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Arterial hypertension has remained the world's leading cause of morbidity and mortality for more than 20 years. While early Genome-Wide Association Studies raised the hypothesis that a precision medicine approach could be implemented in the treatment of hypertension, the large number of single nucleotide polymorphisms that were found to be associated with blood pressure and their limited impact on the blood pressure values have initially hampered these expectations. With the development and refinement of gene-editing and RNA-based approaches allowing selective and organ-specific modulation of critical systems involved in blood pressure regulation, a renewed interest in genetic treatments for hypertension has emerged. The CRISPR-Cas9 system, antisense oligonucleotides (ASO) and small interfering RNA (siRNA) have been used to specifically target the hepatic angiotensinogen (AGT) production, with the scope of safely but effectively reducing the activation of the renin-angiotensin system, ultimately leading to an effective reduction of the blood pressure with extremely simplified treatment regimens that involve weekly, monthly or even once-in-life injection of the drugs. Among the various approaches, siRNA and ASO that reduce hepatic AGT production are in advanced development, with phase I and II clinical trials showing their safety and effectiveness. In the current manuscript, we review the mode of action of these new approaches to hypertension treatment, discussing the results of the clinical trials and their potential to revolutionize the management of hypertension.

Xanthine oxidoreductase (XOR) is an enzyme involved in the oxidation of hypoxanthine and xanthine to uric acid. XOR has two isoforms: xanthine dehydrogenase and xanthine oxidase (XO). XO plays a major role in oxidative stress, causing the formation of reactive oxygen species. In the present study, we aimed to summarize the evidence on the association between XO and pregnancy complications. The PRISMA checklist guided the reporting of the data. We conducted systematic searches in the PubMed and Web of Science databases to identify all human studies investigating XO in pregnancy diseases up to June 2024. A total of 195 references have been identified and 14 studies were included. Most studies focused on women with PE and GD. Overall, all the included studies found a statistically significant increase in maternal, placental, and/or fetal XO levels, activity, or tissue expression in women with pregnancy complications, compared to those with uncomplicated pregnancies. Although promising, the quality and dimension of the included studies do not allow for a definitive answer to the question of whether XO may play a crucial role in pregnancy complications. Future studies are warranted to confirm if XO could represent a prognostic and therapeutic marker in pregnancy complications and their impact on long-term maternal and offspring cardiovascular health.

Atherosclerotic cardiovascular diseases (ASCVDs) remain leading causes of mortality and disability in Western countries [...]

Background and aimsFast-track care have been proved to reduce the short-term risk of stroke after transient ischemic attack (TIA). We aimed to investigate stroke risk and to characterize short- and long-term stroke predictors in a large cohort of TIA patients undergoing fast-track management.MethodsProspective study, enrolling consecutive TIA patients admitted to a Northern Italy emergency department from August 2010 to December 2017. All patients underwent fast-track care within 24 h of admission. The primary outcome was defined as the first stroke recurrence at 90 days, 12 and 60 months after TIA. Stroke incidence with 95% confidence interval (CI) at each timepoint was calculated using Poisson regression. Predictors of stroke recurrence were evaluated with Cox regression analysis. The number needed to treat (NNT) of fast-track care in preventing 90-day stroke recurrence in respect to the estimates based on baseline ABCD2 score was also calculated.ResultsWe enrolled 1,035 patients (54.2% males). Stroke incidence was low throughout the follow-up with rates of 2.2% [95% CI 1.4–3.3%] at 90 days, 2.9% [95% CI 1.9–4.2%] at 12 months and 7.1% [95% CI 5.4–9.0%] at 60 months. Multiple TIA, speech disturbances and presence of ischemic lesion at neuroimaging predicted stroke recurrence at each timepoint. Male sex and increasing age predicted 90-day and 60-month stroke risk, respectively. Hypertension was associated with higher 12-month and 60-month stroke risk. No specific TIA etiology predicted higher stroke risk throughout the follow-up. The NNT for fast-track care in preventing 90-day stroke was 14.5 [95% CI 11.3–20.4] in the overall cohort and 6.8 [95% CI 4.6–13.5] in patients with baseline ABCD2 of 6 to 7.ConclusionOur findings support the effectiveness of fast-track care in preventing both short- and long-term stroke recurrence after TIA. Particular effort should be made to identify and monitor patients with baseline predictors of higher stroke risk, which may vary according to follow-up duration.

Although whole grains have well-recognized protective effects against the development of cardiometabolic diseases, whole grain foods are poorly consumed by the general population. The aim of our study was to establish, at a population level, the vascular impact of a low intake of whole grain foods. From the initial cohort of the Brisighella Heart Study, we identified a population sample of 1503 individuals—including 720 men (47.9%) and 783 women (52.1%)—who overall largely consumed refined grain products. Diet quality was estimated by the Short Healthy Eating Index (sHEI), and women were found to have an eating pattern that was overall healthier than men (44.1 ± 8.5 vs. 36.3 ± 8.1, p < 0.001). The development of an age- and blood pressure (BP)-adjusted multiple linear regression model found that carotid–femoral pulse wave velocity (cfPWV) was significantly predicted by the estimated glomerular filtration rate (eGFR, B = −0.148, 95% Confidence Interval (CI) −0.259–−0.038, p < 0.001), serum uric acid (SUA, B = 0.220, 95%CI 0.095–0.320, p = 0.001) and sHEI (B = −0.231, 95%CI −327–−0.089, p < 0.001) in men, and by eGFR (B = −0.152, 95%CI −0.266–−0.052, p < 0.001), body mass index (BMI, B = 0.174, 95%CI 0.111–0.331, p = 0.002), SUA (B = 0.278, 95%CI 0.158–0.354, p < 0.001) and sHEI (B = −0.218, 95%CI −308–−0.115, p < 0.001) in women. Ultimately, a low sHEI score was a significant predictor of arterial stiffness also in a population cohort with a high consumption of refined grain products.

