Current Status of Primary, Secondary, and Tertiary Prevention of Coronary Artery Disease

Abstract

Fifty percent of all death from cardiovascular diseases is due to coronary artery disease (CAD). This is avoidable if early identification is made. Preventive health care has a major role in the fight against CAD. Atherosclerosis and atherosclerotic plaque rupture are involved in the development of CAD. Modifiable risk factors for CAD are dyslipidemia, diabetes, hypertension, cigarette smoking, obesity, chronic renal disease, chronic infection, high C-reactive protein, and hyperhomocysteinemia. CAD can be prevented by modification of risk factors. This paper defines the primary, secondary, and tertiary prevention of CAD. It discusses the mechanism of risk factor–induced atherosclerosis. This paper describes the CAD risk score and its use in the selection of individuals for primary prevention of CAD. Guidelines for primary, secondary, and tertiary prevention of CAD have been described. Modification of risk factors and use of guidelines for prevention of CAD would prevent, regress, and slow down the progression of CAD, improve the quality of life of patient, and reduce the health care cost.

Coronary artery disease (CAD) is due to atherosclerosis in the coronary artery. Progression of atherosclerosis and rupture of atherosclerotic plaques produce occlusion of the coronary arteries which manifest in clinical syndrome, such as stable angina and acute coronary syndrome, including ST-segment-elevated myocardial infarction (STEMI) and non-ST-segment-elevated myocardial infarction (NSTEMI). ¹ Risk factors for CAD include nonmodifiable and modifiable. Nonmodifiable risk factors ² include age, gender, race, and genes. Modifiable risk factors include dyslipidemia, ^{3 4} diabetes, ^{5 6} hypertension, ^{7 8} cigarette smoking, ^{9 10} obesity, ¹¹ chronic renal disease, ¹² chronic infection, ¹³ C-reactive protein (CRP), ¹⁴ hyperhomocysteinemia (HHcy), ¹⁵ advanced glycation end products (AGE)–receptor for AGE (RAGE) stress, ^{16 17 18} oxidative stress, ^{19 20 21} and caffeine. ²² Modification of risk factors can prevent, regress, and slow the progression of CAD and improve the quality of life of patients. The prevention of CAD has been divided into three categories: primary, secondary, and tertiary. Primary prevention is for the people with risk factors but have not developed clinical manifestation of CAD. This is the prevention of CAD before it occurs. Secondary prevention is for people with established CAD. Tertiary prevention is to soften the impact of CAD. The objective in this case is to improve the quality of life by reducing disability, delaying complications, and restoring cardiac function. This paper provides a brief review of the modifiable risk factors and their mechanisms of induction of atherosclerosis, and measures for primary, secondary, and tertiary prevention of CAD. These measures would prevent, regress, and slow the progression of CAD, improve quality of life of patients, and reduce health care cost.

Mechanisms of Modifiable Risk Factors–Induced Atherosclerosis

Dyslipidemia

Hypercholesterolemia (Total Cholesterol)

Hypercholesterolemia-induced atherosclerosis has been reported to be associated with an increase in the levels of reactive oxygen species (ROS) in blood and aortic tissue. ^{4 19 20 23 24} Hypercholesterolemia induces atherosclerosis through generation of ROS in various ways. It increases the synthesis and release of platelet-activating factor (PAF) which in turn would increase the synthesis and release of interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Hypercholesterolemia increases the synthesis and release of PAF ^{22 25} and arachidonic acid. ²² The intermediate steps in the biosynthesis of prostaglandin and leukotrienes generate ROS and leukotriene B ₄ from leukotrienes. ²² PAF increases the release of IL-1 ²⁶ and TNF-α. ²⁷ Hypercholesterolemia activates complement C ₃ and C ₅ (C3a and C5a). ²⁸ It increases production of superoxide anion in endothelial cells. ²⁹ Leukotriene B ₄ (LTB ₄ ), ³⁰ PAF, ³¹ IL-1, ³² and TNF-α ³³ are known to stimulate polymorphonuclear leucocyte to generate ROS. ROS and cytokines increase the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin. ³⁴ ROS have been shown to be involved in the development of atherosclerosis. ^{4 20 21 35}

