Clinical Outcomes of 1625 Patients With Primary Aldosteronism Subtyped With Adrenal Vein Sampling.

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.

Gluten-Free Diet and Lipid Profile in Children With Celiac Disease: Comparison With General Population Standards.

OBJECTIVES: A gluten-free diet (GFD) may carry high energy and fat load. We verified lipid profile and dietary indicators cross-sectionally and prospectively in patients with celiac disease (CD). METHODS: In any consecutive child receiving a GFD (group 1) or newly diagnosed as having CD (group 2), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), anthropometric data, physical activity, and a 24-hour food diary were collected during follow-up visits (yearly in group 1 and during the first year of GFD in group 2). RESULTS: In group 1 (132 girls, 73 boys, 10.7 ±â€Š4.2 years), TC (P = 0.006), TG (P = 0.014), and HDL (P = 0.019) were significantly higher in girls than in boys. Compared with the general pediatric population, group 1 girls had higher TC, TG, HDL, and low-density lipoprotein; group 1 boys had lower TC, TG, and low-density lipoprotein and higher HDL. TC was significantly and positively affected by age, sex, and time receiving GFD, whereas HDL was significantly and positively affected by body mass index, diastolic BP, and sex; TG was negatively affected by diastolic BP. Compared with recommendations, group 1 children introduced less calories, iron, and calcium; one-third more sodium; similar amounts of fiber; and twice as many proteins. In group 2 (20 girls, 10 boys, 8.6 ±â€Š3.55 years), TC did not change over time and TG diminished, whereas HDL, blood glucose, and body mass index increased; saturated fats and caloric intake were below recommendations, whereas proteins were excessively introduced. Fibers were optimal. HDL was inversely correlated to calories and saturated fat (R²â€Š= 80, P = 0.011). CONCLUSIONS: Lipid profiles of children with CD differ across sexes and from reference population. GFD, being unexpectedly appropriate in fibers and fat proportion, may be a contributor.

Systolic and diastolic short-term blood pressure variability and its determinants in patients with controlled and uncontrolled hypertension: a retrospective cohort study.

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.

KCNJ5 gene somatic mutations affect cardiac remodelling but do not preclude cure of high blood pressure and regression of left ventricular hypertrophy in primary aldosteronism.

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.

Increased level of p63RhoGEF and RhoA/Rho kinase activity in hypertensive patients.

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: 0.59 ± 0.17 ΔΔCt 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.

Effect of olmesartan medoxomil on number and survival of circulating endothelial progenitor cells and calcitonin gene related peptide in hypertensive patients.

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.

Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism.

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.

Munchausen syndrome: a novel cause of drug-resistant hypertension.

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.

A stress reaction affects assessment of selectivity of adrenal venous sampling and of lateralization of aldosterone excess in primary aldosteronism.

BACKGROUND: A 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). OBJECTIVE: To 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 METHODS: We 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. RESULTS: The 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. CONCLUSIONS: A 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.

Mild hyperparathyroidism: a novel surgically correctable feature of primary aldosteronism.

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 Ca (total and ionized), inorganic P, Mg, K, and the 24-h urinary excretion of Ca, 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 Ca 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 ±â€Š13 to 76 ±â€Š12 ng/l; P = 0.002) and increased ionized Ca(from 1.17 ±â€Š0.04 to 1.22 ±â€Š0.03 mmol/l; P < 0.001). The slope of the inverse PTH/ionized Ca 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 Ca 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.

Uncontrolled hypertension: highlights and perspectives from the European Society of Hypertension Satellite Symposium.

The Padua ESH 2011 Satellite Symposium on uncontrolled hypertension was focused on why only a relatively small percentage of patients under treatment do not reach 'safe' blood pressure levels; the major reason being the modest use of combination therapy. It was also an occasion to discuss new pharmacological and nonpharmacological tools, some of which appear to be efficacious when even the 'appropriate' traditional therapeutic strategy fails to work.

Drug-related hypertension and resistance to antihypertensive treatment: a call for action.

Several drugs can cause hypertension and/or blunt the effect of antihypertensive treatment. They can exacerbate a previously well controlled hypertension and/or render it resistant to therapy. Accordingly, drugs represent a common cause of resistance of hypertension to treatment. Identification of drug-related hypertension can be achieved with a thorough medical history targeted to ascertain concurrent therapies that are prescribed for conditions other than cardiovascular diseases. This can avoid prescribing a more aggressive antihypertensive treatment and may prevent embarking in costly and sometimes invasive diagnostic procedures. Drugs that commonly raise blood pressure include NSAIDs, steroids, oestroprogestinic agents, immunosuppressants, erythropoietin, inhibitors of angiogenesis, anti-HIV agents, and also some high-density lipoprotein-raising agents. As withdrawal of the offending drug is often impracticable, knowledge of the mechanism(s) by which each drug exerts its pressor effects may help selecting the most effective treatment. Purpose of this review is to examine the most common causes of resistant hypertension that are due to drugs or abuse of substances along with their underlying pathophysiological mechanisms. The strategy for selecting the most appropriate treatment and the reasons for 'a call of action' of research in this area are also examined.

PLCß1-SHP-2 complex, PLCß1 tyrosine dephosphorylation and SHP-2 phosphatase activity: a new part of Angiotensin II signaling?

