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Decisione, volizione, libero arbitrio
No full textUn trattato sulle basi anatomo-funzionali, psicodinamiche, filosofiche, antropologiche e morali del libero arbitrio, del processo decisionale e della volizione
Vascular mechanisms of blood pressure rhythms.
No full textA description of our studiies on circardian rhythm of perioheral flow and resistance
Metabolic syndrome: nothing more than a constellation?
No full textIn these last years, the scientific community made a
considerable effort to understand the biology underlying
cardiovascular disease (CVD), the major cause of morbidity
and mortality in the developed world. From the very beginning
it became apparent that several CVD risk factors were
present in the same individual, and the concept of clustering
risk factors was finally labelled in the 1980s by Reaven
as ‘Syndrome X’. This author postulated that a set of
metabolic and cardiovascular risk factors—such as hypertension,
hypertriglyceridaemia, low high-density lipoprotein
(HDL)-cholesterol levels, and hyperinsulinaemia—could have
a common aetiology based on insulin resistance, this latter
also playing per se a pivotal role on pathophysiology of
CVD. Since then, several other features were taken into
account to build the so-called ‘metabolic syndrome’
(MetS). The first operational definition of MetS was proposed
in 1999 by the World Health Organization (WHO), with hyperglycaemia
and/or insulin resistance as a central feature and
other greater than or equal to two related abnormalities
(hypertension, dyslipidaemia, central obesity, or microalbuminuria). In 2001, the National Cholesterol Education
Program (NCEP) proposed a new definition of MetS, no
longer requiring glucose impairment but rather treating
glucose metabolism as of equal importance with the other
components. Three over five criteria were sufficient, and
no one mandatory. Up to date, six different definitions of MetS exist as
described by Wang et al.4 in Table 1 which this editorial
refers to. All include the same core criteria of central
obesity, hyperglycaemia, dyslipidaemia, and hypertension,
but differ as for cut-off, mandatory requirements (central
obesity or insulin resistance) and inclusion of additional
factors (e.g. microalbuminuria). As a consequence of uncertain
criteria, a heated debate about MetS as fact or fiction
came to the limelight.5Coexistence of many definitions leads to the feeling that MetS is nothing more than a container, where different criteria
are clustered time-to-time. Not only, but such
definitions even proceed from the activity of panels of
experts, rather than from prospective epidemiological
evidence, and are therefore arbitrary.6 Finally, it is quite
difficult to compare the data published in the overabundance
of studies, where different definitions have been
used and different genetic background, lifestyle, and
age were considered. The paper by Wang et al. has the
merit to compare in the same non-diabetic population
the prevalence of MetS coming from all the six current definitions. Their analysis demonstrates that each definition
arbitrarily excludes subjects that are arbitrarily included
in another one, so that the different sets of people are
not congruent.
MetS has increased in arbitrariness when in 2001 the NCEP
decided to leave the glucocentric view that was the cornerstone
of the previous criteria. Once left out any sine qua non criterion, the natural consequence was a certain degree of relativism, with all criteria rising to the same
rank. The paper by Wang et al.4 simply originates from
this deal. The decision to cluster equipollent criteria into a constellation called MetS is the concrete answer of epidemiologists to the wish of predicting outcome. The rational of this clustering
is that subjects with more than two criteria should
show higher cardiovascular mortality/morbidity than those
having only two or one criteria. Unfortunately, the Wang’s
paper4 demonstrates this is not the case, as the predictive
power of the constellation is shown not to be higher than
that of its major components. Considering MetS as a risk
predictor has therefore the meaningfulness of a fiction.
We must be aware that, if one single criterion has the
same prognostic value than greater than or equal to three
aggregated criteria, using MetS is nothing more than a diversion
of resources.
Why does not the aggregation work better than single
covariables? At a superficial analysis this is a little
surprising. This phenomenon is probably due to the fact
that, as already mentioned above, aggregation leads to
restriction of the field of interest, with loss of subjects
and increasing specificity to the detriment of sensitivity
(excess false negatives). When we base the diagnosis on
greater tha or equal to three criteria and we employ this
definition for calculating relative risk, we actually
compare subjects at very high risk (those having MetS) with a sub-population at low-to-intermediate-to-high risk
represented by those having 0, 1, or 2 criteria considered
as a whole. It is obvious that the relative risk of this subpopulation is more than one, thus reducing the power of
the predictive analysis.
