Coronary heart disease (CHD) is a multifactorial disease



Cardiovascular disease is a multifactorial disease. The most common type of cardiovascular disease is coronary heart disease (CHD)/coronary artery disease (CAD) which results from atherosclerosis. Coronary heart disease is the leading cause of death in the world and was responsible for more than seven million deaths. Although smoking, dietary factors, alcohol, inactivity, and air pollution are environmental risk factors for cardiovascular disease, gene polymorphisms cause variable responses in individuals exposed to the same risk factors (Talmud, 2006; Sarti, 2000).

Identification of the causes and risk factors of cardiovascular disease in important and has contributed to the 70% reduction in mortality caused by cardiovascular disease in the past 30 years (Brown, 2000). Unfortunately, there is a great deal which is not yet understood about the causes of cardiovascular disease. About half of those who suffer heart attacks have cholesterol levels which are considered acceptable and at least one quarter lack any of the major risk factors for heart disease (Broxmeyer, 2004).

The fraction of patients with atherosclerosis which lack known risk factors is estimated to be between one third and one half (Yang, 2006).

LIPIDS AND LIPOPROTEINS

1) FORWARD CHOLESTEROL TRANSPORT

A) CHYLOMICRONS

The lipids from the diet enter the body from the small intestine. Intestinal mucosa cells produce protein balls which surround the lipids called chylomicrons. Chylomicrons contain the protein apolipoprotein B48 (which is made in the intestinal cells) and a variety of lipids including triglycerides, phospholipids, and cholesterol. These particles are too large to enter blood capillaries and instead enter the lacteal (a lymphatic capillary). Lymphatic vessels will eventually transport the chylomicrons to the brachiocephalic veins, returning them to circulation. Other proteins are added to the chylomicron, such as apolipoprotein E (apoE) and apoC-II.

Lipoprotein lipase is an enzyme produced by endothelial cells that gradually digests lipids, reducing the size of the chylomicron. Lipoprotein lipase is attached to endothelial cells and binds apoC-II in order to function. The fatty acids which result from the breakdown of triglycerides leave the chylomicron, bind albumin in blood plasma, and are transported to adipose where they are reassembled into triglycerides. This process occurs within an hour of ingesting the lipids.

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Liver cells then bind the remnants of the chylomicron (as hepatocyte LDL receptors bind apoE), ingest the particle through receptor mediated endocytosis, and repackage the remaining lipids and lipoproteins as VLDLs (Tulenko, 2002).

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The liver cell synthesizes VLDL particles which contain apoprotein B100, ApoE, and apoC-II. VLDLs are smaller than chylomicrons and transport fewer triglycerides. As VLDL particles travel through the blood, they bind the lipoprotein lipase of endothelial cells (as apoC-II interacts with endothelial LDL receptors, just as was the case with chylomicrons).

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During the course of a half hour, the VLDLs are converted to IDLs as the triglycerides are digested and the fatty acids are liberated. In the liver, hepatic cells bind IDLs and the enzyme hepatic lipase digests additional triglycerides. In the liver, converts IDLs to LDLs.

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LDL particles include an average of 2700 lipid molecules. The only protein in LDLs is apoprotein B-100. LDLs have a half life of several days as they circulate throughout the body. Body cells possess LDL receptors which bind LDL particles and the cholesterol they contain. The particles enter cells through receptor mediated endocytosis (Tulenko, 2002).

A single molecule of apolipoprotein B is present in the LDL and VLDL lipoprotein particles which increase the risk of atherosclerosis. Because the small, dense LDL particles offer greater risk than larger ones, apoprotein B levels may provide a better predictor of coronary heart disease than LDL levels (Van Lennep, 2002).

LDL AND THE RISK OF CARDIOVASCULAR DISEASE

There are a number of factors which vary individual risk of heart disease which exert their influence through LDL particles and forward transport of cholesterol. Some of these factors are determined by the mutations which cause genetic disorders and some by polymorphisms (variations) in the genes which are important in this process. Other risk factors which affect LDL levels are determined (at least in part) by environment and lifestyle.

The role of genes in causing CHD has been estimated to range between 20 and 60%. Those who develop cardiovascular disease at an early age tend to have a greater genetic component to their disease (Nordlie, 2005).

Familial hypercholesterolemia is caused by mutations in the receptor in the LDL receptor gene. Nonfunctional receptors cannot remove LDL particles from the blood and LDL levels are consequently elevated. Heterozygotes for familial hypercholesterolemia have elevated LDL levels while those who are homozygous for a mutation have extremely elevated levels (Nordlie, 2005).

Familial defective apolipoprotein B-100 is a genetic disease involving the apolipoprotein B, the protein which interacts with LDL receptors to remove LDL particles from the blood (Nordlie, 2005).

Familial combined hyperlipidemia and familial hypertriglyceridemia affects 1-2% of people in Western countries and, as such, it is the most common genetic cause of lipid disorders. Affected individuals possess elevated levels of VLDLs, LDLs, APOB and triglycerides (Nordlie, 2005).

