People often think of atherosclerotic disease as a problem that primarily afflicts developed Western countries, but it is a global health problem. Atherosclerosis is a complex process by which arteries become progressively narrowed, impairing the supply of oxygen and nutrients to tissues.
Explain the mechanisms by which poorly controlled diabetes and poorly controlled hypertension contribute to heart disease. Discuss evidence-based strategies for prevention of atherosclerosis, diabetes, and hypertension.
The primary function of the heart and blood vessels is to transport oxygen, nutrients, and byproducts of metabolism.
Note also the the heart is just like any other tissue in that it needs a continuous supply of oxygen and nutrients. The next image is a scanning electron micrograph of an arteriole showing the layers of the artery and blood cells criculation within the lumen adjacent to the endothelium.
This three layered structure is characteristic of both veins and arteries, but veins have thinner walls, because the media is less developed. Another difference between arteries and veins is that veins can have internal valves, which help in maintain blood flow back to the heart. The endothelial cells that line blood vessels provide an active, dynamic interface between the blood stream and the arterial wall. Atherosclerosis is a disease process which is triggered by sometimes subtle physical or chemical insults to the endothelial cell layer of arteries. Homocysteinemia, which results from an inherited metabolic defect that leads to very high levels of the homocysteine, a metabolite of methionine; high concentrations are toxic to the endothelium. Under normal conditions, leukocytes in the blood do not adhere to the endothelial cells that line all blood vessels. The endothelial cells begin to produce cell surface adhesion molecules such as VCAM-1, causing monocytes and T-lymphocytes to adhere to the endothelium and then migrate beneath it by squeezing between the endothelial cells. The endothelial cells also change shape, and the tight junctions between endothelial cells loosen, increasing the permeability to fluid, lipids, and leukocytes.
Fatty streaks are the first signs of atherosclerosis that are visible without magnification.
The right side of the artery has a fairly normal appearance, but an atherosclerotic plaque has evolved on the left side. The image below illustrates the evolution of atherosclerotic plaques and also indicates that there are two possible forms of evolution. In its early stages atheroslerotic disease is asymptomatic, but as the condition progresses, blood supply can become increasing compromised as the blood vessels narrow.
The three videos below provide additional information on some of the more serious sequelae.
It is now well-established that the risk of cardiovascular disease and mortality from coronary artery disease is directly correlated with the concentration of cholesterol in blood. The evidence that high LDL concentrations play a causal role in coronary artery disease (CAD)is quite compelling. Many investigators have convincing demonstrated a progressive increase in risk that correlates directly with LDL concentrations.
Genetic studies analyzing SNPs show that SNPs affecting LDL cholesterol are consistently related to risk of myocardial infarction. The presence of LDL in atherosclerotic plaques provides additional evidence of its direct involvement. Statins act by inhibiting HMG-CoA reductase and shutting off internal cholesterol production. While statins are effective in reducing LDL cholesterol levels, they can be associated with side effects. Muscle damage manifest as pain, tiredness, or weakness is the most common side effect and ranges from mild discomfort to difficulty in climbing stairs or walking.
Liver damage: Statins can also damage liver cells, resulting in elevated levels of liver enzymes in blood.
Because of their effectiveness in reducing CAD in patients at high risk, some advocated expanding the use of statins to people who did not necessarily have elevated cholesterol levels.
Blood levels of HDL are inversely related to risk of coronary artery disease, and it was thought that low HDL levels represented an independent risk factor.
Genetic variants that are associated with high HDL levels are not consistently associated with a reduced risk of CAD.
How is it possible that low HDL is associated with increased risk, but the relationship is not causal? In 1949, Ancel Keys warned of a possible epidemic of obesity that would be caused by a combination of economic and social conditions. Excess body fat is indicative of a metabolic condition that is associated with an increased risk of adverse health events including cardiovascular disease, some cancers, type 2 diabetes, hypertension (high blood pressure), dyslipidemia (for example, high total cholesterol or high levels of triglycerides), stroke, gallstone disease, sleep apnea, and gastroesophageal reflux disease (GERD). Obesity is most commonly quantified by calculating the body mass index (BMI) which expresses total body weight in kilograms indexed to height (expressed as meters squared). For individuals between the ages of 2-20 years of age, classification of obesity uses a nomogram that establishes the individual's percentile of BMI based on age and gender. With obesity there is increased delivery of fatty acids to muscle cells, and this leads to the dysfunctional interaction between insulin and its receptors a defect in insulin signaling through insulin receptor substrate.
The Centers for Disease Control and Prevention (CDC) has published a list of community strategies and guidelinesthat can be undertaken to reduce obesity. The rise in blood sugar after a meal or snack stimulates the secretion of the hormone insulin from the β-cells in the pancreas. Type I Diabetes (also called insulin-dependent diabetes or juvenile diabetes) results from an autoimmune process that destroys the β-cells, causing a lack of insulin.
