Subtyping of Primary Aldosteronism in the AVIS-2 Study: Assessment of Selectivity and Lateralization.

CONTEXT: Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. OBJECTIVES: To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. DESIGN AND SETTINGS: In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. RESULTS: AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. CONCLUSION: Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020).

Gluten Deprivation: What Nutritional Changes Are Found During the First Year in Newly Diagnosed Coeliac Children?

AIM: A gluten-free diet (GFD) can expose children to excessive calories and fat intake. The study is intended to verify whether and how food intake, laboratory parameters, and growth are modified by a year of GFD. METHODS: In 79 CD (coeliac disease) children (mean age 7.9 ± 3.8 years, 52 females, 27 males) diagnosed over 24 months, 24-h food diaries, food-frequency patterns, anthropometric and laboratory parameters (mainly blood sugar, insulin, lipid profile, and homocysteine) were prospectively collected before and during the first year of GFD. Nutrient intakes were compared over time and with recommendations. They were also used as regressors to explain the levels and changes of metabolic and growth variables. p-values < 0.05 were considered statistically significant. RESULTS: Average macronutrient intake did not change during the year. Caloric intake remained below 90% (p ≤ 0.0001) and protein intake above 200% (p ≤ 0.0001) of recommendations. Lipid intake was stable at 34% of overall energy intake. Unsaturated fats increased (less omega-6 and more omega-3 with a ratio improvement from 13.3 ± 5.5 to 8.8 ± 3.1) and so did fibers, while folate decreased. The children who experienced a containment in their caloric intake during the year, presented a slower catch-up growth. Some differences were found across gender and age groups. In particular, adolescents consumed less calories, and females more omega-3. Fiber and simple sugar intakes emerged as implicated in lipid profile shift: fibers negatively with triglycerides (TG) (p = 0.033), simple sugars negatively with high-density lipoprotein (HDL) (p = 0.056) and positively with TG (p = 0.004). Waist-to-height ratio was positively associated with homocysteine (p = 0.018) and Homeostasis Model Assessment (p = 0.001), negatively with fibers (p = 0.004). CONCLUSION: In the short run, GFD is nutritionally very similar to any diet with gluten, with some improvements in unsaturated fats and fiber intake. Along with simple sugars containment, this may offer CD patients the opportunity for a fresh start. Caloric intakes may shift and should be monitored, especially in adolescents.

Sex differences in hypertension-related renal and cardiovascular diseases in Italy: the I-DEMAND study.

AIM: The aim of this study is to evaluate the differences in the prevalence of chronic kidney disease (CKD) and of cardiovascular risk factors and diseases between men and women participating in the Italy Developing Education and awareness on MicroAlbuminuria in patients with hyperteNsive Disease (I-DEMAND) study. METHODS: This is an observational, cross-sectional, multicenter study aimed at assessing prevalence and correlates of CKD among Italian hypertensive patients attending out-patient referral clinics. CKD was defined as glomerular filtration rate (GFR) less than 60 ml/min per 1.73 m(2) [Modification of Diet in Renal Disease (MDRD) study equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation] and/or urine albumin-to-creatinine ratio of at least 2.5 mg/mmol in men and of at least 3.5 mg/mmol in women or both. Left-ventricular hypertrophy (LVH) was diagnosed by either ECG or echocardiography. RESULTS: A total of 3558 study patients with renal data available were considered for this analysis: mean age was 61 ± 4 years and 37% had diabetes mellitus. Female patients (n = 1636, 46%) were older, with a greater prevalence of obesity and lower prevalence of smoking. The prevalence of concomitant coronary artery and peripheral artery diseases, but not of hypertension, diabetes mellitus, or heart failure, was lower in women than in men. The overall prevalence of albuminuria (21 vs. 32%; P = 0.001) and of microalbuminuria (16 vs. 23%; P = 0.001) was lower in women than in men. In women the prevalence of a reduced GFR estimated by both MDRD (33 vs. 21%; P = 0.001) and CKD-EPI equations (32 vs. 23%; P = 0.001) was higher than in men. CKD prevalence was similar in women and men (44 vs. 41%; P = 0.095 and 43 vs. 43%; P = 0.475, respectively, when MDRD and CKD-EPI eGFR estimations were used). The prevalence of LVH (diagnosed by either ECG or echocardiography) was similar in men and women (18 vs. 20%; P = 0.12).The main independent determinants of CKD were age, glycemia, uricemia, pulse pressure, hypertension duration, and previous cardiovascular diseases in men, and increasing age, glycemia, uricemia, pulse pressure, and a lower BMI in women. CONCLUSION: Renal abnormalities are present in a significant number of female hypertensive patients attending hypertension clinics. Prevalence of reduced eGFR and of microalbuminuria, associated risk factors, and clinical conditions are different between men and women, suggesting the need to develop specific therapeutic strategies to prevent renal dysfunction and reduce associated morbidity and mortality.

