Blood Pressure, Thyroid-Stimulating Hormone, and Thyroid Disease Prevalence in Primary Aldosteronism and Essential Hypertension

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1 original contributions nature publishing group Blood Pressure, Thyroid-Stimulating Hormone, and Thyroid Disease Prevalence in Primary Aldosteronism and Essential Hypertension Federica Turchi 1, Vanessa Ronconi 1, Valentina di Tizio 1, Marco Boscaro 1 and Gilberta Giacchetti 1 Background A positive correlation between thyroid-stimulating hormone (TSH) and blood pressure (BP) has been identified in normotensives and in patients with essential hypertension (EH). This study was designed to evaluate, in primary aldosteronism (PA) and in EH, potential association of BP, TSH, and ultrasonographic changes of the thyroid. Methods We studied 188 patients: 92 with PA and 96 matched essential hypertensives. Clinical and ambulatory BP (ABP), and thyroid function were evaluated in all patients. In PA and in a subgroup of EH patients (n = 65) thyroid ultrasonography was performed. Results In PA patients, diastolic office and diastolic ABP increased across TSH quartiles and multivariate analysis confirmed a positive significant correlation between TSH and diastolic BP, independently of aldosterone levels, body mass index (BMI), duration of hypertension, and age. In EH patients, we found a significant linear increase in Primary aldosteronism (PA) represents the most common form of endocrine hypertension 1 and a large body of evidence shows that aldosterone hypersecretion leads to high blood pressure (BP) and promotes the development of cardiovascular, renal, and metabolic complications. 2 Thyroid hormones influence the cardiovascular system and both subclinical and overt hypo- and hyperthyroidism may increase the risk of hypertension. 3 6 Recently, some population-based studies have indicated a linear positive association between thyroid-stimulation hormone (TSH) values, within the reference range, and systolic and diastolic BP 7,8 and higher TSH levels in hypertensive compared with normotensive euthyroid subjects. 9 Moreover, Gumeniak et al. demonstrated a familial aggregation of highnormal TSH concentrations in hypertensive families 10 suggesting that genetic variants may affect both BP and TSH levels. Thyroid function and morphology of patients with PA 1 Department of Internal Medicine, Division of Endocrinology, Università Politecnica delle Marche, Ospedali Riuniti Umberto I-G.M. Lancisi-G. Salesi, Ancona, Italy. Correspondence: Gilberta Giacchetti (g.giacchetti@ospedaliriuniti. marche.it) Received 8 April 2011; first decision 1 May 2011; accepted 10 July American Journal of Hypertension, Ltd. systolic and diastolic ABP with increasing TSH. The prevalence of thyroid dysfunctions was similar in PA and EH (15% and 19%, respectively). In PA patients, we found a higher prevalence of ultrasonographic alterations than in EH (66% vs. 46%, P < 0.05). PA patients presenting morphological abnormalities had higher homeostasis model assessment-insulin resistance levels than patients with normal gland at ultrasonography (4.2 ± 1.8 vs. 3.1 ± 0.8 P < 0.05). Conclusions We found a positive correlation between TSH and BP both in PA and EH patients. Moreover, in PA patients we observed a high prevalence of thyroid morphological alterations. Keywords: adrenal cortex; blood pressure; hypertension; primary aldosteronism; TSH American Journal of Hypertension, advance online publication 18 August 2011; doi: /ajh have been evaluated only in a few studies that demonstrated a higher prevalence of thyroid ultrasonographic abnormalities in PA patients compared with normotensive healthy controls 11 and a higher prevalence of thyroid dysfunction (i.e., abnormal thyroid function and/or presence of thyroid autoantibodies and/or presence of ultrasonographic abnormalities) in patients with PA than in essential hypertensives. 12 Aims of our study were to evaluate a potential correlation between TSH levels and BP in patients with PA and essential hypertension (EH), and to evaluate the prevalence of thyroid disease in PA patients, in order to test the hypothesis of a relationship between aldosterone excess and the development of thyroid alterations. Methods We studied 188 consecutive subjects referred to our endocrine hypertension unit with suspicion of PA: 92 with confirmed primary aldosteronism (33 with aldosterone producing adenoma and 59 with idiopathic hyperaldosteronism) and 96 patients with EH, matched for age, geographical area, body mass index (BMI), sex, and duration of hypertension. Patients receiving thyroxine or drugs potentially affecting thyroid function, were 1274 december 2011 VOLUME 24 NUMBER AMERICAN JOURNAL OF HYPERTENSION

