Coronary heart disease is the leading cause of death in the world and was responsible for more than seven million deaths per year. With the exception of 1918 (the year of the Spanish Flu outbreak), cardiovascular disease has been the leading cause of death in the U.S. since 1900. Three quarters of the deaths caused by cardiovascular disease involve atherosclerosis (Yang, 2007). 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. 

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).  The risk factors which were originally identified for atherosclerosis, such as advanced age, high cholesterol levels, male gender, diabetes, and smoking, account for half of the incidence of heart disease (Fortunato, 2007). Only half of atherosclerosis patients have hyperlipidemia (Hennig, 2007). There is a heritable aspect to heart disease risk and estimates of the increased risk associated from a close relative who suffers from cardiovascular disease ranges from 1.5 to 7 times (Taraboanta, 2008).

     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).




     The lipids from the diet enter the body through 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 lacteals (a lymphatic capillaries in the small intestine).  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 the endothelial cells that line blood vessels 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. 


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).


     The liver cell synthesizes VLDL particles which contain apolipoprotein 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). 


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.  The liver converts IDLs to LDLs. 


LDL particles include an average of 2700 lipid molecules.  The only protein in LDLs is apoprotein B-100, composing 25% of the weight of the particle. Although the lipids are primarily cholesterol esters, there are some associated triglycerides. The polyunsaturated fatty acids in the LDL are prone to oxidation (Wang, 2008). 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.  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 particles can exist in both small and large sizes, both of which contribute to atherosclerosis. Small particles may be more readily oxidized while large particles contain more cholesterol. Large LDL particles are present in those with high fat diets and familial hypercholesterolemia (Mora, 2007).



The progression of plaques is associated with higher LDL levels and low LDL levels reduces plaque progression (Chhatriwalla, 2009). 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). Levels of apolipoprotein B 100 are increased in patients with diabetes and metabolic syndrome (Relimpio, 2002). Immunization against ApoB100 is showing promise as a mechanism to reduce atherosclerosis risk (Hansson, 2009).

Apolipoprotein A-IV (apoA-IV) is made by cells of the small intestine and is incorporated into chylomicrons. It reduces the risk of atherosclerosis by limiting the oxidation of LDL particles (perhaps by binding to them and acting as an antioxidant). Some alleles alter the function of the protein and increase atherosclerosis risk (Wong, 2007). Increased levels of apolipoprotein CI are associated with increased risk of atheroscelerosis (Hamsten, 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).  ApoE functions both in the metabolism of chylomicrons and VLDLs (in forward cholesterol transport) and promotes reverse cholesterol transport as well. ApoE4 is associated with higher LDL and triglyceride levels and lower HDL levels (Granier, 2007). The Apo E2 allele decreases the risk of heart attack as does the genotype E2E3 (Koch, 2008)

     It appears that genetic polymorphisms in other genes 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).


     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 and taken to the liver where they can be metabolized or excreted.    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.  ABCA1 in intestinal cells promotes the transport of cholesterol into the bloodstream, forming about 1/3 of the total number of HDLs. ABCA1 allows macrophages in blood vessel linings to remove their cholesterol (Attie, 2007). 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).


     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).


     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 exert other physiological effects that can affect heart disease risk. 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).


     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).Although variations in ABCA1 can increase atherosclerosis risk, they are rare in the population. Environmental stimuli have a greater effect in controlling the levels of ABCA1 expression. Physical activity and alcohol consumption increase ABCA1 expression and lower the risk of atherosclerosis (Hoang, 2008; Hoang, 2007).

Cholesterol is an essential component of cell membranes of all organisms because it reduces cell membrane fluidity. The majority of animal cells synthesize cholesterol and they can import additional cholesterol from the environment (such as from lipoproteins). Cholesterol cannot be completely metabolized into carbon dioxide. High levels of cholesterol can be toxic to cells as evidenced by the apoptosis triggered in macrophages which have absorbed excess cholesterol. Excess cholesterol can be exported to HDL particles which travel to the liver which can incorporate the cholesterol into bile so that it is excreted in feces (Attie, 2007).

Macrophages express ABCA1 to export the cholesterol they take up (both oxidized and unoxidized forms through their lipoprotein receptors (scavenger receptors) (Attie, 2007).

     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; Tsai, 2008).

    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).


A family of transcription factors, the sterol-regulatory element binding proteins (SREBPs) encode proteins which migrate from the endoplasmic reticulum to the nucleus when cholesterol levels are low. These transcription factors bind to regulatory elements in the genes which are responsible cholesterol synthesis (HMG CoA reductase, HMG CoA synthase, farnesyl diphosphate synthase, and squalene synthesis) and fatty acid synthesis (Acetyl CoA carboxylase, fatty acid synthase, stearoyl CoA desaturase, and lipoprotein lipase). Cholesterol and fatty acids compose the lipid portion of the cell membrane. The most successful drugs used to treat high cholesterol (statins) inhibit HMG CoA reductase and increase expression of LDL receptors which allow cells to clear cholesterol from plasma (Gutierrez, 2008)

Excess cholesterol in cell membranes has a number of negative consequences such as making cell membranes too rigid, reducing responses to factors promoting cell division, and conversion to toxic oxysterols (Gutierrez, 2008)


     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).



