Adhesion Molecules as Prognostic Biomarkers in Coronary Artery Disease.

Atherosclerosis is a progressive disease, culminating in the production of atherosclerotic plaques in arteries through intricate pathophysiological processes. The progression of this disorder is based on the effect of triggering factors -mainly hyperlipidemia, diabetes mellitus, arterial hypertension, and smoking- on the endothelium. Coronary artery disease (CAD) is an atherosclerotic disease with a higher prevalence among individuals. Pro- and anti-inflammatory cytokines are the main contributors to atherosclerotic plaque formation. CAD and its manifestations multifactorial affect patients' quality of life, burdening the global healthcare system. Recently, the role of adhesion molecules in CAD progression has been recognized. Physicians delve into the pathophysiologic basis of CAD progression, focusing on the effect of adhesion molecules. They are proteins that mediate cell-cell and cell-extracellular matrix interaction and adhesion, driving the formation of atherosclerotic plaques. Several studies have assessed their role in atherosclerotic disease in small cohorts and in experimental animal models as well. Furthermore, several agents, such as nanoparticles, have been introduced modifying the main atherosclerotic risk factors as well as targeting the endothelial inflammatory response and atherosclerotic plaque stabilization. In this review, we discuss the role of adhesion molecules in atherosclerosis and CAD progression, as well as the potential to be used as targeting moieties for individualized treatment.

Extracellular Matrix Remodeling Biomarkers in Coronary Artery Disease.

Atherosclerosis and one of its most serious consequences, coronary artery disease, are important sources of morbidity and mortality globally, necessitating early detection and treatment. Considering their complex pathophysiology, including several harmful processes, a comprehensive approach to diagnosis, prognosis, and therapy is very desirable. Extracellular matrix remodeling is a major component of this dangerous cascade, including the cleavage of constituents (collagen, elastin, proteoglycans) and the propagation or exacerbation of the inflammatory response. Several extracellular matrix degradation indicators have been hypothesized to correlate with the existence, severity, and prognosis of coronary artery disease. The potency of matrix metalloproteinases, notably collagenases and gelatinases, has been the most thoroughly investigated in clinical studies. Stromelysins, matrilysins, transmembrane matrix metalloproteinases, collagen and laminin turnover indicators, as well as fibronectin, have also been studied to a lesser level. Among the most well-studied markers, MMP-1, MMP-2, MMP-8, and MMP-9 have been found increased in patients with cardiovascular risk factors such as metabolic syndrome, its components (obesity, dyslipidemia, diabetes mellitus), and smoking. Increasing concentrations are detected in acute coronary syndromes compared to stable angina pectoris and healthy control groups. It should also be stressed that those extracellular matrix biomarkers may also be detected in high concentrations in other vascular pathologies such as peripheral artery disease, carotid artery disease, aortic aneurysms, and dissections. Despite the advances gained, future research should focus on their importance and, more crucially, their added utility as biomarkers in identifying persons at risk of developing overt coronary artery disease. At the same time, determining the prognosis of coronary artery disease patients using such biomarkers may be important for their adequate care.

Pro-inflammatory Cytokines in Acute Coronary Syndromes.

BACKGROUND: Over the last decades, the role of inflammation and immune system activation in the initiation and progression of coronary artery disease (CAD) has been established. OBJECTIVES: The study aimed to present the interplay between cytokines and their actions preceding and shortly after ACS. METHODS: We searched in a systemic manner the most relevant articles to the topic of inflammation, cytokines, vulnerable plaque and myocardial infarction in MEDLINE, COCHRANE and EMBASE databases. RESULTS: Different classes of cytokines (intereleukin [IL]-1 family, Tumor necrosis factor-alpha (TNF-α) family, chemokines, adipokines, interferons) are implicated in the entire process leading to destabilization of the atherosclerotic plaque, and consequently, to the incidence of myocardial infarction. Especially IL-1 and TNF-α family are involved in inflammatory cell accumulation, vulnerable plaque formation, platelet aggregation, cardiomyocyte apoptosis and adverse remodeling following the myocardial infarction. Several cytokines such as IL-6, adiponectin, interferon-γ, appear with significant prognostic value in ACS patients. Thus, research interest focuses on the modulation of inflammation in ACS to improve clinical outcomes. CONCLUSION: Understanding the unique characteristics that accompany each cytokine-cytokine receptor interaction could illuminate the signaling pathways involved in plaque destabilization and indicate future treatment strategies to improve cardiovascular prognosis in ACS patients.

Adenosine stress myocardial perfusion imaging in octogenarians: Safety, tolerability, and long-term prognostic implications of hemodynamic response and SPECT-related variables.