2 Primary Aldosteronism and Thyroid Disease original contributions excluded from the study. The differential diagnosis of PA and EH was established as previously described. 13 Briefly, PA was suspected for an upright serum aldosterone/upright plasma renin activity (PRA) ratio >40 (ng/dl)/(ng/ml/h), together with an upright aldosterone value greater than 15 ng/dl, and confirmed with an aldosterone value >7 ng/dl after a 4-h intravenous saline infusion (2 l of 0.9% NaCl solution). In all patients with confirmed PA subtype, differentiation was obtained by computerized tomography scan with 3 mm contiguous slices and/or magnetic resonance followed by adrenal vein sampling. After exclusion of other forms of secondary hypertension according to standard protocols, all the patients were considered EH. Biochemical and clinical evaluations were performed after discontinuation of any antihypertensive treatment for at least 2 months for mineralocorticoid receptor antagonist, 4 weeks for renin angiotensin system blockers, 2 weeks for β-blockers and 1 week for calcium channel blockers and α-blockers. The study was approved by the institutional review board and informed consent was obtained from all participants. Clinical BP measurement. Office BP was measured in subjects, who had been seated quietly for at least 10 min, using a standard mercury sphygmomanometer with the cuff at the level of the heart and with cuff sizes selected on the basis of the measurement of arm circumference. The average of three readings obtained at 1-min intervals was considered for the study. BP thresholds were defined according to the European Society of Hypertension guidelines. 14 Ambulatory blood pressure measurement. Ambulatory blood pressure monitoring (ABPM) was performed in all subjects with Takeda TM-2430 instrument (A&D, Tokyo, Japan) using oscillometric measurements. For BP analyses, daytime was defined as from 0700 to 2259 h, and night-time from 2300 to 0659 h. Measurements were taken every 15 min during the daytime and every 30 min at night. All patients, instructed to act and work normally, had at least three valid readings per hour. BP thresholds were defined according to the European Society of Hypertension guidelines. 14 Laboratory measurements. All assays were performed in the central laboratory. Serum aldosterone (reference range for upright values 4 31 ng/dl) was measured by a solid-phase radioimmunoassay (RIA) kit (Biodata Diagnostics, Rome, Italy). Upright PRA (reference range ng/ml/h) was measured as the generation of angiotensin I in vitro using a commercially available RIA kit (Radim, Rome, Italy). Plasma insulin concentrations (reference range 0 27 µu/ml) were measured using RIA kit (Medical System, Immunite DPC, Los Angeles, CA), and plasma glucose (reference range mg/dl) was measured by photometric determination. Insulin resistance was assessed using the homeo stasis model assessment insulin resistance index as follows: fasting glucose (mmol/l) fasting insulin (mu/l)/22.5. Serum TSH, free triiodothyronine (FT3) and free thyroxine (FT4) levels were measured using chemiluminescent immunometric assay (ADVIA Centaur; Bayer, Tarrytown, NY). Serum antithyroid antibodies (antitpo, anti- TG) analysis was performed by RIA (Brahams Diagnostica, Berlin, Germany). Reference range were: TSH mui/l, FT ng/dl, FT pg/ml, antibodies anti-tpo <70 UI/ml, anti-tg <70 UI/ml. Thyroid ultrasonography. Thyroid ultrasound examinations were performed in PA patients and in a randomized subgroup of 65 EH patients in both transverse and longitudinal planes in our unit by the same operator with the same machine (ESAOTE BIOMEDICA AU 3 partner, linear probe 7.5 MHz; ESAOTE Spa, Florence, Italy). In accordance to current guidelines for clinical practice for the diagnosis and management of thyroid nodules, 15 a fine needle aspiration was also performed when indicated, and the cytological diagnosis of thyroid carcinoma was confirmed at pathological evaluation after surgery. Statistical analysis. Statistical analysis was performed using the StatView version 4.1 software for Windows (Abacus Concepts, Berkley, CA). Data are expressed as a mean ± s.d.. Statistical significance between groups was assessed by