K562

ATHEROSCLEROSIS


Introduction

Arteriosclerosis is the process of the hardening of the arteries. Atherosclerosis is a specific type of arteriosclerosis. Atherosclerosis is the accumulation of lipids in the walls of the arteries. This process leads to a hardening of the arteries. The primary arteries for atherosclerosis are the coronary arteries, cerebral arteries, and femoral artery; exhibiting coronary heart disease, cerebrovascular disease, and peripheral vascular disease.

Cardiovascular disease is the leading cause of death in men and women in this country. Combining all types of cardiovascular disease, the prevalence is 37.1% for men and women combined. In general, men have a higher prevalence of cardiovascular disease than women.

The prevalence is highest in African Americans; but higher in women more than men.

athero

As a State, Indiana is ranked 38th for the prevalence of cardiovascular disease. Minnesota is the lowest (#1) and Alabama is the highest (#50).

states

pie

Cardiovascular disease consists of

Of which, coronary artery disease is the most prevalent.


The death rates from cardiovascular disease has been dropping since the 1970's. See the figure to the left below.

This is not because the prevalence has been dropping. In fact, the prevalence has been increasing in both men and women. As illustrated in the figure to the right below, the prevalence of cardiovascular disease has been increasing. It is projected that the prevalence will increase dramatically with the obesity epidemic.

death rates

prev

So, why have the deaths from cardiovascular disease been declining? Medical management has improved to control disease. Medical management has improved more for men that women. As the prevalence of cardiovascular disease is lower for women than men, yet the death rate is higher in women than in men.



NATURAL HISTORY OF ATHEROSCLEROSIS

The atherosclerotic process is associated with the aging process. Having been documented in the autopsies of ancient mummies, atherosclerosis appears to be universal in humans throughout the history of mankind. This natural history can be documented in every human.

 

hx

The natural history of atherosclerosis begins at birth. The arteries are patent and clean at birth.

By the age of 10 years old, the walls of the arteries will appear streaked with lipid deposits called Fatty Streaks.

The fatty streaks continue to develop in early adulthood until they protrude into the lumen of the artery and become Fibrous Plaque.

In middle-age, the fibrous plaque invades a large part of the artery, damaging the artery to the extent of precipitating a clinical event. This stage of the disease is called Clinical Lesion.


Again, atherosclerosis is a universal process and, thus, considered an aspect of the aging process because if it's association with age. The earliest document case of atherosclerosis was in the autopsy of Menephtah, an ancient mummy from 1211 BC.

The figure on the right is a CT scan of an abdominal artery atherosclerotic plaque in an ancient Egyptian mummy.

 

Results of other scans can be found in this table.


Atherosclerosis manifests at different ages in different populations. The onset of symptoms is associated with risk factors. Some of these risk factors are controllable and some are not.

Controllable
Uncontrollable
  • High Blood Pressure
    • >140/>90 mm Hg
  • High Cholesterol
    • Total >200 mg/dL
    • HDL <35 mg/dL
    • LDL >130 mg/dL
  • Smoking
  • Obesity
    • BMI >30 kg/m2
    • Waist > 100 cm
  • Diabetes
  • Physical Inactivity
  • Family History of CVD
    • Men < 55 yo
    • Women <65 yo
  • Age
    • Men >45 yo
    • Women >55 yo
  • Sex

The risk of disease increases dramatically with the number of risk factors present.

For Family Hx, a first degree relative (parent, sibling, offspring) must have exhibited cardiovascular disease before the age of 55 yo in men and/or 65 yo in women.

For cholesterol, LDL is the more relevant subfraction.

Smoking is defined as one or more cigarettes.


The section below presents the etiology of atherosclerosis. In studying this etiology, the role of these traditional risk factors becomes questionable. More logical risk factors may be more associated with sources of oxidative stress.

The anatomy of the artery must be defined before we can discuss atherosclerosis.

 

The functions of the endothelium are

  1. Protect the intima and media from foreign invaders.
  2. Provide anti-coagulant properties for platelets on the endothelial wall.
  3. Prevent adhesion of leukocytes or platelets to the wall of the artery
  4. Control of tissue permeability, allowing specific molecules to pass through the endothelium. (i.e. LDL)
  5. Production of vasoactive molecules

The biochemistry of the antiatherogenic activities of the endothelium are summarized below:

 

Oxidative stress compromises the antiatherogenic functions of the endothelium. The biochemical changes are illustrated below:
 

What happens in the atherosclerotic process? What is the etiology of atherosclerosis?


