**2. Epidemiology and impact of life style on atherothrombosis**

Atherothrombosis is a complication of atherosclerosis. The essence of this process consists of closing or narrowing vessel lumen, which is caused by a clot formation following exposure of thrombogenic, lipid rich necrotic core, of the ruptured plaque. Depending on the affected vascular bed, it can manifest as a heart attack or unstable coronary artery disease, transient ischemic episode or stroke, as intermittent claudication or acute limb ischemia [14].

randomized controlled trials (POLSCREEN, EURO-ACTION, POLCARD, DART, GISSI). The above-mentioned trials, as well as other carried out so far, including autopsy studies and clinical and experimental studies, have shed new light on the pathogenesis of atherosclerosis, which for years was believed to be a disease solely degenerative. It is now known that it is a condition characterized by systemic low-grade inflammation [2, 3]. This process begins perinatally [4]. Lipid disorders that occur in the mother increase the sensitivity of the fetus to the risk factors for atherosclerosis. Moreover, the low birth weight correlates positively with an

Inflammation affects the compliance of the arteries. It is a response of vascular walls to agitation and injury of vascular endothelium (*response-to-injury hypothesis*) [2, 7]. It has been shown that endothelial cells are the main component of the vessel wall that is responsible for empowerment of the process of atherogenesis. It has also been suggested that they participate in various stages of development, destabilization and cause for plaque rupture [8]. Under physiological conditions, the cells of proper endothelium produce substances that regulate vascular smooth muscle tension, adhesion and aggregation of platelets and the migration of monocytes and polymorphonuclear leukocytes. Damage to the vascular endothelium, also considered for activation of the inflammation, is characterized by a reduced bioavailability of endothelial vascular distending substances (mainly nitric oxide [NO] and prostacyclin [PGI]), increased permeability of plasma lipoprotein vessel intima and changing the properties from anti-adhesive to pro-adhesive [9, 10]. The state of endothelial cells depends, among other things, on vascular endothelial NO formed under the influence of l-arginine NO synthase [10]. This is the endothelial substance responsible for the anti-atherosclerotic, vascular distention, anti-inflammatory and anti-coagulant activity of vascular endothelium [9, 11]. Factors responsible for endothelium dysfunction include elevated LDL cholesterol, high homocysteine, hypoxia, diabetes, oxidative stress (due to excessive formation of free radicals of oxygen), bacterial and viral infections (Chlamydia pneumoniae, Helicobacter pylori, Herpes virus, Cytomegalovirus). These components of atherogenesis cause mainly functional but also morphological damage. Moreover, shear stress variability in hypertension causes mechanical injury of endothelial cells [9, 12]. Increased sensitivity to the damage is shown in the endothelium of the diabetic patients, as its cells can be stimulated, under the influence of the increased concentration of glucose and the accumulation of advanced glycation end-products. These substances, acting through the receptors for glycation end products, may induce proinflammatory molecule

instance of the metabolic syndrome in adulthood [5, 6].

74 Atherosclerosis - Yesterday, Today and Tomorrow

expression in endothelial cells [13].

**2. Epidemiology and impact of life style on atherothrombosis**

Atherothrombosis is a complication of atherosclerosis. The essence of this process consists of closing or narrowing vessel lumen, which is caused by a clot formation following exposure of thrombogenic, lipid rich necrotic core, of the ruptured plaque. Depending About 80% of deaths from cardiovascular events occur as a result of a stroke or a heart attack. Approximately 17.5 million people die every year due to cardiovascular disease, which is approximately 31% of general mortality in the world. Atherothrombosis is the main cause of mortality due to cardiovascular diseases (CVD). Approximately 75% of the cases of heart attack and approximately 90% of strokes associated with carotid arteries atherosclerosis are caused by thrombosis [15].

CVD is a big financial burden for healthcare systems. In 2009, CVD-related costs totaled 106 billion euros, which was approximately 9% of the total expenditure on health care in the European Union [16]. There exists global trend towards the increase in the incidence of lifestyle diseases and a decrease in cases of premature death as compared to years on disability. In the context of lost years of life and life years on disability, ischemic heart disease (IHD) and stroke are, respectively, in the first and third place in the world [17]. About 85–90% of strokes are of ischemic etiology [18].

In accordance with meta-analysis, based on an analysis of studies involving a total of more than 250,000 people, the risk of death due to CVD in the course of lifetime is approximately 30%, and taken into account the risk of death and all cardiovascular events dating back to it, 50% for both sexes, in each age group [19]. Among diabetics, most of whom die due to CVD, 8 of 10 deaths are due to atherothrombosis [20].

According to the findings of the Global Burden of Disease Study from 2010 onwards, adjusted for age, the mortality due to CVD has fallen approximately 20% during the last 80 years of the twentieth century [21]. The success of the reduction of mortality due to CVD is associated with the development of methods of treatment and better organization of healthcare, as well as preventive activities, including non-pharmacological interventions. To the above, one can also add changes in tobacco legislation, which can lead to a 15% reduction in the risk of hospitalization and a 16% reduction in mortality from coronary heart disease and stroke [22]. Not less important are the lifestyle changes, including eating habits. It has been demonstrated that appropriate physical activity and dietary intervention can contribute to approximately 35% reduction in the risk of death already accepted with adjustment of pharmacologic medication [23]. Proper diet contributes to the reduction of cardiovascular events (CVE) in patients after 55 years of age diagnosed with diabetes or a history of CVE irrespective of the use of drugs in secondary prevention [24].