     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. 

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 capable of damaging essentially every cell type and intracellular organelle in the body. ROS ultimately increases the amount of calcium inside cells. ROS serve as signals in pathways which result in adhesion, inflammation, and apoptosis ( Houston, 2005).

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, smoking, high cholesterol, advanced age, and ketosis produce reactive oxygen species which cause oxidative stress. Higher levels of reactive oxygen species induces the inflammatory response (Tappia, 2006; Yang, 2007; Singh, 2006). As a plaque thickens, hypoxia occurs within the plaque. Increased production of ROS is a macrophage response to decreased oxygen availability (Mayr, 2008). Exposure to ROS can damage cells in a number of ways (such as reacting with cell membrane lipoproteins, interfering with mitochondrial respiration, inactivating ion channels, and damage to DNA (Yang, 2007). ROS can damage mitochondrial DNA, alter mitochondrial protein synthesis, and promote apoptotic steps such as the release of cytochrome c. Low levels of mitochondrial antioxidants promote atherosclerosis and increased levels offer protection from mitochondrial damage. Damage to mitochondria is associated with cardiovascular disease (Yang, 2007). C reactive protein increases the ROS produced by smooth muscle cells and endothelial cells (Singh, 2006). ROS decrease the available amounts of nitric oxide (NO) resulting in vasoconstriction and hypertension ( Houston, 2005).

Myeloperoxidase is a an oxidative enzyme produced by neutrophils and, to a lesser extent, by monocytes and macrophages. Its activity increases the oxidation of LDLs which are subsequently absorbed by macrophages to produce foam cells (Roberts, 2007).

Molecules which are part of the response to oxidative stress can be used as predictors of cardiovascular disease and heart attack. These molecules include 8-isoprostaglandin F 2α (8-iso-PGF 2α), myeloperoxidase, sICAM-1, C-reactive protein (CRP), and the matrix metalloproteinase MMP-9 (Roberts, 2007).

Oxidized LDL particles

     Once they have entered the blood vessel wall, LDL particles can be oxidized by reactive oxygen species (ROS).  High levels of LDL resulting from diet or genetic factors increase the accumulation of oxidized LDL particles (McLaren, 2009).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 attract macrophages and are quickly phagocytized, promoting the formation of foam cells (Wong, 2007; Pryor, 2000). Compared to normal cholesterol, oxidized cholesterol molecules have a greater ability to promote inflammation, migration of white blood cells, production of foam cells, and apoptosis (Poli, 2009). Endothelial cells, macrophages, and smooth muscle cells can absorb oxidized LDL particles after they bind to the receptor LOX-1 (lectin-like oxidized LDL receptor -1). Given that the cells in atherosclerotic plaques at high levels, LOX-1 seems to play a role in atherosclerosis (Aramaki, 2008). The OLR1 gene produces the receptor responsible for the absorption of oxidized LDL into endothelia (Nordlie, 2005). Oxidized LDL particles promote inflammation, vasoconstriction, platelet aggregation, and the retention of macrophages in blood vessel walls (Singh, 2006).

One of the by-products of LDL oxidation is LPC (lysophosphatidylcholine). Even at low levels, this oxidation product can attract macrophages and induce the secretion of inflammatory cytokines. Higher levels of LPC occur in larger plaques with a necrotic core. High levels of LPC are found in the plasma of patients suffering from hyperlipidemia (Olofsson, 2008).



     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). The enzyme paraoxonase 1 (PON1) functions as an antioxidant associated with HDL particles and polymorphisms are associated with heart disease (Fortunato, 2007).

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). Hydrogen peroxide can serve as a signaling molecule which increases cell division in blood vessels. A protein involved in hydrogen peroxide’s signaling pathway, heterogeneous nuclear ribonucleoprotein C (hnRNP-C), can be expressed in higher levels in plaques supporting a role of hydrogen peroxide in the promoting the proliferation of cells during plaque formation (Panchenko, 2009).


One of the earliest steps in atherosclerosis is the migration of monocytes to the blood vessel lining where they become macrophages, perform phagocytosis of lipoprotein particles, become foam cells, and signal smooth muscle cells to migrate from the tunica media to the developing plaque. Smooth muscle cells and extracellular matrix form a fibrous cap around the necrotic center of the plaque and the plaque is initially stable. As the plaque thickens, smooth muscle cells undergo hypoxia (because less oxygen can reach them through the thickening wall) and increase their uptake of lipoproteins. However, the macrophages can continue to release matrix metalloproteinases which degrade the collagen of the fibrous cap and inflammatory signals which induce apoptosis in surrounding cells. As the plaque surface is degraded, it may leak and contact platelets, initiating clot formation (Schrijvers, 2007).

