Sotirios Tsalamandris

Basic Mechanisms in Atherosclerosis: The Role of Calcium.

In the beginning, atherosclerosis was considered to be the result of passive lipid accumulation in the vascular walls. After tremendous technological advancements in research, we are now able to almost admire the complexity of the atherosclerotic process. Atherosclerosis is a chronicinflammatory condition that begins with the formation of calcified plaque, influenced by a number of different factors inside the vascular wall in large and mid-sized arteries. Calcium mineralization of the lumen in the atherosclerotic artery promotes and solidifies plaque formation causing narrowing of the vessel. Soft tissue calcification associated with tissue denegation or necrosis is a passive precipitation event. The process of atherogenesis is mainly driven by CD4+ T cells, CD40L, macrophages, foam cells with elevated transcription of many matrix metalloproteinases, osteoblasts, cytokines, selectins, myeloperoxidases, vascular adhesion molecules (VCAM), and smooth muscle cells. Our knowledge in the genesis of atherosclerosis has changed dramatically in the last few years. New imaging techniques such as intravascular ultrasound or IVUS have made possible to investigate atherosclerosis in early stages. Arterial calcification emerges from two different types, the medial-elastin dependent and the intimal, both of which are directly related to atherosclerosis due to osteoblast differentiation of vascular smooth muscle cells. The deposition of minerals in the form of calcium (Ca(2+)) initially emerges from the inorganing mineral octacalcium phosphate [Ca8H2(PO4)6.5H2O] to the form of Hydroxylapatite [Ca10(PO4)6(OH)2]. This review is devoted to broaden the understanding regarding atherosclerosis and the central role of calcium in the development of the condition.

The Role of Oxidative Stress

Oxidative stress occurs due to the combination of excess reactive oxygen species and insufficient antioxidant capacity. Oxidative stress has been correlated with endothelial dysfunction, the pathogenesis of atherosclerosis as well as with high incidence of cardiovascular disease. A variety of antioxidants have been studied, during the past few years, for the prevention and treatment of atherosclerosis. This chapter provides contemporary data concerning pathophysiology of oxidative stress and its relation to atherogenesis.

Biology of the Vessel Wall

Atherosclerosis is a pathologic process that develops in the arterial wall. Therefore the biology and imaging of the vessel wall is the cornerstone of research, diagnosis, and treatment in patients with atherosclerosis and coronary artery disease. Three functional layers (intima, media, and adventitia) have been recognized that actively orchestrate blood perfusion in tissue and organs; however, changes in the intima layer and especially endothelial damage predispose to atherosclerosis, thrombus formation, and acute coronary events. Over the years additional characteristics have been recognized (i.e., thin cap fibroatheroma, thermal heterogeneity, infiltration with macrophage and inflammatory cells) predisposing to plaque rapture and erosion and acute coronary syndromes, which should orient future research and treatment strategies.

The Role of Inflammation

Atherosclerosis is a disease of arteries and is characterized by endothelial dysfunction, vascular inflammation, and the build-up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. A number of factors commonly characterized as “risk factors” for atherosclerosis have been identified to facilitate the development of atherosclerosis by decreasing nitric oxide bioavailability in the vascular endothelium. The serious clinical manifestations of atherosclerosis (including coronary heart disease, stroke, and peripheral vascular disease) augment the need of performing the appropriate diagnostic methods to the patients. The most important diagnostic methods include the usage of biochemical markers and the invasive and noninvasive imaging techniques assessing endothelial function.

