2. Mechanisms of Inflammation in
Atherogenesis
• A fundamental role for inflammation in
atherogenesis;
– The macrophage foam cells recruited to the artery
wall early in this process serve as a reservoir for
excess lipid. In the established atherosclerotic
lesion, these cells also provide a rich source of
proinflammatory mediators—proteins such as
cytokines and chemokines and various eicosanoids
and lipids such as platelet-activating factor.
Brawnwald Heart Diseases. 10th. edition
3. Representation of formation of foam cells and initiation of atherogenesis LDL
particles enter arterial wall through endothelium; monocytes are recruited and
once in the wall, differentiate into macrophages. These macrophages will
capture LDL particles and the result will be foam cells
Published in Healthcare Technology Letters; Received on 4th December 2013; Revised on 10th
February 2014; Accepted on 11th February 2014
4. The endothelial thrombotic balance. This diagram depicts the anticoagulant
profibrinolytic functions of the endothelial cell (left) and certain
procoagulant and antifibrinolytic functions (right). PAi = plasminogen
activator inhibitor; PGI2 = prostacyclin; t-PA = tissue type plasminogen
activator; vWf = von Willebrand factor.
5. Mechanisms of Inflammation in
Atherogenesis
Innate and adaptive immunity in atherosclerosis. A diagram of the pathways of innate (left) and adaptive
(right) immunity operating during atherogenesis. MF = macrophage, IFN-g = interferon gamma, Th = T
helper. (Adapted from Hansson G, Libby P, Schoenbeck U, Yan Z-Q: Innate and adaptive immunity in
the pathogenesis of atherosclerosis. Circ Res 91:281-291, 2002.)
6. Schematic of the evolution of the
atherosclerotic plaque
1, Accumulation of lipoprotein particles in the intima. The modification of these lipoproteins is depicted by the darker color. Modifications include
oxidation and glycation. 2, Oxidative stress including products found in modified lipoproteins can induce local cytokine elaboration. 3, The cytokines thus
induced increase expression of adhesion molecules for leukocytes that cause their attachment and chemoattractant molecules that direct their migration
into the intima. 4, Blood monocytes, on entering the artery wall in response to chemoattractant cytokines such as monocyte chemoattractant protein 1
(MCP-1), encounter stimuli such as macrophage colony-stimulating factor (M-CSF) that can augment their expression of scavenger receptors. 5, Scavenger
receptors mediate the uptake of modified lipoprotein particles and promote the development of foam cells. Macrophage foam cells are a source of
mediators such as more cytokines and effector molecules such as hypochlorous acid, superoxide anion (O2
-), and matrix metalloproteinases. 6, SMCs in the
intima divide, other SMCs migrate into the intima from the media. 7, SMCs can then divide and elaborate extracellular matrix promoting extracellular
matrix accumulation in the growing atherosclerotic plaque. In this manner, the fatty streak can evolve into a fibro-fatty lesion. 8, In later stages,
calcification can occur (not depicted), and fibrosis continues, sometimes accompanied by SMC death (including programmed cell death, or apoptosis)
yielding a relatively acellular fibrous capsule surrounding a lipid-rich core that may also contain dying or dead cells and their detritus. IL-1 = interleukin-
1; LDL = low-density lipoprotein, SMCs = smooth muscle cells
7. ANTIOXIDANTS & REDOX SIGNALING Volume 25, Number 7,
2016 Mary Ann Liebert, Inc. DOI: 10.1089/ars.2015.6493
8. A schematic relating extracellular matrix metabolism to intimal inflammation during atherogenesis. The lymphocyte can elaborate
gamma interferon (IFN–γ) that inhibits SMC collagen production. The lymphocyte can also signal either by elaboration of soluble
mediators or by contact activation of macrophages. Other cytokines produced in response to products of oxidized lipoproteins, among
other stimuli, can further activate the macrophage. The activated phagocyte can release collagen degrading matrix metalloproteinases,
and elastolytic enzymes including certain nonmetalloenzymes, such as cathepsins S and K. These enzymes promote matrix catabolism.
Thus, in states characterized by heightened intimal inflammation, the extracellular matrix that confers biomechanical strength to the
plaque's fibrous cap is under double attack: decreased synthesis and increased degradation. This results in a weakening and thinning of
the fibrous cap, features associated in pathological studies with fatal atheromatous plaque disruptions and thrombosis. TNF–α = tumor
necrosis factor-alpha; M-CSF = macrophage colony stimulating factor; MCP-1 = monocyte chemoattractant protein-1. (Reproduced
from Libby P: The molecular bases of the acute coronary syndromes. Circulation 91:2844-2850, 1995.)