Hyperparathyroidism can be useful in the identification of primary aldosteronism due to aldosterone-producing adenoma.

Hyperparathyroidism represents as a novel feature of primary aldosteronism (PA). Its occurrence in patients with the surgically correctable aldosterone-producing adenoma (APA) and not in those with bilateral adrenal hyperplasia suggested that the measurement of parathyroid hormone could help in differentiating between these subtypes of PA. To test this hypothesis we measured the plasma levels of intact parathyroid hormone, Ca(2+), and several markers of calcium/phosphorus metabolism in 132 hypertensive patients, including 74 with primary (essential) hypertension and 58 consecutive PA patients. Of the latter, 46 were conclusively diagnosed as APA (by finding of lateralized aldosterone excess, pathology, correction of the hyperaldosteronism, and evidence of a fall of blood pressure after adrenalectomy) and 12 as bilateral adrenal hyperplasia. Based on these diagnoses we used the area under the receiver operator characteristic curve analysis to assess the accuracy of serum parathyroid hormone for identifying the PA cases in the whole group and for distinguishing between APA and bilateral adrenal hyperplasia. In this selected population of hypertensive patients for identifying PA cases, the accuracy of serum parathyroid hormone tended to be lower than that of the aldosterone:renin ratio. However, for discriminating between APA and bilateral adrenal hyperplasia patients it was better than that under the identity line and also that for the aldosterone:renin ratio for pinpointing APA cases among patients with PA. Hence, these findings indicate that raised serum parathyroid hormone levels are a feature of APA that can be useful for selecting the PA patients to be submitted to adrenal vein sampling.

The Adrenal Vein Sampling International Study (AVIS) for identifying the major subtypes of primary aldosteronism.

CONTEXT: In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE: The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS: The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS: Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE: The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS: Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS: Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.

Metabolic syndrome and chronic kidney disease in high-risk Italian hypertensive patients: the I-DEMAND study.

BACKGROUND: Metabolic syndrome (MS) and chronic kidney disease (CKD) are well-known, independent predictors of increased cardiovascular risk. Both conditions are fairly prevalent in the general population. The aim of this study was to assess the relationship between MS or its individual components and CKD in an Italian population of hypertensive patients with normal or mildly to moderately impaired renal function under specialist care. METHODS: A total of 2,916 patients (mean age 62 ± 11 years) among those enrolled in the I-DEMAND study were taken into consideration for this analysis. MS was defined according to the NCEP-ATP III criteria. CKD was defined as an estimated GFR (abbreviated MDRD equation) <60 ml/min/1.73m2 or as the presence of microalbuminuria (mean albumin-to-creatinine ratio =2.5 mg/mmol in men and =3.5 mg/mmol in women). RESULTS: MS was present in 59% of our study patients. The prevalence of microalbuminuria, reduced GFR and CKD was 26%, 25%, and 41%, respectively. Patients with MS had higher urinary albumin excretion (p<0.0001), lower GFR (p=0.0077), and a greater prevalence of CKD (p<0.0001), even after adjusting for age and gender. Multivariate logistic regression analysis revealed that MS was significantly associated with CKD, even after adjusting for several potential confounders including its individual components (OR 1.33, 95%CI 1.03-1.71, p=0.0268). The association between MS and CKD was stronger in nondiabetic patients. CONCLUSIONS: Renal abnormalities and MS are frequently associated in hypertensive patients under specialist care. This relationship is independent of several potential confounding factors including the components of MS.

