This document discusses the pathogenesis of atherosclerosis. It begins with a brief history of atherosclerosis and then discusses the structure of the normal artery and endothelial cells. It describes the response to injury hypothesis for the initiation and progression of atherosclerotic lesions. It discusses complications of atherosclerosis including plaque rupture and thrombosis. It concludes by discussing risk factors for atherosclerosis such as smoking, hypertension, hyperlipidemia, and metabolic syndrome.

1. PATHOGENESIS
OF
ATHEROSCLEROSIS

2. History
 This disease has a venerable history,
having left traces in the arteries of
Egyptian mummies.
 Apparently uncommon in antiquity,
atherosclerosis became epidemic as
populations increasingly survived early
mortality caused by communicable
diseases and malnutrition.

3.  Virchow- viewed atherosclerosis as a
proliferative disease.
 Rokitansky- believed that atheroma
derived from healing and resorption of
thrombi.

4.  Experiments performed in the early part
of the 20th century used dietary
modulation to produce fatty lesions in
the arteries of rabbits and ultimately
identified cholesterol as the culprit.
 These observations, followed by the
characterization of human lipoprotein
particles at mid-century, promoted the
concept of insudation of lipids as a cause
for atherosclerosis

5. ATHEROSCLEROSIS:
Pathology, Pathogenesis, Complications, Natural History

6. ?
 ? - Affects certain regions of the arterial
tree preferentially.
 ? - Clinical manifestations occur only at
certain times.
 ? - Its role in causing narrowing, or
stenosis, of some vessels and ectasia of
others.

7. STRUCTURE OF THE NORMAL ARTERY

8.  Endothelial cells have a common origin
but acquire bed-specific characteristics
during development.
 Arise during embryogenesis from
regions known as the blood islands,
located on the embryo's periphery.
 ?- postnatal life-The endothelial
progenitor cells (EPCs).

9.  Circulating numbers of EPCs, as assayed in
vitro, vary among individuals.
 Those with a higher burden of risk factors for
atherosclerosis have fewer EPCs.
 EPC number may correlate with prognosis in
atherosclerotic patients.
 More aged individuals may have impaired
EPC numbers and hence less ability to repair

10.  Differential expression of endothelial genes
in various types of blood vessels depends on
transcriptional regulation by the local
environment.
 Members of the EPH family of tyrosine
kinase receptors and their ligands, known as
ephrins, display heterogeneous expressions in
arterial versus venous endothelial cells during
development.

11. Arterial Smooth Muscle Cells
 These cells contract and relax and thus control
blood flow through the various arterial beds.
 Abnormal smooth muscle contraction causes
vasospasm, a complication of atherosclerosis .
 SMCs synthesize the bulk of the complex
arterial ECM that plays a key role in normal
vascular homeostasis as well as the formation
and complication of atherosclerotic lesions.

12.  These cells also can migrate and proliferate,
contributing to the formation of intimal
hyperplastic lesions.
 Death of SMC may promote destabilization
of atheromatous plaques or favor ectatic
remodeling and ultimately aneurysm
formation.

13.  In the descending aorta and arteries of
the lower body, the regional mesoderm
serves as the source of smooth muscle
precursors.
 In arteries of the upper body, SMCs can
actually derive from a completely
different germ layer, neurectoderm
rather than mesoderm

14.  SMCs in the coronary arteries derive
from mesoderm, but in a special
way[from pro epicardial organ].
 SMCs show molecular heterogeneity
early during development.
 the promoter of a characteristic smooth
muscle gene, known as SM22, drives
gene expression in venous, but not
arterial.

15.  Differential dependence on CArG
elements in the control of SMC gene
transcription furnishes a molecular basis
for SMC heterogeneity in different
arterial beds.

