Wilu's paper: chapter 4, The correlation between cholesterol and CHD

CHAPTER 4 THE CORRELATION BETWEEN CHOLESTEROL AND CORONARY HEART DISEASE 4.1 The correlations between cholesterol and coronary heart disease Coronary heart disease is usually caused by a condition called atherosclerosis, which occurs when fatty material and a substance called plaque builds up on the walls of your arteries. This causes them to get narrow. As the coronary arteries narrow, blood flow to the heart can slow down or stop, causing chest pain (stable angina), shortness of breath, heart attack, and other symptoms.Plaque is like a firm shell with a soft inner core containing cholesterol. As blood hits it during each heartbeat, the plaque may crack open and expose its inner cholesterol core, which promotes blood clotting. Clots may further reduce blood flow, causing severe pain (angina), or even block it all together. Despite the declining coronary heart disease (CHD) mortality rate, Coronary Heart Disease remains a major cause of premature death and imposes high personal, social and economic costs. Blood cholesterol is an important risk factor for Coronary heart disease but should be considered in the context of other risk factors such as smoking, raised blood pressure and physical inactivity. Blood cholesterol alone is a relatively poor predictor of individual Coronary Heart Disease risk. The majority of Coronary Heart Disease events occur in people with average or low blood cholesterol levels. Cholesterol lowering using statins is effective at reducing Coronary Heart Disease mortality and morbidity. Therapy should be targeted at people who are at high risk of coronary heart disease rather than be based upon cholesterol levels. In asymptomatic people, at low risk of coronary heart disease, the costs of cholesterol lowering using statins are high relative to the benefits and their use is contentious. Cholesterol lowering is one of a number of methods of reducing the risk of cardiovascular disease. Cholesterol plays a central role in many biochemical processes, but is best known for the association of cardiovascular disease with various lipoprotein cholesterol transport patterns and high levels of cholesterol in the blood. The cost-effectiveness of some anti-hypertensives, aspirin and beta-blockers is greater than statins.Greater priority should be given to the appropriate use of other drug treatments and nonpharmacological interventions in the primary and secondary prevention of coronary heart disease. The average level of blood cholesterol within a population an important determinant of the Coronary Heart Disease risk of the population. In countries where the average cholesterol levels of the population are low, Coronary Heart Disease tends to be uncommon. Prospective studies show that groups of individuals with lower levels of cholesterol run less risk of developing Coronary Heart Disease. The association between cholesterol level and future risk Coronary Heart Disease is graded and continuous: there is no threshold above which Coronary Heart Disease risk begins to increase. There has been some concern that low levels of blood cholesterol and triglycerides increase the risk of mortality from causes other than Coronary heart disease, including cancer, respiratory disease, liver disease and accidental/violent death. High blood triglycerides as a Coronary Heart Disease risk factor is a subject that has received some debate. Associated with mild to moderate elevations in plasma triglycerides is the dense (small) LDL subclass pattern, (LDL pattern B), which is a heritable trait determined by a single major dominant gene (the alp locus). Approximately 30-35% of people are heterozygous (one gene pair affected) for alp and another 5% are homozygous (two gene pair affected). 50% of men with heart disease express this trait. This dense LDL subspecies is a marker for a common genetic trait that effects lipoprotein metabolism and increases Coronary Heart disease risk. A gene responsible has been located on chromosome 19, near the genes for the LDL receptor and insulin receptor. Other locations on the human genome have been identified that impact expression of this trait. The LDL pattern B trait is associated with a tendency toward elevated levels of triglyceride, and reduced levels of HDL, however, the LDL pattern B can persist, even when levels of triglyceride and HDL are normal. Many years of scientific investigation at the Lawrence Berkeley Laboratory, and other centers, has elucidated the reasons why the small LDL trait increases heart disease risk so significantly. Lipoproteins can become oxidized which enhances their ability to contribute to atherosclerosis and small LDLs are more susceptible to oxidation than large