Massimo Gustapane

Polymorphonuclear neutrophils and instability of the atherosclerotic plaque: a causative role?

ObjectiveThe aim of this review is to examine the role of polymorphonuclear neutrophils (PMNs) in the evolution of atherosclerosis.IntroductionWhile the role of PMNs in the evolution of atherosclerosic process has failed until recently to attract much attention, a body of research carried out over the last decade has disclosed the unexpectedly complex behavior of these cells, unraveling an unexpected key role for PMNs in the onset and progression of atheroma.MethodsA PubMed database search was performed for studies providing evidences on the role of PMNs in the development and progression of atherosclerotic lesion.Results and ConclusionsActivated PMNs were shown to produce and release reactive oxygen species, inflammatory leukotrienes and proteolytic lysosomal enzymes, directly inducing vascular damage. Activated PMNs also secrete myeloperoxidase, involved in lipoprotein oxidation. PMNs have a finite lifespan and typically die through apoptosis, which thus represents a counter-regulatory mechanism limiting the toxic potential of these short-lived, terminally differentiated cells. Dysregulation of this process probably contributes to the pathogenesis and progression of several inflammatory diseases. Moreover, high circulating levels of PMN–platelet aggregates have been reported in patients with clinical atherosclerosis, and recent studies suggest that these aggregates may play a role in vascular response to injury. It has been suggested that this heterotypic interaction between platelets and leukocytes might represent a link between hemostasis/thrombosis and the inflammatory response.

Microparticles and microRNAs: new players in the complex field of coagulation

Atherosclerosis is a complex process that begins with endothelial dysfunction, and continues with several inflammatory processes leading, eventually, to plaque rupture and formation of arterial thrombus. Increased platelet reactivity and classical coagulation pathways are not the only players of the whole thrombotic process: microparticles (MPs), irregularly shaped small vesicles released from the plasma membrane after cell activation, apoptosis, or exposure to shear stress have been demonstrated to be involved in such a process. MicroRNAs (MiRs), small-non-coding single-strand RNAs acting as post-transcriptional modulator of target gene expression are expressed in the large majority of eukaryotes. MiRs are implicated in several phenomena: control of metabolism, control of cell-differentiation, control of cell-proliferation and control of cell-apoptosis, therefore contributing to physiologic and pathogenic processes in hematologic, genetic, infective and cardiac diseases. Microparticles operate as a delivery system of MiRs, playing an active and important role in processes such as coagulation and thrombosis. These novel findings also suggest MPs and, in particular MIRs, as possible and promising therapeutic targets.

Serum levels of γ-glutamyltransferase and progression of coronary atherosclerosis.

BackgroundProgression of coronary atherosclerosis (ATS) has clinical implications. Serum levels of &ggr;-glutamyltransferase (GGT), a marker of oxidative stress, predict the risk of cardiovascular events. However, the role of GGT levels in the progression of coronary ATS has never been established. Materials and methodsConsecutive patients undergoing two coronary angiographies (CAs) separated by at least 6 months were prospectively enrolled between May 2008 and June 2010. All patients were discharged on statins after the first CA. The severity and extent of coronary ATS were graded according to Bogaty’s score, and the variation ([INCREMENT]) in stenosis score and extent index between follow-up (S2 and E2) and basal values (S1 and E1) were calculated. Predictors of [INCREMENT]S2−1 and [INCREMENT]E2−1 were assessed among clinical and laboratory data, including GGT levels, analyzed as [INCREMENT] between follow-up and basal values ([INCREMENT]GGT2−1). ResultsWe enrolled 100 consecutive patients (age 64±11 years, 68% men). Compliance with statin therapy was 100%. At multiple regression analysis, [INCREMENT]GGT2−1 was the only independent predictor of [INCREMENT]S2−1 (B=0.18, SE=0.07, P=0.05), with [INCREMENT]low-density lipoprotein-cholesterol2−1 levels being of borderline statistical significance (P=0.07). On multiple regression analysis, [INCREMENT]GGT2−1 was the only independent predictor of [INCREMENT]E2−1 (B=0.32; SE=0.11; P=0.04), with active smoking habit and [INCREMENT]fibrinogen2−1 levels being of borderline statistical significance (P=0.08 and 0.06, respectively). Conclusion[INCREMENT]GGT2−1 is associated with angiographic coronary ATS progression in patients with ischemic heart disease on statin treatment, suggesting that oxidative stress may be another therapeutic target for preventing ATS progression beyond that of lipid-lowering therapies.