This atherosclerotic process occurs in most arteries. The following table summarizes the three main forms of this cardiovascular disease. When the atheroma partially blocks the artery, low blood flow or ischemia occurs. When the artery becomes totally blocked the tissue dies. Death of tissue has been termed infarct or necrosis.

Location
Ischemia
Infarct
Coronary Arteries
Angina
Myocardial Infarction
Cerebral Arteries
Transient Ischemic Attack
Cerebral Vascular Accident
Femoral
Claudication
Gangrene

It is also possible for this process to occur in other arteries.


There are several ways to measure endothelial function. The most common was is by Brachial Artery Flow-Mediated Dilation.
Endothelial function, measured as percent of dilation, is called Brachial Artery Flow-Mediated Dilation or FMD.

 


Among the critical functions of the vascular endothelium, vascular tone has been considered the benchmark function reflecting the state of the endothelium. Flow-mediated dilation has been the most frequently used measure of endothelial function.

Although the FMD technique has yet to be perfected, it can distinguish among different pathological states. There are, however, no standards for FMD for specific diseases.

Although FMD cannot be effective in the prognosis of the disease, a low FMD can predict future cardiac events.

athero fmd

Back to the risk factors for atherosclerosis. More reasonable risk factors may be those that subject the artery to oxidative stress. These include:


 

Cigarette Smokecontains 4000 chemicals. Smoking produces free radicals in both the smoke and tar aspects of smoking. These free radicals affect NO bioavailability

smoke

Adults who smoke have a reduced endothelial function as illustrated to the left.

Past smokers continue to have a reduced endothelial function, although it is slightly improved. Thus, smoking continues to compromise the endothelium, even though it has been discontinued.

Quitting smoking has more dramatic effects on lung function than on heart function.

The number of years of smoking contributes to the extent of endothelial dysfunction as illustrated to the right.

Excess body fat is a continuous oxidative state. Adipocytes, or fat cells, secrete TNF-alpha when body fat stores are increased. TNF-alpha is an inflammatory cytokine that provokes oxidative stress. The elevated oxidative stress in overweight and obesity not only contributes to accelerated atherosclerosis, but diabetes as well.

ob

The graph to the left illustrates the excess oxidative stress found at rest in obese adults.

The oxidative stress is higher in those adults with upper body obesity (andriod obesity).

Not only is the oxidative stress is higher in the obese, but the response to oxidative stressors is even higher in the obese than in the nonobese.

The graph to the right illustrates the oxidative response to maximal exercise. Although the nonobese show an increase, it is not statistically significant. Whereas the increase in oxidative stress in the obese is significant.

ob2

The figure to the left is a illustrated summary of excess oxidative stress in obesity.


Food intake contributes directly to endothelial dysfunction and can be detected in the measurement of FMD. The high-fat diet is an atherogenic factor in apparently healthy adults, whereas both the high-fat and high-sugar diets are atherogenic in overweight, metabolic syndrome and diabetes.

The average diet of a healthy North American man provides approximately 50-100 g of fat per day, consumed during 3-6 eating events. Depending on the size and composition of the meal, the postprandial lipemic response can last up to eight hours, and therefore the typical diet results in continuous exposure to postprandial lipemia. Sedentary and overweight adults tend to have higher fat intake, which further intensifies the atherosclerotic oxidative cycle by prolonging, magnifying the adverse absorptive state. Consecutive high-fat meals produce greater endothelial dysfunction and higher oxidative stress for each consecutive meal. Thus, recurring postprandial oxidative stress initiates an nearly continuous cycle of endothelial dysfunction.

high fat meal

The figure to the left illustrates the drop in FMD following a high-fat meal. Healthy adults decrease endothelial function following a high-fat meal; adults with disease exhibit a worse dysfunction.

How does the high-fat meal cause the endothelial dysfunction?

The oxidative stress from lipid peroxidation leads to inflammatory stress, which cycles more oxidative stress. The result is a decrease in eNOS which decreases nitric oxide (NO) leading to a lower FMD.

The new risk factors for atherosclerosis include the consumption of a high fat meal.

athero

In the postprandial state, there is a magnified influx of free fatty acids (FFA) into the muscle, adipose and hepatic tissue as well as vascular endothelial cells resulting in FFA oxidation in the mitochondria.  Increased ß-oxidation and oxidation of FFA-derived acetyl CoA by the tricarboxylic acid (TCA) cycle creates an overproduction of electron donors (NADH and FADH2), thus overloading the mitochondrial electron transport chain (ETC).   As a consequence, complex III of the ETC is blocked, causes accumulation of electrons in coenzyme Q, which donates electrons to molecular oxygen, thus generating superoxide radicals (O2-). The overproduction of O2- results in direct and indirect effects on vascular NO bioavailability .