Macrophages absorb LDL particles from the blood using LDL receptors through a regulated process. Once LDL particles are modified, however (by oxidation, acetylation, or other processes), they can be absorbed through receptor mediated endocytosis using different receptors, such as those of the scavenger receptor class A type I/II (for acetylated LDLs), CD36, LOX-1, macrosialin (for oxidized LDLs), CD14, and LDL receptor-related protein (for mildly oxidized LDL particles which can also bind to LDL receptors). Oxidized LDL particles cannot be effectively degraded and begin to accumulate in macrophage lysosomes, resulting in foam cell production (Schrijvers, 2007; Alfred, 2007). Macrophages produce superoxide and nitric oxide which in turn oxidize the LDL particles (Wang, 2008) As oxidized LDL particles accumulate, macrophages increase their expression of proinflammatory signals, reactive oxygen species, and increase the activation of metalloproteinases (Schrijvers, 2007). Macrophages secrete inflammatory cytokines, absorb lipids, and produce reactive oxygen and nitrogen species. Macrophages are thus cells which promote inflammation, and as they absorb more lipids, they promote more inflammation until a chronic state of inflammation can be reached (Gutierrez, 2008).

New blood microvessels may begin to form in the plaque, introducing platelets and red blood cells. Red blood cells can be oxidized and phagocytized by macrophages, although this releases iron which may further oxidize LDLs. Platelets can also be phagocytosized by macrophages which results in pro-atherosclerotic changes in the macrophages. These microvessels may ruptures, perhaps because of the action of metalloproteinases, and intraplaque hemorrhage often occurs in advanced atherosclerosis (Schrijvers, 2007).



Although cholesterol is a relevant factor in atherosclerosis, atherosclerosis is best understood as an inflammatory disorder (Hansson, 2009). 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).  VCAM-1 is expressed at high levels in atherosclerotic plaques (Petersen, 2008).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).  Foam cells represent the foundation of fatty streaks, the beginning of atherosclerotic plaques. These fatty streaks may never progress to a level of clinical significance or they can form more complex plaques, known as atheromas, which also incorporate activated T cells and foam cells derived from smooth muscle cells (McLaren, 2009).

T helper cells, cytotoxic T cells, and natural killer cells all migrate to atherosclerotic lesions. Although their roles are not fully known, they can contribute to inflammation (Hansson, 2009). The production of additional smooth muscle and extracellular matrix causes the blood vessel wall to thicken and the lumen to shrink (Tulenko, 2002). Inflammatory signals and oxidized LDL particles cause endothelial cells to express adhesion molecules (such as sICAM-1 and sE-selectin) which increase the migration of macrophages into the blood vessel wall (Roberts, 2007). The signal endothelin-1 attracts smooth muscle cells and promotes their division, the remodeling of the surrounding tissue, and the release of inflammatory signals (Ivey, 2008). C-reactive protein was one of the first inflammatory markers recognized to be elevated in association with heart disease (Hansson, 2009).

     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; Katakami, 2009). One allele of interleukin 6 decreases risk of atherosclerosis and hypertension (Hulkkonen, 2009). Some evidence suggests that polymorphisms in genes which mediate inflammation (such as TNF beta) affect risk of heart disease (Porto, 2005). Although interferon gamma catalyzes a number of reactions which decrease atherosclerosis risk (such as oxidation of cholesterol), it promotes the formation of foam cells from macrophages (by increasing their cholesterol uptake). The overall result of increased production of interferon gamma is to increase atherosclerosis risk (McLaren, 2009).

Many of the endothelial inflammatory molecules which cause the progression of atherosclerosis are produced in response to the transcription factor KB which is in turn induced by factors such as oxidized LDL, oxidizing agents, and the stress caused by non-laminar flow through a blood vessel. Nuclear factor KB is inhibited by cyclopentenone prostaglandins are anti-inflammatory and reduce atherosclerosis risk (Gutierrez, 2008).

Unstable plaques are associated with a higher degree of inflammation along the entire blood cells than stable plaques (Tavora, 2009). About a fifth of plaques are infiltrated by T lymphocytes which contribute to inflammation (Tavora, 2009).

      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).


Serious atherosclerosis often occurs with a number of autoimmune diseases such as lupus, rheumatoid arthritis, and systemic sclerosis. If atherosclerosis is an autoimmune disorder, then vaccines which promote tolerance to self might hold promise in its treatment (Blasi, 2008). Autoimmune diseases, such as rheumatoid arthritis and lupus, produce chronic states of inflammation and those who suffer from rheumatic autoimmune diseases also experience higher levels of atherosclerosis (Hahn, 2007; de Leeuw, 2009). The monocytes of patients of type 2 diabetes express more proteins associated with inflammation than those of normal individuals (Giuletti, 2007). Immune reactions follow exposure to a specific antigen. Oxidized LDL particles are the primary autoantigen which triggers the response of macrophages and T cells, although heat shock proteins may also contribute (Hansson, 2009).