Low–Density Lipoprotein–Cholesterol

According to oxidative hypothesis ^{21 22 36} low-density lipoprotein (LDL) is mildly oxidized to yield minimally modified LDL (MM-LDL). This is further oxidized to form maximally oxidized LDL (OX-LDL). MM-LDL and OX-LDL are involved in the initiation of development of atherosclerosis. MM-LDL stimulates smooth muscle cells and endothelial cells of blood vessels to produce monocyte chemoattractant protein-1 (MCP-1) which helps in the migration of monocytes from the endothelial surface to subendothelial space. Monocytes/macrophages have LDL receptor which can combine with native LDL but the amount of LDL is not enough to produce foam cells. However, OX-LDL is ligand for scavenger receptor developed in tissue macrophages and monocyte. MM-LDL stimulates the endothelial cells to produce monocyte colony stimulating factor (MC-SF) which enhances monocyte/macrophage differentiation. Differentiated tissue macrophage has receptor for OX-LDL to produce foam cells which is a major component of fatty streak. It is the initial stage of atherosclerosis. Macrophages produce several growth stimulating factors. ²² Fatty streaks develop into full-flagged atherosclerosis which progresses to give rise to atherosclerotic plaques. Plasma concentration of OX-LDL is associated with risk of acute CAD events. ³⁷

Triglycerides

There are numerous postulated mechanisms by which triglycerides (TG) may contribute to atherosclerosis and CAD. First, TG increases production of ROS and secretion of TNF-α and IL-1β ^{38 39} which are involved in atherosclerosis. Second, TG induces production of cytokines (TNF-α), IL-1, IL-6, IL-8, ICAM-1, and VCAM-1 which are involved in the development of atherosclerosis. ^{40 41 42} Third high levels of TG are associated with low levels of high-density lipoprotein–cholesterol (HDL-C) and presence of small dense LDL-C ⁴³ which are atherogenic.

High-Density Lipoprotein–Cholesterol

HDL-C, the so-called good cholesterol, has numerous antiatherosclerotic actions. HDL-C increases the production of atheroprotective signaling molecule of nitric oxide. ⁴⁴ It inhibits expression of cell adhesion molecules. ^{45 46} It has antioxidant activity ⁴⁷ and inhibits oxidation of LDL-C. ⁴⁸ HDL-C has reverse cholesterol transport function, that is, it carries bad cholesterol (LDL-C) from arteries including atherosclerotic plaques to liver, where it will be redistributed to other tissue or removed from the body by gall bladder. ⁴⁹ MCP-1 production is reduced by HDL-C. ⁵⁰ It is known that HDL-C neutralizes the proinflammatory activity of CRP. ⁵¹ HDL-C is inversely correlated with TG. ⁴¹ These data suggest that the antiatherogenic effect of HDL-C is because of reduction in cell adhesion molecules, MCP-1 production and LDL-oxidation, antioxidant activity, neutralization of proinflammatory effects of CRP, and its reverse cholesterol transport function. In conclusion, low serum levels of HDL-C is atherogenic.

Diabetes

AGE–RAGE stress, oxidative stress, and protein kinase-C are probably the main causes of atherosclerosis in diabetes. The levels of AGE, RAGE, and soluble RAGE (sRAGE) are elevated in diabetes. ^{52 53} The elevation AGE is greater than sRAGE in diabetes. The mechanism of AGE–RAGE stress-induced atherosclerosis will be described in the section on “AGE–RAGE stress” below. Oxidative stress is elevated due to glucose autooxidation, increased AGE–RAGE stress, and activated protein kinase-C. ⁵⁴ ROS levels are elevated in diabetes. ^{55 56} The main sources of ROS in diabetes are mitochondria. ⁵⁷ ROS have been implicated in the development of atherosclerosis. ^{4 20 21 35} The mechanism of oxidative stress–induced atherosclerosis is described below on the section on “oxidative stress.”