In contrast, Type II Diabetes (also known as adult onset diabetes or non-insulin dependent diabetes) is primarily due to insulin resistance. Both type 1 diabetes and type 2 diabetes are independent risk factors for coronary artery disease, and diabetes may predispose to multiple small coronary and peripheral vessels.
The complications of diabetes develop gradually, but they can be disabling and can eventually be fatal.
Increased susceptibility to infection: Poorly controlled diabetes is associated with an increased risk of soft tissue infections and gum disease. An increasing number of patients have diabetes and its attendant complications, and this trend is predicted to continue.
Type 2 diabetes increases the risk for coronary artery disease by 2 to 4 times in the overall population. This prospective cohort study followed 84,941 female nurses from 1980 to 1996; the subjects were initially free of diagnosed cardiovascular disease, diabetes, and cancer. After 6 years of follow-up, the study found that overweight or obesity was the single most important predictor of type 2 diabetes. Tuomilehto J, et al Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. A Finnish group conducted a randomized clinical trial to test whether lifestyle changes could prevent type 2 diabetes. Subjects were randomly assigned to an intervention group receiving individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity.
An editorial on this report acknowledged that it convincingly showed that type 2 diabetes was delayed in the short term, but raised the question of whether the lifestyle changes could be maintained and how long the reduced incidence of diabetes would last. The studies in the previous section focus on the efficacy of lifestyle changes in preventing the development of type II diabetes.
In the 1970s several observations pointed to a potential relationship between diet and coronary heart disease. This study, using the Nurses' Health Study cohort, analyzed data from 80,082 women free of diagnosed coronary heart disease (CHD) in 1980. In essence, this analysis uses different percentages of carbohydrate intake as a reference (the horizontal purple line) and compares the risk expected with substitution of a given percentage of energy from fat (trans fat, saturated, monounsaturated, or polyunsaturated). The Women's Health Initiative conducted a very large randomized clinical trial to examine the effect of a low fat diet on breast cancer and heart disease.
Dean Ornish has also advocated a multi-pronged approach with lifestyle changes that include low-fat vegetarian food, smoking cessation, regular exercise, and meditation.
The studies described above point to the potential importance of different types of dietary fat.
This example shows a triglyceride (fat) molecule with three saturated fatty acids with the same number of carbon atoms in each of the three chains. Stearic acid, 18:0 is a saturated fatty acid because it has no double bonds between the carbon atoms in the hydrocarbon chain. EPA is a highly polyunsaturated fatty acid that is found in fish oil from deep water fish like salmon. DHA is also a highly polyunsaturated fatty acid that is found in fish oil from deep water fish like salmon. Triglycerides from naturally occurring sources can have a wide variety of fatty acids, and the table below illustrates some of this variability.
Note in the table that canola oil and olive oil have a very high percentage of oleic acid, a monounsaturated fatty acid with 18 carbon atoms and a single double bond in the 9 position. Many clinicians recommend dietary supplementation with fish oil, but the efficacy of fish oil supplementation remains controversial.
Nevertheless, more recent large trials have failed to confirm the efficacy of fish oil supplementation in high risk patients. The ORIGIN Trial Investigators n–3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia.
These investigators conducted a multi-center, double-blind, placebo-controlled trial to examine the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil and of the plant-derived alpha-linolenic acid (ALA) in 4837 elderly patients who had already had a myocardial infarction. In 2012 this study group conducted a meta-analysis of randomized clinical trials examining the effectiveness of fish oil supplementation in patients with known coronary heart disease.
In the same issue of the Archives of Internal Medicine there was an invited commentary by Dr. Another explanation could be that the patients in the more recent trials received much better treatment with statins and antithrombotic and antihypertensive medications than those in earlier trials. Another important question is whether fish oil has different effects in primary and secondary prevention of CVD. The failure of the newer trials to replicate the apparent benefits seen in earlier trials may be due to the fact that patients in the newer trials are already receiving optimal medical therapy with statins and antithrombotic and antihypertensive medications, while patients in the earlier trials for secondary prevention were not. In 2003 Antonia Trichopoulou and colleagues published the results of a prospective cohort study conducted in Greece showing that close adherence to a Mediterranean style diet was associated with a significant reduction in mortality from cardiovascular disease and cancer. The US Food and Drug Administration (FDA) now requires that nutrition labels must indicate the content of trans fatty acids, and the US Department of Agriculture recommends reducing intake of trans fats.
There is growing evidence indicating that dietary flavonoids have a beneficial effect on endothelial function and blood pressure.
These researchers used data from the Nurses' Health Study to examine the relationship between anthocyanins and other flavonoids and the risk of MI. Red meat has been suspected of being a risk factors for heart disease for a number of years, and recent studies have provided evidence for such an association. Other recent studies suggest that the association between consumption of red meat and heart disease may be related to the metabolism of dietary choline and carnitine in the human intestine. A 2013 publication in the New England Journal of Medicine provided evidence for the conversion of dietary choline to TMAO by gut microbes.