Postbiotics could exert different metabolic activities in animal models of non-alcoholic fatty liver disease (NAFLD) and in humans affected by metabolic syndrome. This is a randomized, double-blind, placebo-controlled, parallel-group clinical trial that enrolled a sample of 50 Caucasian healthy individuals with NAFLD, defined as liver steatosis, and metabolic syndrome. After a 4-week run-in, the enrolled individuals were randomized to take a food for special medical purposes with functional release, one tablet a day, containing calcium butyrate (500 mg/tablet), zinc gluconate (zinc 5 mg/tablet), and vitamin D3 (500 IU/tablet), or an identical placebo for 3 months. Liver and metabolic parameters were measured at baseline and at the end of the study. No subject experienced any adverse events during the trial. In both groups, a significant decrease in total cholesterol (TC) and triglycerides (TG) plasma levels was observed at the randomization visit vs. pre-run-in visit (p < 0.05). Regarding liver parameters, after treatment, the fatty liver index (FLI) improved significantly vs. baseline values (p < 0.05) and vs. placebo group (p < 0.05) in the active treatment group, and the hepatic steatosis index (HSI) improved significantly vs. baseline values (p < 0.05). Moreover, after active treatment, TC, TG, and gamma-glutamyl transferase (gGT) improved significantly vs. baseline values (p < 0.05), and TC and TG improved vs. placebo group (p < 0.05), as well. In the placebo group, liver parameters remained unchanged after treatment; only TG improved significantly vs. baseline values (p < 0.05). In our study, we observed that the butyrate-based formula improved FLI and plasma lipid patterns in individuals affected by liver steatosis and metabolic syndrome.

The objective of this study was to investigate the longitudinal association of metabolically healthy overweight/obese adults with major adverse cardiovascular events (MACE) and the effect of LDL-cholesterol levels on this association. This study was conducted with 15,904 participants from the URRAH study grouped according to BMI and metabolic status. Healthy metabolic status was identified with and without including LDL-cholesterol. The risk of MACE during 11.8 years of follow-up was evaluated with multivariable Cox regressions. Among the participants aged p = 0.012). However, when LDL-cholesterol < 130 mg/dL was included in the definition of healthy metabolic status, no increase in risk was found in the overweight/obese adults compared to the normal weight individuals (hazard ratio 0.70 (0.07–6.71, p = 0.75). The present data show that the risk of MACE is increased in metabolically healthy overweight/obese individuals identified according to standard criteria. However, when LDL-cholesterol is included in the definition, metabolically healthy individuals who are overweight/obese have no increase in risk.

High levels of serum uric acid (SUA) and triglycerides (TG) might promote high-cardiovascular-risk phenotypes, including subclinical atherosclerosis. An interaction between plaques xanthine oxidase (XO) expression, SUA, and HDL-C has been recently postulated. Subjects from the URic acid Right for heArt Health (URRAH) study with carotid ultrasound and without previous cardiovascular diseases (CVD) (n = 6209), followed over 20 years, were included in the analysis. Hypertriglyceridemia (hTG) was defined as TG ≥ 150 mg/dL. Higher levels of SUA (hSUA) were defined as ≥5.6 mg/dL in men and 5.1 mg/dL in women. A carotid plaque was identified in 1742 subjects (28%). SUA and TG predicted carotid plaque (HR 1.09 [1.04–1.27], p < 0.001 and HR 1.25 [1.09–1.45], p < 0.001) in the whole population, independently of age, sex, diabetes, systolic blood pressure, HDL and LDL cholesterol and treatment. Four different groups were identified (normal SUA and TG, hSUA and normal TG, normal SUA and hTG, hSUA and hTG). The prevalence of plaque was progressively greater in subjects with normal SUA and TG (23%), hSUA and normal TG (31%), normal SUA and hTG (34%), and hSUA and hTG (38%) (Chi-square, 0.0001). Logistic regression analysis showed that hSUA and normal TG [HR 1.159 (1.002 to 1.341); p = 0.001], normal SUA and hTG [HR 1.305 (1.057 to 1.611); p = 0.001], and the combination of hUA and hTG [HR 1.539 (1.274 to 1.859); p = 0.001] were associated with a higher risk of plaque. Our findings demonstrate that SUA is independently associated with the presence of carotid plaque and suggest that the combination of hyperuricemia and hypertriglyceridemia is a stronger determinant of carotid plaque than hSUA or hTG taken as single risk factors. The association between SUA and CVD events may be explained in part by a direct association of UA with carotid plaques.

Introduction There is growing interest in head-to-head comparison between different lipid-lowering nutraceuticals. The aim of our study was to test the lipid-lowering effect of dietary supplementation with low-dose monacolins from red yeast rice (2.8 mg per daily dose) combined with berberine (Armolipid Plus®) or highly standardized artichoke extract versus placebo. Material and methods 60 overall healthy adult volunteers with polygenic hypercholesterolemia (baseline low-density lipoprotein cholesterol (LDL-C) = 160.2 ±9.2 mg/dl) were enrolled in a 3-arm, double-blind, non-inferiority, randomized, parallel-group clinical trial. After 4-week diet standardization, enrolled individuals were randomized to be treated for 8 weeks with red yeast rice and highly standardized artichoke extracts (ATC group), Armolipid Plus®, or placebo. Results At the enrolment visit, LDL-C values were similar in the compared groups. After 8 weeks, all actively treated subjects experienced significant improvements in baseline total cholesterol (TC), LDL-C and apolipoprotein B (Apo-B) (all p < 0.01) (ATC group: TC = –18.9%, LDL-C = –26.7% (placebo-corrected: –12.4%), Apo-B = –19.6%; Armolipid Plus®: TC = –18.4%, LDL-C = –25.8% (placebo-corrected: –12.1%), Apo-B = –23.2%; placebo: TC = –6.2%, LDL-C = –8%, Apo-B = –8.4%). Participants in the ATC group attained significantly lower body mass index (BMI) values (–2.1%), while individuals treated with Armolipid Plus® showed improvements in baseline high-density lipoprotein cholesterol (HDL-C) (+8.7%) and triglyceride (TG) (+17.5%) levels. Finally, baseline hepatic steatosis index (HSI) values significantly decreased in both actively treated groups (by –2.4% and –2.4% in ATC and in Armolipid Plus®, respectively). Conclusions Patients with polygenic hypercholesterolemia experienced a significant improvement in several cardiovascular risk factors in both ATC and Armolipid Plus® groups.

