The concept of vulnerable plaque has developed into a new concept of vulnerable patient as the concept of pathogenesis of atherosclerosis was linked to a person s susceptibility to coagulation and thus vascular events, which can be influenced by many personal factors such as genetics (e.g. procoagulant prothombin gene mutation), coexisting condition (e.g. diabetes), and lifestyle factors (e.g. smoking, obesity). https://www.textbookofcardiology.org/wiki/Atherosclerosis 11/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology Progression of coronary atherosclerosis can be gradual (bottom) or can lead to plaque rupture with acute occlusion of a coronary vessel due to clot formation Complications of atherosclerosis The clinical complications of atherosclerosis are highly dependent on the location and size of affected vessels, the duration of the chronic process, and the type of plaque, since the severity of impairment of atherosclerosis differs throughout the vasculature. For example, stable plaque can easily result into angina pectoris due to its thick fibrous cap that directly affects the diameter of the relatively small coronary vessels. On the other hand, vulnerable plaque is non- Figure 11. Most common locations of atherosclerosis Dorsal section of the abdominal aorta Proximal coronary arteries Popliteal arteries Descending thoracic aorta Internal carotid arteries Renal arteries stenotic, but can easily cause acute therefore myocardial thrombosis and infarction due to its fragility towards rupture when located at physically stressed areas such as bifurcations. Often with vulnerable plaques there are relatively few symptoms, however they are more numerous and dispersed throughout the arteries compared to stable plaque . Thus, you can either have an occlusion due to the growing plaque or due to the embolization of the ruptured fragments of the original plaque. Due to the difficult detection of vulnerable plaques while they are widely dispersed, it is highly important to tackle the risk factors prior to plaque rupture. Thus in the following paragraph, we will highlight the clinical risk factors associated four major with atherosclerosis. The clinical consequences of atherosclerosis are listed and explained below. Figure 12. Complications of atherosclerosis 1. Acute narrowing of the vessel lumen: When the plaque ruptures, it will release its pro-coagulants in the bloodstream and that will lead to the formation of thrombus at the rupture site. The rupture often occurs at sites of erosion and fissuring on the fibrous cap surface. This thrombus may cause a complete occlusion of a particular vessel and result in ischemic necrosis (infarction) of the tissue that this particular vessel is supplying to. Clinically this is manifested as stroke, MI, gangrene of several possible organs such as intestine, spleen or lower extremities. These occlusions may also dissolve spontaneously due to pro-fibrinolytic enzymes such as streptokinase and tissue plasminogen activator (TPA). 2. Chronic occlusion: When the occlusion is gradual and incomplete, it may chronically disturb the blood supply to tissues in the distribution of the affected vessel. This can result in chronic ischemia of those tissues that can additionally lead to complaints of angina pectoris or intermittent claudication or to organ atrophy (e.g. atrophy of kidney, intestines and skin due to impairment of blood flow in renal artery, mesenteric artery, peripheral vasculature among diabetics.). https://www.textbookofcardiology.org/wiki/Atherosclerosis 12/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology 3. Embolism: Embolization is the transfer of the fragments of disrupted atheroma to distal vascular sites, which results into occlusion of those sites. For example, fragments of thrombi in abdominal aorta may transfer to the popliteal artery subsequently resulting in gangrene of the leg. Ulceration of atheroma may also produce cholesterol crystal emboli . This type of emboli is visualized as needle- shaped areas in affected tissues, mostly detected in the kidney. 4. Aneurysm: After a chronic period, atherosclerotic lesion may extend into the medial layer, resulting into atrophy and loss of elastic tissue. This can subsequently cause dilatation and weakness of the artery, forming aneurysm. Over time, aneurysms may suddenly rupture and result in a life- threatening situation for the patients. Risk factors of atherosclerosis Recent studies have shown that atherosclerosis is not just the inevitable process of aging, but also a process with many modifiable components. A worldwide INTERHEART study has established the importance of nine potentially modifiable risk factors for atherosclerosis, which account for over 90% of the population-attributable risk of a first MI (figure 12). A variety of non-modifiable risk factors such as advanced