High Blood Pressure & Cardiovascular Prevention

https://doi.org/10.1007/s40292-020-00368-z

REVIEW ARTICLE

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience

of the URRAH (Uric Acid Right for Heart Health) Project
Alessandro Maloberti1,2 · C. Giannattasio1,2 · M. Bombelli2,3 · G. Desideri4 · A. F. G. Cicero5 · M. L. Muiesan6 ·
E. A. Rosei6 · M. Salvetti6 · A. Ungar7 · G. Rivasi7 · R. Pontremoli8 · F. Viazzi8 · R. Facchetti2 · C. Ferri4 · B. Bernardino4 ·
F. Galletti9 · L. D’Elia9 · P. Palatini10 · E. Casiglia10 · V. Tikhonoff11 · C. M. Barbagallo12 · P. Verdecchia13 · S. Masi14 ·
F. Mallamaci15 · M. Cirillo16 · M. Rattazzi11,17 · P. Pauletto17 · P. Cirillo18 · L. Gesualdo18 · A. Mazza19 · M. Volpe20,21 ·
G. Tocci20,21 · G. Iaccarino22 · P. Nazzaro23 · L. Lippa24 · G. Parati2,25 · R. Dell’Oro2,3 · F. Quarti‑Trevano2,3 · G. Grassi2,3 ·
A. Virdis14 · C. Borghi5 · Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension
(SIIA)

Received: 14 December 2019 / Accepted: 4 March 2020

© Italian Society of Hypertension 2020

Abstract
The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardio-
vascular risk factors that should be evaluated in order to stratify patient’s risk. In fact, it has been extensively evaluated and
demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infrac-
tion, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to
be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in
women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the
negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid
and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary
objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a
significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Keywords  Uric acid · Cardiovascular mortality · Cardiovascular events · URRAH

1 Introduction argument, that include 29 prospective studies with a total of

The latest Guidelines of Arterial Hypertension (2018, Euro-
pean Society of Cardiology/European Society of Hyperten-
sion—ESC/ESH) have officially introduced Uric Acid (UA)
evaluation among the CardioVascular (CV) risk factors that
should be evaluated in order to stratify patient’s risk [1].
The way to get this recognition has been very long from
the first identification of the relationship between UA and
CV events in 1967 in the Framingham cohort [2]. From that
study, many other researchers identified UA as an independ-
ent determinant of all-cause and CV mortality but also of
single CV events (principally Myocardial Infarction—MI—
and Stroke) [3–8]. One of the biggest meta-analysis on the
* Alessandro Maloberti
alessandro.maloberti@ospedaleniguarda.it
Extended author information available on the last page of the article
958,410 subjects, found a Hazard Ratio (HR) of 1.13 (95%
CI 1.05–1.21) for MI and 1.27 (95% CI 1.16–1.39) for CV
mortality [9].
Furthermore, UA has been related also to the develop-
ment of Heart Failure (HF) [10, 11] and to a higher mortality
in this group of patients [12, 13]. Finally, it has also been
found as a significant determinant of in-hospital mortality
during acute coronary syndrome [14–16] and to be related
to the development of atrial fibrillation [17].
Despite the important number of papers about this topic,
two question still need to be answered: first, if there’s a cut-
off value which impacts on cardiovascular risk; second, if
pharmacological reduction of UA leads to a reduction of
CV. This Latter point will be elucidated by on-going ran-
domized clinical trial undertaken both in symptomatic and
asymptomatic hyperuricemia [18–20]. Instead, there are no
data about the UA threshold in the context of cardiovascular