Another genetic disorder known as atherosclerosis susceptibility increases the number of small, dense LDL particles in the blood (Nordlie, 2005).

There are three common alleles of Apolipoprotein (apo) E in humans: E2, E3, and E4. Although the E4 alleles have been shown to be associated with increased risk of coronary heart disease, one study indicated that this is not because of a general link between E4 and heart disease but rather because of an interaction between E4 alleles and smoking so that smokers with E4 alleles have a much greater than normal risk of coronary heart disease.

Of the three alleles of apo E, apoE2 offers the greatest protection against oxidation, E3 offers less, and the apo E4 allele offers the least (Talmud, 2006).

Acyl-CoA: cholesterol acyltransferase enzymes (ACAT1 and ACAT2) are required for the absorption of cholesterol from the intestine. Macrophages require utilize ACAT 1 and mutant macrophages without ACAT 1 undergo apoptosis which aggravates atherosclerosis. The breast cancer drug Tamoxifen lowers atherosclerosis risk by functioning as an ACAT1 inhibitor (Stein, 2005).

It appears that some genetic polymorphisms offer protection from atherosclerosis, even in patients with hypercholesterolemia.

One of these genes is the liver x receptor (LXR) affects the amount of dietary lipids which is absorbed from the small intestine using proteins of the ATP-binding cassette family (Stein, 2002).

Although lowering blood cholesterol may decrease risk from heart disease, it may increase the risk of other hazards. Cholesterol levels which are too low can result in nervous, cardiovascular, and digestive abnormalities and can cause abnormal development in children. Although lowering cholesterol levels can decrease risk of dying of cardiovascular disease, it has been linked to aggression and the risk of violent death. Low cholesterol levels can also increase cancer risk (Stehbens, 2001).

REVERSE TRANSPORT

Triglycerides can be broken down inside cells while cholesterol cannot. Low levels of cholesterol promote atherosclerosis in endothelial cells and high levels can be toxic. Thus, cholesterol must be removed from endothelial cells. HDL particles perform this function. HDL particles are small, dense lipoproteins which include a central region composed of cholesteryl esters, cholesterol, and triglycerides. Phospholipids and apolipoproteins surround this core. The primary apolipoproteins are apoA-I and apoA-II although a variety of other apolipoproteins may be present (such as apoA-IV, apoA-V, apoC-I, apoC-II, apoC-III, apoD, apoE, apoJ, and apoL). There are different classes of HDLs: some possess only apoA-I while others possess a mixture of apoA-I and apoA-II (Barter, 2003).

Discoidal HDL particles containing apo A-I are synthesized in the liver and intestine. HDL particles absorb cholesterol molecules from the surfaces of other cells. HDL receptors (SR-B1) attach HDL particles to cells and ABCA1 mediates the transfer of cholesterol to the HDL particle. On the surface of the HDL particle, apo A-I activates the enzyme which converts cholesterol to cholesteryl esters which enter the HDL and form the hydrophobic core of the particle. The surface is now free to bind additional cholesterol molecules. The HDL gradually changes from being discoidal to spherical as it fills with cholesteryl esters (in addition to apo C-II and apoE from VLDLs and IDLs) (Tulenko, 2002).

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In the liver, hepatocyte LDL receptors bind the apo E of HDL particles and absorb them (and the cholesterol they contain) into the cell (Tulenko, 2002).

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After interacting with CETP proteins, HDL cholesteryl esters are transferred to liver cells, cells which metabolize steroids, LDLs and VLDLs (Barter, 2003).

In addition to lipid transport, HDL particles stimulate endothelial cells, decrease the production of platelet-activating proteins, and prevent coagulation around erythrocytes (Barter, 2003). HDLs decrease the amount of LDL oxidation and reduce the effects of oxidized LDL. HDL particles also inhibit the expression of cell adhesion molecules (Wilcox, 2000).

HDL AND THE RISK OF CARDIOVASCULAR DISEASE

Because HDL particles remove lipids from blood vessel walls, low HDL levels can result in the buildup of plaques. Although evidence suggests that low HDL levels represent an independent risk of coronary heart disease, some of the danger of low HDL levels may be related to the relative concentrations of the other lipids (Barter, 2003). Low HDL levels pose a risk for cardiovascular disease even when LDL levels are not high (Van Lennep, 2002).

There are a number of factors which vary individual risk of heart disease which exert their influence through HDL particles and reverse transport of cholesterol. Some of these factors are determined by the mutations which cause genetic disorders and some by polymorphisms (variations) in the genes which are important in this process. Other risk factors which affect HDL levels are determined (at least in part) by environment and lifestyle.

Genetic mutations in a number of different genes (HDL lipoproteins, LPL, and LCAT) can lower HDL levels. For overweight individuals with a low HDL level, sustained weight loss usually raises HDL levels. Alcohol increases HDL levels and smoking decreases them (Barter, 2003).

Mutations in the ABCA1 gene can lower HDL levels which is consistent with its role of transferring cholesterol to HDL particles. ABCA1 is the cholesterol efflux regulatory protein (CERP) whose mutation is responsible for the increased risk of heart disease in Tangier disease (Wilcox, 2000; Saleheen, 2006).