LDLs. Because of their small size, they weasel their way into the arterial wall more rapidly than larger LDLs. The ability of the blood vessel to respond normally to contraction and relaxation is impaired by the small LDL, and, it also interferes with some aspects of normal blood coagulation. Individuals with small LDLs also tend to have higher blood insulin levels and higher blood pressure. The reverse cholesterol transport system appears to be impaired and is reflected by low HDL and in particular, low HDL. In coronary heart disease regression trials, patients with a predominace of small LDL, and/or a reduction in small LDL have been linked to improvement in blocked arteries. Cholesterol lowering medications and low fat diet, have different effects based on the LDL subclass pattern. Thus, it is important to determine an individuals pattern in order to select the correct treatment. Heart disease is caused by narrowing of the coronary arteries that feed the heart. Like any muscle, the heart needs a constant supply of oxygen and nutrients, which are carried to it by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by cholesterol and fat deposits--a process called atherosclerosis--and cannot supply enough blood to the heart, the result is coronary heart disease (CHD). If not enough oxygen-carrying blood reaches the heart, you may experience chest pain called angina. If the blood supply to a portion of the heart is completely cut off by total blockage of a coronary artery, the result is a heart attack. This is usually due to a sudden closure from a blood clot forming on top of a previous narrowing. Coronary Heart disease which caused by high blood cholesterol may represent as Angina Pectoris. A person who suffers from angina pectoris has coronary arteries that are wide enough to supply blood to the heart during normal activities, but too narrow to deliver sufficient blood and oxygen when extra work is required of the heart. An attack of angina develops when the heart must work harder than normal and the muscle cells that make up the heart do not receive enough oxygen. Angina is typically felt as a heavy, squeezing pain in the center of the chest. The pain may also spread to the neck, jaw, back, and left arm. An attack of angina may last for several minutes and is often brought on by physical activity, emotional stress, cold weather, or digestion of a heavy meal—all factors that can increase the heart’s workload. There are three types of angina : Stable angina, Unstable angina, and Variant angina (coronary spasm) Stable angina: A type of angina brought on by an imbalance between the heart’s need for oxygen-rich blood and the amount available. It is "stable," which means the same activities bring it on; it feels the same way each time; and is relieved by rest and/or oral medications. Stable angina is a warning sign of heart disease and should be evaluated by a doctor. If the pattern of angina changes, it may progress to unstable angina. Unstable angina: This type of angina is considered an acute coronary syndrome. It may be a new symptom or a change from stable angina. The angina may occur more frequently, occur more easily at rest, feel more severe, or last longer. Although this angina can often be relieved with oral medications, it is unstable and may progress to a heart attack. Usually more intense medical treatment or a procedure is required. Unstable angina is an acute coronary syndrome and should be treated as an emergency. Variant angina: A coronary artery can go into spasm, disrupting blood flow to the heart muscle (ischemia). It can occur in people without significant coronary artery disease. However, two thirds of people with variant angina have severe disease in at least one vessel, and the spasm occurs at the site of blockage. This type of angina is not common and almost always occurs when a person is at rest - during sleep. You are at increased risk for coronary spasm if you have: underlying coronary artery disease, smoke, or use stimulants or illicit drugs (such as cocaine). If a coronary artery spasm is severe and occurs for a long period of time, a heart attack can occur. Other major independent risk factors (smoking, high blood pressure, diabetes, physical inactivity, and obesity) also exist and should be considered in defining individual risk of coronary heart disease. Smokers with high blood pressure have three times the risk of dying of coronary heart disease compared to non-smokers with low blood pressure where both have the same level of blood cholesterol. Risk scoring systems developed from the Heart study were no more accurate in predicting who suffered from coronary heart disease with blood cholesterol included than without, highlighting the importance of these