Comparison of methods for determination of glomerular filtration rate in hypertensive subjects with normal serum creatinine.

BACKGROUND: Glomerular filtration rate (GFR) measured through technetium-99m diethyl triamine penta-acetic acid (Tc(99m)DTPA) renal scintigraphy (rsGFR) was compared with that estimated (eGFR) from 24-h creatinine clearance (CrCl) and, using both the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas, in a population of hypertensive subjects (HTs) with normal serum creatinine (SCr) levels. PATIENTS AND METHODS: In 200 normoalbuminuric (<30 mg/24 h) HTs 55-75 years old, without diabetes and history of coronary and cerebrovascular diseases, Pearson's correlation assess the relationship between rsGFR and eGFR. The Bland-Altman method was used to assess the agreement between rsGFR and eGFR, separately in subjects with low (<60 ml/min/1.73 m(2)) and normal (≥60 ml/min/1.73 m(2)) rsGFR. The span between -1.96 and +1.96 standard deviations of mean difference (bias) was calculated and used for this purpose. RESULTS: In 76 subjects, an unknown low renal function was found by Tc(99m)DTPA renal scintigraphy. In subjects with normal rsGFR the Bland-Altman analysis showed that the smallest span between rsGFR and eGFR was evident for ClCr values (26.0 ml/min/1.73 m(2)), whereas higher values were detected with the CG and MDRD formulas (41.0 and 40.4 ml/min/1.73 m(2), respectively). The same results were observed for low rsGFR, where a smaller span was found for ClCr (21.2 ml/min/1.73 m(2)), whereas CG and MDRD methods gave greater results (30.4 and 31.8 ml/min/1.73 m(2) respectively); no differences were found between genders. The degree of agreement for eGFR estimated with the CG and MDRD formulas was wider than that derived from ClCr, reflecting a greater between-methods variability and a considerable discrepancy of rsGFR values in the former than in the latter. CONCLUSIONS: In HTs with normal SCr values, Tc(99m)DTPA renal scintigraphy discovered un known renal organ damage in 38% of cases. If this methodology is not available, ClCr measurement should be preferred to estimate GFR whereas CG and MDRD formulas are of limited efficacy.

Within-patient reproducibility of the aldosterone: renin ratio in primary aldosteronism.

The plasma aldosterone concentration:renin ratio (ARR) is widely used for the screening of primary aldosteronism, but its reproducibility is unknown. We, therefore, investigated the within-patient reproducibility of the ARR in a prospective multicenter study of consecutive hypertensive patients referred to specialized centers for hypertension in Italy. After the patients were carefully prepared from the pharmacological standpoint, the ARR was determined at baseline in 1136 patients and repeated after, on average, 4 weeks in the patients who had initially an ARR > or =40 and in 1 of every 4 of those with an ARR <40. The reproducibility of the ARR was assessed with Passing and Bablok and Deming regression, coefficient of reproducibility, and Bland-Altman and Mountain plots. Within-patient ARR comparison was available in 268 patients, of whom 49 had an aldosterone-producing adenoma, on the basis of the "4-corner criteria." The ARR showed a highly significant within-patient correlation (r=0.69; P<0.0001) and reproducibility. Bland-Altman plot showed no proportional, magnitude-related, or absolute systematic error between the ARR; moreover, only 7% of the values, for example, slightly more than what could be expected by chance, fell out of the 95% CI for the between-test difference. The accuracy of each ARR for pinpointing aldosterone-producing adenoma patients was approximately 80%. Thus, although it was performed under different conditions in a multicenter study, the ARR showed a good within-patient reproducibility. Hence, contrary to previously claimed poor reproducibility of the ARR, these data support its use for the screening of primary aldosteronism.