Diabetes directly contributes to endothelial dysfunction as well as indirectly. The indirect effects will be discussed in the diabetes section of this course.

 

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Advanced Glycolated End Products (AGEs) are a source of oxidative stress in diabetes. Glycosylation is a process that occurs on proteins and lipids in conditions of excess glucose. Glycosylation is a non-enzymatic reaction that reflects the concentration of excess glucose. Once formed AGEs can fluoresce to produce reactive oxygen species and form cross-links. These AGEs play a significant role in the complications of diabetes, including atherosclerotic cardiovascular disease.

The role of exercise in oxidative stress is more complicated. Oxidative stress is associated with most types of exercise. Oxidative stress is related to the intensity of exercise. That is, the higher the exercise intensity, the higher the oxidative stress.

Moderate exercise produces a moderate oxidative stress that the body appears to respond to by increasing antioxidant defense. Thus, moderate exercise training decreases the oxidative stress response to exercise through an enhanced antioxidant defense.


How does exercise & physical activity affect endothelial function?

Physical activity is recommended for the prevention and treatment of atherosclerotic cardiovascular disease, metabolic syndrome, and diabetes.   Both acute exercise and chronic exercise training have been found to enhance endothelial function in hypertension, metabolic syndrome, smoking, diabetes, aging, hyperlipidemia, coronary heart disease, and congestive heart failure.   

training

Several studies report increases in FMD following training.

  • In overweight, adults and children
  • Metabolic syndrome
  • Diabetes
  • Heart Disease

Both a single session of exercise and habitual exercise can improve endothelial function.

Habitual exercise can reduce vascular oxidative stress and enhance antioxidant defense specifically, superoxide dismutase activity.  Both a single session of exercise and exercise training reduces postprandial lipemic load.  Exercise training also improves glucose control and insulin resistance. Exercise can also reduce inflammation. 

The figure below, illustrates the possible pathways in which exercise is effective in endothelial function.

model

 


Single Session of Exercise

  • Shear Stress:  One of the proposed mechanisms for the effectiveness of physical activity on endothelial function is the shear forces stimulus to increase vascular endothelial NO.  Unidirectional laminar shear stress stimulates NO production, decreases ROS production, and exerts anti-inflammatory effects on the vascular endothelium.  Within seconds following the onset of shear stress, eNOS is activated via a transient increase in intracellular calcium, enhancing calmodulin binding to eNOS, thus increasing eNOS activity and producing NO.  Shear stress can also activate eNOS through a phosphorylation of specific sites on the enzyme, facilitating the flow of electrons from the reductase to the oxygenase domains of eNOS.  Finally, an upregulation of eNOS expression (↑ in eNOS mRNA transcription) has been found several hours following laminar shear stress.


Exercise and physical activity is the most physiologically relevant source of unidirectional laminar shear stress in vivo.  Habitual physical activity and exercise training provides repeated bouts of hyperemia in the vasculature.  In addition, the shear stress from exercise is not isolated to the site of muscle contraction.  Tanaka and colleagues found shear stress to increase in the nonworking limb (brachial artery) proportionally to the intensity (up to maximal capacity) of supine leg cycling.  We too have found an incremental increase in shear stress in the brachial artery up to two hours into recovery after walking (45 min) at 25%, 50% and 75%  (VO2peak) in overweight men. 

Tinken and colleagues demonstrated the role of shear stress in acute exercise by preventing the exercise induced increase in shear stress in one arm while allowing the exercise induced shear stress in the other. The model used is illustrated to the right.

The top panel illustrates the shear rate at rest (black) and the shear rate during exercise (white) for normal exercise shear rates. Whereas the bottom panel illustrates the shear rates for the occluded arm.

It is easy to see that the resting shear rates were the same and the exercise shear rates increased in the "non-occluded" arm and similar to rest in the occluded arm.

The resulting FMDs, before and after exercise, are illustrated in red and white. Red is the FMD before exercise whereas the white is following exercise. These graphs demonstrate that FMD is increased in the arm with no occlusion (shear stress increased with exercise), yet no change in the arm where the exercise induced shear stress was prevented.

