Professor Antonio Salvetti passed away on 18 February 2021, at the age of 84 years. We express our deepest condolences to his wife, children and grandchildren. Professor Salvetti was born in Lerici, a village at the border between Liguria and Tuscany, on 4 December 1936. He obtained his medical degree at the University of Pisa in 1960 and the Postgraduate Speciality in Cardiology at the University of Turin, 2 years later. After completing his studies, he was immediately asked to join the staff of the Division of Internal Medicine of the Medical School and the Santa Chiara Hospital of the University of Pisa, which was then under the Chairmanship of Professor Fabio Tronchetti. In that Division, he has worked for his entire academical carrier, starting as a young ‘voluntary’ assistant and climbing all steps of the academical ladder up to the position of Full Professor of Medical Therapy in 1984 and then Full Professor of Internal Medicine in 1990. Over his long and productive clinical, teaching and scientific activity, he was appointed Director of the Department of Internal Medicine (2000–2008), Director of the Postgraduate School of Internal Medicine, Director of the Division of General Medicine of the newly formed Azienda Ospedaliero-Universitaria Pisana and Director of the Hospital Department of Medicine from 2001 to his retirement in 2007. Antonio Salvetti was an expert clinician, which made him a reference figure among the hospital doctors when help was needed to resolve difficult clinical cases. However, there is no question that his clinical and scientific preference was directed, since almost the beginning of his carrier, to hypertension where he achieved national and international recognition. In 1980, Professor Salvetti founded the Center for Diagnosis and Treatment of Hypertension, which over the years became a Regional Reference Center and a European Excellence Center for the Diagnosis and Treatment of this condition, being ranked fourth among all European Hypertension Centers for the quality of scientific research. He was a founding member of the Italian Society of Nephro-Cardiology and of the Italian Society of Hypertension for which he served for several years first as Secretary and then as President. He was part of the group, which decades ago gave birth to the World Hypertension League, translating into reality an idea of professor Bartorelli from Milan and Dr Strasser from WHO. He received the Award of the Italian Society of Hypertension for excellence in research on hypertension in 2000 and was awarded in 2007, the prestigious Cherubino Honor for scientific merits by the University of Pisa. He was also appointed Professor Emeritus of the University of Cordoba (Argentina) in 2001. He has often been an invited lecturer at international Meetings on hypertension, those organized by the International and the European Societies of Hypertension, in particular. The sharpness and directness of his criticism made him an especially desired participant in debates, which the audience enjoyed very much. The scientific interests of Professor Salvetti covered the pathogenetic mechanisms of arterial hypertension, with special attention to the role of the renin--angiotensin system, the endothelial dysfunction and the vascular and cardiac structural alterations related to this disease. Many of his observations were pioneering at the time they were made, as also testified by publication of his articles (over 400) in prestigious international peer-reviewed journals. Professor Antonio Salvetti was a person of great scientific and clinical knowledge and depth of thinking. In the fields he was involved with as an investigator, he was a forerunner and exhibited a translational approach that always aimed at finding a relationship between clinical investigations in humans and experimental models of hypertension. His passion for medical research was contagious and passed onto many medical students and colleagues. At clinical level, he blended his wide medical culture with daily clinical practice, in which he displayed the ability to listen and interpret the patient symptoms, ultimately resulting in precise diagnoses and tailored therapeutic decisions. Nothing was ever left to chance by him when patients were involved, and above all, every decision had to be substantiated by solid clinical and scientific evidence. Professor Salvetti was not known to be an easily approachable person, and people were sometimes a bit disconcerted by his competitiveness and directness. Behind the appearance, however, he was a very generous man, ready to understand the problems of those who turned to him and to help them whenever this was possible. He had three great passions: family, work and sport. He considered the sport as a serious affair on which to translate his view of work as something requiring the best of yourself and all efforts to win the confrontation. However, he used in sport what he did in life, that is, the moral values of loyalty, sincerity and extreme correctness. There is no doubt that Antonio Salvetti has been an example, a leader and a teacher to people around him. Not only he introduced the study of arterial hypertension in Pisa, founding one of the most important clinical hypertension centers in Italy, but he was able to create a stimulating scientific environment for his young collaborators, providing them with the opportunity to fully exploit their clinical and research potentialities. Although he has left us, the cultural and scientific heritage he was able to create will not be lost.ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men (P<0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P=0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications (P<0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P<0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01234220.

