1) Cardiovascular disease places a major burden on public health and healthcare systems. The endothelium plays a key role in the development of atherosclerosis. 2) The endothelium is a single layer of cells lining the entire vascular system. During exposure to risk factors like hypertension and smoking, endothelial dysfunction occurs, disrupting balance and leading to atherosclerosis. 3) Various imaging modalities have evolved to clinically evaluate vascular structure and function in health and disease. Noninvasive techniques assess microvascular and macrovascular endothelial function.

1. Oleh: dr. Enggar Sari K.
Pembimbing: dr. Abdul Halim Raynaldo, Sp.JP(K)
1
Textbook Reading divisi Rehabilitasi dan Prevensi Kardiovaskular
2023

2. 01
Cardiovascular disease
incurs a major burden to the
public health and health care
system.
02
Understanding of the complexities of
vascular structure and function and
the significance of the endothelium
in the development of
atherosclerosis
03
Atherosclerosis is a ubiquitous,
complex disease process that is
dynamic and multifactorial. Genetic
and various environmental factors,
with their complex interactions, lead
to the initiation and progression of
atherosclerosis during decades
04
Various invasive and noninvasive
imaging modalities have evolved in
the last several decades to clinically
evaluate structure and function of
various vascular beds in health and
disease states. 2
More commonly the arteriosclerosis results from the bad use of good vessels.
William Osler (The Principles and Practice of Medicine, 1892)

3. ENDOTHELIUM AND ENDOTHELIAL PHYSIOLOGY:
GENERAL OVERVIEW
The endothelium is a 0.2- to 4- m-thick
monolayer of squamous endothelial
cells lining the entire surface of the
vasculature, including endocardium,
arteries, arterioles, capillaries, venules,
veins, adventitial vasa vasorum, and
other microcirculation
1
2 During exposure to risk factors such as
hypertension, diabetes mellitus, and
tobacco smoking, dysfunction of
endothelium ensues, thus disturbing the
fine balance and subsequently resulting in
atherosclerosis

4. Vasomotion Endothelin 1 Inflammation
Hemostasis
and
Thrombosis
Vascular
Growth and
Remodeling
Nitric Oxide
Pathway
4
ENDOTHELIUM AND ENDOTHELIAL PHYSIOLOGY:
GENERAL OVERVIEW

5. Vasomotion
• Regulation of vascular tone by endothelium is achieved
by generation and secretion of vasoactive substances
 both vasodilation and vasoconstriction
5
Vasodilation
• Nitric oxide (NO) and
prostacyclins (PGI2).
Vasoconstriction
• secretion of angiotensin II,
platelet-derived growth factors,
platelet-activating factor, and
endothelin 1
Vasodilator effects of
prostacyclins are dependent on
expression
of receptors in vascular smooth
muscles

6. Endothelin 1
• Potent vasoconstrictor generated in the endothelial cells along with other cell
lines
• Shear stress, cyclic stress and hypoxia stimulate generation of ET-1 from
endothelial cells
• Augments the vascular actions of other vasoactive peptides (such as angiotensin
II, norepinephrine, and serotonin), participates in leukocyte and platelet
activation, and thus facilitates a prothrombotic state.
• Inhibitory effect on renin release from juxtaglomerular cells
• Enhances release of endothelium-derived relaxing factor and PGI2 and
modulates vascular remodeling.
6

7. NO and Inflammation
• The endothelium serves as a potent anti-inflammatory tissue
• Disease states or exposures such as hypertension and atherosclerosis constitute inflammatory
changes in the vascular wall
• NO released from endothelial cells aids in limiting leukocyte adhesion.
• NO has an inhibitory effect on release of prothrombotic substances, such as von Willebrand
factor and P-selection
• Endothelial dysfunction, as a result of oxidative stress in the endothelial cells, results in
activation of NF-κB, a redox-sensitive transcription factor.
• release of chemoattractant proteins such as monocyte chemotactic protein 1 and expression
of adhesion molecules (E-selectin, P-selectin, intercellular adhesion molecule 1 [ICAM-1], and
vascular cell adhesion molecule 1 [VCAM-1]).
7

