Primary Aldosteronism and Drug Resistant Hypertension: A "Chicken-Egg" Story.

Drug-resistant arterial hypertension (RH) is a major risk factor for cardiovascular disease, often due to overlooked underlying causes. Identification of such causes poses significant clinical challenges. In this setting, primary aldosteronism (PA) is a frequent cause of RH and its prevalence in RH patients is likely higher than 20%.The pathophysiological link between PA and the development and maintenance of RH involves target organ damage and the cellular and extracellular effects of aldosterone excess that promote pro-inflammatory and pro-fibrotic changes in the kidney and vasculature.The feasibility of adrenal vein sampling in PA patients with RH, and the clinical benefit achieved by adrenalectomy, further emphasize the need to implement systematic screening for this common form of secondary hypertension in the management of a high-risk population as RH patients.: We herein review the current knowledge of the factors that contribute to the RH phenotype with a focus on PA and discuss the issues regarding the screening for PA in this setting and the therapeutic approaches (surgical and medical) aimed at resolving RH caused by PA.

Serum levels of autoantibodies against the angiotensin II type I receptor are not associated with serum dicarbonyl or AGE levels in patients with an aldosterone-producing adenoma.

Patients with an aldosterone-producing adenoma (APA) carry a higher risk of cardiovascular disease and commonly have high levels of autoantibodies (AT1AA) that may activate the angiotensin II type 1 receptor (AT1R). AT1R activation is linked to an increase of the glucose metabolite methylglyoxal (MGO), a potential precursor of advanced glycation endproducts (AGEs) and driver of vascular inflammation. We investigated whether serum AT1AA levels are associated with serum MGO and AGE levels in APA patients. In a case series of 26 patients with APA we measured levels of dicarbonyls MGO, glyoxal (GO) and 3-deoxyglucosone (3-DG), and dicarbonyl-derived AGEs 5-hydro-5-methylimidazolone (MG-H1), Nε-(carboxyethyl)lysine (CEL) and Nε-(carboxymethyl)lysine (CML) with UPLC-MS/MS. We also measured AT1AA by ELISA. These measurements were repeated 1-month after adrenalectomy in a subset of 14 patients. Panels of inflammation and endothelial function were also measured by immunoassays. Although baseline higher AT1AA levels tended to be correlated with higher baseline serum MGO, GO and 3-DG levels (r = 0.18, p = 0.38; r = 0.20, p = 0.33; r = 0.23, p = 0.26; respectively), these correlations were not statistically significant. We observed no obvious correlations between higher AT1AA levels and protein-bound and free MG-H1, CEL and CML levels, and markers of inflammation and endothelial function. No decrease was observed in any of the dicarbonyls, protein-bound AGE levels and markers of inflammation and endothelial function after adrenalectomy. In patients with APA the serum levels of AT1AA were not significantly correlated with serum dicarbonyls, protein-bound and free AGE levels. Increased signalling of the AT1AA receptor may therefore be unlikely to overtly increase systemic dicarbonyl levels.

Monozygotic twins discordant for primary aldosteronism: a case report.

This corrects the article DOI: 10.1038/jhh.2017.41.

Characterisation of sleep disturbances in postural orthostatic tachycardia syndrome: a polysomnography-based study.

BACKGROUND AND AIM: Postural orthostatic tachycardia syndrome (PoTS) has been frequently associated with sleep disturbances but objective sleep data are lacking. In addition, although regional autonomic denervation has been described, less is known about autonomic nervous activity overnight in these patients. PATIENTS/METHODS: A full polysomnography and heart rate variability were performed on 37 patients diagnosed with PoTS . In addition, a multiple sleep latency test (MSLT) was conducted on a subgroup of patients with excessive daytime sleepiness. RESULTS: The polysomnographic data did not show major pathological findings except the percentage spent in rapid eye movement (REM) sleep which was slightly reduced at 18.4%. The MSLT did not confirm excessive daytime sleepiness as median mean sleep latency was 14.4 min (11.8-17.5). When comparing patients with and without subjective daytime sleepiness, it was found that the latter had a reduced parasympathetic activation at night as expressed by the average high frequency [6936.5 ms(2) (6028.2-8675.5) vs. 4689.5 (3922.7-7685.2) p < 0.05]. CONCLUSION: Patients with PoTS do not exhibit polysomnographic findings consistent with relevant sleep pathologies nor objective daytime sleepiness. Subjective daytime sleepiness is associated with enhanced activation of the parasympathetic nervous system.

