S. Quartuccio

Association between HMGB1 and COPD: A Systematic Review

HMGB1 is an alarmin, a protein that warns and activates inflammation. Chronic obstructive pulmonary disease (COPD) is characterised by a progressive airflow obstruction and airway inflammation. Current anti-inflammatory therapies are poorly effective in maintaining lung function and symptoms of COPD. This underlines the need for finding new molecular targets involved in disease pathogenesis in order to block pathology progression. This review aims to analyse latest advances on HMGB1 role, utilisation, and potential application in COPD. To this purpose we reviewed experimental studies that investigated this alarmin as marker as well as a potential treatment in chronic obstructive pulmonary disease. This systematic review was conducted according to PRISMA guidelines. In almost all the studies, it emerged that HMGB1 levels are augmented in smokers and in patients affected by COPD. It emerged that cigarette smoking, the most well-known causative factor of COPD, induces neutrophils death and necrosis. The necrosis of neutrophil cells leads to HMGB1 release, which recruits other neutrophils in a self-maintaining process. According to the results reported in the paper both inhibiting HMGB1 and its receptor (RAGE) and blocking neutrophils necrosis (inducted by cigarette smoking) could be the aim for further studies.

Pathophysiological mechanism and therapeutic role of S100 proteins in cardiac failure: a systematic review

AbstractS100 proteins are a family of highly acidic calcium-binding proteins involved in calcium handling in many tissues and organs. Some of these proteins are highly expressed in cardiac tissue, and an impairment of some specific S100 proteins has been related to heart failure. To check this hypothesis, we decided to review the literature since 2008 until May 2015. According to the studies collected, recovering S100A1 levels may enhance contractile/relaxing performance in heart failure, reverse negative force–frequency relationship, improve contractile reserve, reverse diastolic dysfunction and protect against pro-arrhythmic reductions of sarcoplasmic reticulum calcium. The safety profile of gene therapy was also confirmed. Increased S100B protein levels were related to a worse outcome in chronic heart failure. S100A8/A9 complex plasma levels, as well as other inflammatory biomarkers, were significantly higher in chronic heart failure patients. S100A2 seems to increase both contractile and relaxation performance in animal cardiomyocytes. Otherwise, S100A6 cardiac expression seems to have no effects on contractility. S100A4 KO mice showed reduced cardiac interstitial fibrosis. Data collected encourage a potential prospective application in human. These proteins could be exploited as biomarkers in stadiation and prognosis of chronic heart failure, as well as therapeutic target to rescue failing heart. Registration details The study protocol has been registered in PROSPERO (http://www.crd.york.ac.uk/PROSPERO/) under registration number CRD42015027932.

Circulating progenitor cells in hypertensive subjects: Effectiveness of a treatment with olmesartan in improving cell number and miR profile in addition to expected pharmacological effects

CD34+ circulating progenitor cells (CD34+CPCs) are a population of multipotent cells which can delay the development of atherosclerosis and cardiovascular disease (CVD) in conditions of increased CV risk. MicroRNAs (miRs) 221 and 222 modulate different genes regulating angiogenesis and inflammation; moreover, miR221/22 have beenshown to participate in differentiation and proliferation of CD34+CPCs, inhibiting cell migration and homing. miR221/222 in CD34+CPCs from hypertensive subjects are also increased and associated with CD34+cell number and reactive oxygen species (ROS). We evaluated CD34+CPC number, intracellular miR221/222 and ROS levels, arterial stiffness (AS)and echocardiography indices at baseline (T0).Then, after a six-month treatment with olmesartan, 20 mg/day (T1), in 57 hypertensive patients with left ventricular hypertrophy (LVH) and with no additional risk factor for CVD, and in 29 healthy controls (baseline),fibrinogen, C-reactive protein (CRP), glucose and lipid profiles were also evaluated.At T1, blood pressure values, CRP and fibrinogen levels, ROS and miR221/222 were significantly decreased (all p <0.001), as were AS indices and LV mass index (p<0.001), while cell number was increased (p<0.001). Olmesartan is effective in reducing miR and ROS levels in CD34+CPCs from hypertensive subjects, as well as in increasing CD34+CPC number, providing multilevel CV protection, in addition to its expected pharmacological effects.

