Novel Techniques, Biomarkers and Molecular Targets to Address Cardiometabolic Diseases.

Cardiometabolic diseases (CMDs) are interrelated and multifactorial conditions, including arterial hypertension, type 2 diabetes, heart failure, coronary artery disease, and stroke. Due to the burden of cardiovascular morbidity and mortality associated with CMDs' increasing prevalence, there is a critical need for novel diagnostic and therapeutic strategies in their management. In clinical practice, innovative methods such as epicardial adipose tissue evaluation, ventricular-arterial coupling, and exercise tolerance studies could help to elucidate the multifaceted mechanisms associated with CMDs. Similarly, epigenetic changes involving noncoding RNAs, chromatin modulation, and cellular senescence could represent both novel biomarkers and targets for CMDs. Despite the promising data available, significant challenges remain in translating basic research findings into clinical practice, highlighting the need for further investigation into the complex pathophysiology underlying CMDs.

Local sources of vulnerability to climate change and armed conflicts in East Africa.

While socioeconomic and institutional factors are crucial in explaining the onset and evolution of conflicts, recent research suggests that climate change is a further indirect driver acting as a "threat multiplier". This paper focuses on the concept of vulnerability to both climate change and conflicts to explain why some locations are more likely to engage in armed conflicts than others in the presence of a similar level of exposure to climatic changes. In particular, by means of a Spatial Autoregressive Model, we identify a set of local-specific vulnerability factors that increase conflict risk in East Africa. We employ a georeferenced database with a resolution of 25 × 25 km, covering the period 1997-2016. Results from our analysis provide some interesting insights: first, climate change does not increase conflict risk per se, but only in the presence of pre-existing vulnerabilities. Second, resource access and socioeconomic factors play a key role in driving the climate-conflict nexus especially in urban areas. In particular, vulnerability is increased whenever power is not distributed in such a way as to ensure an equitable distribution of resources. Overall, our findings suggest that, by addressing vulnerability factors that prevent adaptive capacity and an equitable distribution of resources, societies may benefit in terms of both diminished conflict risk and alleviation of climate change impacts.

Serum Uric Acid/Serum Creatinine Ratio and Cardiovascular Mortality in Diabetic Individuals-The Uric Acid Right for Heart Health (URRAH) Project.

Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied (n = 2230). The risk of CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals.

Triglyceride-glucose Index and Mortality in a Large Regional-based Italian Database (Urrah Project).

PURPOSE: Recently, a novel index (triglyceride-glucose index-TyG) was considered a surrogate marker of insulin resistance (IR); in addition, it was estimated to be a better expression of IR than widely used tools. Few and heterogeneous data are available on the relationship between this index and mortality risk in non-Asian populations. Therefore, we estimated the predictive role of baseline TyG on the incidence of all-cause and cardiovascular (CV) mortality in a large sample of the general population. Moreover, in consideration of the well-recognized role of serum uric acid (SUA) on CV risk and the close correlation between SUA and IR, we also evaluated the combined effect of TyG and SUA on mortality risk. METHODS: The analysis included 16,649 participants from the URRAH cohort. The risk of all-cause and CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. RESULTS: During a median follow-up of 144 months, 2569 deaths occurred. We stratified the sample by the optimal cut-off point for all-cause (4.62) and CV mortality (4.53). In the multivariate Cox regression analyses, participants with TyG above cut-off had a significantly higher risk of all-cause and CV mortality, than those with TyG below the cut-off. Moreover, the simultaneous presence of high levels of TyG and SUA was associated with a higher mortality risk than none or only one of the two factors. CONCLUSIONS: The results of this study indicate that these TyG (a low-cost and simple non-invasive marker) thresholds are predictive of an increased risk of mortality in a large and homogeneous general population. In addition, these results show a synergic effect of TyG and SUA on the risk of mortality.