Prospective appraisal of the prevalence of primary aldosteronism in hypertensive patients presenting with atrial flutter or fibrillation (PAPPHY Study): rationale and study design.

Primary aldosteronism (PA) is the most common endocrine form of hypertension and may carry an increased risk of atrial flutter or fibrillation (AFF). The primary goal of this multicentre cohort study is thus to prospectively establish the prevalence of PA in consecutive hypertensive patients referred for lone (non-valvular), paroxysmal or permanent AFF. Secondary objectives are to determine: (1) the predictors of AFF in patients with PA; (2) the rate of AFF recurrence at follow-up after specific treatment in the patients with PA; (3) the effect of AFF that can increase atrial natriuretic peptide via the atrial stretch and thereby blunt aldosterone secretion, on the aldosterone-to-renin ratio (ARR), and thus the case detection of PA; (4) the diagnostic accuracy of ARR based on plasma renin activity or on the measurement of active renin (DRA) for diagnosing PA in AFF patients. Case detection and subtyping of PA will be performed according to established criteria, including the 'four corners criteria' for diagnosing aldosterone-producing adenoma. Pharmacologic or direct current cardioversion will be undertaken whenever indicated following current guidelines. The hormonal values and ARR will be compared within patient between AFF and sinus rhythm. Organ damage, cardiovascular events and recurrence of AFF will also be assessed during follow-up in patients with PA.

The Medical and Endovascular Treatment of Atherosclerotic Renal Artery Stenosis (METRAS) study: rationale and study design.

It is unclear whether revascularization of renal artery stenosis (RAS) by means of percutaneous renal angioplasty and stenting (PTRAS) is advantageous over optimal medical therapy. Hence, we designed a randomized clinical trial based on an optimized patient selection strategy and hard experimental endpoints. Primary objective of this study is to determine whether PTRAS is superior or equivalent to optimal medical treatment for preserving glomerular filtration rate (GFR) in the ischemic kidney as assessed by 99mTcDTPA sequential renal scintiscan. Secondary objectives of this study are to establish whether the two treatments are equivalent in lowering blood pressure, preserving overall renal function and regressing target organ damage, preventing cardiovascular events and improving quality of life. The study is designed as a prospective multicentre randomized, un-blinded two-arm study. Eligible patients will have clinical and angio-CT evidence of RAS. Inclusion criteria is RAS affecting the main renal artery or its major branches either >70% or, if <70, with post-stenotic dilatation. Renal function will be assessed with 99mTc-DTPA renal scintigraphy. Patients will be randomized to either arms considering both resistance index value in the ischemic kidney and the presence of unilateral/bilateral stenosis. Primary experimental endpoint will be the GFR of the ischemic kidney, assessed as quantitative variable by 99TcDTPA, and the loss of ischemic kidney defined as a categorical variable.

Progress in primary aldosteronism: present challenges and perspectives.

Primary Aldosteronism (PA) is a disorder of the adrenal zona glomerulosa (ZG) in which aldosterone secretion is increased and is relatively autonomous of normal regulatory mechanisms. A recent conference in Munich organized by Prof. Reincke addressed advances and challenges related to the screening, diagnosis, and identification of uni- and bilateral involvement of the diseased adrenal of PA. Some infrequently addressed issues are described herein. We postulate that most cases of PA are due to the activation by unknown mechanisms of subset of cells resulting in the formation of a multiple foci or nodules of hyperactive zona glomerulosa cells. This implies that one or several yet unidentified stimuli can drive aldosterone overproduction, as well as the proliferation of aldosterone-producing cells. Current diagnostic procedures allow to determine whether inappropriate aldosterone production is driven by one or both adrenal glands and thus to establish optimal treatment.