Association of renal damage with cardiovascular diseases is independent of individual cardiovascular risk profile in hypertension: data from the Italy - Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease study.

OBJECTIVES: In the past years, several risk charts have been created to increase the accuracy of cardiovascular risk stratification. The most widely used and validated algorithms do not included target organ damage as risk prediction. The aim of the present study was to evaluate whether preclinical renal damage is associated with cardiovascular diseases independently of individual risk profile assessed by risk charts. METHODS: The study population was that of Italy-Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease, a large observational study conducted on hypertensive patients in Italy. The Framingham Risk Score (FRS), Systematic COronary Risk Estimation (SCORE) and Progetto Cuore Risk Score (Progetto Cuore RS) were computed in each eligible patient. Chronic kidney disease was defined by the presence of albuminuria or by a reduction of glomerular filtration rate. RESULTS: Study participants were categorized to have low, medium and high risk according to the tertiles of the three charts. Prevalence of total cardiovascular diseases progressively and significantly increased according to the degrees of risk assessed by the three charts, the highest prevalence being in participants with a high-risk profile (both high and medium vs. low risk <0.01 for FRS, SCORE and Progetto Cuore RS). The presence of chronic kidney disease was associated with total cardiovascular diseases, independently of FRS (odds ratio 1.64, 95% confidence interval 1.33-2.02, P < 0.001), SCORE (odds ratio 1.55, 95% confidence interval 1.21-1.98, P < 0.001) and Progetto Cuore RS (odds ratio 1.59, 95% confidence interval 1.22-2.07, P < 0.001). Moreover, inclusion of renal damage in the logistic model significantly increased the accuracy of the FRS (P < 0.05), SCORE (P < 0.01) and Progetto Cuore RS (P < 0.01) to identify patients with overt cardiovascular diseases. CONCLUSION: Identification of patients with preclinical renal damage should be encouraged in the hypertension cardiovascular risk stratification setting in order to achieve a more accurate individual risk computation. The presence of renal damage could improve cardiovascular risk prediction over the widely used risk stratification charts.

Independent association of ECG abnormalities with microalbuminuria and renal damage in hypertensive patients without overt cardiovascular disease: data from Italy-Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease study.

OBJECTIVES: Renal abnormalities are strongly associated with cardiac damage in essential hypertension. Detection of preclinical cardiac and renal abnormalities is a key clinical step in hypertension management. This study investigated the relationship between ECG abnormalities and microalbuminuria (MAU) in hypertensive patients without overt cardiovascular disease. This relationship, in fact, has never been extensively studied. METHODS: The study population was that of Italy-Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease, a large observational study including 4121 hypertensive patients in Italy. Patients with overt cardiovascular diseases were excluded from the present analysis. ECGs were centrally read and urinary albumin/creatinine ratio was carefully assessed. Chronic kidney disease was defined by the presence of albuminuria or by a reduction of glomerular filtration rate. RESULTS: The presence of ECG abnormalities was significantly and directly associated with chronic kidney disease [odds ratio (OR) 1.66, 95% confidence interval (CI) 1.32-2.07, P<0.001], particularly with MAU (OR 1.81, 95% CI 1.39-2.36, P<0.001). Main selected ECG abnormalities were also significantly associated with MAU [rhythm abnormalities (OR 2.94, 95% CI 1.77-4.88, P<0.001), intraventricular conduction defects (OR 1.95, 95% CI 1.32- 2.87, P<0.01), ventricular repolarization alterations (OR 1.84, 95% CI 1.26-2.70, P<0.01) and left-axis deviation (OR 1.87, 95% CI 1.26-2.79, P<0.01)]. After adjustment for confounders, an abnormal ECG and all the main ECG abnormalities remained significantly associated with MAU. CONCLUSION: This is the first large and systematic analysis of the relationship between detailed ECG abnormalities and MAU/chronic kidney disease in hypertensive patients without overt cardiovascular diseases. We report a significant and independent relationship between the presence of ECG abnormalities and renal damage in a preclinical stage of hypertension. Identification of ECG abnormalities in hypertension should prompt physicians to careful detection for renal damage, also in order to achieve an accurate risk stratification.

