Atherosclerosis

dr. Adrianus
VOSmed Medical Course
Jakarta – Bandung – Semarang – Jogjakarta - Surabaya
 Risk Factors
• In the early 20th century, it was widely believed that atherosclerosis was
an inevitable process of aging.
• But in 1948, the landmark Framingham Heart Study began to examine
the relationship between specific attributes and cardiovascular disease,
establishing the concept of atherosclerotic risk factors.
• Modifiable risk factors  aberrant levels of circulating lipids
(dyslipidemia), tobacco smoking, hypertension, diabetes mellitus, lack
of physical activity and obesity.
• Nonmodifiable risk factors  advanced age, male sex, and heredity— a
history of coronary heart disease among first degree relatives at a young
age (before age 55 for a male relative or before age 65 for a female
relative).
Risk Factors
 Dyslipidemia
• A large and consistent body of evidence establishes abnormal
circulating lipid levels as a major risk factor for atherosclerosis.
• The coronary risk is approximately twice as high for a person with a
total cholesterol level of 240 mg/dL compared with a person whose
cholesterol level is 200 mg/dL.
• In particular, elevated levels of circulating LDL correlate with an
increased incidence of atherosclerosis and coronary artery disease.
• When present in excess, LDL can accumulate in the subendothelial
space and undergo the chemical modifications that further damage the
intima, as described earlier, initiating and perpetuating the
development of atherosclerotic lesions.
– Thus, LDL is commonly known as “bad cholesterol.”
 Dyslipidemia
• Conversely, elevated high-density lipoprotein (HDL) particles appear to
protect against atherosclerosis, likely because of HDL’s ability to
transport cholesterol away from the peripheral tissues back to the liver
for disposal (termed “reverse cholesterol transport”) and because of its
putative antioxidative and anti-inflammatory properties.
– Thus, HDL has earned the moniker “good cholesterol.”
 Dyslipidemia
• Elevated serum LDL may persist for many reasons, including a high-fat
diet or abnormalities in the LDL-receptor clearance mechanism.
– Patients with genetic defects in the LDL receptor, which leads to a condition
known as familial hypercholesterolemia, cannot remove LDL from the circulation
efficiently.
• Increasing evidence also implicates triglyceride- rich lipoproteins, such
as very low density lipoprotein (VLDL) and intermediatedensity
lipoprotein (IDL), in the development of atherosclerosis.
– However, it remains undetermined whether these particles participate directly
in atherogenesis or simply keep company with low levels of HDL cholesterol.
 Dyslipidemia: Lipid-Altering Therapy
• The guidelines specify an “optimal” LDL cholesterol level as <100
mg/dL.
– Patients with established atherosclerosis, or those who have equivalent risk (e.g.,
diabetes), should receive treatment to attain this goal.
• An even lower goal of <70 mg/dL is recommended for patients with
atherosclerotic disease at the highest risk of future vascular events
(those who have recently sustained an acute coronary syndrome and
those with multiple risk factors, especially diabetes, the metabolic
syndrome, or tobacco smoking).
 Dyslipidemia: Lipid-Altering Therapy
• Diet and exercise comprise two important components of the risk-
reduction arsenal.
• When lifestyle modifications fail to achieve target values, pharmacologic
agents can improve abnormal lipid levels.
• The major groups of lipid-altering include HMG-CoA reductase inhibitors
(also known as statins), niacin, fibric acid derivatives, cholesterol
intestinal absorption inhibitors, and bile acid–binding agents.
 Dyslipidemia: Lipid-Altering Therapy
• The statins have emerged as the most effective LDL-lowering drugs.
– They inhibit the rate limiting enzyme responsible for cholesterol biosynthesis.
– The resulting reduction in intracellular cholesterol concentration promotes
increased LDL-receptor expression and thus augmented clearance of LDL
particles from the bloodstream.
