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Objective: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults.... more
Objective: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults. Research Design and Methods: A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n=296) from the VIenna Transdanube Aging (VITA) study, a prospective community-based cohort study. Participants were followed-up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n=90) was employed to validate our findings. Results: Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to HbA1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort. Conclusion: We found a set of circulating lncRNAs which independently portends incident type 2 diabetes in older adults ...
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Introduction The mechanisms underlying endothelial dysfunction (ED) in obesity are poorly understood. Neurofibromin 2 (NF2) is a scaffold-like protein involved in cell growth and survival. However, its role in the vascular endothelium is... more
Introduction The mechanisms underlying endothelial dysfunction (ED) in obesity are poorly understood. Neurofibromin 2 (NF2) is a scaffold-like protein involved in cell growth and survival. However, its role in the vascular endothelium is unknown. Purpose To investigate NF2 function in obesity-related ED. Methods Human aortic endothelial cells (HAECs) were exposed to palmitic acid (PA, 200 uM) or vehicle for 48 hours. Gene silencing of NF2 was performed by small interfering RNA (siRNA). Gene and protein expression were assessed by real time PCR and Western blot, respectively. The interaction of NF2 with endothelial proteins was investigated by co-immunoprecipitation. A constitutive active mutant form of NF2 (Ala518) was employed to study the effects of NF2 gain-of-function. To specifically investigate NF2 role in the vascular endothelium, we generated mice with endothelium-specific deletion of NF2 (NF2 ECKO) by crossing NF2flox/flox mice with tamoxifen-inducible endothelial-specific ...
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Background Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light... more
Background Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light on the mechanisms underlying the excess of cardiovascular mortality associated with both chronic kidney disease and hyperuricemia and lead to better risk stratification. Our main goal was to study the relationships between serum uric acid and kidney disease measures (namely estimated GFR [eGFR] and albuminuria) in a large cohort of individuals at cardiovascular risk from the URic acid Right for heArt Health (URRAH) Project database. Methods Clinical data of 26,971 individuals were analyzed. Factors associated with the presence of hyperuricemia defined on the basis of previously determined URRAH cutoffs for cardiovascular and all-cause mortality were evaluated through multivariate analysis. Chronic kidney disease was defined as eGFR < 60 ml/min pe...
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Purpose: To evaluate the potential confounding effect of concomitant pneumonia (PNM) on lung ultrasound (LUS) B-lines in acute heart failure (AHF).Methods: We enrolled 86 AHF patients with (31 pts, AHF/PNM) and without (55 pts, AHF)... more
Purpose: To evaluate the potential confounding effect of concomitant pneumonia (PNM) on lung ultrasound (LUS) B-lines in acute heart failure (AHF).Methods: We enrolled 86 AHF patients with (31 pts, AHF/PNM) and without (55 pts, AHF) concomitant PNM. LUS B-lines were evaluated using a combined antero-lateral (AL) and posterior (POST) approach at admission (T0), after 24 h from T0 (T1), after 48 h from T0 (T2) and before discharge (T3). B-lines score was calculated at each time point on AL and POST chest, dividing the number of B-lines by the number of explorable scanning sites. The decongestion rate (DR) was calculated as the difference between the absolute B-lines number at discharge and admission, divided by the number of days of hospitalization. Patients were followed-up and hospital readmission for AHF was considered as adverse outcome.Results: At admission, AHF/PNM patients showed no difference in AL B-lines score compared with AHF patients [AHF/PNM: 2.00 (IQR: 1.44–2.94) vs. AH...
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Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely... more
Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (end...
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Endothelial dysfunction can be considered the first, asymptomatic step of the atherosclerotic process. It is characterised by an imbalance between substances with vasodilating, antimitogenic and anti-thrombogenic properties (first of all... more
Endothelial dysfunction can be considered the first, asymptomatic step of the atherosclerotic process. It is characterised by an imbalance between substances with vasodilating, antimitogenic and anti-thrombogenic properties (first of all nitric oxide, NO) and substances with vasoconstricting, prothrombotic and proliferative characteristics (also known with the generic term endothelium-derived contracting factors, EDCFs).
