Hoofdstuk 9: artherosclerose
Atherosclerosis is characterized by the presence of intimal lesions called
atheromas (or atheromatous or atherosclerotic plaques). Atheromatous plaques
are raised lesions composed of soft grumous lipid cores (mainly cholesterol and
cholesterol esters, with necrotic debris) covered by fibrous caps. Risks (these are
multiplicative): (1) Genetics. Family history is the most important independent
risk factor for atherosclerosis. Certain mendelian disorders are strongly
associated with atherosclerosis. Most familial risk is related to polygenic traits
that go handin-hand with atherosclerosis, such as hypertension and diabetes, as
well as other genetic polymorphisms. (2) Age. Atherosclerosis usually remains
clinically silent until lesions reach a critical threshold in middle age or later. Thus,
the incidence of myocardial infarction increases five-fold between the ages of 40
and 60. (3) Gender. All other factors being equal, premenopausal women are
relatively protected against atherosclerosis (and its consequences) compared
with age-matched men. Thus, myocardial infarction and other complications of
atherosclerosis are uncommon in premenopausal women in the absence of other
predisposing factors such as diabetes, hyperlipidemia, or severe hypertension.
After menopause incidence of atherosclerosis-related diseases increases and, in
old age, even exceeds that in men. (5) Hyperlipidemia—and, more specifically,
hypercholesterolemia—is a major risk factor for development of atherosclerosis
and is sufficient to induce lesions in the absence of other risk factors. (6)
Hypertension is another major risk factor for development of atherosclerosis.
(7) Cigarette smoking is a well-established risk factor in men and probably
accounts for the increasing incidence and severity of atherosclerosis in women.
(8) Diabetes mellitus is associated with raised circulating cholesterol levels and
markedly increases the risk of atherosclerosis. (9) Inflammation: Inflammatory
cells are present during all stages of atheromatous plaque formation and are
intimately linked with plaque progression and rupture. (10) CRP secreted by cells
within atherosclerotic plaques can activate endothelial cells, increasing
adhesiveness and inducing a prothrombotic state. Its clinical importance lies in its
value as a circulating biomarker: CRP levels strongly and independently predict
the risk of myocardial infarction, stroke, peripheral arterial disease, and sudden
cardiac death, even among apparently healthy persons. (11)
Hyperhomocysteinemia. Serum homocysteine levels correlate with coronary
atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis. (12)
Metabolic syndrome. Associated with central obesity, this clinical entity is
characterized by insulin resistance, hypertension, dyslipidemia (elevated LDL and
depressed HDL), hypercoagulability, and a proinflammatory state, which may be
triggered by cytokines released from adipocytes. (13) Lipoprotein(a) levels.
Lipoprotein(a) levels are correlated with coronary and cerebrovascular disease
risk, independent of total cholesterol or LDL levels. (14) Elevated levels of
procoagulants are potent predictors of risk for major cardiovascular events.
Response-to-injury hypothesis: the model views atherosclerosis as a chronic
inflammatory response of the arterial wall to endothelial injury. Lesion
progression involves interaction of modified lipoproteins, monocyte derived
macrophages, T lymphocytes, and the cellular constituents of the arterial wall.