The cholesteryl ester transfer protein (CETP) functions in the transport of cholesteryl esters from HDL particles to liver cells. Mutations which inactivate this protein result in HDL particles which have little ability to transport cholesterol. Increasing the activity of this protein may decrease risk of atherosclerosis (Wilcox, 2000). CETP polymorphisms have been associated with risk of CHD in some studies and in one study the positive effect of one genotype was only observed in nonsmokers. The drug Torcetrapib inhibits CETP (Stein, 2005).

Medications such as fibrates and statins increase HDL levels (Barter, 2003).

The enzyme lipoprotein lipase causes the release of triglycerides from

lipid particles and the production of HDL particles. Mutations cause elevations in blood triglycerides and reduced amounts of HDL (Nordlie, 2005).

The HDL subclass of apo A-I levels may represent a better predictor of coronary heart disease risk than HDL levels in general (Van Lennep, 2002).

Lipoprotein(a) can bind to LDL particles and evidence suggests that it is a risk factor for heart disease. Lipoprotein(a) levels can be reduced by nicotinic acid and estrogen (in hormone replacement therapy).

Although there is strong evidence for the involvement of lipid metabolism in atherosclerosis, there are other factors involved and lipid abnormalities should not be considered to the exclusion of all other factors. There have been criticisms that much of the data which originally supported the lipid and cholesterol causation of atherosclerosis was faulty. Studies have indicated that the majority of patients who suffer from CHD do not have hypercholesterolemia and that there is an enormous overlap between the distribution of plasma cholesterol levels between patients of CHD and those who do not suffer from CHD. It is often difficult to evaluate the severity of individual risk factors (such as lipid levels) given that many of them are interrelated with other risk factors hypertension, diabetes, and obesity (Stehbens, 2001).

OXIDATION

Of the diverse chemical reactions which can occur in the body, many involve the removal of electrons from a reacting atom or molecule. This is known as oxidation and oxygen is a major mediator of this oxidation.

Oxidized LDL particles

Once they have entered the blood vessel wall, LDL particles can be oxidized by reactive oxygen species (ROS). Oxidized particles are much more likely to remain trapped in the blood vessel wall (Mann, 2004).

Oxidized LDL particles damage endothelial cells, stimulates the production of local hormones from the blood vessel wall, attracts macrophages and discourages their exit. Oxidized LDL particles are ingested by macrophages in foam cell production (Pryor, 2000). The OLR1 gene produces the receptor responsible for the absorption of oxidized LDL into endothelia (Nordlie, 2005).

Reactive Oxygen Species (ROS)

Abnormally high levels of oxidation can be detrimental and even toxic to cells. A number of environmental and lifestyle variables can affect the levels of oxidation that a cell undergoes. Oxidative stress can be caused by reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide, and hydroxyl ions and other oxidants such as peroxynitrite and hypochlorous acid. ROS are produced from a variety of sources such as air pollution, leukocytes, fibroblasts, endothelial cells, mitochondria, certain enzymes (xanthine oxidases, nitric oxide synthase, and NADPH oxidases, for example), and the oxidation of catecholamines. These ROS ions affect the regulation of calcium inside cardiac muscle cells and cause a variety of changes. Hyperglycemia, hypertension, and ketosis produce reactive oxygen species which cause oxidative stress. Higher levels of reactive oxygen species induces the inflammatory response (Tappia, 2006).

Antioxidants prevent the damage and apoptotic signaling of ROS and reduce inflammation, blood pressure, and the damage to blood vessel linings (Tappia, 2006).

Vitamin E is the primary fat-soluble anti-oxidant in the body. Its proposed role in the reduction of risk in coronary artery disease is that it reduces the oxidation of LDL lipids into oxidized lipids which can initiate damage of blood vessels. Vitamin E can decrease the likelihood of platelets binding each other. Vitamin E has been determined to be safe and the levels used to reduce risk of heart disease are higher than one can be obtained through diet alone.

LDL particles include an average of 5-9 vitamin E molecules and other antioxidants (such as beta carotene and tocopherol; less than one per particle). It has been suggested that a synergistic effect between the total variety of antioxidants is more important in determining risk than the level of any one antioxidant. (Pryor, 2000; Tappia, 2006).

ROS as Signals

Not only can ROS be formed through processes which are detrimental to the body, the body can also synthesize its own ROS which function as signals. Evidence indicates the reactive oxygen species can actually function as signals which induce heart muscle cells to release local hormones and inflammatory molecules (Elahi, 2006). These signals then catalyze processes which can alter the risk of cardiovascular disease. Heart muscle cells, endothelial cells, and circulating leukocytes can all release reactive oxygen species which function as signals. The effects of these signals include the conversion of LDL to oxidized LDL, the adhesion/migration of leukocytes to the endothelial lining, the hypertrophy of muscle cells, inflammation, and apoptosis (Elahi, 2006).

