5- and ATP2B3-mutated APAs had clear cell dominant features (KCNJ5: clear 59.8% [54.4-64.6%] vs compact 40.2% (35.4-45.6%), P = .0022; ATP2B3: clear 54.3% [48.2-62.4 %] vs compact 45.7% (37.6-51.8 %), P = .0696). ATP1A1- and CACNA1D-mutated APAs presented with marked intratumoral heterogeneity. A significantly positive correlation of immunoreactivity was detected between CYP11B2 and CYP17A1 in tumor cells of KCNJ5-mutated APAs (P = .0112; ρ = 0.7237), in contrast, significantly inverse correlation was detected in ATP1A1-mutated APAs (P = .0025; ρ = -0.8667). CONCLUSION: KCNJ5-mutated APAs, coexpressing CYP11B2 and CYP17A1, were more deviated in terms of zonation-specific differentiation of adrenocortical cells than ATP1A1- and ATP2B3-mutated APAs.

9.
J Hypertens ; 38(1): 3-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31385870

RESUMO

OBJECTIVES: In experimental animal models, exogenous aldosterone excess has been linked to the progression of renal disease. However, the evidence of an increased risk of renal damage in patients affected by primary aldosteronism remains controversial. We aimed at evaluating the association between primary aldosteronism and renal damage through a meta-analysis. METHODS: We performed a quantitative review of studies evaluating parameters of renal function in patients affected by primary aldosteronism compared with hypertensive patients without primary aldosteronism and in patients affected by primary aldosteronism before and after treatment. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1960 up to April 2019. RESULTS: Forty-six studies including 6056 patients with primary aldosteronism and 9733 patients affected by arterial hypertension without primary aldosteronism were included. After 8.5 years from hypertension diagnosis, patients with primary aldosteronism had an increased estimated glomerular filtration rate (eGFR) compared with hypertensive patients without primary aldosteronism [by 3.37 ml/min IQR (0.82-5.93)] and a more severe albuminuria [standard mean difference 0.55 (0.19-0.91)], resulting into an association with microalbuminuria [odds ratio (OR) 2.09 (1.40; 3.12)] and proteinuria [OR 2.68 (1.89;3.79)]. Following primary aldosteronism treatment, after a median follow-up of 12 months, a reduction in eGFR was observed [by -10.69 ml/min (-13.23; -8.16)], consistent in both medically and surgically treated patients. Similarly, a reduction in albumin excretion and an increase in serum creatinine were observed after treatment. CONCLUSION: Patients affected by primary aldosteronism, compared with patients affected by arterial hypertension without primary aldosteronism, display a more pronounced target organ damage, which can be mitigated by the specific treatment.

10.
Hypertension ; 75(1): 163-172, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760886

RESUMO

Primary aldosteronism is recognized as the most frequent cause of secondary hypertension, and its screening is expected to become a routine evaluation in most patients with hypertension. The interference of antihypertensive therapies with the aldosterone-to-renin ratio during screening process is a major confounder. Renin-angiotensin-aldosterone system Triple-A analysis is a novel liquid chromatography/tandem mass spectrometry diagnostic assay that allows simultaneous quantification of aldosterone, equilibrium Ang I (angiotensin I), and Equilibrium Ang II in a single sample of serum. We performed a comparative evaluation of the diagnostic performance of the aldosterone-to-Ang II ratio and 5 renin-based diagnostic ratios, differing in methods to determine aldosterone levels and renin activity in a cohort of 110 patients with hypertension (33 patients with confirmed primary aldosteronism and 77 with essential hypertension). All ratios showed comparable areas under the curves ranging between 0.924 and 0.970 without significant differences between each other. The evaluation of the Ang II-to-Ang I ratio revealed persistent drug intake in some patients as cause for suppressed renin-based diagnostic ratios, while aldosterone-to-Ang II ratio remained unaffected. The Youden index optimal cutoff value for the aldosterone-to-Ang II ratio was 6.6 ([pmol/L]/[pmol/L]) with a sensitivity of 90% and a specificity of 93%, proving noninferiority compared with the aldosterone-to-renin ratio while pointing to the potential for an interference-free application in patients under ACE (angiotensin-converting enzyme) inhibitor therapy. This study shows for the first time the accuracy and reliability of renin-angiotensin-aldosterone system triple-A analysis for the screening of primary aldosteronism that can be applied in clinical routine.