According to this model atherosclerosis results from the following pathogenic
events: Endothelial injury—and resultant endothelial dysfunction—leading to
increased permeability, leukocyte adhesion, and thrombosis, Accumulation of
, lipoproteins (mainly oxidized LDL and cholesterol crystals) in the vessel wall,
Platelet adhesion, Monocyte adhesion to the endothelium, migration into the
intima, and differentiation into macrophages and foam cells, Lipid
accumulation within macrophages, which release inflammatory cytokines,
Smooth muscle cell recruitment due to factors released from activated
platelets, macrophages, and vascular wall cells, Smooth muscle cell
proliferation and ECM production. Early human atherosclerotic lesions begin at
sites of intact, but dysfunctional, endothelium. The two most important causes of
endothelial dysfunction are hemodynamic disturbances and
hypercholesterolemia. Dyslipoproteinemias can result from mutations in genes
that encode apoproteins or lipoprotein receptors, or from disorders that derange
lipid metabolism. Chronic hyperlipidemia, particularly hypercholesterolemia, can
directly impair endothelial cell function by increasing local oxygen free radical
production; among other things, oxygen free radicals accelerate NO decay,
damping its vasodilator activity. With chronic hyperlipidemia, lipoproteins
accumulate within the intima, where they are hypothesized to generate two
pathogenic derivatives, oxidized LDL and cholesterol crystals. LDL is oxidized
through the action of oxygen free radicals generated locally by macrophages or
endothelial cells and ingested by macrophages through the scavenger receptor,
resulting in foam cell formation. Early in atherogenesis, however, dysfunctional
endothelial cells express adhesion molecules that promote leukocyte adhesion;
vascular cell adhesion molecule-1 (VCAM-1), in particular, binds monocytes and T
cells. After these cells adhere to the endothelium, they migrate into the intima
under the influence of locally produced chemokines. Monocytes differentiate into
macrophages and avidly engulf lipoproteins, including oxidized LDL and small
cholesterol crystals. T lymphocytes recruited to the intima interact with the
macrophages and also contribute to a state of chronic inflammation. As a
consequence of the chronic inflammatory state, activated leukocytes and
vascular wall cells release growth factors that promote smooth muscle cell
proliferation and matrix synthesis. Intimal smooth muscle cell proliferation
and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into
a mature atheroma, thus contributing to the progressive growth of atherosclerotic
lesions. Atherosclerotic plaques have three principal components: (1) cells,
including smooth muscle cells, macrophages, and T cells; (2) extracellular matrix,
including collagen, elastic fibers, and proteoglycans; and (3) intracellular and
extracellular lipid. The periphery of the lesions shows neovascularization
(proliferating small blood vessels).
Atherosclerosis is characterized by the presence of intimal lesions called
atheromas (or atheromatous or atherosclerotic plaques). Atheromatous plaques
are raised lesions composed of soft grumous lipid cores (mainly cholesterol and
cholesterol esters, with necrotic debris) covered by fibrous caps. Risks (these are
multiplicative): (1) Genetics. Family history is the most important independent
risk factor for atherosclerosis. Certain mendelian disorders are strongly
associated with atherosclerosis. Most familial risk is related to polygenic traits
that go handin-hand with atherosclerosis, such as hypertension and diabetes, as
well as other genetic polymorphisms. (2) Age. Atherosclerosis usually remains
clinically silent until lesions reach a critical threshold in middle age or later. Thus,
the incidence of myocardial infarction increases five-fold between the ages of 40
and 60. (3) Gender. All other factors being equal, premenopausal women are
relatively protected against atherosclerosis (and its consequences) compared
with age-matched men. Thus, myocardial infarction and other complications of
atherosclerosis are uncommon in premenopausal women in the absence of other
predisposing factors such as diabetes, hyperlipidemia, or severe hypertension.
After menopause incidence of atherosclerosis-related diseases increases and, in
old age, even exceeds that in men. (5) Hyperlipidemia—and, more specifically,
hypercholesterolemia—is a major risk factor for development of atherosclerosis
and is sufficient to induce lesions in the absence of other risk factors. (6)
Hypertension is another major risk factor for development of atherosclerosis.
(7) Cigarette smoking is a well-established risk factor in men and probably
accounts for the increasing incidence and severity of atherosclerosis in women.