Statins Reduce Incidence of Early Perioperative Complications and Length of in-Hospital Stay after Coronary Artery Bypass Graft Surgery

Background: Coronary artery bypass grafting (CABG) is associated with several perioperative complications that may significantly prolong length of in-hospital stay, increase costs and provide worse long term outcome. The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, exert anti-inflammatory and vascular protective effects. We hypothesized that pre-operatory statin therapy may reduce incidence of early perioperative complications and length of in-hospital stay following CABG.Methods: We retrospectively enrolled 103 patients (age 67±3; 18 females), who underwent CABG. Patients were allocated into 2 groups: 57 patients on statin therapy prior to CABG (St Group) and 46 patients not on statin therapy (n-St group). Demographic and clinical features, pre-operative medications use and the incidence of early adverse postoperative events were collected. Pre-operative risk of death using the European System for Cardiac Operative Risk Evaluation (EuroSCORE) was also calculated. The primary end-point was the composite of early complications occurring after surgery, including infections, bleedings, sustained ventricular and supra-ventricular tachyarrhythmias, cardiogenic shock, myocardial infarction and mortality. As secondary end-points single perioperative complications were considered. In-hospital stay length was also evaluated.Results: Clinical features, cholesterol levels and EuroSCORE were similar between two groups. Statin therapy and EuroSCORE emerged as predictors of the composite adverse outcome. n-St patients had a significant higher rate of early complications if compared with St patients: the primary endpoint occurred in 18 St patients (31%) versus 25 (54%) non-St patients (p=0.019). Multivariate analysis confirmed pre-operative statin therapy and EuroSCORE as independent predictors of the primary endpoint (OR=0.307, 95% CI=0.123-0.766, p=0.011 and OR= 2.114, 95% CI= 1.213- 4.407, p= 0.002 respectively) showing a protective role of the statin therapy.The incidence of secondary end-points did not differ significantly between the groups, while in-hospital stay was longer in n-St group if compared with St group (7.7±3,9 days vs 5,6±1,8 days; p=0,001).Conclusion: Our data suggest that statin therapy may reduce early perioperative complications after coronary artery bypass grafting. This effect is independent from cholesterol basal levels, thus supporting pre-operative statin use in patients undergoing CABG.

Myeloperoxidase as possible diagnostic and prognostic marker of acute coronary syndrome

Myeloperoxidase (MPO) is an enzyme stored in azurophilic granules of polymorphonuclear neutrophils and macrophages and released into extracellular fluid during inflammatory processes. Several studies have shown its involvement into oxidative stress and inflammation. Recently, MPO has been considered its role as a possible marker of plaque instability and a useful tool for the prognostic evaluation of patients with coronary artery disease. Aim of this review is to provide an overview of patophysiological, analytical and clinical characteristics of MPO and to summarize the evidence about its usefulness as diagnostic and prognostic marker in the setting of acute coronary syndrome.

Inflammatory markers in heart failure: hype or hope?

Heart failure is a growing global epidemic that involves in its pathophysiology a proinflammatory state. Since the first description of elevated cytokine levels in this setting, there has been increasing interest in understanding the role of these molecules in left-ventricular remodeling and function. Over the years, intense research on the ‘cytokine theory’ of heart failure has allowed evaluation of the role of inflammatory biomarkers not only as pathogenetic mediators, but also as potential tools in the diagnosis and risk stratification of heart failure patients. Whereas current evidence does not support the use of inflammatory biomarkers for the diagnosis of heart failure, the assessment of their levels and the connection between their changes and changes in clinical status and prognosis has been well validated. At present, the utility of anti-inflammatory therapies in heart failure is still debated, since trials of anti-inflammatory agents in this setting have pointed out controversial results. On the contrary, established treatments of heart failure, including &bgr;-blockers, renin–angiotensin system antagonists, and aldosterone-receptor blockers seem able to act by modulating cytokine expression, suggesting a new role for these molecules in guiding heart failure therapy. Therefore, the binomial topic of heart failure and inflammation still has a number of fields not completely explored: our aim is to update current knowledge and future perspectives.

