27 research outputs found
GWAS, prevenzione cardiovascolare e medicina di precisione (GWAS, cardiovascular prevention and precision medicine)
Genome-wide association studies provide a great opportunity for medical research and for clinical
practice that goes from discovery of new possible therapeutic targets to the identification of subjects
with beneficial (or detrimental) response to drugs. In this review, we highlight some examples that
path the way to a precision medicine approach in cardiovascular prevention: e.g. the use of genetic information
to identify subjects with better response to statin therapy, and a genome-wide analysis identifying
carriers of variants responsible for higher cardiovascular mortality rate during intensive glycemic
control in type 2 diabetes. While further studies are warranted before the clinical translation of
these findings, it is conceivable that similar precision medicine approaches will not be long in coming
HIV clinical indicator diseases prior to HIV diagnosis are correlated to clinical progression in Late Presenters
I fibrati: dal loro impiego in terapia agli studi di farmacogenetica (Fibrates: from clinical practice to pharmacogenetic studies)
Over the last decades, the use of fibrates has been pursued as a strategy to reduce cardiovascular risk.
These drugs are agonists of peroxisome proliferator-activated receptor-alpha (PPAR-a) - a transcription
factor that regulates lipid metabolism via several routes, but mostly via direct up-regulation of specific
PPAR-a target genes. The main effects of fibrates on lipid metabolism are a decrease in serum
triglycerides (TG), an increase in HDL cholesterol, and an increase in the size of LDL particles,
making them less atherogenic. Additionally, fibrates reduce systemic inflammation independently
from their effect on lipid metabolism. Despite such beneficial effects, results from clinical trial have
been overall disappointing, for this reason, their use in clinical practice for cardiovascular prevention is
not generally recommended. At the same time, meta-analysis of post-hoc studies in specific subgroups
of patients, i.e. subjects with atherogenic dyslipidemia (= high TG combined with low HDL cholesterol
levels) have consistently showed a cardiovascular benefit of fibrates. For this reason, fenofibrate might
be considered to reduce residual cardiovascular risk (aiming to reduce levels of non-HDL cholesterol)
as second or third line treatments among patients with atherogenic dyslipidemia. Interest in these
drugs have been increased also by recent genetic and epidemiological studies reinvigorating the
possible beneficial effect of improving lipid profile beyond LDL-cholesterol reduction. Furthermore,
pharmacogenetic studies suggest the possibilities of further optimizing fibrate therapy with a
“precision medicine” approach based also on genetic markers. This approach looks promising but will
need further confirmation before its translation in clinical practice
Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucose-lowering treatments. A multicenter retrospective study in Italian specialist care
Aim Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI. Methods We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs. Results MAFLD (defined by HSI > 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI < 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was > threefold higher among subjects with HSI > 36 than among those with HSI < 30. Notably, HSI declined significantly similar to 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide. Conclusion About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D
Sindrome metabolica e infiammazione sistemica
SommARIo
La sindrome metabolica (SM), intesa come l’associazione di condizioni cliniche specifiche (obesità androide,
iperglicemia, ipertensione arteriosa, dislipidemia e iperuricemia) è nota fin dal 18° secolo. Tuttavia
il riconoscimento e il passaggio da sindrome a malattia, per cui è necessario riconoscere un fattore
eziopatogenico comune, è ancora in corso. Reaven ipotizzò che l’insulino-resistenza (IR) fosse il “primum
movens” della SM e tale linea di pensiero si è mantenuta fino al riscontro di altri due possibili fattore
determinanti: l’obesità centrale e l’infiammazione sistemica. Numerosi studi hanno dimostrato il ruolo