Why are there three black and three white bars for each arm measurement for shear stress? That is because there are two separate components of shear stress. The three bars represent the mean shear stress which is the sum of positive (antegrade) and

negative (retrograde) shear stress. The two figures above illustrate antegrade and retrograde blood flow associated with blood flow. The flow above the red line is antegrade whereas the blood flow under the red line is retrograde. Why is this important?

Different types of exercise produce different patterns of antegrade to retrograde flow. It may be the pattern of these two flows that lead to changes in FMD with exercise. It appears as though only cardiovascular exercise can alter FMD. Resistance exercise may not.

Okamoto and colleagues demonstrated opposite FMD changes to

  • Aerobic before resistance (red circle)
  • Resistance before aerobic (black triangle)
  1. Anti-inflammatory Activity:

Both a Single Session of Exercise and Training

  • Insulin Sensitivity:   A single session of most types of exercise, including resistance exercise is sufficient to increase insulin sensitivity, in healthy, obese, and type 2 diabetic adults.  Similarly, exercise training improves insulin sensitivity regardless of age, in healthy, obese and type 2 diabetic adults; even with no change in VO2max.  Changes in insulin sensitivity associated with exercise vanish within 3-5 days; and can be regained after a single exercise session. 
  •  

  • Postprandial LipemiaDynamic exercise (acute or chronic) causes a significant, moderately large decrease in postprandial lipemia.   There appears to be no influence of exercise intensity, duration, or time between exercise and the meal on the attenuation of postprandial lipemia.   The sequence of the exercise, before or after the meal, did not affect the decrease in postprandial lipemia. Even the accumulation of intermittent physical activity throughout a single day is as effective in reducing postprandial lipemic load as one session of continuous exercise.  The exercise-induced reduction in postprandial lipemia is independent of the metabolic substrate utilized during exercise.   The exercise-associated attenuation in postprandial lipemia has also been reported in men with hypertriglyceremia.   Insulin sensitivity may play a role in decreasing postprandial lipemia associated with exercise; however, more research is warranted for populations at risk for atherosclerotic cardiovascular disease.  

padilla

Our work has shown that a single session of exercise can counteract the endothelial dysfunction of a high-fat meal.

The red line to the left is the decrease in FMD following a high-fat meal. The green line shows an increase in FMD when the same meal is combined with 40 minutes of treadmill walking.

In another study, we found that adults who are active did not have the same response to the meal as adults who were inactive. The figure to the right illustrates the decrease (red line) in FMD found in inactive adults who ate a high-fat meal, yet no change in for the active adults (yellow line). meal

Triglycerides were different between active and inactive. The lipid load was higher in the inactive.

Thus, the oxidative stress was higher in the inactive.

The antioxidant defense also decreased in the inactive.

Leading to the lower endothelial function.

CHRONIC EXERCISE TRAINING

  • Nitric Oxide:
nitric oxide

Maeda and colleagues observed nitric oxide during a training-detraining in eight young healthy adults. The figure to the left illustrates the change in nitrate and nitrite concentrations with training and detraining.

Thus, one possible mechanism for exercise to improve endothelial function is through an increase in nitric oxide.

Oxidative Stress:  Oxygen uptake, essential to sustained physical activity, produces reactive oxygen species crucial for energy production; often resulting in oxidative stress, depending on exercise intensity and training.  High-intensity physical activity produces greater oxidative stress; whereas trained populations exhibit less oxidative stress due to higher antioxidant defense to a given intensity.   More recently, exercise-induced oxidative stress has been considered to have a beneficial impact rather than compromise health.  A major benefit of moderate intensity exercise is to induce a moderate oxidative stress which stimulates expression of antioxidant enzymes (such as superoxide dismutase & glutathione peroxidase).    Similar to healthy controls, diabetic patients with higher VO2max exhibit lower oxidative stress and higher antioxidant defense to a single session of exercise than those with low physical work capacity. 

Body Fat: Body fat reduces with exercise.

The FMD response to exercise is improved with training in overweight men.

The decrease in FMD illustrated in the figure to the right probably reflects the increase in oxidative stress in overweight men and women following exercise (red line).

Whereas, the overweight adults who exercise regularly, exhibit an increase in FMD following exercise (yellow line).

Our studies are attempting to show the increase in FMD following exercise in active men is due to antioxidant defense.

harris

Hence, Endothelial dysfunction leads to atherosclerotic cardiovascular disease. Physical activity has a role in its etiology as well as its treatment.

 


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