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The long-term event-free survival (EFS) after acute myocardial infarction (AMI) is largely uninvestigated. We analyzed noninvasive clinical variables in association with long-term EFS after AMI. The present prospective study included 504 consecutive patients with AMI at 3 hospitals from 1995 to 1998 (Adria, Bassano, Conegliano, and Padova Hospitals [ABC] study). Thirty-seven variables were examined, including demographics, cardiovascular risk factors, in-hospital characteristics, and blood components. The end point was 10-year EFS. Logistic and Cox regression models were used to identify the predictive factors. We compared 3 predictive models according to the goodness of fit and C-statistic analyses. At enrollment, the median age was 67 years (interquartile range 58 to 75), 29% were women, 38% had Killip class >1, and the median left ventricular ejection fraction was 51% (interquartile range 43% to 60%). The 10-year EFS rate was 19%. Both logistic and Cox analyses identified independent predictors, including young age (hazard ratio 1.2, 95% confidence interval 1.1 to 1.3, p = 0.0006), no history of angina (hazard ratio 1.4, 95% confidence interval 1.1 to 1.8, p = 0.009), no previous myocardial infarction (hazard ratio 1.4, 95% confidence interval 1.1 to 1.7, p = 0.01), high estimated glomerular filtration rate (hazard ratio 0.8, 95% confidence interval 0.7 to 0.9, p = 0.001), low albumin/creatinine excretion ratio (hazard ratio 1.2, 95% confidence interval 1.1 to 1.3, p <0.0001), and high left ventricular ejection fraction (hazard ratio 0.8, 95% confidence interval 0.7 to 0.9, p = 0.006). These variables had greater predictive power and improved the predictive power of 2 other models, including Framingham cardiovascular risk factors and the recognized predictors of acute heart damage. In conclusion, 10-year EFS was strongly associated with 4 factors (ABC model) typically neglected in studies of AMI survival, including estimated glomerular filtration rate, albumin/creatinine excretion ratio, a history of angina, and previous myocardial infarction. This model had greater predictive power and improved the power of 2 other models using traditional cardiovascular risk factors and indicators of heart damage during AMI., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

Context: The assessment of selectivity of blood sampling is a fundamental step for a proper interpretation of the results of adrenal vein sampling (AVS), which is a "must" for identifying the surgically curable subtypes of primary aldosteronism. However, uncertainties remain on how to best achieve this goal., Objective: The aim of the study was to investigate whether chromogranin A (ChA) is tonically released in adrenal vein blood and might be used to assess the selectivity of AVS., Design and Methods: In consecutive patients undergoing AVS, we compared the plasma cortisol and ChA levels in the adrenal veins and infrarenal inferior vena cava blood. We then calculated and compared the selectivity index based on cortisol with that based on ChA., Results: Thirteen patients had cortisol and ChA levels assessed simultaneously. Besides the expected step-up of cortisol, they showed a step-up of ChA levels between the inferior vena cava and blood from either adrenal vein. The selectivity index determined with ChA was weakly correlated with that calculated with cortisol; the former was much smaller (3- and 4- fold on the right and left side, respectively) than the latter. This translated into a proportional error at Bland-Altman plot between selectivity indexes. Accordingly, only 53% of AVS were bilaterally selective using the selectivity index determined with ChA, as compared to 84% with selectivity index determined with cortisol (P = 0.0001)., Conclusions: These findings indicate that ChA is tonically released by the adrenal gland but do not support the usefulness of using ChA instead of cortisol for assessing the selectivity of blood sampling during AVS, perhaps with the exception of aldosterone-producing tumors that cosecrete cortisol.

Adrenal vein sampling is the gold standard for identification of surgically curable primary aldosteronism, but its accuracy might be hindered by blood dilution from accessory vein blood. We prospectively investigated the presence of accessory veins draining into adrenal veins and their effect on the selectivity index (SI) in 74 consecutive patients undergoing adrenal vein sampling. On the right side, the venous anatomic pattern could be conclusively determined in 91.8% of the cases: we detected hepatic accessory veins in 12.1%, no accessory veins in 42.4%, and renal capsular veins in 45.5%. On the left side there was a phrenico-adrenal trunk in 89.4% and renal capsular accessory veins in 10.6% of the cases. On both sides, renal capsular and phrenic accessory veins did not affect the SI. At variance, on the right side, hepatic accessory veins were associated with SI values approximately 3-fold lower than that found when such accessory veins were absent (median: 3.10 [range: 0.80 to 84.2] versus median: 1.10 [range: 0.70 to 2.20]; P=0.01). However, superselective adrenal catheterization resulted into higher SI values (median: 23.88; range: 4.80 to 84.20) in these cases. Thus, hepatic accessory veins sharing egress into the inferior vena cava with the right adrenal vein occurred in approximately 12% of the patients and imply a low SI, likely because of adrenal blood dilution by hepatic blood carrying a low cortisol concentration. In the presence of this anatomic variation, superselective catheterization of the right adrenal vein should be undertaken to determine the lateralization of aldosterone secretion.

The beneficial or detrimental effects of androgens on the cardiovascular system are debated. Endothelial progenitor cells are bone-marrow-derived cells involved in endothelial healing and angiogenesis, which promote cardiovascular health. Oestrogens are potent stimulators of endothelial progenitor cells, and previous findings have indicated that androgens may improve the biology of these cells as well. In the present study, we show that testosterone and its active metabolite dihydrotestosterone exert no effects on the expansion and function of late endothelial progenitors isolated from the peripheral blood of healthy human adult males, whereas they positively modulate early 'monocytic' endothelial progenitor cells. In parallel, we show that castration in rats is followed by a decrease in circulating endothelial progenitor cells, but that testosterone and dihydrotestosterone replacement fails to restore endothelial progenitor cells towards normal levels. This is associated with persistently low oestrogen levels after androgen replacement in castrated rats. In a sample of 62 healthy middle-aged men, we show that circulating endothelial progenitor cell levels are more directly associated with oestradiol, rather than with testosterone, concentrations. In conclusion, our results collectively demonstrate that androgens exert no direct effects on endothelial progenitor cell biology in vitro and in vivo.

Zidovudine (AZT) is an antiretroviral drug widely used in the treatment of human immunodeficiency virus (HIV)-infected patients, whose prolonged administration was found to cause toxic lesions in cardiomyocytes in humans and experimental animals. Alterations in adrenocortical secretion were frequently observed in HIV patients, but it is not clear whether medication is involved in the production of these complications. Hence, we studied in vivo and in vitro, the effects of AZT on the rat adrenal cortex. The prolonged AZT administration (100 mg/kg per day for 4 months) did not cause overt qualitative morphological alterations of adrenocortical cells, which, however, underwent a net hypertrophy. Hypertrophy is associated with increases in the volume and surface area per cell of the mitochondrial compartment and smooth endoplasmic reticulum (where the enzymes of steroid synthesis are located), and a marked decrease in the volume of the lipid-droplet compartment (where cholesterol and its esters, the precursors of steroid hormones, are stored). AZT chronic treatment induced rises in the plasma concentrations of aldosterone and corticosterone, and in the basal and ACTH-stimulated in vitro secretion of these hormones from adrenal slices. The 24-h exposure to AZT (10(-5) M) did not significantly affect either secretory activity or proliferation and apoptotic rates of cultured rat adrenocortical cells. Taken together, these findings suggest that AZT chronic treatment enhances the growth and steroidogenic capacity of rat adrenal cortex, probably by activating the central branch of the hypothalamic-pituitary-adrenal axis. The toxic activity of AZT is thought to depend on increased production of ROS. On these grounds, it is likely that the lack of toxic effect of AZT on adrenocortical cells is due to their very elevated content in vitamin C, which prevents the deleterious effect of the AZT-induced increase in intracellular ROS production.