Lymphocytes can be present in lesions from their initiation and their reaction against self may worsen the plaque. Reductions of lymphocyte numbers can decrease the size of a plaque. Variants of the tyrosine phosphatase gene is associated with both autoimmune diseases and atherosclerosis. Autoimmune reactions act against oxidized LDL particles and heat shock proteins. Heat shock proteins are part of the stress response to insure the proper folding or proteins. They are expressed at higher levels in plaques and antibodies against heat shock proteins occur in atherosclerosis. Apoptosis can produce autoantibodies. Oxidized LDL particles can react with autoantibodies ont their own or (in a rare genetic disease) after binding to the plasma protein beta2 glycoprotein I (Blasi, 2008). Oxidation can change proteins, forming protein adducts which antibodies may bind (Kurien, 2008)

In response to a variety of stresses, including oxidative stress, cells produce heat shock proteins. While the heat shock proteins which remain within cells are protective, those which are released from cells attract immune cells. (Immune cells react to heat shock protein 90 especially, since it is similar to the heat shock protein produced by many bacteria during infection). Heat shock protein 90 is produced in plaques by smooth muscle cells and is present in higher levels in the sera of patients with atherosclerosis. Plaques can contain T cells which react against HSP90 in atherosclerotic plaques, indicating that progression of atherosclerosis can involve an autoimmune reaction against the heat shock proteins produced within plaques. The reaction against HSP90 also seems to be involved in other autoimmune diseases such as rheumatoid arthritis and lupus (Businaro, 2009). Infection by a number of different organisms can trigger a number of autoimmune diseases and is a candidate for a causal mechanism of atherosclerosis. Infections agents may release heat shock proteins during the course of an infection. The similarity of the protein sequences of bacterial and human heat shock protein sequences is about 70%. A high number of the lymphocytes in atherosclerotic plaques can react against microbes such as Chlamydia and live microbes can be found within plaques (Blasi, 2008).

Diabetics have a much higher production of heat shock proteins and IgA antibodies which react against them (Blasi, 2008). Dendritic cells ingest oxLDL and heat shock proteins and present them to T cells, recruiting their reaction in atherosclerosis. Hypercholesterolemia seems to be an essential factor in initiating this autoimmune response (Blasi, 2008).

Autoimmune diseases sometimes follow an infection by agents such as Chlamydia, Helicobacter, herpes, hepatitis, and other agents. For example, there is support that an immune reaction against the heat shock proteins of an infectious agent could prepare the immune system to combat the host heat shock proteins released in a plaque. It may be that Chlamydia can even establish a chronic infection at plaque after escaping from macrophages which have ingested it (Blasi, 2008).

Dendritic cells are the most important APCs. They bind to autoantigens in the subendothelial space and subsequently attract T cells (Blasi, 2008).

Atherosclerosis may involve a loss of Treg cells given its autoimmune reaction and reduction of TGF function (Blasi, 2008).


Although heart disease affects health later in life, there are lifestyle attributes of young people, such as inactivity, diets rich in fat or simple carbohydrates, and smoking, which can predispose individuals to atherosclerosis later in life. Exercise and diet modification in young people with this lifestyle results in measurable changes in levels of inflammatory signals and oxidative stress agents (Roberts, 2007).  

    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.  A number of compounds common in fruits and vegetables inhibit oxidation and may offer protection from the effects of environmental pollutants (Hennig, 2007).Important dietary antioxidants include vitamin E, β carotene, and lycopene (in tomatoes) (Ignarro, 2007). Evidence indicates that lycopene offers protection from the oxidation of LDLs, decreases cholesterol synthesis. Polyphenols in fruit juices, tea, coffee, red wine, cereal, and other sources are the most abundant antoxidants in the diet (Ignarro, 2007). Vitamin C reduces blood pressure and promotes vasodilation and diets rich in vitamin C are associated with decreased rates of heart disease ( Houston, 2005).

Garlic, green and black tea, has been shown to blood pressure ( Houston , 2005).More than 4000 different flavonoids (flavonols, flavones, and isoflavones) are known in fruits, vegetables, tea, and other sources. They reduce levels of ROS and the risk of atherosclerosis, heart disease, high blood pressure, and stroke. Some , such as diadzein and genistein in soy, lower blood cholesterol. Quercetin from red wine lowers levels of oxidized LDL ( Houston, 2005).

