1. Endothelial function: Changing the pattern of treating CV disease
Content Points:
• Cutting edge research is beginning to unravel the complex pattern of malfunctions responsible for causing cardiovascular disease (CVD).
• The fundamental thread running through this pattern of malfunctions is endothelial dysfunction.
• In this presentation, some of the classic and recent research addressing this connection between endothelial dysfunction and CVD will be addressed. Additionally, treatments that ameliorate endothelial dysfunction will be discussed.

2. Educational objectives
Content Points:
The overall educational objectives are as follows:
– Understand the role of the endothelium in health and in    disease
– Conceptualize the mechanisms behind endothelial damage    in 4 common disorders: diabetes, hypertension, dyslipidemia,    and coronary artery disease (CAD), including heart failure
– Learn how endothelial function can be improved by using    appropriate treatment strategies

3. Content outline
Content Points:
• The approximately 130 slides in this presentation will address the following topics:
   – CV system gatekeeper: The endothelium
   – Regulation of endothelial function (renin-angiotensin system)       · Fibrinolytic system
   – Sources of endothelial dysfunction       · Hypertension       · Diabetes       · Dyslipidemia       · Coronary heart disease (heart failure)       · Summary
   – Clinical management: Improving endothelial function       · Hypertension       · Dyslipidemia       · Coronary heart disease       · Summary
   – Summary

4. The endothelium
Content Points:
Some flattened, elongated endothelial cells are located in the upper left hand corner of this scanning electron micrograph of a vessel that has been partially denuded by a catheter.
In a normal blood vessel, endothelial cells create the conduit that separates blood from, and allows blood to flow through, tissues. Small vessels, capillaries, are composed primarily of endothelial cells while larger vessels have additional layers of connective tissue and smooth muscle to add strength and tone to the vessel. Some of this connective tissue and smooth muscle can be seen in denuded regions of the vessel in the photomicrograph.

5. The endothelium: A living organ
Content Points:
Healthy endothelial cells have multiple functions. They form a barrier between the blood and the tissues.
As shown in this transmission electron micrograph, endothelial cells compose the innermost layer of blood vessels. The cells tightly interlock so that passage from the blood into the tissue occurs through the endothelial cell.
The endothelium, however, is much more than a passive filter. Endothelial cells actively transport substances into and out of the blood. They also secrete active substances that regulate the local milieu.

6. The endothelium maintains vascular health
Content Points:
The endothelium works to maintain vascular health through a variety of mechanisms.1
In response to signals such as shear force on the vessel wall, hormonal and other regulatory substances, endothelial cells produce and secrete vasoactive substances that can dilate or constrict blood vessels. In this way, the endothelium maintains an appropriate blood pressure (BP).
Endothelial cells also produce and release factors that promote or inhibit growth of smooth muscle.
A number of antithrombotic, anticoagulant, and fibrinolytic factors are released by the endothelium. These factors help to keep the endothelial surface nonadhesive and keep the blood stream flowing smoothly. Some examples of these compounds include tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) and prostacyclin.
Endothelial cells also release anti-inflammatory and antioxidant agents.
Many of these functions of the endothelium will be discussed in greater detail throughout this presentation.

7. Causes and consequences of endothelial dysfunction
Content Points:
Certain disorders affect the endothelium adversely, causing an imbalance in endothelial regulation of vascular function. Endothelial dysfunction leads to further abnormalities, pushing the CV system into a vicious cycle of disease.2
Some contributors to endothelial dysfunction that will be highlighted in this presentation include hypertension, diabetes, hyperlipidemia, and heart failure.
The frequent outcome of endothelial dysfunction is atherosclerosis which, in turn, leads to further disruption of the endothelium.

8. Risk factors and endothelial dysfunction: Mediator role of oxidative stress
Content Points:
• The mechanisms by which CVD risk factors lead to endothelial malfunction are gradually being revealed.
• A common denominator among these risk factors is oxidative stress.