Adrenocorticotropic hormone administration was proposed to overcome the biases associated with pulsatile aldosterone secretion during adrenal venous sampling, but the usefulness of different protocols of stimulation was never systematically assessed. We, therefore, compared the effects of a high dose (HD; 250 microg IV as a bolus), a very low dose (VLD; 250 pg IV), and an intermediate dose (ID; 50 microg/h) of adrenocorticotropic hormone on the selectivity index (SI) and the lateralization index in primary aldosteronism patients, using the diagnosis of aldosterone-producing adenoma, based on pathology and follow-up data, as a reference. The HD (n=47) significantly increased plasma cortisol concentration in infrarenal inferior vena cava (+79%) blood and the SI on both sides (SI(RIGHT)+113% and SI(LEFT)+131%), as compared with baseline values. The ID (n=14) also markedly increased both plasma cortisol concentration inferior vena cava (+93%) and the SI (SI(RIGHT)+690% and SI(LEFT)+410%); the very low dose (n=6) had no effect on either the plasma cortisol concentration or SI. In the patients with unilateral aldosterone-producing adenoma, the increase of selectivity with the HD and ID was counterbalanced by a confounding effect on the correct identification of the aldosterone-producing adenoma side, which was attributed to the wrong side in 3.0% and 12.5% with HD and ID, respectively. In conclusion, the HD and the ID, but not the very low dose, adrenocorticotropic hormone stimulation protocol facilitated the ascertainment of selectivity of adrenal vein catheterization. However, this favorable effect was overridden by a confounding effect on the identification of lateralized aldosterone excess to the aldosterone-producing adenoma side. Hence, we do not recommend adrenocorticotropic hormone stimulation.

Background/aims: Predictors of microalbuminuria in the early stage of hypertension are not well known. We did a prospective study to investigate whether glomerular hyperfiltration assessed from serum cystatin C predicts development of microalbuminuria in hypertension., Methods: We assessed 101 treatment-naive subjects screened for stage 1 hypertension and followed-up for a median 3.1 years. Cystatin C was measured at entry and glomerular filtration rate was estimated using the Hoek formula (CystGFR). Urinary albumin and ambulatory blood pressure were measured at entry and during the follow-up., Results: Subjects in the top CystGFR tertile (>115 ml/min/1.73 m(2)) were leaner (p = 0.002) and developed microalbuminuria more frequently (p = 0.02) than the rest of the group. In univariate Cox regression, CystGFR was associated with future microalbuminuria (hazard ratio, 1.06, 95% confidence interval (CI), 1.02-1.10, p = 0.001). After controlling for baseline albumin excretion rate and several confounders, CystGFR remained a significant predictor of microalbuminuria development (hazard ratio, 1.19, 95% CI, 1.03-1.37, p = 0.019). The association between future microalbuminuria and creatinine clearance or glomerular filtration rate estimated with the Cockroft-Gault or the Modification of Diet in Renal Disease formula did not attain the level of statistical significance in this sample., Conclusions: The present findings indicate that CystGFR is more sensitive than creatinine clearance or estimated glomerular filtration rate for predicting microalbuminuria development in the early stage of hypertension and confirm that hyperfiltration precedes microalbuminuria in this clinical entity., ((c) 2009 S. Karger AG, Basel.)

Background: Albumin excretion rate has been found to be associated with increased risk of mortality in several clinical settings. We assessed the relationship between urinary albumin and 7-year mortality in a cohort of patients with acute myocardial infarction (AMI)., Methods: In this prospective study, we examined 505 white patients admitted with AMI to the intensive care unit of 3 hospitals. Main end points were nonearly all-cause and cardiovascular (CV) mortality. Albumin-to-creatinine ratio (ACR) was measured by radioimmunoassay on the first, third, and seventh days after admission. Risk estimates were made using Cox proportional-hazard model and relative odds. Forty patients (7.9%) died early inhospital, and 175 (34.7%) died during the rest of the follow-up (nonearly mortality)., Results: The ACR measured on the third day predicted the occurrence of 7-year nonearly all-cause and CV mortality. Hazard ratios for ACR > or =0.97 mg/mmol were 3.0 (95% confidence limit 2.2-4.1), P < .0001, for nonearly all-cause mortality and 3.5 (95% confidence limit 2.5-5.0), P < .0001, for CV mortality. Correspondent fully adjusted hazard ratios were 1.9 (95% CI 1.4-2.6), P < .0001, and 2.2 (95% CI 1.5-3.2), P < .0001, respectively. By adding ACR to the 18-variable predictive model, ACR improved significantly both the goodness of fitting of the model for nonearly all-cause (P < .0001) and CV mortality (P < .0001) and the C-statistic value (P < .0001 and P = .002 for nonearly all-cause and CV mortality, respectively). Similar results were obtained for ACR measured on the first day or the seventh day., Conclusions: An early increase of urinary albumin in AMI is a strong independent predictor of long-term adverse clinical outcome. The ACR improved clinical prediction over and above baseline traditional multivariable risk models.

Context: Adiponectin is suspected to exert antiatherogenic, antiinflammatory, and insulin-sensitizing effects. However, the relative importance of the genetic and environmental factors in influencing plasma adiponectin levels (ADPN) remains unclear., Objective: The aim of the study was to investigate whether ADPN and body mass index (BMI) are genetically determined., Design, Setting, Participants, and Main Outcome Measures: In a series of 60 pairs of healthy twins, we estimated genetic variance and heritability of ADPN and BMI using both ANOVA and path analysis methods. Twins were genotyped at two biallelic single nucleotide polymorphisms (SNPs) at the gene encoding adiponectin: the +45 T/G (on exon 2) and the -11377 G/C (on the promoter)., Results: A total of 30 pairs of twins were Monozygotic (MZ), and 30 were dizygotic (DZ). The mean ADPN (+/-SD) was 10.6 +/- 5.7 in MZ and 11.1 +/- 4.5 in DZ twins (nonsignificant). Three tests of heritability (within pair = 1.13, P < 0.0001; among components = 1.62, P = 0.005; and intraclass correlation 1.34, P < 0.0001) consistently showed ADPN heritability. The preferred model of a likelihood-based analysis included an additive genetic influence and an individually unique environmental influence for ADPN, accounting for 88% and 12% of ADPN variance, respectively. We found a significantly higher within-pair difference of ADPN in DZ than in MZ pairs, and in +45 T/G SNP discordant compared with concordant DZ twins, indicating a significant effect of this adiponectin gene SNP on ADPN., Conclusions: ADPN shows significant genetic variance and heritability, which is independent of BMI and partly accounted for by the +45 T/G, but not the -11377 G/C adiponectin gene SNP.