ROS signals can cause the enzyme phospholipase D to produce phosphatidic acid, a signal which alters intracellular calcium levels in cardiac muscle cells, even in normal individuals. (ROS apparently oxidize a cysteine residue in the active site of tyrosine phosphatases which prevents their ability to counteract the tyrosine kinases which activate phospholipase D). Phospholipase D also stimulates a number of kinase enzymes which can induce apoptotic or necrotic cell death (Tappia, 2006).

Reactive oxygen species produced by white blood cells are a factor in the systemic inflammatory response experienced by many patients of cardiovascular disease (Elahi, 2006).

INFLAMMATION

When LDL levels are high, LDL particles and their oxidized products accumulate in blood vessel walls. These particles induce inflammatory responses (in which the transcription factor NF kappa B plays an important role). The inflammatory response includes the release of signaling molecules, some of which attract macrophages to the area.

One of the earliest steps of atherosclerosis seems to be the adhesion of monocytes to the endothelial lining (mediated by cell adhesion molecules such as VCAM-1, ICAM-I, and E-selectin). When the lipids are oxidized, the monocytes enter into the blood vessel wall, transform into macrophages, and begin to make a number of growth factors and cytokines. LDLs and oxidized LDLs induce the macrophages to release even more inflammatory signals, such as TNF-α, serum amyloid A, and interleukins 1,6, and 10. These signals may attract more macrophages to the area and stimulate the growth of smooth muscle cells in the area. Macrophages ingest the cholesterol and become “foam cells”, filled with lipid droplets. The fatty streak formed by the macrophages and smooth muscle cells is the precursor to a plaque (Barter, 2003; Robinson, 2006). The production of additional smooth muscle and extracellular matrix causes the blood vessel wall to thicken and the lumen to shrink (Tulenko, 2002).

Genetic polymorphisms can affect the degree to which inflammatory responses are initiated in different individuals and thus risk of cardiovascular disease. Reduced activity of proteins which control monocyte/macrophage movement can reduce risk of atherosclerosis, even in the presence of high lipid levels. These proteins include monocyte chemotactic protein-1, C-C chemokine receptor 2, macrophage colony stimulating factor, and vascular cell adhesion molecule (Stein, 2002). Some evidence suggests that polymorphisms in genes which mediate inflammation (such as TNF beta) affect risk of heart disease (Porto, 2005).

Inflammation of the heart is also a factor in cardiovascular disease. Congestive heart failure can be considered as a state of chronic inflammation of the heart (Rutschow, 2006). The inflammation of the heart, myocarditis, can be caused by infectious agents and other factors. Inflammation in the heart contributes to cardiovascular disease in several ways. It causes cardiac hypertrophy and induces apoptosis. It also affects the structure of the heart through remodeling of the collagen framework of the extracellular matrix of the heart (Rutschow, 2006).

Ischemia followed by reperfusion causes more damage than ischemia alone due to the increase in oxygen radicals, increased stretch, changes in calcium levels, and inflammation (Kunapuli, 2006).

HOMOCYSTEINE

The amino acid homocysteine is produced during the metabolism of the amino acid methionine. This reaction is performed by a variety of enzymes which are present throughout the body. Homocysteine can then be converted to cysteine (in a reaction dependent on vitamin B6) or methionine (in a reaction dependent on B12 and folate) (Merkell, 2004). Homocysteine can cause inflammation of endothelial cells which increase the secretion of interleukin (Shai, 2004). Homocysteine can modify proteins and these proteins, known as homocysteine adducts, can contribute to cardiovascular disease (Yang, 2006). Although elevated homocysteine levels are currently considered as a minor risk for coronary artery disease, homocysteine can interact with other risk factors to amplify their effect (Cesari, 2005).

Plasma levels of homocysteine can be elevated in normal individuals because of an insufficient amount of vitamins (folate, B6, and B12) in the diet and genetic defects in the pathways which synthesize homocysteine from methionine or convert it to other amino acids. One common genetic polymorphism which results in reduced activity of the enzyme methylenetetrahydrofolate reductase (MTHFR; part of the pathway which converts homocysteine to methionine) results in 20-50% elevations in homocysteine levels. About 10% of the population is affected by this increase and are homozygous while about 43% are heterozygotes (Merkell, 2004).

DIET

Increased lipid in the diet will increase the blood concentration of LDL and VLDL particles. Diets rich in protein (especially from animal sources) contain methionine which can be converted to homocysteine. Omega-6 fatty acids compose the major polyunsaturated acids in the typical Western diet. Arachidonic acid is the primary omega-6 fatty acid. It can be converted to a variety of local hormones (such as prostaglandins and leukotrienes), many of which mediate inflammation and other atherogenic, prothrombotic changes (Robinson, 2006).

Antioxidants can be incorporated in the diet from fruits, vegetables, and vitamin supplements which limit oxidation and inflammation.

Folic acid is a factor determining the production of nitric oxide and tetrahydrobiopterin (H4B) (Das, 2003).

Vitamin B6 increases the production of the anti-inflammatory prostaglandin E1 which promotes vasodilation and inhibits platelet aggregation (Das, 2003).

