Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Ventricular and vascular stiffening in aging and hypertension.

The assessment of arterial stiffness, a common feature of aging, exacerbated by pathological conditions like hypertension, has become an attractive tool for identifying structural and functional changes of the arteries even in an early stage of the atherosclerotic disease. Arterial stiffness has been recognized as an important physio-pathological determinant for the age-related rise in systolic blood pressure, demonstrating also an independent predictive value for cardiovascular events. In the recent decades, many techniques and indices to evaluate vascular stiffness have been developed and extensive data concerning their prognostic value have been collected. Moreover, it has become clear that vessel and heart must be considered as a unique system, in which combined stiffness of vessel and heart interacts to limit cardiovascular performance. In this review, main methods and indices used to estimate arterial and ventricular stiffness are presented, focusing on their alteration in physiological aging and arterial hypertension. Furthermore, the concept of ventricular-arterial coupling is explained in order to give an insight to the interplay between arterial and ventricular stiffness in aging and hypertension.

Different patterns of H2S/NO activity and cross-talk in the control of the coronary vascular bed under normotensive or hypertensive conditions.

Hydrogen sulfide (H2S) and nitric oxide (NO) play pivotal roles in the cardiovascular system. Conflicting results have been reported about their cross-talk. This study investigated their interplays in coronary bed of normotensive (NTRs) and spontaneously hypertensive rats (SHRs). The effects of H2S- (NaHS) and NO-donors (sodium nitroprusside, SNP) on coronary flow (CF) were measured in Langendorff-perfused hearts of NTRs and SHRs, in the absence or in the presence of propargylglycine (PAG, inhibitor of H2S biosynthesis), L-NAME (inhibitor of NO biosynthesis), ODQ (inhibitor of guanylate cyclase), L-Cysteine (substrate for H2S biosynthesis) or L-Arginine (substrate for NO biosynthesis). In NTRs, NaHS and SNP increased CF; their effects were particularly evident in Angiotensin II (AngII)-contracted coronary arteries. The dilatory effects of NaHS were abolished by L-NAME and ODQ; conversely, PAG abolished the effects of SNP. In SHRs, high levels of myocardial ROS production were observed. NaHS and SNP did not reduce the oxidative stress, but produced clear increases of the basal CF. In contrast, in AngII-contracted coronary arteries of SHRs, significant hyporeactivity to NaHS and SNP was observed. In SHRs, the vasodilatory effects of NaHS were only modestly affected by L-NAME and ODQ; PAG poorly influenced the effects of SNP. Then, in NTRs, the vascular actions of H2S required NO and vice versa. By contrast, in SHRs, the H2S-induced actions scarcely depend on NO release; as well, the NO effects are largely H2S-independent. These results represent the first step for understanding pathophysiological mechanisms of NO/H2S interplays under both normotensive and hypertensive conditions.

Discovery of a novel isoxazoline derivative of prednisolone endowed with a robust anti-inflammatory profile and suitable for topical pulmonary administration.

A novel glucocorticoids series of (GCs), 6α,9α-di-Fluoro 3-substituted C-16,17-isoxazolines was designed, synthesised and their structure-activity relationship was evaluated with glucocorticoid receptor (GR) binding studies together with GR nuclear translocation cell-based assays. This strategy, coupled with in silico modelling analysis, allowed for the identification of Cpd #15, an isoxazoline showing a sub-nanomolar inhibitory potency (IC50=0.84 nM) against TNFα-evoked IL-8 release in primary human airways smooth muscle cells. In Raw264.7 mouse macrophages, Cpd #15 inhibited LPS-induced NO release with a potency (IC50=6 nM)>10-fold higher with respect to Dexamethasone. Upon intratracheal (i.t.) administration, Cpd #15, at 0.1 µmol/kg significantly inhibited and at 1 µmol/kg fully counteracted eosinophilic infiltration in a model of allergen-induced pulmonary inflammation in rats. Moreover, Cpd #15 proved to be suitable for pulmonary topical administration given its sustained lung retention (t1/2=6.5h) and high pulmonary levels (>100-fold higher than plasma levels) upon intratracheal administration in rats. In summary, Cpd #15 displays a pharmacokinetic and pharmacodynamic profile suitable for topical treatment of conditions associated with pulmonary inflammation such as asthma and COPD.

Effect of acute and chronic vitamin D administration on systemic renin angiotensin system in essential hypertensives and controls.