Objective: We evaluated the acute effects of low-dose oral estradiol and sequential progesterone on the insulin-like growth factor (IGF)/growth hormone (GH) axis, IGF-binding proteins (IGFBPs) 1 and 3, and plasma levels of sex hormone-binding globulin (SHBG) in postmenopausal subjects., Study Design: Thirty healthy normal-weight women (mean age: 54.2 +/- 5.7 years) spontaneously postmenopausal for at least 6 months were enrolled. None had used hormone replacement therapy (HRT). Appropriate investigations excluded renal, glucose, lipid and coagulation abnormalities. Breast X-ray and endometrial ultrasound examinations excluded organic pathologies. They received oral cyclical HRT for 1 year, based on the administration of oral estradiol (1 mg/day) for 28 consecutive days plus progesterone (200 mg/day) from day 15 to day 28; out of the whole group, 15 subjects received progesterone orally (group A), while in 15 progesterone was administered transvaginally (group B). On the day before treatment (T0), on day 14 (T14) and on day 28 (T28) of the first cycle, plasma levels of estradiol, progesterone, SHBG, GH, IGF-I and -II, IGFBP-1 and -3, insulin and C-peptide were assayed in all patients. The same parameters were evaluated at T14 and T28 during the 12th month of treatment., Results: At T14, we observed significant increases in the levels of estradiol (from 20 +/- 16 to 115 +/- 71 pg/ml, p < 0.001), SHBG (from 132 +/- 42 to 182 +/- 55 nmol/l, p < 0.001) and IGFBP-1 (from 92 +/- 57 to 127 +/- 87 ng/ml, p < 0.004), while the level of IGF-I decreased (from 197 +/- 138 to 129 +/- 85 ng/ml, p < 0.003). At T28, progesterone levels were significantly higher in the women receiving it orally than transvaginally (8.4 +/- 6.1 vs. 3.7 +/- 3.2 ng/ml, p < 0.025). However, while oral progesterone did not affect the estrogen-induced variations, transvaginal progesterone abrogated the increase in the levels of IGFBP-1. The levels of IGF-II, IGFBP-3, GH, glucose, C-peptide and insulin did not change at any time. At 1 year, the values maintained the same trends. The estrogen-induced variations of SHBG were correlated directly with those of estradiol (r = 0.48) and inversely with those of IGF-I (r = -0.424)., Conclusions: Low-dose oral estradiol reduces plasma levels of IGF-I and increases IGFBP-1 and SHBG concentrations, while GH is unchanged. These effects, significant and immediate, lead us to hypothesize a direct action of estradiol on hepatocytes.

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

Objectives: This study sought to investigate the impact of a common T(-786)C single-nucleotide polymorphism (SNP) in the promoter of the endothelial nitric oxide synthase (eNOS, NOS3) gene on cardiovascular (CV) death in a prospective cohort study., Background: The T(-786)C SNP eNOS gene implies a blunted endothelium-dependent vasodilation in hypertensive patients and was associated with multivessel coronary artery disease in cross-sectional studies, but it remained unsettled whether it carried prognostic information., Methods: In consecutive white patients of the GENICA (Genetic and Environmental Factors in Coronary Atherosclerosis) study, who underwent coronary angiography between 1999 and 2001, we determined the incidence of CV death at follow-up. The eNOS T(-786)C and the exon 7 G(894)T SNPs were determined by melting curve analysis of amplicons from allele-specific fluorescence resonance energy transfer probes. Plasma levels of nitrate/nitrite, nitrotyrosine, and myeloperoxidase were also measured. The Kaplan-Meier and Cox regression analyses were used to assess the impact of SNPs on event-free survival., Results: Complete follow-up data were obtained in 1,086 (98%) patients. After a median follow-up of 1,296 days (range 4 to 2,057 days), we observed 85 (8.2%) CV deaths. There was a significant impact of the T(-786)C eNOS genotype on CV death-free (p = 0.0102) survival, but no differences in CV death rates across G(894)T genotypes. The TT individuals, who showed a lower survival, exhibited higher plasma myeloperoxidase (p < 0.0001) and lower levels of nitrotyrosine (p < 0.0001) than CC patients., Conclusions: The T(-786)C SNP in the promoter of eNOS bears independent prognostic information and is associated with changes in markers of oxidant stress in high-risk white patients referred for coronary angiography.

Factors related to the development of microalbuminuria in hypertension are not well known. We did a prospective study to investigate whether glomerular hyperfiltration precedes the development of microalbuminuria in hypertension. We assessed 502 never-treated subjects screened for stage 1 hypertension without microalbuminuria at baseline and followed up for 7.8 years. Creatinine clearance was measured at entry. Urinary albumin and ambulatory blood pressure were measured at entry and during the follow-up until subjects developed sustained hypertension needing antihypertensive treatment. Subjects with hyperfiltration (creatinine clearance >150 ml/min/1.73 m2, top quintile of the distribution) were younger and heavier than the rest of the group and had a greater follow-up increase in urinary albumin than subjects with normal filtration (P<0.001). In multivariable linear regression, creatinine clearance adjusted for confounders was a strong independent predictor of final urinary albumin (P<0.001). In multivariable Cox regression, patients with hyperfiltration had an adjusted hazard ratio for the development of microalbuminuria based on at least one positive measurement of 4.0 (95% confidence interval (CI), 2.1-7.4, P<0.001) and an adjusted hazard ratio for the development of microalbuminuria based on two consecutive positive measurements of 4.4 (95% CI, 2.1-9.2, P<0.001), as compared with patients with normal filtration. Age, female gender, and 24 h systolic blood pressure were other significant predictors of microalbuminuria. In conclusion, stage 1 hypertensive subjects with glomerular hyperfiltration are at increased risk of developing microalbuminuria. Early intervention with medical therapy may be beneficial in these subjects even if their blood pressure falls below normal limits during follow-up.

Ouabain, an inhibitor of the Na+/K+-ATPase, has been reported to affect the secretory activity of the adrenal cortex, and especially of zona glomerulosa (ZG). However, conflicting results were obtained, depending on the experimental condition used since ouabain appears to interact with angiotensin-II (Ang-II) and its action to be influenced by the electrolyte balance. Hence, we investigated the effects of prolonged (4-month) infusion with ouabain on the rat adrenal cortex. Ouabain raised the plasma concentrations of aldosterone, corticosterone and endothelin-1 (ET-1), without affecting either systolic blood pressure (SBP) or plasma renin activity (PRA). The treatment caused a marked hypertrophy of ZG and ZG cells, which mainly ensued from increases in the volume of the mitochondrial and smooth-endoplasmic-reticulum compartments, where the enzymes of steroid synthesis are located. Conversely, the volume of the lipid-droplet compartment, which stores cholesterol utilized in steroid-hormone production, underwent a striking decrease. Zona fasciculata and its parenchymal cells were not affected. Basal and maximally agonist (ACTH, Ang-II and ET-1)-stimulated in vitro mineralocorticoid secretion from adrenal slices was also notably enhanced by ouabain administration. Collectively, these findings indicate that prolonged treatment with ouabain selectively stimulates the growth and steroidogenic capacity of the rat adrenal ZG. The possibility that the activation of the renin-angiotensin system may be involved in this effect of ouabain is ruled out by the lack of significant changes in SBP and PRA. Instead, our results suggest the possible involvement of ET-1, the plasma level of which is elevated in ouabain-infused rats.

Adrenomedullin (AM), a potent vasodilatory hypotensive peptide, is expressed in the heart, where it is known to play a protective action. Light-microscopy immunocytochemistry (ICC) demonstrated the presence of AM immunoreactivity not only in the coronary-vessel wall and ventricular myocytes of the human and rat heart, but also in sparse voluminous cells located in the perivascular space. These cells displayed the same location of toluidine blue-positive mast cells, and electron microscopy ICC showed AM-immunogold staining over the granules of rat cardiac mast cells. The incubation of rat left ventricle fragments with the mast-cell histamine releaser compound 48/80 evidenced groups of AM-positive cells undergoing degranulation and caused an increase of approximately 50% in the AM concentration in the incubation medium. Collectively, our findings provide evidence that at least a subset of cardiac mast cells are able to synthesize and store AM, and upon stimulation to release it near coronary arterioles and venules.