BACKGROUND: Evaluation of tolerability, safety, and prognostic implications of adenosine stress myocardial perfusion imaging (MPI) in octogenarians. METHODS: 370 octogenarians (49% known coronary artery disease) were studied. Hemodynamic response, MPI-related data, and rest-left ventricular ejection fraction (LVEF) based on echocardiography were registered per patient, and prospective follow-up was performed to document all-cause death (ACD), cardiac death (CD), myocardial infarction (MI), and late revascularization. RESULTS: No deaths or MIs were observed during adenosine infusion or the short-term post-infusion period. 86% of patients were able to tolerate a 6-minute infusion. All side effects terminated spontaneously after infusion cessation, except for one case of pulmonary oedema. After 9.3 years, there were 124 ACDs, 62 CDs, 16 MIs, and 35 revascularizations. Differences between survival curves of summed stress score (SSS)-based risk groups were significant for all end points (P < .001). SSS and LVEF were independent predictors of all end points (P ≤ .01) and lung uptake of cardiac end points. ΔHR <10 bpm (OR = 1.78, P = .004) and inability to increase HR by >10 bpm and decrease systolic blood pressure by >10 mmHg (OR = 2, P = .02) during adenosine infusion were independent predictors of ACD and CD, respectively. Hemodynamic response variables, SSS, and lung uptake provided incremental prognostic value over pre-test data for ACD and CD. CONCLUSIONS: In octogenarians, adenosine stress MPI is well tolerated and provides effective long-term risk stratification.

Long-term prognostic implications of myocardial perfusion imaging in octogenarians: an all-comer, cohort study.

PURPOSE: Evaluation of the long-term prognostic value of myocardial perfusion imaging (MPI) in octogenarians. METHODS: Six hundred and twenty-nine octogenarians [51% previous myocardial infarction (MI) or revascularization] who underwent single-isotope MPI (78% 201Tl, 22% 99mTc-tetrofosmin) with exercise (38% Bruce, 2% leg ergometry) or pharmacologic (58% adenosine, 2% dobutamine) stress were studied. All patients had LVEF determined by echocardiography within 1 month from MPI. Myocardial perfusion scoring was performed on a 17-segment LV-model with a 5-point grading system and three summed stress score (SSS)-based risk categories were formed [high-(SSS > 12), low-(SSS < 4), medium]. Prospective follow-up was performed to document all-cause (ACD), cardiac death (CD), MI, and revascularization. Revascularization was used to censor follow-up in survival analysis regarding ACD, CD, and CD/MI. For analysis of the CD, MI, or late revascularization (LR) composite, only revascularizations within 3 months from MPI (early revascularizations) were used for censoring. RESULTS: After 9.3 years there were 187 ACDs, 86 CDs, 28 MIs, and 77 revascularizations, including 28 early revascularizations. Adjusting for LVEF and stress-modality type, SSS was identified as an independent predictor of ACD [HR 1.03 (1.01-1.05)], CD [HR 1.05 (1.03-1.08)], CD,MI [HR 1.05 (1.02-1.07)], and CD,MI or LR [HR 1.05 (1.03-1.07)] (p ≤ 0.001 in all cases). Increased lung uptake had independent prognostic value only for the CD, MI, or LR end-point [HR 3 (1.2-7.7), p = 0.02]. Survival modeling demonstrated that LVEF and SSS, but not non-perfusion scintigraphic data provided incremental prognostic value over pre-test available clinical and historical information for all end-points. Differences between Kaplan-Meier survival curves of SSS-based risk groups were significant for all end-points (p < 0.001 in all cases). CONCLUSIONS: In octogenarians, MPI provides effective long-term risk stratification, regardless of stress type used or underlying cardiac function.

Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches.

Asymmetric dimethylarginine (ADMA) is a competitive endogenous inhibitor of nitric oxide synthase with a key role in the pathophysiology of endothelial dysfunction, in the progression of atherosclerosis and in cardiovascular diseases. Statins, renin-angiotensin-aldosterone system inhibitors, blood glucose lowering agents, insulin sensitizers, beta-blockers, estrogen replacement therapy, antioxidants, complex B vitamins, L-arginine and acetylsalicylic acid have been evaluated for their ability to reduce ADMA levels or inhibit its actions. Despite the major beneficial effects of these agents in cardiovascular disease, research has shown that their favorable actions are only partially mediated by reducing ADMA levels or by bypassing its effect in nitric oxide synthesis. Novel therapeutic approaches targeting selectively ADMA are encouraging, but have only been tested in vitro or in animal studies and further research is needed in order to conclude on how therapeutic strategies modulating ADMA actions can affect atherosclerosis progression and cardiovascular diseases.

The Role and Predictive Value of Cytokines in Atherosclerosis and Coronary Artery Disease.

Atherosclerosis is currently regarded as a chronic inflammatory disease that is mediated by several types of cells and molecules. Emphasis has been placed on the role of cytokines and the way they act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are invariably expressed by all cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leukocytes and other vascular residing cells. In the present paper our aim is to review current information on the role of the most commonly discussed cytokines in the process of atherogenesis and to discuss the prognostic significance of these cytokines in atherosclerosis and coronary artery disease.