Prognostic Value and Relative Cutoffs of Triglycerides Predicting Cardiovascular Outcome in a Large Regional-Based Italian Database.

BACKGROUND: Despite longstanding epidemiologic data on the association between increased serum triglycerides and cardiovascular events, the exact level at which risk begins to rise is unclear. The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension has conceived a protocol aimed at searching for the prognostic cutoff value of triglycerides in predicting cardiovascular events in a large regional-based Italian cohort. METHODS AND RESULTS: Among 14 189 subjects aged 18 to 95 years followed-up for 11.2 (5.3-13.2) years, the prognostic cutoff value of triglycerides, able to discriminate combined cardiovascular events, was identified by means of receiver operating characteristic curve. The conventional (150 mg/dL) and the prognostic cutoff values of triglycerides were used as independent predictors in separate multivariable Cox regression models adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, serum uric acid, arterial hypertension, diabetes, chronic renal disease, smoking habit, and use of antihypertensive and lipid-lowering drugs. During 139 375 person-years of follow-up, 1601 participants experienced cardiovascular events. Receiver operating characteristic curve showed that 89 mg/dL (95% CI, 75.8-103.3, sensitivity 76.6, specificity 34.1, P<0.0001) was the prognostic cutoff value for cardiovascular events. Both cutoff values of triglycerides, the conventional and the newly identified, were accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.211 (95% CI, 1.063-1.378, P=0.004) and 1.150 (95% CI, 1.021-1.295, P=0.02), respectively. CONCLUSIONS: Lower (89 mg/dL) than conventional (150 mg/dL) prognostic cutoff value of triglycerides for cardiovascular events does exist and is associated with increased cardiovascular risk in an Italian cohort.

The Results of the URRAH (Uric Acid Right for Heart Health) Project: A Focus on Hyperuricemia in Relation to Cardiovascular and Kidney Disease and its Role in Metabolic Dysregulation.

The relationship between Serum Uric Acid (UA) and Cardiovascular (CV) diseases has already been extensively evaluated, and it was found to be an independent predictor of all-cause and cardiovascular mortality but also acute coronary syndrome, stroke and heart failure. Similarly, also many papers have been published on the association between UA and kidney function, while less is known on the role of UA in metabolic derangement and, particularly, in metabolic syndrome. Despite the substantial number of publications on the topic, there are still some elements of doubt: (1) the better cut-off to be used to refine CV risk (also called CV cut-off); (2) the needing for a correction of UA values for kidney function; and (3) the better definition of its role in metabolic syndrome: is UA simply a marker, a bystander or a key pathological element of metabolic dysregulation?. The Uric acid Right for heArt Health (URRAH) project was designed by the Working Group on uric acid and CV risk of the Italian Society of Hypertension to answer the first question. After the first papers that individuates specific cut-off for different CV disease, subsequent articles have been published responding to the other relevant questions. This review will summarise most of the results obtained so far from the URRAH research project.

The renal resistive index is associated with microvascular remodeling in patients with severe obesity.

BACKGROUND: Renal hemodynamics is impaired since the early stage of cardiometabolic disease. However, in obesity, its noninvasive ultrasound assessment still fails to provide pathophysiologic and clinical meaningfulness. We aimed to explore the relationship between peripheral microcirculation and renal hemodynamics in severe obesity. METHODS: We enrolled fifty severely obese patients with an indication for bariatric referring to our outpatient clinic. Patients underwent an extensive reno-metabolic examination, paired with Doppler ultrasound and measurement of the renal resistive index (RRI). On the day of the surgery, visceral fat biopsies were collected to perform an ex-vivo complete microcirculatory assessment. Media-to-lumen ratio (M/L) and vascular response to acetylcholine (ACh), alone or co-incubated with N G -nitro arginine methyl ester (L-NAME), were measured. RESULTS: Patients were stratified according to their normotensive (NT) or hypertensive (HT) status. HT had lower estimated glomerular filtration rate and higher RRI compared to NT, while the presence and extent of albuminuria were similar between the two groups. Concerning microcirculatory assessment, there were no differences between groups as regards the microvascular structure, while the vasorelaxation to ACh was lower in HT ( P = 0.042). Multivariable analysis showed a relationship between M/L and RRI ( P  = 0.016, St. ß 0.37) and between albuminuria and the inhibitory response of L-NAME to Ach vasodilation ( P   =  0.036, St. ß = -0.34). Notably, all these correlations were consistent also after adjustment for confounding factors. CONCLUSIONS: The RRI and albuminuria relationship with microvascular remodeling in patients affected by severe obesity supports the clinical implementation of RRI to improve risk stratification in obesity and suggests a tight pathophysiologic connection between renal haemodynamics and microcirculatory disruption.