Wang et al. took into consideration an elderly population,
so stressing that in particular cohorts some criteria
probably become too inclusive, creating problems. For
example, as in western society, blood pressure increases
with growing old while the ‘130/85’ criterion is fixed,
it is only natural to find a very high prevalence of arterial
hypertension in the elderly. When dealing with
MetS in the elderly—where about all subjects finish to be
considered hypertensive—the criterion ‘arterial hypertension’
is therefore emptied of any statistical power.
Finally, a couple of words about cut-off values and continuous
variables. It has been recently pointed out that all
the items considered for labelling MetS are continuous,
meaning that their relative risk increases linearly without
any definite cut-off. Falsely dichotomizing continuously distributed variables are prone to error. If this is accompanied
by fickleness of criteria, the result is misclassification of
diseased subjects as healthy and viceversa. An example is
represented by those criteria that, according to clinical
guidelines, became more and more inclusive. For instance,
when passing from the cut-off of hypertension
‘140/90 mmHg’ (WHO, 1998–99) to ‘130/85 mmHg’
(Updated NCEP, 2005),7 in our experience þ24% subjects
have hypertension, and passing from ‘6.1 mmol/L’ to
‘5.6 mmol/L’ þ109% have glucose intolerance, and are
therefore automatically incorporated in MetS. So, as criteria
become more elastic, MetS becomes more prevalent in
general population. It would be a better choice to employ
variables showing curvilinear relation with cardiovascular
risk, making possible the identification of clear and definit inflection points. As regards dyslipidaemia, we could suggest
low-density lipoprotein (LDL) instead of HDL-cholesterol, as
the former has, at least in the elderly, shows an inflection
point that the latter has not. Any effort should
be make in order to find similar inflection points for any
possible variables implicates in the assessment of CVD risk
L'ANNUARIO DEI FARMACI - AGGIORNAMENTO
No full textAggiornamento del trattato L'ANNUARIO DEI FARMACI degli stessi autori
L'ICTUS CEREBRI NELLA POPOLAZIONE ANZIANA: STIMA DEL RISCHIO
No full textPUBBLICAZIONE DIDATTICA GIORNALISTIC
MEDICINA D'URGENZA E DI PRONTO SOCCORSO
No full textTrattato di medicina d'urgenza e di pronto soccorso sviluppato in 25 capitoli e 4 appendici
IL RISCHIO GLOBALE DELL'ANZIANO IPERTESO
No full text1° QUAD. DEL GRUPPO DI RIFLESSIONE DULL'IPERTENSIONE ART. NELL'ANZIAN
Evolving concepts of left ventricular hypertrophy
No full textAdaptative left ventricular hypertrophy mainly derives from
pressure or volume overload. Nevertheless, in the general population,
about one-fifth of normotensives develop left ventricular
hypertrophy despite a normal pressure load, while more than
one-third of hypertensives do not develop it in response to
pressure overload (Table 1). It is unclear why some subjects
become hypertrophic while others do not. Hypoxic or ischaemic myocyte loss could account for a limited number of such cases.
The natural history of left ventricular hypertrophy is also very
different, with some subjects developing heart failure and premature
death and others who seem to be free of these prognostic
effects1. Both left ventricular hypertrophy and its consequences
are complex integrating multigenic traits acting in the long
term. It has been known since the 1990s that biochemical signalling
events and changes in gene expression (including an increase of
immediate early genes and re-expression of fetal genes) are
important for the hypertrophic response. These phenomena
lead to increased protein synthesis and cell size which are characteristic of a hypertrophic pattern. In recent years, several transcription factors have been identified as determinants modulating gene
expression during hypertrophy in differentiated cells. The promoter
region of specific genes involved in the hypertrophic response
is a key point for signal integration. The complete mechanism
describing development/decompensation of myocardial hypertrophy
has not been fully clarified, but it is known that hypertrophy
signalling occurs through multiple parallel pathways, including
those linked with activation of the heterotrimeric G-protein Gq,
encoded by the GNAQ gene.