Ranolazine: Beyond the Treatment of Chronic Stable Angina Pectoris

The aims in the treatment of angina are relief of pain and prevention of disease progression through risk reduction. A number of patients may have contraindications or remain unrelieved from anginal discomfort with conventional drugs. Among newer alternatives, ranolazine indirectly prevents the intracellular calcium overload involved in cardiac ischemia and it is a considered as a valid addition to traditional treatments. Recent findings showed potential positive side effect of ranolazine in the treatment of arrhythmias. This review gives an overview of the basic principles of ranolazine in the treatment of myocardial ischemia and examines its applications in the new field of anti-arrhythmic effects.

Same heart and different sleep? A brief review of the association between sleep apnea syndrome and heart failure based on two clinical cases.

The research in the field of sleep medicine has increased during the whole twentieth century, principally for the involvement of sleep-related disordered breathing (SDB) in cardiovascular disease. If sleep encompasses about a third of one’s life, the reasons are mostly linked to its effects on the cardiovascular and respiratory systems. Sleep is a physiological phenomenon characterized by changes in the human body leading to a state of quiescence of the cardiovascular, respiratory and metabolic systems [1]. The importance of these events becomes more evident if we Review Article British Journal of Medicine & Medical Research, 4(1): 34-45, 2014 35 consider what happens in their absence, that is, during SDB syndromes. These syndromes include habitual snoring, sleep apnea, Cheyne-Stokes breathing syndrome and sleep hypoventilation syndrome [2]. Sleep apnea syndromes are characterized by several apneic events during the night, which consist in absence of the airflow or its reduction by more than 90% lasting more than 10 seconds, with consequent oxyhemoglobin desaturation and arousal [2]. These events provoke microawakening and sleep fragmentation that represent, along with hypoxemia, important harmful triggers on the cardiovascular system. In fact, SDB presents as a highly prevalent comorbidity in patients with heart failure (HF); both diseases are related to each other in a bidirectional way through multiple mechanisms: apneic events raise cardiac afterload, and at the same time impaired cardiac function itself may contribute to the development of sleep apnea. HF is a clinical syndrome characterized by signs or symptoms due to the inability of the heart to provide a normal tissue perfusion: the failing cardiac pump is not able to maintain an adequate output for this task. Typical features of HF are represented by shortness of breath, resting or exertion dyspnea, fatigue, fluid retention leading to pulmonary congestion or ankle swelling, and objective evidence of a structurally or functionally abnormal heart at rest [1,3].

GENE EXPRESSION PROFILING IN CIRCULATING MICROPARTICLES OF PATIENTS WITH ACUTE CORONARY SINDROME

Results: 168 genes were investigated. Compared to controls, mRNA expression analysis identified 5 modulated genes for the atherosclerosis pathway between NSTEMI and SA ( 3 upand 2 down-regulated in NSTEMI vs SA). Elastin, Matrix Metalloproteinase -1 (MMP-1) and Selectin showed differences in mRNA with a fold change > 5 in NSTEMI vs SA (p<0.05). On the contrary, Angiotensin I Converting Enzyme (ACE) and Neuropeptide Y (NPY) mRNA were down-regulated in NSTEMI(p<0.05).The transcription factors-related pathway revealed 8 modulated genes (1 upand 7 downregulated in NSTEMI patients). Androgen receptor (AR), forkhead box 01 (FOX01), were down-regulated with a fold-change > 10 (p<0,05); MYC associated factor X (MAX), Nuclear factor of kappa light polypeptide gene (NFKB1), Vrelreticuloendotheliosis viral oncogene (RELA) and signal transducer and activatorof transcription 4 (STAT4), were down-regulated with a fold expression > 5 in NSTEMI vs SA (p<0,05). General transcription factor IIB was up-regulated in NSTEMI with a fold change >3 (p<0,05).