Absolute blood pressure (BP) values are not the only causes of adverse cardiovascular consequences. BP variability (BPV) has also been demonstrated to be a predictor of mortality for cardiovascular events; however, its determinants are still unknown. This study considers 426 subjects with ambulatory BP monitoring (ABPM) measuring 24-h, diurnal and nocturnal absolute BP values and their standard deviations of the mean, along with nocturnal fall, age, sex and current treatment. Patients were divided in two subgroups, controlled and uncontrolled BP, and BPV of patients with "true" and "false" resistant hypertension was also analyzed. Nocturnal and 24-h BPV were higher in the group with uncontrolled hypertension. Multiple regression analysis showed that absolute BP, age, nocturnal fall, but not sex predicted BPV. Patients with "true" resistant hypertension had greater BPV than "false" resistant hypertension patients. Absolute BP resulted as the main determinant of 24-h and nocturnal BPV but not daytime BPV. Also nocturnal BP fall and age resulted as predictors of BPV in treated and untreated patients. Patients with "true" resistant hypertension have a higher BPV, suggesting a higher sympathetic activation. Evidence is still limited regarding the importance of short-term BPV as a prognostic factor and assessment of BPV cannot yet represent a parameter for routine use in clinical practice. Future prospective trials are necessary to define which targets of BPV can be achieved with antihypertensive drugs and whether treatment-induced reduction in BPV is accompanied by a corresponding reduction in cardiovascular events.

Background and aims: The independent role of serum uric acid (SUA) as a marker of cardio-renal risk is debated. The aim of this study was to assess the relationship between SUA, metabolic syndrome (MS), and other cardiovascular (CV) risk factors in an Italian population of hypertensive patients with a high prevalence of diabetes.Methods and results: A total of 2429 patients (mean age 62 +/- 11 years) among those enrolled in the I-DEMAND study were stratified on the basis of SUA gender specific quartiles. MS was defined according to the NCEP-ATP III criteria, chronic kidney disease (CKD) as an estimated GFR (CKD-Epi) < 60 ml/min/1.73 m(2) or as the presence of microalbuminuria (albumin-to-creatinine ratio >= 2.5 mg/mmol in men and >= 3.5 mg/mmol in women).The prevalence of MS, CKD, and positive history for CV events was 72%, 43%, and 20%, respectively. SUA levels correlated with the presence of MS, its components, signs of renal damage and worse CV risk profile. Multivariate logistic regression analysis revealed that SUA was associated with a positive history of CV events and high Framingham risk score even after adjusting for MS and its components (OR 1.10, 95% CI 1.03-1.18; P = 0.0060; OR 1.28, 95% CI 1.15-1.42; P < 0.0001). These associations were stronger in patients without diabetes and with normal renal function.Conclusions: Mild hyperuricemia is a strong, independent marker of MS and high cardio-renal risk profile in hypertensive patients under specialist care. Intervention trials are needed to investigate whether the reduction of SUA levels favorably impacts outcome in patients at high CV risk. (C) 2014 Elsevier B.V. All rights reserved.

Objective: Aldosterone exerts detrimental cardiovascular effects, and patients with an aldosterone-producing adenoma (APA) carrying somatic mutations in the KCNJ5 K+ channel (mutAPA) have higher plasma aldosterone concentration than wild-type APA (wtAPA) patients. We therefore investigated whether mutAPA patients develop a more prominent cardiovascular damage than wtAPA patients.Methods and findings: From 257 consecutive primary aldosteronism patients, we identified 176 who had both a diagnosis of APA by the 'four corners' criteria and high-quality echocardiographic data. Of them, 129 with KCNJ5 sequencing information and long-term follow-up data were compared for echocardiographic changes according to presence (mutAPA, 26%) or absence (wtAPA, 74%) of the KCNJ5 mutations. At baseline, the mutAPA were similar to the wtAPA for blood pressure (BP) and need for antihypertensive medications. However, they had higher left ventricular mass index (59 +/- 19 vs. 51 +/- 13 g/h(2.7); P< 0.05) and plasma aldosterone concentration [49 (32-68) vs. 36 (25-52) ng/dl); P = 0.048] than the wtAPA patients. In spite of their more prominent cardiac involvement, the mutAPA patients exhibited a fall of BP and plasma aldosterone similar to wtAPA, and a regression of left ventricular mass index.Conclusions: Compared to the wild-type APA patients those with KCNJ5 mutations showed more prominent cardiovascular damage. Notwithstanding this, their chances of being cured from the hyperaldosteronism and the high BP, and of regression of left ventricular hypertrophy after adrenalectomy, were not compromised by the presence of these mutations.