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Healthcare systems encumbered by cardiovascular diseases demand adequate cardiovascular prevention. Indeed, even with the most novel therapies, the residual cardiovascular risk still fuels morbidity and mortality. Addressing inflammation... more
Healthcare systems encumbered by cardiovascular diseases demand adequate cardiovascular prevention. Indeed, even with the most novel therapies, the residual cardiovascular risk still fuels morbidity and mortality. Addressing inflammation as a putative mediator of this risk has brought along promising in vitro results, though large clinical trials have only in part confirmed them. To fully exploit the therapeutic potential between the inflammatory hypothesis, a change of viewpoint is required. Focus on microcirculation, whose dysfunction is the primary driver of cardiometabolic disease, is mandatory. Several factors play a pivotal role in the capacity of microvascular inflammation to promote a health-to-disease transition: the adipose tissue (in particular, perivascular and epicardial), the mitochondria function, the hyperglycemic damage and their epigenetic signature. Indeed, the low-grade inflammatory response, which is now an acknowledged hallmark of cardiometabolic disease, is promoted by these mediators and leaves a permanent epigenetic scar on the microvasculature. Even if a more profound knowledge about the mechanisms of metabolic memory has been brought to light by recent evidence, we still have to fully understand its mechanisms and clinical potential. Addressing the detrimental role of inflammation by targeting the microvascular phenotype and leveraging epigenetics is the road down which we must go to achieve satisfactory cardiovascular prevention, ultimately leading to disease-free ageing.
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Introduction: High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during SARS-CoV-2 infection. However, its determinants remain partially unknown. We aimed to assess the relationship between severity of... more
Introduction: High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during SARS-CoV-2 infection. However, its determinants remain partially unknown. We aimed to assess the relationship between severity of inflammatory response/coagulation abnormalities and hsTnT in Coronavirus Disease 2019 (COVID-19). We then explored the relevance of these pathways in defining mortality and complications risk and the potential effects of the treatments to attenuate such risk.Methods: In this single-center, prospective, observational study we enrolled 266 consecutive patients hospitalized for SARS-CoV-2 pneumonia. Primary endpoint was in-hospital COVID-19 mortality. Results: hsTnT, even after adjustment for confounders, was associated with mortality. D-dimer and CRP presented stronger associations with hsTnT than PaO2. Changes of hsTnT, D-dimer and CRP were related but only D-dimer was associated with mortality. Moreover, low molecular weight heparin showed attenuation of the ...
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Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence... more
Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality.Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality.Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardio...
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Purpose A derangement of the coagulation process and thromboinflammatory events have emerged as pathologic characteristics of severe COVID-19, characterized by severe respiratory failure. CC motive chemokine ligand 2 (CCL2), a chemokine... more
Purpose A derangement of the coagulation process and thromboinflammatory events have emerged as pathologic characteristics of severe COVID-19, characterized by severe respiratory failure. CC motive chemokine ligand 2 (CCL2), a chemokine originally described as a chemotactic agent for monocytes, is involved in inflammation, coagulation activation and neoangiogenesis. We investigated the association of CCL2 levels with coagulation derangement and respiratory impairment in patients with COVID-19. Methods We retrospectively evaluated 281 patients admitted to two hospitals in Italy with COVID-19. Among them, CCL2 values were compared in different groups (identified according to D-dimer levels and the lowest PaO2/FiO2 recorded during hospital stay, P/Fnadir) by Jonckheere-Terpstra tests; linear regression analysis was used to analyse the relationship between CCL2 and P/Fnadir. We performed Mann-Whitney test and Kaplan-Meier curves to investigate the role of CCL2 according to different clinical outcomes (survival and endotracheal intubation [ETI]). Results CCL2 levels were progressively higher in patients with increasing D-dimer levels and with worse gas exchange impairment; there was a statistically significant linear correlation between log CCL2 and log P/Fnadir. CCL2 levels were significantly higher in patients with unfavourable clinical outcomes; Kaplan-Meier curves for the composite outcome death and/or need for ETI showed a significantly worse prognosis for patients with higher (> median) CCL2 levels. Conclusions CCL2 correlates with both indices of activation of the coagulation cascade and respiratory impairment severity, which are likely closely related in COVID-19 pathology, thus suggesting that CCL2 could be involved in the thromboinflammatory events characterizing this disease.