It is therefore clear that researchers involved in the field of
cardiac hypertrophy have to deal with these complex signalling
pathways that are under genetic control, not only to answer
some unanswered questions about the pathophysiology of left ventricular
hypertrophy but also from a prognostic and therapeutic
viewpoint.
Cardiologists are in general sceptical about genetics. Cardiovascular
disease is multifactorial, and responds to a mosaic of genes
that interact in common pathways to yield a synergistic mechanism
of action, adding further experimental uncertainty to the merely
probabilistic value of classical risk factors. Futhermore, association
studies based on the analysis of several polymorphisms have often
been disappointing for cardiologists. However, it must be emphasized
that the study of Frey et al.8 discussed here is not a mere
study of association, but rather a wide spectrum of research
going ‘from genetics, to molecular characterization, to a large
clinical study’.
One of the principal candidate signalling pathways for cardiac
hypertrophy is stimulation of the G protein Gq through its
G-protein-coupled receptors. The aim of the study by Frey
et al.8 was to investigate in humans the Gq protein overexpression
encoded by the GNAQ gene and to identify Gq promoter polymorphism
and specific transcription factors that regulate gene
expression, as already observed in animal models. In a recent
study by Clerk et al., they first characterized the GNAQ promoter
looking for a possible polymorphism suspected to play a prominent
role in disease susceptibility. They then identified the transcription
factors and their binding sites, and clarified whether the
Gq promoter was inducible by circulating stimuli, and whether
the novel single polymorphism was really able to increase Gq
expression resulting in enhanced activation of the Gq pathway
and in enhanced cell growth in a signal-dependent manner.
After identification of the promising GC(–695/–694)TT GNAQ
polymorphism and in vitro experiments highlighting its functional
expression, they checked in a population survey for its possible
association with left ventricular mass. Finally, applying multiple
regression models in subjects from the general population, the
authors concluded that the GC allele was more common in individuals with than without left ventricular hypertrophy, and -
more importantly—that, in contrast, the above-mentioned
polymorphism explained a significant part of the variance, really
predicting left ventricular hypertrophy.
Every effort was made to demonstrate that this polymorphism
was important and functional, by reproducing step by step the
entire pathway from identification of a novel polymorphism to
its phenotypic expression, ‘from genetics, to molecular characterization,
to a large clinical study’. The in vitro study was carried out
on fresh human atria, as there are no well-established continuous
cell lines that can be used to study cardiomyocyte development
and growth. The investigation showed that this single-nucleotide
polymorphism had functional implications, with the GC allele
increasing Gq expression (contrasting findings shown by others
could be attributable to the different setting14) and enhancing
signal transduction via Gq-coupled receptors. In particular, in the
GC allele carriers, Gq expression was found to be more inducible
by stimulation with angiotensin II, which is of interest as there are
higher circulating levels of this hormone in chronic disease, with
increased workload leading to heart failure. The greatest merit
of the study is to provide confirmation to the hypothesis that
cardiomyocyte Gq signalling is both necessary for pressure
overload hypertrophy3,4 and sufficient to produce overload-like
hypertrophy even in the absence of haemodynamic stress,15
giving support to the pathological and physiological mass increase.
In the population study, the effect of being GC allele carriers was
more prominent (odds ratio 5.52) in women than in men, possibly
explaining at the level of Gq mRNA expression why in populationbased
studies women have on average higher left ventricular mass
and higher prevalence of left ventricular hypertrophy than men.
Although the study needs to be confirmed in further population
cohorts respecting the criteria for internal validity of an association
study, Frey et al. have opened a way through better knowledge of
the onset and natural history of cardiac hypertrophy
[Hypertension in pregnancy: therapeutic aspects].
No full textUna review circa gli aspettivi diagnostici e terapeutici dell'ipertensione in gravidanza, in tema più volte ripreso in diversi ambiti dal prof. Casiglia nel corso degli anni
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