OBJECTIVE:Injury of vascular endothelium, crucial in vascular disease, is repaired via circulating endothelial progenitor cells (cEPCs). In hypertension, cEPCs number is reduced and function impaired adding further risk for cardiovascular (CV) events. Angiotensin II (Ang II)-induced oxidative stress (OxSt), accelerates cEPCs senescence. Calcitonin gene-related peptide (CGRP), able to prevent and reverse Ang II-induced cEPCs senescence, is reduced in hypertension and stimulated by the antioxidant and anti-inflammatory heme oxygenase (HO)-1. In essential hypertensive patients olmesartan reduced OxSt and markers of CV remodeling and increased HO-1. This study reports in essential hypertensive patients the effect of 6 months treatment with olmesartan on plasma level of CGRP and number and survival of cEPCs. METHODS AND RESULTS:In 20 essential hypertensive patients treated with olmesartan medoxomil (20  mg per day for 6 months), cEPCs (CD34(+)KDR(+), CD133(+)KDR(+) and CD34(+)CD133(+)KDR(+)) (direct 3-color flow cytometry analysis), apoptosis of cEPCs (CD133(+)KDR(+) cells with Annexin V expression), CGRP determination (ELISA) and HO-1 protein level (western blot) were assessed at baseline and after 3 and 6 months of treatments. Olmesartan normalized blood pressure (P < 0.001), increased cEPCs from baseline (CD34(+)KDR(+): P < 0.003; CD133(+)KDR(+): P < 0.0002; CD34(+)CD133(+)KDR(+): P = 0.0008), reduced cEPCs apoptosis (P < 0.001) and increased CGRP (P < 0.013) and HO-1 (P = 0.039). CONCLUSION:These results provide a mechanistic rationale for the olmesartan's antioxidant and anti-inflammatory potential translation toward antiatherosclerotic and antiremodeling effects reported on clinical ground.

A young patient presented with a history of resistant arterial hypertension, associated with disabling symptoms. He was subjected to an enormous number of tests to identify a pheochromocytoma that was never found. He was eventually discovered to make factitious use of amphetamine to mimic this condition in order to gain medical attention. Munchausen syndrome was thus diagnosed. The patient was discharged and was lost to follow-up until he presented again in 2012 for 'resistant hypertension' in our outpatient clinic. He reported that because of poor blood pressure, he had been referred to a Cardiology department where transcatheter renal denervation was performed with no effect on blood pressure. Thereafter, he was presented to an Endocrinology unit where a left adrenalectomy was performed with diagnosis of pheochromocytoma that was not found at pathology.Munchausen syndrome is a rare psychiatric condition that leads affected patients to cause intentionally signs and symptoms of an illness or injury by inflicting medical harm to their body to attract the attention of the physician and get admission to the hospital.To our knowledge, this is the first case of causing drug-resistant hypertension and leading to unnecessary renal denervation and adrenalectomy.

Hypothesis: The detection of prorenin in plasma of patients with Primary Aldosteronism (PA) suggests that prorenin plays a pathophysiologic role in PA by acting via the Pro-Renin Receptor (PRR). We therefore sought for the presence of the PRR in the normal human zona glomerulosa (ZG) and in aldosterone producing adenoma (APA), and investigated the functional response of PRR activation by prorenin on ERK1/2 phosphorylation in an adrenocortical cell line. Methods and Results: Expression levels of PRR gene were 15- and 12-fold higher than those of the housekeeping gene PBGD in the normal human adrenal cortex (n=8) and in the APAs (n=11), respectively. Similar high expression levels were found in the the H295R and HAC15 cells. The PRR protein expression was confirmed by immunohistochemistry in the human and rat normal ZG, as well as in a pure population of APA cells obtained with an immunoseparation-based technique specifically targeted to the membrane CD56. Immunoblotting, confocal and immuno-gold electron m...