AIM: To investigate the systemic renin-angiotensin system (RAS) in essential hypertensives (EH) and controls (C) after short- and long-term vitamin D receptor activation. DESIGN: Ten consecutive EH (under controlled low-salt diet) and 10 C underwent calcitriol administration (0.25 µg bid) for 1 week (Group A). Eighteen consecutive EH under angiotensin II receptor antagonist therapy received a single oral dose of 300,000 IU of cholecalciferol and were followed up for 8 weeks (Group B). METHODS: In basal conditions and at the end of the study (1 week in Group A and 8 weeks in Group B), plasma renin activity (PRA), plasma active renin, aldosterone, and angiotensin II were evaluated, as well as blood pressure, plasma 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH. RESULTS: In Group A, plasma 25(OH)D levels in EH and C were below the normal range, although lower levels were found in the former. No association between basal plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS components was observed either in the whole group or in the two subgroups. Calcitriol administration did not affect any RAS parameter either in EH or in C. In Group B, cholecalciferol significantly increased 25(OH)D and 1,25(OH)2D levels without interfering with the angiotensin II receptor antagonist-induced increase in RAS components. No correlation was found between plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS parameters before and after cholecalciferol administration. CONCLUSIONS: The present data suggest that, in our experimental conditions, vitamin D receptor activation is unable to influence systemic RAS activity.

[Prevention of patient's falls in University Hospital to Sassari, Italy]. / La prevenzione delle cadute in ospedale: progetto dell'Azienda Ospedaliero-Universitaria di Sassari.

The University Hospital has addressed the issue of prevention of falls in hospital with some goals: empowerment of practitioners, patients and their families, development of a tool for classification of the patient to the risk of falls, development of an instrument of signal detection and analysis ofthe fall. Were defined: (a) a scale for assessing risk falls, to be completed upon acceptance by the nurse, made up of several indicators with a score corresponding to each of them, can help to define the patient: low risk, medium risk and high risk, (b) a statement of measures to be implemented depending on the severity of the risk falls, (c) a reportingformfor all fall divided into two sections: nursing and medical (d) a brochure to be delivered at the time acceptance in the department that contains behavioral suggestions for patients and families/caregivers, useful for the prevention of falls. Experimentation of the project took place during the months of October-December 2009 in three UU.00. (Clinic Pulmonology, Neurology and Medical Clinic) with a broad membership of the personnel involved (directors, nursing coordinators, Doctors, Nurses). The results of the trial (of 287 total admissions in the three UO involved, with 90% of evaluation forms filled out, reports offalls were 19 (8%), 17 without loss (85%) and 2 with injury (15%), analyzed for both single UO, which together, have allowed the Department to evaluate the project and to act positively in April 2010 approval of the developed tools and their dissemination to all UO inpatient Company. Were analyzed all report forms received from May 2010 to December 2011. The total admissions in University Hospital, for the whole period examined, were 25,847. The U.O. occurred where the falls are 11 reported (in which the total admissions were 13,791). The reports of falls were 55 (0.40%), of which 29 (53%) from the upright position, 18 (33%) falls out of bed, of which 4 (8%) had fallen from the wheelchair seat and # 4 (8%) falls undetectable; 26 without damage (48%) and 29 with damage (53%).

High serum levels of CXC (CXCL10) and CC (CCL2) chemokines in untreated essential hypertension.

Hypertension has been suggested to exert pro-inflammatory actions through increased expression of several mediators, including chemokines. Chemokines are involved in inflammatory and autoimmune disorders, and in the formation of atherosclerotic lesions through promotion of inflammatory cell migration. The aim of this study is to evaluate the influence of high blood pressure on circulating levels of the prototype chemokines C-X-C motif ligand (CXCL)10 and C-C motif ligand (CCL)2 in 140 patients with essential hypertension not affected by thyroid disorders or overt autoimmune or inflammatory diseases, and 140 gender- and age-matched healthy controls. Mean CXCL10 and CCL2 levels were significantly higher in hypertensive patients than in controls. Among hypertensive patients, chemokines levels were higher in those with systo-diastolic hypertension compared to those with isolated systolic hypertension. In a multiple linear regression model using CXCL10 or CCL2 as dependent variables and age, body mass index, glycemia, serum creatinine, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, triglycerides, and systolic or diastolic blood pressure values as covariates, only systolic or diastolic blood pressure values were significantly related to CXCL10 or CCL2 levels. In conclusion, this study demonstrates increased circulating levels of the prototype chemokines CXCL10 and CCL2 in patients with hypertension.