age, gender and hereditary coronary heart disease are important to recognize in patients with atherosclerosis. Recently the role of several biological markers associated with the development of cardiovascular events is accentuated since one out of five cardiovascular events occurs in patients lacking the earlier mentioned risk factors. Figure 13. Nine modifiable risk factors for atherosclerosis according to INTERHEART study Dyslipidemia Tabacco smoking Lack of physical activity Abdominal obesity Psychosocial factors Daily consumption of fruits and vegetables Regular alcohol consumption Hypertension Diabetes Mellitus Common risk factors Dyslipidemia One of the major modifiable risk factors for atherosclerosis is hypercholesterolemia. Studies show that dyslipidemia (defined as an elevated apo B to apo A-1 ratio) was responsible for 49% of the population- attributable risk of a first MI. In countries with high consumption of saturated fat and high cholesterol levels (e.g. the United States), observational studies have shown that the mortality rates from coronary disease are higher compared with countries with traditionally low consumption of saturated fat and cholesterol levels (e.g. Japan). Several trials have shown that the risk of ischemic heart disease positively correlates with higher total serum cholesterol levels. For example, the impact of hypercholesterolemia can be illustrated by an observational result from the Framingham Heart Study, which shows that a person with a total cholesterol level of 240 mg/dl has twice the coronary risk a person would have with a cholesterol level of 200 mg/dl. However, it is a mistake to think that all lipoproteins consisting of cholesterol are harmful since cholesterol can provide critical functions to all cells that need to form membranes and to synthesize products such as steroid hormones and bile salts. Incidence of atherosclerosis and coronary artery disease increases with higher levels of LDL particles. As mentioned earlier, LDL can accumulate in the intima of the artery in excess and undergo chemical modifications that activate endothelial cells to proceed to atherosclerosis. When people generally refer to https://www.textbookofcardiology.org/wiki/Atherosclerosis 13/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology Figure 14. Recommendations regarding dyslipidemia General recommendations: A varied and balanced diet Regular fish intake (n 3 fatty acids) Fruits and vegetables, 3-5 portions per day, cereals and grain products, skimmed dairy products, and low-fat meat Restriction of fatty products and products with a high caloric density. The total fat intake should not be higher than 30% of calory intake. The saturated fat intake should not be higher than 30% of total lipids The cholesterol intake should be under 300 mg per day Specific diet recommendations: Avoid hard margarines and products of animal origin (meat, dairy products) Increase intake of omega-3 fatty acids from fish oils and certain vegetal oils Increase intake of polyunsaturated fatty acids, soluble fibres, and phytosterols Exercise and body weight reduction within obese group Normalization of glycaemia in diabetic patients Reduce the intake of refined sugars and replace them with complex sugars from fruits, vegetables, and grain products bad cholesterol , they are referring to LDL particles. On the other hand, high levels of high-density lipoprotein (HDL) constitute good cholesterol since it protects against atherosclerosis by reversing the cholesterol transport from peripheral tissues to the liver for disposal and functions as an antioxidant. In order to give additional explanation to what is bad cholesterol, all lipid and lipoprotein abnormalities that are associated with higher coronary risk will be named subsequently: increased total cholesterol, increased LDL-cholesterol, ratio, hypertriglyceridemia, increased non-HDL-cholesterol, elevated lipoprotein A, elevated apolipoprotein B (apo B is primarily found in LDL), decreased apolipoprotein A-I (apo A-1 is found in HDL), small and dense LDL particles. low HDL-cholesterol, elevated total-to-HDL-cholesterol There are several causes for persistent elevated levels of LDL, such as high fat consumption or genetic abnormalities (e.g. familial hypercholesterolemia). Familial hypercholesterolemia is a condition with deficient LDL receptors that cannot efficiently dispose LDL from the circulation. There are two types of this disease with different manifestations. Patients with the heterozygote type have only one defective gene for the receptor and suffer from high serum level of LDL, easily developing atherosclerosis. Homozygotes have a complete lack of normal LDL receptors and thus may experience cardiovascular events already in the first decade of life. In the absence of genetic abnormalities, the quantity of cholesterol in serum is