Background: Resistant hypertension is common in clinical practice. The aim of our study was to evaluate inappropriate aldosterone activity in causing resistance to antihypertensive therapy., Methods: Among the patients consecutively evaluated for the first time between 1995 and 2001, we selected all those (n = 157) with an aldosterone-to-renin ratio (ARR) >or=25 (ng/dL)/(ng/mL/h), and plasma aldosterone >or=12 ng/dL. Eight patients with Conn adenoma were excluded from the study. Fifty-eight were diagnosed as idiopathic aldosteronism (IHA), the other 91 patients, who did not meet the criteria for primary aldosteronism, were operatively classified as aldosterone-associated hypertension (AAH). As a control group, we randomly chose 160 patients with essential hypertension and plasma aldosterone <12 ng/dL (EH). Antihypertensive treatment was given in accordance to World Health Organization Guidelines (1999). The study end point was blood pressure (BP) <140/90 mm Hg., Results: During follow-up (22 +/- 2 months), 24 (41.4%) patients with IHA, 35 (38.5%) with AAH, and 72 (54.0%) with EH reached the end point. According to survival analysis, AAH and IHA patients reached the end point in a smaller fraction and in a longer time compared with EH patients, with no difference between IHA and AAH. At the end of follow-up, IHA and AAH patients had higher diastolic BP than EH patients with no difference between IHA and AAH., Conclusions: Patients with elevated aldosterone plasma levels develop resistant hypertension, even in the absence of clinically diagnosed primary aldosteronism. Their identification will allow a targeted therapy and a more effective BP reduction.

Objective: Diagnosing aldosterone-producing adenoma (APA) involves a demonstration of the lateralization of aldosterone oversecretion because adrenal incidentalomas are common in hypertensive individuals and many small-sized APA escape identification with available imaging techniques. However, because of the pulsatile pattern of aldosterone secretion this can be a difficult undertaking. Stimulation of aldosterone secretion before adrenal vein sampling (AVS) can overcome this difficulty, but anecdotal data exist. We, therefore, prospectively investigated the usefulness of AVS with dynamic testing in primary aldosteronism (PA) patients., Methods: We enrolled 24 consecutive consenting patients with a biochemical diagnosis of PA from a tertiary referral centre to measure the effects of adrenocorticotrophic hormone (ACTH) on selectivity, the lateralization of aldosterone secretion to the APA side, and adverse effects. After correcting the hypokalemia we performed bilateral AVS. After 3 h supine resting, blood was simultaneously obtained from both sides. A high-dose ACTH (250 mug intravenous) bolus was then administered and AVS was repeated after 30 min., Results: AVS was bilaterally selective in 88% of patients; no adverse effects occurred. Of the 21 patients with bilaterally selective AVS, three had idiopathic hyperaldosteronism and 18 an APA that was surgically removed in 12 with an ensuing fall in blood pressure at follow-up. After ACTH patients showed a significant increase (P = 0.007) of aldosterone from contralateral adrenal vein blood, but not from the APA gland. Therefore, lateralization of aldosterone secretion on the APA side did not improve., Conclusion: AVS is safe and accurate for identifying APA. However, at a statistical power of 99%, these results do not support the usefulness of high-dose ACTH testing to improve the diagnostic accuracy of AVS.

Oxidative stress plays a role in cardiovascular dysfunction. This is of interest in diabetes, a clinical condition characterized by oxidative stress and increased prevalence of cardiovascular disease. The role of p66(shc) in oxidative stress-related response has been demonstrated by resistance to and reduction of oxidative stress and prolonged lifespan in p66(shc-/-) mice. In this study we assess p66(shc) gene expression in peripheral blood mononuclear cells (PBM) from type 2 diabetic patients and healthy subjects. The p66(shc) mRNA level was assessed using RT-PCR with two sets of primers mapping for different p66(shc) regions. p66(shc) is expressed in both monocytes and lymphocytes. The level of p66(shc) mRNA was significantly higher in type 2 diabetic patients compared with controls (0.38 +/- 0.07 densitometric units vs. 0.13 +/- 0.08; P < 0.0001). In addition, total plasma 8-isoprostane levels, a marker of oxidative stress, were higher in type 2 diabetics (0.72 +/- 0.04 ng/ml) than in normal subjects (0.43 +/- 0.04, P < 0.001) and were significantly correlated to the p66(shc) mRNA level in PBM from type 2 diabetics (r(2) = 0.47; P = 0.0284). In conclusion, diabetes induces p66(shc) gene expression in circulating PBM; this up-regulation in expression is significantly associated with markers of oxidative stress. p66(shc) gene expression in PBM may represent a useful tool to investigate the oxidative stress involved in the pathogenesis of long-term diabetic complications.

Objective: Microalbuminuria (MA) is a marker of adverse outcome in hypertension. The aim of this study was to investigate the association of MA with cardiovascular risk factors and glomerular hyperfiltration in the early stage of hypertension and to assess its predictive value for the development of sustained hypertension requiring antihypertensive treatment., Design and Participants: We studied 1041 young stage 1 hypertensive subjects. Study variables were 24-h ambulatory blood pressure and heart rate, anthropometric measures, metabolic variables, creatinine clearance and lifestyle factors analyzed as a function of ascending urinary albumin measured from 24-h collections. Subjects were followed until they developed sustained hypertension and were eligible for antihypertensive medication according to current guidelines., Setting: Seventeen outpatient clinics in Italy., Results: Eighty-five percent of the subjects were normoalbuminuric, 9% had borderline MA, and 6% had overt MA. No between-group differences were found for age, body mass index, heart rate, lifestyle factors and biochemistry in both genders. Creatinine clearance was greater in the subjects with overt MA and borderline MA than in the normoalbuminuric subjects (P = 0.003 and 0.011, respectively). In a two-way ANCOVA, microalbuminuric subjects both with hyperfiltration (P < 0.001) and with normal filtration (P = 0.04) had higher 24-h systolic blood pressure than subjects with normoalbuminuria and normal filtration. In a Cox analysis, neither MA nor hyperfiltration were significant predictors of development of sustained hypertension., Conclusion: MA is not associated with an adverse metabolic risk profile in the early stage of hypertension. MA is associated with greater hemodynamic load and with glomerular hyperfiltration in this clinical setting, but does not help in predicting those subjects destined to develop sustained hypertension requiring antihypertensive therapy.