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risk. The actual hyperuricemia cut-off (> 6 mg/dL in women
and 7 mg/dL in men) is principally based on the saturation
point of UA but previous evidence suggests that probably
also at lower level it could act negatively on the CV system
[6, 21, 22]. This could also suggest that urate crystals pre-
cipitation is only one of the possible causes that determine
the relationship between UA and CV events. In fact, many
other potential mechanisms have been postulated to explain
this association; one of the most probably factors implicated
in the cardiovascular damage is the oxidative stress deter-
mined into the two final reactions that convert hypoxanthine
in xanthine by the Xanthine Oxidase [23]. During this reac-
tion, superoxide anions are generated and concur to a higher
oxidative stress. Furthermore, UA has been related to the
development of arterial hypertension [24], Diabetes Mellitus
(DM) [25] and metabolic syndrome [26]. Finally, also the
development of Target Organ Damage (TOD) at the heart,
vessels and renal level has been related to UA and hyper-
uricemia [27].
In this context, the Working Group on uric acid and CV
risk of the Italian Society of Hypertension has designed the
Uric acid Right for heArt Health (URRAH) project. The
primary objective of this project is to define the level of
uricemia above which the independent risk of CV disease
may increase significantly in a general Italian population.
2 The URRAH Study
The protocol of this study has been described extensively
in a previous publication [28]. Briefly, this is a multicentre,
retrospective, observational cohort study which has involved
the collection of data on outpatients (principally hyperten-
sives) and subjects from general population with a follow-up
period of at least 20 years up to 31 July 2017.
Data from the involved centers have been collected and
included into a general database. The cohorts included come
from various Italian Centres of Hypertension, distributed in
almost all the Italian regions and recognised by the Italian
Society of Hypertension. The involved centers are listed in
the Acknowledgements.
Inclusion criteria were the availability of at least one or
serum UA levels determination and of complete informa-
tion’s about demographics, CV risk factor (known history
of arterial hypertension, diabetes mellitus, smoking habit,
overweight/obesity defined through body mass index and
waist circumference), previous CV events, CV drug thera-
pies, blood pressure values, biochemical data (total and frac-
tioned cholesterol, triglycerides and renal function estimated
using a standardized serum creatinine assay and the Chronic
Kidney Disease Epidemiology Collaboration—CKD-EPI—
equation) and target organ damage at the carotid (Intima-
Media Thickness—IMT—and plaque presence), cardiac
A. Maloberti et al.
(Left Ventricular Hypertrophy—LVH) and renal level (uri-
nary albumin excretion).
At the end of the follow-up, the following hard endpoints
(based on the International Classification of Diseases, Tenth
Revision—ICD-10) has been evaluated: all-cause mortality,
CV mortality, fatal and non-fatal acute myocardial infarc-
tion, coronary revascularization, fatal and non-fatal stroke
and heart failure. Renal outcome has been established as a
double increment of serum creatinine.
Statistical analysis varies in the different protocols of the
URRAH project and has been described in detail in the rela-
tive papers.
Ethical approval has been done from Ethical Committee
of the coordinating centre (Division of Internal Medicine,
University of Bologna).
3 Population Characteristics
Depending on the aim and on the variable need for the
specific analysis, total number of the subjects used could
vary between different sub-studies but, in general, the total
population is composed by 23,475 subjects, which presents
a mean age of 57 ± 15 years; 49% were females and Systolic
and Diastolic Blood Pressure (SBP and DBP respectively)
were 143/85 ± 24/13 (Table 1). Regarding CV risk factor, the
average population was overweight (mean BMI 27 ± 4.3),
63.5% of subject present a diagnosis of arterial hypertension,
10% of DM and 25% were smokers.
The mean level of UA was 4.9 mg/dL and only a small
number of subjects present a history of gout or allopurinol
use (1.08 and 1.4%). Finally, 16.7% of the subjects has eGFR
levels compatible with a diagnosis of CKD (mean eGFR
value 83.3, Interquartile range 66.4–102.4).
Regarding medication, the most prescribed one were diu-
retics, followed by ACEi/ARBs and statins.
4 Uric Acid Cut‑off for Total
and Cardiovascular Mortality
The first analysis of the URRAH study was focused on the
determination of a UA threshold for total and CV mortal-
ity [29]. During a median follow up time of 134 months,
a total of 3279 deaths were recorded, of which 1571 were
due to CV causes. Firstly, we have confirmed that UA levels
are associated with all-cause and CV mortality, indepen-
dently from other CV risk factors or validated score risk
algorithm. In fact, at the univariate Cox model, UA was sig-
nificantly associated with an increased risk of all-cause (HR
1.24, 95% CI 1.21–1.27, p < 0.001) and CV mortality (HR
1.28, 95% CI 1.24–1.33, p < 0.001). Not only these associa-
tions remained significant also after the addition of all the
Hyperuricemia and Risk of Cardiovascular Outcomes