Vitamin B6 increases the production of the anti-inflammatory prostaglandin E1 which promotes vasodilation and inhibits platelet aggregation (Das, 2003). Folic acid is a factor determining the production of nitric oxide and tetrahydrobiopterin (H4B) (Das, 2003). Sterols from margarine decrease LDL levels (Ho, 2005).

The presence of whole grain foods in the diet decreases the risk of cardiovascular disease (Mellen, 2008). It is not known how fiber decreases atherosclerosis risk, although it may involve a reduction of the infloammatory signal C-reactive protein (Ignarro, 2007).

The digestion of food can produce bioactive peptides which can act in a way similar to hormones. They range from 2 to 20 amino acids in size. Some peptides from dairy products, fish, soy, and other products (such as casokinins and lactokinins) lower blood pressure by inhibiting ACE. While some depend on proline residues, others end in tyrosine or phenylalanine. Some bioactive peptides are potent antioxidants, especially if they possess a Pro-His-His sequence (Erdmann, 2008).

Increased sodium can increase platelet activity, stroke risk, and heart disease ( Houston, 2005).


     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).


     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).


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).


The gene peroxisome proliferator-activated receptor-gamma2 (PPAR-_2) is involved in the regulation of lipid and glucose metabolism and the formation of fat cells. There are different alleles of this gene which vary physiologic responses to dietary fat and provide a mechanism for gene-diet interaction in the progression of metabolic syndrome (Andreassi, 2008). Antioxidants from consumption of cruciferous vegetables (such as broccoli and cauliflower) decrease risk of heart disease but only in those with functional GSTT1 enzymes (Andreassi, 2008).



Endothelial nitric oxide synthase produces nitric oxide from L-arginine which functions in a protective role against atherosclerotic changes. It promotes vasodilation and inhibits inflammation, oxidation of lipoproteins, coagulation and platelet plug formation. Certain alleles of the gene increase risk of heart disease, especially in smokers (Rios, 2007).

L-arginine reduces monocyte adhesion, promotes vasodilation, and lessens the severity of atherosclerosis. L-arginine is the natural source of nitric oxide which removes ROS and promotes vasodilation. Oxidized LDLs may decrease the uptake of l-arginine and thus deplete NO, leading to an increase in ROS (Ignarro, 2007).

The endocannibinoid system plays a role in regulating appetite. It has long been known that the active compound in marijuana, THC, could promote food craving and weight gain. Obesity is associated with higher levels of natural endocannibinoids. While blocking CB1 receptors would be beneficial due to the resulting weight loss, increased adiponectin, decreased lipid levels, and decreased insulin resistance, decreased activity of CB2 receptors worsens atherosclerosis (Szmitko, 2008)


An inactive lifestyle increases the expression of vascular NADPH oxidase which increases ROS production (Laufs, 2005; Ignarro, 2007). Exercise (such as walking 4 km per day) reduces the severity of heart disease in those with atherosclerosis (Sato, 2008).

Exercise decreases the risk of atherosclerosis, hypertension, lowers resting blood pressure and heart rate, increasing antioxidant levels, and promoting vasodilation (Zanesco, 2007). The levels of endothelial adhesion molecules which increase the migration of macrophages into the blood vessel wall can be reduced with exercise (Roberts, 2007).MMP levels can be decreased in with exercise and diet modification (Roberts, 2007). Exercise increases the number of antioxidant enzymes (like superoxide dismutase) and other antoxidants (such as acorbic acid) (Alfred, 2007). Although exercise reduces the risk of a number of conditions which are aggravated by oxidized molecules, oxidized particles are released during exercise and additional research is required to determine how exercise lowers atherosclerosis risk (Alfred, 2007).


Adiposopathy (“sick fat”) refers to the accumulation of visceral fat and the hypertrophy of fat cells. Hypertrophied fat cells release fatty acids into circulation. These fatty acids eventually decrease the liver’s ability to metabolize fatty acids and its ability to respond to insulin. The liver produces C-reactive protein (under the influence of interleukin 6), an indicator of inflammatory level. These fatty acids may also decrease the ability of muscle to metabolize fatty acids (referred to as “inflexible muscle) and result in the deposition of lipids in muscle cells. These free fatty acids also increase the production of inflammatory signals and may impair the ability of the pancreas to produce insulin (Bays, 2009).

Although subcutaneous fat increases the risk of heart disease, the location of this subcutaneous fat is relevant to the degree of risk. Abdominal adipose increases atherosclerosis risk moreso than adipose in other regions. In addition to the subcutaneous adipose under the skin, adipose can be found around viscera in body cavities. This visceral adipose (which can only be measured using MRI or CT) is a greater determinant of heart disease risk than abdominal subcutaneous fat (Celik, 2009). The fat around the epicardium can release pro-inflammatory cytokines (such as TNF-alpha, plasminogen activator inhibitor-1, and free fatty acids) at levels which are higher than those of abdominal fat (Tavora, 2009).

