Gina Biasillo

Inflammatory markers, cholesterol and statins: pathophysiological role and clinical importance.

Abstract Statins are one of the most important medications in cardio-vascular diseases since they block cholesterol synthesis by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase and thus reduce low density lipoprotein concentrations. In the last years, numerous pleiotropic properties of statins have been described, beyond their well-known lipid lowering function. In particular, they are able to modulate inflammation, which plays a pivotal role in the atherosclerotic process. Several trials have shown a direct correlation between statin therapy and lower C-reactive protein concentrations. Moreover, a large body of pathophysiological studies has demonstrated that statins lower cytokine concentrations and inhibit recruitment, migration and cell adhesion to endothelium by attenuating chemokine production. They also inhibit inflammatory pathways regulated by proteins as Ras and Rho, and increase nitric oxide production which exerts a protective effect on endothelium. In addition to reducing inflammation in coronary atherosclerosis, statins also have beneficial effects in chronic inflammatory and autoimmune diseases, such as psoriasis, and they could induce clinical improvement. Statins seem to exert benefits even in settings of infection. These results suggest that initiating and monitoring statin therapy on the basis of inflammatory markers, in particular C-reactive protein, may improve cardiovascular prevention and treatment. Clin Chem Lab Med 2010;48:1685–91.

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.

Different Apparent Prognostic Value of hsCRP in Type 2 Diabetic and Nondiabetic Patients with Acute Coronary Syndromes

BACKGROUND C-reactive protein (CRP) is an established prognostic marker in acute coronary syndromes (ACS); however, no study has specifically addressed its prognostic role in type 2 diabetes with ACS. We evaluated the prognostic role of CRP separately in diabetic and nondiabetic patients with ACS. METHODS We enrolled 251 patients with unstable angina and measured serum concentrations of high sensitivity (hs)CRP. Ninety-seven patients underwent coronary angiography with evaluation of atherosclerotic disease severity and extent by Bogaty score. Assessed endpoint was the combined occurrence of myocardial infarction (MI) and death at 1 year. RESULTS No significant differences were found in hs-CRP between patients with and without diabetes. By Cox regression, hsCRP was not associated with 1-year follow-up events in diabetic patients but was strongly associated with events in nondiabetic patients (P = 0.0012). Coronary angiography exhibited a higher extent index in patients with diabetes than in those without (P = 0.04). hsCRP concentrations were not associated with angiographic atherosclerotic burden. By Cox analysis, hsCRP and extent score were associated with events in patients who underwent coronary angiography (P < 0.001 and P = 0.034, respectively). In nondiabetic patients, hsCRP was the only predictor of events at 1-year follow-up (P < 0.001), whereas in diabetic patients, hsCRP was not associated with events and a weak association was observed for extent score (P = 0.06). CONCLUSIONS Our study suggests that different pathophysiological mechanisms may be responsible for MI and death in unstable angina patients with or without diabetes and that severity of coronary artery disease plays a major role in diabetes (and inflammation in the absence of diabetes).

Biomarkers in Acute Coronary Syndrome

Background Evaluation of patients who present to the hospital with acute undifferentiated chest pain or other symptoms and signs suggestive of Acute Coronary Syndrome (ACS) is often a clinical challenge. The initial assessment, requiring a focused history (including risk factors analysis), a physical examination, an electrocardiogram (EKG) and serum cardiac marker determination, is time-consuming and troublesome. Recent investigations have indicated that increases in biomarkers of necrosis, inflammation, ischemia and myocardial stretch may provide earlier assessment of overall patient risk, help in identifying the adequate diagnostic and therapeutic management for each patient and allow for prevention of substantial numbers of new events. Approach and Content The purpose of this review is to provide an overview of the characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. Patho-physiology, analytical and clinical characteristics have been evaluated for each marker, underlying the properties for potential routine clinical use. Summary The biomarkers discussed in this review are promising and might lead to improved diagnosis and risk stratification of patients with ACS, however their clinical application requires further studies. It is important to define their clinical role as diagnostic markers, their predictive value and the specificity, standardization and detection limits of the assays.

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.

Response to Letter Regarding Article, “Growth Properties of Cardiac Stem Cells Are a Novel Biomarker of Patients’ Outcome After Coronary Bypass Surgery”

We appreciate the interest of Drs Li and Shen in our study,1 which emphasizes the critical role that the insulin-like growth factor-1 (IGF-1) and IGF-1 receptor system has in defining the growth properties of human cardiac stem cells (hCSCs). We shared their view that IGF-1 positively interferes with the consequences of diabetes mellitus and dyslipidemia, and possibly with other cardiovascular pathologies. Based on our interest in IGF-1, a transgenic mouse model with cardiomyocyte-restricted overexpression of IGF-1 was developed.2 With this strategy, an increase in the number of ventricular myocytes was obtained, resulting in a significantly lower systolic and diastolic stress at the cellular level, together with an enhanced ability of the myocardium to sustain increases in pressure or volume loads. Overexpression of IGF-1 prevents the manifestation of the diabetic myopathy and is associated with a …

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).