Table 1  Baseline characteristics of the population with available fol- 0.725, p < 0.001; Fig. 1c) and correctly reclassified 33.5%
low up data (n = 22,714) of subjects with events over the Heart Score at a cost of
Characteristics Mean (SD) or false allocation of 7.74% non-event patients to higher risk,
median (IQR) providing a significant Net Reclassification Improvement of
or % 0.26 over the Heart Score (p < 0.001).
Clinical variables The optimal cut point for CV mortality was 5.6 mg/dL
Age, years 57 (15) (Fig. 1b), which is associated with an HR of 1.59 (95% CI
Sex, female, % 11,134 (49.03) 1.43–1.76, p < 0.001). As for total mortality, the addition of
Smokers, n (%) 5542 (25.24) UA values further increases the productivity of Heart Score
BMI, kg/m2 27 (4.3) (Harrell’s C 0.780 vs 0.754, p < 0.001; Fig. 1d) and correctly
Waist Circumference, ­cma 90 (82–99) reclassified 40.06% of subjects without events over the Heart
Systolic blood pressure, mmHg 143 (24) Score at the cost of a false negative association of 12.28%,
Diastolic blood pressure, mmHg 85 (13) providing a significant Net Reclassification Improvement of
Uric Acid, mg/dLa 4.9 (4–5.9) 0.27 over the Heart Score (p < 0.001).
Total Cholesterol, mg/dL 212 (40) When both analyses were repeated after excluding sub-
HDL Cholesterol, mg/dL 55 (19) jects with gout diagnosis or taking allopurinol, results did
Triglycerides, mg/dLa 108 (78–154) not change.
Gout, n (%) 137 (1.08)
Diabetes mellitus, n (%) 2382 (10.52)
Chronic Kidney Disease, n (%) 3627 (16.70)
5 Uric Acid Cut‑off for Fatal Myocardial
eGFR 83.3 (66.4–102.4)
Infarction
Arterial hypertension, n (%) 14,392 (63.51)
Medications
Regarding MI, 445 participants experienced a fatal event
Allopurinol, n (%) 192 (1.40)
(231 women and 214 men) with a significant associa-
ACE-inhibitors, n (%) 2558 (14.88)
tion with UA in the total population (HR 1.146, 95% CI
Angiotensin Receptor Blockers, n (%) 1571 (11.03)
1.060–1.239, p = 0.0007) [30].
Β-Blockers, n (%) 1927 (9.44)
At ROC analysis the best cut-off for fatal events was
Diuretics, n (%) 3442 (16.79)
5.70 mg/dL with an incidence of 2.6% among the individuals
 Hydrochlorothiazide 541 (7.93)
below and 4.8% for those above the threshold (p < 0.0001).
 Indapamide 77 (1.13)
As shown in Fig. 2, also gender specific analysis were
 Chlortalidone 196 (1.95)
done confirming the significant association in women (HR
 Loop diuretics 492 (4.10)
0.136, 95% CI 0.058–0.215, p < 0.001) but not in men (HR
Statins, n (%) 1123 (5.21)
0.088, P = 0.2).
a
 Non-normally distributed variables Two cut-offs with little differences were found: 5.26 mg/
dL in women and 5.49 mg/dL in men. While the first one
discriminate between women that will experience the events
classic CV risk factor into the model (age, sex, smoking,
and who not, obviously, the same was not for men. On the
DM, hypertension, total cholesterol, alcohol use, creatinine
role of gender on the relationship between UA and CV
and CKD, haematocrit and use of diuretics) but they became
disease, we will discuss in detail in the last section of this
further more significant, particularly for CV mortality (all-
review.
cause mortality HR 1.53, 95% CI 1.21–1.93, p < 0.001; CV
mortality HR 2.08, 95% CI 1.46–2.97, p < 0.001). Finally,
these results are confirmed also by the exclusion of interac-
tion with age, DM and CKD. 6 Future Directions
As in the aim of this multicentre study, we identified two
different cut-offs for optimal prediction of all-cause and CV The aim of the present paper was to review the already pub-
mortality from ROC curve analysis. For total mortality, the lished data derived from the URRAH database, but also to
best cut-off value was 4.7 mg/dL. UA above this level were describe future direction and development for further pub-
associated an HR of 1.51 (95% CI 1.40–1.63, p < 0.001) of blications. In fact, some other analysis has been already
all-cause mortality and this remain significant after addition planned. Firstly, we will complete the data regarding the role
of CV risk factor and Heart Score into the model (Fig. 1a). of UA and cardiovascular events with two articles, focused
More important the addition of UA to the Heart Score incre- on cerebrovascular events and heart failure. In fact, as we
mentally predicted all-cause mortality (Harrell’s C 0.747 vs already stated in the introduction, UA has been related to
 A. Maloberti et al.