Primary aldosteronism: an update on screening, diagnosis and treatment.

BACKGROUND: Primary aldosteronism is much more common than previously held; it implies an excessive organ damage to the heart, vessels and kidney, which translates into an excess of cardiovascular events. These two features, along with the fact that the arterial hypertension and the hypokalemia can be corrected with a timely diagnosis and an appropriate therapy, warrant an aggressive diagnostic approach in hypertensive patients. OBJECTIVES: To provide updated information on the screening and exclusion tests for primary aldosteronism and to illustrate the strategy that can be followed for primary aldosteronism subtype differentiation. DESIGN: Review of the literature and personal experience of the authors. RESULTS: The available evidence showed that a cost-effective strategy for the screening of patients with primary aldosteronism can be exploited at most centres. At variance, the identification of primary aldosteronism subtypes, for example, the differentiation of patients with an aldosterone-producing adenoma from those with idiopathic hyperaldosteronism should be undertaken at tertiary referral centres. CONCLUSION: The identification of a curable form of primary aldosteronism can be much rewarding for the patient and the doctor. Thus, an aggressive diagnostic approach is mandatory at least in some subgroups of hypertensive patients who are at higher prior risk of primary aldosteronism or can benefit more from an accurate diagnosis.

Target organs of individuals with diabetes caught between arterial stiffness and damage to the microcirculation.

Hypertension and diabetes mellitus occur together frequently. There is general consensus in the literature that in patients with hypertension and diabetes, the heart and kidneys are locked in a vice, between arterial stiffening and damage to the microcirculation, with each condition feeding the other in a vicious cycle of events. Decreased glucose tolerance is associated with increased thickness and stiffness of large blood vessels, which contributes to increased blood pressure, macrovascular complications and impaired renal function. Large artery stiffness causes damage to the microvasculature, which in turn increases both capillary rarefaction, initially generated by hypertension and diabetes, and wave reflection. Systolic and pulse pressure are consequently increased, which results in completion of the cycle with more microvascular damage. In addition, macro and microvascular damage appears to increase blood pressure and impair tissue perfusion to target organs, and alterations to the vascular structure of peripheral microvessels in hypertension are related to the impairment of coronary vasodilator capacity. These mechanisms are supported by a large body of data from studies investigating the effects of diabetes and hypertension on the morphology and function of the microvasculature, some of which appear to occur in impaired glucose metabolism, preceding the development of full-blown diabetes. These changes also have important prognostic value, with direct correlations between coronary artery vasoconstriction and the incidence of cardiovascular events. Interventions to break the cycle of events are available, and regimens containing angiotensin-converting enzyme inhibitors have demonstrated good efficacy in increasing coronary reserve. Some of the mechanisms appear to be centred around the inhibition of bradykinin degradation rather than an effect on the renin-angiotensin-aldosterone system.

Homocysteine, left ventricular dysfunction and coronary artery disease: is there a link?

Experimental and observational studies support a role of plasma homocysteine levels (tHcy) in coronary artery disease (CAD). In the GENICA (Genetic and Environmental factors In Coronary Atherosclerosis) study, we found that high tHcy predicted cardiovascular mortality in hypertensive, but not in normotensive, patients independently of CAD and history of myocardial infarction. Moreover, despite not being associated with the coronary atherosclerotic burden, tHcy was inversely associated with left ventricular (LV) ejection fraction. This inverse relationship between LV systolic function and tHcy, which has been independently confirmed, might explain the association of tHcy with the risk of incident heart failure documented in the Framingham Heart Study. Thus, additional mechanistic investigation taking into consideration the effects of tHcy on LV function is necessary to further explore the potential therapeutic usefulness of tHcy lowering treatment in CAD.