Aims/hypothesis: Diabetes mellitus is associated with increased mortality in subjects with acute myocardial infarction (AMI). We aimed to estimate the risk of mortality in AMI patients with and without diabetes using the urinary albumin : creatinine ratio (ACR)., Methods: This is a prospective study of 121 consecutive, non-selected diabetic AMI patients, 121 age- and sex-matched non-diabetic AMI patients and 61 diabetic non-AMI outpatients as control subjects. All data were obtained during the first 7 days of hospitalisation and each AMI patient was followed for a period of exactly 3 years. Baseline ACR RIA measurements were made on the 1st, 3rd and 7th days of admission., Results: Adjusted ACR values were significantly higher in the diabetic AMI patients than in the diabetic control outpatients ( p<0.0001), and a significant difference was observed between the weekly ACR slopes for these two groups ( p<0.0001). Microalbuminuria was more prevalent in the diabetic AMI patients than in the non-diabetic AMI patients on the 1st day (62% vs 46%, p=0.01) and 3rd day (41% vs 29%, p=0.04). Among the AMI patients with normoalbuminuria (ACR <30 microg/mg), the mortality rate was 11.6% for the patients without diabetes and 33.8% for those with diabetes ( p=0.001). The mortality rate was much higher among the AMI patients with microalbuminuria (ACR >/=30 microg/mg) and similar for the diabetic (68.0%) and non-diabetic patients (74.3%). In a multivariable Cox model, ACR ( p<0.0001) and diabetes status ( p=0.01) were associated with adverse outcome even when several other clinical variables were included in the model. Furthermore, a negative interaction was found between diabetes and ACR ( p=0.01)., Conclusions/interpretation: Microalbuminuria frequently occurs in diabetic and non-diabetic AMI patients during the first 3 days of admission to hospital and can be used to identify subjects at high risk of mortality.

Background: Low-density lipoprotein (LDL) can be oxidatively modified by reactive oxygen species, thus generating oxLDL. The latter induce formation of specific antibodies (oxLDLAb), which are detectable in patients with atherosclerosis, in which they might play a pathogenic or a protective role. Thus, we aimed to investigate the association of antibodies with oxidized LDLs (oxLDL) (oxLDLAbs) with coronary artery disease (CAD) and acute coronary syndromes., Methods and Results: In a cross-sectional study of 529 consecutive patients undergoing quantitative coronary angiography for suspected CAD, we measured the titer of IgG oxLDLAbs by ELISA. With regression analysis techniques, we also investigated the determinants of oxLDLAb titer and the association of oxLDLAbs with CAD severity. We found no significant differences of oxLDLAb titer between groups of patients without and with different CAD severity. The oxLDLAb titer was 18.6 enzyme units (EU) (11.5 to 25.7 EU/mL) (mean, 95% CI) in patients without CAD; 16.8 EU (9.6 to 24.2 EU) in patients with stenosis <50%; and 19.9 EU (15 to 24.8 EU), 17.2 (13.8 to 20.6 EU), and 14.7 EU (12.1 to 17.3 EU) in those with in 1-, 2-, or 3-vessel > or =50% stenosis, respectively. Similarly, no differences of oxLDLAb titer between patients without and with acute coronary syndrome were found. The oxLDLAb titer correlated weakly with aging and with serum total, LDL, and HDL cholesterol and plasma homocysteine levels; however, only age and HDL cholesterol remained significant predictors of the oxLDLAb titer at a stepwise regression analysis., Conclusions: The results of this study, which was adequately powered from the statistical standpoint, provided no evidence for an association of IgG oxLDLAb titer with angiographically assessed CAD in whites.

Background: Many studies conducted in the last two decades have aroused interest in the role of glomerular hyperfiltration in the pathogenesis of renal damage in hypertension. Glomerular hyperfiltration has been mainly attributed to intraglomerular hypertension and overactivity of the renin-angiotensin system, but not much is known about the role of excessive renal proximal tubule Na+ reabsorption, which may activate tubuloglomerular feedback and increase glomerular filtration. Therefore, we evaluated the relationships between glomerular hemodynamics, plasma atrial natriuretic peptide (ANP) concentration, proximal tubule Na+ reabsorption, assessed by renal Li+ reabsorption, and sodium-lithium exchange (NLE) in circulating erythrocytes ex vivo, a marker of increased protein expression of isoform 3 of the sodium-proton exchanger (NHE-3) in the proximal tubule, in essential hypertensive patients., Methods: 32 patients with essential hypertension were investigated after a two week placebo wash out period and after four-weeks treatment with open-label angiotensin converting enzyme inhibitors (ACEI). Before and after active treatment the following parameters were assessed: blood pressure (mercury sphygmomanometry), glomerular filtration rate (GFR), renal plasma flow, and lithium clearance (clearances of inulin, PAH and orally administered lithium, respectively), plasma ANP (radioimmunoassay), and, only at baseline, plasma renin activity, plasma and urinary aldosterone (radioimmunoassay) and NLE (sodium stimulated lithium efflux)., Results: Baseline GFR was positively correlated with NLE, Li+ clearance and ANP, and the patients with elevated NLE (> or =0.4 mmol/L cell/h) (31%) had higher GFR and ANP than the patients with normal NLE, but similar plasma renin activity, plasma and urinary aldosterone. ACEI reduced GFR and its change was negatively correlated with pretreatment GFR and NLE and positively with the change of proximal tubule Na+ reabsorption. After ACEI, ANP increased in patients with normal NLE but not in those with high NLE (p<0.001 for the difference)., Conclusion: Increased proximal tubule Na+ reabsorption contributes to the pathophysiology of glomerular hyperfiltration in patients with essential hypertension, and is compensated by increased ANP levels. It can be corrected by short-term ACEI treatment.

Aims: Urinary albumin excretion increases during acute myocardial infarction but little is known on the prognostic significance and the pathophysiological mechanisms of microalbuminuria in this clinical setting. The primary aim of the study was to examine whether urinary albumin excretion has predictive power for 1-year mortality after acute myocardial infarction. A secondary objective was to gain insight into the pathophysiological mechanisms of increased urinary albumin in myocardial infarction., Methods and Results: This is a prospective cohort study conducted in three coronary care units (Northeast Italy). Four hundred and thirty-two unselected, consecutively enrolled patients with acute myocardial infarction (66.3+/- 12.3 years of age) were studied. The incidence of mortality was related to the baseline urinary albumin:creatinine ratio. The best cut-off for total mortality approximated to 50 mg x g(-1)on the first day after myocardial infarction, 30 mg x g(-1)on the third day, and to 20 mg x g(-1)on the seventh day. At multivariable Cox analysis, the albumin:creatinine ratio was the strongest among several independent predictors of mortality (adjusted relative risks: 3.6 (95% CI, 2.1--6.2) on the first day, 4.9 (95% CI, 2.9--8.2) on the third day and 4.0 (95% CI, 2.3--6.8) on the seventh day). Independent determinants of urinary albumin were plasma aldosterone on the first day, and inflammatory markers on the third and seventh days., Conclusion: Urinary albumin assessed in the first week after acute myocardial infarction is a strong prognostic marker for 1-year mortality., (Copyright 2001 The European Society of Cardiology.)

