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Introduction: Inclisiran is a novel posttranscriptional gene silencing therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis by RNA interference and has a potent, dose-dependent, durable effect in lowering LDL-C, and therefore is an effective drug to treat dyslipidemia, reducing the risk for acute cardiovascular (CV) events. It is safe and well-tolerated. Areas covered: This paper aims to review the mechanism of action of inclisiran while evaluating its efficacy and safety in the treatment of dyslipidemia from data of the clinical trials in the ORION program. Expert opinion: Data from the clinical trials in the ORION program demonstrated efficacy and safety of inclisiran in patients with dyslipidemia. Adverse events were similar in the inclisiran and placebo groups in the clinical trials, although injection-site reactions were more frequent with inclisiran than with placebo. Although the combination of efficacy and safety makes inclisiran a good option for the treatment of dyslipidemia compared to other PCSK9 targeting therapeutic strategies, however, further studies should exclude the possibility that inclisiran, through lower-affinity interactions, may influence other mRNAs in the physiological milieu.

Analisi critica dello Studio ACCORD

[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

The drug discovery process is very long, costly, and challenging but essential in medical sciences. Advancements in new techniques to improve the efficacy of drug development are therefore needed. The 3D cell culture technique represents a step forward in studying human tissues and diseases, and developed in vitro 3D tissue models can be an excellent alternative to traditional 2D cell cultures and animal testing. They can replicate the physiological microenvironment of the living tissue-mimicking extracellular matrix (ECM), cell-cell/cell-ECM interactions, and the spatial cellular arrangement, thus such models are useful systems to evaluate better and comprehend drug responsiveness. The 3D bioprinting technique brings many advantages in the fabrication of 3D tissue models, such as custom-made microarchitecture, high-throughput capability, and co-culture ability. However, this technique has challenges related to cells and materials requirements as well as tissue maturation and functionality. This review introduces the leading bioprinting technologies (extrusion-based, inkjet-based and laser-assisted) and summarizes and discusses their applications to build organ models such as liver, intestine, cardiac, and tumor tissues for applications in drug discovery and drug toxicity studies. The different bioprinting approaches and 3D printed tissue constructs employed to evaluate drug dose-response and drug metabolism are critically reviewed and discussed.

The primary and secondary prevention strategies of atherosclerotic cardiovascular disease (ASCVD) largely rely on the management of arterial hypertension and hypercholesterolemia, two major risk factors possibly linked in pathophysiological terms by the renin-angiotensin system activation and that often coexist in the same patient synergistically increasing cardiovascular risk. The classic pharmacologic armamentarium to reduce hypercholesterolemia has been based in the last two decades on statins, ezetimibe, and bile acid sequestrants. More recently numerous novel, additive resources targeting different pathways in LDL cholesterol metabolism have emerged. They include drugs targeting the proprotein convertase subtilisin/kexin type 9 (PCSK9) (inhibitory antibodies; small-interfering RNAs), the angiopoietin-like protein 3 (inhibitory antibodies), and the ATP-citrate lyase (the inhibitory oral prodrug, bempedoic acid), with PCSK9 inhibitors and bempedoic acid already approved for clinical use. With the potential of at least halving LDL cholesterol levels faster and more effectively with the addition of ezetimibe than with high-intensity statin alone, and even more with the addition of the novel available drugs, this document endorsed by the Italian Society of Hypertension proposes a novel paradigm for the treatment of the hypertensive patient with hypercholesterolemia at high and very high ASCVD risk. Our proposal is based on the use as a first-line of a preferably fixed combination of lipid-lowering drugs, under the motto "Our goal: achieve control. No setback: combine and check".

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.

Hypertension is a major contributor to fatal/nonfatal cardiovascular diseases, and timely identification and appropriate management of factors affecting hypertension and its control are mandatory public health issues. By inducing neurohormonal alterations and metabolic impairment, sleep disorders have an impact on a variety of cardiovascular risk factors, including hypertension, and ultimately increase the risk of cardiovascular events. There is evidence that qualitative and quantitative sleep disorders are associated with resistant hypertension and with impaired circadian blood pressure variations. However, sleep disturbances are often unrecognized, or heterogeneity exists in their management by non-specialists in the field. This document by the Italian Society of Hypertension summarizes the updated evidence linking sleep disorders to hypertension and cardiovascular diseases, the major underlying mechanisms, and the possible management strategies. A simplified, evidence-based diagnostic and therapeutic algorithm for comorbid hypertension and common sleep disorders, namely obstructive sleep apnoea and insomnia, is proposed.