Adiponectin (a hormone secreted by fat) increases the production of ABC1 transporters in macrophages and, thus, cholesterol efflux into HDL particles in reverse cholesterol transport (Tsubakio-Yamamoto, 2008).


     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. 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). The angiotensin system and the sympathetic division of the ANS regulate blood volume and pressure and can contribute to hypertension.

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). Angiotensin II increases the production of ROS in endothelial cells ( Houston, 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).

In addition to the classical components of the rennin-angiotensin system (the kidney, liver, and lung), the reactions which convert angiotensinogen to angiotensin I to angiotensin II can also occur locally in tissues including the heart, blood vessel linings, the kidney, and brain (Fukuda, 2008). The angiotensin system is also expressed in the bone marrow where it promotes the differentiation of bone marrow cells in to cells which can migrate to the blood vessel lining. Angiotensin II can increase monocyte migration to the blood vessel lining when expressed there (Fukuda, 2008).

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). Increased activation of the sympathetic nervous system can contribute to coronary heart disease (Narita, 2007; Wehrens, 2004).

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).


     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). The systemic increase in inflammatory state in many diabetes patients increases atherosclerosis risk (Ray, 2009).

     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). 


     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. When plaques rupture, they introduce tissue factor into the blood which causes clot formation and may result in death (McLaren, 2009).

     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; Green, 2008).Elevated fibrinogen levels in the age bracket of mid-20s to mid-30s increases atherosclerosis risk later in life (Green, 2009). Elevated levels of thrombomodulin (TM) lower atherosclerosis risk. TM allows thrombin to activate protein C which degrades clotting factor VIII (Aleksic, 2008). 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). 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).


     Programmed cell death, apoptosis, can occur after hypoxia (reduced oxygen supply to a tissue such as the heart), 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).

In advanced atherosclerotic lesions, a number of cell types (such as macrophages, T lymphocytes and smooth muscle cells) undergo apoptosis which can be induced by high levels of intracellular cholesterol, oxidized LDLs outside cells, and the inflammatory signals and ROS released by macrophages. Apoptotic cells are normally phagocytosized by macrophages and dendritic cells. Although this does occur inside plaques, it is impaired because the macrophages are already full and several aspects of atherosclerosis (such as the abundance of oxidized LDL particles which compete for phagocytosis and the autoantibodies which bind to these cells) inhibit normal phagocytosis. The cell membranes of apoptotic cells express phosphatidylserine which promotes the formation of clots upon contact with platelets. Although much of the phagocytosis performed by macrophages contributes to atherosclerosis, the removal of oxidized LDL particles and apoptotic cells is a necessary function which limits damage in the region (Schrijvers, 2007).

     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).

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


     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). DNA from different types of microbes (both disease-causing microbes and those which exist in a commensalist relationship) has been found in atherosclerotic plaques (Renko, 2008).

      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).

Chlamydia pneumoniae is associated with increased prevalence of cardiovascular disease (Wang, 2007). Chronic HIV infection worsens atherosclerosis (Lorenz, 2007). Other infectious agents which have been considered for a role in cardiovascular disease include Heliobacter pylori (Broxmeyer, 2004). There are a number of diseases which have been reported to affect risk of heart disease (such as cytomegalovirus (CMV), herpes simplex virus-1 (HSV-1), Helicobacter pylori and Chlamydia pneumoniae). There is an increased frequency of these disease-causing agents associated with lower overall education and this may be responsible for the inverse relationship between education level and heart disease incidence (Aiello, 2008).


     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). Alcohol decreases platelet activity, promotes vasodilation, inhibits apoptosis, and lowers the levels of certain clotting factors. Alcohol and polyphenols from wine increase the production of certain fibrinolytic compounds (such as tPA) which lessen the probability of clot. The components of red wine (other than alcohol) lessen inflammation and platelet aggregation (Booyse, 2007). 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). One of the components of red wine which is being considered for its reduction of heart disease risk is resveratrol. Resveratrol decreases atherosclerosis levels in mice fed high fat diets (Rocha, 2009).

Light to moderate drinkers have a lesser probability of developing heart disease than nondrinkers or heavy drinkers (Booyse, 2007). Those who begin drinking alcohol when middle age experience a drop in mortality and atherosclerosis severity (King, 2008). Binge drinking, however, increases the risk of atherosclerosis (Rantakomi, 2008).

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.  Different alleles of the alcohol dehydrogenase gene affect the beneficial results of moderate alcohol consumption (Andreassi, 2008).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). While alcohol consumption generally increases HDL levels, gender and ethnic differences are observed in the effects of alcohol on LDL and triglyceride levels (Volcik, 2008)


     Throughout the world, 1.3 billion people are smokers. Most of those who smoke in the U.S. eventually suffer from cardiovascular disease. About 100,000 deaths from cardiovascular disease are linked to smoking, including 40,000 associated with second-hand smoke (Yang, 2007). Smoking is a risk factor for developing atherosclerosis early in life ( Henderson, 2008; Liang, 2009; Thomas, 2008). 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.   In middle-aged women, smoking may be responsible for half of all cardiovascular problems (Bermudez, 2002). Exposure to cigarette smoke is associated with atherosclerotic changes in blood vessel walls in young adults, children, infants, and the umbilical cords of newborns. Exposure to cigarette smoke increases the production of macrophage-attracting signals. Smoking causes mitochondrial changes in the placenta (Yang, 2007).