17. Normal Artery

18. Response to injury hypothesis
* Injury to the endothelium
(dysfunctional endothelium)
* Chronic imflammatory response
* Migration of SMC from media to intima
* Proliferation of SMC in intima
• Excess production of ECM
• Enhanced lipid accumulation

19. Response to injury hypothesis (I)
1. Chronic EC injury (subtle?)
 EC dysfunction
 Increased permeability
 Leukocyte adhesion (via VCAM-1)
 Thrombotic potential

20. Response to injury hypothesis
(II)
2. Accumulation of LDL (cholesterol)
3. Oxidation of lesional LDL
4. Adhesion & migration of blood
monocytes; transformation into
macrophages and foam cells
5. Adhesion of platelets
6. Release of factors from platelets,
macrophages and ECs

21. Response to injury hypothesis
(III)
7. Migration of SMC from media to intima
8. Proliferation of SMC
9. ECM production by SMC
10. Enhanced lipid accumulation
Intracellular (SMC and macrophages)
Extracellular

22. Response to Injury

23. ATHEROSCLEROSIS INITIATION

24. Endothelial Dysfunction

26. Initiation of Fatty Streak

27. Fatty Streak

28. Fatty Streak-Aorta

29. Fibro-fatty Atheroma

32. Evolution of atheroma

33.  Smooth Muscle Cell Death During
Atherogenesis.
 The Arterial Extracellular Matrix.
 Angiogenesis in Plaques.
 Plaque Mineralization

35. The Focality of Lesion Formation

36. Lesion progression

37. COMPLICATIONS OF ATHEROSCLEROSIS
 Plaque Rupture and Thrombosis.
 Thrombosis Caused by Superficial
Erosion of Plaques.

39. Plaque Rupture and Thrombosis

40. Thrombosis Caused by Superficial Erosion of Plaques

42. Fibrous Plaques Complicated Lesions

43.  ? small atheroma cause most
myocardial infarctions .

45. AHA Classification of atherosclerosis
Fig. 11.7

49. Novel Invasive Imaging Modalities

50. OPTICAL COHERENCE TOMOGRAPHY

51. INTEGRATED BACKSCATTER ANALYSIS
(“VIRTUAL HISTOLOGY”).

52.  INTRACORONARY THERMOGRAPHY.
 PALPOGRAPHY.
 COMPUTATIONAL FLOW DYNAMICS.

54. SPECIAL CASES OF ARTERIOSCLEROSIS
 Restenosis After Arterial Intervention.
 Accelerated Arteriosclerosis Following
Transplantation.

55. Restenosis After Arterial Intervention
 After balloon angioplasty, luminal
narrowing recurs in approximately one-
third of cases within 6 months.
 These observations renewed interest in
adventitial inflammation with scar
formation and wound contraction as a
mechanism of arterial constriction
following balloon angioplasty[negative
remodeling].

56. Restenosis After Arterial Intervention
 The widespread introduction of stents
has changed the face of the restenosis
problem.
 The process of in-stent stenosis, in
contrast with restenosis after balloon
angioplasty, depends uniquely on
intimal thickening.

57.  Histological analyses reveal that a great
deal of the volume of the in-stent
restenotic lesion is made up of
myxomatous tissue.
 It comprises occasional stellate SMCs
embedded in a loose and highly
hydrated extracellular matrix.

58.  The introduction of stents has reduced the
clinical impact of restenosis because of the
very effective increase in luminal diameter
achieved by this technique.
 stents that elaborate antiproliferative and
antiinflammatory substances have shown
great benefit in terms of preventing in-stent
stenosis.

59. Accelerated Arteriosclerosis Following
Transplantation

61. Aneurysmal Disease
 Atherosclerosis produces not only
stenoses but also aneurysmal disease .
 Data from the Pathobiological
Determinants of Atherosclerosis in
Youth Study (PDAY) show that the
dorsal surface of the infrarenal
abdominal aorta has a particular
predilection .