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Research Interests: Inflammation, Multivariate Analysis, Humans, Hypertension, Female, and 15 moreMale, Regression Analysis, Acetylcholine, The, Risk factors, Endothelial dysfunction, Clinical Sciences, Middle Aged, C reactive protein, Adult, Risk Factors, Creatinine, Glomerular Filtration Rate, Essential Hypertension, and renal insufficiency
Research Interests: Medicine, Glucose, Hyperglycemia, Blood Glucose, Insulin, and 7 moreLiver, Animals, Male, Endocrine, Triglycerides, Clinical Sciences, and Swine
Aortic stiffness is an important clinical parameter for predicting cardiovascular events. Carotid–femoral pulse wave velocity (cf-PWV) has been proposed for performing this evaluation non-invasively; however, it requires dedicated... more
Aortic stiffness is an important clinical parameter for predicting cardiovascular events. Carotid–femoral pulse wave velocity (cf-PWV) has been proposed for performing this evaluation non-invasively; however, it requires dedicated equipment and experienced operators. We explored the possibility of measuring aortic stiffness using ultrasound scans of the abdominal aorta coupled with the Bramwell–Hill equation. Healthy subjects were investigated; measurements of cf-PWV were taken by arterial tonometry and aortic systo-diastolic pressure difference was estimated using a validated model. Pulsatility of an abdominal tract of aorta was assessed by automated processing of ultrasound scans. Through a Bland–Altmann analysis, we found large biases when estimating each parameter by applying the Bramwell–Hill equation to the measured values of the other two paramters (bias, ± 1.96 SD; PWV, about 2.1 ± 2.5 m/s; pulsatility, 12 ± 14%; pressure jump, 47 ± 55 mmHg). These results indicate that the ...
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AIMS Therapeutic modulation of blood vessel growth holds promise for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely posttranslational histone modifications,... more
AIMS Therapeutic modulation of blood vessel growth holds promise for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely posttranslational histone modifications, participate in angiogenic response suggesting that chromatin-modifying drugs could be beneficial in this setting. Apabetalone (APA), a selective inhibitor of bromodomain (BRD) and extra-terminal (BET) proteins, prevents BRD4 interactions with chromatin thus modulating transcriptional programs in different organs. We sought to investigate whether APA affects angiogenic response in diabetes. RESULTS As compared to vehicle, APA restored tube formation and migration in human aortic endothelial cells (HAECs) exposed to high glucose (HG) levels. Expression profiling of angiogenesis genes showed that APA prevents HG-induced upregulation of the anti-angiogenic molecule Thrombospondin-1 (THBS1). ChIP-seq and chromatin immunoprecipitation (ChIP) assays in HG-treated HAECs showed the enrichment of both BRD4 and active marks (H3K27ac) on THBS1 promoter, whereas BRD4 inhibition by APA prevented chromatin accessibility and THBS1 transcription. Mechanistically, we show that THBS1 inhibits angiogenesis by suppressing VEGFA signaling, while APA prevents these detrimental changes. In diabetic mice with hindlimb ischemia, epigenetic editing by APA restored THSB1/VEGFA axis thus improving limb vascularization and perfusion as compared to vehicle-treated animals. Finally, epigenetic regulation of THSB1 by BRD4/H3K27ac was also reported in DM patients with PAD as compared to non-diabetic controls. INNOVATION This is the first study showing that BET protein inhibition by APA restores angiogenic response in experimental diabetes. CONCLUSIONS Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in diabetic PAD.
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Current data suggest that advances in cardiovascular (CV) treatment have resulted in significant reduction in CV mortality but also in prolongation of life with disability. Focus on CV prevention is likely to reverse this unfavourable... more
Current data suggest that advances in cardiovascular (CV) treatment have resulted in significant reduction in CV mortality but also in prolongation of life with disability. Focus on CV prevention is likely to reverse this unfavourable trend. In this review we provide information on the new European guidelines on CV prevention and discuss biomarkers and vascular imaging techniques which can assist in refining CV risk prediction. Finally, we provide new information on lifestyle and pharmacological advances which are likely to result in significant CV risk reduction.