Primary aldosteronism (PA), a common cause of high blood pressure (BP), induces left ventricular (LV) hypertrophy and an excess rate of cardiovascular events. Whether its treatment provides long-term cure of hypertension and regression of cardiovascular damage remains uncertain. To the aim of assessing the effect of treatment of PA on BP and LV changes, we prospectively recruited 323 patients in a long-term follow-up study entailing serial echocardiography evaluations. Of them, 180 had PA and were assigned to either adrenalectomy (n=110) or medical therapy (n=70) on the basis of the adrenal vein sampling. The remaining 143 were consecutive optimally treated primary hypertensive patients. At baseline, the PA patients had more inappropriate LV mass than PH patients (27.1% versus 16.2%; P=0.020), despite similar BP values. At a median follow-up of 36 months (range, 6-225), BP was lowered (P<0.0001 versus baseline) to similar values in adrenalectomized (135±15/83±9 mm Hg), medically treated PA (133±11/83±7 mm Hg), and PH (139±15/86±9 mm Hg) patients. To this end, the adrenalectomized patients required significantly less drugs than the other groups. In PA patients, the LV mass index and the rate of LV hypertrophy fell through LV inward remodeling to the level of optimally treated PH patients, indicating that the LV work markedly decreased. Findings were similar when long-term (≥5 and ≥10 years) data were examined. Thus, an early diagnosis and a specific treatment of PA warrant normalization of BP and reversal of detrimental LV changes at long term.

HomeHypertensionVol. 62, No. 4Effectiveness of Adrenalectomy and Aldosterone Antagonists for Long-Term Treatment of Primary Aldosteronism Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEffectiveness of Adrenalectomy and Aldosterone Antagonists for Long-Term Treatment of Primary Aldosteronism Norman Kaplan Norman KaplanNorman Kaplan Hypertension, Division Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas Search for more papers by this author Originally published5 Aug 2013https://doi.org/10.1161/HYPERTENSIONAHA.113.01754Hypertension. 2013;62:e13Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 To the Editor:The data published by Rossi et al1 provide additional evidence for the well-established efficacy of mineralocorticoid receptor (MR) blockers for the treatment of autonomous hyperaldosteronism whether caused by an aldosterone-producing adenoma or bilateral adrenal hyperplasia.2 The data are interpreted as showing a better outcome for adrenalectomy for patients with an aldosterone-producing adenoma than for MR blocker therapy for those with bilateral adrenal hyperplasia in the provision of a cure (42% versus 0) and the number of antihypertensive drugs needed for the long-term control of hypertension (1.76 versus 2.73).However, at follow-up the adrenalectomized aldosterone-producing adenoma patients had a high prevalence of inappropriate left ventricular hypertrophy, as did the MR blocker–treated patients with bilateral adrenal hyperplasia (49.5% versus 50.8%).Because such inappropriate left ventricular hypertrophy has been shown to be associated with an increase in cardiovascular events,3 the superiority of surgery over medical therapy remains unproven, despite the statement that their data “might suggest the superiority of adrenalectomy over medical therapy in regressing left ventricular hypertrophy.”1Rossi et al also state that their “results provide an explanation for the improved prognosis of those submitted to adrenalectomy,” quoting the results of observational study of mortality by Reinke et al in treated primary aldosteronism.4 However, in the study of Reinke et al, 47% had adrenalectomy and 53% were treated medically with no indication of a superiority of either mode of treatment.In addition, the data of Rossi et al shown in Figures 1 and 4 of continued increases in atrial fibrillation in the treated patients suggest that relief of autonomous hyperaldosteronism does not provide protection against this bothersome complication.In the larger scenario, Funder5 has shown the inadequacy of the current evaluation and treatment of primary aldosteronism as practiced by Rossi et al, stating that “We do not have the resources to diagnose primary aldosteronism but we have the ability to treat it,” alluding to the routine use of MR blockers in all hypertensive patients.The need for adequately managing all patients who have primary aldosteronism, 11.2% of the referred patients seen by Rossi et al, imposes an impossible burden on both practitioners and patients. The adoption of Funder’s recommendation provides a probable solution. Moreover, the current management, including aldosterone:renin ratios, confirmatory suppression testing, adrenal venous sampling, and laparoscopic adrenalectomy, costs ≈$32 000 in our setting, whereas the cost of MR blocker therapy is $40 per year. Both money and complications can be saved by routine use of MR blockers as advocated by Funder5 and further documented by Rossi et al.1Norman KaplanHypertensionDivision Department of Internal MedicineUniversity of Texas Southwestern Medical Center at DallasDisclosuresNone. References 1. Rossi GP, Cesari M, Cuspidi C, Maiolino G, Cicala MV, Bisogni V, Mantero F, Pessina AC. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism.Hypertension. 2013; 62:62–69.LinkGoogle Scholar2. Colussi G, Catena C, Sechi LA. Spironolactone, eplerenone and the new aldosterone blockers in endocrine and primary hypertension.J Hypertens. 2013; 31:3–15.CrossrefMedlineGoogle Scholar3. Muiesan ML, Salvetti M, Paini A, Monteduro C, Galbassini G, Bonzi B, Poisa P, Belotti E, Agabiti Rosei C, Rizzoni D, Castellano M, Agabiti Rosei E. Inappropriate left ventricular mass changes during treatment adversely affects cardiovascular prognosis in hypertensive patients.Hypertension. 2007; 49:1077–1083.LinkGoogle Scholar4. Reincke M, Fischer E, Gerum S, et al; German Conn’s Registry-Else Kröner-Fresenius-Hyperaldosteronism Registry. Observational study mortality in treated primary aldosteronism: the German Conn’s registry.Hypertension. 2012; 60:618–624.LinkGoogle Scholar5. Funder JW. Ultimately we are in furious agreement.J Hypertens. 2012; 30:1903–1905.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 2013Vol 62, Issue 4 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.113.01754PMID: 23918755 Originally publishedAugust 5, 2013 PDF download Advertisement SubjectsHypertension