AGE–RAGE Stress

AGE–RAGE stress has been defined as a shift in the balance between stressors (AGE and RAGE) and antistressors (sRAGE) in favor of stressors. ¹⁷ AGE acts as atherogenic agent in two ways, directly and by interaction with RAGE. LDL-C is glycated by AGE. ⁵⁸ Glycated LDL-C is more sensitive to oxidation, ⁵⁷ increases the smooth muscle cell proliferation and differentiation, ⁵⁹ and decreases its recognition by LDL-C receptors. ⁶⁰ AGE interferes with HDL-C-mediated reverse cholesterol transport. ⁶¹ Interaction of AGE with RAGE generates ROS ⁶² which through activation of nuclear factor kappa B (NF- k B) activates numerous inflammatory genes, such as TNF-α, TNF-β, IL-1 (IL-1, IL-6, and LL-8), ^{62 63} AGE–RAGE interaction enhances the expression of cell-adhesion molecules (ICAM-1, VCAM-1, and E-selectin), ^{62 63 64} MCP-1, ⁶⁵ GM-CF, ⁶⁶ and transforming growth factor. ⁶⁷

Oxidative Stress

Oxidative stress is defined as a shift in the balance between the generation of ROS and antioxidants in the body in favor of generation of ROS. ROS through various mechanisms induce atherosclerosis. It oxidizes LDL-C to form MM-LDL and OX-LDL. ⁶⁸ ROS activates NF- k B which in turn increases the expression of VCAM-1 and MCP-1in human aortic endothelial cells. ⁶⁹ It also increases the expression of VCAM-1 ⁷⁰ and GM-CSF (granulocyte macrophage colony-stimulating factor). ⁷¹ OX-LDL, MM-LDL, NF- k B, MCP-1, and VCAM-1 are involved in the development of atherosclerosis as described earlier. Mechanisms of oxidative stress-induced atherosclerosis have been described in detail by Yang et al. ²¹ The data suggest that ROS through various mechanisms induce atherosclerosis.

Hypertension

Oxidative stress ^{72 73 74} and AGE–RAGE stress ⁷⁵ have been implicated in hypertension. Hypertension is associated with elevation of serum levels of ROS. ⁷⁶ There is an increase in the ROS producing activity of PMNLs (polymorphonuclear leucocytes) and a decrease in the levels of antioxidant enzymes in patients with essential hypertension. ⁷⁷ Serum levels of AGE ⁷⁸ are elevated while the levels of sRAGE ⁷⁹ are reduced in patients with hypertension. Levels of cell adhesion molecules are elevated in hypertensive patients. ⁸⁰ Serum levels of GM-CSF and MCP-1 ⁸¹ and proinflammatory cytokines ⁸² are elevated in hypertensive patients. These data suggest that hypertension could induce and accelerate atherosclerosis.

Cigarette Smoking

Cigarette smoking is involved in development and progression of atherosclerosis. ^{9 10} There are numerous factors that can lead to the development of atherosclerosis in cigarette smokers. Cigarette smokers have significantly higher levels of serum cholesterol, TG and LDL-C, and lower levels of serum HDL-C than nonsmokers. ⁸³ The levels of VCAM-1, ICAM-1, and E-selectin are elevated in cigarette smokers. ^{84 85} Cigarette smoking is associated with increased levels of CRP, IL-6, and TNF-α. ^{84 86 87} OX-LDL levels are elevated in cigarette smokers. ⁸⁸ Kalra et al ⁸⁹ have reported that cigarette smoking increases production of ROS from PMNLs. Cigarette smoking increases the serum levels of AGE and decreases the serum levels of sRAGE ⁹⁰ and thus increases the AGE–RAGE stress. ¹⁷ Expression of MCP-1 is elevated in smokers. ⁹¹

Obesity

Obesity is a major risk factor for atherosclerosis and is associated with hypertension, hyperinsulinemia, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and reduced HDL-C concentration. ^{92 93} The mechanisms by which hypertension, hypercholesterolemia, hypertriglyceridemia, hyperglycemia (diabetes), and low HDL-C produce atherosclerosis have been described above in this section. Proinflammatory cytokines ⁹⁴ and GM-CSF ⁹⁵ are elevated in obesity. The plasma levels of MCP-1 is elevated in obese adults as compared with lean control patients. ⁹⁶ Individuals with metabolically healthy obesity have higher sICAM-1 (soluble intracellular adhesion molecule-1), E-selectin, and P-selectin compared with metabolically healthy lean patients. ⁹⁷ The levels of these cell adhesion molecules are lower in insulin sensitive compared with insulin resistant metabolically healthy obese patients. Oxidative stress is markedly elevated in obesity. ⁹⁸ AGE formation is markedly increased in hyperglycemia ^{99 100} and can produce atherosclerosis.