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

The 2023 hypertension guidelines of the European Society of Hypertension (ESH) have been published in the December issue of the official Journal of the Society (Journal of Hypertension),1 where they are freely available online. Compared to the guidelines published 5 years ago,2 the new guidelines address issues never or only marginally addressed before, including a large number of comorbidities to hypertension that may change the approach to antihypertensive management. [...]

The aim of this study was to assess whether dietary supplementation with a nutraceutical blend comprising extracts of bergamot and artichoke—both standardized in their characteristic polyphenolic fractions—could positively affect serum lipid concentration and insulin sensitivity, high-sensitivity C-reactive protein (hs-CRP), and indexes of non-alcoholic fatty liver disease (NAFLD) in 90 healthy individuals with suboptimal cholesterol levels. Participants were randomly allocated to treatment with a pill of either active treatment or placebo. After 6 weeks, the active-treated group experienced significant improvements in levels of triglycerides (TG), apolipoprotein B-100 (Apo B-100), and apolipoprotein AI (Apo AI) versus baseline. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (Non-HDL-C), and hs-CRP also significantly decreased in the active-treated group compared to both baseline and placebo. At the 12-week follow-up, individuals allocated to the combined nutraceutical experienced a significant improvement in TC, LDL-C, Non-HDL-C, TG, Apo B-100, Apo AI, glucose, alanine transaminase (ALT), gamma-glutamyl transferase (gGT), hs-CRP, several indexes of NAFLD, and brachial pulse volume (PV) in comparison with baseline. Improvements in TC, LDL-C, Non-HDL-C, TG, fatty liver index (FLI), hs-CRP, and endothelial reactivity were also detected compared to placebo (p < 0.05 for all). Overall, these findings support the use of the tested dietary supplement containing dry extracts of bergamot and artichoke as a safe and effective approach for the prevention and management of a broad spectrum of cardiometabolic disorders.

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.

Childhood obesity has become a worldwide epidemic in the 21st century. Its treatment is challenging and often ineffective, among others due to complex, often not obvious causes. Awareness of the existence and meaning of psychosocial and environmental risk factors seems to be an essential element in the prevention and treatment of obesity and its complications, especially arterial hypertension. In this review, we will discuss the role of that risk factors linking obesity and increased cardiovascular disorders including the role of nutritional factors (including the role of unhealthy diet, inadequate hydration), unhealthy behaviors (e.g. smoking, alcohol and drugs, sedentary behavior, low physical activity, disrupted circadian rhythms, sleep disorders, screen exposure), unfavorable social factors (such as dysfunctional family, bullying, chronic stress, mood disorders, depression, urbanization, noise, and environmental pollution), and finally differences in cardiovascular risk in girls and boys.

Summary: Background: Arterial stiffening is central to the vascular ageing process and a powerful predictor and cause of diverse vascular pathologies and mortality. We investigated age and sex trajectories, regional differences, and global reference values of arterial stiffness as assessed by pulse wave velocity (PWV). Methods: Measurements of brachial-ankle or carotid-femoral PWV (baPWV or cfPWV) in generally healthy participants published in three electronic databases between database inception and August 24th, 2020 were included, either as individual participant-level or summary data received from collaborators (n = 248,196) or by extraction from published reports (n = 274,629). Quality was appraised using the Joanna Briggs Instrument. Variation in PWV was estimated using mixed-effects meta-regression and Generalized Additive Models for Location, Scale, and Shape. Findings: The search yielded 8920 studies, and 167 studies with 509,743 participants from 34 countries were included. PWV depended on age, sex, and country. Global age-standardised means were 12.5 m/s (95% confidence interval: 12.1–12.8 m/s) for baPWV and 7.45 m/s (95% CI: 7.11–7.79 m/s) for cfPWV. Males had higher global levels than females of 0.77 m/s for baPWV (95% CI: 0.75–0.78 m/s) and 0.35 m/s for cfPWV (95% CI: 0.33–0.37 m/s), but sex differences in baPWV diminished with advancing age. Compared to Europe, baPWV was substantially higher in the Asian region (+1.83 m/s, P = 0.0014), whereas cfPWV was higher in the African region (+0.41 m/s, P

Background: Wearable devices represent a new approach for monitoring key clinical parameters, such as ECG signals, for research and health purposes. These devices could outcompete medical devices in terms of affordability and use in out-clinic settings, allowing remote monitoring. The major limitation, especially when compared to implantable devices, is the presence of artifacts. Several authors reported a relevant percentage of recording time with poor/unusable traces for ECG, potentially hampering the use of these devices for this purpose. For this reason, it is of the utmost importance to develop a simple and inexpensive system enabling the user of the wearable devices to have immediate feedback on the quality of the acquired signal, allowing for real-time correction. Methods: A simple algorithm that can work in real time to verify the quality of the ECG signal (acceptable and unacceptable) was validated. Based on simple statistical parameters, the algorithm was blindly tested by comparison with ECG tracings previously classified by two expert cardiologists. Results: The classifications of 7200 10s-signal samples acquired on 20 patients with a commercial wearable ECG monitor were compared. The algorithm has an overall efficiency of approximately 95%, with a sensitivity of 94.7% and a specificity of 95.3%. Conclusions: The results demonstrate that even a simple algorithm can be used to classify signal coarseness, and this could allow real-time intervention by the subject or the technician.