9. Positive remodelling
• During the first part of the life history of an
atheromatous lesion, growth of the plaque is outward,
in an abluminal direction, rather than inward in a way
that would lead to luminal stenosis.
• This outward growth of the intima leads to an increase
in caliber of the entire artery. This so-called positive
remodeling or compensatory enlargement must involve
turnover of extracellular matrix molecules to
accommodate the circumferential growth of the artery.
• Luminal stenosis tends to occur only after the plaque
burden exceeds about 40 percent of the cross-sectional
area of the artery.
Brawnwald Heart Diseases. 10th. edition
10. Positive remodelling
Atherosclerotic vessel growth model used in the computational simulations. A: schematic description of the positive
coronary remodeling described by Glagov et al. (14) and included in our model. Plathick, plaque thickness; Remodindex,
arterial remodeling index. B: for a given remodeling index, the main parameters describing plaque morphology, i.e., cap
thickness (Capthick), necrotic core thickness (Corethick), and necrotic core arc angle (Coreangle), were varied. A total of
5,500 distinct plaque geometries were considered. Dark gray, arterial wall; gray, fibrosis; light gray, necrotic core.
Published 2008 in American journal of physiology. Heart and…
DOI:10.1152/ajpheart.00005.2008
11. Classification of coronary lesions
Schematic representation of the histopathologic classification of coronary lesions
proposed by the AHA. Adapted from Stary et al.15
14. Coronary thrombosis
• This evolution in our view of the pathogenesis of the acute coronary
syndromes places new emphasis on thrombosis as the critical
mechanism of transition from chronic to acute atherosclerosis.
• Understanding of the mechanisms of coronary thrombosis has
advanced considerably. We now appreciate that a physical disruption
of the atherosclerotic plaque commonly causes acute thrombosis.
Several major modes of plaque disruption provoke most coronary
thrombi.[
• The first mechanism, accounting for nearly two-thirds of acute
myocardial infarctions, involves a fracture of the fibrous cap of the
plaque .
• Another mode involves a superficial erosion of the intima, accounting
for up to one-quarter of acute myocardial infarctions in highly selected
referral cases from medical examiners on individuals who have
succumbed to sudden cardiac death.
• Superficial erosion appears more frequently in women than in men as
a mechanism of sudden cardiac death.[
Brawnwald Heart Diseases. 10th. edition
21. Coronary Flow cont.
Phasic coronary arterial inflow and
venous outflow at rest and during
adenosine vasodilation. Arterial
inflow primarily occurs during
diastole.
During systole (dotted vertical
lines), arterial inflow declines as
venous outflow peaks, reflecting
the compression of
micocirculatory vessels during
systole.
After adenosine administration,
the phasic variations in venous
outflow are more pronounced.
(Modified from Canty JM Jr, Brooks
A: Phasic volumetric coronary
venous outflow patterns in
conscious dogs. Am J Physiol
258:H1457, 1990.)
22. Coronary flow and oxygen
consumption
Fick equation and the relation between heart
rate (HR)–systolic blood pressure (SBP) double
product and myocardial oxygen consumption
(MVO2).
A, Increases in MVO2 are primarily met by
increases in coronary flow and linearly
related to the double product. A doubling of
HR, SBP, or contractility each results
in approximately 50% increases in myocardial
oxygen consumption. B, Beta blockade
allows the same external workload to be
accomplished at a lower cardiac workload
(MVO2) by reducing the double product and
myocardial contractility.
CaO2 = coronary arterial oxygen content; CBF =
coronary blood flow; CvO2 = coronary
venous oxygen content.
Brawnwald Heart Diseases. 10th. edition
23. Coronary Autoregulatoin
Autoregulatory relation under basal conditions and after
metabolic stress (e.g., tachycardia). Left, The normal heart
maintains coronary blood flow constant as regional coronary
pressure is varied over a wide range when the global
determinants of oxygen consumption are kept constant (red
lines). Below the lower
autoregulatory pressure limit (approximately 40 mm Hg),
subendocardial vessels are maximally vasodilated and
myocardial ischemia develops. During vasodilation (blue
lines), flow increases four to five times above resting values at
a normal arterial pressure. Coronary flow ceases at a pressure
higher than right atrial pressure (PRA), called zero flow
pressure (Pf=0), which is the effective back pressure to flow in
the absence of coronary collaterals. Right, After stress,
tachycardia increases the compressive
determinants of coronary resistance by decreasing the time
available for diastolic perfusion and thus reduces maximum
vasodilated flow. LV hypertrophy and microvascular
disease also limit maximal blood flow per gram of
myocardium. In addition, increases in myocardial oxygen
demand or reductions in arterial oxygen content (e.g., from
anemia or hypoxemia) increase resting flow. These changes
reduce coronary flow reserve, the ratio between dilated and
resting coronary flow, and cause ischemia to
develop at higher coronary pressures. Hb = hemoglobin; HR =
heart rate; SBP = systolic blood pressure.