In terms of cardiovascular risk reduction, the introduction of statin therapy was the pharmacological milestone. This has proven effective in reducing CVE and mortality due to CVD [25]. What's more, their use in low-risk populations decreased by approximately 30% the relative risk in this population. In addition, for patients intolerant of statins or for those who despite optimal therapy fail to achieve their therapeutic goal, Ezetimibe or Evolucumab can be currently used, new drugs of proven efficacy and safety of therapy [26, 27]. Ezetimibe connects with Niemann-Pick C1-like 1 (NPC1L1) proteins preventing absorption of cholesterol from the gastrointestinal tract. Used together with simvastatin, it significantly reduced the risk of mortality compared to statin monotherapy. Evolocumab is a monoclonal antibody interacting with enzyme PCSK9 (proprotein convertase subtilisin kexin type-9) and significantly lowering LDL-cholesterol and total cholesterol and reducing CVE rate in combination with a statin as compared to statin monotherapy [26, 27].

(AMI)—which includes STEMI and NSTEMI or sudden cardiac death (SCD). Atherosclerosis in carotid arteries can lead to transient ischemic attacks (TIA) or ischemic stroke. The cause for these complexes, known as cardiovascular syndromes, is a blood thrombosis, forming on the surface of the damaged endothelium, a narrowed coronary artery or carotid artery, most

Atherothrombosis as a Leading Cause of Acute Coronary Syndromes and Stroke: The Main…

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Pathophysiological studies have shown that the most common cause of formation of a blood clot is rupture of the fibrous cap, which separates the contents of the plaque from the blood [9, 13, 33, 35]. This was confirmed in intravascular ultrasound (IVUS) with virtual histology (VH-IVUS), optical coherence tomography (OCT) and magnetic resonance imaging (MRI) [36, 37]. This mechanism applies to approximately 55–60% (in some studies dating back to the 80%) cases of ACS [33, 35, 36]. Other mechanisms are damage of endothelial cells known as erosion on the surface of atherosclerotic plaque (plaque erosion) consisting of 30–35% of the ACS and of approximately 2–7% endovascular calcifications (calcified nodules) [33, 35]. Inflammatory changes ongoing in the atherosclerotic plaque cause a loss of stability making it vulnerable to rupture, the so-called unstable atherosclerotic plaque (vulnerable plaque). Unstable plaque is characterized by a thin fibrous cap (thin cap fibroatheroma—TCFA) covering the big necrotic core around which revolves the inflammatory process and positive remodeling of the artery [9, 32, 33, 35]. A similar transformation in the atherosclerotic plaque has also been observed in the ICA. This location is responsible for TIA and strokes [9]. Positive remodeling of the artery proves that narrowing of its lumen does not have to be relevant, and it may not exceed 50–70% [9, 33]. The widespread use of statin drugs, especially atorvastatin and rosuvastatin, also likely ACE inhibitors, and lifestyle changes in developed countries have resulted in better control of inflammatory changes ongoing inside atherosclerotic plaque. This results in reduction in the incidence of strokes (primary stroke prevention) and ACS in the form of STEMI, but higher prevalence of NSTEMI and UA [9, 13, 32]. As a result, this has led to decreased cardiovascular mortality in many countries. It cannot be excluded that control of inflammation in the vessel wall by commonly used statins lowers the incidence of share in causes for destabilizing plaque rupture leading to occlusion of the artery. Because the total number of ACS and cerebral ischemic events remains at a similar level, this finding probably reveals other mechanisms leading to intravascular thrombosis with a smaller share of acute inflammation within the plaque rupture-induced accumulation of oxygen-modified LDL cholesterol (oxy-LDL) leading to destabilization. These mechanisms include endothelial injury by vascular flow disorders caused by artery stenosis, abnormal healing processes of the damaged endothelium, infectious pathogens as well as autoimmune responses against

frequently internal carotid artery (ICA) [9, 32].

modified plaque components [9, 13, 35, 38, 39].

**4.1. Vulnerable plaque**

**4. The evolution of stable coronary artery disease to ACS**

Endocrine endothelial function, which consists in the synthesis and secretion of NO and PGI, is a prerequisite for the preservation of its integrity and correct relationship between

Very important element of therapy is patient's compliance. Adherence of the patient affects the effectiveness of the therapy. The review of approximately 20 studies involving a total of over 375,000 patients showed only 42–61% of adherence to treatment in patients receiving cardiovascular drugs as primary prevention and 62–76% adherence in secondary prevention [28].

There are some differences in CVD mortality among different races. Black people have a higher risk of death from coronary heart disease and 2–4 times higher risk of ischemic stroke than white people. The Asian race and the people of the Pacific Islands are at the highest risk for hemorrhagic stroke [29].

Appropriate prevention would reduce the CVD cases by 80% [19, 30]. Unfortunately, there are still inequalities between countries. About 80% of deaths from CVD take place in countries with low-to-moderate prosperity, in which the frequency of multiple risk factors, especially obesity and diabetes mellitus (DM), tends to increase significantly [16]. Interestingly, despite the general decline in the consumption of tobacco products, there currently exists three times higher risk for smoking in women because of the trend to start the habit at a younger age.

Among patients with CAD, the most common manifestations of atherothrombosis are myocardial infarctions with ST segment elevation (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI). In-hospital mortality in STEMI varies, according to a variety of records, around 6–14%. Despite the development of pharmacotherapy and the invasive therapy, the mortality rate in 6 months after STEMI is still approximately 12%. Over the last decade, the proportion of STEMI has been reduced as compared to NSTEMI. Although, in the early years, the population of patients with NSTEMI acute coronary syndrome is characterized by lower mortality; after about 2 years, it is similar as in patients with STEMI [31].