Oxidative stress-related proteins in a Conn's adenoma tissue. Relevance for aldosterone's prooxidative and proinflammatory activity.

BACKGROUND AND AIM: Angiotensin II (Ang II) induces oxidative stress (OxSt), which is essential for cardiovascular remodeling. Aldosterone also induces fibrosis and remodeling through direct effect on non-classical mineralocorticoid (MR) target tissues. However, studies on the role of aldosterone on OxSt and related factors in humans are lacking. MATERIALS AND METHODS: We assessed gene and protein expression of p22phox (RT-PCR and Western blot), NAD(P)H oxidase subunit essential for superoxide production and gene expression of transforming growth fator (TGF) beta, plasminogen activator inhibitor (PAI)-1, and heme oxygenase (HO)-1, effectors of OxSt (RT-PCR), in a Conn's adenoma, removed from a patient with primary hyperaldosteronism. Ang II type 1 (AT1R) and MR receptors expression were also evaluated (RT-PCR). The normal adrenal tissue adjacent to the adenoma was used as control. RESULTS: p22phox gene and protein expression were higher (31% and 53%, respectively) in the adrenal adenoma. TGFbeta, PAI-1, and HO-1 gene expression were also higher (25%, 129%, and 25%, respectively) in the adrenal adenoma while AT1R gene expression was similar (8%). The expression of MR in the adenoma was documented. CONCLUSIONS: This report demonstrates in a human model that the increased aldosterone production has effects on enzyme systems related to OxSt, enhancing the systemic fibrogenic effects of aldosterone excess through TGFbeta and PAI-1 expression which was previously demonstrated only indirectly in vitro and in animal models. The presence of MR expression in the adenoma may link the hormone with the adenoma growth. Therefore, the results of this study derived from a single case might represent an important working hypothesis for further research in a larger number of cases to clarify the role of aldosterone overproduction on OxSt and its clinical relevance.

Detection of EGFR and KRAS mutations on trans-thoracic needle aspiration of lung nodules by high resolution melting analysis.

BACKGROUND: EGFR and KRAS are the target genes for tumour response to epidermal growth factor receptor (EGFR) inhibitors. AIMS: To investigate EGFR and KRAS mutational status with high resolution melting (HRM) analysis applied to cytological material obtained from trans-thoracic needle aspiration (TTNA) in order to better select patients for targeted therapy. METHODS: DNA was extracted from fixed material of 108 TTNAs under CT guidance, from 108 consecutive patients. In 77 TTNAs (71.3.%) that were positive for non-small cell lung cancer, the variant in exon 21 (the missense mutation at codon 858, L858R) and the deletion in exon 19 (in frame deletion at codons 747-749) of the EGFR gene, and the point mutation in exon 2 of KRAS were investigated with HRM assay using sequencing as the reference "gold standard". RESULTS: Nine (11.7%) samples were positive for KRAS exon 2 mutations, and two (2.6%) samples were positive for the EGFR exon 21 missense mutation by HRM assay. No deletion at exon 19 for EGFR was detected by HRM analysis. All HRM results were confirmed by direct DNA sequencing. CONCLUSIONS: HRM analysis of cytological material was accurate for the detection of two major EGFR mutations and KRAS mutations in exon 2. HRM analysis was fast, easy to apply, cheap, highly reproducible, and could be used with small amounts of material, such as is obtainable with needle lavage. Therefore, it may be useful as an adjunct to the cytological report that yields valuable molecular information.

Primary aldosteronism - part I: prevalence, screening, and selection of cases for adrenal vein sampling.

Over the last few years compelling evidence has been gathered to support the view that primary aldosteronism (PA) is far more prevalent than usually held: its prevalence rate among consecutive newly diagnosed hypertensive patients referred to hypertension centers can be as high as 11.2%. Moreover, about 4.8% of cases are a surgically curable endocrine form of hypertension, and the majority of cases do not exhibit hypokalemia at the time of clinical presentation. The impact of these results on the strategy to be used in the clinical investigation of patients with hypertension is discussed in light of novel information on the optimal screening strategy to be used for pinpointing the PA patients from the vast array of hypertensive patients.