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Accelerated biological aging contributes to the evolution of cardiovascular disease. However, its influence on subclinical organ damage remains unclear. Leukocyte telomere length (LTL) is emerging as a marker of biological cardiovascular... more
Accelerated biological aging contributes to the evolution of cardiovascular disease. However, its influence on subclinical organ damage remains unclear. Leukocyte telomere length (LTL) is emerging as a marker of biological cardiovascular aging. We performed a systematic review and meta-analysis to assess the association between LTL and measures of end-organ damage. PubMed, Medline, Embase, Cinahl Plus, ClinicalTrials.gov, and grey literature databases were searched for studies that assessed the association of LTL with arterial pulse wave velocity (aPWV), carotid intima-media thickness (cIMT), left ventricular mass (LVM or LVMI), renal outcomes, coronary artery calcium (CAC) and presence of carotid plaques. In a sample of 7256 patients, we found that cIMT (pooled correlation coefficient (r) = -0.249; 95%CI -0.37, -0.128) and aPWV (pooled r = -0.194; 95% CI -0.290, -0.100) inversely correlate with LTL. Compared to aPWV, cIMT had a stronger correlation with LTL. Patients without carotid plaques had longer telomeres than patients with carotid plaques. Quantitative analyses documented LTL association with renal outcomes and CAC, but not with LVM/LVMI. Among measures of end-organ damage, cIMT and aPWV provide the most accurate information on the contribution of biological aging to the process of vascular remodeling/damage.
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Supplemental Digital Content is available in the text. Objective: Inflammation, oxidative stress, and endothelial dysfunction are known to contribute to ischemia-reperfusion injury. Remote ischemic preconditioning (RIPC) protects from... more
Supplemental Digital Content is available in the text. Objective: Inflammation, oxidative stress, and endothelial dysfunction are known to contribute to ischemia-reperfusion injury. Remote ischemic preconditioning (RIPC) protects from endothelial dysfunction and the damage induced by ischemia-reperfusion. Using intensive periodontal treatment (IPT), an established human model of acute systemic inflammation, we investigated whether RIPC prevents endothelial dysfunction and modulates systemic levels of inflammation and oxidative stress. Approach and Results: Forty-nine participants with periodontitis were randomly allocated to receive either 3 cycles of ischemia-reperfusion on the upper limb (N=24, RIPC) or a sham procedure (N=25, control) before IPT. Endothelial function assessed by flow-mediated dilatation of the brachial artery, inflammatory cytokines, markers of vascular injury, and oxidative stress were evaluated at baseline, day 1, and day 7 after IPT. Twenty-four hours post-IPT, the RIPC group had lower levels of IL-10 (interleukin-10) and IL-12 (interleukin-12) compared with the control group (P<0.05). RIPC attenuated the IPT-induced increase in IL-1β (interleukin-1β), E-selectin, sICAM-3 (soluble intercellular adhesion molecule 3), and sTM (soluble thrombomodulin) levels between the baseline and day 1 (P for interaction <0.1). Conversely, oxidative stress was differentially increased at day1 in the RIPC group compared with the control group (P for interaction <0.1). This was accompanied by a better flow-mediated dilatation (mean difference 1.75% [95% CI, 0.428–3.07], P=0.011). After 7 days from IPT, most of the inflammatory markers, endothelial-dependent and -independent vasodilation, were similar between groups. Conclusions: RIPC prevented acute endothelial dysfunction by modulation of inflammation and oxidation processes in patients with periodontitis following exposure to an acute inflammatory stimulus. Registration: URL: https://clinicaltrials.gov/ct2/show/NCT03072342; Unique identifier: NCT03072342.
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SIGNIFICANCE The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and associates with atherosclerotic vascular complications and high mortality. Although multifactorial interventions, vascular... more
SIGNIFICANCE The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and associates with atherosclerotic vascular complications and high mortality. Although multifactorial interventions, vascular residual risk remains high in this patient population, suggesting the need for breakthrough therapies. The mechanisms underpinning obesity-related vascular disease remain elusive and represent an intense area of investigation. Recent advances: Epigenetic modifications - defined as environmentally-induced chemical changes of DNA and histones which do not affect DNA sequence - are emerging as a potent modulator of gene transcription in the vasculature and might significantly contribute to the development of obesity-induced endothelial dysfunction. DNA methylation and histone posttranslational modifications cooperate to build complex epigenetic signals altering transcriptional networks implicated in redox homeostasis, mitochondrial function, vascular inflammation and perivascular fat homeostasis in patients with cardiometabolic disturbances. CRITICAL ISSUES Deciphering the epigenetic landscape in the vasculature is extremely challenging due to the complexity of epigenetic signals and their function in regulating transcription. An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease. This would enable the employment of precision medicine approaches in this setting. FUTURE DIRECTIONS Current and future research efforts in this field entail a better definition of the vascular epigenome in obese patients as well as the unveiling of novel, cell-specific chromatin-modifying drugs able to erase specific epigenetic signals responsible for maladaptive transcriptional alterations and vascular dysfunction in obese patients.