The objectives of this study were to investigate the usefulness of adrenal vein sampling in identifying the etiology of primary aldosteronism (PA) in patients with equivocal CT and MR findings. Between 1990 and 1999, 104 referred hypertensive patients (45 women and 59 men, aged 49.6 +/- 11.6 yr) were diagnosed to have PA with inconclusive computed tomography scan and magnetic resonance results, based on established criteria. Adrenal vein sampling (AVS) for measurement of plasma aldosterone (A) and cortisol (C) levels was performed in all. Selectivity of AVS was assessed by the ratio between C levels in each adrenal vein and in the infrarenal inferior vena cava plasma (C(side)/C(IVC)). A receiver operator characteristics analysis was carried out to establish 1) the best AVS-derived index, 2) the degree of selectivity that could provide an accurate diagnosis, and 3) whether a correct diagnosis could be made from a unilaterally selective AVS. An aldosterone-producing adenoma (average diameter, 12.2 +/- 0.08 mm) was eventually diagnosed in 41 patients (39.4%) and was excluded in the rest. Adrenal vein rupture leading to partial adrenal loss occurred in 1 patient (0.9% complication rate). By assuming a cut-off value of C(side)/C(IVC) > or = 1.1, AVS was selective in 85.7% and 94.1% of cases on the right and left sides, respectively, and bilaterally in 80.6% of cases. Of all AVS-derived indexes, the A/C of one over the A/C contralateral side [(A/C)(side)/(A/C)(contralateral side)] furnished the best diagnostic accuracy. With a bilaterally selective AVS, a value of (A/C)(side)/(A/C)(contralateral side) > or = 2 provided a conclusive etiological diagnosis of PA in 79.7% of cases. At variance, no accurate diagnosis could be made from unilaterally selective AVS. AVS was feasible and safe in most PA patients with inconclusive computed tomography and magnetic resonance scans. When bilaterally selective (i.e. C(side)/C(IVC) > or = 1.1) a ratio of (A/C)(side)/(A/C)(control) > or = 2 provided the best compromise of sensitivity and false positive rate for lateralization of the etiology of PA.

The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available -mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance (SVR), left forearm blood flow (LFBF), left leg blood flow (LLBF), RPF, glomerular filtration rate (GFR), UNaV, plasma renin activity (PRA), plasma concentration of antidiuretic hormone (ADH), and the serum levels of nitrite and nitrate (NOx) were evaluated in 25 cirrhotic patients with ascites (17 without HRS and 8 with type 2 HRS) before and during the 6 hours following the oral administration of 15 mg of midodrine. During the first 3 hours after the drug administration, a significant increase in MAP (89.6 +/- 1.7 vs. 81.80 +/- 1.3 mm Hg; P < .0001) and SVR (1, 313.9 +/- 44.4 vs. 1,121.2 +/- 60.1 dyn . sec . cm-5; P < .0001) accompanied by a decrease in HR (69 +/- 2 vs. 77 +/- 3 bpm; P < .005) and CI (2,932.7 +/- 131.4 vs. 3,152.5 +/- 131.4 mL . min-1 . m2 BSA; P < .0025) was observed in patients without HRS. No change was observed in LFBF and LLBF. The improvement in systemic hemodynamics, which was also maintained during the the 3- to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 +/- 43.1 vs. 385.7 +/- 39.9 mL . min-1; P < .005), GFR (93.1 +/- 6.5 vs. 77.0 +/- 6.7 mL . min-1; P < .025), and UNaV (92.7 +/- 16.4 vs. 72.2 +/- 10.7 microEq . min-1; P < .025). In addition, a decrease in PRA (5.33 +/- 1.47 vs. 7.74 +/- 2.17 ng . mL-1 . h; P < .05), ADH (1.4 +/- 0.2 vs. 1.7 +/- 0.2 pg . mL-1; P < .05), and NOx (33.4 +/- 5.0 vs. 49.3 +/- 7.3 micromol-1; P < .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorter. Accordingly, regardless of a significant decrease in PRA (15.87 +/- 3.70 vs. 20.70 +/- 4.82 ng . mL-1 . h; P < .0025) in patients with HRS, no significant improvement was observed in RPF, GFR, or UNaV. In conclusion, the acute oral administration of midodrine is associated with a significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. As a result, renal perfusion and UNaV also improve in these patients. By contrast, midodrine only slightly improves systemic hemodynamics in patients with type 2 HRS, with no effect on renal hemodynamics and renal function.

Objective: To assess the risk of mortality associated with hypertension and microalbuminuria in patients with acute myocardial infarction., Design: A prospective study., Setting: Intensive care units in three Italian general hospitals., Patients: In total 309 consecutive patients (including 97 women) aged 66.6 +/- 12.5 years, admitted to hospital for acute myocardial infarction., Main Outcome Measures: Albumin excretion rate measured by radioimmunoassay of 24 h urine samples, on the first and third days after admission to hospital. In-hospital mortality rate among the patients stratified according to their history of hypertension and albumin excretion rate., Results: Of the patients, 147 had histories of hypertension. Forty-four per cent of the normotensive and 43% of the hypertensive subjects had microalbuminuria on the first day. On the third day the percentages were 25 and 29%, respectively. Twenty-two patients died before discharge from hospital. Patients were divided into four groups according to whether they had microalbuminuria or not and likewise for hypertension. Mortality rate among the subjects with hypertension and microalbuminuria combined was greater than those among the other three groups (P < 0.0001 on the first and third days). The relative hazard ratio was 11.7 on the first day, and 15.6 on the third day. In a multivariate Cox's model hypertension and microalbuminuria combined had a greater predictive power for mortality than either variable alone. Killip class, age, and creatinine kinases MB level were other significant predictors of death., Conclusions: These results show that the combination of hypertension and microalbuminuria is associated with a greater risk of in-hospital mortality among subjects with acute myocardial infarction, independently of degree of heart failure and other possible confounders.

Background: This study was undertaken to assess whether albumin excretion rate (AER) increases during acute myocardial infarction (AMI) and whether it predicts in-hospital mortality., Methods and Results: The study was carried out in 496 subjects admitted to hospital for suspected AMI. Of these, 360 had evidence of AMI. The other 136 were studied as control subjects. AER was assessed by radioimmunoassay in three 24-hour urine collections performed on the first, third, and seventh days after admission. Left ventricular ejection fraction was measured by two-dimensional echocardiography in 254 subjects. AER adjusted for several confounders was higher in the AMI than the non-AMI group on the first (69.2+/-5.2 versus 27.3+/-8.5 mg/24 h, P<.0001) and third (30.3+/-2.7 versus 12.5+/-4.4 mg/24 h, P=.001) days, whereas no difference was present on the seventh day. When the subjects with heart failure were excluded, the difference between the two groups remained significant (first day, P<.0001; third day, P=.001). On the basis of classification of the 26 AMI patients who died in hospital according to whether they had normal AER, microalbuminuria, or overt albuminuria, mortality rate progressively increased with increasing levels of AER (P<.0001). In a Cox's proportional hazards model, AER was a better predictor of in-hospital mortality than Killip class or echocardiographic left ventricular ejection fraction. A cutoff value of 50 mg/24 h for first-day AER and 30 mg/24 h for third-day AER yielded a sensitivity of 92.3% and of 88.5% and a specificity of 72.4% and of 79.3%, respectively, for mortality. Adjusted relative risks for the two cutoff values were 17.3 (confidence limits, 4.6 to 112.7) and 8.4 (confidence limits, 2.4 to 39.3), respectively., Conclusions: These data show that AER increases during AMI and that it yields prognostic information additional to that provided by clinical or echocardiographic evaluation of left ventricular performance.