Note that these recommendations do not include specific recommendations based on some of the newest scientific evidence cited above. Several well done studies have demonstrated substantial benefits of exercise in reducing the risk of coronary heart disease.
Manson J, et al: A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. In this prospective cohort study Manson and her colleagues examined the association physical activity and coronary heart disease events in 72,488 female nurses who were 40 to 65 years old in 1986 and who had no know heart disease or cancer at the beginning of the observation period. The rate ratio for each quintile was calculated using the incidence rate in the less active women (quintile #1) as the reference group. Hu FB, et al: Adiposity as Compared with Physical Activity in Predicting Mortality among Women. These authors used the Nurses' Health Study to examine the associations of BMI and physical activity with death among 116,564 women. They concluded that both obesity and reduced physical activity are strong and independent predictors for death.
Blood pressure is a measure of the force of blood pushing against the arterial walls as the heart pumps blood around the body. Methodology: We used mathematical models to calculate the risk of dengue infection based on force of infection taking into account the estimated proportion of mosquito bites that occur in school and the proportion of school time that children wear the impregnated uniforms.
Principal findings: The use of insecticide-impregnated uniforms has efficacy varying from around 6% in the most pessimistic estimations, to 55% in the most optimistic scenarios simulated.
Conclusions: Reducing contact between mosquito bites and human hosts via insecticide-treated uniforms during school time is theoretically effective in reducing dengue incidence and may be a valuable additional tool for dengue control in school-aged children. Dengue is the most important mosquito-borne disease of humans that has not only increased in numbers but also expanded geographically (1–3). We previously hypothesized that impregnated school uniforms could be a potential strategy to reduce dengue infections in school-aged children (12). To test this hypothesis, school-based intervention trials at various settings are necessary. Note that the use of insecticide-impregnated uniforms has efficacy varying from around 6% in the most pessimistic, up to 55% in the most optimistic scenarios simulated.
The mass distribution of insecticide-treated bed nets as part of the Roll Back Malaria (RBM) partnership is expected to contribute majorly towards successful malaria control (24). In summary, based on mathematical modeling, the use of insecticide-impregnated uniforms has an efficacy varying from around 6% in the most pessimistic scenarios, to 55% in the most optimistic scenarios simulated. The authors have not received any funding or benefits from industry or elsewhere to conduct this study. Effectiveness of peridomestic space spraying with insecticide on dengue transmission; systematic review.
Hypothesis: impregnated school uniforms reduce the incidence of dengue infections in school children. The impact of insecticide-treated school uniforms on dengue infections in school-aged children: study protocol for a randomised controlled trial in Thailand. Threshold conditions for a non-autonomous epidemic system describing the population dynamics of dengue. An approximate threshold condition for non-autonomous system: an application to a vector-borne infection. Cost risk benefit analysis to support chemoprophylaxis policy for travellers to malaria endemic countries. Distribution of dengue and Japanese encephalitis among children in rural and suburban Thai villages.


Predicting changing malaria risk after expanded insecticide-treated net coverage in Africa.
From intervention to impact: modelling the potential mortality impact achievable by different long lasting, insecticide-treated net delivery strategies. Evaluation of the effectiveness of insecticide treated materials for household level dengue vector control. Loss of household protection from use of insecticide-treated nets against pyrethroid-resistant mosquitoes, Benin. It is estimated that 80% of deaths from cardiovascular disease worldwide occur in low-income and middle-income countries. Impaired blood flow can result in ischemia and cause symptoms such as angina or intermittent claudication. Oxygenated and nutrient rich blood is distributed to tissues via the arterial system, which branches into smaller and smaller blood vessels from arteries to arterioles to capillaries (where most exchange occurs).
The receives its blood supply from coronary arteries, which arise from the root of the aorta. The outermost layer is the adventia, which consists of connective tissue and also contains nerves and small blood vessels supplying the artery itself. Without valves in the veins of the leg, venous blood would tend to pool in the lower leg when standing or sitting. Their most obvious function is to provide a semi-permeable barrier that regulates the exchange of fluid, nutrients, gases, and waste between the blood and tissues. However, injury to endothelial cells provokes an inflammatory response as illustratedbelow.
Circulating monocytes and T-lymphocytes are attracted to the sites of injury by chemoattractant cytokines (chemokines). Lipoprotein particles, and especially low-density lipoprotein (LDL), enter the arterial wall and undergo oxidation. They consist of lipid-containing foam cells in the arterial wall just beneath the endothelium. Injury to the endothelium triggers monocyte adhesion, a loosening of endothelial cell junctions, and migration of monocytes beneath the endolthelium where they differentiate into macrophages.
They secrete cytokines that eventually induce smooth muscle cells to migrate from the media to the intima.