9. Oxidative stress: The activators
Content Points:
The L-arginine/nitric oxide synthase (NOS) system is affected by a number of pathophysiological conditions: for example, hypertension, hypercholesterolemia, aging, smoking, and heart failure.3
L-arginine is the substrate for NOS, thus linking it to NO, a powerful vasodilator. However, L-arginine appears to have some independent beneficial effects on vascular tone that are not presently fully understood.
The NOS enzyme (eNOS) is altered by several conditions including high levels of oxidized low density lipoprotein cholesterol (LDL-C). NO bioactivity is reduced under conditions of oxidative stress. Infusion of ascorbic acid, an antioxidant, has been shown to improve vascular responses in people with hypertension, smokers, and diabetic individuals.
These findings clearly indicate that the NO system is damaged by oxidative stress and this damage probably arises from insults at numerous points in the system.
Tetrahydrobiopterin is a vital cofactor in the NOS system. It seems to affect the ability of the enzymes to bind L-arginine. Recent physiological studies indicate that levels of tetrahydrobiopterin may be abnormal in diabetes and hypercholesterolemia.
Superoxide is a free radical generated under conditions of oxidative stress that impairs the function of a variety of substances including NO.
Research conducted within the past 5 years has uncovered the existence of membrane-bound oxidases within the endothelium and the vascular smooth muscle that utilize NADH and NADPH as substrates for electron transfer to molecular oxygen.
This vascular oxidase seems to modulate NO activity.
Angiotensin II (A II), in addition to several cytokines, regulates the activity of vascular oxidase.
P22phox is a small protein subunit of the membrane oxidase cytochrome. Studies indicate that p22phox has an important role in control of vascular superoxide production and its modulation by angiotensin and hypertension.

10. Endothelial dysfunction leads to imbalance of factors resulting in vascular disease
Content Points:
As discussed earlier in the presentation, normal endothelium maintains vascular tone, retards adhesion of platelets and leukocytes, and inhibits smooth muscle growth and blocks accumulation of LDL-C in the vessel walls.4
When CVD risk factors are present, the balance is tipped toward vascular constriction and accompanying hypertension, cell adhesion and thrombosis, smooth muscle growth, and lipid accumulation.
Together these changes contribute to the development of artherosclerotic plaques in the dysfunctional endothelium.

11. Spectrum of vascular remodeling
Content Points:
Injury to blood vessels can lead to vascular remodeling.5
Vascular remodeling is a dynamic process; endothelial secretions such as growth factors and vasoactive compounds as well as hemodynamic stimuli all contribute to the process.
There are 3 common types of injury, each of which causes a different type of remodeling.
Increased pressure may have 1 of 2 effects on blood vessels. As shown in the first example, the medial layer of the vessel may thicken, thus reducing the luminal diameter. In the second situation, shown in example 2, hypertensive vascular disease occurs without medial hypertrophy.
Flow has differing effects depending on its rate. Decreased flow leads to reductions in vessel diameter as shown in the third example while increased flow causes vasodilation as seen in example 4. If cell loss and matrix proteolysis accompany vasodilation, the result could be an aneurysm.
Vascular injury, as shown in examples 5 and 6, can lead to neointimal hyperplasia and atherosclerosis as lipids containing foam cells invade the vessel walls, matrix production increases and inflammatory processes occur. In late stages, plaques may become fibrous with an increased likelihood of rupture.
These models graphically depict the consequences of endothelial dysfunction resulting from the presence of risk factors that lead to CVD.

12. Atherosclerosis timeline
Content Points:
The degeneration of healthy endothelium via the pathogenesis of atherosclerosis occurs slowly over decades. It appears to begin with a subtle form of endothelial injury that alters function. Foam cells are the earliest sign of endothelial dysfunction. They are macrophages that contain oxidized LDL-C and are most frequent in infants and children.
Foam cells may then infiltrate the vessel, progressing to a fatty streak. As the lesion progresses to an intermediate lesion, small pools of extracellular lipid form within the smooth muscle layers, disrupting the intimal lining of the vessel.
Progression to an advanced lesion occurs when the accumulated lipid, cells, and other components of the plaque disrupt the artery wall. This lesion is termed an atheroma.
Once the plaque becomes fibrous, it is primed to rupture. This type of advanced lesion can be found from the fourth decade of life onward.
The endothelium itself appears to participate in some of this remodeling through secretion of specific compounds.5

13. Unifying model: Endothelial dysfunction to CVD
Content Points:
Several conditions, such as hypertension, dyslipidemia, heart disease, diabetes, and smoking cause physiological and structural changes that can lead to CVD.
In each disorder, 1 of the earliest changes to occur is an alteration of the oxidative metabolism in the endothelium leading to an increase in the level of oxidative stress. This change causes the endothelial cells to decrease production of some compounds and increase production of others. Thus, NO production is decreased, facilitating vasoconstriction. Other compounds are released that allow plaque and thrombosis formation.5
In subsequent slides, the changes that take place in the endothelium will be discussed in greater detail.