other major risk factors. If you have more than two of the risk factors listed, you should discuss your risk factors with your doctor. Your goal is to decrease your risk factors and lessen your risk for future heart disease events. This is true if you do not have heart or blood vessel disease, if you are being treated medically for heart or blood vessel disease, or you have undergone a procedure (angioplasty, stents, bypass surgery) for heart or blood vessel disease. The example of the other disease which related to Coronary Heart disease caused by high blood cholesterol is Heart Failure. Heart failure means the heart is unable to pump blood as well as it should. Heart failure does not mean the heart has stopped working. Coronary artery disease causes decreased blood flow to the heart muscle. If the arteries become blocked, the heart becomes starved for oxygen and nutrients (ischemia). In a short time, damage to the heart muscle (a heart attack) occurs. The damaged area can not pump normally, causing heart failure. Other causes include: Cardiomyopathy: damage to the heart muscle from infection, alcohol or drug abuse, pregnancy or no apparent cause Conditions that overwork the heart: high blood pressure (hypertension), valve disease, thyroid disease, kidney disease, diabetes mellitus or heart defect 4.2 The correlations with the Subject A population approach focuses more on trying to reduce levels of risk factors in the population as a whole. The logic here is that even though coronary heart disease risk for any individual may be lowered by only a small amount, the population effect could be substantial because so many people are affected. Furthermore, a large percentage of events occur in people who are at only average risk and who would otherwise be missed by approaches targeted at those at high risk. Public health policy is based on a combination of population and targeted approaches. Although blood cholesterol is an important risk factor, by itself it is a relatively poor predictor of who will go on to have a coronary heart disease event. The relationship between blood cholesterol and coronary heart disease rates in men, only 42% of those who will suffer an event over 15-years have blood cholesterol over 6,5 mmol/l. The other research shows that the distribution of blood cholesterol in men aged 40-60 who subsequently went on to suffer from coronary heart disease and those who did not, overlap considerably. The prevalence of raised cholesterol increases with age in both men and women. In men the proportion with cholesterol levels of 5.0mmol/l and above increases from 26% in those aged 16-24 to around 80% in those aged 45-64, with a slight decrease in the two oldest age groups. In women cholesterol levels of 5.0mmol/l or above increase from 31% in those aged 16-24 to 84% in those aged 55-64, with, like men, a slight decrease in those over 65 years. Men with the lowest cholesterol levels have higher rates of total mortality than men with higher (but still well below average) levels. Several studies have now demonstrated that this phenomenon is mostly, entirely, due to the fact that this group of people with low cholesterol levels includes a disproportionate number whose cholesterol has been reduced by illness – early cancer, respiratory disease, gastrointestinal disease and alcoholism, among others. Thus it is the pre-existing disease which causes both the low cholesterol and raised mortality and not the low cholesterol levels themselves which produce the elevated mortality rates. So, men in their 40s have a higher risk of CHD than women. But, as women get older, their risk increases so that it is almost equal to a man's risk. 4.3 The correlations with the Geography and Year Differences in average levels of blood cholesterol between communities or populations are largerly determined by differences in diet. Cities with high dietary saturated fat intake and a low ratio of polyunsaturated to saturated fatty acids like in West Jakarta, have high average cholesterol levels. Randomised controlled trials in Jakarta Institutional settings demonstrate that if components of the diets of individuals are changed substantially then large changes in blood cholesterol levels can be achieved. Mean total blood cholesterol levels in both men and women in West Jakarta fell between 1994 and 1998, but remained stable between 2001 and 2006. The prevalence of raised total cholesterol fell between 1997 and 2001, but increased slightly between 2001 and 2006. This increase was not consistent across all age groups but was concentrated in the younger age groups. In older age groups (55 and older in men and 65 and older in women) the prevalence of raised total cholesterol has fallen steadily over the past decade.