Objective:The presence of microalbuminuria is related to renal, cardiac and cerebral organ damage and is considered to be an early sign of Arterial Hypertension.Cystatin C (CC), inhibitor of proteases, eliminated for glomerular filtration, reabsorption and degradation of the tubular cells de, can represent an excellent and sensible plasmatic marker of the speed of the glomerular filtration and can be considered as an early marker of organ damage in hypertensive patients, even earlier than microalbuminuria (MA).Methods: We examined first 70 patients (40 males and 30 females), non-smokers, who presented at our practice in the period of 30 days, aged 45-65 with a 2 year verified history of arterial hypertension, with no history of diabetes and with negative family and personal history of cardiovascular disease, with normal levels of ematic lipids.They underwent hematochemical examinations (as per the guide 2003) and also Cystatin C (done with a nephelometric method BNA II and value between 0.53 and 0.95 mg/I), had an Echo-Doppler supra-aortic trunks and electrocardiogram.Results: All patients have normal values of microalbuminuria, glycaemia and normal creatinine clearance.35 patients (20 males and 15 females) have a medium increase of CC over 1,2+/-0,2; from these 20 (18 males and 2 females) presented an increase of medio-intimal thickening >0,9 mn (mean average 1,2) and 15 (9 males and 6 females) IVS with an indicator of left ventricular mass >110gr/m 2 for females and 125gr/m 2 for males.Conclusion: Cystatin C can be considered an early economic and sensible marker of cardiac and cerebral organ damage.It is not influenced by age, sex, weight, muscular masses, inflammatory states or by anything else so its increase should push us to investigate and evaluate the state of the heart, brain, kidneys and vases in hypertensive patients.We are evaluating the behaviour of CC in follow-up of these patients and if it can be used as an indicator of the evolution of the verified organ damage.