Dietary Supplement, Containing the Dry Extract of Curcumin, Emblica and Cassia, Counteracts Intestinal Inflammation and Enteric Dysmotility Associated with Obesity.

Intestinal epithelial barrier (IEB) impairment and enteric inflammation are involved in the onset of obesity and gut-related dysmotility. Dietary supplementation with natural plant extracts represents a useful strategy for the management of body weight gain and systemic inflammation associated with obesity. Here, we evaluate the efficacy of a food supplement containing the dry extract of Curcumin, Emblica and Cassia in counteracting enteric inflammation and motor abnormalities in a mouse model of obesity, induced by a high-fat diet (HFD). Male C57BL/6 mice, fed with standard diet (SD) or HFD, were treated with a natural mixture (Curcumin, Emblica and Cassia). After 8 weeks, body weight, BMI, liver and spleen weight, along with metabolic parameters and colonic motor activity were evaluated. Additionally, plasma LBP, fecal calprotectin, colonic levels of MPO and IL-1ß, as well as the expression of occludin, TLR-4, MYD88 and NF-κB were investigated. Plant-based food supplement administration (1) counteracted the increase in body weight, BMI and metabolic parameters, along with a reduction in spleen and liver weight; (2) showed strengthening effects on the IEB integrity; and (3) reduced enteric inflammation and oxidative stress, as well as ameliorated the colonic contractile dysfunctions. Natural mixture administration reduced intestinal inflammation and counteracted the intestinal motor dysfunction associated with obesity.

Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study.

High serum uric acid (SUA) and triglyceride (TG) levels might promote high-cardiovascular risk phenotypes across the cardiometabolic spectrum. However, SUA predictive power in the presence of normal and high TG levels has never been investigated. We included 8124 patients from the URic acid Right for heArt Health (URRAH) study cohort who were followed for over 20 years and had no established cardiovascular disease or uncontrolled metabolic disease. All-cause mortality (ACM) and cardiovascular mortality (CVM) were explored by the Kaplan-Meier estimator and Cox multivariable regression, adopting recently defined SUA cut-offs for ACM (≥4.7 mg/dL) and CVM (≥5.6 mg/dL). Exploratory analysis across cardiometabolic subgroups and a sensitivity analysis using SUA/serum creatinine were performed as validation. SUA predicted ACM (HR 1.25 [1.12-1.40], p < 0.001) and CVM (1.31 [1.11-1.74], p < 0.001) in the whole study population, and according to TG strata: ACM in normotriglyceridemia (HR 1.26 [1.12-1.43], p < 0.001) and hypertriglyceridemia (1.31 [1.02-1.68], p = 0.033), and CVM in normotriglyceridemia (HR 1.46 [1.23-1.73], p < 0.001) and hypertriglyceridemia (HR 1.31 [0.99-1.64], p = 0.060). Exploratory and sensitivity analyses confirmed our findings, suggesting a substantial role of SUA in normotriglyceridemia and hypertriglyceridemia. In conclusion, we report that SUA can predict ACM and CVM in cardiometabolic patients without established cardiovascular disease, independent of TG levels.