Slowly growing plaques expand gradually due to accumulation of lipid in foam cells and migration and proliferation of smooth muscle cells. This can lead to a variety of symptomatic problems, depending on the location of the atherosclerotic plaques. The figure below summarizes this relationship in a large group of men from the MRFIT study. In other words, genetic variants associated with elevated LDL levels are consistently associated with increased risk. They act by inhibiting the action of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, which is the rate-limiting enzyme in the sequence of steps by which cholesterol is synthesized in the liver. Fatty acids and amino acids in the LDL are recycled, and the cholesterol enters the cholesterol pool in the liver cell. In this way, statins reduce cholesterol concentrations in liver cells, which causes increased production of LDL receptors and increased uptake of LDL by the liver.
Statins very rarely cause severe, life-threatening rhabdomyolysis which can result in severe muscle pain, liver damage, kidney failure, and death.
A number of large, well-done clinical trials have demonstrated that statins can reduce the risk of CAD in low-risk individuals, but most experts caution against this because of the cost and the risk of side effects. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. This led to a concerted effort to identify treatments that might prevent CAD by raising HDL concentrations. In fact, the same study that found that SNPs associated with high LDL were consistently associated with increased risk failed to show that SNPs associated with HDL had any relationship to risk of CAD. The most likely answer is that low HDL is a marker for other risk factors that do increase risk. The graphs to the left shows the relationship between BMI and risk of death from cardiovascular disease, cancer, and other causes for a large cohort of men and women.
The figure below shows the nomogram for males and provides several examples for hypothetical boys plotted as shown by the blue dots. Resistance to insulin leads to generalized insulin resistance and increased release of fatty acids from fat cells. These factors include abdominal obesity, atherogenic dyslipidemia (elevated triglyceride, small LDL particles, low HDL cholesterol), raised blood pressure, insulin resistance (with or without glucose intolerance), and prothrombotic and proinflammatory states.
As a result, glucose cannot enter fat or muscle cells, so blood levels of glucose rise, and there is increasingly greater reliance on breakdown of fat and protein to provide an alternate source of fuel.
Despite adequate levels of insulin, at least initially, the interaction between insulin and its receptor is dysfunctional. The risk of stroke is two to four times higher for people with diabetes, and the death rate from heart disease is two to four times higher for people with diabetes than for people without the disease, according to the American Heart Association. High concentrations of blood sugar cause endothelial dysfunction which can injure capillaries supplying peripheral nerves, especially in the legs.
Damage to the blood vessels and capillaries in the kidney can lead to kidney failure or irreversible end-stage kidney disease. Diabetes can damage the blood vessels of the retina (diabetic retinopathy), potentially leading to blindness.
The combination of neuropathy, endothelial cell dysfunction, and atherosclerotic disease that interferes with arterial supply to the legs can result in loss of sensation, unrecognized trauma, blisters, ulcers, and serious infections which can ultimately require amputation. More than 3 out of 4 diabetic patients die of causes related to atherosclerosis, in most cases (75%) because of coronary artery disease. In the United States, the number of diabetic patients is expected to increase from 15 million to 22 million by 2025. Haffner and colleagues found that diabetic patients with no history of coronary artery disease have the same risk for future myocardial infarction as do nondiabetic patients with known disease.
They concluded that the majority of cases of type 2 diabetes could be prevented by the adoption of a healthier lifestyle.
The investigators enrolled 522 middle-aged overweight subjects who were pre-diabetic based on glucose tolerance tests.
A separate but related question is whether lifestyle changes are beneficial in preventing adverse cardiovascular events after type II diabetes has already developed. The Seven Countries Study by Ancel Keys found that the per capita consumption of dietary cholesterol and saturated fat correlated with mortality from coronary heart disease, and studies in animals also pointed to dietary lipids as a risk factor for atherosclerosis.
Dietary composition for each subject was assessed diet in 1980 using a 61-item food frequency questionnaire, and the assessment was repeated at 4-year intervals. Low-fat dietary pattern and risk of cardiovascular disease the Women's Health Initiative Randomized Controlled Dietary Modification Trial.
The Mediterranean diet was mostly vegetarian and consisted of a variety of vegetables, fruits, legumes, nuts, seeds and unrefined cereals. His findings suggest that adopting this type of lifestyle can not only stop the progression of coronary arterial disease but actually reverse it. Like EPA, it is an omega-3 fatty acid because the first double bond is located after the third carbon from the methyl end of the acyl chain, which the on the left here.
The fatty acid on the left is oleic acid, which has a cis double bond which characteristically produces a kink in the chain. It is important to note that none of the fats in the table below consist of just a single species of fatty acid; they are all mixtures.
Early ecologic studies identified low rates of CHD in Japan and Greenland, which raised the possibility that consumption of fish might be beneficial, possibly by inhibiting platelet adhesion and blood clotting, by reducing blood triglyceride concentrations, or perhaps by reducing arrhythmias.