Western Dietary Pattern Is Associated With Severe Coronary Artery Disease

The independent predictive value of an unhealthy diet on the severity of coronary artery disease (CAD) requires further investigation. We assessed the impact of dietary pattern on CAD severity. In this cohort study, we included 188 symptomatic stable patients with CAD. Patients were categorized as having severe CAD or nonsevere CAD by coronary angiography. Among several demographics and clinical characteristics, all patients were tested using a semiquantitative food frequency questionnaire. Concerning baseline demographic characteristics, there was no difference between patients with severe CAD and nonsevere CAD. Principal component analysis revealed 8 distinct dietary patterns. The first component Western dietary pattern (increased intake of fat, red meat, and carbohydrates and minimal consumption of fruits and green leafy vegetables) was predictive of severe CAD (area under the curve: 0.73, 95% confidence intervals: 0.64-0.83, P < .001). In conclusion, an unhealthy Western type of diet is associated with the severity of coronary artery lesions in patients with stable CAD. These findings highlight the role of dietary patterns when estimating cardiovascular risk for the management of patients with CAD.

ENDOTHELIAL FUNCTION PREDICTS ANTHRACYCLINE-INDUCED CARDIOTOXICITY

Anthracyclines are the cornerstone of chemotherapy for breast cancer, but its use is limited by cardiotoxicity development, which has been linked with nitric oxide (NO) bioavailability. We explored the association of brachial flow mediated dilation (FMD) with cardiotoxicity development after

Anti-Inflammatory Treatment

The underlying role of inflammation in atherosclerosis has been widely described and is critical in all the stages of atherogenesis, from plaque formation to plaque rupture and the development of acute coronary syndromes. Despite the efficacy of therapies targeting serum lipid abnormalities, atherosclerosis remains the most significant cause of death in the world. It seems that the measurement of circulating levels of inflammatory molecules can be useful in risk assessment or even in the design of therapeutic approaches against the development and progression of coronary atherosclerosis. However, current treatment of coronary artery disease (CAD) primarily targets in the reduction of serum lipoprotein levels rather than altering the detrimental effects of acute and chronic inflammation. Over the last decades, basic studies and clinical trials have shed light on the potential benefits of treatments targeting inflammation in CAD.

Stem-Cell Therapy

Permanent loss of cardiomyocytes in advance atherosclerosis and particularly after myocardial infarction results in an irreversible damage to the cardiac function. Cardiac repair is, therefore, essential to restore function of the heart. Existing therapies lower early mortality rates and reduce the risk of further heart attacks. However, there is a need for treatment to improve the infarcted area by replacing the damaged cells after myocardial infarction. Thus, the cardiac tissue regeneration with the application of stem cells may be an effective therapeutic option. Regenerative cell-based therapy has the potential to become effective adjuvant treatment for patients with atherosclerotic disease. Although data from animal studies support this notion, clinical studies undertaken in patients with acute and chronic coronary artery disease do not conclusively demonstrate benefits of such therapy. The potential benefits and the ability to improve cardiac function with the stem cell-based therapy need to be further addressed.

Anti-Oxidant Treatment

A variety of antioxidants have been studied, during the past few years, for the prevention and treatment of atherosclerosis. Early observational studies, focusing on dietary antioxidants, demonstrate an inverse association between antioxidant intake and major cardiovascular events, and supported a number of large-scale, randomized, placebo-controlled clinical trials, which investigated the effect of selected antioxidant therapies on primary and secondary cardiovascular prevention. However, the findings appear controversial because disappointing results have been reported from many studies with little or no decrease in cardiovascular risk while others showed significant reduction of the oxidative stress and improvement of endothelial function. A few rational explanations of these controversial findings have been proposed and should be taken into account in future clinical studies. This chapter provides contemporary data concerning the potential role of antioxidant therapy in reducing cardiovascular risk via primary and secondary prevention.

OMEGA-3 POLYUNSATURATED FATTY ACIDS MAY FAVORABLY AFFECT INFLAMMATORY BIOMARKERS & NOVEL INDICES OF LEFT VENTRICLE FUNCTION IN PATIENTS WITH HEART FAILURE

Introduction: Omega-3 polyunsaturated fatty acids (PUFAs) exert anti-inflammatory properties and have been tested in patients with systolic heart failure (HF). Soluble suppression of tumorigenicity2, is a member of the interleukin 1 (IL1) receptor family and is released from cardiomyocytes and