Endothelial aging and gender.

The endothelium plays a pivotal role in maintaining vascular homeostasis, mainly by the production of the relaxing factor nitric oxide, which protects the vessel wall from the development of atherosclerosis. Aging is a powerful cardiovascular risk factor, associated with endothelial dysfunction both in normotensive subjects and in hypertensive patients. Premenopausal normotensive women are protected against the deleterious effect of aging on endothelial function, and age-related impairment of endothelial function is attenuated in premenopausal hypertensive women. This protective effect on endothelium seems to be mediated by endogenous estrogen, which preserves nitric oxide availability by activating the l-arginine-NO pathway in normotensive women and by inhibiting reactive oxygen species generation. Whether endogenous androgen may modulate endothelial function and the mechanisms involved are still unsolved issues, since data concerning the effect of testosterone on endothelium are scanty and contradictory.

Hypertension in the elderly: an evidence-based review.

The progressive ageing of world population, and the increasing prevalence hypertension in elderly people are leading to the consideration that hypertension in the elderly is one of the main topic in hypertension treatment. Multiple mechanisms, including stiffening of large arteries, endothelial dysfunction, cardiac remodeling, autonomic dysregulation, renal aspects, contribute to the great prevalence of hypertension in the elderly and to increased cardiovascular morbidity and mortality. Treatment of hypertension can hardly put back older patients in a low risk category, especially if target organ damage is present. Nevertheless, blood pressure control can successfully prevent stroke, cognitive decline, coronary heart disease and heart failure, and reduce mortality in the elderly, and even in patients > 80 years, as recently demonstrated. Blood pressure should be lowered below 140/90 mmHg also in older patients. However the HYVET study suggests that a goal of 150/90 mmHg can be reasonable in patients aged 80 years or more. Drug treatment should be titrated with particular caution to adverse responses and excessive blood pressure lowering.

[Perceived quality assessment in the University Hospital Authority in Sassary, Italy]. / Valutazione della qualità percepita nell'azienda Ospedaliero Universitaria di Sassari.

In line with the health legislation that introduced a system to monitor and review the quality, the Hospital Authority of University of Sassari has placed among its main objectives the satisfaction of patients/clients and has made an initial assessment of customer satisfaction for users hospitalized in their facilities with the methodology of the questionnaire. It was drawn up a questionnaire to closed questions, with default value scales, divided into 4 areas: 1) Hospitality, 2) Hotel treatment, 3) Professionalism of staff-information related pathology, informed consent, 4) personal opinion of the patient upon discharge. The questionnaire was administered the day of discharge, to users hospitalized of six UO of Hospital Authority in the months of September and October 2009, and patients discharged within 2 months were given a total of 514, of them have completed the testing 290 (54% of discharged patients). The questionnaires were analyzed in the results of both the individual UO involved in both the overall result, persons responsible for each facility was sent a report with the results of its own. The survey results are satisfactory with regard to both positive aspects, that is the overall grade average of 86.23% which to criticism, to which they are planning initiatives for their solution.

Cigarette smoking and hypertension.

Cigarette smoking is a powerful cardiovascular risk factor and smoking cessation is the single most effective lifestyle measure for the prevention of a large number of cardiovascular diseases. Impairment of endothelial function, arterial stiffness, inflammation, lipid modification as well as an alteration of antithrombotic and prothrombotic factors are smoking-related major determinants of initiation, and acceleration of the atherothrombotic process, leading to cardiovascular events. Cigarette smoking acutely exerts an hypertensive effect, mainly through the stimulation of the sympathetic nervous system. As concern the impact of chronic smoking on blood pressure, available data do not put clearly in evidence a direct causal relationship between these two cardiovascular risk factors, a concept supported by the evidence that no lower blood pressure values have been observed after chronic smoking cessation. Nevertheless, smoking, affecting arterial stiffness and wave reflection might have greater detrimental effect on central blood pressure, which is more closely related to target organ damage than brachial blood pressure. Hypertensive smokers are more likely to develop severe forms of hypertension, including malignant and renovascular hypertension, an effect likely due to an accelerated atherosclerosis.

[Observational study of adverse events in admissions in general hospital of Sassari about corporate planning of clinical risk management]. / Studio osservazionale degli eventi avversi relativi ai ricoveri del 2005, nell'ambito di un programma di gestione del rischio clinico della ASL di Sassari.