Fig. 1  Kaplan-Mayer curves for total (a) and cardiovascular mortality (b); ROC curves for total (c) and cardiovascular mortality (d). CV cardio-
vascular, UA uric acid, HS heart score, AUC​area under the curve

Fig. 2  Kaplan-Mayer curves for

fatal myocardial infarction for
the whole population and for
males and females separately

both these CV events [3–7, 10–13] but, to the best of our
knowledge, no specific threshold has been identified.
Furthermore, we will further increase the knowledge on
the role of UA as a possible determinant of CV TOD. In fact,
data about the association of UA with LVH, carotid IMT and
plaque and PWV has been published with heterogeneous
results. The majority of studies were cross-sectional [31–35],
with only few of them evaluating longitudinally [36–38] this
relation. UA levels could be associated with TOD principally
through its ability to determine oxidative stress and due to
its pro-inflammatory effects. Furthermore, it activates the
local renin-angiotensin system that, together with the two
Hyperuricemia and Risk of Cardiovascular Outcomes
previously cited effects, leads to molecular mechanisms
able to determine the thickening and stiffening of the vas-
cular wall via promoting proliferation and differentiation of
smooth muscle cells and endothelial dysfunction [39, 40]. At
the heart level pathological mechanism linking UA to LVH
concern again oxidative stress and the activation of the local
renin-angiotensin system [41]. Furthermore, in vitro studies
found that UA is able to promote cardiomyocyte differentia-
tion through inflammatory mediators such as tumor necrosis
factor-alpha and platelet-derived growth factor [42, 43].
Our big database could help with significant pieces of
information on this topic as well as in another important field
such as the prognostic CV significance of diuretic associated
hyperuricemia. In fact, diuretic use (particularly Hydrochlo-
rothiazide—HCT) is clearly associated with hyperuricemia
due to an increase in urate reabsorption in the proximal renal
tubules. Although the majority of patients on diuretic experi-
ences an asymptomatic elevation in UA, leading us to the
idea that this is a “benign” collateral, an association with
clinical gout has also been described [44–46], arising the
hypothesis on a possible role of diuretic-related hyperurice-
mia in CV disease. This is an “orphan” topic since no pub-
lication has been published on the differences in CV events
between diuretic and non-diuretic associated hyperuricemia
and we are yet working on such an analysis.
Finally, a study on the effects of hyperuricemia and renal
events has been planned, in order to find a specific cut-off
also for this outcome. The relationship between UA and
renal dysfunction is complex and bidirectional, representing
the cause but also the consequence of renal impairment. Uric
acid could determine renal damage throughout a number of
mechanisms. These include the deposition of uric acid into
the renal tubules due to hyperuricosuria and crystal forma-
tion [47]. Furthermore, oxidative stress has been found to
increase tubular-interstitial inflammation, which is able to
cause an afferent arteriolopathy with intimal hyperplasia,
muscular hypertrophy, and hyalinosis as well as interstitial
inflammation and fibrosis [48, 49]. On the other hands, when
GFR decreases also urate excretion decreases determining
a vicious circle that lead to complex interpretation of renal
outcome results.
7 Conclusions
The results of published studies from the URRAH database
further strengthen the role of UA in CV disease, not only for
classic CV events but also for HF.
The identified Cut-offs, although their performances need
to be confirmed in validation studies on other cohorts, could
help clinician to effectively define when to consider subjects
at a higher CV risk. As it has been reviewed, different cut-
offs have been found for different outcomes. Summarizing
it, we found a cut-off of 4.7 mg/dL for prediction of total
mortality, 5.6 mg/dL for CV mortality and 5.7 mg/dL for
fatal MI. All these cut-offs share their being much lower that
the classic hyperuricemia diagnostic cut-off confirming that
mechanisms others than urate deposition are implicated in
CV damage.
Another point of our studies should be discussed, i.e. the
role of gender into the relationship between UA and CV
events. In fact, into the MI analysis also a gender-specific
cut-off has been evaluated, founding that the association is
confirmed in females but not in males.
This is concordant with the evidence provided by previ-
ous longitudinal studies in patients with gout showing that
women are at increased risk for CV events as compared with
men [50, 51]. The most likely explanation of these findings
is that SUA metabolism is genetically controlled and gen-
der differences exist in gene function [52]. Another possible
explanation is also the relationship with the menopausal sta-
tus. In fact, it has been previously reported that hyperurice-
mia has been associated to left ventricular mass index in
post-menopausal women but no in premenopausal one [53].
As already stated, our database has been planned with the
aim of founding CV specific cut-off for UA. Unfortunately,
it will not help in answering another important question, i.e.
if the reduction of UA with specific therapy will determine
a reduction in CV events. In fact, many therapies are avail-
able for UA reduction (allopurinol, febuxostat, probenecid
and lenisurad) and many other are under evaluations [54].
While some of these drugs are able to reduce some interme-
diate endpoints (such as BP or TOD [55–57]), no big rand-
omized trials has been published on this question. Actually,
some of them are ongoing, such as the FAST (Protocol of
the Febuxostat versus Allopurinol Streamlined Trial) that is
comparing allopurinol vs febuxostat in gout patients without
previous CV events [18]. Important information will also
come from the ALL-HEART that is recruiting patients with
previous CV events but with asymptomatic hyperuricemia
randomizing them to allopurinol vs placebo [20].
Acknowledgements  URRAH Project participating centres and inves-
tigators: Dipartimento di Scienze Mediche e Chirurgiche Alma Mater
Studiorum, Università di Bologna. Claudio Borghi (coordinator),
Arrigo F.G. Cicero. Dipartimento di Scienze Cliniche e Sperimentali,
Università di Brescia. Maria Lorenza Muiesan (coordinator), Enrico
Agabiti Rosei, Massimo Salvetti. Dipartimento di Geriatria e Terapia
Intensiva Geriatrica, Università di Firenze, Azienda Ospedaliero Uni-
versitaria Careggi, Firenze. Andrea Ungar (coordinator), Giulia Rivasi.
Dipartimento di Medicina Interna e Specialità Mediche, Università
degli Studi di Genova e Policlinico Universitario San Martino-IST
Genova. Roberto Pontremoli (coordinator), Francesca Viazzi. Dipar-
timento di Medicina Clinica, Sanità Pubblica, Scienze della Vita e
dell’Ambiente, Università degli Studi dell’Aquila. Giovambattista
Desideri. Dipartimento di Scienze della Salute, Università di Milano-
Bicocca, Ospedale S Gerardo dei Tintori, Monza (MB). Guido Grassi
(coordinator), Michele Bombelli, Rita Facchetti. Dipartimento di
Medicina Clinica, Sanità Pubblica, Scienze della Vita e dell’Ambiente,