1. Low-to-normal renin renovascular hypertension (RVH) and the accuracy of renal vein renin ratios were investigated in 129 consecutive patients referred for suspected RVH. Forty-nine had essential hypertension, 24 unilateral renoparenchymal hypertension and 56 renal artery obstruction. Of the latter, 86% were diagnosed retrospectively as RVH, based on fall in blood pressure with correction of renal ischaemia. We measured baseline, captopril-stimulated and renal vein plasma renin activity (PRA) levels, as well as several other parameters. 2. PRA was low-to-normal in 37% of the RVH patients [low-to-normal renin (LNR-) RVH group] and elevated in the remaining 63% [high-renin (HR-) RVH group]. In the LNR-RVH group, low-to-normal renin levels, by immunoreactive active renin and plasma renin concentration measurements, and a blunted response of PRA to captopril, were seen. As compared with HR-RVH, LNR-RVH patients had a longer duration of hypertension (P < 0.05), higher serum K+ (P = 0.04) and lower diastolic blood pressure (P = 0.02). However, they did not differ for the other variables, including the fall in blood pressure after correction of renal ischaemia. Although the number of bilateral stenoses was similar in the two groups, no patient in the LNR-RVH group had total renal artery occlusion compared with 53% in the HR-RVH group (P = 0.00015). The accuracy of renal vein renin indices were high enough to justify their use only in the patients with total occlusion of a renal artery. 3. Thus LNR-RVH is common in patients with longstanding hypertension without a totally occluded renal artery. Since the sensitivity of renin measurements is low, cure of hypertension would be precluded for more than one third of RVH patients, if these tests were a prerequisite for identifying RVH.

Unlabelled: To study the relationship between plasma renin activity (PRA) and coffee consumption, cigarette smoking, alcohol intake and physical activity habits., Setting: The multicentre HARVEST trial, involving 17 Hospital Centres in Northeast Italy., Subjects: 351 borderline to mild hypertensive men (mean age +/- SEM 22.7 +/- 0.47 years), never treated for hypertension., Interventions: Office and 24-hour blood pressure measurement, supine and standing PRA levels, and urinary catecholamines output., Main Outcome Measures: PRA levels according to coffee intake and physical activity status., Results: Coffee intake showed a major effect on PRA. Supine PRA levels were 40% higher in the subjects abstaining from coffee (n = 94) than in the coffee drinkers and was similar in the moderate (n = 223) and heavy (n = 34) drinkers. A weaker negative association was found between coffee use and PRA on standing. Office and whole-day blood pressure and heart rate, and urinary catecholamines did not differ according to coffee intake. Supine PRA was lower in the subjects performing regular physical activity than in the inactive subjects. Office and whole-day diastolic blood pressure and heart rate, and urinary norepinephrine were lower in the active than in the sedentary men. No relationship was found between PRA measured either in the supine or the upright posture and tobacco or alcohol use. In a multiple linear regression model supine PRA was negatively correlated with age, coffee consumption and physical activity habits., Conclusions: Chronic coffee intake and physical training showed an inverse relationship with PRA in mild hypertensive men, while tobacco and alcohol use were unrelated to PRA.

Objective: To investigate the role of ouabain in human hypertension and to establish whether immunoreactive endogenous ouabain is secreted by the adrenal gland under the influence of dopaminergic regulation., Methods: We measured plasma levels of endogenous ouabain by immunoassay, together with other variables, including plasma renin activity and aldosterone levels, in 91 clinically selected hypertensives and 19 healthy volunteers. We also measured endogenous ouabain in adrenal venous blood and the effect of DA2 dopaminergic receptor blockade and stimulation. After a thorough clinical evaluation, 64 patients were diagnosed with essential hypertension and 24 with primary aldosteronism., Results: Plasma levels of endogenous ouabain were higher in essential hypertensives than in controls. Multiple regression analysis showed a significant relationship of mean blood pressure with plasma endogenous ouabain, age and body mass index, but not with other measured parameters. The plasma levels of endogenous ouabain were more than two standard deviations above the mean value for normotensives in 45% of patients with essential hypertension in whom plasma renin activity was normal. Higher plasma levels of endogenous ouabain were found in patients with aldosterone excess, specifically affecting 56% of 17 patients with surgically confirmed adrenal cortical adenoma and one (14%) of seven patients with idiopathic causes. Removal of adenomas lowered blood pressure in half of the patients in whom plasma levels of endogenous ouabain normalized after surgery. Plasma endogenous ouabain levels were similar in venous blood from the adrenal and inferior vena cava, and plasma levels were not influenced by DA2 dopaminergic blockade and stimulation., Conclusion: Approximately half of Caucasian patients with essential hypertension and with hyperaldosteronism exhibit elevated circulating levels of endogenous ouabain. The latter do not appear to be secondary to hypertension, are unrelated to plasma renin activity, and may not involve adrenal type-2 dopaminergic receptors.

Aim of the Study: To evaluate the profile of albumin excretion rate (AER) in the first days of acute myocardial infarction (AMI), its relationship with serum enzymes and the presence of heart failure, and the effect of thrombolytic therapy., Methods: Two hundred and thirty-one consecutive patients admitted to coronary care unit for suspected AMI were examined. Patients with diabetes mellitus, urinary tract infections or proteinuric diseases were excluded. In 135 patients (95 males, 40 females) AMI diagnosis was confirmed. The remaining 96 (56 males, 40 females) were considered as controls. AER was measured by radioimmunoassay in 24-hour urine samples at the first, third and seventh day after admission and expressed as mg/24h. Statistical analysis was performed after AER logarithmic transformation using repeated measure ANOVA:, Results: Mean age was 66.9 +/- 12.2 years (range = 35 -91) in the AMI group and 63.2 +/- 12.3 years (range = 33-91) in the controls (p = 0.023) Age-adjusted blood pressure was lower in the AMI group than in the controls (p < 0.0001 for both systolic and diastolic), while no difference was found in heart rate. Plasma cholesterol, triglycerides, creatinine and uric acid were similar in the 2 groups. Mean AER was 43.4 +/- 64.8, 26.9 +/- 51.2 and 23.9 +/- 52.7 mg/24h at 1st, 3rd and 7th day respectively in the AMI group and 24.9 +/- 58.2, 13.7 +/- 25.8 and 17.9 +/- 44.1 mg/24h respectively in the controls (p = 0.014). In the AMI group, first day AER significantly and positively correlated with CPK (r = 0.287, p = 0.001), CPK-MB (r = 0.239, p = 0.007) and GOT (r = 0.300, p = 0.001). Within the patients with AMI, those who developed heart failure (n = 57), had higher AER (48.6 +/- 68.4, 29.7 +/- 54.9 and 28.1 +/- 55.8 mg/24h at 1st, 3rd and 7th day in patients with mild heart failure -2nd Killip Class- and 100.0 +/- 141.7, 50.3 +/- 66.4 and 64.2 +/- 74.4 mg/24h in those with severe heart failure -3rd and 4th Killip Class-) than those who did not (31.0 +/- 41.7, 19.6 +/- 45.6 and 16.5 +/- 45.7 mg/24h respectively) (p = 0.004). In a multiple linear regression model AER was significantly related to peak values of GOT (1st day) and CPK (3rd day) and to presence of heart failure (3rd and 7th day). Thrombolytic therapy (n = 48) did not influence AER., Conclusions: The results of the present study show that AER increases following AMI, chiefly in the subjects who develop heart failure. AER correlates with serum enzymes peak levels at 1st and 3rd day and with presence of heart failure at 3rd and 7th day after admission, and is not influenced by thrombolytic therapy. These data suggest that in AMI the initial increase in AER is due to the inflammatory process which accompanies cardiac necrosis, while in a later phase its rise is mainly due to the increased intraglomerular capillary pressure consequent to heart failure.