strongly related to saturated fat consumption. Lipid-Altering therapy Controlling serum lipids is a key step to limit the consequences of atherosclerosis. Major clinical trials have shown that coronary events and mortality significantly decreased when total and LDL-cholesterol levels were reduced for the primary and secondary prevention of CAD events. One of the most important strategies to reduce the complications of atherosclerosis is diet and exercise. In order to decrease cholesterol, Mediterranean diet is often recommended. Mediterranean diet consists of low animal fat, high olive oil, moderate energy consumption, nuts, vegetables, regular and moderate https://www.textbookofcardiology.org/wiki/Atherosclerosis 14/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology wine, lots of whole grains and beans. A meta-analysis of six randomized trials showed that Mediterranean diet low fat diets among led to greater reduction in total cholesterol than overweight/obese population. Mediterranean-styled diet in this context means replacement of saturated fats with polyunsaturated fats such as omega-3 fatty acid and -linolenic acid. Polyunsaturated fats are potential anti-atherogenic due to their inhibiting action on cytokine-induced expression of leukocyte adhesion molecules at endothelial cells. Exercise and loss of excessive weight also contributes to improve abnormal lipid levels by reducing triglycerides and increasing HDL. In primary prevention, pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors (statins), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In the clinical setting, statins are widely used, being the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower levels of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet. Large studies, which have evaluated the effects of statin therapy, showed that ischemic cardiac events, the occurrence of MI and mortality rates were significantly reduced by implementing statin therapy. This significant improvement did not only apply to people with known preexisting atherosclerotic disease, but also to people within lower ranges of LDL and without preexisting atherosclerotic disease. For example, West of Scotland Coronary Prevention Study (WOSCPS trial) evaluated the effect of pravastatin on rates of nonfatal MI or CHD death, nonfatal MI, all cardiovascular deaths and total mortality among patients with hypercholesterolemia without preexisting CVD for five years. Use of pravastatin resulted in 31% risk reduction (p<0.001) in nonfatal MI or CHD death, and a 32% risk reduction (p=0.033) in all cardiovascular deaths as compared to the control group. Inhibiting HMG-CoA reductase results in several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, the anti-thrombotic and anti-inflammatory profile is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to the anti-inflammatory profile. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR- . Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation. Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still a need for additional risk-reducing therapies. Thus, a new idea was developed to raise HDL cholesterol as a treatment for atherosclerosis. With the finding of the high-HDL phenotype of a human genetic deficiency of cholesteryl ester transfer protein (CETP), a new class of drugs was developed, which inhibits CETP. CETP functions as a mediator for transfer of cholesteryl ester from HDL to VLDL/LDL, which is then cleared by LDL receptors in liver. Thus when CETP is inhibited, this transfer process is inhibited and the direct hepatic HDL clearance pathway takes over. This leads to less fractional clearance https://www.textbookofcardiology.org/wiki/Atherosclerosis 15/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology of HDL from plasma, which is beneficial for atherosclerosis. Although the absolute clearance rate of HDL remains the same, the key step for atherosclerosis, which is the removal of cholesterol from macrophage foam cells in artery wall by HDL, is reduced. The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with an undiscovered off-target effect. Anacetrapib and dalcetrapib are still under active clinical investigation, since they lack the off-target effects of torcetrapib. Tobacco smoking Tobacco use, including environmental smoking exposure, is known to increase the risk of atherosclerosis and ischemic heart disease based on numerous studies. For example, INTERHEART study shows that smoking is responsible for 36% of the population-attributable risk of a first MI. Other studies showed that smoking is an independent major risk factor for coronary heart disease, cerebrovascular disease and total atherosclerotic cardiovascular disease. The Atherosclerosis Risk in Communities Study measured the direct effect of smoking on the development of atherosclerosis. They measured