11.
Hypertension ; 74(6): 1532-1540, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31679423

RESUMO

The association between primary aldosteronism (PA) and obstructive sleep apnea (OSA) has been a matter of debate. 2016 Endocrine Society guideline recommends screening for PA all hypertensive patients with OSA. We designed a multicenter, multiethnic, cross-sectional study to evaluate the prevalence of PA in patients with OSA and the prevalence of OSA in unselected patients with PA. Two hundred and three patients with OSA (102 whites and 101 Chinese) were screened for PA, and 207 patients with PA (104 whites, 100 Chinese, and 3 of African descent) were screened for OSA by cardiorespiratory polygraphy. Eighteen patients with OSA (8.9%) had PA (11.8% of white and 5.9% of Chinese ethnicity). In patients without other indications for PA screening, the prevalence of PA dropped to 1.5%. The prevalence of OSA in patients with PA was 67.6%, consistent in both white and Chinese patients. A correlation between aldosterone levels and apnea/hypopnea index was observed in white patients with PA (R2=0.225, P=0.016) but not in Chinese patients. Multinomial logistic regression confirmed a significant and independent association between plasma aldosterone levels and moderate to severe OSA diagnosis in white patients (odds ratio, 1.002; P=0.002). In conclusion, aldosterone levels may contribute to the severity of OSA in white patients with hyperaldosteronism, but patients with OSA are not at high risk of PA. Results of the present study challenge the current recommendation of the Endocrine Society guideline that all patients with OSA should be screened for PA, irrespective of the grade of hypertension.

12.
High Blood Press Cardiovasc Prev ; 26(6): 493-499, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31625119

RESUMO

Accurate measurement of blood pressure (BP) has a pivotal role in the management of patients with arterial hypertension. Recently, introduction of unattended office BP measurement has been proposed as a method allowing more accurate management of hypertensive patients and prediction of hypertension-mediated target organ damage (HMOD). This approach to BP measurement has been in particular proposed to avoid the white coat effect (WCE), which can be easily assessed once both attended and unattended BP measurements are obtained. In spite of its interest, the role of WCE in predicting HMOD remains largely unexplored. To fill this gap the Young Investigator Group of the Italian Hypertension Society (SIIA) conceived the study "Evaluation of unattended automated office, conventional office and ambulatory blood pressure measurements and their correlation with target organ damage in an outpatient population of hypertensives". This is a no-profit multicenter observational study aiming to correlate attended and unattended BP measurements for quantification of WCE and to correlate WCE with markers of HMOD, such us left ventricular hypertrophy, left atrial dilatation, and peripheral atherosclerosis. The Ethical committee of the Federico II University hospital has approved the study.


Assuntos
Assistência Ambulatorial , Determinação da Pressão Arterial/métodos , Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea , Hipertensão/diagnóstico , Visita a Consultório Médico , Estudos Transversais , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Itália , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etiologia , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Projetos de Pesquisa , Fatores de Risco , Hipertensão do Jaleco Branco/complicações , Hipertensão do Jaleco Branco/diagnóstico por imagem , Hipertensão do Jaleco Branco/fisiopatologia
13.
Hypertension ; 74(2): 359-367, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31230554

RESUMO

Patients affected by primary aldosteronism (PA) display an increased risk of cardiovascular events compared with essential hypertension (EH). Endothelial dysfunction favors initiation and progression of atherosclerosis and circulating extracellular vesicles (EVs), reflecting endothelial cell activity, could represent one of the mediators of endothelial dysfunction in these patients. The aim of this study was to characterize circulating EVs from patients diagnosed with PA and to explore their functional significance. Serum EVs were isolated from 12 patients with PA and 12 with EH, matched by sex, age, and blood pressure, and compared with 8 normotensive controls. At nanoparticle tracking analysis, EVs concentration was 2.2× higher in patients with PA ( P=0.033) compared with EH and a significant correlation between EV number and serum aldosterone and potassium levels was identified. Fluorescence-activated cell sorting analysis demonstrated that patients with PA presented a higher absolute number of endothelial-derived EVs compared with both patients with EH and normotensive controls. Through EV mRNA profiling, 15 up-regulated and 4 down-regulated genes in patients with PA compared with EH were identified; moreover, EDN1 was expressed only in patients with PA. Microarray platform was validated by quantative real-time polymerase chain reaction on 4 genes ( CASP1, EDN1, F2R, and HMOX1) involved in apoptosis, inflammation, and endothelial dysfunction. After unilateral adrenalectomy, EVs number and expression of CASP1 and EDN1 significantly decreased in patients with PA ( P<0.05). Additionally, the incubation with PA-derived EVs reduced angiogenesis and induced apoptosis in vitro. Circulating EVs might not only represent a marker of endothelial dysfunction but also contribute themselves to vascular dysfunction in patients with PA.