All patients had a past history of myocardial infarction, stroke, angina with documented ischemia, or revascularization, and all had marginally abnormal fasting blood sugars. It should be noted here also that all of these subjects with previously documented heart disease were also receiving state-of-the-art antihypertensive, antithrombotic, and lipid modifying therapy. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. They concluded that there was insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease.
To date, there is no conclusive evidence to recommend fish oil supplementation for primary or secondary prevention of CVD. This also leaves unanswered the question regarding the efficacy of fish oil for primary prevention of coronary heart disease. Of interest, while the degree of adherence to a Mediterranean diet was associated with reduced mortality, there was no significant association with any particular diet component.
The New York City Department of Health and has asked restaurants and food suppliers to stop using partially hydrogenated oils.
Flavonoids are believed to improve endothelial function through an anti-inflammatory effects which reduces oxidation of LDL and increased synthesis of nitric oxide in endothelial cells.
Intake of flavonoid subclasses was calculated from validated food-frequency questionnaires collected every 4 years.
Phoshatidylcholines (lecithins) are a family of phospholipids that are important components of all cell membranes, and dietary phosphatidylcholine the major dietary source of choline, which has several metabolic roles besides being a major component of cell membranes. Taken together, these observations provide evidence of a complex interaction among humans, their resident gut flora, and environmental and behavioral factors (diet).
Detailed information on physical activity was first collected in 1986 and was updated in 1988 and 1992.
They found that higher levels of physical activity reduced the risk of death at all levels of obesity, but but did not eliminate the adverse effect of obesity. Blood pressure is highest when the heart contracts (systole), and falls when the heart is relaxing and refilling (diastole), and pressures in the arteries during these alternating phases are referred to as systolic and diastolic pressures. The efficacy of this strategy, however, is dependent on the compliance of the target population in terms of proper and consistent wearing of uniforms and, perhaps more importantly, the proportion of bites inflicted by the Aedes population during school time.
Global reports of dengue haemorrhagic fever (DHF) have increased five-fold in the past 20 years (4).
The principal vector, Aedes aegypti (Stegomyiaaegypti), is now well established in much of the tropical and subtropical world, and as a peri-domestic species, it is particularly well established in urban and semi-urban areas, thriving on proximity with humans.
Vector control (both adulticidal and larvicidal) has shown some impact but for various reasons has not resulted in the significant reduction of dengue (10, 11).
Because children of this age group spend a considerable amount of their day at school, the rationale is to develop strategies that reduce human–mosquito contact to protect against the day-biting habits of Aedes mosquitoes at schools. Cross-immunity (if any) is short-lived such that each dengue infection can be considered independently, although the phenomenon of antibody enhancement is known to be involved in haemorrhagic dengue. 1 shows the impact of the strategy on the proportion of seropositive children after 1 year of the intervention as a function of B. 1, we consider various realities that combine the facts that efficacy is never 100%, as the knock down effect is around 80% in ideal laboratory conditions, but will theoretically be much lower in real world conditions where uniforms do not cover the full body, uniforms are not worn the whole day, and uniforms are not worn during the weekends. The current target of universal access to long-lasting, insecticide-treated nets is 80% coverage which aims to reduce malaria deaths by 75% by 2015 (25).The cost-effectiveness and general applicability of insecticide-treated bed nets to control malaria has turned this strategy into a sort of gold-standard of malaria control (26). Using mathematical models, it is possible to define rational expectations about insecticide-impregnated clothes to control dengue, in the same way these models were used to quantify the impact of the use of bed nets to control malaria (24). Of course the efficacy of this strategy is very much dependent on the compliance of the target population in properly and consistently wearing the uniforms, and, perhaps more importantly, the proportion of bites the Aedes population inflicts during school time [parameters A and B in eq. If such a strategy is shown to be safe and culturally acceptable in field conditions, then even a theoretical reduction of dengue incidence by only 6 to 55% may justify implementing this approach to control dengue in school aged children. Cardiovascular disease is the number one cause of death worldwide, and it has become the leading cause of death in many developing countries.
Atherosclerotic plaques can also rupture, triggering acute formation of a clot and an abrupt loss of blood supply to tissues that results in infarction. Deoxygenated blood and metabolic byproducts are returned from capillaries via venules and then vein.
The innermost layer of a blood vessel (the intima) is lined with endothelial cells, which are in direct contact with blood.
The uni-directional valves (see the drawing on the right) prevent blood from flowing back down.
This theory holds that the earliest event in atherogenesis is injury to the endothelium, which can be triggered by any number of insults, either alone or in combination. Oxidation of LDL in the arterial wall occurs as a result of its exposure to nitric oxide, macrophages, and some enzymes such as lipoxygenase. The image below on the left is a photograph of the inside of an artery; one can see two yellowish fatty streaks beneath the thin endothelial lining of the artery.