intima-medial thickness of the carotid artery of 10,914 patients for three years with ultrasound. Their result showed that current smokers had a 50% increased progression of atherosclerosis in comparison to nonsmokers during the study period. Also patients with environmental tobacco smoke exposure (passive smokers) had 20% higher rate of atherosclerotic progress versus patients without environmental smoke exposure. Tobacco smoking can lead to many mechanisms that contribute to atherosclerosis. Smoking also leads to increased LDL levels, decreased HDL levels in blood and elevated insulin resistance. In addition it enhances oxidative modification of LDL by releasing free radicals and reduces generation of nitric oxide. This can promote endothelial dysfunction and thus lead to impairment of vasodilatation of coronary arteries and reduction of coronary flow reserve even in passive smokers. Tobacco smoking inappropriately stimulates sympathetic nervous system, increasing heart rate, blood pressure and perhaps coronary vasoconstriction. Smoking promotes a prothrombotic environment through inhibition of endothelial release of tissue plasminogen activator, elevation of fibrinogen concentration in blood, enhancement of platelet activity (possibility related to sympathetic activation) and enhanced expression of tissue factor. Smoking can even damage the vessel wall and ultimately cause a decrease in the elasticity of the artery, enhancing the stiffness of vessel wall. Smoking has been associated with increased C-reactive protein and fibrinogen, suggesting a correlation with inflammatory response, which is an important part of atherogenesis. There have also been findings that show higher expression of leukocyte adhesion molecules among smokers than nonsmokers. Smoking may additionally induce tissue hypoxia through displacement of oxygen with carbon monoxide in hemoglobin. To stop smoking is known as one of the most effective preventive measures of CVD and their complications. Soon after cessation, cardiac risks due to smoking decreases in a short period, and continues to diminish when cessation is permanently preserved. The risk for cardiovascular disease among patients with coronary heart disease decreases 7-47%. Not only does cessation of smoking reduce risk of CVD, but also substantially reduce the risk of all-cause mortality. Lack of physical activity https://www.textbookofcardiology.org/wiki/Atherosclerosis 16/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology INTERHEART study showed that lack of exercise accounted for 12% of the population- attributable risk of a first MI. Recent evidence shows that physical activity of even a moderate degree can protect against coronary heart disease and all-cause mortality .The beneficial effects of physical exercise are a decrease of triglyceride levels and blood pressure, elevation of HDL, enhancement of insulin sensitivity and production of NO by the endothelial cells, and of course weight loss. Although large scale randomized primary prevention trials are lacking, physical activity should be promoted to anyone with risk of developing atherosclerosis. Physical Activity Obesity The American Heart Association has published an article, identifying obesity as an independent risk factor for coronary heart disease. Obesity is for several correlated with atherosclerosis such as hypertension, insulin resistance, glucose intolerance, decreased HDL serum level and hypertriglyceridemia. Weight loss is an important treatment to prevent many obesity-related risk factors for atherosclerosis that has just been mentioned. risk factors Diet A healthy diet reduces CVD risk. In general, when following the rules for a healthy diet, no dietary needed. N-3 polyunsaturated fatty acid (PUFA) consumption mainly from oily sh, is potentially associated with bene cial effects on cardiac risk factors, notably reduction in triglycerides but not all trials have shown randomized, controlled reductions current recommendations are to increase PUFA intake through sh consumption, rather than from supplements. Recently, the largest study ever conducted with a so-called Mediterranean diet, supplemented with extra-virgin olive oil or supplements are in CV events Thus https://www.textbookofcardiology.org/wiki/Atherosclerosis 17/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology nuts, incidence of major cardiovascular events in patients at high risk of CV events but without prior CV disease.