Assuntos
Hipertensão Essencial/fisiopatologia , Vesículas Extracelulares/genética , Regulação da Expressão Gênica/genética , Hiperaldosteronismo/genética , Neovascularização Patológica/genética , Adulto , Apoptose/genética , Estudos de Casos e Controles , Células Cultivadas , Hipertensão Essencial/genética , Feminino , Humanos , Hiperaldosteronismo/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência
14.
Hypertension ; 73(2): 481-490, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30624994

RESUMO

Automated office blood pressure (AOBP) has emerged as a valuable tool to assess patient's BP status, but the lack of strong evidence to establish a threshold value for hypertension diagnosis limits its use in clinical practice. We aimed at synthesizing the published literature through a meta-analysis of studies comparing AOBP with other BP measurement techniques and at analyzing the differences between AOBP and physician's office BP, nonphysician's office BP, daytime ambulatory BP monitoring, and home BP monitoring. We searched PubMed database for articles published up to April 2018; eligible studies compared AOBP with office and out-of-office measurement techniques and reported the BP differences or BP values obtained. Twenty-six studies, for a total of 7116 patients, were included in the analysis. AOBP values were lower than physician (systolic BP, -10.48 mm Hg; 95% CI, -13.15 to -7.81/diastolic BP, -4.44 mm Hg; 95% CI, -6.07 to -2.80) and nonphysician office ones (systolic BP, -6.89 mm Hg; 95% CI, -8.75 to -5.04/diastolic BP -3.82 mm Hg; 95% CI, -4.86 to -2.78). No significant differences were found between AOBP and daytime ambulatory BP monitoring (systolic BP, -1.85; 95% CI, -4.50 to 0.79/diastolic BP, 0.12; 95% CI, -1.42 to 1.66) and home BP monitoring (systolic BP, -2.65; 95% CI, -8.42 to 3.12/diastolic BP, -1.67; 95% CI, -4.20 to 0.87). AOBP readings did not differ significantly from out-of-office blood pressure, still remaining an office technique; it may improve hypertension diagnosis by overcoming some of office BP limitations, including the white coat effect.


Assuntos
Determinação da Pressão Arterial/métodos , Hipertensão/diagnóstico , Monitorização Ambulatorial da Pressão Arterial , Humanos , Hipertensão do Jaleco Branco/diagnóstico
15.
J Hum Hypertens ; 32(11): 745-751, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30082690

RESUMO

Primary aldosteronism (PA) is the most common endocrine cause of resistant hypertension. Individuals with PA are at increased cardiovascular risk, and an appropriate management and treatment would ideally reduce such risk. Screening and diagnosis of PA requires a specific diagnostic test which is considered time- and cost-consuming and, as a result, is underperformed in clinical practice. An online survey reviewing available diagnostic procedures, laboratory testing, and clinical protocols for screening and confirmation of PA diagnosis was conducted among clinical lead of Reference and Excellence centers of the Italian Hypertension Society. A total of 102 questionnaires were sent and 62 centers participated in the survey. Assessment of the plasma renin (plasma renin activity/direct renin concentration) and plasma aldosterone concentration (PAC) was available in all centers. Captopril challenge test (CCT) and saline infusion test (SIT) were available in 60% and 61% of the centers, respectively. Fludrocortisone suppression test was available in 32% of the units. Adrenal vein sampling was accessible in 32% of the centers. We found discrepancies in cutoff levels of aldosterone-to-renin ratio (ARR) and PAC after SIT. Other discrepancies involved the duration of the wash-out period before ARR testing and dosage of captopril administered during CCT. In conclusion, although all centers are sufficiently equipped to perform PA screening, often patients should be referred to other centers to confirm the diagnosis of PA. A greater uniformity across centers to define precise cutoffs for screening and confirmatory testing for the diagnosis of PA would be of utility.