The more permeable endothelium also permits LDL to enter the intima of the artery, and macrophages begin engulfing the LDL by phagocytosis. Bear in mind also, that atherosclerosis tends to be a diffuse process; if an individual has evidence of atherosclerosis in one location, they are likely to have blockages at other sites as well. The liver has two sources of cholesterol: it can take up LDL particles from the blood, or it can synthesis cholesterol using HMG-CoA reductase.
Note that if the liver cell synthesizes cholesterol, this too will be added to the cholesterol pool. This ultimately results in a lowering of blood concentrations of LDL cholesterol, and this generally results in a slower progression of atherosclerotic plaques and a reduced risk of plaque rupture. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease.
This area has been very controversial, but recent evidence suggests that although low HDL is inversely correlated with risk of CAD, the relationship is not causal. These authors also reported that a genetic variant that specifically and substantially increases plasma HDL cholesterol, did not reduce risk of myocardial infarction. The table below shows the most commonly used classification of obesity based on the BMI in adults.
The liver synthesizes and secretes increased amounts of very low-density lipoprotein (VLDL). Individuals with this constellation of risk factors have an increased risk for coronary artery disease, stroke, and type 2 diabetes. Binding to the receptor triggers phosphorylation of a protein called 'insulin receptor substrate' or IRS-1. As a result, GLUT4 transporters are not efficiently inserted into the membranes of fat and muscle cells, and glucose concentrations in blood rise (hyperglycemia), leading to endothelial cell dysfunction. This may cause tingling, numbness, burning or pain that begins at the tips of the toes or fingers and gradually spreads upward. Diabetes also increases the risk of other serious vision conditions, such as cataracts and glaucoma.
Yet, 70% of diabetic persons do not believe they are at serious risk for cardiovascular disease.


This increase correlates strongly with increasing obesity and is reflected in the development of diabetes at an earlier age. The National Cholesterol Education Program considers diabetes to be a coronary disease equivalent in their lipid guidelines.
This question was addressed in a multi-center randomized clinical trial [The Look AHEAD Research Group: Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. These studies spawned the widespread recommendations for decreasing dietary cholesterol, decreasing the percentage of dietary calories obtained from fat, and replacing dietary saturated fat with polyunsaturated fat. During the subsequent 14 years of follow-up, there were 939 cases of acute myocardial infarction or death from coronary heart disease. There is high intake of olive oil, but low intake of saturated fat, moderately high intake of fish, low-to-moderate intake of dairy products (mostly cheese or yogurt), low intake of meat and poultry, and regular but moderate intake wine. All triglycerides have the same basic structure and consist of a three carbon glycerol backbone with fatty acids (acyl groups) attached to each of the carbons in the glycerol backbone as illustrated below.
Examples of some of the more common naturally occurring fatty acids are shown in the table below. Similarly, corn oil and sunflower oil are referred to as polyunsaturated fats, because they contain a high percentage of linoleic acid. There have been a number of studies that have found beneficial effects, but others that did not. It should be noted that, given their past history of heart disease, all of these subjects were already receiving optimal medical therapy that included medications to control blood pressure, aspirin or other anticoagulant therapy, statins, and smoking cessation counseling. The investigators formulated four margarines that were supplemented with one of the following: EPA-DHA, ALA, EPA-DHA+ALA, or placebo. However, a diet high in fatty fish (≥2 servings of marine fish per week) should continue to be recommended for the general population and for patients with existing CVD because fish not only provides omega-3 fatty acids but also may replace less healthy protein sources, such as red meat.
The use of trans fats is increasingly being discouraged, but they were commonly used in fried foods, and in the manufacture of margarines and commercial baked goods, such as donuts, cookies, and crackers. Flavonoids are found in a variety of plants and can be consumed as fruits, vegetables, tea, and wine.
It is involved in lipid metabolism and it is a precursor for the synthesis of the neurotransmitter acetylcholine. Eggs are rich in cholesterol, but there is no evidence that eating eggs (even daily) increases plasma cholesterol or risk of heart disease. The table demonstrates that there was an inverse relationship between activity and coronary events, and there was a clear biologic gradient.
Increasing walking time or combining walking with vigorous exercise appears to be associated with even greater risk reductions. The figure below shows changes in pressure within large arteries during a single cardiac cycle of contraction and relaxation.
It typically breeds in clean stagnant water, particularly in artificial containers, and is therefore well adapted to urban life.
There is an urgent need to evaluate additional control strategies, in particular, for children. School uniforms are a cultural norm in many developing countries and are worn throughout the day on an almost daily basis. However, such trials are costly and difficult to implement and it will take some years before the results will be available.
The second term refers to the probability that there were (y–1) individuals at time t in the I condition and that one susceptible individual x acquired the infection in the period.