(8) Diabetes mellitus is associated with raised circulating cholesterol levels and
markedly increases the risk of atherosclerosis. (9) Inflammation: Inflammatory
cells are present during all stages of atheromatous plaque formation and are
intimately linked with plaque progression and rupture. (10) CRP secreted by cells
within atherosclerotic plaques can activate endothelial cells, increasing
adhesiveness and inducing a prothrombotic state. Its clinical importance lies in its
value as a circulating biomarker: CRP levels strongly and independently predict
the risk of myocardial infarction, stroke, peripheral arterial disease, and sudden
cardiac death, even among apparently healthy persons. (11)
Hyperhomocysteinemia. Serum homocysteine levels correlate with coronary
atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis. (12)
Metabolic syndrome. Associated with central obesity, this clinical entity is
characterized by insulin resistance, hypertension, dyslipidemia (elevated LDL and
depressed HDL), hypercoagulability, and a proinflammatory state, which may be
triggered by cytokines released from adipocytes. (13) Lipoprotein(a) levels.
Lipoprotein(a) levels are correlated with coronary and cerebrovascular disease
risk, independent of total cholesterol or LDL levels. (14) Elevated levels of
procoagulants are potent predictors of risk for major cardiovascular events.
Response-to-injury hypothesis: the model views atherosclerosis as a chronic
inflammatory response of the arterial wall to endothelial injury. Lesion
progression involves interaction of modified lipoproteins, monocyte derived
macrophages, T lymphocytes, and the cellular constituents of the arterial wall.
According to this model atherosclerosis results from the following pathogenic
events: Endothelial injury—and resultant endothelial dysfunction—leading to
increased permeability, leukocyte adhesion, and thrombosis, Accumulation of
, lipoproteins (mainly oxidized LDL and cholesterol crystals) in the vessel wall,
Platelet adhesion, Monocyte adhesion to the endothelium, migration into the
intima, and differentiation into macrophages and foam cells, Lipid
accumulation within macrophages, which release inflammatory cytokines,
Smooth muscle cell recruitment due to factors released from activated
platelets, macrophages, and vascular wall cells, Smooth muscle cell
proliferation and ECM production. Early human atherosclerotic lesions begin at
sites of intact, but dysfunctional, endothelium. The two most important causes of
endothelial dysfunction are hemodynamic disturbances and
hypercholesterolemia. Dyslipoproteinemias can result from mutations in genes
that encode apoproteins or lipoprotein receptors, or from disorders that derange
lipid metabolism. Chronic hyperlipidemia, particularly hypercholesterolemia, can
directly impair endothelial cell function by increasing local oxygen free radical
production; among other things, oxygen free radicals accelerate NO decay,
damping its vasodilator activity. With chronic hyperlipidemia, lipoproteins
accumulate within the intima, where they are hypothesized to generate two
pathogenic derivatives, oxidized LDL and cholesterol crystals. LDL is oxidized
through the action of oxygen free radicals generated locally by macrophages or
endothelial cells and ingested by macrophages through the scavenger receptor,
resulting in foam cell formation. Early in atherogenesis, however, dysfunctional
endothelial cells express adhesion molecules that promote leukocyte adhesion;
vascular cell adhesion molecule-1 (VCAM-1), in particular, binds monocytes and T
cells. After these cells adhere to the endothelium, they migrate into the intima
under the influence of locally produced chemokines. Monocytes differentiate into
macrophages and avidly engulf lipoproteins, including oxidized LDL and small
cholesterol crystals. T lymphocytes recruited to the intima interact with the
macrophages and also contribute to a state of chronic inflammation. As a
consequence of the chronic inflammatory state, activated leukocytes and
vascular wall cells release growth factors that promote smooth muscle cell
proliferation and matrix synthesis. Intimal smooth muscle cell proliferation
and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into
a mature atheroma, thus contributing to the progressive growth of atherosclerotic
lesions. Atherosclerotic plaques have three principal components: (1) cells,
including smooth muscle cells, macrophages, and T cells; (2) extracellular matrix,
including collagen, elastic fibers, and proteoglycans; and (3) intracellular and
extracellular lipid. The periphery of the lesions shows neovascularization
(proliferating small blood vessels).