Clinical impact of angiotensin I converting enzyme polymorphisms in subjects with resistant hypertension

Angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism is thought to affect renin–angiotensin system (RAS) activity and development of cardiovascular disease; significant associations between I/D polymorphism and atherosclerosis, stroke, nephropathy, and early mortality were already found. We investigated whether Southern Italy resistant hypertensives presented an association between the presence of I and/or D alleles and early vascular damage, inflammation, and insulin resistance. One-hundred-fifty resistant hypertensives were enrolled, studied, and genotyped; carotid intima-media thickness (cIMT), arterial stiffness (AS), and HOMA indices were also evaluated. D allele was more prevalent, and 74 patients presented DD homozygosis. Sixty-eight patients had metabolic syndrome (MetS), without significant differences between DD and I allele carriers. DD genotype appeared strongly associated with higher HOMA values (p < 0.001), and also with both Augmentation Index (AIx, p = 0.003) and Pulse Wave Velocity (PWV, p = 0.023). A significant association was found between DD genotype and cIMT (p < 0.005), while no association between ACE genotype and the presence of carotid plaques. HOMA was correlated with AS (PWV: p < 0.001; AIx: p < 0.01). DD genotype appeared to be associated with AS and HOMA index, but not with inflammation, independently from blood pressure values and the presence of other MetS factors, confirming D allele as an independent risk marker. Vascular damage may develop and progress independently from other risk factors in resistant hypertensives, likely through the interplay between ACE gene, RAS activity, and insulin resistance.

Association between HMGB1 and asthma: a literature review

BackgroundRecently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders. Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated to airway hyper-responsiveness and airway inflammation.ObjectiveThis literature review aims to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma.MethodsWe reviewed experimental studies that investigated the pathogenetic role of HMGB in bronchial airway hyper-responsiveness, inflammation and the correlation between HMGB1 level and asthma.ResultsA total of 19 studies assessing the association between HMGB1 and asthma were identified.ConclusionsWhat emerged from this literature review was the confirmation of HMGB-1 involvement in diseases characterised by chronic inflammation, especially in pulmonary pathologies. Findings reported suggest a potential role of the alarmin in being a stadiation method and a marker of therapeutic efficacy; finally, inhibiting HMGB1 in humans in order to contrast inflammation should be the aim for future further studies.

Interleukin 31 and skin diseases: A systematic review.

BACKGROUND Although the pathophysiology of pruritus has been extensively studied in recent years, with many resultant advancements, management of pruritus is still enigmatic, particularly in chronic cutaneous diseases, such as atopic dermatitis, chronic urticaria, allergic contact dermatitis, cutaneous T-cell lymphoma, and uremic pruritus. The recent finding of the involvement of interleukin (IL) 31 in the pathogenesis of chronic pruritus has provided a novel approach to the management of chronic inflammatory skin disorders. The present report provided an in-depth overview of the role of IL-31 in chronic skin diseases and the possible diagnostic and therapeutic applications in the management of these diseases. METHODS A systematic review of IL-31 was conducted by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS A review of a total of 45 published research articles revealed that the majority of these articles focused on the role of IL-31 in causation of pruritus and in the worsening of the disease in atopic dermatitis. Other publications examined interleukin in other pruritic diseases (cutaneous T-cell lymphoma, uremic pruritus, allergic contact dermatitis, chronic urticaria). In almost every disease, IL-31 levels were reported to be correlated with the pathology and often with pruritus. The cutaneous injection of IL-31 resulted in a long-lasting itching sensation, and the use of monoclonal antibodies that targeted IL-31 led to a reduction in pruritus. CONCLUSION The use of monoclonal antibodies against mediators involved in the pathogenesis of chronic skin diseases has shown promising results. Antibodies that target IL-31, in particular, its receptor A, showed interesting results in atopic dermatitis and decreased pruritus. In subsequent years, the use of these new therapeutic strategies could change the scenario of pruritic skin diseases. However, further studies are needed to more rigorously examine the effects of IL-31 cascade blockage in different chronic skin diseases and to confirm efficacy and the safety of these new therapeutic approaches.

Effect of type D personality on smoking status and their combined impact on outcome after acute myocardial infarction

Smoking cessation is correlated with several psychological, social, biological, and pharmacological aspects. The combined tendency to experience negative emotions and to inhibit the expression of these emotions is indicated as “type D personality,” an independent risk marker for clinical outcome in cardiac disease. Despite this effect of type D personality on cardiovascular disease, it is still unclear whether this personality trait may influence smoking cessation after a myocardial infarction.

Renal Denervation, “Last Resort” or Alternative Therapy?