Coffee

Those who drink more than five cups of coffee per day suffer an increased risk of myocardial infarction. There is no evidence to suggest that heavy tea drinking increases risk of coronary heart disease and tea may actually result in a reduced risk (Tofler, 2001).

Obviously, variations in diet can contribute to risk of cardiovascular disease.

Fatty Acids from Fish

Omega-3 fatty acids benefit the cardiovascular system in a number of ways. Two of these acids originate from fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They decrease blood pressure and decrease the likelihood of developing an arrhythmia (including atrial fibrillation). EPA and DHA decrease the blood concentration of triglycerides by accelerating the breakdown of chylomicrons and the conversion of VLDLs to LDLs. EPA metabolism produces local hormones which are less atherogenic and prothrombotic than those derived from omega-6 fatty acids (thromboxane B3 and leukotriene B5 instead of thromboxane B2 and leukotriene B4, for example). EPA and DHA inhibit production of the inflammatory signal interleukin-6. They stabilize plaques and decrease the amount of plasma clotting factors. Alpha linolenic acid from plants can also reduce coronary heart disease (Robinson, 2006; Brouwer, 2006).

Unfortunately, it is not yet clear what amount of fish consumption is optimal to reduce the risk of heart disease while balancing the risk of methylmercury present in fish (Konig, 2005). In addition to adverse effects on the nervous system, methylmercury increases the risk of cardiovascular disease. The mechanism for this increased risk seems to be the oxidizing effects of methylmercury on lipids (Stern, 2005).

HYPERTENSION

The volume of blood and the degree of vasoconstriction are major factors in determining blood pressure and hypertension. These factors, in turn are controlled by multiple mechanisms.

Angiotensin System

The hormone rennin, secreted by the kidneys, activates angiotensinogen to produce angiotensin I. Angiotensin-converting enzyme (ACE) removes two amino acids from angiotensin I to produce the octapeptide angiotensin II. ACE also represses the activity of bradykinin and kallikrein. Decreases in hypertension and the severity of congestive heart failure result from blocking ACE activity or binding of the angiotensin II type 1 receptor. Mutations in these genes contribute to risk of coronary heart disease (Wang, 2000; Nordlie, 2005).

Genetic polymorphisms in the gene for the angiotensin-converting enzyme (ACE) are associated with increased risk of hypertension, hypertrophy of the left ventricle, and some complications of atherosclerosis (Wang, 2000).

A polymorphism of the gene for angiotensinogen is associated with risk of hypertension (Wang, 2000).

Sympathetic Division of the ANS

When cardiac muscle contraction is lessened, the sympathetic division of the ANS compensates with a number of mechanisms which will ultimately damage the cardiovascular system. Epinephrine causes vasoconstriction which increases blood pressure. Elevated activation of the sympathetic division results in prolonged exposure to epinephrine which alters calcium concentrations and subsequently the activity of the cardiac ryanodine receptor. This ryanodine receptor’s activity is a factor in abnormal contractibility and cardiac arrhythmias. Beta blockers help to normalize this receptor’s function (Wehrens, 2004).

The sympathetic nervous system can contribute to coronary heart disease (Wehrens, 2004).

Hypertension can be caused by increased body weight and increased salt intake. Increased amounts of fruits, vegetables, calcium, magnesium, and potassium reduce risk of hypertension (Hankey, 2001).

DIABETES

Diabetics suffer a rate of cardiovascular disease which is 2-3 times higher than non-diabetics (Marks, 2000; Jimenez-Corona, 2006). About three quarters of diabetics die of cardiovascular disease. Diabetic women experience a greater risk than diabetic men (Van Lennep, 2002).

The presence of protein in the urine (proteinuria) is one of the best predictors of the severity of cardiovascular disease in Type I diabetics (Marks, 2000). Among diabetics, ECG abnormalities can be a better predictor of death than other variables, such as proteinuria (Jimenez-Corona, 2006).

In diabetics, HDL levels are lower and triglyceride levels are higher (Van Lennep, 2002).

High levels of blood glucose (hyperglycemia) can damage blood vessel linings. Hyperglycemia also causes changes in proteins (glycation and peroxidation) which can do the same (Marks, 2000).

High levels of insulin (hyperinsulinemia) is a risk factor for cardiovascular disease, whether or not it is accompanied by diabetes. Hyperinsulinemia can raise blood pressure, increase LDL levels, and decrease HDL levels (Marks, 2000).

In diabetics, elevated levels of extracellular matrix proteins are produced in the heart (as well as in the kidneys and peritoneum). The accumulation of these proteins cause hypertrophy of the heart and narrow the lumen of blood vessels. Fibrosis can result from local hormones (such as TGF beta1) which are produced in response to elevated glucose levels and the response to the reactive oxygen species produced by high glucose levels (Asbun, 2006).

Insulin stimulates the production of biopterin. The reduction of biopterin in insulin-resistant states of obesity, hypertension, hyperglycemia, and diabetes may be the cause of the increased concentration of oxygen radicals in these conditions (Das, 2003).