Brawnwald Heart Diseases. 10th. edition
24. Effects of extravascular tissue pressure on
transmural perfusion. Compressive effects
during diastole (A) are related to tissue
pressures that decrease from the
subendocardium (Endo) to subepicardium
(Epi). At diastolic LV pressures greater than 20
mm Hg, preload determines the effective back
pressure to coronary diastolic perfusion. During
systole (B), cardiac contraction increases
intramyocardial tissue pressure surrounding
compliant arterioles and venules. This produces
a concealed arterial “backflow” that reduces
systolic epicardial artery inflow, as depicted in
Figure 49-1. Compression of venules
accelerates venous outflow. (Modified from
Hoffman JI, Spaan JA: Pressure-flow relations
in the coronary circulation. Physiol Rev
70:331, 1990.)
Brawnwald Heart Diseases. 10th. edition
25. Schematic of components of coronary vascular
resistance with and without a coronary stenosis
R1 is epicardial conduit artery
resistance, which normally is
insignificant; R2 is resistance
secondary to metabolic and
autoregulatory adjustments in
flow and occurs in arterioles and
small arteries; and R3 is the time-
varying compressive resistance
that is higher in subendocardial
than subepicardial layers. In the
normal heart (upper panel), R2 >
R3 ≫ R1. The development of a
proximal stenosis or
pharmacologic vasodilation
reduces arteriolar resistance (R2).
In the presence of a severe
epicardial stenosis (lower panel),
R1 > R3 > R2.
Brawnwald Heart Diseases. 10th. edition
26. Schematic representation of biochemical processes of plaque formation, key
molecules and cells, endothelium junctions and intima + media
Published in Healthcare Technology Letters; Received on 4th December 2013; Revised
on 10th February 2014; Accepted on 11th February 2014
28. Schematic representation of the role of arterial stiffness in assuring blood flow
through the peripheral circulation
Kidney International August 2, 2012Volume 82, Issue 4, Pages 388–
400
29. Endothelium-dependent control of vascular
tone.
Brawnwald Heart Diseases. John M. Canty Jr.,, Dirk J. Duncker
In the normal coronary circulation, endothelium-dependent vasodilation occurs after increases in luminal flow or shear stress, as well as in response to
agonists (e.g., released from platelets or cardiac nerves) that bind to receptors on the endothelial surface. These stimulate the production of NO, EDHF, or
EETs (epoxyeicosatrienoic acid products), which diffuse into vascular smooth muscle and cause relaxation. Prostacyclin, or prostaglandin I2 (PGI2), is
produced in the coronary endothelium of collateral vessels and causes tonic vasodilation. The endothelium also produces endothelin (ET), which activates
protein kinase C in vascular smooth muscle to produce coronary constriction and competes with endothelium-derived relaxing factors. Impaired
endothelium-dependent vasodilation can result from the lack of production of relaxing factors (e.g., disrupted endothelium) or by inactivation of nitric oxide
in disease states associated with oxidative stress and superoxide anion production (e.g., NO and O2
− combining to produce peroxynitrite). In these
circumstances, the effect of autacoids on vascular tone can be converted to vasoconstriction because of their direct effects on vascular smooth muscle (not
shown). AA = arachidonic acid; ACh = acetylcholine; Bk = bradykinin; 5-HT = 5-hydroxytryptamine [serotonin]; KCa = calcium-activated potassium
channel; TGFβ = transforming growth factor-beta-1; Thr = thrombin.
30. As the plaque burden increases, the
atherosclerotic mass tends to stay
external to the lumen, which allows the
diameter of the lumen to be maintained;
this is known as the Glagov effect, or
positive remodeling.1As plaque
encroaches into the lumen, the coronary
artery diameter decreases. Myocardial
ischemia results from a discordant ratio
of coronary blood supply to myocardial
oxygen consumption. Luminal narrowing
of more than 65 to 75 percent may result
in transient ischemia and angina. In acute
coronary syndromes, vulnerable plaque
is a more important factor than is the
degree of stenosis; acute coronary events
result from ulceration or erosion of the
fibrous cap, with subsequent intraluminal
thrombosis.2,3 Vulnerable plaque within
the vessel wall may not be obstructive
and thus may remain clinically silent
until it causes rupture and associated
consequences. (The figure has been
modified from Greenland et al.,4 with
permission.)
Typical Progression of Coronary Atherosclerosis.
N Engl J Med 2005; 352:2524-2533 DOI: 10.1056/NEJMcp042317