C-Reactive Protein

CRP is an independent risk factor of atherosclerosis. ¹⁰¹ It induces atherosclerosis through various mechanisms described here. It mediates uptake of OX-LDL by macrophages ¹⁰² and induces inflammatory cytokines. ^{103 104} CRP induces generation and secretion of MCP-1 ¹⁰⁵ and increases the expression of cell adhesion molecules in human endothelial cells. ¹⁰⁶ Both CRP and E-selectin are elevated in carotid artery atherosclerosis. ¹⁰⁷ Most importantly, CRP increases the generation of ROS from white blood cells. ¹⁴

Hyperhomocysteinemia (HHcy)

HHcy promotes atherosclerosis through impaired endothelial function and increased oxidative stress. ¹⁰⁸ It increases oxidative stress through various mechasnisms. ^{14 109 110} Homocysteinemia increases the mRNA levels VCAM-1, E-selectin and P-selectin, ^{111 112} and expression of MCP-1. ¹¹³ It has been reported that HHcy increases the mRNA levels of oxidized LDL receptor (LOX-1) in mononuclear cells. ¹¹⁴ These attributes of HHcy would induce and accelerate atherosclerosis.

Infection

Chlamydia pneumonia , Porphyromonas gingivalis , Helicobacter pylori , influenza A virus, and hepatitis C virus have been linked to atherosclerosis. Lipopolysaccharides from P. gingivalis increases the expression of GM-CSF, IL-1b, IL-10, and IL-12 in both macrophages and foam cell. ¹¹⁵ Infection with C-pneumonia is associated with increased levels of TG, total cholesterol (TC), LDL-C, and decreased concentration of HDL-C. ^{116 117} C-pneumonia induces generation of IL-1, IL-6, and TNF-α in mononuclear leucocytes. ¹¹⁸ ROS production is increased in inflammation. ^{22 119} OX-LDL levels are increased in chronic infection. ¹²⁰ Multiple infections upgrades the expression of cell adhesion molecules. ¹²¹ C-pneumonia increases the expression of receptor for OX-LDL(LOX-1). ^{122 123} The data suggest that infection can produce atherosclerosis through numerous mechanisms described above.

Alcohol

Epidemiological data suggest an inverse correlation between moderate alcohol consumption and CAD. Heavy consumption of alcohol, however, induces atherosclerosis through numerous mechanisms. Alcohol consumption increases plasma levels of TG. ¹²⁴ The levels of TC, HDL-C, and ratio of LDL-C-to-HDL-C are elevated in heavy alcohol drinker. ¹²⁵ There are various sources of ROS from alcohol consumption. ^{126 127 128}

Coffee

The role of coffee consumption in atherosclerosis is very controversial. Some effects of coffee suggest that it could induce atherosclerosis, but other effects of coffee suggest that it may have protective effects against atherosclerosis. Consumption of unfiltered coffee increases the serum levels of TC, LDL-C, and TG, and the increases are related to the levels of consumption. ¹²⁹ Consumption of unfiltered coffee significantly increases of serum LDL-C and reduces the serum levels of TGs. ¹³⁰ Moderate consumption of paper-filtered coffee increases serum levels of TC, LDL-C, and E-selectin but did not significantly change the serum levels of hs-CRP (high sensitivity- C-reactive protein), IL-1β, IL-6, TNF-α, sVCAM-1, and sICAM-1. ¹³¹ Consumption of filtered coffee increases the serum levels of HDL-C. ¹³² Caffeine progressively induces hypertension. ¹³³ It acts as an antioxidant by increasing activity of antioxidant enzymes. ¹³⁴

Prevention of Coronary Artery Disease

Primary Prevention of Coronary Artery Disease

Primary prevention is the earliest possible intervention to thwart CAD before it begins, that is use of measures to prevent the initiation of atherosclerosis. Initial information is required to assess if the patients fall in the category of primary prevention. Lifestyle information, such as smoking status, levels of physical activity, use of alcohol, body mass index (BMI), family history, blood pressure, waist circumference, and lipid measurement, in individuals should be known along with hypertension, obesity, and diabetes. Age information is also important. Individuals between the age group of 40 and 49 years, metabolic risk factors (hypertension, diabetes, and dyslipidemia) are more prevalent. In middle-aged women, premature menopause becomes an additional risk factor. Population over 70 years of age forms the largest proportion of high-risk individuals. A CAD risk score has been developed by American College of Cardiology ASCVD risk estimator. ¹³⁵ This risk score is similar to that ACC/AHA2019 risk score developed by Arnett et al. ¹³⁵ CAD risk score which takes into consideration the age, sex, race, cholesterol levels, blood pressure, diabetes, smoking, and use of medicine is an estimation of 10-year risk of having CAD or stroke. CAD risk score is expressed as percentage: 0.0 to 4.9% risk is considered as low, 5.0 to 7.4% is considered as borderline, 7.5 to 20.0% is considered as intermediate, and >20.0 is considered as high risk. CAD risk score should be used for selecting individuals for primary prevention.