8. Hemostasis and
Thrombosis
• The endothelium serves
as a lining of a
compartment that
maintains blood flow
while permitting delivery
of important nutrients to
other organs in the body
 inhibiting platelet
aggregation and clotting
cascade activation
8
•- Anticoagulants
(antithrombin III,
thrombomodulin, tissue
factor pathway inhibitor,
protein C, and heparan
sulfate proteoglycans)
•- Fibrinolytics (tissue-type
plasminogen activators and
urokinase-type plasminogen
activators),
•- Platelet inhibitors (NO,
prostacyclins, and ADPase
[CD39])
- Procoagulants (thrombin
receptor, protein C receptor,
tissue factor, and
coagulation factor binding
sites) and
- Antifibrinolytics
(plasminogen activator
inhibitor 1) and
- Promotion of platelet
activation (von Willebrand
factor and platelet activating
factor).
Antithrombotic
Prothrombotic

9. Vascular growth and
remodeling
• Close relationship exists between endothelial cells and the hematopoietic cell
lineage
• Endothelium along with the vasa vasorum contributes to angiogenesis and
neovessel formation in atheromas. These neovessels are instrumental in
atherosclerotic plaque progression, instability, and rupture
• In addition to leukocyte migration, microvessels cause intraplaque
neovascularization, thus leading to hyperpermeability, and result in
microhemorrhage and thrombosis
9

10. Nitric Oxide Pathway
• NO is the most recognized
molecule; it is pivotal in
maintaining vascular tone and
mediates inhibition of
coagulation, platelet
activation, smooth muscle cell
proliferation, and
inflammation.
• Inadequate or lack of NO is
implicated in endothelial
dysfunction.
10

11. Schematic representation of mechanisms of decreased NO bioavailability
resulting in endothelial dysfunction.
• Reactive oxygen species decrease the
bioavailability of NO in endothelium by three
different mechanisms:
• (1) superoxide reacts with NO to form
peroxynitrite anions, causing a
diminished bioavailability of NO
• (2) reactive oxygen species cause an
increased concentration of ADMA, an
endogenous inhibitor of eNOS; and
• (3) uncoupling of eNOS enzyme due to
degradation of BH4
12

12. ENDOTHELIAL DYSFUNCTION
13

13. Endothelial Dysfunction
• No single definition of endothelial dysfunction exists, given the complex
and ubiquitous nature of endothelial biology
• Endothelial dysfunction was first described as structural changes or loss of
anatomic integrity in the context of atherosclerosis
• Any imbalance between injury and repair may result in endothelial
dysfunction
14

14. Oxidative Stress and
Endothelial Dysfunction
• Oxidative stress refers to a state whereby the rate
of formation of reactive oxygen species exceeds
the capacity of physiologic antioxidant defense
mechanisms
• NO is a key mediator in vascular homeostasis as it
serves as an antiatherogenic molecule, promotes
vasodilation, and counteracts inflammation,
platelet aggregation, and vascular smooth muscle
proliferation.
15

15. Role of Endothelial Dysfunction in the Presence of Specific
Risk Factors and Atherosclerotic Disease
• Several risk factors may play a critical role in contributing to endothelial
dysfunction and thus atherosclerosis.
• Traditional and novel cardiovascular risk factors, including smoking, aging,
hyperlipidemia, hypertension, diabetes, and family history of premature
atherosclerosis, among others, are associated with a loss or attenuation
of endothelium-dependent vasodilation in both children and adults.
• Elevated C-reactive protein, chronic systemic infection, obesity, and
several immune-mediated diseases are also associated with impaired
endothelial function.
• Given its complex biology, the term endothelial dysfunction applies
broadly to the various perturbations that contribute over time to the
development and clinical expression of atherosclerosis.
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16. ENDOTHELIAL VASOMOTOR
FUNCTION TESTING
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17. 21
Invasive Measures of Coronary
Vasoactivity
Ludmer and colleagues in the 1980s, first described impaired endothelium-dependent
vasomotor function with intracoronary injection of acetylcholine and quantitative
coronary angiography in humans
Endothelial function is most commonly measured as the vasomotor response to
pharmacologic stimuli, such as acetylcholine, methacholine, bradykinin,
serotonin, papaverine, and substance P, or to a physical stimulus, such as shear
stress (increased blood flow velocity), exercise, cold pressor test, and mental
stress.
Endothelial function in resistance vessels (microcirculation) is also critical in the
assessment of endothelial vasomotor function. Resistance vessels regulate blood flow
in response to changes in perfusion pressure (autoregulation) and metabolic needs
(metabolic regulation).

