Giovanni Davı̀ works in General Cardiology affiliated with University of Chieti-Pescara.
Giovanni Davì was a Professor of Internal Medicine at the G. d'Annunzio University of Chieti-Pescara. He served as Chief of the Department of Internal Medicine at the University Hospital of Chieti and as Director of the Postgraduate Schools of Internal Medicine and Hematology. His research centered on platelet function and its role in cardiovascular and metabolic diseases.
339 pubs · 20,751 cites · h-index 72
MD
University of Palermo
1973
Full Professor of Internal Medicine
G. d'Annunzio University of Chieti-Pescara · 2017
Chief of the Department of Internal Medicine
University Hospital of Chieti
Director of the Postgraduate School of Internal Medicine
G. d'Annunzio University of Chieti-Pescara
Director of the Postgraduate School of Hematology
G. d'Annunzio University of Chieti-Pescara
Researcher
Università Cattolica del Sacro Cuore · 1980 - Present
Acute hyperglycemia warrants caution in type 2 diabetes for thrombotic risk; confirms causal platelet activation in RCT.
General / Preventive / Lipids · Sapienza University of Rome
This study provides the first evidence that one-fifth of NVAF patients had an ABI?0.90, indicating that it may represent a simple and cheap method to better define the prevalence of vascular disease in NVAF
Journal of the American College of CardiologyVioli et al.
This review provides a comprehensive overview of the left atrial appendage, its role in thromboembolism in atrial fibrillation, and current management strategies including imaging and occlusion devices.
OBJECTIVE Obesity is associated with an increased risk of type 2 diabetes and cardiovascular complications. The risk depends significantly on adipose tissue distribution. Liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We determined whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese subjects with prediabetes or early type 2 diabetes. RESEARCH DESIGN AND METHODS Sixty-two metformin-treated obese subjects with prediabetes or newly diagnosed type 2 diabetes, were randomized to liraglutide (1.8 mg/day) or lifestyle counseling. Changes in SAT and VAT levels (determined by abdominal MRI), insulin sensitivity (according to the Matsuda index), and β-cell function (β-index) were assessed during a multiple-sampling oral glucose tolerance test; and circulating levels of IGF-I and IGF-II were assessed before and after a comparable weight loss (7% of initial body weight). RESULTS After comparable weight loss, achieved by 20 patients per arm, and superimposable glycemic control, as reflected by HbA1c level (P = 0.60), reduction in VAT was significantly higher in the liraglutide arm than in the lifestyle arm (P = 0.028), in parallel with a greater improvement in β-index (P = 0.021). No differences were observed in SAT reduction (P = 0.64). IGF-II serum levels were significantly increased (P = 0.024) only with liraglutide administration, and the increase in IGF-II levels correlated with both a decrease in VAT (ρ = −0.435, P = 0.056) and an increase in the β-index (ρ = 0.55, P = 0.012). CONCLUSIONS Liraglutide effects on visceral obesity and β-cell function might provide a rationale for using this molecule in obese subjects in an early phase of glucose metabolism dysregulation natural history.