pro-infiammatorio dell’eccesso di tessuto adiposo e il ruolo dell’infiammazione sistemica cronica di basso
grado come nuovo fattore di rischio cardio-vascolare. Recentemente abbiamo confermato come, in una
popolazione anziana, la relazione tra elevati valori di PCR e SM sia fortemente condizionata dalla presenza
di obesitĂ androide, e indipendentemente dalla presenza di IR. Successivamente abbiamo dimostrato
che il trans-signalling dell’IL-6 (cioè la diffusione del segnale dell’IL-6 a tutti i tessuti dell’organismo con
un effetto sistemico e cronicizzato) è correlato esclusivamente alla presenza di IR. Questi risultati suggeriscono
due diversi aspetti nel rapporto tra SM e infiammazione sistemica. Da un lato viene confermato
come l’infiammazione, legata all’aumento di citochine quali IL-6 e IL-18, sia sostanzialmente dipendente
dall’adiposità viscerale. Dall’altro, la diffusione del segnale infiammatorio a livello sistemico (trans-signalling
della IL-6) sembra correlato alla presenza di IR. Appare quindi evidente come, oltre alla IR, anche
infiammazione sistemica e obesitĂ addominale siano ormai da considerare due fattori determinanti nella
patogenesi della SM
Association of 1513CC P2X7 receptor genotype with age
Aging is a progressive degenerative process associated with chronic low-level inflammation. P2X7R is
a receptor for extracellular ATP that plays an important role in inflammation and has been associated
with different age-related pathologies. The 1513A>C P2RX7 polymorphism causes an impairment in
receptor responses with complete loss-of-function in 1513CC P2RX7 homozygous.
We carried out a literature analysis to verify an association between the 1513CC genotype frequency
and age. Our analysis shows no association between these parameters in the overall population or
extra- European subjects. However, frequency of 1513CC P2RX7 homozygous increased with age in
Caucasian European subjects. This result was confirmed when we examined genetic data from two
genome-wide association studies including USA Caucasian cohorts.
In conclusion, this study suggest that Caucasian individuals with an anti-inflammatory P2X7 receptor
phenotype could have a longer life expectancy in high-income countries where the main causes of
death are chronic inflammatory diseases
Sindrome delle apnee ostruttive nei pazienti obesi: effetti sul profilo metabolico e cardiovascolare e risposta a 6 mesi alla terapia comportamentale.
Sindrome delle apnee ostruttive nei pazienti obesi: effetti sul profilo metabolico e cardiovascolare e risposta a 6 mesi alla terapia comportamentale. 30° Congresso Nazionale Società Italiana Studio Aterosclerosi, Roma, 20-22 novembre 2016
Role of metabolic abnormalities of the metabolic syndrome in prostatic adenomyomatosis and prostate cancer.
Aim: Aim of this study was to evaluate the possible association between the metabolic abnormalites
characteristic of the Metabolic Syndrome (MetS), according to NCEP-ATPIII, and the prostatic
adenomyomatosis or prostate cancer.
Methods: 111 patients were enrolled. Subjects underwent a medical examination including digital rectal
exploration (DRE), prostate-specific antigen (PSA) determination and, when indicated a transrectal
ultrasonography (TRUS) with prostate biopsy. Patients were subsequently divided into 3 groups: subjects
with DRE -, TRUS - and PSA < 4 ng/ml (controls, n=24); patient with histological diagnosis of prostate
cancer (PC n=32) and patient with prostatic alterations (DRE+ and/or TRUS + and/or PSA > 4 mg/dl)
without histological evidence of prostate cancer (DRE/TRUS/PSA+/Bio- n=55).
Results: Total cholesterol, LDL-chol and not-HDL-chol were significantly lower in the DRE/TRUS/PSA
+/Bio - group compared to controls and PC group. Triglycerides, glycemia, HDL-chol and insulin
sensitivity, estimated with HOMA index, were not significantly different however the prevalence of the
glycemic criteria for MetS was significantly higher in the DRE/TRUS/PSA +/biopsy - group. The three
groups did not differ in terms of adiposity index except for BMC which was significantly lower in PC group.
Prevalence of MetS was similar in the 3 groups however subjects in the DRE/TRUS/PSA+ Bio - group
met a significantly higher number of diagnostic criteria for MEtS.
