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.

Acute Coronary Syndrome with Non-ruptured Plaques (NONRUPLA): Novel Ideas and Perspectives.

PURPOSE OF REVIEW: In this review article, we focus on the mechanisms and features of acute coronary syndromes (ACS) with no ruptured plaque (NONRUPLA) highlighting the uncertainties over diagnostic evaluation and treatment. RECENT FINDINGS: The most common cause of ACS is obstruction due to atherosclerotic plaque ruptured or erosion. In 14% of patients who present in the Emergency Department as myocardial infarction, the final diagnosis is ACS with NONRUPLA. Although the clinical presentation of NONRUPLA may mimic myocardial infarction, the underlying pathogenesis is different, and it may guide therapeutic approaches and overall prognosis that vary according to etiology. The possible mechanisms of ACS with NONRUPLA are coronary embolism, acute dissection of the aorta or coronary artery, vasospasm, microvascular dysfunction, the imbalance between oxygen demand and supply, coronary trauma and stent complications, direct cellular toxicity and damage, Takotsubo syndrome, and myocardial infarction with non-obstructive coronary arteries (MINOCA).

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.

Plasma signature of apoptotic microvesicles is associated with endothelial dysfunction and plaque rupture in acute coronary syndromes.

OBJECTIVE: Circulating microvesicles (MV) are surrogate biomarkers of atherosclerosis. However, their role in acute coronary syndromes (ACS) has not been fully elucidated yet. We sought to examine the association of circulating apoptotic MVs with ACS pathophysiology. APPROACH AND RESULTS: One hundred and fifty-three patients (n = 153) were included in the study; 49 patients with ST-elevation myocardial infarction (STEMI), 35 with non-STEMI (NSTEMI), 38 with unstable angina, 15 with stable coronary artery disease and 16 control individuals. Flow cytometry analysis was used to quantify circulating apoptotic/non-apoptotic (phospatidyloserine+/phospatidyloserine-) endothelial cell (EMV), red blood cell (RMV) and platelet (PMV) derived MV. Flow-mediated dilatation (FMD) of the brachial artery was assessed by ultrasound to estimate endothelial function. The inflammatory profile was assessed by serum C-reactive protein (hsCRP) levels. Apoptotic only (but not non-apoptotic) MV were increased in patients with ACS (EMV, P = 2.32 × 10-9; RMV, P = .0019; PMV, P = .01). Hierarchical clustering of the total population of ACS patients (n = 122) by circulating levels of phospatidyloserine+ EMV, RMV and PMV identified two discreet clusters of patients without any differences in traditional risk factors, but significant differences in brachial FMD (5.2% (2.5) vs. 4.1% (2.3), P < .05) that remained significant after adjustment for co-variates. The prevalence of STEMI, a surrogate for plaque rupture and vessel thrombotic occlusion, was significantly higher in the patient cluster with impaired endothelial function (60% vs 32%, P = .016, adjusted odds ratio for STEMI, 3.041, 95%CI, 1.160 to 7.968, p = .024). CONCLUSION: Our findings indicate that the circulating levels of apoptotic MV are increased in ACS patients and their plasma profiles associate with endothelial dysfunction and thrombotic complications in ACS patients.

The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives.

Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.

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.

Biomarkers in Atrial Fibrillation and Heart Failure.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice and an important contributor to cardiovascular morbidity and mortality. Although the exact mechanisms behind AF are not completely elucidated, the underlying pathophysiological changes have been well described. Predisposal factors for AF include the older age, the increased left atrial size, the decreased left atrial function, the presence of heart failure and left ventricular systolic dysfunction and the presence of coronary heart disease or pulmonary or mitral valve disease. In addition to these factors, emerging evidence demonstrate that myocardial strain, fibrosis and inflammation, are associated with AF as well as the pathogenesis of the arrhythmia. The natruretic peptide system including Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP) and C-type Natriuretic Peptide (CNP) is indicative of the level of myocardial strain which may predispose to AF. As a result, the aforementioned peptides are increased in AF patients. The levels of myocardial fibrosis biomarkers, such as ST2 and Galectin-3, are elevated suggesting atrial structural abnormalities, while the increased levels of CRP and Interleukin-6 supplement the inflammatory profile of AF patients. Emerging data for the aforementioned biomarkers are discussed in the present review.

Redox State in Atrial Fibrillation Pathogenesis and Relevant Therapeutic Approaches.