unpaired t test in normally distributed data. Data were analyzed by analysis of variance for multiple comparisons, as appropriate. Bonferroni s correction was then applied to reduce the probability of differences arising by chance. The Mann Whitney test and Spearman rank correlation were used for PRA values, which did not follow a normal distribution. The relationship between different variables was examined by linear regression analysis. Multivariate logistic regression analysis was then performed including potential confounding variables (age, duration of hypertension, plasma aldosterone levels, and BMI). Model based on quartiles of TSH levels were used to test for a progressive increase of BP across quartiles. Observed differences with P < 0.05 were considered statistically significant. Results Clinical and biochemical characteristics of the study populations are reported in Table 1. Compared with essential hypertensives, patients with PA presented higher clinical and ABP levels and, as expected from the diagnosis, higher serum aldosterone and aldosterone to PRA ratio values, lower PRA, and serum potassium concentrations. Moreover, mean TSH level was lower and mean FT4 value was higher in PA than EH patients. Correlation between TSH levels and BP in PA patients In PA patients, we found different BP values stratifying TSH levels in quartiles. Office diastolic blood pressure (DBP) progressively increased across the TSH quartiles (P < 0.05) and the results were statistically different between the first and fourth quartiles (P < 0.01). The same trend across the TSH quartiles was found for 24 h ABP: mean day-time DBP and night-time DBP values in the fourth quartile were significantly higher than levels in the first quartile (P < 0.05), as represented in Figure 1. Moreover, in the PA group, linear regression analysis showed that TSH levels were directly correlated with office DBP (r = 0.34, P < 0.01), mean daytime DBP (r = 0.32, P < 0.01), AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 12 december

3 original contributions Primary Aldosteronism and Thyroid Disease Table 1 Clinical and biochemical characteristics of PA and EH patients PA (n = 92) EH (n = 96) P value Age (years) 51 ± ± Male (%) Duration of HT (years) 10.3 ± ± BMI (kg/m 2 ) 28.2 ± ± SBP (mm Hg) 158 ± ± 13 <0.05 DBP (mm Hg) 100 ± 8 96 ± 6 <0.01 SBP dt (mm Hg) 151 ± ± 10 <0.05 DBP dt (mm Hg) 91 ± 7 87 ± 6 <0.01 SBP nt (mm Hg) 145 ± ± 12 <0.01 DBP nt (mm Hg) 83 ± 9 79 ± 7 <0.01 Serum K+ (meq/l) 3.7 ± ± 0.3 < h Urinary K+ (meq/l) 58 ± ± h Urinary Na+ (meq/l) 152 ± ± Plasma aldosterone (ng/dl) 49.8 ± ± 11.3 <0.01 PRA (ng/ml/h) 0.3 ( ) 3 ± 4.7 <0.01 Aldosterone to PRA ratio (ng/dl/ng/ml/h) 110 (71 188) 12 ± 13.2 <0.01 TSH (mui/l) 1.48 ( ) 1.67 ( ) <0.05 FT4 (pg/ml) 1.17 ± ± 0.19 <0.01 FT3 (ng/dl) 2.98 ± ± Data are reported as mean ± s.d. or as median (25th 75th percentile). BMI, body mass index; DBP, diastolic blood pressure; dt, daytime; EH, essential hypertension; FT3, free triiodothyronine; FT4, free thyroxine; HT, hypertension; K+, potassium; Na+, sodium; nt, night-time; PA, primary aldosteronism; PRA, plasma renin activity; SBP, systolic blood pressure; TSH, thyroid-stimulating hormone. and mean night-time DBP (r = 0.30, P < 0.05). No significant correlation was observed between TSH concentrations and office and ambulatory systolic blood pressure (SBP) (P > 0.05), plasma aldosterone (P > 0.05), PRA (P > 0.05), and serum and urinary electrolytes(p > 0.05). To confirm these relationships, multiple regression analysis was performed considering BP as the dependent variable. Including in the model, age, duration of hypertension, plasma aldosterone levels, and BMI, the analysis identified TSH levels as an independent predictor of office DBP (P < 0.05), mean daytime DBP (P = 0.01), and mean night-time DBP (P < 0.05) as shown in Table 2(A). The same correlations between TSH and BP were found in patients independently from presence/absence of thyroid dysfunction, presence of thyroid antibodies, and morphological alterations. Correlation between TSH levels and BP in EH patients Similar correlations between TSH levels and BP were found also in a matched group of patients with EH. As reported in Figure 2, 24 h BP increased significantly with increasing of TSH values (P < 0.05 for daytime DBP, P < 0.01 for night-time DBP, P < 0.05 for daytime SBP, P < 0.05 for night-time SBP). Analyzing the single quartiles, different daytime DBP values were found between the first and second (P < 0.05), between the first and the third (P < 0.05) and between the first and the fourth (P < 0.05). For a mm Hg b mm Hg * (n = 22) (n = 24) (n = 25) (n = 21) (n = 22) (n = 24) (n = 25) (n = 21) DBP dt DBP nt Figure 1 Office diastolic blood pressure (a) daytime diastolic blood pressure and (b) night-time diastolic blood pressure values across TSH quartiles in patients with PA. DBP, diastolic blood pressure; dt, daytime; nt, night-time; PA, primary aldosteronism; TSH, thyroid-stimulating hormone. 