Introduction: Hypertesion is the leading cause of morbidity and mortality, worldwide, and its prevalence has been increasing in several countries, including Italy. Aims: To assess hypertension prevalence, awareness, treatment, and control in a real-world sample of adults with self-reported diabetes compared with nondiabetic individuals. Methods: Following the 2018 World Hypertension Day, a nationwide, cross-sectional epidemiological survey on cardiovascular risk factors (“Abbasso la Pressione!”) in 3956 Italian pharmacies enrolled 47217 self-presenting volunteers (≥18 years). Participants underwent standardized blood pressure (BP) measurements and answered a questionnaire on cardiovascular risk factors and lifestyle habits. Questions included if they had an established diagnosis of diabetes, hypertension or were on a BP medication. Hypertension prevalence was defined as systolic BP ≥140 and/or diastolic BP ≥90 mmHg. A double definition for hypertension control based on the recent European and US guidelines on hypertension was applied. Results: Diabetic individuals (N=5695, 12%) had higher rates of hypertension prevalence (80% vs. 54.7%, p < 0.001), awareness (85.6% vs 77.3%, p < 0.001) and treatment (85.8% vs. 76.7%, p < 0.001), but lower hypertension control rates (36.1% vs. 39.6% according to the 2018 European guidelines, p < 0.001; 25.4% vs 30.8% according to the 2017 US guidelines, p < 0.001) than nondiabetics. Diabetic participants tended to be older, sedentary, overweight/obese, dyslipidemic men, with higher 10-years cardiovascular risk than nondiabetics (p < 0.001). Uncontrolled hypertension was associated with male gender, diabetes, body mass index, unhealthy lifestyle habits, and older age. Conclusions: Elevated hypertension awareness and treatment rates in diabetic adults do not translate into adequate BP control in the real world. Concomitant unfavorable metabolic features and unhealthy lifestyle habits might contribute to this observation.

Proteins play a crucial role in metabolism, in maintaining fluid and acid-base balance and antibody synthesis. Dietary proteins are important nutrients and are classified into: 1) animal proteins (meat, fish, poultry, eggs and dairy), and, 2) plant proteins (legumes, nuts and soy). Dietary modification is one of the most important lifestyle changes that has been shown to significantly decrease the risk of cardiovascular (CV) disease (CVD) by attenuating related risk factors. The CVD burden is reduced by optimum diet through replacement of unprocessed meat with low saturated fat, animal proteins and plant proteins. In view of the available evidence, it has become acceptable to emphasize the role of optimum nutrition to maintain arterial and CV health. Such healthy diets are thought to increase satiety, facilitate weight loss, and improve CV risk. Different studies have compared the benefits of omnivorous and vegetarian diets. Animal protein related risk has been suggested to be greater with red or processed meat over and above poultry, fish and nuts, which carry a lower risk for CVD. In contrast, others have shown no association of red meat intake with CVD. The aim of this expert opinion recommendation was to elucidate the different impact of animal vs vegetable protein on modifying cardiometabolic risk factors. Many observational and interventional studies confirmed that increasing protein intake, especially plant-based proteins and certain animal-based proteins (poultry, fish, unprocessed red meat low in saturated fats and low-fat dairy products) have a positive effect in modifying cardiometabolic risk factors. Red meat intake correlates with increased CVD risk, mainly because of its non-protein ingredients (saturated fats). However, the way red meat is cooked and preserved matters. Thus, it is recommended to substitute red meat with poultry or fish in order to lower CVD risk. Specific amino acids have favourable results in modifying major risk factors for CVD, such as hypertension. Apart from meat, other animal-source proteins, like those found in dairy products (especially whey protein) are inversely correlated to hypertension, obesity and insulin resistance.

Extra virgin olive oil (EVOO) intake is associated with reduced cardiovascular risk, and its phenolic compound oleocanthal (OC) has anti-oxidant and anti-inflammatory properties. The cardiometabolic effects of EVOO with a high OC concentration have not been fully elucidated. We administered EVOO with a high OC concentration daily to 23 subjects with the metabolic syndrome (MetS) and hepatic steatosis (15 men and 8 women, age: 60 &plusmn, 11 years) for 2 months. Anthropometric data, metabolic parameters, hepatic steatosis (by fatty liver index, FLI), abdominal fat distribution (by ultrasound), and pro- and anti-inflammatory cytokines were assessed before and after the intervention. EVOO supplementation was associated with a reduction in body weight, waist circumference, body mass index (BMI), alanine transaminase and FLI, as well as interleukin (IL)-6, IL-17A, tumor necrosis factor-&alpha, and IL-1B, while IL-10 increased. Maximum subcutaneous fat thickness (SFT max) also increased, with a concomitant decrease in the ratio of visceral fat layer thickness/SFT max. Correlation analysis revealed positive associations between changes in body weight and BMI and those in SFT max, along with an inverse association between changes in IL-6 and those in SFT max. In conclusion, ingestion of EVOO with a high OC concentration had beneficial effects on metabolic parameters, inflammatory cytokines and abdominal fat distribution in MetS subjects with hepatic steatosis, a category of patients at high cardiometabolic risk.