CLOTTING

As cardiovascular disease progresses, the risk of blood clots (and thus heart attack and stroke) increase. The irregular surfaces of atherosclerotic plaques can cause platelets to break and large plaques can actually have exposed collagen on their surfaces which will initiate coagulation. As atherosclerosis narrows the lumen of blood vessels, blood clots are more likely to occlude the vessel and block blood flow. There are significant variations in the population regarding the likelihood of forming clots. Some of these variations are caused by polymorphisms in genes while others are affected by diet and lifestyle choices.

The risk of heart disease increases with increased plasma levels of fibrinogen, factor VII, vactor VIII, von Willebrand factor, and plasminogen activator inhibitor-1 (Robinson, 2006). Diets which are high in cholesterol and saturated fats have been shown by several studies to increase the concentrations of several clotting factors in the blood (Miller, 2005).

Platelets possess collagen receptors formed by a complex of glycoprotein Ia-IIa. The higher the level of these receptors which are expressed on platelets, the greater the risk of myocardial infarction. Polymorphisms in the genes for the glycoprotein IIb/IIIa platelet receptors and thrombospondin receptors also may have effects on cardiovascular disease (Nordlie, 2005).

Polymorphisms in the plasminogen activator inhibitor-1 (PAI-1) gene are associated with different risk levels for blood clotting (Nordlie, 2005).

Polymorphisms in the interleukin 6 gene are associated with different risk levels for CHD (Nordlie, 2005).

Levels of certain clotting factors (such as fibrinogen and factor VII) can increase in response in obesity. High levels of fat in the diet can increase levels of clotting factor VII (Hankey, 2001).

Fibrinogen levels are higher in women and are increased by smoking, weight gain, and the use of oral contraceptives (Van Lennep, 2002).

Nitric oxide offers protection from atherosclerosis by inhibiting the increase of smooth muscle and by preventing the association of platelets. Mutations in the gene for endothelial cell nitric oxide synthase (ecNOS) can contribute to coronary artery disease (Nordlie, 2005).

APOPTOSIS

Programmed cell death, apoptosis, can occur after hypoxia, myocardial infarction, atherosclerosis, and heart hypertrophy. Although apoptosis in adult hearts is not common in normal adult hearts, it is essential for the normal development of the heart. Abnormal apoptosis during the development of the conducting tissue of the heart can result in heart block and abnormal pathways (Kunapuli, 2006).

Given that apoptosis is a factor in the development of cardiovascular diseases, the inhibition of apoptosis may offer new opportunities for therapy (Kunapuli, 2006).

DISEASE

White blood cells respond to both disease and inflammation. The total white blood cell count in a person’s blood can be correlated with the risk of heart disease. One study concluded that a patient with 10,000 leukocytes per microliter of blood had twice the risk of myocardial infarction as a person with 4,000 leukocytes per microliter. Elevated leukocyte levels have been correlated with risk of stroke as well (Hoffman, 2004).

Cardiomyopathy often occurs after infections with enteroviruses (such as CVB3), cytomegalovirus, Ebstein-Barr virus, parvovirus, hepatitis C virus, and adenoviruses. Bacteria and protists such as trypanosomes can also cause infections of the heart. After infection, endothelial cells may express abnormal proteins (such as HLA human leukocyte antigens) on their cell surface. There is evidence that autoimmune reactions play a role in the inflammation of the heart and cardiomyopathy. Dendritic cells are antigen-presenting cells in the heart that also present self antigens on their cell surface. They attract cells and play a role in autoimmune reactions in the heart (Eriksson, 2004).

Tuberculosis infections include a number of characteristics which may be relevant for consideration in heart disease: mycobacteria requires cholesterol, mycobacteria invade the arterial wall, cholesterol lowering drugs called statins also inhibit tuberculosis, there is considerable overlap in the regions of the United States where heart disease is most prevalent and where tuberculosis is most prevalent, infection could cause some of the inflammatory signals associated with cardiovascular disease, and elevated homocysteine levels (by reductions in folate concentration) can occur in tuberculosis (Broxmeyer, 2004).

Other infectious agents which have been considered for a role in cardiovascular disease are Chlamydia and Heliobacter pylori (Broxmeyer, 2004).

ALCOHOL

Pure alcohol raises HDL levels. An estimated half of the atherosclerosis risk reduction which results from the consumption of alcohol results from alcohol’s increase in HDL levels and decrease of LDL levels. Alcohol also modifies lipoproteins, reacts with lipids to form “abnormal” lipids in lipid particles, and influences the levels of certain plasma proteins (such as cholesteryl ester transfer protein, phospholipids transfer protein, lipoprotein lipase, hepatic lipase, phospholipases, and lecithin:cholesterol acyltransferase) (Hannuksela, 2003).

Although drinking moderate quantities of alcohol can reduce the risk of cardiovascular disease, red wine and dark beer offer greater protection than alcohol alone. Flavonoid compounds in red wine have been shown to increase NO production and function as antioxidants (Mann, 2004).