Nicotine is a vasoconstrictor which increases blood pressure.  Smoking reduces HDL levels (Van Lennep, 2002). Oxidizing agents are included in the more than 4000 chemical compounds produced in cigarette smoke. Cigarette smoking can cause mutations which promote atherosclerosis (Manfredi, 2007). Smoking increases the risk of atherosclerosis, damages endothelial cells and increases fibrinogen concentrations, the risk of clot formation, ROS and inflammation (Lavie, 2007; Hussey, 2003). Smoking causes mitochondrial damage and increased necrosis in human monocytes and smooth muscle cells (Yang, 2007). Smoking has a number of deleterious effects on endothelial cells such as the expression of heat shock proteins, abnormal mitochondrial function, and the suppression of the cell cycle in G1 which inhibits repair( Henderson, 2008). Smoking results in abnormal functions in both the endothelial lining and smooth muscle, primarily due to an increase in oxidative stress and increases in inflammatory signals (Antoniades, 2008; Lavie, 2008)

Smoking interacts with other risk factors to worsen their effects. The expression of proteins involved in inflammation (C reactive protein, interleukin 6, sICAM-1, and selectins) is associated with increased risk of cardiovascular disease. The levels of these proteins are elevated in smokers (Bermudez, 2002). Sleep apnea is a risk factor for cardiovascular disease, apparently because of the increased production of pro-inflammatory stimuli. Smoking interacts with sleep apnea to increase cardiovascular disease even more (Lavie, 2007; Lavie, 2008)

Genetic polymorphisms result in different risks resulting from smoking in different individuals. Nonfunctional mutations in enzymes that detoxify ingested compounds, such as GSTM1 and GSTT1, are associated with higher incidence and greater severity of heart disease among smokers. These enzymes not only detoxify carcinogens in cigarette smoke, they also offer protection from environmental pollutants (Manfredi, 2007). Different alleles of ApoE and GST enzyme genes alter the risk of atherosclerosis associated with cigarette smoking (Andreassi, 2008).


     Gender has implications in the calculation of risk of cardiovascular disease. Sex steroid hormones can affect both fat cells, the activity of enzymes involved in cholesterol metabolism (such as lipoprotein lipase), and reduce the size of VLDLs (Vaidya, 2008).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).  Estrogen levels are associated with more favorable lipid profiles although after menopause women typically experience higher cholesterol, LDL, fatty acids and lower HDL levels(Vaidya, 2008).

     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).

Men have a shorter lifespan than women in the vast majority of countries throughout the world (Martin, 2007). Until age 75, male deaths due to atherosclerosis are 2 ½ to 4 ½ times higher than those of women (Martin, 2007; Martin, 2003a).

Some of the effects of androgens seem to promote atherosclerosis while others offer some degree of protection from atherosclerosis. Androgens seem to have gender-specific effects. Artery walls and macrophages express more androgen receptor in males than in females. In men, but not women, androgen exposure promotes macrophage migration, adhesion to endothelial linings, and foam cell production (Martin, 2007; Martin, 2003a). In women, increased androgen levels in polycystic ovary syndrome are associated with increased cardiovascular disease (Martin, 2007; Martin, 2003a). The adrenal androgen DHEA promotes foam cell formation from macrophages (Martin, 2003b). In animal studies, increasing testosterone levels decreases the severity of atherosclerosis. Decreases in testosterone levels are typical in men as they age (Li, 2008)

Men with abnormally low levels of testosterone suffer and increased predisposition to heart disease. Low testosterone levels may contribute to metabolic disease (Martin, 2007; Martin, 2003a). Low androgen levels are associated with the metabolic syndrome whose symptoms include low HDL levels and elevated LDL levels (Wu, 2003; Simon, 1997).In animal studies, increasing testosterone levels decreases the severity of atherosclerosis. Decreases in testosterone levels are typical in men as they age (Li, 2008). Different androgens reduce size of VLDLs in men (testosterone) compared to women (DHEA) (Vaidya, 2008). Increased sex hormone binding levels reduce the number of VLDLs and LDLs but increase the number of HDLs (Vaidya, 2008).