Background Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. Methods and findings We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel–Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD −14.94%; 95% CI −17.31%, −12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD −18.17%; 95% CI −21.14%, −15.19%; p < 0.001), low-density lipoprotein cholesterol (MD −22.94%; 95% CI −26.63%, −19.25%; p < 0.001), low-density lipoprotein particle number (MD −20.67%; 95% CI −23.84%, −17.48%; p < 0.001), apolipoprotein B (MD −15.18%; 95% CI −17.41%, −12.95%; p < 0.001), high-density lipoprotein cholesterol (MD −5.83%; 95% CI −6.14%, −5.52%; p < 0.001), high-density lipoprotein particle number (MD −3.21%; 95% CI −6.40%, −0.02%; p = 0.049), and hsCRP (MD −27.03%; 95% CI −31.42%, −22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD −1.51%; 95% CI −3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI −9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD −1.83%; 95% CI −5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. Conclusions Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety., Maciej Banach and colleagues discuss the efficacy and safety of bempedoic acid, a drug that designed to lower LDL-C levels., Author summary Why was this study done? Lowering low-density lipoprotein cholesterol (LDL-C) is effective for reducing cardiovascular events over time. A number of phase II and phase III randomized controlled trials (RCTs) are already available showing encouraging results of bempedoic acid treatment on LDL-C. We aimed to perform a systematic review and meta-analysis on the clinical evidence available to date to better define the efficacy and tolerability profile of treatment with bempedoic acid. What did the researchers do and find? In this analysis of bempedoic acid that included 10 randomized clinical trials (n = 3,788 patients) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]), we confirmed that bempedoic acid significantly reduced total cholesterol (by 15%), non-high-density lipoprotein cholesterol (by 18.2%), LDL-C (by 22.9%), low-density lipoprotein particle number (by 20.7%), apolipoprotein B (by 15.2%), and high-sensitivity C-reactive protein (hsCRP) (by 27%), while negatively affecting serum levels of high-density lipoprotein cholesterol (−5.8%) and high-density lipoprotein particle number (−3.2%). Our results also confirmed that the therapy is overall safe and well tolerated, with no significant increase of serious adverse effects. What do these findings mean? The current meta-analysis demonstrates the multiple positive effects of bempedoic acid on lipid profile and hsCRP serum levels, as well as acceptable safety profile. This could be relevant in a setting where statin intolerance is very frequent and the LDL-C target suggested by international guidelines for dyslipidemia management is hard to achieve with standard therapies. An ongoing long-term cardiovascular outcomes trial will answer questions on the effect of bempedoic acid on cardiovascular events and mortality as well as on the drug’s safety issues.

Serum uric acid (SUA) levels discriminating across the different strata of cardiovascular risk is still unknown. By utilizing a large population-based database, we assessed the threshold of SUA that increases the risk of total mortality and cardiovascular mortality (CVM). The URRAH study (Uric Acid Right for Heart Health) is a multicentre retrospective, observational study, which collected data from several large population-based longitudinal studies in Italy and subjects recruited in the hypertension clinics of the Italian Society of Hypertension. Total mortality was defined as mortality for any cause, CVM as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. A total of 22 714 subjects were included in the analysis. Multivariate Cox regression analyses identified an independent association between SUA and total mortality (hazard ratio, 1.53 [95% CI, 1.21–1.93]) or CVM (hazard ratio, 2.08 [95% CI, 1.146–2.97]; P P

Introduction Red yeast rice (RYR) is an effective cholesterol-lowering nutraceutical reversibly inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. As liver damage is a possible (albeit rare) side effect of HMG-CoA inhibitors, it make sense to focus on the tolerability of the liver to RYR extracts. The aim of this paper is to offer an expert opinion on the risk of liver damage by the use of RYR extract. Methods A review of the available literature has been carried out and critically reviewed by the authors. Results According to a large meta-analysis of 53 randomized clinical trials comprising 112 treatment arms, which included 8535 subjects with 4437 in the RYR arm and 4303 in the control arm of the study, RYR administration was not associated with increased risk of Drug Induced Liver Injury (DILI) during RYR treatment. Single cases of DILI have been associated with the use of RYR supplements. Even if the causal relationship is hardly demonstrable, it is possible that products containing impurities or toxic elements such as citrinin or unstandardized dosages of bioactive compounds like monacolins, could be implicated in liver toxicity. Conclusion DILI associated with RYR intake are exceptional and hardly associated to RYR per se rather than to low-quality products. Nutrivigilance and stricter manufacturing regulations should be implemented and are recommended in order to protect consumers from low quality and potentially dangerous dietary supplements.

Regular physical activity is a cornerstone in the prevention and treatment of atherosclerotic cardiovascular disease (CVD) due to its positive effects in reducing several cardiovascular risk factors. Current guidelines on CVD suggest for healthy adults to perform at least 150 min/week of moderate intensity or 75 min/week of vigorous intensity aerobic physical activity. The current review explores the effects of physical activity on some risk factors, specifically: diabetes, dyslipidemia, hypertension and hyperuricemia. Physical activity induces an improvement in insulin sensitivity and in glucose control independently of weight loss, which may further contribute to ameliorate both diabetes-associated defects. The benefits of adherence to physical activity have recently proven to extend beyond surrogate markers of metabolic syndrome and diabetes by reducing hard endpoints such as mortality. In recent years, obesity has greatly increased in all countries. Weight losses in these patients have been associated with improvements in many cardiometabolic risk factors. Strategies against obesity included caloric restriction, however greater results have been obtained with association of diet and physical activity. Similarly, the beneficial effect of training on blood pressure via its action on sympathetic activity and on other factors such as improvement of endothelial function and reduction of oxidative stress can have played a role in preventing hypertension development in active subjects. The main international guidelines on prevention of CVD suggest to encourage and to increase physical activity to improve lipid pattern, hypertension and others cardiovascular risk factor. An active action is required to the National Society of Cardiology together with the Italian Society of Sports Cardiology to improve the prescription of organized physical activity in patients with CVD and/or cardiovascular risk factors.