BIBLIOGRAPHY Sokolow, Mourice. Clinical Cardiology. Los Altos, California: Lange Medical Publications;2000 Mosca L, Banka CL, Benjamin EJ, et al. Evidence-Based Guidelines for Cardiovascular Disease Prevention in Men: 2006 Update. Circulation. 2006; Published online before print February 19, 2006 . http://www.emedicinehealth.com/coronary_heart_disease.htm/ Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006 May 16;113(19):2363-72 . Boden WE, O'rourke RA, Teo KK, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med. 2007 Mar 26; [Epub ahead of print] . http://www.heartstats.org/ American Heart Association. Heart Disease and Stroke Statistics — 2006 Update. Dallas, Texas: American Heart Association; 2006. Blane D, Hart C, Davey Smith G. Association of cardiovascular disease risk factors with socioeconomic position during childhood and during adulthood. BMJ, 1996: 313; 1434-8.

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Wilu's paper: chapter 3, coronary heart disease

CHAPTER 3 CORONARY HEART DISEASE 3.1 Definition Coronary Heart Disease (CHD), also known as Coronary Artery Disease, develops when fat, calcium, and plaque (or scar tissue) build up in the arteries that lead to the heart. Coronary arteries allow the heart to receive oxygen and other nutrients that are required for pumping blood to the rest of the body. CHD, however, causes the arteries to harden and constrict, impeding both blood flow and delivery of these vital nutrients. Coronary heart disease is the end result of the accumulation of atheromatous plaques within the walls of the arteries that supply the myocardium (the muscle of the heart) with oxygen and nutrients. While the symptoms and signs of coronary heart disease are noted in the advanced state of disease, most individuals with coronary heart disease show no evidence of disease for decades as the disease progresses before the first onset of symptoms, often a "sudden" heart attack, finally arise. After decades of progression, some of these atheromatous plaques may rupture and (along with the activation of the blood clotting system) start limiting blood flow to the heart muscle. 3.2 Etiology Coronary heart disease (CHD) is the leading cause of death in the United States for men and women. According to the American Heart Association, more than 15 million people have some form of the condition. In West Jakarta, more than 100 case of coronary heart disease caused death in 2006. Men in their 40s have a higher risk of CHD than women. But, as women get older, their risk increases so that it is almost equal to a man's risk. 3.3 Epidemiology Coronary heart disease is the most common cause of morbidity and mortality in the developed world. More than 50,000 deaths a year are attributed to coronary heart disease in Indonesia. At least a third of the individuals that die of coronary heart disease are younger than 55 years of age. This disease costs much per year in medical treatment and lost income. 3.4 Signs and symptoms The classic symptom of Coronary Heart Disease is angina, the direct result of inadequate flow of oxygen to the myocardium. It’s usually described as a burning, squeezing, or tight feeling in the substernal or precordial chest that may radiate to the left arm, neck, jaw, or shoulder blade. Approximately 50% of women don’t present with the typical symptoms of angina. These women experience vague symptoms such as fatigue, shortness of breath, abdominal pain, nausea, or vomiting. Symptoms are less visible in females, the elderly, and people with diabetes. Other symptoms include: pressure,fullness or a squeezing pain in chest for more than a few minutes,pain going from chest to shoulders and arms,more chest pain,pain in upper abdomen,shortness of breath,sweating,impending sense of doom, lightheadedness, fainting, nausea and vomiting, choking feeling, lightheadedness, dizziness, weakness 3.5 Causes and Risk Factors Heart disease is caused by narrowing of the coronary arteries that feed the heart. Like any muscle, the heart