62.  Absence of vasa vasorum.
 The relative lack of blood supply to the
tunica media in this portion of the
abdominal aorta.
 the lumbar lordosis of the biped human
may alter the hydrodynamics of blood
flow in the distal aorta, yielding flow
disturbances

63.  Transmural destruction of the arterial architecture occurs in aneurysmal
disease.
 Many studies have documented overexpression of matrix-degrading
proteinases, including matrix metalloproteinases in human aortic
aneurysm specimens.
 Current clinical trials are testing the hypothesis that MMP inhibitors can
reduce the expansion of aneurysms

64. Consequences of
Atherosclerosis

66. Altered Vessel Function
 Vessel change  Consequence
 Plaque narrows  Ischemia, turbulence
lumen  Aneurysms, vessel
 Wall weakened rupture
 Narrowing, ischemia,
 Thrombosis embolization
 Athero-embolization
 Breaking loose of
plaque
 Loss of elasticity  Increase systolic blood
pressure

67. Common Consequences of
Atherosclerosis in Specific
Vessels

68. Aorta
 Aneurysm
 Pulsatile abdominal mass
 Abdominal pain
 Bleeding
 Atheroembolization
 Narrowing of lumen
 Usually not a problem

69. Aortic Aneurysm

70. Carotids and Cerebral
Circulation
 Atherosclerosis with thrombosis can
lead to brain infarction
 Red or white
 Coagulative or liquefactive
 Can lead to transient ischemic attacks
(TIA), if narrowing is aggravated by
mural thrombus or vasospasm

71. Celiac and Mesenteric Arteries
 Narrowing primarily at aorta
bifurcation
 Ischemia uncommon because of
collateral circulation
 Ischemia can occur if more than 1 artery
severely affected - ischemic entercolitis

72. Renal Artery
 Progressive ischemic atrophy of kidney
leads to gradual kidney failure
(nephrosclerosis)
 Renal hypertension due to decreased
perfusion

73. Iliac and Femoral Arteries
 Aneurysms
 Vessel occlusion by plaque and
thrombus
 Ischemia of leg muscles, especially during
exercise (intermittent claudication)
 Ulcers of skin of legs and feet
 Gangrene of feet

74. Non-Modifiable Risk Factors
 Age
 A dominant influence
 Atherosclerosis begins in the young, but does not
precipitate organ injury until later in life
 Gender
 Men more prone than women, but by age 60-70
about equal frequency
 Family History
 Familial cluster of risk factors
 Genetic differences

75. Modifiable Risk Factors
(potentially controllable)
 Hyperlipidemia
 Hypertension
 Cigarette smoking
 Diabetes Mellitus
 Elevated Homocysteine
 Factors that affect hemostasis and thrombosis
 Infections: Herpes virus; Chlamydia
pneumoniae
 Obesity, sedentary lifestyle, stress

76. NOVEL ATHEROSCLEROTIC RISK FACTORS.

77. Smoking
 Other than advanced age, smoking is the
single most important risk factor for
coronary artery disease.
 Landmark studies in the early 1950s first
reported strong positive associations
between cigarette smoke exposure and
coronary heart disease.
 smoking may enhance oxidation of low-
density lipoprotein (LDL) cholesterol
and impair endothelium-dependent
coronary artery vasodilation.

78.  Smoking has adverse hemostatic and inflammatory effects,
including increased levels of CRP, soluble ICAM-1,
fibrinogen, and homocysteine.
 Cessation of cigarette consumption overwhelmingly
remains the single most important intervention in
preventive cardiology.
 Smoking predicts better outcome following various
reperfusion strategies (the so-called “smoker's paradox”) ---
smokers are likely to undergo such procedures at a much
younger age and hence have on average lower comorbidity

79. Hypertension
 Most epidemiological studies now recognize
the joint contributions of SBP&DBP to the
development of CV risk.
 ISH has at least as much importance as DBP
for the outcomes of total CV &CVA .

80.  Treatment of systolic hypertension is
well supported, even in the elderly.
 Isolated systolic hypertension thus
appears to represent a distinct
pathophysiological state.
 In ISH elevated blood pressure reflects
reduced arterial elasticity not necessarily
associated with increased peripheral
resistance or an elevation in mean
arterial pressure.