Background: Polyphenols are bioactive compounds that can be found mostly in foods like fruits, cereals, vegetables, dry legumes, chocolate and beverages such as coffee, tea and wine. They are extensively used in the prevention and treatment of cardiovascular disease (CVD) providing protection against many chronic illnesses. Their effects on human health depend on the amount consumed and on their bioavailability. Many studies have demonstrated that polyphenols have also good effects on the vascular system by lowering blood pressure, improving endothelial function, increasing antioxidant defences, inhibiting platelet aggregation and low-density lipoprotein oxidation, and reducing inflammatory responses. Methods: This review is focused on some groups of polyphenols and their effects on several cardiovascular risk factors such as hypertension, oxidative stress, atherogenesis, endothelial dysfunction, carotid artery intima-media thickness, diabetes and lipid disorders. Results: It is proved that these compounds have many cardio protective functions: they alter hepatic cholesterol absorption, triglyceride biosynthesis and lipoprotein secretion, the processing of lipoproteins in plasma, and inflammation. In some cases, human long-term studies did not show conclusive results because they lacked in appropriate controls and in an undefined polyphenol dosing regimen. Conclusion: Rigorous evidence is necessary to demonstrate whether or not polyphenols beneficially impact CVD prevention and treatment.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non–lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

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Effect of a nutraceutical containing Ortosiphon stamineus leaf extract on blood pressure and metabolic syndrome components in hypertensive dyslipidaemic patients treated with calcium-channel blockers, or angiotensin converting enzyme inhibitors: a randomized clinical trial.

Despite advances in pharmacological treatment, diabetic nephropathy is still the leading cause of end-stage renal disease and an important cause of morbidity and mortality in diabetics. Glycosaminoglycans are long, unbranched mucopolysaccharides that play an important role in establishing a charge-selective barrier that restricts the passage of negatively charged molecules, such as albumin and other proteins, at the level of the glomerular basal membrane. Their loss is associated with loss of selectivity and proteinuria. Extensive preclinical evidence and some clinical trials suggest that glycosaminoglycans replacement is associated with improvement of glomerular selectivity and of proteinuria. Sulodexide could also have some other effects, potentially useful to reduce the renal damage and the cardiovascular disease associated with proteinuria, such as improvement of haemorheological and blood lipid parameters, an endothelium protective effect and anti-inflammatory action. This review will discuss the evidence supporting the potential nephroprotective effects of sulodexide and other glycosaminoglycans.

The aim of this study was to evaluate the effect of an oral glucose tolerance test (OGTT) on the level of endothelial dysfunction and vascular inflammation markers in healthy subjects (H) and diabetic overweight patients (D). We enrolled 256 healthy subjects and 274 type 2 diabetic patients. We evaluated blood glucose (BG), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), high-sensitivity C reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and tumor necrosis factor-alpha (TNF-alpha) at baseline and after OGTT. We observed that BG, sICAM-1, IL-6, hs-CRP, sVCAM-1, sE-selectin, and TNF-alpha values were higher in D group than in H group. In a large sample of adult healthy subjects and type 2 diabetics we observed that both answer to an OGTT with a significant increase in biomarkers of systemic low-grade inflammation and endothelial dysfunction such as hsCRP, IL-6, TNF-alpha, sICAM-1, sVCAM-1, and sE-selectin. Type 2 diabetics experienced, however, a more significant increase in TNF-alpha, and sE-selectin.

Serum uric acid is representative for xanthine-oxidase, the key enzyme involved in the production of uric acid, which is up-regulated in the failing heart, and may play an important role in the pathophysiologic process that leads to heart failure. In our study, we investigated the relation between stroke volume, cardiac output and serum uric acid in a large sample of overall healthy pharmacologically untreated subjects. The Brisighella Heart Study included 2,939 men and women between the ages of 14-84 without prior coronary heart disease or cerebrovascular disease who were not taking antihypertensive therapy at baseline. For this study, we selected 734 adult subjects enrolled in the last Brisighella population survey not taking antihypertensive, antidiabetic, lipid-lowering and uric acid-lowering drugs, and who were also not affected by chronic heart failure or by gout. The main predictors of cardiac functionality parameters were mean arterial pressure (MAP), HR, SUA and age (all p < 0.001), while gender, BMI, LDL-cholesterol, HDL-cholesterol, triglycerides, fasting plasma glucose, creatinine, estimated glomerular filtration rate, physical activity and smoking habit were not significantly associated (all p > 0.05). In particular, there is a strong relation between estimated cardiac output and serum uric acid (B = -0.219, p < 0.001) and between stroke volume and serum uric acid (B = -3.684, p < 0.001). These observations might have an impact on future considerations about serum uric acid as an early inexpensive marker of heart function decline in the general population

Lo studio di Brisghella iniziato nel 1972 per volontà del Professor Giancarlo Descovich è articolato in varie fasi. Una prima osservazionale longitudinale, con lo scopo di monitorare, con controlli quadriennali, l'andamento dei principali fattori di rsichio per le malattie cardiovascolari. Nel 1984 iniziò una fase di intervento che prevedeva una azione multipla: sulla popolazione generale, sulla popolazione scolastica (elementari e medie), sui soggetti definiti ad alto rischio cardiovascolare. La stragtegia di intervento ha portato ad una riduzione dei livelli lipidici, del numero di fattori di rischio che si associano nei singoli cittadini e del numero degli eventi cardiovascolari nella popolazione. Dopo il 1990 si è proseguito con una nuova fase longitudinale con controlli quadriennali. I dati di Brisighella dimostrano una correlazione forte tra i livelli lipidici e pressione arteriosa, definendo la colesterolemia un fattore correlato all'innalzamento dei livelli pressori in accordo con altri studi internazionali. Sono stati studiati i fattori associati allo sviluppo di diabete di tipo 2 e la stima della prelevalenza della Iperlipoprotenemia Familiare Combinata. E' stata valuta la correlazione fra ormoni sessuali, adipochine e patter metabolico e la correlazione tra attività fisica ed eventi cardiovascolari. Brisighella ha fornito dati come popolazione di controllo all'interno dell'ambizioso progetto DIAL-ER (Diagnostica avanza in lipidologia-Emilia-Romagna). Qust'anno è iniziato il survey di popolazione arruolata all'inizio (40 anni fa), che prevede anche l'arruolamento degli offsprings ed include la valutazione di parametri strumentali su tutta la popolazione (pulse-Wave Anlysis, Pulse Wave Velocity, Augmentation Index, ABI) ed un set di marcatori laboratoristici di rischio cardiometabolico quali microalbuminuria, marcatori di insulino-resistenza, flogosi sistemica e di metabolismo del tessuto adiposo.