needs a constant supply of oxygen and nutrients, which are carried to it by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, the result is coronary heart disease. If not enough oxygen-carrying blood reaches the heart, you may experience chest pain called angina. If the blood supply to a portion of the heart is completely cut off by total blockage of a coronary artery, the result is a heart attack. This is usually due to a sudden closure from a blood clot forming on top of a previous narrowing. The following are confirmed independent risk factors for the development of Coronary Heart Disease, in order of decreasing importance: Hypercholesterolemia (specifically, serum LDL concentrations) Smoking Hypertension (High systolic pressure seems to be most significant in this regard) Hyperglycemia (due to diabetes mellitus or otherwise) Type A behavioural Patterns, TAPB. Added in 1981 as an independent risk factor after a majority or research into the field discovered that TAPB’s were twice as likely to cause CHD than any other personality type. Hereditary differences in such diverse aspects as lipoprotein structure and that of their associated receptors, homocysteine processing/metabolism. The significant but indirect risk factors, include : Lack of exercise, Stress, Diet rich in saturated fats, Diet low in antioxidants, Obesity and Men over 50. 3.6 Complications When your coronary arteries narrow, your heart may not receive enough blood when demand is greatest - particularly during physical activity. This can cause chest pain or shortness of breath. If a cholesterol plaque ruptures, complete blockage of your heart artery may trigger a heart attack. The lack of blood flow to your heart during a heart attack leads to irreversible damage to your heart muscle. The amount of damage depends in part on how quickly you receive treatment. If your heart has been damaged and can't pump enough blood to meet your body's needs, you may experience heart failure 3.7 Screening and diagnosis Many tests help diagnose CHD. Usually, your doctor will order more than one test before making a definite diagnosis.Tests may include: Electrocardiogram (ECG), Exercise stress test, Echocardiogram, Nuclear scan, Coronary angiography/arteriography, Electron-beam computed tomography (EBCT) to look for calcium in the lining of the arteries -- the more calcium, the higher your chance for CHD, Coronary CT angiography, and Magnetic resonance angiography 3.8 Treatments Coronary Heart Disease can be treated with a variety of drugs that help reduce the effects that the disease has on its host body. One of the most commonly used drugs to treat Coronary Heart Disease is aspirin, which reduces the tendency of blood to form clots over a rupturing artery (a common cause of heart attacks). Another type of medication, beta-blockers, decreases the heart rate and blood pressure so that the heart's demand for oxygen lowers. Statins drugs, also a popular means of treating Coronary Heart Disease, reduce the amount of fats and cholesterol in your blood so that plaques are less likely to form or increase in size in the blood vessels.For extreme cases of Coronary Heart Disease the only option is often bypass surgery. 3.9 Preventions Coronary heart disease is the most common form of heart disease. Prevention centers on the modifieable risk factors, which include decreasing cholesterol levels, addressing obesity and hypertension, avoiding a sedentary lifestyle, making healthy dietary choices, and stopping smoking. It has been suggested that coronary heart disease is partially reversible using an intense dietary regime coupled with regular cardio exercise. 3.10 Prognosis Everyone recovers differently. Some people can maintain a healthy life by changing their diet, stopping smoking, and taking medications exactly as the doctor prescribes. Others may need medical procedures such as angioplasty or surgery. Although everyone is different, early detection of Coronary Heart Disease generally results in a better outcome.