CASE REPORT:A young patient presented with a history of resistant arterial hypertension, associated with disabling symptoms. He was subjected to an enormous number of tests to identify a pheochromocytoma that was never found. He was eventually discovered to make factitious use of amphetamine to mimic this condition in order to gain medical attention. Munchausen syndrome was thus diagnosed. The patient was discharged and was lost to follow-up until he presented again in 2012 for 'resistant hypertension' in our outpatient clinic. He reported that because of poor blood pressure, he had been referred to a Cardiology department where transcatheter renal denervation was performed with no effect on blood pressure. Thereafter, he was presented to an Endocrinology unit where a left adrenalectomy was performed with diagnosis of pheochromocytoma that was not found at pathology.DISCUSSION:Munchausen syndrome is a rare psychiatric condition that leads affected patients to cause intentionally signs and symptoms of an illness or injury by inflicting medical harm to their body to attract the attention of the physician and get admission to the hospital.CONCLUSION:To our knowledge, this is the first case of causing drug-resistant hypertension and leading to unnecessary renal denervation and adrenalectomy.

Objective:p63RhoGEF, a guanine nucleotide exchange factor, has been reported in vitro' as key mediator of the angiotensin II-induced RhoA/Rho kinase activation leading to vasoconstriction and cardiovascular remodeling. We assessed p63RhoGEF gene and protein expression and RhoA/Rho kinase activity in essential hypertensive and Bartter's and Gitelman's syndrome patients, a human model opposite to hypertension; the latter have, in fact, increased plasma angiotensin II, activation of the renin-angiotensin system, yet normotension/hypotension, reduced peripheral resistance and lack of cardiovascular remodeling due to an endogenously blunted angiotensin II type 1 receptor signaling.Methods:Mononuclear cell p63RhoGEF gene and protein expression and the phosphorylation status of the myosin phosphatase target protein-1 (MYPT-1), marker of Rho kinase activity, were assessed in essential hypertensive patients, Bartter's/Gitelman's patients and healthy individuals by quantitative real-time PCR and western blot.Results:p63RhoGEF mRNA and protein level and MYPT-1 phosphorylation status were higher in hypertensive patients and lower in Bartter's/Gitelman's patients compared with healthy individuals: p63RhoGEF mRNA level: 0.590.17 Ct vs. 0.37 +/- 0.17 vs. 0.20 +/- 0.19, analysis of variance (ANOVA): P<0.016; p63RhoGEF protein level 1.35 +/- 0.14 vs. 1.09 +/- 0.05 vs. 0.90 +/- 0.09 densitometric units, ANOVA: P<0.0001; MYPT-1: 1.39 +/- 0.34 vs. 1.01 +/- 0.12 vs. 0.81 +/- 0.06, ANOVA: P<0.0001. p63RhoGEF mRNA was significantly correlated with both SBP and DBP in both hypertensive patients (R=0.79, P<0.02 and R=0.78, P<0.02) and in Bartter's syndrome/Gitelman's syndrome patients (R=0.87, P<0.001 and R=0.86, P<0.001), respectively.Conclusion:Increased p63RhoGEF mRNA and protein level and Rho kinase activity are shown for the first time in essential hypertensive patients, whereas the opposite was found in Bartter's/Gitelman's patients, a human model opposite to hypertension. These results combined with other in-vitro' studies strongly support the crucial importance of p63RhoGEF in Ang II-mediated signaling involved in the regulation of blood pressure and its long-term complications in humans.

Aldosterone exerts detrimental cardiovascular (CV) effects, and aldosterone producing adenoma (APA) patients carrying somatic mutations in the KCNJ5 K+ channel (mutAPA) have higher plasma aldosterone concentration (PAC) than those wild-type (wtAPA). We therefore investigated whether mutAPA patients develop a more prominent CV and renal damage than wtAPA patients. From 250 consecutive PA patients, we identified 170 who had a diagnosis of APA by the 'four corners' criteria and high-quality echocardiographic data. Of them 106 with KCNJ5 sequencing information and long-term follow-up data could be compared for echocardiographic changes and eGFR (by CKD-EPI equation) according to presence (mutAPA, 18.8%) or absence (wtAPA, 81.2%) of the KCNJ5 mutations. At baseline the mutAPA had lower eGFR (75±29 ml/min vs 84±20, p<0.05), and higher left ventricular mass index (LVMI, 61.9±21.4 mg/h2.7vs 49.5±11.3, p=0.001), PAC (48.9 [37.4-77.1] ng/dl vs 37.0 [24.9-48.5]), <0.0001), aldosterone-renin-ratio (ARR, 173.5 [92.2-229.6] ng/dl/ng/ml/h vs 144.3 [69.9-252.1], <0.0001), than the wtAPA patients. They were similar for blood pressure (BP) and need for antihypertensive medications. After adrenalectomy BP, PAC, ARR, and LVMI normalized in all groups, with no difference between mutAPA vs wtAPA. Compared to the wild-type APA patients those with KCNJ5 mutations showed more prominent cardiovascular and renal damage, likely because of the higher PAC. However, the presence of these mutations did not compromise the chances of being cured from the hyperaldosteronism and the high blood pressure, or the regression of LVMI after adrenalectomy.