18. 22
Plots of forearm blood flow to acetylcholine in normal subjects, hypercholesterolemic patients, long-
term smokers, and patients with hypercholesterolemia who smoked.

19. Venous occlusion plethysmography is an invasive
technique that indirectly measures microvessel
function as forearm blood flow in response to an
intra-arterial infusion of a vasoactive substance
such as acetylcholine, substance P, or adenosine
into either the brachial artery or radial artery or
to reactive hyperemia (increased shear stress).
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Invasive Assessment of Forearm Microcirculation
(Venous Occlusion Plethysmography)

20. • Flow-mediated
vasodilatation (FMD)
• Endothelium-dependent
• Baseline measurements
• Reactive hyperemia
• Sublingual nitroglycerin
response (NTG)
• Endothelium-
independent
25
Noninvasive Assessment of Peripheral Conduit
Vascular Reactivity: Brachial Artery Ultrasound

21. Noninvasive Assessment of Peripheral Conduit
Vascular Reactivity: Brachial Ultrasound
26
Schematic diagram of the brachial artery B-mode
ultrasound imaging protocol for brachial artery vasoactivity
testing.
Time course of brachial artery flow-mediated
vasodilation by upper arm occlusion shear
stress stimulus in a healthy individual

22. EMERGING TECHNIQUES OF
VASCULAR FUNCTION
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23. Laser Doppler Flowmetry: Measure for Cutaneous
Microvessels
29
Semiquantitative measure
of blood flow in the small
blood vessels of the
microvasculature. These
vessels have low-velocity
flows associated with
nutrient blood flow delivery,
regulation of skin
temperature, and vascular
resistance in the capillaries,
arterioles, and venules

24. Diagram of aortic pressure wave
Applanation tonometry (SphygmoCor CPV, AtCor Medical, Sydney,
Australia) is a method used for pulse wave analysis to derive the
central aortic pressure waveform and pulse wave velocity.
30
Arterial Compliance and Arterial Stiffness
• Each pulsation of the
heart generates a velocity
of the pressure wave
(pulse wave velocity) that
is transmitted centrifugally
throughout the peripheral
vascular system.
• Pulse wave analysis is a
stable, easy to perform,
highly reproducible
technique that relates
arterial structure to
vascular tone.

25. LIFESTYLE MODIFICATIONS AND
THERAPEUTICS
• Experimental and clinical techniques have demonstrated various
manifestations of endothelial dysfunction in the presence of traditional and
novel cardiovascular risk factors and in diseases such as diabetes,
dysmetabolic syndrome, hypertension, and coronary artery disease.
• The focus on specific perturbations of endothelial dysfunction allows the
application of noninvasive imaging and hemodynamic techniques with or
without concurrent biomarkers.
• Numerous studies employing flow-mediated vasodilation as a marker of
endothelial vasomotor dysfunction have demonstrated impairment (less
vasodilation in response to shear stress) in various conditions and
improvement with such interventions as lifestyle modifications and
therapeutics
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26. CLINICAL
TRIALS
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27. CONCLUSION
• Understanding of the pathophysiology of endothelial dysfunction due to
underlying injury and repair has made significant progress.
• applied to further study the endothelial vasomotor dysfunction in the wake
of the discoveries made in NO biology and oxidative injury
• Ultrasound assessment of brachial artery flow-mediated vasodilation has
yielded important information about vascular function in health and
disease, yet several new technologic advances and techniques have
emerged to expand the scope in the detection of mechanisms of and
impairments in vascular structure and function.
• Prospective studies comparing vascular function testing with modalities
such as intravascular ultrasound, carotid intima-media thickness,
multidetector computed tomography, and computed tomographic
angiography in the context of interventions and prognosis will further
define the potential clinical role for ultrasound measures of brachial artery
vasoactivity testing with other emerging techniques and biomarkers to
assess cardiovascular health and disease.
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28. THANK YOU
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