BACKGROUND: The metabolic syndrome (MetS) is a cluster of risk factors for the development of cardiovascular diseases (CVD) and type 2 diabetes (T2DM). According to several meta-analyses, it has been shown that the cardiovascular (CV) risk conferred by the MetS is higher in women in comparison with men. There are many possible reasons to explain a higher CV risk in women with MetS: the most important differences can be attributed to distribution of central adiposity, lipid profile and hormones, but also differences in platelet biology and biochemistry play an important role. METHODS: In this article we performed a research using PubMed database reviewing the evidence in literature (in particular clinical trials and meta-analyses) or lack of evidence/ biased information regarding the distribution by gender of MetS components and associated CV risk and we intended to provide a consequent gender perspective to the treatment of MetS and CV risk. RESULTS: Twenty-three papers were evaluated searching for sex differences in the prevalence of MetS and CV risk. We also identified fifty-six papers dealing with sex differences in adiposity, insulin resistance and hormonal regulation. In terms of gender-specific expression of MetS in chronic disease we analyzed thirty-one papers focusing the attention on non-alcoholic fatty liver disease, polycystic ovarian syndrome, gestational diabetes mellitus, rheumatoid arthritis and HIV infection. We also evaluated twenty papers focusing on gender differences in platelet biology/reactivity and thirty-three papers on the gender approach in the treatment of MetS. The CV risk conferred by MetS segregates differently according to gender; differences between sexes may depend on the different representation of MetS components, gender-specific genetic, acquired metabolic and hormonal milieu and finally on a differential interaction between known risk factors and genderspecific properties, resulting in different degrees of pathophysiological events eventually leading to atherothrombosis. Regarding a potential sex-related therapeutic approach, even if gender-related differences exist in the pharmacokinetics of drugs for differences in body composition, plasma protein binding, metabolizing enzymes and difference in excretion characteristics, we have to acknowledge that women are under-represented in clinical trials, thus preventing from adequately challenging the efficacy and safety of drugs in this gender. CONCLUSION: While ncreasing knowledge exists regarding pathophysiological differences between genders in the prevalence of MetS components as well as in the associated cardiometabolic risk, underrepresentation of women in clinical trials and underutilization of guideline therapy, for instance in women with ischemic heart disease, largely flaw the interpretation of epidemiological and clinical evidence. Efforts should be undertaken to fight the so-called "Yentl syndrome" and to promote gender-specific drug trials, or at least studies where subgroup analyses by gender are pre-specified.
The hypothesis that increased oxidative stress in breast cancer (BC) patients could induce enhanced lipid peroxidation, which, in turn, would contribute to platelet activation and poor clinical outcome is attractive. To address this issue, we investigated pre-surgical urinary 8-iso-prostaglandin (PG)F2α (marker of in vivo oxidative stress) and 11-dehydro-thromboxane (TX)B2 (marker of in vivo platelet activation) levels in patients with primary BC (n = 115) compared with control women paired for comorbidities and their association with patients' metabolic profile and clinical prognostic factors. The results obtained showed that presurgical urinary excretion of both biomarkers was enhanced in BC patients compared to controls and was associated with patients' estrogen receptor (ER) expression, but not HER2 status or Ki67 proliferation index. Accordingly, both urinary biomarkers were increased in patients with luminal-like BC molecular subtypes compared with triple negative or HER2-enriched tumors. ER status was an independent predictor of 8-iso-PGF2α urinary levels, which, in turn, significantly predicted 11-dehydro-TXB2 urinary levels together with disease stage and ER status. The prognostic value of 11-dehydro-TXB2 was then evaluated showing a significant correlation with BC pathological response to neoadjuvant treatment. Furthermore, among relapsing patients, those with elevated urinary biomarker levels were more likely to develop distant metastasis rather than local recurrence. In conclusion, we may speculate that enhanced oxidative stress due to estrogen-related mechanisms might cause a condition of persistent platelet activation capable of sustaining BC growth and progression through the release of bioactive stored molecules, ultimately contributing to tumor invasiveness. Further studies specifically addressing this hypothesis are presently needed.