Primary aldosteronism: part II: subtype differentiation and treatment.

After discussing in Part I (Rossi et al, J Nephrol. 2008;21:447-454) the screening strategy to identify the hypertensive patients with primary aldosteronism (PA), we report here an update on the methodology for the further diagnostic work-up and treatment of PA patients. The most common forms of PA are aldosterone-producing adenoma (APA) and adrenocortical hyperplasia (BAH), which are unilateral or bilateral sources of aldosterone excess secretion, respectively. Since APA needs a surgical approach, in contrast to BAH which requires medical treatment, it is crucial to clearly delineate a diagnostic work-up aimed at discriminating the 2 forms. Clinical usefulness and accuracy of adrenal vein sampling, imaging tests (e.g., computed tomography and magnetic resonance) and mineralocorticoid adrenocortical scintigraphy are discussed in detail.

Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases.

BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.

Low plasma adiponectin is associated with coronary artery disease but not with hypertension in high-risk nondiabetic patients.

OBJECTIVE: To investigate the association of plasma adiponectin levels with coronary artery disease (CAD), arterial hypertension (HT), and insulin resistance (IR) in nondiabetic Caucasian patients. DESIGN: We measured plasma adiponectin levels, IR (HOMA index), and the CAD atherosclerotic burden (angiography-based modified Duke Index score) in 400 nondiabetic patients undergoing coronary angiography. HT was diagnosed by the European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines or if patients were on antihypertensive treatment. RESULTS: Coronary artery disease was found in 62% of the patients and ruled out in the rest (non-CAD group). Plasma adiponectin levels were inversely related to the CAD score (beta = -0.12, P = 0.029) and predicted the coronary atherosclerotic burden independent of other cardiovascular risk factors. However, they were similar in NT and HT and showed no correlation with blood pressure values. In non-CAD, but not in CAD patients, they were lower in patients with than without IR (8.3 +/- 1.2 vs. 11.3 +/- 1.3, respectively; P = 0.007). CONCLUSIONS: In nondiabetic high-risk Caucasian patients plasma adiponectin levels are inversely related to CAD severity and IR; however, they are not strongly related to blood pressure values.

Veralipride-induced acute coronary syndrome unmasking a non-secreting pheochromocytoma.

The administration of veralipride, a centrally acting dopaminergic type 2 (DA2) receptor antagonist, can decrease hot flushes and improve bone density in post-menopausal women (1). Therefore, it entails an alternative to hormone replacement therapy (HRT) in women who have contraindications to estrogen (1). We herein describe the case of a 52-yr-old lady who presented with an acute coronary syndrome shortly after taking veralipride. Based on knowledge that DA2 receptor antagonists trigger catecholamine release (2), a pheochromocytoma was suspected and thereafter diagnosed and excised. Therefore, this is the first case reporting on veralipride unmasking a silent pheochromocytoma.

Homocysteine-lowering treatment in coronary heart disease.

Homocysteine (Hcy) is a sulphur-containing amino acid product of methionine's metabolism. Hyperhomocysteinemia (HHcy) is considered an independent risk factor for cardiovascular (CV) disease, at least in high-risk patients. In fact, evidence indicates that although mild HHcy may be regarded as a minor risk factor for CHD in low-risk patients, it can play a role in triggering new events in patients with known CHD, also by interacting with the "classical" CV risk factors. This is of much interest because HHcy represents a correctable risk factor, inasmuch vitamin supplementation as has been shown to effectively lower total homocysteine plasma levels (tHcy). While case-control and cross-sectional studies have consistently demonstrated an association of HHcy with CV disease, prospective studies have given conflicting results. Moreover, the effect of the homocysteine-lowering treatment in preventing CV events is still under debate. Thus, it remains unclear which patients should be screened for HHcy and which ones should be treated to lower tHcy. In this paper we shall report and discuss knowledge on the potential role of HHcy in the development of CHD and on the benefits due to tHcy-lowering treatment with vitamins.

G protein receptors 7 and 8 are expressed in human adrenocortical cells, and their endogenous ligands neuropeptides B and w enhance cortisol secretion by activating adenylate cyclase- and phospholipase C-dependent signaling cascades.