The aim of this study was to evaluate whether there were significant sex x time interactions in lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) response to treatment with the Proprotein Convertase Subtilisin/Kexin type 9 inhibitor (PCSK9i) Evolocumab, in a real-life clinical setting. For this purpose, we pooled data from 176 outpatients (Men: 93; Women: 83) clinically evaluated at baseline and every six months after starting Evolocumab. Individuals who had been on PCSK9i for less than 30 months and nonadherent patients were excluded from the analysis. Over time, absolute values of Lp(a) plasma concentrations significantly decreased in the entire cohort (p-value < 0.001) and by sex (p-value < 0.001 in men and p-value = 0.002 in and women). However, there were no sex-related significant differences. Absolute plasma concentrations of LDL-C significantly decreased over time in the entire cohort and by sex (p-value < 0.001 always), with greater improvements in men compared to women. The sex x time interaction was statistically significant in LDL-C (all p-values < 0.05), while absolute changes in Lp(a) were not influenced by either sex or time (all p-value > 0.05). Our data partially reinforce the presence of differences in response to treatment to PCSK9i between men and women and are essential to gain a better understanding of the relationship between LDL-C and Lp(a) lowering in response to PCSK9i. Further research will clarify whether these sex-related significant differences translate into a meaningful difference in the long-term risk of ASCVD.

High lipoprotein(a) (Lp(a)) plasma levels are significantly associated with an increased risk of developing atherosclerotic cardiovascular diseases (ASCVD). The aim of this analysis was to estimate the prevalence and characteristics of patients potentially eligible for Lp(a)-lowering therapies in a real-world setting (i.e., patients with ASCVD and Lp(a) levels > 70 mg/dL). For this reason, we pooled data from a large cohort of Italian outpatients (N = 5961; men: 2879, women: 3982) with dyslipidemia. A binary logistic regression analysis was used to determine the significant predictors of ASCVD in the cohort, which were age (Odds Ratio (OR): 1.158, 95% Confidence Interval (CI): 1.114 to 1.203, p < 0.001), low-density lipoprotein cholesterol at entry (OR: 1.989, 95% CI: 1.080 to 1.198, p = 0.020) and Lp(a) (OR: 1.090, 95% CI: 1.074 to 1.107, p < 0.001). In our cohort, almost half of patients with ASCVD (44.7%) may be eligible to be treated with Lp(a)-lowering agents. Interestingly, patients who do not meet the treatment criteria despite high Lp(a) (50–70 mg/dL), respectively, account for 4.7% and 7.3% of those in primary and secondary ASCVD prevention. In conclusion, in our large cohort of outpatients with dyslipidemia, the prevalence of individuals with ASCVD and very high Lp(a) plasma levels is quite high, even with a conservative estimation.

Plant sterols are well-known natural lipid-lowering agents. The DESCO (Diet and plant sterols in the control of cholesterolemia) study was a single-center, randomized, double-blind, placebo-controlled, two-way crossover clinical trial designed to investigate the effect of a once-a-day ready-to-drink dietary supplement containing 2.5 g of phytosterols on the lipid profile, also in relation to the quality of the diet, in a cohort of 50 Italian individuals with polygenic hypercholesterolemia and low global cardiovascular risk. Eligible individuals were enrolled in a run-in period of 2 weeks. Then, participants who qualified for continuation in the study were randomly allocated (1:1) to a 3-week treatment with either phytosterols or placebo. After a 2-week washout period, enrolled individuals were crossed over to receive the alternative treatment. Dietary supplementation with phytosterols was associated with significant improvement in plasma levels of total cholesterol (TC; −11.8 ± 4.0 mg/dL, p = 0.016), low-density lipoprotein cholesterol (LDL-C; −7.8 ± 7.7 mg/dL, p = 0.021), and apolipoprotein B-100 (Apo B-100, −3.7 ± 4.1 mg/dL, p = 0.048) compared to baseline. The changes in TC and LDL-C were also significant compared to placebo, and greater adherence to the Mediterranean diet was significantly associated with greater reductions in LDL-C. Dietary supplementation with phytosterols was well tolerated and adherence to treatment was high. According to the findings of DESCO, the once-a-day ready-to-drink dietary supplement we tested is able to quickly and significantly decrease plasma levels of TC, LDL-C, and Apo B-100, with a greater effect in individuals more adhering to the Mediterranean dietary pattern.

Limited data suggests possible gender-specific association between serum uric acid (SUA) and cardiovascular disease (CVD) incidence. The aim of the present analysis was to evaluate the association between SUA levels and 10-year CVD incidence (2002–2012) in the ATTICA study participants. Overall, 1687 apparently healthy volunteers, with SUA measurements, residing in the greater metropolitan Athens area (Greece), were included. Multivariable Cox-regression models were used to estimate the hazard ratios for SUA in relation to 10-year CVD incidence. Receiver operating curve analysis was conducted to detect optimal SUA cut-off values. Participants in the 2nd and 3rd SUA tertile had 29 and 73% higher 10-year CVD incidence compared with those in the 1st tertile (p < 0.001). In gender-specific analysis, only in women SUA was independently associated with CVD incidence; women in the 3rd SUA tertile had 79% greater 10-year CVD event risk compared to their 1st tertile counterparts. Obese in the 3rd SUA tertile had 2-times higher CVD incidence compared to those in the 1st tertile. Similar findings were observed in metabolically healthy (vs. unhealthy) and metabolically healthy obese. SUA thresholds best predicting 10-year CVD incidence was 5.05 and 4.15 mg/dL (0.30 and 0.25 mmol/L) in men and women, respectively. In conclusion, increased SUA levels were independently related to 10-year CVD event rate in women, obese and metabolically healthy individuals. SUA could predict 10-year CVD incidence even at low levels. Further studies are warranted to identify SUA cut-off values that may improve the detection of individuals at higher CVD risk in clinical practice.

Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin‐angiotensin system inhibitors (RASi) in adults with COVID‐19. We therefore performed a meta‐analysis to assess the safety and efficacy of RASi in adults with COVID‐19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID‐19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all‐cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow‐up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all‐cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69–1.30]) either overall or in subgroups defined by COVID‐19 severity or trial type. Network meta‐analysis identified no difference between angiotensin‐converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33–1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05–3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta‐analysis of randomized controlled trials evaluating angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID‐19 found no difference in all‐cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID‐19.

