SRI DEVRAJ URS UNIVERSITY

Pathophysiology of the metabolic syndrome leading to

atherosclerotic CV disease
Genetic variation Environmental factors

Abdominal obesity

Adipokines Cytokines

Adipocyte Inflammatory markers Monocyte/

Insulin resistance
macrophage
↑ TG Metabolic syndrome ↓ HDL
↑ BP

Atherosclerosis

Plaque rupture/thrombosis

Reilly & Rader 2003;

Eckel et al 2005 Cardiovascular events
€ Normal histology of a vessel wall includes
components of: smooth muscle cells, elastin, and
collagen making up the three tunics (Tintima, Tmedia,
Tadventitia).
€ Any alterations in these key components leads to
hardening, thickening and loss of elasticity of the
vessel walls a leading cause of illness and death.
€ Atherosclerosis is a general term used to describe
these changes of these diseases.
€Arteriosclerosis is the most common type of
atherosclerosis that effects medium and large
arteries call the lesion a atheroma.
€Response to injury theory “the lesions of
atherosclerosis are initiated as a response to
some form of injury to arterial endothelium”
first eluded to in 1856 by Virchow.
 Ischemic Heart
Disease

CerebroVascular
Disease

Peripheral Vascular
Disease

Transition from chronic to acute atheroma

€ Atherosclerosismay effect all arterial vessels, but the aorta,
coronary, cerebral, carotid and iliofemoral arteries are the
most commonly affected.
€ Clinical Problems:
Occlusion of vessels – obstruction of blood flow results in
ischaemia and infarction of the tissue supplied by the vessel in
question.
Thrombosis and potential embolism – may block and upstream
arteriole etc. ischaemia.
Aneurysm – weakening of vessel walls may dilate the vessel at
the site of injury or rupture.
Most organs (eg kidney, spleen, brain) the infracted areas
appears as wedges on sections (reflects the
geographical distribution of the arteries involved).
Myocardial infarctions are not wedge shaped, but involve
a partial or full thickness of the myocardium and its
overlying layers (endocardium and /or the pericardium).
Typical tissue damage excites an acute inflammatory
response & replacement of necrotic tissue by granulation
tissue (glial cells in the brain; gliosis) fibrous repair and
scaring.
Atherosclerosis of coronary arteries
accounts for the majority of cases of MCI
and gives rise to 4 main clinical syndromes:

Angina pectoris (chest pains on exertion)

Acute myocardial infarction.
Chronic ischemic heart disease
Sudden cardiac death (immediate fatal MCI)
Acute MCI has two main forms:
Transmural infarction – involves the full thickness of a
segment of the ventricle wall – associated with the complete
blockage of the main coronary artery via thrombosis and
Atherosclerosis.
Subendocardial myocardial infarction – myocardial necrosis
is limited to cells in the inner third of the ventricle wall and
tends to involve Atherosclerotic narrowing of both the right
and left coronary arteries. Here the infarction involves a
limitation of blood flow to the ends of the arteries supplying
the inner regions of the ventricle.
 Plaque
Occlusive Rupture/
Fatty FibrousAtherosclerotic Fissure &
Normal Streak Plaque
Unstable
Plaque Thrombosis Angina

MI

Coronary
Death
Effort Angina
Stroke
Clinically Silent Claudication
Critical Leg
Ischemia
Increasing Age
Courtesy of P Ganz.
Systemic
inflammatory
markers in
atherosclerosis
The
macrophage
as an
inflammatory
mediator
Intima
Lipid
Fibrous core
cap
Lumen
Media

– T lymphocyte
– Macrophage
foam cell (tissue factor+)
– “Activated” intimal SMC (HLA-DR
– Normal medial SMC

Libby P. Lancet. 1996;348:S4-S7.

 „ Weakening of
the fibrous cap
„ Thrombogenicity
of the lipid core

Illustration courtesy of Michael J. Davies, M.D.

 Pathogenesis of coronary artery thrombosis

•Most myocardial infarctions involve total occlusion of the coronary artery that is
principally due to thrombus
• Thrombosis of the vessel results from rupture of the atherosclerotic plaque and
exposure of its thrombogenic components to the blood stream.
(De-Wood et al. 1980. N Eng J Med 303:897-902)
Cellular players
in
atherogenesis
and plaque
rupture
 esis Brea
Sy nth kd own

Collagen-degrading Fibrous
IFN-γ Proteinases
– cap

CD-40L + + + +
IL-1
+ TNF-α
+ MCP-1
M-CSF
Tissue Factor
Lipid core Procoagulant

Libby P. Circulation 1995;91:2844-2850.

 Fissures in
the fibrous
cap

Davies MJ. Circulation. 1996;94:2013-2020.

Schematic representation of
the phases of atherosclerotic
lesion progression, and the
associated pathologic lesion
types and clinical
syndromes

Gutstein, D. E. et al. Cardiovasc Res 1999

41:323-333;
 Foam Fatty Intermediate Fibrous Complicated
cells streak lesion Atheroma plaque lesion/rupture

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 10A).

 Stable Plaque

Unstable Plaque Plaque Growth

(Erosion, Rupture)
 Plaque Biology = Clinical Events

“Vulnerable” plaque

Lumen
Lipid
core
area of
detail

Lumen – T lymphocyte
Lipid – Macrophage
core
foam cell (tissue factor+)
– “Activated” intimal SMC (HLA-DR+)
“Stable” plaque – Normal medial SMC
 Acute vs. Chronic Coronary Syndromes:
Plaque Composition
Lipid Content >40% Macrophages (%) Smooth Muscle (%)

Stable Unstable Stable Unstable Stable Unstable

Histopathologic section of a human coronary atheroma

Gutstein, D. E. et al. Cardiovasc Res 1999 41:323-333

Photomicrograph demonstrating plaque rupture in a human coronary atherosclerotic lesion with
overlying occlusive thrombus (T)

Gutstein, D. E. et al. Cardiovasc Res 1999 41:323-333

 Life style is a Driver of CVD
Physical Excessive
Life style inactivity food intake
intervention
Smoking Stress

Obesity
Hypertension
Risk factor Diabetes
modification Dyslipidaemia

Atherosclerosis Atherosclerosis

Arterial & venous Arrhythmia

Chronic thrombosis/
heart failure cardiac & cerebral events
 Risk Factors
Endothelial Dysfunction
Atherosclerosis
CAD
Myocardial Ischemia
Coronary Thrombosis
Myocardial Infarction
Arrhythmia & Loss of Muscle
Remodeling
Ventricular Dilation
Congestive Heart Failure
Endstage Heart Disease
KNOW TO PREVENT DISEASE
DEATH AND SUFFERING