Introduzione. Il ruolo dell’acido urico nella patologia aterosclerotica è oggetto di dibattito. Le proprietà antiossidanti dell’acido urico sono ben note, d’altro canto molti studi mostrano una associazione tra elevati livelli di acido urico ed ipertensione, diabete, sindrome metabolica e malattie cardiovascolari. Lo scopo di questo studio era di verificare la relazione tra i livelli di acido urico, la rigidità arteriosa e la aterosclerosi subclinica. Metodi. Il Brisighella Heart Study è uno studio epidemiologico prospettico di popolazione che coinvolge 2939 soggetti scelti casualmente (1491 uomini e 1448 donne), di età compresa tra 14 e 84 anni, privi di malattia cardiovascolare al momento dell’arruolamento, residenti a Brisighella, una città rurale, del centro-nord Italia. Da questo gruppo storico è stato randomizzato un sottocampione di 619 soggetti (248 maschi), di età compresa tra 53,5±11,2 anni. E’ stata valutata la aterosclerosi preclinica misurando lo spessore della intima-media (IMT). La rigidità arteriosa è stata determinata misurando la velocità dell’onda di polso (PWV) carotide-femorale per mezzo di un tonometro validato. Risultati. La analisi di regressione lineare mostrava una relazione significativa fra i livelli di acido urico, i valori di IMT (r=0.20, p0.001) (global trend: p

Background. La capacità del siero di promuovere l’efflusso di colesterolo dai macrofagi è inversamente correlato con i valori dello spessore intima-media carotidei e la probabilità di malattia coronarica, indipendentemente dai valori di HDL. Abbiamo studiato la relazione tra la capacità di efflusso del colesterolo sierico e la velocità dell’onda di polso (PWV), come indicatore della rigidità arteriosa, in soggetti sani. Metodi e risultati. Sono stati selezionati dalla coorte del Brighella Heart Study 99 soggetti (40 maschi e 59 femmine), non fumatori, non-diabetici, non trattati con antiipertensivi, farmaci ipolipemizzanti od antidiabetici, e senza placche aterosclerotiche carotidee rilevabili eco graficamente. La capacità sierica di efflusso del colesterolo è stata misurata come la diffusione acquosa, efflusso di colesterolo dipendente da ATP binding cassette A1 (ABCA1) (indice della funzione della HDL). La PWV è direttamente correlata con la diffusione acquosa basale di colesterolo (R=0.224, p=0.042). PWV non correla con l’efflusso di colesterolo totale (R=0.023, p=0.830). In una analisi multivariata che include età, indice di massa corporea, pressione arteriosa media, colesterolo LDL, colesterolo HDL, efflusso di colesterolo dipendente da ABCA1, la diffusione acquosa, i migliori predittori di PWV sono stati pressione arteriosa media (B=0.83, IC 95% 0.0058-0.108), età (B=0.051, 95% CI 0.028-0.073) e ABCA1efflusso colesterolo dipendente (B=-0298, 95% CI, 0.531-0.066). Conclusioni. La capacità di efflusso di colesterolo dipendente da ABCA1 e non i livelli di colesterolo HDL, è un predittore significativo di PWV nei soggetti sani. Questa scoperta sottolinea la importanza della funzione delle HDL nella modulazione vascolare e nella prevenzione della rigidità arteriosa a lungo termine.

The association of chronic kidney disease (CKD) and hearing disorders is well known, and was first reported more than 80 years ago by Alport, who described a case of familial kidney disease associated with hearing loss. Subsequently, a number of rare conditions or syndromes were described as occurring with a close link between hearing impairment and CKD (see Table 1). Moreover, some observational, cross-sectional, population-based studies concerning patients with CKD, or on dialysis therapy, confirmed this association suggesting the possibility that the linkage between the ear and the kidney is more than casual. In particular, Vilayur et al. report several physiological, ultrastructural and antigenic similarities between the kidney and the cochlea that strongly support the link between the hearing impairment and CKD [1]. The inner ear and the kidney share a series of basic processes for water and ion regulation as well as some specific cellular water channels known as aquaporins, which are known to have a crucial role in the functional activity of both organs. Moreover, the presence of a kidney-specific ion transport system has recently been demonstrated in the rat and human endolymphatic sac that, to date, represents the only known localization outside the kidney [2]. Once again this underlines a strict correspondence between the kidney and the inner ear, with both organs involved in highly energy-requiring processes linked to the strict necessity of maintaining the balance of ions and a stable pH. In particular, a derangement in the mechanisms regulating fluid and electrolyte homeostasis has been hypothesized both in the cochlear striavascularis, and in the kidney, to explain the possible association of inner ear and kidney diseases. A further contribution in order to clarify the importance of the analogies between kidney and inner ear comes from the progress in genetic research, revealing a possible common ground of dysfunction [3]. Finally, some cardiovascular risk factors such as age, diabetes, hypertension, electrolyte disorders and hemodialysis can affect both the ear and the kidney, and separately contribute to the development and the progression of organ-specific diseases [1]. Nevertheless, these reported connections and analogies between the ear and the kidney deserve to be considered according to a more comprehensive hypothesis. In particular, we speculate that a baseline condition of hemodynamic imbalance leading to a different extent of transient ischemia and hypoxia may elicit similar mechanisms of disease in both organs. Over the last decade, we have provided several observations supporting the hypothesis that some inner ear disorders of undetermined origin may depend on a large decrease in blood pressure values associated with an abnormal peripheral vasoconstriction [4]. This mechanism can be activated either in subjects without major cardiovascular risk factors (other than a generic sympathetic hyperreactivity), or in patients treated for hypertension or chronic congestive heart failure. In ‘‘healthy’’ subjects, the proposed model can provide a theoretical explanation for the cases of inner ear diseases usually labeled as ‘‘idiopathic’’, as well as for the different inner ear disturbances including the largely unexplained Meniere’s disease [5]. In patients with cardiovascular diseases, the symptoms of A. Pirodda Department of Specialist Surgical and Anesthesiological Sciences, S. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138 Bologna, Italy