Resistin is an adipokine that promotes inflammation and insulin resistance by targeting several cells including platelets. We hypothesised that in type 2 diabetes (T2DM), resistin may foster in vivo oxidative stress, thromboxane-dependent platelet activation and platelet-derived inflammatory proteins release, key determinants of atherothrombosis. A cross-sectional comparison of circulating resistin, sCD40L, as a marker of platelet-mediated inflammation, asymmetric dimethylarginine (ADMA), endothelial dysfunction marker, Dickkopf (DKK)-1, reflecting the inflammatory interaction between platelets and endothelial cells, and urinary 8-iso-PGF₂α and 11-dehydro-TxB₂, reflecting in vivo lipid peroxidation and platelet activation, respectively, was performed between 79 T2DM patients and 30 healthy subjects. Furthermore, we investigated the effects of the α-glucosidase inhibitor acarbose and the PPARγ agonist rosiglitazone, targeting hyperglycaemia or insulin resistance, versus placebo, in 28 and 18 T2DM subjects, respectively. Age- and gender-adjusted serum resistin levels were significantly higher in patients than in controls. HOMA (β=0.266, p=0.017) and 11-dehydro-TXB₂ (β=0.354, p=0.002) independently predicted resistin levels. A 20-week treatment with acarbose was associated with significant reductions (p=0.001) in serum resistin, DKK-1, urinary 11-dehydro-TXB₂ and 8-iso-PGF₂α with direct correlations between the change in serum resistin and in other variables. A 24-week rosiglitazone treatment on top of metformin was associated with significant decreases in resistin, DKK-1, 11-dehydro-TXB₂ and 8-iso-PGF₂α, in parallel with HOMA decrease. In conclusion, resistin, antagonising insulin action in part through PPARγ activation, may favour insulin resistance and enhance oxidative stress, endothelial dysfunction and platelet activation. The adipokine-platelet interactions may be involved in platelet insulin resistance and their consequent pro-aggregatory phenotype in this setting.
Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.
The relationship between exercise and oxidative stress is extremely complex, depending on the mode, intensity, and duration of exercise. These conflicting effects and outcomes may be explained by the hormesis theory, in which low doses of an agent that is detrimental at high doses, induces an adaptive beneficial effect on the cells or organism.
The term microparticle (MP) identifies a heterogeneous population of vesicles playing a relevant role in the pathogenesis of vascular diseases, cancer and metabolic diseases such as diabetes mellitus. MPs are released by virtually all cell types by shedding during cell growth, proliferation, activation, apoptosis or senescence processes. MPs, in particular platelet- and endothelial-derived MPs (PMPs and EMPs), are increased in a wide range of thrombotic disorders, with an interesting relationship between their levels and disease pathophysiology, activity or progression. EMP plasma levels have been associated with several cardiovascular diseases and risk factors. PMPs are also shown to be involved in the progressive formation of atherosclerotic plaque and development of arterial thrombosis, especially in diabetic patients. Indeed, diabetes is characterised by an increased procoagulant state and by a hyperreactive platelet phenotype, with enhanced adhesion, aggregation, and activation. Elevated MP levels, such as TF+ MPs, have been shown to be one of the procoagulant determinants in patients with type 2 diabetes mellitus. Atherosclerotic plaque constitutes an opulent source of sequestered MPs, called "plaque" MPs. Otherwise, circulating MPs represent a TF reservoir, named "blood-borne" TF, challenging the dogma that TF is a constitutive protein expressed in minute amounts. "Blood-borne" TF is mainly harboured by PMPs, and it can be trapped within the developing thrombus. MP detection and enumeration by polychromatic flow cytometry (PFC) have opened interesting perspectives in clinical settings, particularly for the evaluation of MP numbers and phenotypes as independent marker of cardiovascular risk, disease and outcome in diabetic patients.
Patients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11-dehydro-thromboxane (TX) B2 (11-dehydro-TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)-α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6-week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8-iso-PGF2α and 11-dehydro-TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8-iso-PGF2α and 11-dehydro-TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX-dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF-α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.