Università degli Studi dell’Aquila. Claudio Ferri (coordinator), Bruno
Bernardino. Dipartimento di Medicina Clinica e Chirurgia, Università
degli Studi di Napoli “Federico II”. Ferruccio Galletti (coordinator),
Lanfranco D’Elia. Dipartimento di Medicina, Università di Padova.
Paolo Palatini. Dipartimento di Medicina, Università di Padova.
Edoardo Casiglia (coordinator), Valerie Tikhonoff. Dipartimento Bio-
medico di Medicina Interna e Specialistica, Università degli Studi di
Palermo. Carlo M. Barbagallo. Dipartimento di Medicina, Ospedale
di Assisi (PG). Paolo Verdecchia. Dipartimento di Medicina Clinica
e Sperimentale, Università di Pisa. Agostino Virdis (coordinator),
Stefano Masi. Azienda Ospedaliera “Bianchi-Melacrino-Morelli” &
CNR-IFC, Reggio Calabria. Francesca Mallamaci. Dipartimento di
Scuola medica Salernirtana, Università di Salerno. Massimo Cirillo.
Dipartimento di Medicina, Ospedale Ca’ Foncello, Azienda ULSS 2
Marca Trevigiana, Treviso. Marcello Rattazzi (coordinator), Paolo
Pauletto. Dipartimento di Emergenza e Trapianto d’Organo, Azienda
Ospedaliero-Universitaria Consorziale Policlinico, Università “Aldo
Moro”, Bari. Pietro Cirillo (coordinator), Loreto Gesualdo. Ospedale
Santa Maria della Misericordia, Rovigo. Alberto Mazza. Dipartimento
Cardio-toraco-vascolare A. De Gasperis, ASST Grande Ospedale
Metropolitano Niguarda, Milano. Cristina Giannattasio (coordinator),
Alessandro Maloberti. Dipartimento di Medicina Clinica e Molecolare,
Università di Roma Sapienza, Ospedale S Andrea, Roma. Massimo
Volpe (coordinator), Giuliano Tocci. Dipartimento di Medicina Interna,
Chirurgia e Odontoiatria, Scuola Medica Salernitana, Università di
Salerno. Guido Iaccarino. Dipartimento di Neuroscienze ed Organi di
Senso, Università degli Studi di Bari. Pietro Nazzaro.
Compliance with Ethical Standards  14. Kojima S, Sakamoto T, Ishihara M, Japanese Acute Coronary
Funding  This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest  All the authors declares that they have no conflict
of interest.
Ethical approval  All procedures performed in studies involving human
participants were in accordance with the ethical standards of the insti-
tutional and/or national research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
Informed consent  Informed consent was obtained from all individual
participants included in the study.
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 A. Maloberti et al.