[1] reduced the The following activities have similar benefits to health: Activity Duration Washing and waxing a car 45-60 minutes Washing windows or floors 45-60 minutes Alcohol consumption Playing volleyball 45 minutes Alcohol is harmful when used chronic or excessive and can lead to various complications such as liver and heart failure, increased cancer risk, neurological complications and injuries. However despite effects, these moderate drinking (US parameters; women: <2 drinks per day, men: <3 drinks per day) may to have protective benefits with regards coronary heart disease according to several prospective cohort studies. These studies showed that moderate drinking resulted in a reduction of risk in coronary heart disease by 40-70% compared to no or heavy drinkers. This beneficial effect was seen in various groups without or with known risk for coronary heart disease and adults older than 65 years old. In a meta-analysis study, alcohol drinkers had lower relative risk for CVD mortality (0.75, 95% CI 0.70-0.80), coronary heart disease mortality (0.75, 0.68-0.81) and incidence of coronary heart disease (0.71, 0.66-0.77) than nondrinkers. Wheeling self in wheelchair 30-40 minutes Bicycling - 8 km 30 minutes Pushing a pushchair - 2.5 km 30 minutes adverse Walking - 3 km 30 minutes Swimming laps 20 minutes Playing basketball 15-20 minutes Psychosocial factors Mentioned by INTERHEART study, psychosocial factors may directly contribute to the early development of atherosclerosis. Psychological stress may directly damage endothelium and indirectly aggravate other common risk factors such as smoking, dyslipidemia and hypertension. Due to the difficulty in quantifying the extent of atherosclerosis, studies showing the relationship between stress and atherosclerosis have been limited. Epidemiologic studies have shown stronger link between psychosocial factors (loss of job, depression and bereavement) and MI and sudden death. Estrogen Status Women and men have different risk for cardiovascular diseases throughout life. For example, at young age, men have an estimated four- to fivefold higher risk than women. However this difference diminishes and the age point of no difference is strongly related to the moment of menopause. From this observation, it has been suggested that estrogen may play athero-protective roles, since the levels of estrogen declines after menopause. In premenopausal women, estrogen raises HDL levels and reduces LDL levels in blood. Estrogen can even exhibit antioxidant and antithrombotic properties and can improve endothelium-dependent vasodilatation. In the past, hormone replacement therapy has been suggested by several studies due to the findings of potential athero-protective roles of estrogen. However, these findings were not confirmed in the randomized primary prevention study of the Women s Health Initiative not in the HERS trial of secondary prevention. These studies showed that hormone replacement therapy (estrogen-progestin https://www.textbookofcardiology.org/wiki/Atherosclerosis 18/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology replacement) may increase cardiovascular risk in women and have no cardioprotective effect. Thus hormone replacement therapy is currently not recommended for reducing cardiovascular risk, due to its possible harmfulness consequences according to current clinical trials. Biomarkers Biomarkers can serve to identify patients with subclinical atherosclerotic disease that are at risk of developing cardiovascular events. Homocysteine Homocysteine is an intermediary amino acid produced during the conversion of methionine to cysteine. A significant positive correlation was found between the serum levels of homocysteine and the incidence of cardiovascular diseases. Although the clear mechanism of this correlation is undetermined, the overall result of the most current evidence suggests that homocysteine can modestly contribute to cardiovascular risk by inducing vascular injury. Homocysteine promotes oxidative stress, intimal thickening, disruption of elastic lamina, hypertrophy of smooth muscle cells, vascular inflammation platelet accumulation and production of occlusive thrombi when elevated in blood. Several conditions can cause hyperhomocystinemia, such as genetic defects in methionine metabolism or insufficient consumption of folic acid, which is involved in the methionine pathway. Such disorders cause premature and severe atherosclerosis. Despite this observational relationship, there is no data yet that proves reducing high serum level of homocysteine will lead to a decrease in atherosclerosis or its complications. Lipoprotein A Some studies have concluded that lipoprotein (a) is an independent risk factor for coronary artery disease. As lipoprotein (a) contains apo (a), which structurally resembles plasminogen, lipoprotein (a) interferes with fibrinolysis by competing with plasminogen binding with molecules. This leads to impairment of plasminogen activation, plasmin generation and lysis of fibrin clots. In addition, lipoprotein (a) binds with macrophages through a high-affinity receptor, promoting foam cell production and deposition of cholesterol in atherosclerotic plaques. As with homocysteine, not all studies support