CD93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp), is a transmembrane glycoprotein encoded by a gene located on 20p11.21 and composed of 652 amino acids. CD93 can be present in two forms: soluble (sCD93) and membrane-bound (CD93). CD93 is mainly expressed on endothelial cells, where it plays a key role in promoting angiogenesis both in physiology and disease, such as age-related macular degeneration and tumor angiogenesis. In fact, CD93 is highly expressed in tumor-associated vessels and its presence correlates with a poor prognosis, poor immunotherapy response, immune cell infiltration and high tumor, node and metastasis (TNM) stage in many cancer types. CD93 is also expressed in hematopoietic stem cells, cytotrophoblast cells, platelets and many immune cells, i.e., monocytes, neutrophils, B cells and natural killer (NK) cells. Accordingly, CD93 is involved in modulating important inflammatory-associated diseases including systemic sclerosis and neuroinflammation. Finally, CD93 plays a role in cardiovascular disease development and progression. In this article, we reviewed the current literature regarding the role of CD93 in modulating angiogenesis, inflammation and tumor growth in order to understand where this glycoprotein could be a potential therapeutic target and could modify the outcome of the abovementioned pathologies.

Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details.

Abstract Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD.

Introduction. Cluster of Differentiation (CD) 93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp) is a transmembrane glycoprotein that can also be present in a soluble (sCD93) form. Recent studies have investigated the role of this protein in cardiovascular disease (CVD). The present systematic review aims to assess the associations between CD93 and cardiovascular (CV) risk factors and disease at both the proteomic and genomic levels. Methods. We conducted systematic searches in the PubMed, EMBASE, and Web of Science databases to identify all human studies since inception to February 2023 that investigated the role of CD93 in CV risk factors, CVD, and CV-associated outcomes. The data collection and analysis have been independently conducted by two reviewers. The search terms included: cardiovascular, heart failure, acute stroke, myocardial infarction, stroke, peripheral artery disease, cardiovascular death, MACE, hypertension, metabolic syndrome, hyperuricemia, diabetes, cd93, c1qr, C1qR1, complement protein 1 q subcomponent receptor. Results. A total of 182 references were identified, and 15 studies investigating the associations between CD93 protein levels or CD93 genetic polymorphisms and the development or prevalence of CV risk factors (i.e., hypertension, dyslipidemia, and obesity) and CVD (i.e., heart failure, coronary artery disease, and ischemic stroke) were included. Although promising, the quality and dimension of the analyzed studies do not allow for a definitive answer to the question of whether CD93 may hold diagnostic and prognostic value in CVD.

Worldwide, population aging and unhealthy lifestyles have increased the incidence of high-risk health conditions such as cardiovascular diseases, sleep apnea, and other conditions. Recently, to facilitate early identification and diagnosis, efforts have been made in the research and development of new wearable devices to make them smaller, more comfortable, more accurate, and increasingly compatible with artificial intelligence technologies. These efforts can pave the way to the longer and continuous health monitoring of different biosignals, including the real-time detection of diseases, thus providing more timely and accurate predictions of health events that can drastically improve the healthcare management of patients. Most recent reviews focus on a specific category of disease, the use of artificial intelligence in 12-lead electrocardiograms, or on wearable technology. However, we present recent advances in the use of electrocardiogram signals acquired with wearable devices or from publicly available databases and the analysis of such signals with artificial intelligence methods to detect and predict diseases. As expected, most of the available research focuses on heart diseases, sleep apnea, and other emerging areas, such as mental stress. From a methodological point of view, although traditional statistical methods and machine learning are still widely used, we observe an increasing use of more advanced deep learning methods, specifically architectures that can handle the complexity of biosignal data. These deep learning methods typically include convolutional and recurrent neural networks. Moreover, when proposing new artificial intelligence methods, we observe that the prevalent choice is to use publicly available databases rather than collecting new data.

Throughout life, most of us eat at least three meals a day for 365 days a year [...]

Purines, such as adenine and guanine, perform several important functions in the cell. They are found in nucleic acids; are structural components of some coenzymes, including NADH and coenzyme A; and have a crucial role in the modulation of energy metabolism and signal transduction. Moreover, purines have been shown to play an important role in the physiology of platelets, muscles, and neurotransmission. All cells require a balanced number of purines for growth, proliferation, and survival. Under physiological conditions, enzymes involved in purines metabolism maintain a balanced ratio between their synthesis and degradation in the cell. In humans, the final product of purine catabolism is uric acid, while most other mammals possess the enzyme uricase that converts uric acid to allantoin, which can be easily eliminated with urine. During the last decades, hyperuricemia has been associated with a number of human extra-articular diseases (in particular, the cardiovascular ones) and their clinical severity. In this review, we go through the methods of investigation of purine metabolism dysfunctions, looking at the functionality of xanthine oxidoreductase and the formation of catabolites in urine and saliva. Finally, we discuss how these molecules can be used as markers of oxidative stress.

The purpose: To evaluate longitudinal trends in the prevalence of hyperuricaemia and chronic kidney disease (CKD) in Czech adults with and without arterial hypertension (HT). Materials and methods: Two independent cross-sectional surveys were performed in 2006–2009 and 2015–2018, each screening involving 1% population random sample of the general population of nine districts of the Czech Republic aged 25–64 years, stratified by age and gender. Hyperuricaemia was defined as serum uric acid ≥ 420 μmol/l in men, and ≥ 360 μmol/l in women. CKD was defined as estimated glomerular filtration rate < 60 ml/min/1.73 m2 and/or albumin/creatinine ratio ≥ 3 mg/mmol. Results: Final analyses included 3504 individuals examined in 2006–2009, and 2309 in 2015–2018. The overall prevalence of hyperuricaemia increased from 16.4% to 25.2% in men (p