Recently primary-prevention guidelines for CAD have been provided by Arnett et al. ¹³⁵ These guidelines include the following:

• Team-based approach.

• Adults between 40 and 75 years of age should undergo 10-year atherosclerotic cardiovascular disease risk assessment before pharmaceutical therapy, such as antihypertensive therapy, statin, aspirin, and coronary artery calcium scanning, in selected individuals should be started. Adults should consume healthy diets such as fruits, vegetables, nuts, whole grain, lean vegetables, or animal protein and fish. Consumption of transfat, red meat, processed meat, added sugars, saturated fat, sweetened beverages, and sodium should be reduced. Obese people should be advised to restrict caloric diet to maintain reduced weight.

• People should perform 150 minutes/week of moderate intensity physical activity or 75 minutes/week of high intensity physical activity.

• Tobacco use should be stopped. Cigarette smokers should be encouraged/assisted in quitting smoking.

• Infrequent use of aspirin.

• Control diet, exercise, and medicine if needed should be advised to diabetic patients.

• Statin should be used if serum LDL-C levels are ≥190 mg/dL and the individual is diabetics and has sufficient risk for CAD.

• Nonpharmacological intervention for adults with elevated blood pressure or hypertension is advised. Pharmacological therapy for hypertensive patients with a target of less than 130/80 is recommended.

Since there are numerous atherogenic factors, one should also consider the following interventions:

• Consumption of food containing high cholesterol (sausage, bacon, red meat, kidney liver, coconut oil, full fat dairy products, and palm oil) should be restricted. Food such as flaxseed that lowers the serum levels of TC and LDL-C and raises the levels of HDL-C should be advised. ¹³⁷ Use of whey protein that lowers TC and LDL-C should be useful. Use of grapefruit which contains resveratrol should be advised. Resveratrol reduces the serum levels of TC and LDL-C, raises HDL-C levels, inhibits expression of CRP, and lowers serum levels of AGE. ¹³⁶ Some foods (bean and legumes, whole grain, high fiber fruit, nuts, and chia seeds) that raise the serum levels of HDL-C ¹³⁷ should be recommended in the guideline for primary prevention of CAD.

• Since AGE–RAGE is a risk factor for atherosclerosis, the levels of AGE in the body should be reduced. The levels of AGE in the body can be lowered by reduction in AGE intake. Foods such as red meat, cheese, cream, animal fat, sweetened pastry are rich in AGE content. ^{138 139 140} The consumption of these foods should be reduced. Individuals should be advised to cook food at low temperature in moist heat for short duration. ¹³⁹ Cooking at high temperature in dry heat (frying, broiling, grilling, and/or roasting) increases the AGE formation more than cooking in moist heat (poaching, stewing, and/or boiling). ¹³⁸

• Oxidative stress should be reduced with nutritional and psychosocial interventions. ¹⁴¹ Consumption of foods (flaxseed, fruits, and vegetables) that have antioxidant activity ^{136 142} should be advised. People should be advised not to indulge in heavy alcohol drinking because it causes atherosclerosis.

Secondary Prevention of Coronary Artery Disease

Secondary prevention is a therapeutic measure to prevent further progression of the disease, and damage after the diagnosis of CAD has been made. Its main focus is on the reduction of the impact of disease by early diagnosis before critical and permanent damage have occurred. Secondary prevention slows the progression of the disease or regress it. The question arises as to who are the people that qualify for secondary prevention. The people who have current symptoms of CAD, had heart attack, and had received percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) qualify for secondary prevention of CAD. The objectives are to slow the progression of CAD, regress CAD, and reduce the risk of repeat events or death. The measures should be taken to prevent cardiovascular symptoms, cardiac damage, and acute coronary symptoms which if occur, it is too late for secondary prevention. Secondary prevention apply to the people without established disease if 10-year risk score is >20%. The guidelines for secondary prevention are as described by Smith et al, ¹⁴³ Hall and Lorenc, ¹⁴⁴ Jankowski et al, ¹⁴⁵ and Jones et al ¹⁴⁶ with some modifications. The guidelines are based on lifestyles and risk factor modification. It is briefed hereinafter:

1. Lifestyle modification

   1. Diet: the diets for secondary prevention are similar to that for primary and tertiary prevention of CAD and have been described in the section on primary prevention of CAD.