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Research Interests: Medicine and Hypertension
Background Smoking has been consistently associated with increased cardiovascular risk in adults. Although exposure to tobacco products often starts in early life, evidence for the possible adverse effects on the cardiovascular system of... more
Background Smoking has been consistently associated with increased cardiovascular risk in adults. Although exposure to tobacco products often starts in early life, evidence for the possible adverse effects on the cardiovascular system of the young is scarce. We sought to derive pooled estimates of smoking effects on indices of early vascular damage in children and adolescents. Design and methods We performed a systematic review and meta-analysis of clinical studies involving young individuals up to 21 years old that provided data on smoking exposure (active or passive) and flow-mediated dilatation, carotid to femoral pulse wave velocity and maximum carotid intima-media thickness. We employed three distinct methodologies of random-effects data synthesis, including the Sidik-Jonkman estimator, the Hartung and Knapp correction and a Bayesian method with a well-informed prior on the level of between-study variance. Results In 12 studies and 5279 individuals in total, smoking exposure wa...
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The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting combined (fatal... more
The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension conceived and designed an ad hoc study aimed at searching for prognostic cut-off values of serum uric acid (SUA) in predicting combined (fatal and non-fatal) cerebrovascular (CBV) events in the whole database. The URic acid Right for heArt Health study is a nationwide, multicenter, observational cohort study involving data on subjects aged 18–95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 120.7 ± 61.8 months. A total of 14,588 subjects were included in the analysis. A prognostic cut-off value of SUA able to discriminate combined CBV events (>4.79 mg/dL or >284.91 µmol/L) was identified by means of receiver operating characteristic curve in the whole database. Multivariate Cox regression analysis adjusted for confounders (age, sex, arterial hypertension, diabetes, chronic kidney disease, smoking habit, ethanol intake, body mass index, low-density lipoprotein cholesterol, and use of diuretics) identified an independent association between SUA and combined CBV events in the whole database (HR 1.249, 95% confidence interval, 1.041–1.497, p = 0.016). The results of the present study confirm that SUA is an independent risk marker for CBV events after adjusting for potential confounding variables, including arterial hypertension, and demonstrate that >4.79 mg/dL is a valid prognostic cut-off value.
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Objective: To assess the prognostic cut-off values of serum uric acid (SUA) in predicting fatal and morbid heart failure in a large Italian cohort in the frame of the Working Group on Uric Acid and Cardiovascular Risk of the Italian... more
Objective: To assess the prognostic cut-off values of serum uric acid (SUA) in predicting fatal and morbid heart failure in a large Italian cohort in the frame of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension. Methods: The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, cohort study involving data on individuals aged 18–95 years, recruited on a community basis from all regions of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 128 ± 65 months. Incident heart failure was defined on the basis of International Classification of Diseases Tenth Revision codes and double-checked with general practitioners and hospital files. Multivariate Cox regression models having fatal and morbid heart failure as dependent variables, adjusted for sex, age, SBP, diabetes, estimated glomerular filtration rate, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol, previous diagnosis of heart failure and use of diuretics as possible confounders, were used to search for an association between SUA as a continuous variable and heart failure. By means of receiver operating characteristic curves, two prognostic cut-off values (one for all heart failure and one for fatal heart failure) were identified as able to discriminate between individuals doomed to develop the event. These cut-off values were used as independent predictors to divide individuals according to prognostic cut-off values in a multivariate Cox models, adjusted for confounders. Results: A total of 21 386 individuals were included in the analysis. In Cox analyses, SUA as a continuous variable was a significant predictor of all [hazard ratio 1.29 (1.23–1.359), P < 0.0001] and fatal [hazard ratio 1.268 (1.121–1.35), P < 0.0001] incident heart failure. Cut-off values of SUA able to discriminate all and fatal heart failure status were identified by mean of receiver operating characteristic curves in the whole database: SUA more than 5.34 mg/dl (confidence interval 4.37–5.6, sensitivity 52.32, specificity 63.96, P < 0.0001) was the univariate prognostic cut-off value for all heart failure, whereas SUA more than 4.89 mg/dl (confidence interval 4.78–5.78, sensitivity 68.29, specificity 49.11, P < 0.0001) for fatal heart failure. The cut-off for all heart failure and the cut-off value for fatal heart failure were accepted as independent predictors in the Cox analysis models, the hazard ratios being 1.645 (1.284–2.109, P < 0.0001) for all heart failure and 1.645 (1.284–2.109, P < 0.0001) for fatal heart failure, respectively. Conclusion: The results of the current study confirm that SUA is an independent risk factor for all heart failure and fatal heart failure, after adjusting for potential confounding variables and demonstrate that a prognostic cut-off value can be identified for all heart failure (>5.34 mg/dl) and for fatal heart failure (>4.89 mg/dl).