Neuropeptides B and W (NPB and NPW) are regulatory peptides that act via two subtypes of G protein-coupled receptors, named GPR7 and GPR8. RT-PCR demonstrated the expression of these receptors in both zona glomerulosa and zona fasciculata-reticularis (ZF/R) cells of the human adrenal cortex. NPB and NPW did not affect aldosterone secretion from dispersed zona glomerulosa cells but enhanced cortisol production from ZF/R cells, NPB being more effective than NPW. NPB evoked sizable cAMP and inositol triphosphate responses from ZF/R cells, which were abrogated by the adenylate cyclase inhibitor SQ-22536 and the phospholipase C inhibitor U-73122, respectively. Cortisol response to NPB was lowered by either SQ-22536 and the protein kinase (PK) A inhibitor H-89 or U-73122 and the PKC inhibitor calphostin-C and abolished by the simultaneous exposure to H-89 and calphostin-C. NPW elicited only a rise in cAMP production from dispersed ZF/R cells, and its cortisol response was suppressed by both SQ-22536 and H-89. PreproNPB and preproNPW mRNAs were detected in human adrenal cortexes. We conclude that: 1) NPB and NPW exert a secretagogue action on human ZF/R cells, probably acting in an autocrine-paracrine manner; and 2) the effect of NPB is mediated by both the adenylate cyclase/PKA and the phospholipase C/PKC cascades, whereas that of NPW involves only the activation of the former signaling pathway.

Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA(1)c.

AIMS/HYPOTHESIS: Patients with diabetes mellitus are well known to be at high risk for vascular disease. Circulating endothelial cells (CECs) have been reported to be an ex vivo indicator of vascular injury. We investigated the presence of CECs in the peripheral blood of 25 patients with diabetes mellitus and in nine non-diabetic control donors. METHODS: Endothelial cells were isolated from peripheral blood with anti-CD-146-coated immunomagnetic Dynabeads, and were stained with acridine orange dye and counted by fluorescence microscopy. The cells were also stained for von Willebrand factor and Ulex europaeus lectin 1. RESULTS: Patients with diabetes mellitus had an elevated number of CECs (mean 69+/-30 cells/ml, range 35-126) compared with healthy controls (mean 10+/-5 cells/ml, range 3-18) (p<0.001). The increase in CECs did not correlate with the levels of HbA(1)c. Circulating endothelial cell numbers were elevated regardless of glucose levels, suggesting that, even with control of glucose levels, there is increased endothelial cell sloughing. CONCLUSIONS: Our study suggests that the higher number of CECs in patients with type 2 diabetes may reflect ongoing vascular injury that is not directly dependent on glucose control.

Emergency system prospective performance evaluation for cardiac arrest in Lombardia, an Italian region.

BACKGROUND: The aim of this research is to evaluate quality of out-of-hospital medical services in our country, using performance indicators and a new computerised database. METHODS: (a) EXPERIMENTAL DESIGN: Data were collected prospectively in three emergency dispatch centres for 90 days. Follow-up was evaluated at 1 day and 1 month after the event. This paper presents data on the cardiac arrest cohort only. (b) SETTING: Three emergency dispatch centres in Lombardia. (c) PATIENTS: One hundred and seventy-eight patients in non-traumatic cardiac arrest were enrolled. (d) INTERVENTIONS: None. The study was observational only. RESULTS: Mean interval between phone call and arrival on scene was 8.5+/-3.5 min. BLS manoeuvres were carried out from bystanders only in 15% of the cohort; this was associated with significant mortality reduction (85.7 versus 95.8%, chi(2) P<0.05). One hundred and thirty-three patients (75%) received assistance from BLS crews while only 45 patients (25%) were assisted by ALS medical personel, with a significant mortality reduction (ALS deaths 86.7%, BLS deaths 97%). Total 24 h survival was 9% and survival at 1 month declined to 6.17%. CONCLUSIONS: Quality monitoring produces objective information on interventions and outcomes. Only with this information, is it possible to implement improvement programmes that are planned according to the data presented.