BACKGROUND: Myocardial redox state is a critical determinant of atrial biology, regulating cardiomyocyte apoptosis, ion channel function, and cardiac hypertrophy/fibrosis and function. Nevertheless, it remains unclear whether the targeting of atrial redox state is a rational therapeutic strategy for atrial fibrillation prevention. OBJECTIVE: To review the role of atrial redox state and anti-oxidant therapies in atrial fibrillation. METHOD: Published literature in Medline was searched for experimental and clinical evidence linking myocardial redox state with atrial fibrillation pathogenesis as well as studies looking into the role of redoxtargeting therapies in the prevention of atrial fibrillation. RESULTS: Data from animal models have shown that altered myocardial nitroso-redox balance and NADPH oxidases activity are causally involved in the pathogenesis of atrial fibrillation. Similarly experimental animal data supports that increased reactive oxygen / nitrogen species formation in the atrial tissue is associated with altered electrophysiological properties of atrial myocytes and electrical remodeling, favoring atrial fibrillation development. In humans, randomized clinical studies using redox-related therapeutic approaches (e.g. statins or antioxidant agents) have not documented any benefits in the prevention of atrial fibrillation development (mainly post-operative atrial fibrillation risk). CONCLUSION: Despite strong experimental and translational data supporting the role of atrial redox state in atrial fibrillation pathogenesis, such mechanistic evidence has not been translated to clinical benefits in atrial fibrillation risk in randomized clinical studies using redox-related therapies.

Inflammatory Biomarkers in Atrial Fibrillation.

During the last few years, a significant number of studies have attempted to clarify the underlying mechanisms that lead to the presentation of atrial fibrillation (AF). Inflammation is a key component of the pathophysiological processes that lead to the development of AF; the amplification of inflammatory pathways triggers AF, and, in tandem, AF increases the inflammatory state. Indeed, the plasma levels of several inflammatory biomarkers are elevated in patients with AF. In addition, the levels of specific inflammatory biomarkers may provide information regarding to the AF duration. Several small studies have assessed the role of anti-inflammatory treatment in atrial fibrillation but the results have been contradictory. Large-scale studies are needed to evaluate the role of inflammation in AF and whether anti-inflammatory medications should be routinely administered to patients with AF.

Atrial Fibrillation: Biomarkers Determining Prognosis.

Atrial fibrillation (AF) is a common cardiac arrhythmia known to incite increased thromboembolic and mortality risks, especially among patients not under anticoagulant therapy when indicated. Several routine scores exist to help stratify AF patients, such as the CHAD2DS2-VASc score and upon which physicians are based to decide whether to administer anticoagulant therapy. Being that anticoagulant regimen is a double- edged situation with both benefits and risks, decision-making process demands a definite and reliable, evidence-based set of data to rely on. Blood-based biological elements known as biomarkers are measurable indices that can provide crucial insights concerning not only underlying disease mechanisms but also prognostic and risk stratifying information. As AF is constituted by an overwhelming range of pathophysiological aspects such as inflammation, fibrosis, hypercoagulable states and myocardial damage, identifying and assessing relevant biomarkers will evidently support the clinician's prognostication efforts. The current reviewpresents studied biomarkers with proven prognostic potential in AF as well as possible enhancement of risk-scores when incorporated to them.

Coronary Microcirculation and the No-reflow Phenomenon.

The no-reflow phenomenon refers to the post-percutaneous coronary intervention condition in which, despite re-establishing epicardial coronary vessel patency, the flow to the previously ischemic myocardium is markedly reduced. When it does occur, it attenuates the beneficial effect of reperfusion therapy and substantial regions of the myocardium fail to receive adequate perfusion. The pathophysiology of this phenomenon is not completely understood. The possible mechanisms could be related to alterations in the microvascular circulation. Various mechanisms such as activation of inflammatory pathways, vascular damage and hemorrhage, leukocyte infiltration, and cellular edema may be responsible. As the no-reflow phenomenon is associated with adverse clinical consequences, it is of great importance to identify exact responsible mechanisms and apply effective preventive and therapeutic strategies. In this review, we describe an updated overview of the pathophysiological mechanisms and the current preventive tools for no-reflow as well as therapeutic interventions in order to improve coronary blood flow and consequently the prognosis for these patients.

Statins and inflammation in cardiovascular disease.

BACKGROUND: Chronic inflammation and immune system activation underlie a variety of seemingly unrelated cardiac conditions including not only atherosclerosis and the subsequent coronary artery disease but also peripheral artery disease, hypertension with target organ damage and heart failure. The beneficial effects of HMG-CoA reductase inhibitors or statins are mainly attributed to their ability to inhibit hepatic cholesterol biosynthesis. Beyond their lipid lowering activity, ample evidence exists in support of their potent anti-inflammatory properties which initiate from the inhibition of GTPase isoprenylation, activating a cataract of secondary pathways and extend to the inhibition and blocking of immune cell activation and interaction. OBJECTIVE: To summarize the anti-inflammatory mechanisms of statins in clinical and experimental settings in cardiovascular disease. METHODS: A systematic search of PubMed and the Cochrane Database was conducted in order to identify the majority of trials, studies, current guidelines and novel articles related to the subject. RESULTS: In vitro, statins have immuno-modulatory and anti-inflammatory effects, and they can exert anti-atherosclerotic effects independently of their hypolipidemic actions. In addition, positive results have emerged from mechanistic and experimental studies on the active role of HMG-CoA reductase inhibitors in HF. By extrapolating those data in clinical setting, we further understand how HMG-CoA reductase inhibitors can beneficially affect not only systolic but also diastolic HF. CONCLUSION: In this review article, we present the basic pathophysiologic data supporting the anti-inflammatory actions of statins in clinical and experimental settings and we link these mechanisms with confirmatory clinical data on the potent non lipid lowering effects of HMG-CoA reductase inhibitors.