Assuntos
Hiperaldosteronismo/diagnóstico , Centros de Cuidados de Saúde Secundários/estatística & dados numéricos , Humanos , Itália , Inquéritos e Questionários
16.
Hypertension ; 72(2): 306-313, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29967035

RESUMO

Pharmacological treatment is indicated in children and adolescents with hypertension unresponsive to lifestyle modifications, but there is not enough evidence to recommend 1 class of antihypertensive drugs over others. We performed a network meta-analysis to compare the results of available randomized clinical trials on pharmacological treatment of pediatric hypertension. From a total of 554 potentially relevant studies, 13 randomized placebo-controlled clinical trials enrolling ≥50 patients and a follow-up ≥4 weeks were included. The reduction of systolic blood pressure (SBP) and diastolic BP (DBP) after treatment were the coprimary end points. A total of 2378 pediatric patients, with a median age of 12 years, were included in the analysis. After a median follow-up of 35 days, lisinopril and enalapril were found to be superior to placebo in reducing SBP and DBP, whereas only for DBP, losartan was found to be superior to placebo and lisinopril and enalapril were found to be superior to eplerenone. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were associated with a greater SBP and DBP reduction compared with placebo, likewise the mineralocorticoid receptor antagonist was inferior to angiotensin-converting enzyme inhibitors in DBP reduction. The analysis was adjusted for study-level mean age, percentage of women, mean baseline blood pressure, and mean weight, only the latter significantly affected DBP reduction. According to the present analysis, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers could represent the best choice as antihypertensive treatment for pediatric hypertension. However, because of the paucity of available data for the other classes of antihypertensive drugs, definitive conclusions are not allowed and further randomized controlled trials are warranted.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Metanálise em Rede , Adolescente , Criança , Humanos , Hipertensão/fisiopatologia
17.
Int J Mol Sci ; 19(6)2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29874863

RESUMO

Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3ß-hydroxyl-steroid dehydrogenase (Hsd3b6), the murine counterpart to the human type I 3ß-hydroxyl-steroid dehydrogenase (HSD3B1) gene. In the present study, we evaluated the role of CRY1 and CRY2 genes, and their potential interplay with HSD3B isoforms in adrenal pathophysiology in man. Forty-six sporadic aldosterone-producing adenomas (APAs) and 20 paired adrenal samples were included, with the human adrenocortical cells HAC15 used as the in vitro model. In our cohort of sporadic APAs, CRY1 expression was 1.7-fold [0.75⁻2.26] higher (p = 0.016), while CRY2 showed a 20% lower expression [0.80, 0.52⁻1.08] (p = 0.04) in APAs when compared with the corresponding adjacent adrenal cortex. Type II 3ß-hydroxyl-steroid dehydrogenase (HSD3B2) was 317-fold [200⁻573] more expressed than HSD3B1, and is the main HSD3B isoform in APAs. Both dehydrogenases were more expressed in APAs when compared with the adjacent cortex (5.7-fold and 3.5-fold, respectively, p < 0.001 and p = 0.001) and HSD3B1 was significantly more expressed in APAs composed mainly of zona glomerulosa-like cells. Treatment with angiotensin II (AngII) resulted in a significant upregulation of CRY1 (1.7 ± 0.25-fold, p < 0.001) at 6 h, and downregulation of CRY2 at 12 h (0.6 ± 0.1-fold, p < 0.001), through activation of the AngII type 1 receptor. Independent silencing of CRY1 and CRY2 genes in HAC15 cells resulted in a mild upregulation of HSD3B2 without affecting HSD3B1 expression. In conclusion, our results support the hypothesis that CRY1 and CRY2, being AngII-regulated genes, and showing a differential expression in APAs when compared with the adjacent adrenal cortex, might be involved in adrenal cell function, and in the regulation of aldosterone production.