– Statins also lower the rate of VLDL synthesis by the liver (thus lowering
circulating triglyceride levels), and raise HDL by an unknown mechanism.
 Tobacco Smoking
• Tobacco smoking could lead to atherosclerotic disease in several ways,
including enhanced oxidative modification of LDL, decreased circulating
HDL levels, endothelial dysfunction owing to tissue hypoxia and
increased oxidant stress, increased platelet adhesiveness, increased
expression of soluble LAM, inappropriate stimulation of the sympathetic
nervous system by nicotine, and displacement of oxygen by carbon
monoxide from hemoglobin.
• Numerous studies have shown that tobacco smoking increases the risk
of atherosclerosis and ischemic heart disease.
– Even minimal smoking increases the risk, and the heaviest smokers have the
greatest risk of cardiovascular events.
 Hypertension
• Elevated blood pressure (either systolic or diastolic) augments the risk
of developing atherosclerosis, coronary heart disease, and stroke.
• Hypertension may accelerate atherosclerosis in several ways. Animal
studies have shown that elevated blood pressure injures vascular
endothelium and may increase the permeability of the vessel wall to
lipoproteins.
• In addition to causing direct endothelial damage, increased
hemodynamic stress can augment the number of scavenger receptors
on macrophages, thus enhancing the development of foam cells.
Diabetes Mellitus and the Metabolic Syndrome
• With a three- to fivefold increased risk of acute coronary events, 80% of
diabetic patients succumb to atherosclerosis-related conditions,
including coronary heart disease, stroke, and peripheral artery disease.
• The predisposition of diabetic patients to atherosclerosis may relate in
part to the nonenzymatic glycation of lipoproteins, or to a
prothrombotic tendency and antifibrinolytic state that is often present.
• Diabetics frequently have impaired endothelial function, gauged by the
reduced bioavailability of NO and increased leukocyte adhesion.
Diabetes Mellitus and the Metabolic Syndrome
• Tight control of serum glucose levels in diabetic patients reduces the
risk of microvascular complications, such as retinopathy and
nephropathy.
• At least one study has also demonstrated a reduction in macrovascular
outcomes, such as myocardial infarction and stroke, in patients with
type 1 diabetes who followed an intense antidiabetic regimen.
• The metabolic syndrome (previously known as the “insulin resistance
syndrome” or “syndrome X”) is a descriptor for a clustering of risk
factors, including hypertension, hypertriglyceridemia, reduced HDL,
cellular insulin resistance (often leading to glucose intolerance), and
visceral obesity (excessive adipose tissue in the abdomen).
 Lack of Physical Activity
• Exercise may mitigate atherogenesis in several ways.
• In addition to its beneficial effects on the lipid profile and blood
pressure, exercise enhances insulin sensitivity and endothelial
production of NO. Long-term prospective studies of both men and
women indicate that even modest activities, such as brisk walking, for
as little as 30 minutes per day can protect against cardiovascular
mortality.
 Estrogen Status
• Cardiovascular disease dominates over other causes of mortality in
women, including breast and other cancers. Before menopause, women
have a lower incidence of coronary events than men.
– After menopause, however, men and women have similar rates.
• This observation suggests that estrogen (the levels of which decline
after menopause) may have atheroprotective properties. Physiologic
estrogen levels in premenopausal women raise HDL and lower LDL.
Experimentally, estrogen also exhibits potentially beneficial antioxidant
and antiplatelet actions and improves endothelium dependent
vasodilation.
 Atherosclerosis Pathophysiology
• Commonly known as “hardening of the arteries,” atherosclerosis
derives its name from the Greek roots athere-, meaning “gruel,” and -
skleros, meaning “hardness.”
 Atherosclerosis Pathophysiology
• The arterial wall consists of three layers:
– The intima, closest to the arterial lumen and therefore most “intimate” with the
blood
– The media, which is the middle layer
– The outer layer, the adventitia
• The intimal surface consists of a single layer of endothelial cells that
acts as a metabolically active barrier between circulating blood and the
vessel wall.