Since the proposed strategy is aimed only at a small sample of school children, this term can be neglected, such that eq. Assuming that a given proportion of children are expected to wear the insecticide-impregnated clothes during their school period, and the proportion of school time (that is the school time in hours divided by 24 hours) children wear the uniform, we can estimate the impact of this strategy as dependent on the proportion of all the mosquitoes’ bites that occur during that period.
The figure shows only the mean annual incidence as a function of the proportion of bites during school time [parameter B in eq. They conclude that of the available vector-control strategies adulticide application is the most effective, followed by reduction of contact with the mosquito’s bites, search and destroying breeding places, and, finally, larvicides. This is justified by the assumption that the small cohort of children in the experiment is subjected to the force of infection of their original population but that this number is too small to influence it. Cardiovascular disease in developing countries currently claims an estimated 12 billion lives annually, and the toll that it takes continues to climb.
They provide unique surface that generally allows the cellular elements of blood to flow with adhering to the vessel lining unless some insult has perturbed the cells. Once they have migrated into the intima, monocytes differentiate into macrophages and begin to take up oxidized LDL that has gotten into the intima. Over time there is a progressive accumulation of lipid and smooth muscle cells in the intima, and eventually the growing lesion begins to raise the endothelium and encroach on the lumen of the artery. If the concentration of cholesterol in the liver cells exceeds a certain level, HMG CoA reductase is inhibited, and the synthesis of LDL receptors is also inhibited.
However, observers occasionally report regression of atherosclerotic plaques in patient on statins.
In other words, low HDL levels are a marker for other factors that cause progression of CAD.
Sekar Kathiresan, one of the coauthors of the article cited above was quoted in the New York Times as saying that a number of other risk factors track with low HDL, including obesity, being sedentary, smoking, insulin resistance, having small LDL particles, and increased coagulation of blood.
Exercise reverses these abnormalities by diverting fatty acids in muscle toward mitochondrial oxidation. This, in turn, triggers the insertion of specialized glucose transporters (GLUT4) into the cell membrane, where they act as a conduit to facilitate the entry of glucose from the blood stream into the cell. Without proper control of diabetes, the neuropathy can progress to the point of causing a complete loss of sensation in the affected limbs. The younger age at onset portends an increased future prevalence of premature coronary artery disease and resource utilization that will exceed the current $100 billion annual expenditure in the United States.
Moreover, it was shown that the likelihood of prevention of diabetes was directly associated with changes in lifestyle.
For the analysis, the cohort was divided into quintiles for the percentage of energy obtained from each type of fat, and for each type of fat, the rate ratio for each quintile was computed using the group with the lowest intake of a given fat type as the reference.
The inclusion of vegetables, seeds, fish, and olive oil provide a source of omega-3 and monounsaturated fatty acids. Individuals who are unable or unwilling to eat fish or related products should consider increasing their consumption of plant-derived omega-3 fatty acid (α-linolenic acid). Intestinal microbial organisms (microbiota) metabolize dietary choline to trimethylamine (TMA), which is then absorbed by the intestine and tranported to the liver, where it is converted into timethylamine-N-oxide (TMAO). The cholesterol in an egg will be absorbed by the intestine and packaged into chylomicrons and distributed, but ultimately the exogenous cholesterol will temporarily result in increased cholesterol levels in liver cells; this will down-regulate (turn off) endogenous production of cholesterol in the liver.
During the subsequent 8 years of follow-up, there were 645 incident coronary events (nonfatal myocardial infarction or death from coronary disease). The World Health Organization (WHO) estimates that there are 50–100 million infections worldwide every year, of which 21,000 are fatal (3). Aedes is a daytime feeder (3), which means that strategies need to be employed to prevent mosquito–human contact during the daytime. Insecticide-treated school uniforms may therefore result in a reduction of dengue infections in school-aged children. We set out to estimate the potential impact of impregnated school uniforms on the incidence of dengue in school-aged children using mathematical modelling.
The value of such a strategy also depends on whether such impregnated uniforms are culturally acceptable and that no skin irritations or other adverse events will occur.
The high mortality is partly due to lack of access to care in many areas, but the problem will not be solved by better medical care. When perturbation occurs, endothelial cells secrete cytokines that trigger and maintain an inflammatory response. Over time, they can evolve into atherosclerotic plaques or they can remain stable or even regress. This is depicted in the image below, which shows a cross-section of an artery at the site of an atherosclerotic plaque. Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. Thus, the current thinking is that HDL is not a causal factor, but rather a marker for the presence of other causal factors. These events are depicted in the image below showing how glucose molecules in a capillary enter a muscle cell. Diabetic neuropathy can also cause digestive problems (nausea, vomiting, diarrhea or constipation) and can contribute to erectile dysfunction in men. Consequently, this study shows that type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects. This study also found no effect on plasma HDL cholesterol or triglycerides, possibly because of poor adherence resulting in minimal difference in fat intake.
Note that some of his dietary recommendations differ markedly from the Mediterranean style diet.