1: first TSH quartile (TSH between 0.01 and 0.96 mui/l); 2: second TSH quartile (TSH between 0.97 and 1.48 mui/l); 3: third TSH quartile (TSH between 1.49 and 1.94 mui/l); 4: fourth TSH quartile (TSH between 1.95 and 10.7 mui/l). *P = 0.01 between first and fourth quartile. P = 0.01 between first and fourth quartile. P < 0.05 between first and fourth quartile. Table 2 Multivariate regression analysis in PA and EH patients for TSH and blood pressure including into the model age, duration of hypertension, BMI, and aldosterone levels Covariate B coefficent 95% CI P TSH with age, duration of hypertension BMI and aldosterone levels in the model (A) PA patients DBP office <0.05 DBP dt <0.05 DBP nt <0.05 (B) EH patients DBP dt <0.05 DBP nt <0.05 SBP dt <0.05 SBP nt <0.05 BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; dt, daytime; EH, essential hypertension; nt, night-time; PA, primary aldosteronism; SBP, systolic blood pressure; TSH, thyroid-stimulating hormone. night-time DBP, significantly different values characterized the first and the second quartiles (P < 0.01), the first and the third (P < 0.01), the first and the fourth (P < 0.01), the second and the third (P < 0.05). Different daytime SBP distinguished the first and the fourth quartiles (P < 0.05). Higher night-time SBP levels characterized the first quartile by the third (P < 0.01), the first by 1276 december 2011 VOLUME 24 NUMBER 12 AMERICAN JOURNAL OF HYPERTENSION

4 Primary Aldosteronism and Thyroid Disease original contributions a b * (n = 25) (n = 26) (n = 23) (n = 22) (n = 25) (n = 26) (n = 23) (n = 22) DBP dt DBP nt SBP dt SBP nt Figure 2 Ambulatory blood pressure levels across TSH quartiles in patients with EH. (a) Daytime diastolic blood pressure, night-time diastolic blood pressure, (b) daytime systolic blood pressure, night-time systolic blood pressure values across TSH quartiles in patients with EH. DBP, diastolic blood pressure; dt, daytime; EH, essential hypertension; nt, night-time; SBP, systolic blood pressure; TSH, thyroid-stimulating hormone. 1: first TSH quartile (TSH between 0.02 and 1.07 mui/l); 2: second TSH quartile (TSH between 1.08 and 1.67 mui/l); 3: third TSH quartile (TSH between 1.68 and 2.85 mui/l); 4: fourth TSH quartile (TSH between 2.86 and mui/l). *P < 0.05 between first and second quartile, between first and third quartile and between first and fourth quartile. P < 0.01 between first and third quartile and between first and fourth quartile. P < 0.05 between first and fourth quartile. P < 0.01 between first and third quartile and between first and fourth quartile. P < 0.05 between second and third quartile and between second and fourth quartile. the fourth (P < 0.01), the second by the third (P < 0.05), and the second by the fourth (P < 0.05). Furthermore, TSH levels were positively correlated with mean daytime DBP (r = 0.20, P < 0.05), mean night-time DBP (r = 0.25, P < 0.05), mean daytime SBP (r = 0.27, P < 0.05), and mean night-time SBP (r = 0.31, P < 0.01), while the relation between TSH and office BP was not statistically significant. The multivariate analysis validated that the relationship of TSH with daytime and night-time systolic (P < 0.05) and daytime and night-time diastolic blood pressure (P < 0.05) was independent of aldosterone levels, BMI, duration of hypertension, and age as shown in Table 2(B). Prevalence of thyroid function and morphology alterations in PA and EH patients The prevalence of thyroid function alterations were similar in the two groups. Thyroid dysfunction occurred in 15% of patients with PA (n = 16): six patients (6%) presented subclinical hypothyroidism, eight patients (9%) had subclinical hyperthyroidism, and one showed overt hypothyroidism (1%). The prevalence of function alterations in EH was 19% (n = 18); in particular, 13 patients had subclinical hypothyroidism (14%), two patients had subclinical hyperthyroidism (2%), and three patients had overt hypothyroidism (3%). The prevalence