BACKGROUND: Circulating pentraxin 3 (PTX3), the main regulator of the inflammatory response, rapidly increases following cardiovascular events, and low PTX3 is associated with high body mass index. METHODS AND RESULTS: We conducted a 12-month longitudinal study, to test the hypothesis that laparoscopic adjustable gastric banding (LAGB)-induced weight loss was associated with changes in platelet activation markers and PTX3. Twelve obese patients, scheduled to undergo LAGB, were enrolled at the University Obesity Center. Urinary 11-dehydro-thromboxane (Tx)B2excretion rate was measured on radioimmunoassay, and PTX3 and CD40L were determined on immunoassay. Plasma PTX3 increased by 178.8 and 214.9% (P<0.0001), respectively, 6 and 12 months after LAGB. High-sensitivity CRP decreased by 24 and 29.7% (P<0.0001), whereas CD40L decreased by 64.3 and 58.6% (P=0.002), respectively. Urinary 11-dehydro-TxB2decreased from 1,443 to 715 and 564 pg/mg creatinine, respectively 6 months and 12 months after LAGB (P<0.0001). PTX3 was inversely related to platelet activation markers, 11-dehydro-TxB2and CD40L. Moreover, multiple regression analysis on pooled data showed that plasma PTX3 was an independent predictor of urinary 11-dehydro-TxB2. CONCLUSIONS: There is an association between inflammation, platelet activation and metabolic dysfunction in obesity, and PTX3 is a key player within these circuits.
Supports sulodexide for extended prevention after anticoagulation in unprovoked VTE; extends secondary prevention options beyond standard anticoagulants.
May inform COX-1 turnover-guided personalization; leaves open aspirin's role in diabetes primary prevention.
Regulatory mechanisms of ALX/FPR2, the lipoxin A4 receptor, expression have considerable relevance in inflammation resolution. Because microRNAs (miRs) are emerging as key players in inflammation resolution, here we examined microRNA-mediated regulation of ALX/FPR2 (lipoxin A4 receptor/formyl peptide receptor 2) expression. By matching data from bioinformatic algorithms, we found 27 miRs predicted to bind the 3′-UTR of ALX/FPR2. Among these, we selected miR-181b because of its link with inflammation. Using a luciferase reporter system, we assessed miR-181b binding to ALX/FPR2 3′-UTR. Consistent with this, miR-181b overexpression in human macrophages significantly down-regulated ALX/FPR2 protein levels (−25%), whereas miR-181b knockdown gave a significant increase in ALX/FPR2 (+60%). miR-181b levels decreased during monocyte to macrophage differentiation (−50%), whereas ALX/FPR2 expression increased significantly (+60%). miR-181b overexpression blunted lipoxin A4 (0.1–10 nm)- and resolvin D1 (0.01–10 nm)-stimulated phagocytic activity of macrophages. These results unravel novel regulatory mechanisms of ALX/FPR2 expression and ligand-evoked macrophages proresolution responses mediated by miR-181b, thus uncovering novel components of the endogenous inflammation resolution circuits. Background: The ALX/FPR2 receptor recognizes the proresolution mediators lipoxin A4 (LXA4) and resolvin (Rv) D1, thus modulating immune responses. Results: miR-181b binds to the 3′-UTR of the ALX/FPR2 gene, regulating its expression. mir-181b blunted LXA4- and RvD1-induced macrophage phagocytosis. Conclusion: miR-181b controls ALX/FPR2 expression. This mechanism modulates proresolution signals in macrophages. Significance: miR regulation of ALX/FPR2 expression may be exploited for innovative anti-inflammatory strategies.