Prospective evaluation of the saline infusion test for excluding primary aldosteronism due to aldosterone-producing adenoma.

BACKGROUND: Data on the performance of the tests used to confirm the diagnosis of primary aldosteronism (PA) are limited. OBJECTIVE: To prospectively investigate the accuracy of the saline infusion test (SIT). METHODS: Three hundred and seventeen (26.9%) out of 1125 patients screened in the PAPY study underwent measurement of plasma aldosterone, cortisol and renin activity after infusion of 2 l of isotonic saline intravenously over 4 h. They comprised patients with a baseline aldosterone/renin ratio (ARR) > 40 and one every four patients not fulfilling such criterion. The area under the receiver-operator characteristic curves (AUC) of aldosterone values after SIT was used as a measure of accuracy for diagnosing PA, aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). RESULTS: One hundred and twenty (37.9%) patients had PA that was due to an APA in 46 (38.3%) and to IHA in 74 (61.7%). No untoward effect occurred with the SIT. The AUC (0.811 +/- 0.026, 0.878 +/- 0.040 and 0.784 +/- 0.034 for identification of PA, APA and IHA, respectively) was higher (P < 0.0001) than that under the diagonal. By sensitivity/specificity versus criterion values plot, the best aldosterone cut-off values for identifying APA and IHA were 6.75 and 6.91 ng/dl, respectively. However, even at these optimal cut-offs, sensitivity and specificity were moderate because of values overlapping between patients with and without the disease. Moreover, there were no differences of AUC and aldosterone cut-offs between APA and IHA. CONCLUSION: In a multicenter study the SIT was safe and specific for excluding PA, but had no place for discriminating between an APA and IHA.

A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients.

OBJECTIVES: We prospectively investigated the prevalence of curable forms of primary aldosteronism (PA) in newly diagnosed hypertensive patients. BACKGROUND: The prevalence of curable forms of PA is currently unknown, although retrospective data suggest that it is not as low as commonly perceived. METHODS: Consecutive hypertensive patients referred to 14 hypertension centers underwent a diagnostic protocol composed of measurement of Na+ and K+ in serum and 24-h urine, sitting plasma renin activity, and aldosterone at baseline and after 50 mg captopril. The patients with an aldosterone/renin ratio >40 at baseline, and/or >30 after captopril, and/or a probability of PA (by a logistic discriminant function) > or =50% underwent imaging tests and adrenal vein sampling (AVS) or adrenocortical scintigraphy to identify the underlying adrenal pathology. An aldosterone-producing adenoma (APA) was diagnosed in patients who in addition to excess autonomous aldosterone secretion showed: 1) lateralized aldosterone secretion at AVS or adrenocortical scintigraphy, 2) adenoma at surgery and pathology, and 3) a blood pressure decrease after adrenalectomy. Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA). RESULTS: A total of 1,180 patients (age 46 +/- 12 years) were enrolled; a conclusive diagnosis was attained in 1,125 (95.3%). Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA. There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable. CONCLUSIONS: In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA.

Renal damage in primary aldosteronism: results of the PAPY Study.

Primary aldosteronism (PA) has been associated with cardiovascular hypertrophy and fibrosis, in part independent of the blood pressure level, but deleterious effects on the kidneys are less clear. Likewise, it remains unknown if the kidney can be diversely involved in PA caused by aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Hence, in the Primary Aldosteronism Prevalence in Italy (PAPY) Study, a prospective survey of newly diagnosed consecutive patients referred to hypertension centers nationwide, we sought signs of renal damage in patients with PA and in comparable patients with primary hypertension (PH). Patients (n = 1180) underwent a predefined screening protocol followed by tests for confirming PA and identifying the underlying adrenocortical pathology. Renal damage was assessed by 24-hour urine albumin excretion (UAE) rate and glomerular filtration rate (GFR). UAE rate was measured in 490 patients; all had a normal GFR. Of them, 31 (6.4%) had APA, 33 (6.7%) had IHA, and the rest (86.9%) had PH. UAE rate was predicted (P < 0.001) by body mass index, age, urinary Na+ excretion, serum K+, and mean blood pressure. Covariate-adjusted UAE rate was significantly higher in APA and IHA than in PH patients; there were more patients with microalbuminuria in the APA and IHA than in the PH group (P = 0.007). Among the hypertensive patients with a preserved GFR, those with APA or IHA have a higher UAE rate than comparable PH patients. Thus, hypertension because of excess autonomous aldosterone secretion features an early and more prominent renal damage than PH.