Study objective: This systematic review and meta-analysis aimed to assess the efficacy and safety profile of treatment with inclisiran, a drug that has been recently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Design: A systematic literature search was conducted in order to identify randomized controlled trials (RCTs) assessing the effect on lipoproteins and the safety profile of inclisiran. Results: Data were pooled from 5 RCTs, which included 4226 subjects. Meta-analyses of data suggested that the multiple-dose regimens of inclisiran yielded a significant reduction in serum levels of proprotein convertase subtilisin/kexin type 9 (MD = −78.23%, 95%CI: −86.74, −69.71) and low-density lipoprotein cholesterol (MD = −45.48%, 95%CI: −50.36%, −40.61%) throughout the studies. Furthermore, treatment with inclisiran significantly affected total cholesterol (MD = −13.67%, 95%CI: −20.78%, −6.57%), high-density lipoprotein cholesterol (MD = 8.29%, 95%CI: 4.66%,11.93%), non-HDL cholesterol (MD = −39.45%, 95%CI: −43.6%, −35.31%), apolipoprotein B (MD = −34.58%, 95%CI: −38.78%, −30.78%) and lipoprotein(a) (MD = −20.9%, 95%CI: −25.8%, −15.99%). Multiple-dose regimens of inclisiran were associated with increased risk of injection-site reactions (any reaction: OR = 5.86, 95%CI: 3.44, 9.98; mild reactions: OR = 5.19, 95%CI: 1.68, 16.07; moderate reactions: OR = 13.37, 95%CI: 3.17, 56.46), and bronchitis (OR = 1.58, 95%CI: 1.10, 2.26), while the incidence of the pre-specified exploratory CV endpoint significantly decreased at 18 months (OR = 0.74, 95%CI: 0.58, 0.94). Conclusion and relevance: Inclisiran has favourable effects on serum lipid levels and an acceptable safety profile. Further well-designed RCTs are needed to explore its longer-term safety.

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.

Recent advancements in smart, wearable technologies have allowed the detection of various medical conditions. In particular, continuous collection and real-time analysis of electrocardiogram data have enabled the early identification of pathologic cardiac rhythms. Various algorithms to assess cardiac rhythms have been developed, but these utilize excessive computational power. Therefore, adoption to mobile platforms requires more computationally efficient algorithms that do not sacrifice correctness. This study presents a modified QRS detection algorithm, the AccYouRate Modified Pan–Tompkins (AMPT), which is a simplified version of the well-established Pan–Tompkins algorithm. Using archived ECG data from a variety of publicly available datasets, relative to the Pan–Tompkins, the AMPT algorithm demonstrated improved computational efficiency by 5–20×, while also universally enhancing correctness, both of which favor translation to a mobile platform for continuous, real-time QRS detection.

Even though coffee consumption has been clearly related to a number of benefits to the cardiovascular system, its effect on blood pressure (BP) has not been fully elucidated. In this sub-analysis of the Brisighella Heart Study (BHS), we compared central and peripheral BP values in a sub-cohort of 720 men (47.9%) and 783 women (52.1%) reporting the drinking of different amounts of coffee each day, for whom a full set of clinical, laboratory and hemodynamic parameters was available. According to our observations, moderate coffee drinking was associated to either higher levels of systolic BP (SBP) compared to those with heavy coffee consumption or lower SBP than that in the non-coffee drinking group (p-value for trend 3 cups per day had lower SBP than non-coffee drinkers by 5.2 ± 1.6 mmHg (p = 0.010) and 9.7 ± 3.2 mmHg, respectively (p = 0.007). Similar trends were also observed for peripheral pulse pressure (PP), aortic BP and aortic PP. In the age-adjusted multiple linear regression model, negative predictors of SBP, PP, aortic BP and aortic PP were the estimated glomerular filtration rate (eGFR), female sex and coffee consumption. Positive predictors included body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C). Then, our findings show that regular coffee drinking is associated with lower SBP, PP, aortic BP and aortic PP, but with similar arterial stiffness.

The principle of ketogenic diet (KD) is restriction of carbohydrates to a maximum of 5–10% of the total daily caloric intake, aiming at shifting body metabolism toward ketone bodies. Different studies suggested promising results of KD to help patients to lose weight, to reduce insulin requirements in diabetes, to supplement cancer protocols, to treat neurological conditions and to optimize control of metabolic and cardiovascular diseases. However, literature about the anti-inflammatory properties of KD in rheumatic diseases is still limited. The beneficial effects of weight loss in patients with inflammatory arthritis can be explained by biomechanical and biochemical factors. Obesity is associated with macrophage activation and production of pro-inflammatory cytokines including TNF-α, IL-1b, and IL-6. The clinical effect of KD may be primarily attributed to improvement of insulin sensitivity. Insulin resistance is associated with an increase of TNF-α, IL-1α, IL-1β, IL-6, and leptin. Moreover, reduction of body's adipose tissue and weight loss account for part of the anti-inflammatory effects and for the impact of KD on cardiovascular health. In rheumatoid arthritis, fasting was shown to be effective in reducing disease symptoms, possibly through the production of β-hydroxybutyrate (BHB), the main ketone body. BHB may exert inhibitory effects also on IL-17 and intermittent fasting improved the clinical manifestations of psoriatic arthritis. In ankylosing spondylitis, current literature doesn't allow to draw conclusion about the effects of KD. Future prospective studies will be needed to elucidate the potential beneficial effects of KD on specific domains and clinical outcomes in patients with inflammatory arthritis.

Objective Postacute COVID-19 syndrome (PACS) is an emerging entity characterised by a large array of manifestations, including musculoskeletal complaints, fatigue and cognitive or sleep disturbances. Since similar symptoms are present also in patients with fibromyalgia (FM), we decided to perform a web-based cross-sectional survey aimed at investigating the prevalence and predictors of FM in patients who recovered from COVID-19.Methods Data were anonymously collected between 5 and 18 April 2021. The collection form consisted of 28 questions gathering demographic information, features and duration of acute COVID-19, comorbid diseases, and other individual’s attributes such as height and weight. The American College of Rheumatology (ACR) Survey Criteria and the Italian version of the Fibromyalgia Impact Questionnaire completed the survey.Results A final sample of 616 individuals (77.4% women) filled the form 6±3 months after the COVID-19 diagnosis. Of these, 189 (30.7%) satisfied the ACR survey criteria for FM (56.6% women). A multivariate logistic regression model including demographic and clinical factors showed that male gender (OR: 9.95, 95% CI 6.02 to 16.43, p

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 cardiovascular mortality, stratified based on eGFR (>90, between 60 and 90 and