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Background Bacterial and fungal superinfections may complicate the course of hospitalized patients with COVID-19. Objectives To identify predictors of superinfections in COVID-19. Methods Prospective, observational study including... more
Background Bacterial and fungal superinfections may complicate the course of hospitalized patients with COVID-19. Objectives To identify predictors of superinfections in COVID-19. Methods Prospective, observational study including patients with COVID-19 consecutively admitted to the University Hospital of Pisa, Italy, between 4 March and 30 April 2020. Clinical data and outcomes were registered. Superinfection was defined as a bacterial or fungal infection that occurred ≥48 h after hospital admission. A multivariate analysis was performed to identify factors independently associated with superinfections. Results Overall, 315 patients with COVID-19 were hospitalized and 109 episodes of superinfections were documented in 69 (21.9%) patients. The median time from admission to superinfection was 19 days (range 11–29.75). Superinfections were caused by Enterobacterales (44.9%), non-fermenting Gram-negative bacilli (15.6%), Gram-positive bacteria (15.6%) and fungi (5.5%). Polymicrobial in...
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Reactive oxygen species (ROS) are oxygen derivates and play an active role in vascular biology. These compounds are generated within the vascular wall, at the level of endothelial and vascular smooth muscle cells, as well as by... more
Reactive oxygen species (ROS) are oxygen derivates and play an active role in vascular biology. These compounds are generated within the vascular wall, at the level of endothelial and vascular smooth muscle cells, as well as by adventitial fibroblasts. Physiologically, ROS generation is counteracted effectively by the rate of elimination. In hypertension, a ROS excess occurs, which is not counterbalanced by the endogenous antioxidant mechanisms, leading to a state of oxidative stress. Angiotensin II, the active peptide of the renin-angiotensin-system (RAS), is a significant stimulus for ROS generation within the vasculature. It was also documented that at the level of subfornical cerebral regions an inappropriate RAS stimulation may lead to an increased vascular sympathetic activity. More recently, in conditions of fetal undernutrition, it was also proposed an increased vascular sympathetic activity secondary to inappropriate RAS activation, leading to the development of hypertension in adult life. The present review will discuss the complex interaction between RAS activation, vascular ROS generation and increased sympathetic outflow in hypertension.
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The presence of a skin-brain connection whereby alterations in the skin can inform on mechanisms underlying neurodegenerative diseases is increasingly recognized. In this study, we used a discovery (n = 321) and replication (n = 147)... more
The presence of a skin-brain connection whereby alterations in the skin can inform on mechanisms underlying neurodegenerative diseases is increasingly recognized. In this study, we used a discovery (n = 321) and replication (n = 147) sample from the Twins UK population to test the association between naevus count and memory function, and its mediation by telomeres. Memory function was assessed in 1999 and 2009 using the paired associates learning test (PAL), while naevus count and leucocyte telomere length (LTL, assessed by the terminal restriction fragment assay) were measured once. Higher baseline naevus count was significantly associated with fewer errors at the baseline and follow-up PAL, as well as with change in PAL score over 10 years. This association was significantly attenuated after adjustment for LTL. The significant association between naevus count and PAL score was reproduced in the replication sample. These findings suggest that melanocytes might be used as model syst...