In a recent clinical study, it’s proved a variable proportion (approximately 5-15%) of the general population of the patients with hypertension in treatment, which refer to the Centres of Excellence for the diagnosis and treatment hypertension, may be considered suffering from resistant hypertension [1]. It‘s evident that 5-15% of patients with hypertension, Whereas 20% of the Western population is suffering from hypertension, is easy to understand the true dimension of the phenomenon. So the choice of treatment, comes to a crossroad. Should we insist with the combination of more than three medications, or choose the path of renal denervation? What are the main defects of drug therapy with the combination of four or more antihypertensive? Combination of antihypertensive drugs, overcoming the limit of the three drugs, increases the risk of treating with non-beneficial, or even dangerous associations. A typical example is the combination of a beta-blocker with an ACE inhibitor or an AT1-antagonist useful in the patient with heart failure, but absolutely not effective to improve control of blood pressure. Beta-blockers also should not be associated with the nondihydropyridine calcium channel blockers because these drugs would add their effects chronotropic, dromotropic and inotropic effects. A dangerous association could be given from the interaction between an α1-blocker and clonidine as their effects will cancel each other and therefore blood pressure can even be increased again. Also betablockers and clonidine: the ‘paroxysmal increase in blood pressure observed 18-36 hours after withdrawal of clonidine can be worsened by the simultaneous administration of a beta-blocker. Although it seems to overcome, increasing the number of drugs for the treatment of a chronic illness, you risk getting a poor adherence to medical therapy. More and more often in hypertensive patients, coexist morbidities that are not compatible with the use of antihypertensive drugs: An example is the use of tiazhide-like diuretic that should be under the control of renal function in chronic renal failure and therefore it is often replaced by the loop diuretic that in terms of blood pressure control does not have the same effect daily. Still under study, as well as the subject of debate, the renal denervation is a procedure that consists of the insert of a catheter totally similar to the one used for cardiac revascularization. It’s moved forward to the renal arteries. When it is placed, the catheter sends a signal of radio-frequency which is able to destroy the nerve fibers of the artery of the sympathetic renal system and inhibits, consequently, its activity, permitting (or allowing) a significant decrease of pressure values.

[OP.8A.09] EFFICACY OF MONOCLONAL ANTIBODIES ANTI-PROPROTEIN CONVERTASE SUBTILISIN-KEXIN TYPE 9 IN IMPROVING LIPID PROFILE AND ARTERIAL STIFFNESS IN PATIENTS AFFECTED BY FAMILIAL HYPERCHOLESTEROLEMIA

Objective: monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9), have emerged as a new class of drugs that effectively lower LDL cholesterol levels. Hypercholesterolemic patients present early signs of vascular inflammation and damage. We investigate whether after six months of treatment with anti-PCSK9 monoclonal antibodies we can find any improvement of pro-atherogenic profile and of arterial stiffness (AS) in patients affected by familial hypercholesterolemia already in treatment with the maximally tolerated statin therapy. Design and method: We enrolled 34 people who had decided to start treatment with anti-PCSK9 drugs; of these, 32 have completed the 6-months observation period. At enrollment and 6 months later we evaluated anthropometrics, laboratory profile, pulse wave velocity (PWV) and carotid intima-media thickness (cIMT). Results: After 6-months of treatment we found a significant decrease of inflammatory markers (Hs-CRP: −46.5%; Fibrinogen: −18.9%), LDL-C and lipoprotein (a) levels (respectively −65.9% and −34.2%). PWV (−9.5%) appeared to be improved; cIMT remained unchanged. PWV reduction appeared to be correlated with fibrinogen and LDL-C reduction. However, reduced PWV appeared to be not dependent on LDL-C and fibrinogen by the multiple regression analysis. Conclusions: After 6 months of treatment with monoclonal antibodies anti-PCSK9 the levels of CRP, Fibrinogen, LDL-C, and Lp (a), as well AS indices, are significantly improved as compared to baseline. We report the important evidence that a treatment with anti-PCSK9 monoclonal antibodies may improve significantly the arterial stiffness in patients affected by familial hypercholesterolemia.

[PP.04.35] PREVALENCE AND OPREDICTORS OF PULMONARY HYPERTENSION IN A GENERAL COMMUNITY-BASED POPULATION

Objective: The exact prevalence of PH in Italy is not known. Echocardiography is useful in the screening of patients with suspected PH by estimation of the pulmonary artery systolic pressure (PASP) by regurgitant tricuspid flow velocity evaluation, according to the simplified Bernoulli equation. Design and method: We conducted a retrospective study to estimate the prevalence of PH in 7005 patients who underwent echocardiography. Clinical data and echocardiographic results were used to determine etiological group of PH. PH causality was coded using criteria and subcategories of the ESC classifications. Results: The mean age of the study population was 57.1 ± 20.5 years with 55.3% male. The prevalence of intermediate probability of PH was 8.6%, with nearly equal distribution between men and women (51.3 vs 48.7%; P = NS) whereas the prevalence of high probability of PH was 4.3%, with slightly but not significant higher prevalence in female patients (43.2 vs 56.8; p = ns); PH is more prevalent in patients with chronic obstructive pulmonary disease (COPD) or left ventricle (LV) systolic dysfunction. PH prevalence increased with age. Also, sPAP was significantly associated with left atrial enlargement, left ventricular ejection fraction and, in addition, an increased sPAP was related to an enlargement of the right atrium and right ventricle. Conclusions: PH as measured by echocardiography has low prevalence in our general population, but the estimates may be higher in specific subgroups. Analysis of the registry data could be an instrument for quality control and might help identify weak points in assessment and treatment of these patients.