Objective: To project the 10-year clinical outcomes associated with single pill combination (SPC) therapies compared with multi-pill regimens for the management of hypertension in five countries (Italy, Russia, China, South Korea and Mexico). Methods: A microsimulation model was designed to project health outcomes between 2020 and 2030 for populations with hypertension managed according to four different treatment pathways: current treatment practices (CTP), single drug with dosage titration then sequential addition of other agents (start low and go slow, SLGS), free choice combination with multiple pills (FCC) and combination therapy in the form of a single pill (SPC). Model inputs were derived from the Global Burden of Disease 2017 dataset. Simulated outcomes of mortality, chronic kidney disease (CKD), stroke, ischemic heart disease (IHD), and disability-adjusted life years (DALYs) were estimated for 1,000,000 patients on each treatment pathway. Results: SPC therapy was projected to improve clinical outcomes over SLGS, FCC and CTP in all countries. SPC reduced mortality by 5.4% in Italy, 4.9% in Russia, 4.5% in China, 2.3% in South Korea and 3.6% in Mexico versus CTP and showed greater reductions in mortality than SLGS and FCC. The projected incidence of clinical events was reduced by 11.5% in Italy, 9.2% in Russia, 8.4% in China, 4.9% in South Korea and 6.7% in Mexico for SPC versus CTP. Conclusions: Ten-year projections indicated that combination therapies (FCC and SPC) are likely to reduce the burden of hypertension compared with conventional management approaches, with SPC showing the greatest overall benefits due to improved adherence.

Emerging research and epidemiological studies established the health benefits of the Mediterranean diet, whose hallmark is the high consumption of olives and olive oil as the primary source of dietary fatty acids and major sources of antioxidants. The aim of this study was to evaluate the effect of daily dietary supplementation with highly standardized polyphenols—mainly hydroxytyrosol—which are derived from olive oil production by-products of an Italian olive variety (Coratina Olive) on the plasma cholesterol of a sample of hypercholesterolemic individuals. This single-arm, non-controlled, non-randomized, prospective pilot clinical study involved a sample of 30 volunteers with polygenic hypercholesterolemia. The study design included a 2-week run-in and a 4-week intervention period. Patients were evaluated for their clinical status and by the execution of a physical examination and laboratory analyses before and after the treatment. The intervention effect was assessed using Levene’s test followed by the independent Student’s t test after the log-transformation of the non-normally distributed continuous variables. Dietary supplementation with highly standardized polyphenols that are derived from Coratina Olive (namely SelectSIEVE® OptiChol) was associated with a significant improvement in systolic blood pressure, pulse pressure, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, non-HDL-C, fasting plasma glucose, and uric acid compared to baseline values. Furthermore, SelectSIEVE® OptiChol was well tolerated by volunteers. We acknowledge that the study has some limitations, namely the small patient sample, the short follow-up, and the lack of randomization and control procedures. However, these results are consistent with previous literature that referred to extracts from different olive varieties. Definitely, our observations lay further foundations for the use of polyphenolic-rich olive extract from Coratina Olive in the prevention and treatment of first-stage metabolic syndrome.

Recently released position papers by the European Society of Hypertension (ESH) and the Italian Society of Hypertension (SIIA) provide therapeutic recommendations for the use of nutraceuticals in the management of high blood pressure (BP) and hypertension, opening up new perspectives in the field. This not-randomized diet-controlled clinical study aimed to evaluate if daily dietary supplementation with black garlic and pomegranate (namely SelectSIEVE® SlowBeat) could advantageously affect BP in individuals with high-normal BP or stage I hypertension. Enrolled subjects were adhering to a Mediterranean DASH (Dietary Approaches to Stop Hypertension) diet for two weeks before deciding whether to continue following Mediterranean DASH diet alone or in association with SelectSIEVE® SlowBeat. At the end of the study, dietary supplementation with SelectSIEVE® SlowBeat was associated with significant improvement in systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared to baseline (Pre-treatment: SBP = 134.3 ± 4.2 and DBP = 88.2 ± 3.4; 4-Week Follow-up: SBP = 130.1 ± 2.8 and DBP= 83.7 ± 2.6). SBP improved also in comparison with control. In conclusion, the study shows that dietary supplementation with extracts from black garlic and pomegranate safely exert significant improvements in BP in healthy individuals adhering to a Mediterranean DASH diet.

Diabetic kidney disease (DKD) is a common complication of type 1 and 2 diabetes and often presents during adolescence and young adulthood. Given the growing incidence of both type 1 and type 2 diabetes in children and adolescents, DKD represents a significant public health problem. Acute kidney injury (AKI) in youth with diabetes is strongly associated with risk of DKD development. This review will summarize the epidemiology and pathophysiology of AKI in children with diabetes, the relationship between AKI and DKD, and the potential therapeutic interventions. Finally, we will appraise the impact of the recent COVID-19 infection pandemic on AKI in children with diabetes.

Abstract Background Chronic obstructive pulmonary disease (COPD) and heart failure (HF) often coexist. Moreover, elderly patients suffering from HF have a higher incidence of COPD, which further complicates their clinical condition. Indacaterol/glycopirronium has shown benefits in the treatment of COPD, with few cardiologic adverse effects. We evaluated the safety and efficacy of this therapy in patients with history of HF. Methods We enrolled 56 patients with a history of HF (New York Heart Association [NYHA] classes II and III) and stable COPD. We evaluated blood samples, clinical assessment, echocardiograms and basal spirometry at baseline and after 6 months of therapy with indacaterol/glycopirronium. In addition, the number of re-hospitalizations during the treatment period was evaluated. Results The treatment was well tolerated. Brain natriuretic peptide (BNP) levels were significantly reduced compared with baseline (p

The coronavirus disease 2019 (COVID-19) has already killed more than 6 million people around the world. A growing body of epidemiological evidence suggests that low 25-hydroxy vitamin D (25-OH-vitamin D) plasma levels are associated with an increased risk of developing COVID-19 and —most importantly—with a higher risk of developing more severe COVID-19 and dying. On the other hand, vitamin D supplementation during the early phases of COVID-19 has been related to a decreased length of hospital stay, less frequent need for oxygen, and a reduced mortality rate in inpatients. This seems to be particularly true when high dosages are used. In light of this evidence, further studies are needed to define the best timing for vitamin D supplementation and the most effective dosage schedule.