this theory of correlation, although increased risk of cardiovascular events appear to correlate with people with highest lipoprotein (a) serum level. C-Reactive Protein and other markers of inflammation Since the participation of inflammatory cells and mediators in atherosclerosis is well established, markers of inflammation have received a lot of attention. Several markers of inflammation such as C- reactive protein (CRP), fibrinogen and amyloid A are produced by hepatocytes in an acute phase under the influence of cytokines such as IL-6 when they mobilize from intima to the liver during the fatty streak stage. From these markers, CRP has shown the greatest association with atherosclerosis as a marker of low-grade systemic inflammation. A significant association between elevated CRP level in blood and prevalence of atherosclerosis has been shown in more than 30 epidemiologic studies. Different studies showed that higher basal CRP levels (four-fold higher) were found in patients with MI as compared to controls. Several studies have proposed that elevated plasma CRP can be an independent predictor for many cardiovascular diseases based on the result that CRP plasma value was able to predict the long-term risk of first MI, ischemic stroke or peripheral vascular disease among the male group. In addition, recent studies have shown that CRP also has a role as a mediator in atherogenesis. By inducing https://www.textbookofcardiology.org/wiki/Atherosclerosis 19/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology adhesion molecule expression and release of IL-6 and monocyte chemoattractant protein-1 via endothelial cells, CRP sustains the inflammatory state of atherosclerosis by recruiting monocytes and lymphocytes. Infection A variety of infectious agents such as Chlamydia pneumonia, cytomegalovirus and Helicobacter pylori were identified in the lesions of atherosclerosis and this observation raised the suggestion that these infectious agents may contribute to atherogenesis. However, to date, the definite proof of this theory is lacking and also there haven t been any clinical studies that showed significant relationship between the antibiotic treatment against these infectious agents and the risk of cardiac events of the survivors of acute coronary syndromes. Chlamydia is a strong candidate among other infectious agents, since they produce heat shock protein 60 (HSP-60) that activates macrophages and stimulates the production of matrix metalloproteinases. Furthermore, HDP-60 can also stimulate foam cell formation, lipoprotein oxidation, and increased pro-coagulant activity, which are the major attributing components of atherosclerosis. Although there is no evidence to date, some researchers believe that exogenous pathogens can cause endothelial injury and inflammation that can lead to initiation or exacerbation of atherosclerosis. Co-morbidity groups Hypertension Hypertension is defined as a systolic blood pressure (SBP) 140mmHg and/or a diastolic blood pressure (DBP) 90mmHg. Elevated blood pressure is a well established risk factor for atherosclerosis, including mortality from coronary heart disease and stroke. For example, cardiovascular disease doubles with every 20 mmHg increase in SBP or every 10 mmHg increase in DBP. One of the mechanisms of hypertension contributing to atherosclerosis is injury of vascular endothelium by elevated hemodynamic stress. Injury of endothelium may increase the permeability of the vessel wall to lipoproteins. Increased blood pressure may also increase the number of scavenger receptors on macrophages, which enhances the development of foam cells. Furthermore, increased cyclic circumferential strain in hypertensive arteries can result into promoting LDL accumulation in the intima and facilitation of their oxidative modification. Finally, hypertension can contribute to atherogenesis due to the presence of Angiotensin II, which not only works as a vasoconstrictor, but also as a pro- inflammatory cytokine. Antihypertensive therapy Figure 16. Lifestyle recommendations for hypertension can Antihypertensive lifestyle consist either or interventions pharmacotherapy. Lifestyle modifications consist of diet, body weight reduction, increased of activity, therapy of Weight reduction in overweight individuals Reduction of salt consumption to < 6g daily Restriction of alcohol intake to < 10-30g/day (men) and < 10-20g/day (women) Regular physical activity Smoking cessation and cessation https://www.textbookofcardiology.org/wiki/Atherosclerosis 20/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology smoking. As for diet, high consumption of fruits, vegetables, dairy products low in fat, fish oils, potassium and reduced consumption of sodium and alcohol are recommended. The indication for pharmacotherapy depends on the severity of hypertension and on the assessment of