This review article is intended to describe how oxidative stress regulates cardiovascular disease development and progression. Epigenetic mechanisms related to oxidative stress, as well as more reliable biomarkers of oxidative stress, are emerging over the last years as potentially useful tools to design therapeutic approaches aimed at modulating enhanced oxidative stress "in vivo", thereby mitigating the consequent atherosclerotic burden. As a paradigm, we describe the case of obesity, in which the intertwining among oxidative stress, due to caloric overload, chronic low-grade inflammation induced by adipose tissue dysfunction, and platelet activation represents a vicious cycle favoring the progression of atherothrombosis. Oxidative stress is a major player in the pathobiology of cardiovascular disease (CVD). Reactive oxygen species (ROS)- dependent signaling pathways prompt transcriptional and epigenetic dysregulation, inducing chronic low-grade inflammation, platelet activation and endothelial dysfunction. In addition, several oxidative biomarkers have been proposed with the potential to improve current understanding of the mechanisms underlying CVD. These include ROS-generating and/or quenching molecules, and ROS-modified compounds, such as F2-isoprostanes. There is also increasing evidence that noncoding micro- RNA (mi-RNA) are critically involved in post- transcriptional regulation of cell functions, including ROS generation, inflammation, regulation of cell proliferation, adipocyte differentiation, angiogenesis and apoptosis. These molecules have promising translational potential as both markers of disease and site of targeted interventions. Finally, oxidative stress is a critical target of several cardioprotective drugs and nutraceuticals, including antidiabetic agents, statins, renin-angiotensin system blockers, polyphenols and other antioxidants. Further understanding of ROS-generating mechanisms, their biological role as well as potential therapeutic implications would translate into consistent benefits for effective CV prevention.
Mean platelet volume has been proposed as a predictor for venous thromboembolism in cancer. We, therefore, investigated the effects of different anti-cancer drugs on mean platelet volume in order to assess its possible value in the risk prediction of a first thromboembolic episode in cancer outpatients during treatment. Pre-treatment mean platelet volumes were retrospectively evaluated in 589 ambulatory patients at the beginning of a new chemotherapy regimen. Moreover, serial changes were evaluated at baseline and before each chemotherapy cycle on 385 of the 589 patients who consented to have additional blood withdrawals during treatment. Cox proportional hazards survival analysis demonstrated a 2.7 hazard ratio (P=0.01) of developing a first venous thromboembolic episode during chemotherapy for patients with baseline mean platelet volumes below the 10(th) percentile (<7.3 fL). This index significantly declined during the first three months of chemotherapy (-6%; P<0.0001) reverting to baseline at the end of treatment. Multivariate regression analysis showed that normal baseline volumes (P=0.012) and platinum-based regimens (P=0.017) were both independent predictors of mean platelet volume decline during chemotherapy which, in turn, was associated with a 2.4 hazard ratio (P=0.044) of venous thromboembolism. In conclusion, low pre-chemotherapy mean platelet volume might be regarded as a predictor of increased venous thromboembolism risk in cancer patients and chemotherapy further decreases platelet volumes, possibly due to drug-induced platelet activation and destruction. Changes in mean platelet volumes during chemotherapy might provide additional information on thromboembolic risk of patients treated with anti-cancer drugs, particularly platinum compounds.
Circulating DKK-1 is increased in T2DM and associated with endothelial dysfunction and platelet activation. Plasma DKK-1 levels are reduced with improvement of glycemic control and low-dose aspirin treatment.
BACKGROUND: Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP-14 has emerged as a powerful predictor of ACS. METHODS AND RESULTS: We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP-8/14 release in the circulation is related to TX-dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low-dose aspirin-treated ACS patients. In ACS patients, plasma MRP-8/14 and urinary 11-dehydro-TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin-treated ACS patients, MRP-8/14 and 11-dehydro-TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11-dehydro-TXB2 significantly predicted higher MRP-8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R(2)=0.463 and adj R(2)=0.497) after multivariable adjustment. Conversely, plasma MRP-8/14 (P<0.001) and higher urinary 8-iso-prostaglandin F2α (P=0.050) levels were significant predictors of residual, on-aspirin, TX biosynthesis in ACS (adjusted R(2)=0.384). CONCLUSIONS: Circulating MRP-8/14 is associated with TX-dependent platelet activation in ACS, even during low-dose aspirin treatment, suggesting a contribution of residual TX to MRP-8/14 shedding, which may further amplify platelet activation. Circulating MRP-8/14 may be a target to test different antiplatelet strategies in ACS.
Should not alter current antiplatelet practice by sex; leaves open differential effects for future prospective research.