To assess the efficacy and safety of different doses of the alpha-1 blocker terazosin on long-term therapy, 12 essential hypertensives (7 males, 5 females, aged 27-61) were investigated. The study was conducted according to the Latin square design and each patient underwent 4 periods of treatment with 2, 5, 10 mg/day terazosin and placebo, in a double-blind, randomized order. Each treatment lasted 4 weeks. In comparison to placebo, a fall in diastolic pressure was observed already with the 2 mg/daily dose, with a decrease > 10 mmHg in 7 patients (responders). Body weight increased in a dose dependent manner, while atrial natriuretic peptide, serum glucose and insulin during oral glucose tolerance test, total cholesterol, HDL and LDL cholesterol, triglycerides were unaffected. It is concluded that terazosin is effective and safe in essential hypertensives already at 2 mg daily dose. Further reduction in blood pressure at higher doses is likely to be counteracted by salt and water retention.

It has been proposed, therefore, that hyperinsulinemia may favor the development of hypertension through sodium retention, sympathetic nervous system activation, and vascular hypertrophy. In insulin-resistant hypertensive subjects, insulin infusion during euglycemic clamp promotes a transient sodium retention by stimulating proximal tubular Na+ reabsorption, but chronic hypertension usually is not associated with extracellular fluid and plasma volume expansion. In essential hypertensive subjects, intracellular potassium is decreased and intracellular sodium increased, which is consistent with insulin resistance. The latter is also associated with high red blood cell Li+/Na+ exchange, and chronic insulin treatment in insulin-dependent diabetics induces a slight increase in Li+/Na+ CT. This is a functioning mode of the Na+/H+ exchange, and its increase may reflect either an increased number of transport units or abnormal kinetic properties. Experiments in vitro and in vivo suggested that any change in insulin concentration and insulin sensitivity may affect Li+/Na+ and Na+/H+ counter-transport. High Li+/Na+ and Na+/H+ CT are associated with a significant cardiac and vascular remodeling in essential hypertension, insulin-dependent diabetes, and familiar hypertrophic cardiomyopathy. Reduced insulin sensitivity is associated with salt-sensitive hypertension. Finally, insulin potentiates the effects of other agonists (eg, thromboxane A2, angiotensin II) on vascular contraction and cell growth. These data indicate that insulin may play a role in the pathogenesis of hypertension and its major complications by amplifying the effects of sodium, vasoconstrictors, and growth factors.

Ascitic cirrhotic patients are a heterogenous population with respect to factors that may affect plasma human atrial natriuretic peptide levels (such as degree of plasma volume and plasma levels of angiotensin II, vasopressin and norepinephrine). Thus the proven variability of plasma human atrial natriuretic peptide values in ascitic cirrhotic patients may be due also to the selection of patients, not only to the study conditions. The response to standardized stepped-care medical treatment of ascites makes it possible to characterize ascitic cirrhotic patients with different patterns of renal sodium excretion, intrarenal sodium handling, plasma renin activity, plasma aldosterone and thus, probably, effective circulating volume. Consequently, we evaluated human atrial natriuretic peptide plasma levels in controls (n = 23), in ascitic cirrhotic patients who underwent spontaneous diuresis (group A, n = 7) and in cirrhotic patients who required diuretic treatment (group B, n = 44). The last group was then divided into two subgroups. Subgroup B-R (n = 25) included patients who responded to spironolactone alone, whereas subgroup B-NR (n = 19) included patients who did not respond to 500 mg/day spironolactone. All patients were maintained on identical normocaloric restricted sodium intake (80 mEq/day) throughout the study. Ascitic cirrhotic patients, as a whole, had higher values of human atrial natriuretic peptide than did controls (70.8 +/- 46.6 pg/ml vs. 41.7 +/- 16.3 pg/ml, p < 0.025). No difference was found in human atrial natriuretic peptide/plasma renin activity between the two groups (87 +/- 160 pg/ng/hr vs. 44 +/- 73 pg/ng/hr, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma thrombin-antithrombin III (T-AT) complexes are reputed to be an indirect manifestation of thrombin generation, and a role for their determination in the diagnosis of deep vein thrombosis (DVT) has been advocated. In order to evaluate the accuracy of T-AT complexes assay for DVT diagnosis, in 166 consecutive outpatients with clinical suspicion of the disease, plasma concentration of T-AT complexes was measured immediately before venography by means of an enzyme-linked immunosorbent assay kit. The result of the T-AT complexes assay was elevated in 29 of the 48 patients with DVT (sensitivity, 60%). The T-AT complexes levels were within the normal range in 104 of the 118 patients with normal venograms (specificity, 88%). The positive and the negative predictive value were 67% and 85%, respectively. The authors conclude that the T-AT complexes assay is of little value for the diagnosis of DVT in outpatients.

Renal tubular sodium handling was evaluated in 27 non-azotemic cirrhotic patients with ascites and positive sodium balance and in 17 controls after at least 5 days of a constant sodium intake using the lithium clearance as an index of fluid delivery to the distal tubule. Plasma renin activity and plasma aldosterone were also evaluated. Sodium fractional excretion, filtered sodium load, absolute sodium distal delivery, lithium fractional excretion and absolute distal sodium reabsorption were significantly lower in cirrhotics than in controls (0.58 +/- 0.11 vs. 1.29 +/- 0.12%, P less than 0.001; 12529 +/- 677 vs. 15707 +/- 796 microEq min-1 1.73 m-2 BSA, P less than 0.005; 2384 +/- 135.2 vs. 3685 +/- 219.3 microEq min-1 1.73 m-2 BSA, P less than 0.001; 19.5 +/- 1.0 vs. 24.2 +/- 1.3%, P less than 0.01; 2299 +/- 127 vs. 3485 +/- 214 microEq min-1 1.73 m-2 BSA, P less than 0.001, respectively). A correlation was found between lithium clearance and sodium clearance only in cirrhotic patients (r = 0.62; P less than 0.01). Distal sodium reabsorption evaluated as a per cent of filtered sodium load was lower in cirrhotics than in controls (19.1 +/- 1.0 vs. 22.4 +/- 1.2%, P less than 0.05) while distal sodium reabsorption evaluated as a per cent of sodium distal delivery was higher in cirrhotics than in controls (96.7 +/- 0.4 vs. 94.4 +/- 0.5%, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

In 69 hypertensive with suspected renovascular hypertension the response of plasma renin and angiotensin I to a single oral dose of Captopril (Captopril test) was determined. In 15 of the 16 patients found to have renal artery stenosis at angiography and cured by either revascularization or nephrectomy, Captopril stimulated both plasma renin activity and plasma angiotensin I to a far greater extent than in the majority of the 53 classified as essential hypertensives. False positives were limited to 8. Sensitivity and specificity were 94% and 85%, respectively. In the same series sequential renal angiophotoscan showed 100% sensitivity but a lower specificity (75%). In comparison, both the sensitivity and the specificity of rapid-sequence intravenous pielography, isotopic renogram and recumbent plasma renin activity were far less satisfactory. It is concluded that this simple, safe and economical test should be preferred to the other diagnostic procedures in the screening of renovascular hypertension. Its use in combination with renal angiophotoscan improves diagnostic reliability.

In this study, the dexamethasone suppression test (DST) and 2 rating scales, the 'Echelle d'Evaluation de Risque Suicidaire' and the Pierce modified form of the Suicide Intent Scale, were administered to a group of 37 subjects admitted to the general hospital of Padua for suicide attempts. The purpose of our study was to verify if these tools could be considered useful in assessing the severity of the attempts. 10 subjects were DST-positive, but the test evidenced very low sensitivity and predictive value. The 2 rating scales demonstrated a good degree of concordance in identifying the adjustment disorder group as being at a lower risk for a serious attempt.