total CVD risk. Several large trials have shown that pharmacotherapy for hypertension can substantially reduce major cardiovascular events such as MI and stroke. Drug therapy is indicated when chronic SBP 160mmHg and/or DBP 100mmHg, or if target organ damage is present. Diabetes Mellitus With estimated global incidence of 170 million people, diabetes mellitus is a large problem worldwide. Diabetes mellitus increases the risk of acute coronary events by three- to five folds and 80% of diabetic patients will face atherosclerosis-related cardiovascular diseases. Risk for atherosclerosis among diabetics is considered to be as high as in patients with previous MI. Based on this observation, the National Cholesterol Education Program report from the United States and guidelines from Europe considers type 2 diabetes to be a CHD equivalent, categorizing it to the highest risk for MI. There are several possible mechanisms that make this group particularly vulnerable to atherosclerosis. An example of mechanism is non-enzymatic glycation of lipoproteins, which promotes uptake of cholesterol by scavenger macrophages. Furthermore, pro-thrombotic and anti-fibrinolytic properties of diabetes can also contribute to this vulnerability. The high prevalence of endothelial dysfunction among diabetes group leads to reduced bioavailability of NO and enhanced leukocyte adhesion. The most effective prevention of atherosclerosis among diabetes group is tight regulation of serum glucose levels. This intervention significantly reduces the risk of microvascular complications such as retinopathy and nephropathy. Furthermore, intense anti-diabetic regime also reduced macrovascular outcomes such as MI and stroke among a group of diabetes type 1. Additionally managing hypertension and dyslipidemia among diabetic groups also significantly reduces the risk of cardiovascular diseases. References 1. Estruch R, Ros E, and Mart nez-Gonz lez MA. Mediterranean diet for primary prevention of cardiovascular disease. N Engl J Med. 2013 Aug 15;369(7):676-7. DOI:10.1056/NEJMc1306659 | 2. Anderson J.L., Carlquist J.F., Muhlestein J.B., et al. 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Fruit and vegetable consumption and risk of stroke: a meta- analysis of cohort studies. Neurology 2005; 65:1193. 12. De Backer G., Ambrosioni E., Borch-Johnsen K., et al. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2003; 10:S1. 13. Downs J.R., Clearfield M., Weis S., Whitney E., Shapiro D.R., Beere P.A., Langendorfer A., Stein EA, Kruyer W, Gotto AM Jr. "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study." JAMA. 1998;279(20):1615. 14. Eckel R.H., York D.A., R ssner S., et al. Prevention Conference VII: Obesity, a worldwide epidemic related to heart disease and stroke: executive summary. 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Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229. 20. Howard G., Wagenknecht L.E., Burke G.L., Diez-Roux A., Evans G.W., McGovern P., Nieto F.J., Tell in G.S. "Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk Communities (ARIC) Study." JAMA. 1998;279(2):119. 21. Jackson R., Scragg R., Beaglehole R. Alcohol consumption and risk of coronary heart disease. BMJ 1991; 303:211. 22. Jee S.H., Suh I., Kim I.S., Appel L.J. "Smoking and atherosclerotic cardiovascular disease in men with low levels of serum cholesterol: the Korea Medical Insurance Corporation Study." JAMA. 1999;282(22):2149. 23. Kannel W.B., D'Agostino R.B., Belanger A.J. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham Study. Am Heart J 1987; 113:1006. 24. Klein S., Burke L.E., Bray G.A., et al. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 2004; 110:2952. 25. Knoops K.T., de Groot L.C., Kromhout D., et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 2004; 292:1433. 26. Kwaliteitsinstituut voor de gezondheidszorg CBO and Nederlandse Huisartsen Genootschap. (2006). Multidisciplinaire richtlijn cardiovasculair risicomanagement 2006. Alphen aan den Rijn: Van Zuiden Communications. 27. Lilly L.S. (ed.). (2007). Pathophysiology of Heart Disease. Baltimore: Lippincott Williams & Wilkins, p. 118 140. https://www.textbookofcardiology.org/wiki/Atherosclerosis 23/26 7/4/23, 12:20 AM Atherosclerosis - Textbook of Cardiology 28. Lilly L.S. (ed.). (2007). Pathophysiology of Heart Disease. Baltimore: Lippincott Williams & Wilkins, p. 118 140. 29. Nordmann A.J., Suter-Zimmermann K., Bucher H.C., et al. Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors. Am J Med 2011; 124:841. 30. Mancia G., Messerli F., Bakris G., et al. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension 2007; 50:299. 31. McCully K.S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56:111. 32. Mendis S., Puska P., Norrving B. (eds.). (2011). Global Atlas on Cardiovascular Disease Prevention and Control. Geneva: World Health Organization.