81. Hyperlipidemia and Elevated Low-Density
Lipoprotein Cholesterol
 In the 1850s, the German pathologist Virchow
recognized in human atheromata “numerous
plates of cholesterine…which display
themselves even to the naked eye as
glistening lamellae.
 Multiple Risk Factor Intervention Trial
(MRFIT).
 Northwick Park Study and the Prospective
Cardiovascular Munster (PROCAM) Cohort .
 the Atherosclerosis Risk in Communities
(ARIC) study.

82.  REVERSAL trial, which monitored
intravascular coronary ultrasound,
PROVE-IT, A-to-Z, and TNT trials, all of
which support more aggressive use of
statin therapy for reduction in hard
clinical endpoints.

85. Metabolic Syndrome, Insulin
Resistance, and Diabetes.

86. Exercise, Weight Loss, and
Obesity.
 Physical exercise reduces myocardial oxygen
demand and increases exercise capacity, both
of which correlate with lower levels of
coronary risk.
 The cardioprotective effects of exercise
include reduced adiposity and diabetes
incidence, lowered blood pressure, and
improvement of dyslipidemia, as well as
vascular inflammation.

87.  Exercise also enhances endothelial
dysfunction, insulin sensitivity, and
endogenous fibrinolysis.
 In the Women's Health Initiative,
walking briskly for 30 minutes five
times/week was associated with a 30
percent reduction in vascular events over
a 3.5-year follow-up.
 In the Women's Health Study, high BMI
was more strongly associated with
adverse cardiovascular biomarkers than
physical activity

88. Mental Stress, Depression, and
Cardiovascular Risk.
 In the INTERHEART study,psychosocial
stress was found to be associated with
vascular risk, with a magnitude of effect
similar to that of the major coronary risk
factors.
 In the Enhancing Recovery in Coronary Heart
Disease Patients (ENRICHD) trial, formal
psychosocial intervention modestly improved
measures of clinical depression but did not
significantly improve event-free survival

90. High-Sensitivity C-Reactive Protein
 Composed of five 23-kDa subunits, CRP is a
circulating member of the pentraxin family
that plays a major role in the human innate
immune response.
 Although derived primarily from the liver,
studies have found that cells within human
coronary arteries, particularly in the
atherosclerotic intima, can also elaborate CRP.

92.  hsCRP levels less than 1, 1 to 3, and higher
than 3 mg/liter should be interpreted as lower,
moderate, and higher relative vascular risk.
 Values of hsCRP in excess of 8 mg/liter may
represent an acute-phase response caused by
an underlying inflammatory disease or
intercurrent infection and should lead to
repeat testing in approximately 2 to 3 weeks.
 consistently high values, however, represent
very high risk of future cardiovascular
disease.

93. Fibrinogen and Fibrin D-Dimer
 fibrinogen associates positively with age,
obesity, smoking, diabetes, and LDL
cholesterol level, and inversely with
HDL cholesterol level, alcohol use,
physical activity, and exercise level.
 Fibrinogen, like CRP, is an acute-phase
reactant and increases during
inflammatory responses.

95.  Despite the consistency of these data,
fibrinogen evaluation has found limited
use in clinical practice because of
suboptimal assay standardization and
consistency across reference laboratories
remains poor.

96. Lipoprotein(a)
 Lipoprotein(a) (Lp[a]) consists of an LDL
particle with its apolipoprotein B-100 (apo B-
100) component linked by a disulfide bridge
to apolipoprotein(a) (apo[a]).
 The close homology between Lp(a) and
plasminogen has raised the possibility that
this lipoprotein may inhibit endogenous
fibrinolysis.

97.  Many but not all prospective cohort studies
have supported a role for Lp(a) as a
determinant of vascular risk.
 Standardization of commercial Lp(a) assays
remains problematic and inaccuracy of
commercial Lp(a) assays has resulted from
the use of techniques sensitive to apo(a)
size.

98.  Women's Health Study have found that
extremely high levels of Lp(a) (greater
than the 90th percentile, or higher than
65.6 mg/liter) are indeed associated with
increased cardiovascular risk,
independent of other traditional risk
factors.