Alcohol Dehydrogenase

Not all individuals metabolize alcohol in the same way and these differences can be relevant in the calculation of risk from heart disease. The alcohol dehydrogenase enzyme is composed of several subunits and polymorphisms exist in the subunits (particularly ADH1C) in human populations. Although alcohol can lower the risk of coronary heart disease, this reduction of risk is greater in homozygotes for the gamma 2 allele of ADH1C than for the gamma 1 allele (Talmud, 2006). Polymorphisms in the alcohol dehydrogenase gene are associated with different risk levels for CHD (Nordlie, 2005).

SMOKING

Smoking has a number of deleterious affects on the cardiovascular system. The risk of coronary heart disease increases with a greater number of cigarettes smoked. If an individual quits smoking, their cardiovascular disease risk drops to that experienced by nonsmokers within 3 years. Nicotine is a vasoconstrictor which increases blood pressure. Smoking reduces HDL levels (Van Lennep, 2002).

GENDER

Gender has implications in the calculation of risk of cardiovascular disease. Much of the difference in heart disease risk determined by gender is the result of the effects of estrogen.

Estrogens seem to offer women some protection from cardiovascular disease. Estrogen and androgen receptors are present in the heart, aorta, and coronary arteries. Estrogen receptors are also present in endothelial cells (Hussey, 2003). The levels of estrogen in a woman’s blood varies over the course of the menstrual cycle from .4 to 2.2 nmol/L. Men’s blood has a level of circulating estrogen of about 18-74 pmol/L, which is similar to that experienced by postmenopausal women. Estrogen is important in the pubertal changes experienced by boys such as the development of the skeletal system. After menopause, the risk of cardiovascular disease in women rises sharply (which seems to be independent of the effects of age due to studies of women who undergo early menopause) (Brown, 2000).

One of the ways in which estrogen decreases the risk of cardiovascular disease is through its effect on lipid transport and metabolism. Estrogen decreases the concentration of apolipoprotein B particles and LDL particles while increasing HDL levels (Brown, 2000). These levels are lower in women than in men until menopause at which point they can actually exceed the levels in men (Van Lennep, 2002).

Blood vessels maintain their tone through the interaction of vasoconstrictors such as angiotensin II, endothelin, and norepinephrine and vasodilators such as prostacyclin and NO (Brown, 2000). Estrogen can cause the vasodilation of blood vessels through the release of nitric oxide. Estrogen lowers the concentration of the vasoconstrictor angiotensin II by inhibiting the angiotensin-converting enzyme which produces it.

The heart and the smooth muscle of blood vessels can synthesize their own estrogen as the aromatase cytochrome P450 enzyme in heart and smooth muscle modifies androstenedione and testosterone (Brown, 2000).

Male hearts lose an estimated one gram of mass (about 64 million cardiac muscle cells) per year. There is no apparent loss in female hearts and it is thought that estrogen offers females protection from apoptosis and necrosis in heart cells (Brown, 2000).

Estrogen decreases blood pressure. Although women have a lower likelihood of developing hypertension and left ventricular hypertrophy, they experience a higher incidence of atrial fibrillation and have faster heart rates (Brown, 2000). Truncal obesity typical in males is a greater risk factor than the peripheral adipose accumulation typical in females (Van Lennep, 2002).

A woman’s heart is likely to be smaller with smaller arteries which are more likely to be blocked in the event of clot formation. Women’s heart rates tend to be higher than men’s heart rates (Hussey, 2003). Women with heart failure are more likely to undergo atrial fibrillation than men (Hussey, 2003). Women suffer a greater detrimental impact of diabetes and lipid levels on their coronary heart disease than do men (Van Lennep, 2002).

In every year since 1985, the number of women who have died from coronary heart disease have outnumbered men. Although age contributes to this disparity since the average woman suffering from myocardial infarction is 3 to 9 years older than the average man, there are differences in the types of care that women receive compared to men. It has been documented that women are less likely to be admitted into intensive care and less likely to receive certain procedures (such as thrombolytic treatment, angiography, angioplasty, and coronary bypass surgery) (Cooke, 2006). Women diagnosed with cardiovascular disease are less likely to be referred to rehabilitation programs and their participation in programs to which they are referred is less than that of men (Abbey, 2000).

ETHNICITY

African-Americans suffer from hypertension at a higher frequency than other ethnic groups. Some data suggests that those of African descent are more salt-sensitive in that their blood pressure is more likely to rise with increasing amounts of salt in their diet (Sosin, 2004).

It has been suggested that alleles of certain genes which are more common in African Americans may be responsible for the increased risk of hypertension and cardiovascular disease. Candidate genes include TGF-B (which may affect hypertension through its stimulation of the vasoconstrictor endothelin), adrenergic receptors, aldosterone synthase, and nitric oxide synthase (Yancy, 2005).

DEPRESSION

Depression is an independent risk factor for heart disease (Abbey, 2000). Some evidence suggests that not only is depression a factor which will negatively affect survival in after a myocardial infarction, it also promotes the development of cardiovascular disease in individuals who initially lacked the disease (Rugulies, 2002).