Expression of telomerase (hTERT) in aldosterone-producing adrenocortical tumors.

Telomerase was found in cancers and immortalized cell lines, but only occasionally in normal tissues, thus suggesting that measurement of its hTERT subunit might help distinguishing benign from malignant tumors. Data on hTERT expression in adrenocortical tumors are scant and mostly confined to non-functioning tumors. Therefore, we investigated whether hTERT expression may predict malignancy in aldosterone producing adrenocortical tumors. We measured hTERT mRNA with a real-time one-step reverse transcription (RT) polymerase chain reaction (PCR) method, based on the use of hTERT-specific fluorescence resonance energy transfer (FRET) probes, in 19 adrenalectomized patients with aldosterone-producing adenomas (APAs), in whom long-term follow-up (median 7 years, range 5-14 years) data were available. We also studied two rare aldosterone-producing carcinomas (APCs), eight adrenocortical carcinomas (ACs), twelve normal adrenal cortexes, and two malignant cell lines (NCI-295H and SW-13). Telomerase activity and hTERT immunoreactivity were also investigated. Of interest, we detected hTERT mRNA in 58% of APAs at levels similar to those of malignant tumors, which all consistently showed hTERT expression. In hTERT expressing tumors, immunocytochemistry showed the nuclear expression of hTERT. No hTERT expression was found in the normal adrenocortical tissue. No histopathology differences were observed between hTERT-positive and -negative APAs; however, a patient originally held to have an hTERT-positive APA was retrospectively classified as APC because of metastatic spread. In conclusion, RT-PCR measurement of hTERT mRNA is a hallmark of malignant adrenocortical tumors, but identifies also a subset of hTERT-expressing APAs that might show metastatic spread at long-term follow-up.

Predictors of congestive heart failure mortality in elderly people from the general population.

Congestive heart failure (CHF) is highly prevalent in the elderly. The aim of this study was to identify the predictors of CHF mortality in patients over 65 years of age who were free of CHF at initial screening. A total of 3,282 elderly subjects were recruited in a population-based frame and 12-year events were recorded. Continuous items were divided into tertiles and for each tertile adjusted the relative risk (RR) with 95% confidence intervals (CI) was derived in both genders from multivariate Cox analysis of CHF mortality. Age > or = 72 years ([RR]: 2.24; 95% CI 1.56 - 3.24), male gender ([RR]: 1.4; 95%CI 1.02 - 1.76), clinical history of coronary artery disease ([RR]: 1.25; 95% CI 1.02 - 1.76), pulse pressure > or = 79 mmHg ([RR]: 1.33; 95% CI 1.03 - 1.87), heart rate > or = 81 bpm ([RR]: 1.32; 95% CI 1.10 - 1.96), atrial fibrillation ([RR]: 1.82; 95% CI 1.18 - 2.81), left ventricular hypertrophy ([RR]: 1.42; 95% CI 1.01 - 2.02), diabetes ([RR]: 1.35; 95% CI 1.02 - 1.78), vital capacity < or = 81% of the theoretical value ([RR]: 2.50; 95% CI 1.88 - 3.32), forced expiratory volume in 1 second < or = 72% of the theoretical value ([RR]: 2.02; 95% CI 1.55 - 2.72) and serum sodium level < or = 139 mmol/L ([RR]: 1.95; 95% CI 1.44 - 2.63) predicted CHF mortality. This model is able to identify elderly people at increased risk of death from CHF.