   2. Body weight: the body weight for obese people should be reduced by 3 to 10% using caloric restriction and physical activity. BMI should be targeted at 18.5 to 24.9 kg/m ² . Waist circumference for men should be targeted at <40 inches for men and <35 inches for women. However, this does not apply for people from China, South Asia, and Japan.

   3. Physical activity: at least 150 minutes/week of moderate intensity physical activity or 75 minutes/week of high intensity physical activity should be performed. Other recommendation is moderate-to-vigorous exercise for 150 minutes/week (30 minutes, five sessions/week). European target goal for physical activity is 30 minutes, three to five times weekly. Other recommendation is to walk at least 10,000 steps a day.

2. Serum lipids: statin, PCSK9 (proprotein convertase subtilsin/ kexin type 9) inhibitor (evolocumab) should be used to lower serum LDL-C. Fibrate or high dose of omega-3 fatty acid should be used if TG level is ≥500 mg/dL or non–HDL-C level is ≥100 mg/dL. ¹⁴⁴ The patients with low serum HDL-C should be treated with statin, and flaxseed, and its components. ¹⁴⁷ Target goals for TC, LDL-C, TG, and HDL-C are <190, <115, TG <150, and >40 mg/dL according to old European target guideline. The latest European guideline target for LDL-C is <55 mg/dL for very high risk, and <40 mg/dL for the highest risk group patients with multiple events. ¹⁴⁸ According to Hall and Lorenc, ¹⁴⁴ the target goal for LDL-C should be less than 100 mg/dL with an optimal goal of <70 mg/dL. The patients with low HDL-C should be treated with statin, flaxseed, and its components.

3. Hypertension: the patients with hypertension should be treated with antihypertensive drugs such as angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), calcium channel blocker, and β-blocker. Restriction on sodium intake and alcohol consumption should be applied. Blood pressure target goal should be 130/80 mm Hg.

4. Cigarette/tobacco: cigarette smoking should be stopped. Patient should be helped in quitting smoking.

5. Antiplatelet drugs should be used if 10-year risk score is ≥10%. Aspirin (81–162 mg/day) or clopidogrel should be used to prevent clotting.

6. Diabetes: there should be normalization of blood glucose with the use of antidiabetic drugs. The target goal for HbA1c should be <7%. The target for blood glucose should be fasting (4–7 mmol/L), 2 hours after meal (5–10 mmol/L), and at bedtime (5–10 mmol/L). Treatment for hypertension and elevated serum cholesterol is advised. End-organ damage from diabetes should be kept in mind.

7. AGE–RAGE stress: The AGE–RAGE stress should be reduced by lowering the levels of AGE and increasing the levels of sRAGE in the body. Serum levels of AGE can be lowered by reducing the dietary intake of AGE and prevention of AGE formation. Reduction in dietary intake of AGE has been already described in the section of primary prevention of CAD. Cigarette smoking increases the serum levels of AGE. ⁹⁰ AGE levels can be reduced by stopping cigarette smoking, and regular moderate exercise and long runs. ^{149 150} Prevention of AGE formation by consuming acidic ingredients such as lemon juice and vinegar, ¹⁵¹ and consumption of linolenic acid and flaxseed, ¹⁵² and vitamins (C, D, and E) ¹⁵³ would also reduce the serum levels of AGE. Elevation of serum sRAGE can be achieved by upregulation of expression of sRAGE with statins, ^{154 155 156} ACE inhibitors, ¹⁵⁷ and rosiglitazone, ¹⁵⁸ and by exogenous administration of sRAGE if available for human use.