In the corporate planning of clinical risk management, we performed an observational retrospective study based on random sampling of admission in General Hospital of Sassari, in 2005. We examined 400 patient clinical documentations in order to find the most frequent adverse events (AE), according to the international literature. We looked for 9 different adverse events; for each of these we elaborated a form personal data and detailed information for each event. During the analysis of the clinical documentations we have found also adverse events not previously classified: they were recorded and classified. We classified the events as explicit, if declared in clinical documentation, and implicit if not declared but clearly present in the records. 47 EA included in the initial 9 categories were found; while other 26 were not included the defined categories, global frequency of AE in our sample resulted: 18.3%. The study is an initial approach to the survey of AE and needs to be refined by determination of liability, severity, predictability, preventability.

Endothelial dysfunction and vascular disease in later life.

The endothelium plays a primary role in the modulation of vascular tone and structure, through production of the relaxing factor nitric oxide, which acts by protecting the vessel wall from the development of atherosclerosis and thrombosis. A dysfunctioning endothelium, characterized by reduced nitric oxide availability, can be a promoter of atherosclerosis. Ageing is a well-documented cardiovascular risk factor. One of the possible physiopathological mechanisms whereby increasing age may lead to cardiovascular damage is the promotion of endothelial dysfunction. In humans, age-related impairment in endothelium-dependent vasodilation has been well documented in different vascular districts and involves the impairment of nitric oxide activity secondary to oxidative stress generation. Regular physical training is an important non-pharmacological intervention which protects the vascular endothelium from ageing-related alterations and ameliorates the cardiovascular risk profile among the elderly population.

Obesity in the childhood: a link to adult hypertension.

The rapid increasing prevalence of obesity worldwide represents a serious health hazard. Obesity predisposes to increased risk for diabetes, hypertension, renal failure. Direct mechanisms link visceral adiposity and the atherosclerosis process through the action of adipose-derived proinflammatory cytokines. In particular, hypertension can be considered the most important cardiovascular risk factor linking obesity to the development of cardiovascular disease. Obesity among children and adolescents has also reaching epidemic proportions in the industrialized world. Childhood obesity strongly predisposes to cardiovascular adult mortality. Recent reports documented a tracking of blood pressure from childhood to adulthood and obesity occurring in young age plays a crucial pathogenic role. Indeed, fighting overweight and obesity in the pediatric and adolescent age may prevent the occurrence of adults with hypertension and cardiovascular disease. The main strategies for prevention and treatment of overweight and obesity in childhood, which need to involve community, school and family, are the promotion of lifestyle interventions, including as a correct dietary approach, rich in fruit and vegetables and low-fat dairy products, and physical activity.

Effect of verapamil, trandolapril and their combination on vascular function and structure in essential hypertensive patients.

AIM: The aim of the present study is to evaluate the effect of treatment with verapamil, trandolapril and their combination on peripheral microcirculation vasoreactivity. METHODS: Twenty hypertensive patients were randomized to receive oral trandolapril (4 mg oid; TRA) or verapamil (240 mg oid; VER) for 6 months and then the combination of the two drugs for additional 6 months. At baseline, 6 months and 12 months, peripheral microcirculation vasoreactivity was evaluated by forearm blood flow technique (venous plethysmography), as vasodilation to an endothelium-dependent (acetylcholine) and an endothelium-independent stimulus (sodium nitroprusside, SNP); minimal forearm vascular resistances (MFVR) were also evaluated. RESULTS: Blood pressure decreased similarly and progressively in both groups throughout the study period. In VER, 6-month verapamil treatment significantly increased vasodilation to acetylcholine, but not to SNP. The superimposition of trandolapril increased the response to SNP, and less to acetylcholine. In TRA group, 6-month treatment with trandolapril improved the response to SNP, but not to acetylcholine. In this group, the superimposition of verapamil caused a significant improvement in the response to acetylcholine, but not to SNP. At the end of the study, MFVR were significantly reduced in both groups, but to a greater extent in TRA. CONCLUSION: The present study demonstrates that chronic treatment with verapamil ameliorates endothelial function in the forearm microcirculation of essential hypertensive patients, while trandolapril protects microcirculation from structural alterations. The combination of the two drugs is potentially a powerful tool to counteract hypertension-related microvascular dysfunction and damage.

Reclamation and agricultural reuse of wastewater: the experience of the Cagliari sewage treatment plant (Sardinia, Italy).