The authors found that neither the EPA-DHA supplemented margarine, nor the ALA supplemented margarine reduced the incidence of major coronary events. While these finding are intriguing, they will need to be confirmed by randomized clinical trials. TMAO is believed to promote atherosclerosis by promoting the transformation of macrophages into foam cells and fostering the deposition of cholesterol in arterial lesions.
Plasma levels of TMAO increased after ingestion of the eggs, but TMAO production was markedly suppressed when broad spectrum antibiotics were given to reduce gut bacteria. None of the garlic treatments had any statistically significant or clinically significant effects on LDL-C or other plasma lipid concentrations in these adults with moderate hypercholesterolemia. The disease is now endemic in more than 100 countries in Asia, Africa, and the Americas with south-east Asia being the most seriously affected.
We will therefore need to wait for the results of a school-based randomized control trial that is currently being conducted in Thailand to know the effectiveness of such a strategy under field conditions (14).
In the United States cardiovascular disease continues to claim about 800,000 deaths per year, despite the widespread use of statins to lower cholesterol and angioplasty to open blocked blood vessel. Conceptually, there is the right side of the heart (right atrium and right ventricle) which receive blood returning from the periphery and send it to the lungs (via the pulmonary artery) for re-oxygenation. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life.
A separate analysis used multiple linear regression and treated dietary fat intakes as continuous variables. They found an inverse relationship between fish consumption reported in 1960 and the rate of coronary heart disease mortality occurring overt the subsequent 20 years of follow-up. However, it should also be noted that the actual consumption of the active agents varied depending on consumption of margarine, and the average consumption of EPA-DHA was only 226 mg of EPA and 150 mg of DHA., which is quite low. These investigators also studied the relationship between fasting plasma levels of TMAO and incident cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography. Moreover, higher plasma L-carnitine concentrations were found in patients with known heart disease, and higher levels of carnitine were also associated with an increased incidence of subsequent cardiovascular events (myocardial infarction, stroke or death) in 2,595 subjects who were followed after cardia evaluation . For example, women who exercised even moderately (quintile #3) had almost a 20% reduction in risk of a severe coronary event (death or infarction).
Also of concern is the possibility of evolution of resistance against the insecticide, a phenomenon already observed in the impregnated bed nets used against the malaria mosquitoes (29, 30). Once blood is re-oxygenated in the lungs it is returned to the left side of the heart via the pulmonary veins.
They then used the coefficients from these models to the estimate the effect of substituting a specific percentage of energy from fat for the same percentage of energy from carbohydrates. Remarkably, while the Mediterranean diet had little effect on plasma lipids, these subjects experiences a 70% reduction in CHD events compared to the AHA control diet.
In addition, fish oil also contains a mixture of saturated, monounsaturated, and polyunsaturated fatty acids. In 2006 Mozaffarian and Rimm conducted a meta-analysis of cohort studies and clinical trials and concluded that a daily intake of 250 mg of EPA and DHA reduced the risk of fatal coronary heart disease by 36%.
Dengue infections in children cause large disruptions in schooling, and loss in parental wage earning (6). After entering the left atrium, blood enters the left ventricle and is pumped into the aortic arch for distribution to the entire body.
The results of this study were largely confirmed in a meta-analysis that included results from 11 cohort studies.
Given the multiple differences between the two diets, it was impossible to attribute the benefits to any particular aspect of diet composition. Second, he recommends dietary supplementation with 3 grams of fish oil per day in order to boost omega-3 fatty acids.
The authors reported that higher intakes of red meat, red meat excluding processed meat, and high-fat dairy were significantly associated with elevated risk of CHD, while higher intakes of poultry, fish, and nuts were significantly associated with lower risk. They concluded that production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota, and that increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events.
However, this did not occur if intestinal microbe populations were suppressed by administration of broad spectrum antibiotics. According to the WHO, the number of disability-adjusted life years (DALYs) worldwide is estimated to range between 528 and 621 per million population (7).
Waning of efficacy over time after repeated washing is another issue that would need to be studied under field conditions. The intervention promoted weight loss through decreased caloric intake and increased physical activity, while the control group received diabetes support and education.
Preliminary adjustment for under-reporting could raise this total to $1.8 billion, and incorporating costs of dengue surveillance and vector control would raise the amount further (8, 9).
Like the previous study, it found that the overall percentage of energy from fat was not associated with risk of CHD. 3.5% at study end) and had reductions in glycated hemoglobin levels and increase in fitness.
The subjects were patients who had had a myocardial infarction, or revascularization of implantation of a defibrillator. They concluded, "Fish oil supplementation was associated with a significant reduction in deaths from cardiac causes but had no effect on arrhythmias or all cause mortality.
The intervention group experienced fewer cardiovascular deaths and fewer myocardial infarctions, but despite a study population consisting of 5,145 subjects, the differences were not statistically significant.



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