Statins in Stable Angina Pectoris.

BACKGROUND: Stable angina is a debilitating and progressive disease caused by narrowing of the coronary arteries, which in turn affects cardiac perfusion. Statins have a well-established role, modifying symptoms and progression of the disease not only through lipid lowering, but also through pleiotropic effects. OBJECTIVE: We sought to evaluate the effect of statins in stable angina pectoris Method: We performed a systematic review of the literature searching MEDLINE via Pubmed for all studies which examine the possible effects of statins in stable angina pectoris. RESULTS: Statins have demonstrated favourable modification of both biochemical markers (oxidative stress, inflammatory and coagulation markers/factors) and clinical symptoms (anginal and ischemic) of the disease. These effects have been demonstrated in vitro, ex vivo and in vivo in animals and humans, independently of the lipid lowering effects. CONCLUSION: With an excellent safety profile and evidence of efficacy in managing patients with stable angina, statins appear an essential part of the therapeutic armoury against atherosclerotic disease.

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.

Risk stratification for large artery or chronic coronary artery disease-related ischemic stroke in octogenarians undergoing exercise stress myocardial perfusion imaging: A cohort study.

OBJECTIVES: To test, if in octogenarians, treadmill exercise with myocardial perfusion imaging (exercise-MPI) can risk stratify for large artery or chronic CAD-related ischemic stroke (LACCIS). METHODS: Exercise-MPI-related data of 237 octogenarians (55% prior MI or revascularization) without previous stroke were registered and prospective follow-up was performed to document LACCIS. LACCIS was defined as acute onset of neurological symptoms with CT/MRI findings of non-lacunar-type infarcts in the absence of atrial fibrillation or intracardiac embolic sources. RESULTS: After 7.3 years, 10 LACCIS were documented. SSS [HR 1.08 (1.02-1.13 95% CIs), SDS [HR 1.1 (1.04-1.16 95% CIs)], and non-sustained VT or transient AV block during exercise [HR 3.9 (1.7-9.0 95% CIs)] were predictors of LACCIS (P < .01 for all). A SSS threshold of 16 had 81% specificity for identification of future LACCIS and risk groups formed according to this cut-off had significantly different LACCIS-free survival (P = .015). CONCLUSION: Exercise-MPI in octogenarians can provide risk stratification markers for LACCIS.

Coronary Artery Atherosclerosis in Hypertensive Patients: The Role of Fibrinogen Genetic Variability.

INTRODUCTION AND OBJECTIVES: We examined whether the rs180070 and rs2070011 polymorphisms of the fibrinogen gene could affect the risk of coronary artery disease in hypertensive patients by modifying the inflammatory process and coagulation. METHODS: A total of 744 participants underwent coronary angiography due to symptoms of stable angina, while hypertension was present in 332 patients. RESULTS: The presence of the A allele (rs180070) was associated with significantly high levels of fibrinogen in hypertensive patients (P=.05). On multivariate analysis, A homozygosity (rs180070) (ß = 0.257 ± 18.6; P<.001), but not hypertension status (ß = 0.05 ± 11.9; P=.29) was an independent predictor of fibrinogen levels. In hypertensive patients, higher fibrinogen levels>443mg/dL (odds ratio = 3.50; 95% confidence interval, 1.14-10.90; P=.029), but not A homozygosity (odds ratio = 3.00; 95% confidence interval, 0.78-11.90; P = .110) were independent predictors of the presence of coronary artery disease. Moreover, interleukin-6 levels were higher in A homozygotes for the rs180070 polymorphism compared with all other genotypes (P=.046). Indeed, this genotype was the only adjusted independent predictor of interleukin-6 levels (ß = 0.151 ± 0.642; P=.032). It was also associated with higher D-dimer levels in hypertension compared with G allele carriers (P=.048). CONCLUSIONS: The presence of A homozygosity (rs180070) is associated with increased levels of inflammatory mediators and a higher incidence of angiographic coronary artery disease. Importantly, fibrinogen is an independent predictor of the angiographic presence of coronary artery disease in hypertensive patients.