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Obesity is a major risk factor for cognitive impairment and increases risk of cardiovascular disease (CVD). As CVD in itself is a risk factor for cognitive impairment, we assessed the influence of cardiovascular (CV) phenotypes on the... more
Obesity is a major risk factor for cognitive impairment and increases risk of cardiovascular disease (CVD). As CVD in itself is a risk factor for cognitive impairment, we assessed the influence of cardiovascular (CV) phenotypes on the association between lifetime exposure to obesity and midlife memory function.(Figure is included in full-text article.) : 233 participants of the National Survey of Health and Development (NSHD) Study, with lifetime measures of BMI (36, 43, 53, and 60-64 years) and CV risk factors, vascular phenotypes (carotid intima-media thickness, cIMT, aortic pulse wave velocity, aPWV, and aortic calcification score, AAC-8) and cognitive data (word memory test, WMT) at 60-64 years were included in this study. Patterns of BMI change over 30 years were identified. Multivariable linear regression models (with adjustments for sex, heart rate, education and CV risk factors) were used to establish the associations between cross-sectional and lifetime measures of adiposit...
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Research Interests: Dentistry, Biology, Atherosclerosis, Causality, Medicine, and 15 moreComorbidity, Disease susceptibility, Hemorheology, Humans, Internal Medicine, Animals, Male, Meta Analysis, Clinical Sciences, Disease Progression, Cross Sectional Studies, Case Control Studies, Brachial artery, Medical and Health Sciences, and Cardiovascular medicine and haematology
Research Interests: Cardiology, Treatment, Positron Emission Tomography, Medicine, Humans, and 13 moreHypertension, Female, Male, Heart, Left Ventricular Dysfunction, Dilated cardiomyopathy, Clinical Sciences, Middle Aged, Blood Flow, Coronary Circulation, Long Term, Myocardial Blood Flow, and Cardiovascular medicine and haematology
Although atherosclerosis has long been regarded as an inevitable degenerative disorder associated with ageing, there is now considerable evidence that the underlying pathological process is highly modifiable and may be prevented by... more
Although atherosclerosis has long been regarded as an inevitable degenerative disorder associated with ageing, there is now considerable evidence that the underlying pathological process is highly modifiable and may be prevented by appropriate management. The vascular damage is known to begin in childhood and develops silently for decades before clinical events such as myocardial infraction or stroke occur. This has been shown in numerous autopsy studies and is being confirmed in the modern era, using intravascular ultrasound [1,2]. The initiation and progression of arterial disease from childhood is influenced by many classical risk factors. Longitudinal studies have shown that risk factor levels measured in childhood are predictive of risk factor level and cardiovascular disease in later life [3,4]. In a recent analysis of the Framingham study, the risk factor analysis at 50 years was highly predictive of future cardiovascular events [5]. This growing body of evidence supports the hypothesis that the cardiovascular system responds to cumulative rather than acute exposure to adverse influences. Thus, effective ‘lifetime’ reduction in cardiovascular events may be best achieved by earlier risk factor management than is currently advocated. In the AREX study, a genetic variant that unexpectedly resulted in modest low-density lipoprotein (LDL) cholesterol lowering from childhood was associated with a very substantial reduction in later clinical events indicating the ‘investment’ opportunity for early risk management [6]. The scientific community, healthcare providers and even politicians have become increasingly interested in the concept of prevention as it becomes clear that the impact of arterial disease on life expectancy in the population cannot be managed solely by better clinical treatment of the disease and its complications. In this review, we will consider how to detect and treat preclinical disease from childhood, new insights into genetic and environmental factors that might influence its development and possible treatment strategies.