Atherosclerosis Pathophysiology
 Atherosclerosis Pathophysiology
• Realizing that immune cells were not the only source of
proinflammatory agents, investigations into the role of “activated”
endothelial and smooth muscle cells in atherogenesis burgeoned.
• This section categorizes these mechanisms into three pathologic stages:
– Fatty streak
– Plaque progression
– Plaque disruption
Atherosclerosis Pathophysiology
Atherosclerosis Pathophysiology
 Fatty Streak
•Fatty streaks represent the earliest visible lesions of atherosclerosis.
On gross inspection, they appear as areas of yellow discoloration on
the artery’s inner surface, but they neither protrude substantially
into the arterial lumen nor impede blood flow.
•They do not cause symptoms, and in some locations in the
vasculature, they may regress over time.
 Fatty Streak
•Endothelial Dysfunction
Injury to the arterial endothelium represents a primary event in
atherogenesis. Such injury can result from exposure to diverse
agents, including physical forces and chemical irritants.
 Fatty Streak
•Lipoprotein Entry and Modification
The activated endothelium no longer serves as an effective barrier to
the passage of circulating lipoproteins into the arterial wall. Increased
endothelial permeability allows the entry of low density lipoprotein
(LDL) into the intima, a process facilitated by an elevated circulating
LDL concentration.
 Fatty Streak
•Leukocyte Recruitment
Recruitment of leukocytes (primarily monocytes and T lymphocytes)
to the vessel wall is a key step in atherogenesis. The process depends
on the expression of LAM on the normally nonadherent endothelial
luminal surface, and on chemoattractant signals (e.g., monocyte
chemotactic protein 1 [MCP-1], IL-8, interferon-inducible protein-10)
that direct diapedesis (passage of cells through the intact
endothelial layer) into the subintimal space.
 Fatty Streak
•Foam Cell Formation
•After monocytes adhere to and penetrate the intima, they
differentiate into phagocytic macrophages and imbibe lipoproteins
to form foam cells. It is important to note that foam cells do not arise
from uptake of LDL by the classic cell–surface LDL-receptor
mechanism, because the high cholesterol content within these cells
actually suppresses expression of the receptor. The lipid-rich center
of a plaque, formed by necrotic foam cells, is often called the necrotic
core.
 Plaque Progression
•Smooth Muscle Cell Migration
The transition from fatty streak to fibrous atheromatous plaque
involves the migration of smooth muscle cells from the arterial
media into the intima, proliferation of the smooth muscle cells within
the intima, and secretion of extracellular matrix macromolecules by
the smooth muscle cells. Foam cells, activated platelets entering
through microfissures in the plaque surface, and endothelial cells all
elaborate substances that signal smooth muscle cell migration and
proliferation.
 Plaque Progression
•Extracellular Matrix Metabolism
As the predominant collagen-synthesizing cell type, smooth muscle
cells should, through their proliferation, favor fortification of the
fibrous cap.
Furthermore, inflammatory cytokines stimulate local foam cells to
secrete collagen- and elastin-degrading MMP, thereby weakening
the fibrous cap and predisposing it to rupture.
 Plaque Disruption
•Plaque Integrity
The tug of war between matrix synthesis and degradation continues
over decades, but not without consequences. Death of smooth
muscle and foam cells, either owing to excess inflammatory
stimulation or by contact activation of apoptosis pathways, liberates
cellular contents, contributing imbibed lipids and cellular debris to
the growing lipid core.
 Plaque Disruption
•The net deposition and distribution of the fibrous cap is an important
determinant of overall plaque integrity.
•Conversely, plaques that have thinner caps (and often appear less
obstructive by angiography) tend to be fragile, and more likely to
rupture and incite thrombosis.