of morphological alterations was higher in PA than in EH patients (P < 0.05). In PA patients, the prevalence of thyroid abnormalities at ultrasonography was 66% (78% in the unilateral adenoma and 59% in the idiopathic hyperaldosteronism): 47% of patients presented multinodular goiter, 16% of them had solitary nodules, and 3% had papillary carcinoma. In essential hypertensives group, 54% of patients had a normal gland, 25% of them had multinodular goiter, and 21% solitary nodules. Fine needle aspiration was performed in 21 out of 61 PA patients with ultrasound abnormalities (35%), and in 17 out of 44 EH patients with thyroid nodules (39%). The prevalence of thyroid antibodies was similar in PA and EH (38% and 35%, respectively, P = 0.82). Interestingly, PA patients with thyroid morphological alterations had significantly higher homeostasis model assessment-insulin resistance levels than patients with normal gland (4.2 ± 1.8 vs. 3.1 ± 0.8, P < 0.05), while in EH patients the trend was the same but the difference was not statistically significant (3.6 ± 1.7 vs. 3.2 ± 1.1, P = 0.17). Discussion In the present study, we investigated the possible correlation between TSH and BP in patients with primary aldosteronism and EH. To our knowledge, data of the present study are the first to reveal a relationship between BP and thyroid hormones in PA patients, also within the reference range of TSH. Furthermore, this correlation persisted after adjusting for age and BMI, two factors that are well known to be positively associated with BP, and was independent of aldosterone levels and duration of hypertension. In several papers, including two large population studies, an association between thyroid function and BP was found in normotensive and hypertensive euthyroid subjects. Asvold et al. in more than 30,000 men and women found a linear increase in systolic and diastolic blood pressure values and in the prevalence of hypertension per milliunit per liter increase in TSH within the reference range. 7 In the Tromso Study systolic and diastolic blood pressure were higher in euthyroid subjects belonging to the highest vs. those in the lowest TSH quartiles and TSH levels were statistically higher in patients with diastolic hypertension. 8 In our study in PA patients, we found that office, mean daytime, and night-time DBP increased linearly with increasing TSH levels. In accordance with literature observations reported above, there was a significant and positive association in our EH patients between 24-h systolic and diastolic blood pressure and TSH. The mean differences in adjusted BP levels between patients in the lowest and patients in the highest TSH quartile ranged between 6.4 and 9.1 mm Hg in PA patients and between 5.5 and 12 mm Hg in EH patients. These differences could be of potential clinical importance, although they need to be confirmed in other studies. The potential mechanisms that may explain these observations are not still understood. TSH receptors have been AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 12 december

5 original contributions Primary Aldosteronism and Thyroid Disease identified in endothelial cells, vascular smooth muscle cells, and cardiomyocytes but their role is unknown Some authors reported a correlation between the degree of endothelial dysfunction and TSH levels in overt and subclinical hypothyroidism as well as in patients with high-normal TSH values, probably due to a reduction in nitric oxide availability and consequent impairment of endothelial dependent vasodilation. 22 In addition, several studies demonstrated that arterial stiffness and atherosclerotic risk were increased in subclinical and overt hypothyroidism. 23,24 These mechanisms could be hypothesized both in PA and EH patients but in PA other factors may be involved. A potential crosstalk between thyroid hormones and renin angiotensin aldosterone system has been suggested by several studies. 25 Some authors observed proportional increase in plasma noradrenaline, adrenaline, cortisol, and/or aldosterone levels despite low PRA during the hypothyroidism state and suggested that sympathetic and/or adrenal activation may contribute to the development of hypertension in hypothyroid patients. 