METABOLIC SYNDROME

A condition known as the metabolic syndrome is identified as the combined occurrence of abdominal obesity, hypertension, insulin resistance, high lipid levels, microalbuminuria, and increased susceptibility to inflammation and blood clotting. The insulin resistance may occur with or without diabetes (Sarti, 2000). Studies estimate that about a quarter of adults in the United States can be diagnosed with this metabolic syndrome. Levels among older adults can exceed 40% (Grundy, 2005). Obesity can worsen all of the major risk factors for coronary heart disease (Hankey, 2001).

CONGENITAL HEART PROBLEMS

The risk of heart disease is often increased by the presence of a congenital heart abnormality.

Almost one percent of infants suffer from a congenital cardiovascular malformation and these disorders cause a third of the infant deaths due to congenital defects. In addition to random mutations, cardiac defects are known to be caused by alcohol, diabetes, fever, maternal PKU, rubella, and thalidomide (Lin, 2005).

A number of abnormalities contribute to cardiovascular disease in young people including arrhythmias, congenital heart defects, and abnormalities of the heart (such as hypertrophy) and blood vessels (Hinton, 2005).

A number of the genes which have been linked to congenital heart defects encode transcription factors (such as NKX2.5, TBX5, GATA4, FOG2, ZIC3, and TFAP2B). Others function as signaling molecules such as PTPN11, JAG1, EVC/EVC2, CRELD1, CFC1, and PROSIT240 (Hinton, 2005).

NKX2.5 is a homeodomain protein homologous to tinman in invertebrates. These genes evolved early in animal history to guide the development of the heart given their roles in vertebrates and invertebrates (Hinton, 2005).

About 6% of those over age 60 experience atrial fibrillation. About a third of those who experience atrial fibrillation have a family history of the disorder. Several polymorphisms in potassium and sodium channel genes are known to cause fibrillation. Some of the negative alleles are inherited in a dominant fashion and so genetic testing can determine which of an affected individuals children (half, on average) are at an increased risk of fibrillation (Roberts, 2006).

STRUCTURE OF THE HEART

Collagen forms a skeletal framework for the heart and the matrix around heart muscle cells protects them, allows the proper transmittal of force, and provides strength. Abnormal accumulations of extracellular matrix contribute to the problems of hypertension, heart failure, and arrhythmias.

The fibroblasts of the extracellular heart matrix express estrogen receptors and evidence suggests that estrogen mediates beneficial changes in these cells (Brown, 2000).

During hypertension, diabetes, alcoholism, and coronary artery disease, the heart can adapt to the disease state by increasing heart muscle size and producing contractile proteins usually limited to fetal development. Although these changes allow the heart to adapt in the short term, increased apoptosis in the heart will cause heart degeneration in the longer term (Kunapuli, 2006).

Inflammation affects the structure of the heart through remodeling of the collagen framework of the extracellular matrix of the heart. The activity of cardiac fibroblasts which produce this collagen skeleton of the heart is influenced by a variety of signals, including those which are release in inflammatory responses (TNF alpha, Il-1beta, and TGF alpha; aldosterone and the stretching of the heart can also influence fibroblasts). In response to these signals, fibroblasts can change the amount of collagen they synthesize and change which of the many collagen genes are used (Rutschow, 2006).

Collagen is broken down by metalloproteinases (MMPs) and serine-proteases; these enzymes respond to inflammatory signals (Rutschow, 2006).

OTHER COMMENTS

Atherosclerosis is now considered a systemic disease and it can negatively affect the risk of stroke and the function of organs throughout the body (Tulenko, 2002).

When cardiac function is no longer capable of meeting the body’s demands for oxygenated blood, a person is said to undergo heart failure. An estimated 51,000 people die of heart failure per year in the United States and 4.8 million currently suffer from heart failure. Women compose more than half the patients with heart failure. Heart failure is estimated to cost $21 billion a year to the economy. The life expectancy following a diagnosis of heart failure is about 5 years and the death rate within the first year may reach 40%. Women suffer a greater mortality than women. An estimated 90% of patients suffer from hypertension. Smoking, obesity, and diabetes also contribute to heart failure (Hussey, 2003).

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Chylomicron

apoC-II

apoE

Apo B48

Endothelial Cell

Lipoprotein Lipase

Fatty acids liberated

Fatty acids liberated

Lipoprotein Lipase

Endothelial Cell

Apo B100

apoE

apoC-II

VLDL

ENDOCYTOSIS OF CHYLOMICRON

LDL RECEPTOR

Liver cell

Apo B48

ApoC-II

apoE

Chylomicron Remnant

Fatty acids liberated

Hepatic Lipase

Liver Cell

Apo B100

apoE

Cholesterol delivery to body cells

IDL

LDL

As cholesterol is added, 9ËF ³ Â FGsÍô

HDL become spherical

ABCA1 transfers cholesterol to HDL

Endothelial Cell

ApoA

apoE

HDL

apoC-II

ENDOCYTOSIS OF HDL AND ITS CHOLESTEROL

LDL RECEPTOR

Liver cell

ApoA

ApoC-II

apoE

HDL

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