Affiliations

Alessandro Maloberti1,2 · C. Giannattasio1,2 · M. Bombelli2,3 · G. Desideri4 · A. F. G. Cicero5 · M. L. Muiesan6 ·

E. A. Rosei6 · M. Salvetti6 · A. Ungar7 · G. Rivasi7 · R. Pontremoli8 · F. Viazzi8 · R. Facchetti2 · C. Ferri4 · B. Bernardino4 ·
F. Galletti9 · L. D’Elia9 · P. Palatini10 · E. Casiglia10 · V. Tikhonoff11 · C. M. Barbagallo12 · P. Verdecchia13 · S. Masi14 ·
F. Mallamaci15 · M. Cirillo16 · M. Rattazzi11,17 · P. Pauletto17 · P. Cirillo18 · L. Gesualdo18 · A. Mazza19 · M. Volpe20,21 ·
G. Tocci20,21 · G. Iaccarino22 · P. Nazzaro23 · L. Lippa24 · G. Parati2,25 · R. Dell’Oro2,3 · F. Quarti‑Trevano2,3 · G. Grassi2,3 ·
A. Virdis14 · C. Borghi5 · Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension
(SIIA)

1 15
Cardiology IV, “A.De Gasperis” Department, Ospedale Reggio Cal Unit, CNR-IFC, Clinical Epidemiology of Renal
Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, Diseases and Hypertension, Reggio Calabria, Italy
20159 Milan, Italy 16
Department of Public Health, “Federico II” University
2
Health Science Department, Milano-Bicocca University, of Naples, Naples, Italy
Milan, Italy 17
Medicina Interna I, Ca’ Foncello University Hospital,
3
Clinica Medica, San Gerardo Hospital, Monza, Italy Treviso, Italy
4 18
Department of Life, Health and Environmental Sciences, Nephrology, Dialysis and Transplantation Unit, Department
University of L’Aquila, L’Aquila, Italy of Emergency and Organ Transplantation, “Aldo Moro”
5 University of Bari, Bari, Italy
Department of Medical and Surgical Science, Alma Mater
19
Studiorum University of Bologna, Bologna, Italy Department of Internal Medicine, Santa Maria della
6 Misericordia General Hospital, AULSS 5 Polesana, Rovigo,
Department of Clinical and Experimental Sciences,
Italy
University of Brescia, Brescia, Italy
20
7 Division of Cardiology, Department of Clinical
Department of Geriatric and Intensive Care Medicine,
and Molecular Medicine, Faculty of Medicine
Careggi Hospital and University of Florence, Florence, Italy
and Psychology, University of Rome Sapienza, Sant’Andrea
8
Department of Internal Medicine, University of Genoa Hospital, Rome, Italy
and Policlinico SanMartino, Genoa, Italy 21
IRCCS Neuromed, Pozzilli, Italy
9
Department of Clinical Medicine and Surgery, “Federico II” 22
Department of Advanced Biomedical Sciences, “Federico II”
University of Naples Medical School, Naples, Italy
University of Naples, Naples, Italy
10
Studium Patavinum, Department of Medicine, University 23
Department of Medical Basic Sciences, Neurosciences
of Padua, Padua, Italy
and Sense Organs, University of Bari Medical School, Bari,
11
Department of Medicine, University of Padua, Padua, Italy Italy
12 24
Biomedical Department of Internal Medicine Italian Society of General Medicine (SIMG), Avezzano,
and Specialistics, University of Palermo, Palermo, Italy L’Aquila, Italy
13 25
Hospital S. Maria della Misericordia, Perugia, Italy Department of Cardiovascular, Neural and Metabolic
14 Sciences, San Luca Hospital, Istituto Auxologico Italiano,
Department of Clinical and Experimental Medicine,
IRCCS, Milan, Italy
University of Pisa, Pisa, Italy