Berberine is an alkaloid that is highly concentrated in the roots, rhizomes, and stem bark of various plants. It affects glucose metabolism, increasing insulin secretion, stimulating glycolysis, suppressing adipogenesis, inhibiting mitochondrial function, activating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway, and increasing glycokinase activity. Berberine also increases glucose transporter-4 (GLUT-4) and glucagon-like peptide-1 (GLP-1) levels. On GLP-1 receptor activation, adenylyl cyclase is activated, and cyclic adenosine monophosphate is generated, leading to activation of second messenger pathways and closure of adenosine triphosphate-dependent potassium channels. Increased intracellular potassium causes depolarization, and calcium influx through the voltage-dependent calcium channels occurs. This intracellular calcium increase stimulates the migration and exocytosis of the insulin granules. In glucose-consuming tissues, such as adipose, or liver or muscle cells, berberine affects both GLUT-4 and retinol-binding protein-4 in favor of glucose uptake into cells; stimulates glycolysis by AMPK activation; and has effects on the peroxisome proliferator-activated receptor γ molecular targets and on the phosphorylation of insulin receptor substrate-1, finally resulting in decreased insulin resistance. Moreover, recent studies suggest that berberine could have a direct action on carbohydrate metabolism in the intestine. The antidiabetic and insulin-sensitizing effect of berberine has also been confirmed in a few relatively small, short-term clinical trials. The tolerability is high for low dosages, with some gastrointestinal complaints appearing to be associated with use of high dosages.

Background. La compromissione della funzione renale è una frequente condizione clinica,che risulta in una aumentata incidenza e prevalenza di malattia renale. Lo scopo dello studio è quello di indagare i determinanti del deterioramento della funzione renale in un campione di popolazione generale. Metodi. Il Brisighella Heart Study è uno studio longitudinale, prospettico, di popolazione coinvolgente 2939 soggetti arruolati in modo casuale, di età compresa fra i 14 e 84 anni, senza patologia cardiovascolare all’arruolamento, residenti in una città rurale del nord Italia, Brisighella. Da questa coorte storica, seguita dal 1972 abbiamo selezionato 694 soggetti (50% uomini) che presentassero un rilievo di informazioni cliniche/laboratoristiche sia nel 2004 (età media 61±12 anni) sia nel 2008 (età media 65±12 anni). Risultati. Rispetto al 2004, nel 2008 i soggetti presentavano un più elevato giro di vita (94±12 vs. 92±12 cm, p

Introduzione. La steatosi epatica non alcolica (NAFLD) è una condizione frequente e correlata ad un aumentato rischio di sviluppare diabete di tipo 2 e patologie cardiovascolari. Lo scopo del nostro studio era quello di valutare se alcuni indici di NAFDL fossero in grado di predire la incidenza di sindrome metabolica (SM) a 4 anni in un ampio campione di popolazione non trattato farmacologicamente. Materiali e metodi. Dal database generale del Brisighella Heart Study abbiamo selezionato 824 soggetti non trattati farmacologicamente e non affetti da sindrome metabolica, alcolismo, diabete mellito di tipo 2 o malattie epatiche note ai controlli effettuati nel 2004 e rivisitati ai controlli del 2012. Di tutti questi soggetti abbiamo calcolato l’hepatic steatosis index (HSI) ed il Prodotto di Accumulo Lipidico (LAP). In seguito, applicando il metodo di Cox (adeguato agli elementi della SM), abbiamo valutato il ruolo predittivo del HSI e del inLAP per la SM. Risultati. Considerando l’intera popolazione, i migliori risultati predittivi di SM risultano essere l’età (OR 1.13, 95% CI 1.12-1.143, p

