Renzo De Toni

Adrenocorticotropic Hormone Stimulation During Adrenal Vein Sampling for Identifying Surgically Curable Subtypes of Primary Aldosteronism. Comparison of 3 Different Protocols

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 &mgr;g IV as a bolus), a very low dose (VLD; 250 pg IV), and an intermediate dose (ID; 50 &mgr;g/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 (SIRIGHT +113% and SILEFT +131%), as compared with baseline values. The ID (n=14) also markedly increased both plasma cortisol concentration inferior vena cava (+93%) and the SI (SIRIGHT +690% and SILEFT +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.

Dynamic testing with high-dose adrenocorticotrophic hormone does not improve lateralization of aldosterone oversecretion in primary aldosteronism patients.

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 μg 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.

Albumin excretion rate increases during acute myocardial infarction and strongly predicts early mortality.

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 Coxs 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.

Antibodies to oxidized low-density lipoproteins and angiographically assessed coronary artery disease in white patients.

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 ≥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.

Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by lithium clearance

Abstract. 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 aldos‐terone 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%, < 0.001; 12529± 677 vs. 15707±796 μEq min−1 1.73 m−2 BSA, <0.005; 2384±135.2 vs. 3685±219.3 μEq min−1 1.73 m−2 BSA, < 0.001; 19.5±1.0 vs. 24.2±l.3%, < 0.01; 2299±127 vs. 3485±214 μEq min−1 1.73 m−2 BSA, <0.001, respectively). A correlation was found between lithium clearance and sodium clearance only in cirrhotic patients (r = 0.62; <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%, <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%,< 0.005). In both groups a correlation was found between log plasma aldosterone and distal sodium reabsorption evaluated as a per cent of absolute sodium distal delivery (r = 0.61, <0.01 and r=0.52,<0.05 respectively).

Impact of Accessory Hepatic Veins on Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism

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 ≈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 ≈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.

Microalbuminuria, renal function and development of sustained hypertension: a longitudinal study in the early stage of hypertension.

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.

Effects of androgens on endothelial progenitor cells in vitro and in vivo.

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.

Relationship of plasma renin activity with caffeine intake and physical training in mild hypertensive men

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.

Albumin excretion in acute myocardial infarction: A guide for long-term prognosis

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.