Assuntos
Adenoma/genética , Criptocromos/genética , Hipertensão/genética , Complexos Multienzimáticos/genética , Progesterona Redutase/genética , Esteroide Isomerases/genética , Adenoma/metabolismo , Adenoma/patologia , Aldosterona/biossíntese , Angiotensina II/genética , Animais , Linhagem Celular Tumoral , Criptocromos/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Hipertensão/patologia , Camundongos
18.
Clin Endocrinol (Oxf) ; 89(4): 385-396, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29758100

RESUMO

Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the "classical" RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low-renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low-renin levels are expression of a physiological response to sodium-volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low-renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low-renin hypertension, enlightening the novelties in genetics of the familial forms.


Assuntos
Hipertensão/diagnóstico , Hipertensão/metabolismo , Renina/metabolismo , Animais , Humanos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/metabolismo , Hipertensão/sangue , Síndrome de Liddle/sangue , Síndrome de Liddle/diagnóstico , Síndrome de Liddle/metabolismo , Renina/sangue
19.
High Blood Press Cardiovasc Prev ; 25(2): 167-176, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29752703

RESUMO

INTRODUCTION: Early uncontrolled studies reported large blood pressure reductions in subjects with resistant hypertension treated with renal denervation, however these results were not confirmed in several of the latest publications. AIM: The aim of the current study was to evaluate the effectiveness of RDN in controlled studies comparing RDN to either a sham procedure or to medical therapy. METHOD: Only controlled studies were included in the analysis. Both the unadjusted and control-adjusted BP changes were calculated. RESULTS: We identified 11 publications of which only 3 were double-blinded RCTs with a sham control, while 8 were open label studies where the control group was treated with medical therapy. Only 2 studies assessed adherence to medical therapy with robust methodologies. Office BP reduction (- 18/8 mmHg) significantly overestimated ABPM change (- 9/- 5 mmHg), with high heterogeneity between the included studies. When the treatment effect was adjusted for the BP change in the control group, BP changes became non significant (ABPM: - 1.8 for systolic BP [95% CI - 4.5 to 0.9] and - 0.6 for diastolic BP [95% CI - 2.3 to 1.2]). These results were confirmed when only the sham-controlled studies were analysed. CONCLUSIONS: In spite of promising results in early reports, renal denervation fails to show superiority to a sham procedure or to medical therapy in recently published controlled studies. Lack of a sham control in most publications and heterogeneity in assessment of treatment adherence may account for part the variability reported in the studies. Renal denervation fails to show superiority to a sham procedure or to medical therapy in recently published controlled studies.


Assuntos
Pressão Sanguínea , Hipertensão/cirurgia , Rim/irrigação sanguínea , Artéria Renal/inervação , Simpatectomia/métodos , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Resistência a Medicamentos , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Simpatectomia/efeitos adversos , Resultado do Tratamento
20.
Curr Opin Endocrinol Diabetes Obes ; 25(3): 155-159, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29629943

RESUMO

PURPOSE OF REVIEW: The aim of the present manuscript is to provide an overview of the most updated studies on the prevalence of primary aldosteronism in primary care and to compare these figures with the actual rate of diagnosis in clinical practice and with the prevalence of primary aldosteronism in specific subgroup of patients. RECENT FINDINGS: Over the last 20 years the clinical spectrum of low renin hypertension and primary aldosteronism has changed dramatically. Once considered only in the presence of severe hypertension and hypokalemia, it is now well known that primary aldosteronism is not uncommon even in patients with mild forms of hypertension and/or normokalemia. Moreover, recent evidence points toward a large proportion of normotensive study participants as being affected by subclinical primary aldosteronism, which represents a strong risk factor for incident hypertension. Moreover, primary aldosteronism patients are exposed to an increased risk of cardio and cerebrovascular events and metabolic comorbidities compared with patients affected by essential hypertension. Disappointingly, primary aldosteronism remains a largely underdiagnosed and undertreated disorder. SUMMARY: These recent findings further highlight the importance of widening the spectrum of patients who should be screened for primary aldosteronism, to reduce the cardiovascular risk associated with this medical condition.


Assuntos
Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/epidemiologia , Atenção Primária à Saúde/estatística & dados numéricos , Adrenalectomia/estatística & dados numéricos , Aldosterona , Pressão Sanguínea , Doenças Cardiovasculares/etiologia , Transtornos Cerebrovasculares/etiologia , Humanos , Hiperaldosteronismo/terapia , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipopotassemia , Renina/sangue , Fatores de Risco
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