Background. Un numero crescente di evidenze supportano la correlazione epidemiologica e fisiopatologica tra ipercolesterolemia ed ipertensione. Il nostro obiettivo era quello di valutare la relazione tra colesterolemia, livelli sierici di apolipoproteina B (apoB) e pressione arteriosa in un ampio campione di popolazione generale. Metodi. Il Brisighella Heart Study(BHS) è uno studio prospettico di popolazione che prevede una indagine epidemiologica longitudinale. Per questo studio abbiamo analizzato i dati campionati nel sondaggio 2008 escludendo dall’arruolamento i soggetti trattati con antiipertensivi e/o farmaci ipolipemizzanti. (M:1134, F:1339). La associazione tra pressione arteriosa, il colesterolo LDL e le ApoB è stata valutata con analisi di regressione lineare multipla. Risultati. In un sesso, con un modello corretto per BMI, abitudine al fumo, livello di attività fisica e valori di creatinina sierica, i livelli di colesterolo LDL (LDL-C) apparivano significativamente correlati con la pressione arteriosa sistolica (PAS) (B=0.077, p

Introduzione. Il vero problema clinico nel trattamento della ipertensione sta nel fatto che, nonostante la disponibilità di diverse classi di antiipertensivi, l’obiettivo terapeutico è lontano dall’essere raggiunto, in termini di conseguimento dei target pressori ottimali. Tra le nuove molecoel, aliskiren rappersenta un farmaco dalle caratteristiche innovative perché in grado di inibire completamente il sistema renina-angiotensina (RAS) e, contemporaneamente, di opporsi agli effetti di contro regolazione che tale inibizione evoca sul RAS stesso determinando una maggiore protezione degli organi bersaglio. Obbiettivi. Valutare gli effetti dell’aliskiren in una popolazione di pazienti ad elevato rischio profilo di rischio cardiovascolare affetti da ipertensione arteriosa resistente. Sono stati raccolti dati riguardanti una popolazione di 70 pazienti ambulatoriali (età 71±10 anni, 4’-87 anni; 45 donne e 25 uomini, BMI=28±3), il 17% dei pazienti aveva avuto un infarto del miocardio, il 39% era diabetico, il 10% aveva avuto un evento ischemico cerebrale ed il 75% era affetto da IRC di grado lieve-moderato. Ai pazienti, tutti affetti da ipertensione arteriosa resistente, veniva prescritto aliskiren al tempo 0 e venivano rivalutati dopo 6 mesi. Risultati. La pressione arteriosa (PAS, sistolica; PAD, diastolica) al basale era (valore medio±DS) 159±11/87±10 mmHg e la frequenza cardiaca(FC) 67±10 bpm. Dopo 6 mesi di terapia i valori erano così modificati: PA 135±9/79±4 (p

Introduzione. La steatosi epatica è una caratteristica comune nei pazienti dislipidemici in sovrappeso ed articoli di recente pubblicazione correlano questo stato ad un aumentato rischio di sviluppare patologie cardiovascolari. Alcuni dati preliminari mostrano inoltre miglioramenti della condizione epatica legati alla assunzione di berberina. Lo scopo del nostro studio era di valutare l’effetto del trattamento con berberina nei pazienti dislipidemici trattati con un nutraceutico ipolipemizzante standardizzato associato o meno a berberina. Materiali e metodi. 39 soggetti (19 M, 20 F; età media 60±11 anni) affetti da dislipidemia mista (LDL>130 mg/dl e TG>200 mg/dl) e steatosi epatica sono stati randomizzati per essere trattati o con un nutraceutico ipolipemizzante a base di monacus purpureus (3 mg monacolina) o con uno a base di monacus purpureus e berberina (Armolipid Plus®) per 8 settimane. L’effetto sul fegato veniva valutato sulla base del Liver Steatosis Index [8 x (GOT/GPT) + BMI (+2 se donna; + 2 se paziente con diabete mellito). Risultati. Tutti i pazienti hanno tollerato il trattamento e non sono stati osservati aumenti delle transaminasi. In entrambi i gruppi si è osservato un miglioramento della colesterolemia LDL (-22%) ma solo nei pazienti trattati con macacus + berberina si è potuto osservare anche una riduzione della trigliceridemia (-25%). Per quanto riguarda l’hepatic steatosis index, nei pazienti trattati solo con il monacus non si sono ottenuti miglioramenti (T0=36±2 vs. T8=35.5±1.4, p>0.05), mentre in quelli trattati con monacus più berberina questo miglioramento è significativo (T0=36.5±1.3, t=4.750, p

Obbiettivo. La inattività fisica è un ben noto fattore di rischio cardiovascolare. Lo scopo questo studio è quello di descrivere la relazione tra la attività fisica (AF) auto valutata durante il tempo libero e la mortalità per malattie cardiovascolari in 2936 soggetti della coorte del Brisighella Heart Study (BHS), uno studio epidemiologico prospettico di popolazione. Metodi. Il significato prognostico a lungo termine (1998-2000) della AF è stato determinato dopo aggiustamenti per età, sesso, abitudine al fumo, colesterolo LDL e storia di diabete mellito di tipo 2. Risultati. Al basale, 377 (25.3%) maschi e 496 (34.3%) femmine hanno riferito scarsa-nulla AF, mentre 1112 femmine (74.7%) e 951 maschi (65.7%) hanno riferito AF medio-intensa. In tutta la popolazione, la mortalità cardiovascolare era 3 volte superiore nei soggetti con scarsa-nulla AFrispetto a quelli con AF media-intensa (p=0001). Questi risultati sono stati confermati sia negli uomini (p=0.0001) che nelle donne (p=0.0028). Una distribuzione categoriale della popolazione per età ha mostrato un più alto rischio di morte cardiovascolare associato a scarsa-nulla AF solo nei soggetti di sesso maschile più giovani (p=0.0032). Conclusioni. Sulla base dei nostri dati la AF è inversamente proporzionale alla mortalità cardiovascolare in un campione della popolazione rurale del Mediterraneo con un più alto rischio negli uomini inattivi di età inferiore a 65 anni.