Background: The parathyroid hormone (PTH) stimulates aldosterone secretion and cell proliferation in human adrenocortical cells; moreover, in rats hyperaldosteronism was associated with hyperparathyroidism. Hence, PTH could drive aldosterone excess in human primary aldosteronism. Method: To test this hypothesis, we recruited 105 consecutive hypertensive patients, of whom 44 had primary aldosteronism due to an aldosterone-producing adenoma (APA) and 61 had primary (essential) hypertension. We measured the plasma levels of (1-84)-PTH, 25(OH)D, 1,25(OH)2D, and serum Ca2+ (total and ionized), inorganic P, Mg2+, K+, and the 24-h urinary excretion of Ca2+, P, and deoxypyridinoline. In primary aldosteronism patients, these measurements were repeated after adrenalectomy or mineralocorticoid receptor blockade. We also sought for PTH receptor (PTHR-1) mRNA and protein in APA tissue. Results: Compared with primary (essential) hypertension patients, those with primary aldosteronism showed significantly higher plasma PTH (+31%), despite comparable urinary Ca2+ excretion and similarly deficient 25(OH) vitamin D levels. In APA patients, who showed the PTHR-1 transcript and protein in tumor tissue, adrenalectomy normalized PTH levels (from 118 ± 13 to 76 ± 12 ng/l; P = 0.002) and increased ionized Ca2+(from 1.17 ± 0.04 to 1.22 ± 0.03 mmol/l; P < 0.001). The slope of the inverse PTH/ionized Ca2+ relationship was steeper in primary aldosteronism than in primary (essential) hypertension, but normalized after adrenalectomy. Conclusion: Hence, in primary aldosteronism an increased sensitivity of parathyroid cells to Ca2+ lowering leads to an increase of PTH. This subtle hyperparathyroidism by acting on PTHR-1 in APA might contribute to maintaining hyperaldosteronism despite suppression of angiotensin II formation.

BACKGROUNDA stress reaction involving increased cortisol release, which has not been documented thus far, might affect the assessment of selectivity of catheterization during adrenal venous sampling (AVS).OBJECTIVETo investigate whether an ACTH-driven cortisol release occurs during AVS and whether it influences the assessment of selectivity by the step-up of cortisol (plasma cortisol concentrations, PCC) between the adrenal vein blood (PCC(SIDE)) and the inferior vena cava (PCC(IVC)), e.g. the selectivity index (SI).DESIGN AND METHODSWe determined the SI in samples obtained simultaneously at starting AVS (t-15) and again after 15  min (t0) in 34 consecutive patients with proven aldosterone-producing adenoma. We then calculated the SI with PCC(SIDE) obtained at t-15 and at t0, and the PCC(IVC) values obtained at the different time point, thus simulating sequential AVS.RESULTSThe PCC(SIDE) and the SI fell significantly from t-15 to t0 on both the sides. When PCC(SIDE) obtained at t-15 was combined with PCC(IVC) at t0, the SI values were higher than those obtained with simultaneously drawn samples. This led to label as selective more AVS studies than with bilaterally simultaneous data, especially when using higher cutoffs for the SI.CONCLUSIONSA transient increase in cortisol release from both adrenal glands occurs in the majority of the patients who undergo AVS. This stress reaction can influence the assessment of both the selectivity of the catheterization during the sequential AVS technique and the lateralization of aldosterone excess.

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.

Revascularization for atherosclerotic renal artery stenosis: another flawed son of the ASTRAL Study