BACKGROUND: Angiotensin II (Ang II) signaling occurs via two major receptors which activate non-receptor tyrosin kinases that then interact with protein tyrosin-phosphatases (PTPs) to regulate cell function. SHP-2 is one such important PTP that also functions as an adaptor to promote downstream signaling pathway. Its role in Ang II signaling remains to be clarified. RESULTS: Using cultured normal human fibroblasts, immunoprecipitation and western blots, we show for the first time that SHP-2 and PLCß1 are present as a preformed complex. Complex PLCß1 is tyr-phosphorylated basally and Ang II increased SHP-2-PLCß1 complexes and caused complex associated PLCß1 tyr-phosphorylation to decline while complex associated SHP-2's tyr-phosphorylation increased and did so via the Ang II type 1 receptors as shown by Ang II type 1 receptor blocker losartan's effects. Moreover, Ang II induced both increased complex phosphatase activity and decreased complex associated PLCß1 tyr-phosphorylation, the latter response required regulator of G protein signaling (RGS)-2. CONCLUSIONS: Ang II signals are shown for the first time to involve a preformed SHP-2-PLCß1 complex. Changes in the complex's PLCß1 tyr-phosphorylation and SHP-2's tyr-phosphorylation as well as SHP-2-PLCß1 complex formation are the result of Ang II type 1 receptor activation with changes in complex associated PLCß1 tyr-phosphorylation requiring RGS-2. These findings might significantly expand the number and complexity of Ang II signaling pathways. Further studies are needed to delineate the role/s of this complex in the Ang II signaling system.

Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling.

Angiotensin II (Ang II) is essential for endothelial progenitor cells (EPCs) function as Ang-II-induced oxidative stress causes senescence of EPCs and endothelial dysfunction and Ang II type 1 receptor blockers increase EPCs. Moreover, EPCs activity is dependent on nitric oxide (NO) and heme oxygenase (HO)-1 as these correlate with EPCs senescence and are reduced in hypertensives. Bartter's/Gitelman's syndrome patients (BS/GS), have increased Ang II yet normo/hypotension along with blunted Ang II signaling, reduced oxidative stress, increased NO and HO-1, thus presenting a unique system to explore EPC biology and its relationship with vascular clinical and biochemical correlates. Circulating EPCs, NO-dependent vasodilation (flow-mediated dilation (FMD)) and HO-1 gene expression were characterized in 10 BS/GS patients and in 10 normotensive subjects. EPCs defined by cell surface antigens CD34+kinase-insert domain receptor (KDR+), CD133+KDR+ and CD133+CD34+KDR+ cells were quantitiated via direct three-color flow-cytometry analysis, HO-1 gene expression by reverse transcription-PCR and FMD by B-mode echo scan of the right brachial artery. Correlation analysis was carried out regarding FMD and EPCs, FMD and HO-1 and EPCs and HO-1. In BS/GS, CD34+KDR+ cell numbers did not differ from controls while CD133+KDR+ and CD133+CD34+KDR+ cell numbers were higher. HO-1 gene expression, as well as FMD, was higher in BS/GS compared with controls. Both CD133+KDR+ and CD133+CD34+KDR+ strongly correlated with both FMD and HO-1. FMD and HO-1 were also strongly correlated. These results document in a human system that EPC numbers and specific populations are related to important clinical and biochemical factors involved in cardiovascular (CV) status and reaffirm the utility of BS/GS patients as a useful system to investigate EPC's role(s) in the pathophysiology of cardiovascular remodeling in humans.

Chronic kidney disease in the hypertensive patient: an overview of the I-DEMAND study.

The kidney has been recognized as a sensor of cardiovascular risk. However, evaluation of urinary albumin excretion and estimated glomerular filtration rate is still too often overlooked in clinical practice. The I-DEMAND (Italy-Developing Education and awareness on MicroAlbuminuria in patients with hyperteNsive Disease) study was designed to assess the prevalence of microalbuminuria and its clinical correlates among Italian hypertensive patients. A total of 4151 patients from 87 specialized care centres were included in the study. Overall, this study demonstrated that approximately one-half of the enrolled patients had chronic kidney disease, with albuminuria being present in one-quarter of the individuals. The presence of renal abnormalities was more prevalent in patients with concomitant cardiovascular risk factors. This article discusses the main results of the study and its potential implications in clinical practice.

Subtyping of primary aldosteronism by adrenal vein sampling: effect of acute D(2) receptor dopaminergic blockade on adrenal vein cortisol and chromogranin A levels.

BACKGROUND: Adrenal vein sampling (AVS) is the gold standard for identifying the surgically curable forms of primary aldosteronism. Dopamine modulates adrenocortical steroidogenesis and tonically inhibits aldosterone secretion via D(2) receptor. However, whether it could also affect the release of cortisol and chromogranin A (ChA), which can be used to assess the selectivity of AVS, is unknown. OBJECTIVE: To investigate whether metoclopramide increased the release of cortisol and ChA and could thereby improve assessment of the selectivity at AVS. DESIGN AND METHODS: We investigated the effect of acute D(2) antagonism with metoclopramide on cortisol and ChA release from the adrenal gland by comparing the adrenal vein and infrarenal inferior vena cava (IVC) hormone levels at baseline and after metoclopramide administration in 34 consecutive patients undergoing AVS. RESULTS: Metoclopramide increased plasma aldosterone in the IVC (P<0.00001) and in the adrenal vein blood (P<0.002) but failed to increase plasma cortisol concentration or ChA levels. Therefore, it did not increase the selectivity index based on the measurement of either hormone. CONCLUSIONS: This study shows that the release of cortisol and ChA is not subjected to tonic D(2) dopaminergic inhibition. Therefore, these findings lend no evidence for the usefulness of acute metoclopramide administration for enhancing the assessment of the selectivity of blood sampling during AVS with the use of either cortisol or ChA assay.