In Sardinia, as in many other Mediterranean regions, recurrent droughts and climate change have dramatically reduced available water resources. As a result of this critical situation, in 1995 the Italian Government declared a state of emergency and drew up a program for financial support by the State and local authorities with the aim of reducing this serious deficit. One of the actions focused on reclaiming and reusing the effluent from the sewage treatment plant of Cagliari. This article reports on the multidisciplinary preliminary study performed by the Ente Acque della Sardegna (ENAS) to evaluate the suitability of reusing Is Arenas effluent for irrigation and on the operation of the tertiary treatment plant.

[Quality of the clinical reports: observational study in Sassari]. / La qualità delle cartelle cliniche: studio osservazionale nella ASL di Sassari.

Within the program of clinical risk management, and in particular in the phase of the "knowledge" of company reality, the work deals with the topic of the case history in Sassari' local health authority. A study is treated where, on a sample of about 400 cases history, four definite aspects are considered, in particular those that are regarded as the most important in the risk management and about medical responsability: 1) formal consent; 2) daily clinical allowance; 3) therapeutic card; 4) operating card. The results we got show the presence of a formal consent filled in correctly in 36 cases (9%), completed a daily allowance in 36 cases (9%), therapeutic card in 14 (3.5%) cases, operation card in 21 cases (19% su 116 surgical cases). These data, that have permitted to estimate the specific company reality as from pointed out critical states, show the necessity of working, with involvement of professional doctors, to build a history case model with clear and shared rules where you can clearly find the clinical path of a patient, where everything made is quoted and easily readable when necessary.

Clinical and methodological aspects of endothelial function in patients with systemic autoimmune diseases.

The endothelium is not merely a barrier but it plays a key role in the maintenance of vascular homeostasis. An alteration of the endothelial function (EF) is an early marker of atherosclerosis, also contributing to the development of atherosclerotic lesions and later clinical complications. Systemic autoimmune diseases are characterized by the occurrence of premature atherosclerosis and cardiovascular disease. In view of the prognostic significance of EF for the development of atherosclerotic disease, many studies have evaluated the endothelium in systemic autoimmune diseases, using different techniques. The aim of the present paper is to review the different available techniques to study EF, their advantages and limitations and the data available on the study of EF in systemic autoimmune diseases. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function. Several techniques were developed to study microcirculation (resistance arteries and arterioles) and macrocirculation (conduit arteries). Studies assessing microvasculature in systemic autoimmune diseases have shown the presence of reduced endothelium dependent vasodilation, while no agreement exists on the presence of endothelium independent alterations. Flow mediated dilation (FMD) has been widely used to evaluate endothelium-dependent vasodilation in peripheral macrocirculation. The majority of studies in systemic autoimmune diseases have shown a decreased brachial artery FMD, whereas endothelium-independent response appears unaffected by the disease in this district. These data strongly underline the different information that could be obtained by different techniques and suggests their combined use in prospective cohorts. Circulating markers of EF include direct products of endothelial cells that change when the endothelium is activated, such as measures of NO biology, inflammatory cytokines, adhesion molecules, as well as markers of endothelial damage and repair. Many of these circulating markers are difficult to measure and quite expensive, and currently are only used in research settings. In view of the complexities in the evaluation of EF, results represent the interaction of several endothelial pathways. No single test currently available is specific for the vascular district tested or the risk factor/diseases considered, and a panel of several tests is therefore needed to characterize the multiple aspects of endothelial biology.

Endothelial function assessment in complicated hypertension.

A large body of evidence indicates that patients with essential hypertension, and even more those with complicated hypertension, are characterized by endothelial dysfunction characterized by impaired NO availability secondary to oxidative stress production. A dysfunctioning endothelium is an early marker of the development of atherosclerotic changes and can also contribute to cardiovascular events. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function. In the last two decades, many studies have evaluated the endothelium in hypertensive patients, using different techniques. Several methodologies were developed to study microcirculation (resistance arteries and arterioles) and macrocirculation (conduit arteries), both in coronary and peripheral vascular districts. This review will centre on the most relevant available techniques in the research on endothelial dysfunction in essential hypertension, their advantages and limitations, focusing on available data on endothelial dysfunction which characterizes patients with complicated hypertension. No available test to assess endothelial function has sufficient sensitivity and specificity to be used in clinical practice. Therefore, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Only the growing concordant results from different reproducible and reliable methods exploring endothelial function with different stimuli will support and strengthen experimental findings, thus providing conclusive answers in this area of research.