 Plaque Disruption
•Current clinical terminology describes the extreme spectrums of
integrity as “stable plaques” (marked by a thick fibrous cap and small
lipid core) or “vulnerable plaques” (marked by a thin fibrous cap, rich
lipid core, extensive macrophage infiltrate, and a paucity of smooth
muscle cells)
 Plaque Disruption
•Thrombogenic Potential
Rupture of atherosclerotic plaque does not inevitably cause major
clinical events such as myocardial infarction and stroke. As described
in the previous section, small nonocclusive thrombi may reabsorb
into the plaque, stimulating further smooth muscle growth and
fibrous deposition.
Atherosclerosis Pathophysiology
Atherosclerosis Pathophysiology
 Reference
•Lily, LS, 2011, Pathophysiology of Heart Disease, 5th edition,
Lippincott Williams & Wilkins : Philadelphia.
Latihan Soal
1. Yang termaksud faktor risiko aterosklerosis yang dapat dikendalikan
adalah?
A. Usia
b. Ras
c. Jenis kelamin
d. Stress
e. Herediter
Jawaban : d. Stress
2. Manisfestasi klinis utama dari aterosklerosis?
a. Aortic aneurysm
b. Coronary heart disease
c. Cerebro vascular disease
d. Periphery vascular disease
e. Renal vascular disease
Jawaban : b. Coronary heart disease
3. Awal pembentukan aterosklerosis?
Jawaban : Endothel Dysfunction
4. Teori tentang Atherosclerosis yang paling
banyak digunakan di dunia adalah?
Jawaban: Reponse of Injury Hypothesis
5. Yang menyebabkan terbentuknya foam cell
adalah?
Jawaban: Makrofag
6. Pemeriksaan radiologi pertama yang dapat
dilakukan untuk mendiagnosa pasien dengan
atherosclerosis?
•Chest X-Ray (Foto toraks)
•Foto toraks adalah pencitraan tubuh melalui penyinaran tubuh pasien dengan
radiasi ionisisasi berenergi tinggi (sinar-X) Perbedaaan penyerapan sinar radiasi oleh
berbagai jaringan tubuh membentuk gambaran (bayangan) yang berbeda di film foto
toraks. Untuk jaringan yang berat struktur atomnya rendah (seperti pada paru-paru)
maka sinar radiasinya ditransmisikan secara baik ke film, oleh karena itu akan
tampak gambaran berwarna warna hitam (radio lusen). Sedangkan Untuk jaringan
yang berat struktur atomya sangat tinggi seperti pada tulang, sinar radiasi akan
diserap dan diblok maka sinar ditransmisikan tidak sempurna/tidak ditransmisikan
sama sekali sampai ke film sehingga tidak menghasilkan gambaran di film atau
menghasilkan gambaran yang transparan (radio opaq). Jantung mudah dibedakan
dari paru-paru karena jantung mengandung darah dengan densitas air lebih besar
dibandingkan udara. Karena darah melemahkan x-ray lebih kuat dibandingkan
dengan udara, jantung relatif tampak berwarna putih (namun kurang putih jika
dibandingkan dengan tulang).
Jawaban : X-ray Thoraks
•Analisis foto toraks untuk penyakit jantung:
•Pembesaran jantung: bentuk dan ukuran
•Tampak keseluruhan: Cardiothoracic ratio (CTR) > 50%
•Pembesaran ruang-ruang jantung tertentu
•Gambaran pericardial yang mencolok
•Perubahan paru-paru yang dihubungkan dengan penampakan jantung
•Analisis mediastinumàukuran dan lokasi aorta dan vena sistemik yang besar
(vena cava superior dan inferior)
•Perubahan pembuluh darah besaràapakah ditemukan kalsifikasi,
perpanjangan, atau aneurisma
•Penampakan posisi dari pacemaker
•Anomali ekstrakardial yang diasosiasikan dengan penyakit jantung
7. Siapa yang pertama kali menemukan
atheroskeloris secara makroskopis?
Jawaban : Leonardo Da Vinci