8. Oxidative stress: antioxidants suppress the development of atherosclerosis. ^{159 160} Prasad and Kalra ¹⁹ have reported that vitamin E significantly prevented the development of hypercholesterolemia-induced atherosclerosis and this was associated with decrease in the hypercholesterolemia-induced oxidative stress in rabbits. Clinical trials in human showed positive benefits. ¹⁶¹ However meta-analysis of use of vitamin E in atherosclerosis did not provide any solid evidence. ¹⁶² Supplementation of vitamin C, D, and E separately have divergent outcomes in subclinical atherosclerosis. ¹⁶³ The long-term effect seems to be minimal. ¹⁶³ Failure of benefits of vitamin E in atherosclerosis may be because of inappropriate doses, lack of combination of antioxidants, use of antioxidants in very advanced stage of atherosclerosis and frequency of drug administration. Vitamin E, while scavenging ROS, gets converted into tocopheryl radical which is toxic. Vitamin C regenerates vitamin E from tocopheryl. ¹⁶⁴ Combination of vitamin E and vitamin C, therefore, would have been useful in the treatment of atherosclerosis. Combination of vitamin E and vitamin C slows down the progression of hypercholesterolemic atherosclerosis in human. ¹⁶⁵ Besides vitamin E, other antioxidants such as probucol, ^{20 166 167} garlic, ¹⁶⁸ and flaxseed lignan complex ²⁴ can be used to reduce oxidative stress.

9. C-reactive protein: there are numerous drugs that are known to reduce the serum levels of CRP. Prasad ¹⁶⁹ has reviewed the drugs which reduce the serum levels of CRP. These drugs include aspirin, clopidogrel, statins, β-adrenoreceptor blocker, ACE inhibitors, ARBs (candesartan), rosiglitazone, and vitamin E. CRP lowering effect of statin is greater than its lipid lowering effect. Vitamin C also lowers the levels of CRP. ¹⁷⁰

Tertiary Prevention of Coronary Artery Disease

Tertiary prevention applies to the people with existing CAD. The main objective is to improve the quality of life of these patients by decreasing disability, delaying/limiting complications, restoring cardiac function. All of the above are achieved by treatment of the CAD and rehabilitation. The team of the treatment is comprised of family physician, cardiologist, cardiac surgeon, exercise specialist, physiotherapist, dietitians and nurses. The treatment modalities for tertiary prevention overlap with the treatment modalities of secondary prevention. Treatment for tertiary treatment includes PCI, CABG, pacemaker, defibrillator, and ventricular-assisted device. Attempts should be made for neovascularization of ischemic myocardium. Numerous measures have been attempted for neovascularization of ischemic myocardium. ^{171 172 173 174}

Perspectives

Some of the guidelines for prevention of CAD are very confusing for the clinicians. For example, PCI, CABG, and MI criteria are included in both the secondary and tertiary prevention of CAD which is not correct. This confusion is because of the definition of the three categories of prevention of CAD. Primary prevention is the earliest possible intervention to thwart atherosclerosis/CAD before it begins. Measures should be taken to prevent initiation of atherosclerosis. Secondary prevention is the early detection and stopping of progression of disease. The measures taken should include prevention of symptoms, ventricular dysfunction, and acute coronary syndrome. Tertiary prevention relates to regression, slowing of progression and arresting the diseasing order to prevent recurrent symptoms, further damage, and subsequent events including MI. PCI, CABG, and MI criteria should be in the tertiary prevention. Lifestyle changes, such as modification of diet, physical activity, cessation of cigarette smoking, BMI control, weight control, reduction of AGE–RAGE stress, and oxidative stress, should apply to all three categories of prevention of CAD. There seems to be some overlap between the guidelines of secondary and tertiary prevention.

Some of the drugs used for one disease can have effects on other risk factor for atherosclerosis. For example, statins not only correct dyslipidemia ¹⁴⁷ but also reduce levels of CRP ¹⁶⁹ and upregulate the expression of sRAGE. ^{154 155 156} ACEI not only is useful in hypertension but also lowers the serum levels of CRP ¹⁶⁹ and upregulates the expression of sRAGE. ¹⁵⁷ Similarly, antidiabetics, such as rosiglitazone, reduces the serum levels of CRP ¹⁶⁹ and increases the expression of sRAGE. ¹⁵⁸ In summary, if a person is taking one of these drugs, he/she gets other advantages in preventing CAD.

Conclusion

In conclusion, primary, secondary, and tertiary prevention of CAD would prevent, regress, and slow down the progression of CAD, improve the quality of life of patient, and reduce the health care cost.