Objective: Altered coagulation parameters in COVID-19 patients is associated with a poor prognosis. We tested whether COVID-19 patients on chronic oral anticoagulants (cOACs) for thromboembolism prophylaxis could receive protection from developing more severe phenotypes of the disease.Approach and Results: We searched the database of the SARS-RAS study (Clinicaltrials.gov: NCT04331574), a cross-sectional observational multicenter nationwide survey in Italy designed by the Italian Society of Hypertension. The database counts 2,377 charts of Italian COVID-19 patients in 26 hospitals. We calculated the Charlson comorbidity index (CCI), which is associated with death in COVID-19 patients. In our population (n = 2,377, age 68.2 ± 0.4 years, CCI: 3.04 ± 0.04), we confirm that CCI is associated with increased mortality [OR: 1.756 (1.628-1.894)], admission to intensive care units [ICU; OR: 1.074 (1.017-1.134)], and combined hard events [CHE; OR: 1.277 (1.215-1.342)]. One hundred twenty-five patients were on cOACs (age: 79.3 ± 0.9 years, CCI: 4.35 ± 0.13); despite the higher CCI, cOACs patients presented with a lower risk of admissions to the ICU [OR 0.469 (0.250-0.880)] but not of death [OR: 1.306 (0.78-2.188)] or CHE [OR: 0.843 (0.541-1.312)]. In multivariable logistic regression, cOACs confirmed their protective effect on ICU admission and CHE. The CCI remains the most important risk factor for ICU admission, death, and CHE.Conclusions: Our data support a mechanism for the continuation of cOAC therapy after hospital admission for those patients who are on chronic treatment. Our preliminary results suggest the prophylactic use of direct cOACs in patients with elevated CCI score at the time of the COVID-19 pandemic even in absence of other risks of thromboembolism.

Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.

Coronavirus disease (COVID-19) may predispose patients to pulmonary embolism (PE), despite standard thromboprophylaxis. Our retrospective study aimed to report the prevalence of PE in patients with COVID-19 and severe respiratory failure (SRF) treated with intermediate- to full-dose enoxaparin. We analyzed data from patients with COVID-19 pneumonia and SRF admitted to our Respiratory Intensive Care Unit (RICU) from February 27 to April 20, 2020. All patients received at least intermediate-dose enoxaparin (40 mg twice daily). Computed tomography pulmonary angiography (CTPA) was used to detect PE. Ninety-two patients with COVID-19 pneumonia and SRF were admitted to our RICU. Twenty-two patients underwent CTPA (24 %), 11 of whom had PEs (12%). We hypothesize that the enoxaparin treatment may be responsible for the lower prevalence of PE as compared to previous reports of similar patients, even if our report had several limitations, mainly the small sample size.

Introduction Whether ACE inhibitors (ACEi) or angiotensin II receptor blocker (ARB) therapy should be continued, initiated or ceased in patients with COVID-19 is uncertain. Given the widespread use of ACEi/ARBs worldwide, guidance on the use of these drugs is urgently needed. This prospective meta-analysis aims to pool data from randomised controlled trials (RCTs) to assess the safety and efficacy of ACEi/ARB therapy in adults infected with SARS-CoV-2.Methods and analysis RCTs will be eligible if they compare patients with COVID-19 randomised to ACEi/ARB continuation or commencement versuss no ACEi/ARB therapy; study duration ≥14 days; recruitment completed between March 2020 and May 2021. The primary outcome will be all-cause mortality at ≤30 days. Secondary outcomes will include mechanical ventilation, admission to intensive care or cardiovascular events at short-term follow-up (≤30 days) and all-cause mortality at longer-term follow-up (>1 month). Prespecified subgroup analyses will assess the effect of sex; age; comorbidities; smoking status; ethnicity; country of origin on all-cause mortality. A search of ClinicalTrials.gov has been performed, which will be followed by a formal search of trial registers, preprint servers, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify RCTs that meet inclusion criteria. To date, a search of ClinicalTrials.gov identified 21 potentially eligible trials for this meta-analysis. We will request trial investigators/sponsors to contribute standardised grouped tabular outcome data.Ethics and dissemination Ethics approval and informed consent will be the responsibility of the individual RCTs. Dissemination of results will occur by peer-reviewed publication. The results of our analysis can inform public health policy and clinical decision making regarding ACEi/ARB use in patients with COVID-19 on a global scale.

[This corrects the article DOI: 10.1371/journal.pone.0237297.].

Aim: Sacubitril valsartan (SV) has revolutionized disease history in patients with heart failure and reduced ejection fraction (HFrEF). Our study assessed SV impact on clinical and echocardiographic parameters in HFrEF outpatients previously treated with optimized therapy. Methods: Forty-nine HFrEF outpatients were retrospectively included in the study. We collected data from transthoracic echocardiography and clinical assessment at baseline and after 3 ± 1 and 12 ± 1 months of treatment with SV. Results were also stratified by sex to analyse possible sex-based differences in reverse remodelling response to SV. Results: After 3 months of treatment we observed a significative improvement of both systolic and diastolic function with a reduction of left ventricular mass and relative wall thickness (RWT). At 12 months we observed a further improvement of all previous parameters, plus systolic pulmonary artery pressure (PAP) and left atrial (LA) diameter. In women, most of the echocardiographic parameters improved after SV initiation, but did not reach the statistical significance, except for left ventricular ejection fraction (LVEF), PAP and LA diameter. As for clinical parameters, SV improved New York Heart Association (NYHA) Class, systolic blood pressure and loop diuretic dosage with a mild but significative increase in serum creatinine and potassium. Conclusion: Our study showed significative reverse remodelling properties of SV with an improvement of LV volumes, mass and systo-diastolic function. NYHA Class, systolic blood pressure and loop diuretic dosage also improved with only mild increase in serum creatinine and potassium. Women showed a lesser extent of reverse remodelling compared with men.