5,26 Regardless of these observations, in our study we did not find any correlation between renin angiotensin aldosterone system and thyroid hormones. In addition, the positive correlation between TSH and BP was observed in both groups of patients despite different hormonal patterns (i.e., patients with PA and EH), independently of PRA and aldosterone values, suggesting that this association could be independent of the cause of hypertension. For these reasons, according to the present study, it seems reasonable to exclude that TSH effects on blood pressure are directly mediated by systemic renin angiotensin aldosterone system. Regarding the prevalence of thyroid hormonal dysfunction, i.e., abnormal TSH and/or FT3 and/or FT4 values, limited to the small sample size of the present study, no difference was observed between patients with PA and EH. The only available study in the literature, evaluating the prevalence of thyroid dysfunction in PA patients compared with EH patients, is the one of Santori and colleagues. This study is however not comparable to the present study as thyroid dysfunction was defined by the presence of either morphological abnormalities or thyroid autoantibodies or thyroid hormonal alterations (defined as abnormal values of TSH, FT3, FT4). 12 No data are reported as for the occurrence of subclinical or overt hypoand hyperthyroidism. As for the morphological aspect, we analyzed ultrasonographic thyroid pattern in PA patients and in a subgroup of EH patients. In the literature, the prevalence of morphological alterations varies according to methods of detection and to the studied population between 13 and 50%. 27 In our PA patients, the prevalence of thyroid ultrasonographic abnormalities was higher (66%) than in the EH control group, in accordance with Armanini s data. 11 Another interesting observation in agreement with literature data was the finding of a prevalence of 3% of papillary carcinoma, exclusively in females. The potential mechanism that could explain the association between PA and multinodular goiter, nodules or papillary thyroid carcinoma are unknown and imbalance between several common growth factors or cytokines could be involved. In a recent study, Ayturk et al. reported a significant increased prevalence of thyroid nodules in patients with metabolic syndrome and showed a correlation between insulin resistance and thyroid nodule formation. 28 A higher prevalence of glycemic abnormalities and metabolic syndrome has been demonstrated in patients with PA compared with essential hypertensives 29,30 and in this study we found statistically significant higher homeostasis model assessment insulin resistance levels in PA patients with thyroid morphological alterations than in patients with normal gland. Thus, it could be hypothesized that the presence of insulin resistance, which characterizes PA patients, might contribute to a higher prevalence of thyroid nodules in such patients. A limitation of this study is the relatively small sample size. Moreover, our results suggest the existence of an association between TSH and BP in PA patients, although due to the methodological limitations of the study design, additional studies are needed to confirm our findings and to determine whether they can be generalized to other forms of hypertension. Another possible limitation is that the design was observational and the study did not focus on the possible pathophysiological mechanisms. Moreover, the conclusion related to structural thyroid abnormalities are limited by the lack of multivariable regression analysis to explore potential confounders. In conclusion, we found a positive linear correlation between TSH levels and both office and ABP monitoring DBP in PA patients and between TSH and systolic and diastolic 24-h BP in EH. Our study suggest that BP as a continuous variable, per se, is mediated by thyroid function regardless of the etiology of hypertension. Moreover, compared with EH, in PA patients we observed a higher prevalence of thyroid morphological alterations, for which insulin-resistance could be hypothesized as a physiopathological mechanism. Although these findings and the possible pathogenetic mechanisms involved need to be confirmed, we suggest to evaluate thyroid function in all hypertensive patients in order to promptly treat hypo- or hyperthyroidism states as well as to perform a thyroid ultrasonographic screening in all patients with primary aldosteronism. Acknowledgment: F.T. was the recipient of an award from the Italian Society of Hypertension. Disclosure: The authors declared no conflict of interest. 1. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F. 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