Purpose: The role of uric acid on atherosclerosis phenomena is a vexed question. The antioxidant properties of uric acid are well known, on the other hand several studies shown an association between higher level of uric acid and hypertension, diabetes, metabolic syndrome and cardiovascular diseases. The aim of this study was to verify the relationship between uric acid values and arterial stiffness and subclinical atherosclerosis. Methods: The Brisighella Heart Study is a prospective, population-based longitudinal epidemiological investigation involving 2939 randomly selected subjects (1491 men and 1448 women), aged 14 to 84 years, free of cardiovascular disease at enrolment, resident in the northern Italian rural town of Brisighella. From this historical cohort, we randomized a sub-sample of 619 subjects (248 males), aged 53.5±11.2. Preclinical atherosclerosis was detected by carotid intima-media thickness (IMT) measurement. Arterial stiffness was determined by measuring the carotid-femoral pulse wave velocity (PWV) by means of a validated tonometer. Results: A linear regression analysis shown a significant relationship between acid uric levels and IMT (r:0.20, p0.001) (global trend: P

Introduzione. I peptidi derivati dal latte isoleucina-prolina-prolina (IPP) e valina-prolina-prolina (VPP) hanno mostrato di ridurre i livelli di pressione arteriosa (PAS), particolarmente nei soggetti di etnia asiatica, mentre l’effetto nelle popolazioni caucasiche è meno consistente. Metodi. E’ stato quindi condotta una metaanalisi secondo i criteri PRISMA per valutare l’effetto di IPP/VPP sulla PAS in soggetti europei e per valutare i determinanti principali di tale effetto. Risultati. Sono stati identificati 12 trials con 13 set di dati (n=1042) che rientravano nei criteri di inclusione. E’ stato impiegato il modello REML per effetti random. Sebbene non tutti i singoli trials mostrassero una significativa riduzione della PAS la combinazione dei dati faceva emergere un effetto significativo di riduzione della PAS da parte dei lactotriptidi rispetto al placebo con effetto globale di 1,29 mmHg (95% CI:[-2.16, -0.42], p?0038). Non vi era evidenza di bias di pubblicazione. L’esplorazione della eterogeneità (sebbene non statisticamente significativa – p=0.068) mostrava, fra le altre caratteristiche un significativo effetto della età media dei pazienti coinvolti negli studi. Ogni anno in più riduceva il calo della PAS di 0.09 mmHg, questo può essere correlato alla maggiore prevalenza nei soggetti più anziani di ipertensione sistolica isolata, condizione relativamente poco responsiva ad interventi terapeutici di primo livello. Discussione. I peptidi IPP/VPP riducono lievemente ma in modo significativo la PAS anche nei soggetti Europei, come già noto nelle popolazioni asiatiche. Sebbene moderato questo calo è simile a quello osservabile con la riduzione del sodio nella dieta. I peptidi IPP/VPP possono quindi essere considerati come una ulteriore arma per controllare i livelli di pressione arteriosa, anche se ulteriori studi sono necessari per definire meglio il tipo di soggetti responsivi a questo trattamento.

Purpose: Serum capacity to promote cholesterol efflux from macrophages correlates inversely with carotid intima–media thickness and the likelihood of angiographic coronary artery disease, independently of the high density lipoprotein (HDL) level. We investigated the relationship between serum cholesterol efflux capacity and Pulse Wave Velocity (PWV), as an indicator of arterial stiffness, in healthy subjects. Methods: 99 subjects (40 males, 59 females) were selected from the Brisighella Heart Study cohort for being non-smokers, non-diabetics, untreated with antihypertensive, lipid-lowering or antidiabetic drugs, and without echographically detectable carotid atherosclerotic plaques. Serum cholesterol efflux capacity was measured as aqueous diffusion, total cholesterol efflux and ATP binding cassette A1 (ABCA1)-dependent cholesterol efflux (reflecting mainly HDL function). Bilateral B-mode carotid artery images for intima-media thickness were acquired using a linear phased multifrequency (7.5-10 MHz). The posterior wall of the distal common carotid artery, one centimeter below the bifurcation, was assessed as recommended by the international guidelines. An eltrectrocardiografic trace was used to acquire image frames only in end-diastole, avoiding IMT variation related to carotid pulsatility. Carotid-femoral PWV was measured with a high-fidelity tonometer. Results: In the unadjusted model, PWV relates directly with basal aqueous cholesterol diffusion (R= 0.224, P= 0.034) and indirectly with ABCA1-dependent cholesterol efflux (R= -0.215, P= 0.042). PWV does not correlate with total cholesterol efflux (R= 0.023, P= 0.830). In a stepwise multivariate analysis including age, body mass index, mean arterial pressure, serum low density lipoprotein level serum HDL level, ABCA1-dependent cholesterol efflux, aqueous diffusion, the best PWV predictors were mean arterial pressure (B= 0.83, 95%CI 0.058-0,108), age (B= 0.051, 95%CI 0.028-0.073) and ABCA1-dependent cholesterol efflux (B= -0.298, 95%CI -0.531- -0.066). Conclusions: ABCA1-dependent cholesterol efflux capacity, but not total serum HDL, is a significant predictor of PWV in healthy subjects. This finding points to the relevance of HDL function in vascular modeling and arterial stiffness prevention along life.