Conclusions: Our results support a possible association between MetS and benign prostatic hyperplasia
while metabolic abnormalities do not seem to be associated with prostate cancer
Determinants and clinical significance of plasma oxidized LDLs in older individuals. A 9 years follow-up study
Oxidized LDLs (ox.LDLs) uptake by macrophages inside the arterial wall is a crucial step in atherosclerotic
disease, and some studies suggest that high ox.LDLs plasma levels might be associated with cardiovascular
disease (CVD). However, whether high ox.LDLs continue to be a CVD risk factors in older persons is
unknown. We investigated the clinical correlates of plasma ox.LDLs, and their role in predicting longterm
CVD/cardiac mortality in 1025 older community dwelling individuals (mean age: 75.5 7.4
years; females: 55%) from the InCHIANTI study. KaplaneMeier curves were fitted to explore the relationship
between tertiles of ox.LDLs (ox.LDL/LDL-C ratio) and time to CVD/cardiac death. Hazard Ratios
(HR) were estimated by Cox regression analysis.
At multivariate analysis, ox.LDLs were independently associated with LDL-C, triglycerides, and HDL-C
(adjusted r2: 0.42; P ÂĽ 0.001). The ox.LDL/LDL-C ratio (the extent of LDLs oxidation) was independently
correlated with HDL-C, triglycerides, and beta-carotene (adjusted r2: 0.15, P ÂĽ 0.001). Among 1025
individuals, 392 died after 9 years, 166 from CVD. The HR for CVD/cardiac mortality was not significantly
different across tertiles of ox.LDLs or ox.LDL/LDL-C ratio, both in the whole sample and in individuals
with prevalent CVD.
We conclude that in an elderly population LDL-C, triglycerides, and HDL-C are the most important
determinants of ox.LDLs levels, indirectly suggesting an association between small dense LDLs and LDLs
oxidation. No association emerged between higher ox.LDLs levels and 9 years CVD/cardiac mortality,
suggesting that in advanced age the prognostic information added by ox.LDLs on CVD/cardiac mortality
might be negligible
Paraoxonase-1 activities in individuals with different HDL circulating levels: Implication in reverse cholesterol transport and early vascular damage.
BACKGROUND AND AIMS:
Epidemiological data showing that high-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular disease have led to the idea that cholesterol contained in this lipoprotein may be protective. Against, recent evidence suggests that the athero-protection from HDLs may result from other functions, unrelated to the carried cholesterol. HDL accessory proteins, such as paraoxonase 1 (PON1), have been suggested to endows HDL with antioxidant and anti-inflammatory properties and to contribute to the athero-protective function of the lipoprotein. We aimed to evaluate whether extreme fluctuation in HDL-C levels correlates with PON1 activity.
METHODS:
Levels of PON1-related arylesterase and lactonase were assessed in subjects with primary hyperalphalipoproteinemia (HAL, HDL-C>90th percentile), hypoalphalipoproteinemia (HA, HDL-C<10th percentile) and controls. Cholesterol efflux capacity (CEC) through several pathways and other metabolic parameters and markers of vascular disease were also determined.
RESULTS:
Despite the marked change in HDL-C and Apoliprotein A1 (APO A1) (p < 0.001 for all comparisons), arylesterase and lactonase were only slightly increased in HAL compared with HA subjects (p < 0.05), but not vs. controls. This change in PON1 activities was no longer significant after adjustment for either HDL-C or APO A1. Both enzymatic activities were positively associated only with aqueous diffusion CEC (r = 0.318, p < 0.05 and r = 0.355, p < 0.05, respectively) and negatively with the presence of plaques (p < 0.05).
CONCLUSIONS:
We showed that extreme high/low HDL-C levels are not associated with equal increase/decrease in PON1 activities. This enzyme appears to contribute to the HDL role in reverse cholesterol transport and anti-atherosclerosis processes. Further investigation is required to corroborate our findings