Some of the changes in the endothelial lining which initiate the process of atherosclerosis can be caused by environmental pollutants such as PCBs and toluene. These changes include the release of inflammatory signals and the attraction of monocytes. Persistent organic pollutants and heavy metals worsen atherosclerosis and levels of atherosclerosis are higher around sites of contamination. PCBs, arsenic, and other pollutants can increase the production of ROS. High levels of mercury exposure are associated with oxidized LDL. (Toborek, 1995, Hennig, 2007). Arsenic increases the production of inflammatory signals, ROS, and signals which attract monocytes and it worsens atherosclerosis (Lee, 2005, Bunderson, 2002; Bunderson, 2004). this risk is higher in individuals who possess specific alleles of p53 and glutathione S-transferase M1, T1, and P1 (Wang, 2007). Methylmercury increases the risk of heart disease (Stern, 2005).

Increased exposure to air pollution increases the expression of proteins which contribute to atherosclerosis such as C-reactive protein, ICAM-1, and proteins involved in clotting (Hennig, 2007). Motorcycle exhaust particles increase vasoconstriction and the production of ROS (Tzeng, 2003). Fine particles from automobile exhaust cause oxidative stress and promote atherosclerosis (Greene, 2008).


Cardiovascular disease occurs more frequently in those with mood and psychiatric disorders. Activity in the amygdala may result in a link between these phenomena. Higher levels of preclinical atherosclerosis have been associated with greater activity in the amygdala and more extensive connections between the amygdala and the pACC (perigenual anterior cingulate cortex) (Gianaros, 2009). Depression and anxiety are risk factors for heart disease (Narita, 2007; 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).

Shift work has been identified as a factor associated with increased risk of heart disease. The risk may stem from added stress, night shifts, or levels of noise or pollution encountered at the job site (Haupt, 2008). Heart attacks are often preceded by periods of emotional distress. During stress, a number pf clotting factors increase in concentration including fibrinogen, clotting factors VII and VIII, and von Willebrand factor. Inflammatory signals such as TNF and interleukin 6 increase during emotional distress (Steptoe, 2008).


     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).


Cardiovascular disease is often associated with osteoporosis and other bone disorders. Osteoprotegerin (OPG) is a local hormone (of the TNF family) which regulates the production of osteoclasts. Mouse studies indicate that OPG offers protection from the calcification which often accompanies atherosclerotic lesions although human studies that higher levels of blood OPG are associated with higher levels of cardiovascular disease (Van Campenhout, 2009). Increases in OPG levels are associated with increased fibrinogen levels and represent an independent variable in atherosclerosis, especially in postmenopausal women (Shargorodsky, 2009).


When blood vessel linings are damaged, young, healthy blood vessels can regenerate well through two separate processes. First, the existing endothelial cells can divide and replace lost or damaged cells. Secondly, signals from the damaged area can stimulate the release of bone marrow cells into circulation called endothelial progenitor cells (EPCs). These cells migrate to damaged regions and interact with existing endothelial cells to repair the tissue (Fadinin, 2007).

Many of the known risk factors for atherosclerosis decrease the numbers of EPCs (which suggests that a component of their effect on cardiovascular disease is through this effect on EPCs). Fewer EPCs are produced with advanced age, in individuals with hypertension, in diabetics, in hyperglycemia, during oxidative stress, due to smoking, with increased amounts of atherogenic lipoproteins (LDLs, oxidized LDLs, VLDLs), decreased HDLs, inflammation, and homcysteine. Exercise, estrogen, quitting smoking, reducing blood pressure with ACE inhibitors, and lowering excessive serum levels of cholesterol and glucose increase the number of EPCs (Fadinin, 2007).


High maternal cholesterol levels and high levels of C-reactive protein (which can be elevated due to inflammation, oxidative stress, and smoking) increase the risk of atherosclerosis in children (Liguori, 2008). Maternal hypercholesterolemia increases the monocyte migration into blood vessel walls and fatty streak formation in fetuses (Napoli, 1997; Napoli, 1999).


Sleep apnea is an independent risk factor for atherosclerosis. It is thought that intermittent hypoxia increases the production of pro-inflammatory signals which initiate atherosclerosis (Levy, 2009). Sleep apnea is also associated with an increase in volume of atherosclerotic plaques (Turmel, 2009).

HIV infection and treatment with anti-viral therapy increase the risk of atherosclerosis (Calza, 2008)

Patients who suffer from COPD are twice as likely to suffer from cardiovascular disease. Although some of this comorbidity may stem from the role of common risk factors, such as smoking, there seems to be common pathological mechanisms which underlie both conditions. These may include an excessive degree of inflammation and remodeling of tissues by metalloproteinases (Back, 2008)



     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).

      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).


     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). MMPs are also active in atherosclerotic plaques where their degradation of collagen and elastin can disrupt the plaque (Roberts, 2007).


Primary cilia may play a role in atherosclerosis given that lesions typically develop in areas which contain more primary cilia. As lipid levels increase, the numbers of primary cilia increase as well (van der Heiden, 2008)

     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).