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Wilu's paper: chapter 2, cholesterol

CHAPTER 2 CHOLESTEROL 2.1 Definition Cholesterol is a sterol (a combination steroid and steroid), a lipid found in the cell membranes of all body tissues, and is transported in the blood plasma of all animals. Trace amounts of cholesterol are also found in plant membranes.The name originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol in solid form in gallstones in 1784. Cholesterol is a soft, fat-like, waxy substance found in the bloodstream and in all your body's cells. It's normal to have cholesterol. Cholesterol is an important part of a healthy body because it's used for producing cell membranes and some hormones, and serves other needed bodily functions. But too much cholesterol in the blood is a major risk for coronary heart disease (which leads to heart attack) and for stroke. Cholesterol also aids in the manufacture of bile (which is stored in the gallbladder and helps digest fats), and is also important for the metabolism of fat soluble vitamins, including vitamins A,D,E and K. It is the major precursor for the synthesis of vitamin D and of the various steroid hormones (which include cortisol and aldosterone in the adrenal glands, and the sex hormones progesterone, the various estrogens, testosterones, and derivates). There are different kinds of cholesterol. The liver converts unburned food metabolites into very low density lipoproteins (VLDL) and secretes them into plasma where they are converted to low-density lipoprotein (LDL) particles and non-esterified fatty acids, which can affect other body cells. In healthy individuals, the relatively few LDL particles are large. In contrast, large numbers of small dense LDL (sdLDL) particles are strongly associated with the presence of atheromatous disease within the arteries. For this reason, LDL is referred to as "bad cholesterol". High-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes, and hence it is commonly called "good cholesterol". In contrast, having small amounts of large HDL particles is independently associated with atheromatous disease progression within the arteries. 2.2 Synthesize of cholesterol Most of the cholesterol is synthesized by the body and some has dietary origin. Although formerly believed, the cholesterol level in blood is not raised by increasing the amount of cholesterol in the diet. Cholesterol is more abundant in tissues which either synthesize more or have more abundant densely-packed membranes, for example, the liver, spinal cord, brain, and atheromata (arterial plaques). Cholesterol plays a central role in many biochemical processes, but is best known for the association of cardiovascular disease with various lipoprotein cholesterol transport patterns and high levels of cholesterol in the blood. Cholesterol is insoluble in blood, but is transported in the circulatory system bound to one of the varieties of lipoprotein, spherical particles which have an exterior composed mainly of water-soluble proteins. Cholesterol is required in the membrane of mammalian cells for normal cellular function, and is either synthesized in the endoplasmic reticulum, or derived from the diet, in which case it is delivered by the bloodstream in low-density lipoproteins. These are taken into the cell by receptor-mediated endocytosis in clathrin-coated pits, and then hydrolysed in lysosomes. Cholesterol is primarily synthesized from acetyl coA through the HMG-CoA reductase pathway in many cells and tissues. About 20-25% of total daily production (~1 g/day) occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands and reproductive organs. For a person fo about 150 pounds (68kg), typical daily dietary intake is 200 to 300 mg. Of the cholesterol input to the intestines via bile production, 92-97% is reabsorbed in the intestines and recycled via enterohepatic circulation. Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, while lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (Sterol Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the SRE (sterol regulatory element) of a number of genes to stimulate their transcription. Among the genes transcribed are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol. 2.3 The Risk Factors You're more likely to have high cholesterol if you're inactive, obese or eat unhealthy foods. Although high cholesterol can lead to heart disease on its own, other factors compound the risk: · Smoking. Cigarette smoking damages the walls of your blood vessels, making them likely to accumulate fatty deposits. Smoking may also lower your level of HDL cholesterol. · High blood pressure. Increased pressure on your artery walls damages your arteries, which can speed the accumulation of fatty deposits. · Diabetes. High blood sugar contributes to high LDL cholesterol and low HDL cholesterol. High blood sugar also damages the lining of your arteries. · Family history of heart disease. If a parent or sibling developed heart disease before age 55, high cholesterol levels place you at a greater than average risk of developing heart disease. 2.4 Screening and Diagnosis Cholesterol screening and diagnosis maybe done either by testing the entire adult population or by making use of routine contacts in primary health care (opportunistic screening). The main screening test for blood cholesterol is the measurement of total blood cholesterol in blood samples obtained by either venepuncture or finger prick. Measurements in cholesterol screening may not accurately reflect the true cholesterol level due to measurement error (bias and imprecision) and natural biological variation in cholesterol levels within an individual. These sources of error can result in misclassification and lead to incorrect diagnosis and the possibility of unnecessary treatment. However, bias can be reduced in laboratory equipment by regular calibration againts a standard, and precision increased by using good equipment and repeat analyses. 2.5 Preventions To keep our cholesterol under control, we must do the following : - Schedule a screening - Eat foods low in cholesterol and saturated fat - Maintain a healthy weight - Exercise regularly - Follow the healthcare professional's advice

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