Research Interests: Life Style, Diet, Risk assessment, Adolescent, Medicine, and 14 moreCardiovascular Risk, Humans, Child, Exercise, Risk factors, Age Factors, Cardiovascular Diseases, Disease Progression, Risk Factors, Risk Assessment, Early Diagnosis, Preventive Health Services, Guideline Adherence, and Cardiovascular medicine and haematology
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The ageing process is accompanied by a variety of cellular modifications, and telomere shortening is a common finding. Large epidemiological studies have reported an association between shorter telomere length in peripheral leukocytes and... more
The ageing process is accompanied by a variety of cellular modifications, and telomere shortening is a common finding. Large epidemiological studies have reported an association between shorter telomere length in peripheral leukocytes and several inflammatory diseases of the elderly including diabetes, atherosclerosis and, recently, periodontitis. The primary aim of this study was to critically discuss available evidence regarding the potential mechanisms relating shorter telomeres to periodontitis. A narrative literature review was performed to report evidence relating shorter telomeres to the ageing process and inflammation. Then, we searched MEDLINE (1950 to May 2012) and ISI WEB OF SCIENCE (1950 to May 2012) databases for the combination of the terms &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;telomere&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;periodontitis&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;. Although these associations suggest a possible role of telomere attrition in the onset or evolution of chronic inflammatory diseases, only two studies addressed the relationship between telomere length and periodontitis. We suggest that the chronic inflammatory burden observed in people with chronic periodontitis could represent the driver of telomere shortening. However, further evidence is needed to confirm whether inflammation is the cause or the consequence of the shorter leukocyte telomere length observed in people with periodontitis.
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Background Recent evidence suggests that both the HIV virus and antiretroviral therapy (ART) are associated with premature atherosclerosis in adults. Increased arterial stiffness as assessed by pulse wave velocity (PWV) has been... more
Background Recent evidence suggests that both the HIV virus and antiretroviral therapy (ART) are associated with premature atherosclerosis in adults. Increased arterial stiffness as assessed by pulse wave velocity (PWV) has been associated with adverse cardiovascular outcome in adults. The relationship between HIV infection and treatment and arterial stiffness has not been evaluated in children. Methods We studied 83 HIV-infected children with a mean ±sd age of 11.0 ±3.1 years and 59 controls aged 12.2 ±2.8 years. Among the HIV-infected children, 48 were receiving ART (23 including a protease inhibitor). Arterial stiffness was assessed non-invasively by carotid–radial PWV. Disease severity was defined according to the CDC classification. Results PWV was significantly increased in HIV-infected children compared with controls ( P<0.05). A significant association between age and PWV was noted in HIV-infected children but not in controls. HIV-infected children receiving ART had signi...
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Introduction Serum uric acid (SUA) has been depicted as a contributory causal factor in metabolic syndrome (MS), which in turn, portends unfavourable prognosis. Aim We assessed the prognostic role of SUA in patients with and without MS.... more
Introduction Serum uric acid (SUA) has been depicted as a contributory causal factor in metabolic syndrome (MS), which in turn, portends unfavourable prognosis. Aim We assessed the prognostic role of SUA in patients with and without MS. Methods We used data from the multicentre Uric Acid Right for Heart Health study and considered cardiovascular mortality (CVM) as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. Results A total of 9589 subjects (median age 58.5 years, 45% males) were included in the analysis, and 5100 (53%) patients had a final diagnosis of MS. After a median follow-up of 142 months, we observed 558 events. Using a previously validated cardiovascular SUA cut-off to predict CVM (> 5.1 mg/dL in women and 5.6 mg/dL in men), elevated SUA levels were significantly associated to a worse outcome in patients with and without MS (all p
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Aims Observational studies suggest elevated blood pressure (BP) as the leading risk factor for incident atrial fibrillation (AF), but whether this relationship is causal remains unknown. In this study, we used Mendelian randomization (MR)... more
Aims Observational studies suggest elevated blood pressure (BP) as the leading risk factor for incident atrial fibrillation (AF), but whether this relationship is causal remains unknown. In this study, we used Mendelian randomization (MR) to investigate the potential causal association of BP levels with the risk of developing AF. Methods and results Genetic variants associated with the BP traits were retrieved from the International Consortium of Blood Pressure-Genome Wide Association Studies (N = 299 024). From 901 reported variants, 894 were assessed in a dedicated Genome-Wide Association Study of AF genetics, including >1 000 000 subjects of European ancestry. We used two-sample MR analyses to examine the potential causal association of systolic BP (SBP) and diastolic BP (DBP) as well as of pulse pressure (PP) with AF. MR analysis identified a potentially causal association between AF and SBP [odds ratio (OR): 1.018 per 1 mmHg increase, 95% confidence interval (CI): 1.012–1.02...