PATHOGENESIS PATHOGENESIS OF OF

ATHEROSCLEROSIATHEROSCLEROSISS

HHistoryistory This disease has a venerable This disease has a venerable

history, having left traces in the history, having left traces in the arteries of Egyptian mummies.arteries of Egyptian mummies.

Apparently uncommon in Apparently uncommon in antiquity, atherosclerosis became antiquity, atherosclerosis became epidemic as populations epidemic as populations increasingly survived early increasingly survived early mortality caused by communicable mortality caused by communicable diseases and malnutrition.diseases and malnutrition.

Virchow- viewed Virchow- viewed atherosclerosis as a proliferative atherosclerosis as a proliferative disease.disease.

Rokitansky- believed that Rokitansky- believed that atheroma derived from healing atheroma derived from healing and resorption of thrombi.and resorption of thrombi.

Experiments performed in the early Experiments performed in the early part of the 20th century used dietary part of the 20th century used dietary modulation to produce fatty lesions in modulation to produce fatty lesions in the arteries of rabbits and ultimately the arteries of rabbits and ultimately identified cholesterol as the culprit. identified cholesterol as the culprit.

These observations, followed by the These observations, followed by the characterization of human lipoprotein characterization of human lipoprotein particles at mid-century, promoted particles at mid-century, promoted the concept of insudation of lipids as the concept of insudation of lipids as a cause for atherosclerosisa cause for atherosclerosis

ATHEROSCLEROSIS:Pathology, Pathogenesis, Complications, Natural History

?? ? - ? - Affects certain regions of the Affects certain regions of the

arterial tree preferentiallyarterial tree preferentially..

? - ? - CClinical manifestations occur linical manifestations occur only at certain times.only at certain times.

? - Its role in causing ? - Its role in causing narrowing, or stenosis, of some narrowing, or stenosis, of some vessels and ectasia of others.vessels and ectasia of others.

STRUCTURE OF THE NORMAL STRUCTURE OF THE NORMAL ARTERYARTERY

Endothelial cells have a common Endothelial cells have a common origin but acquire bed-specific origin but acquire bed-specific characteristics during development.characteristics during development.

Arise during embryogenesis from Arise during embryogenesis from regions known as the blood islands, regions known as the blood islands, located on the embryo's periphery.located on the embryo's periphery.

?- postnatal life-The endothelial ?- postnatal life-The endothelial progenitor cells (EPCs).progenitor cells (EPCs).

Circulating numbers of EPCs, as assayed Circulating numbers of EPCs, as assayed in vitro, vary among individuals. in vitro, vary among individuals.

Those with a higher burden of risk factors Those with a higher burden of risk factors for atherosclerosis have fewer EPCs.for atherosclerosis have fewer EPCs.

EPC number may correlate with EPC number may correlate with prognosis in atherosclerotic patients.prognosis in atherosclerotic patients.

More aged individuals may have impaired More aged individuals may have impaired EPC numbers and hence less ability to EPC numbers and hence less ability to repair breaches in intimal integrity.repair breaches in intimal integrity.

Differential expression of endothelial Differential expression of endothelial genes in various types of blood genes in various types of blood vessels depends on transcriptional vessels depends on transcriptional regulation by the local environment.regulation by the local environment.

Members of the EPH family of Members of the EPH family of tyrosine kinase receptors and their tyrosine kinase receptors and their ligands, known as ephrins, display ligands, known as ephrins, display heterogeneous expressions in heterogeneous expressions in arterial versus venous endothelial arterial versus venous endothelial cells during development.cells during development.

Arterial Smooth Muscle Arterial Smooth Muscle CellsCells

These cells contract and relax and thus These cells contract and relax and thus control blood flow through the various control blood flow through the various arterial beds.arterial beds.

Abnormal smooth muscle contraction Abnormal smooth muscle contraction causes vasospasm, a complication of causes vasospasm, a complication of atherosclerosis .atherosclerosis .

SMCs synthesize the bulk of the SMCs synthesize the bulk of the complex arterial ECM that plays a key complex arterial ECM that plays a key role in normal vascular homeostasis as role in normal vascular homeostasis as well as the formation and complication well as the formation and complication of atherosclerotic lesions.of atherosclerotic lesions.

These cells also can migrate and These cells also can migrate and proliferate, contributing to the proliferate, contributing to the formation of intimal hyperplastic formation of intimal hyperplastic lesions.lesions.

Death of SMC may promote Death of SMC may promote destabilization of atheromatous destabilization of atheromatous plaques or favor ectatic remodeling plaques or favor ectatic remodeling and ultimately aneurysm formation.and ultimately aneurysm formation.

In the descending aorta and arteries In the descending aorta and arteries of the lower body, the regional of the lower body, the regional mesoderm serves as the source of mesoderm serves as the source of smooth muscle precursors.smooth muscle precursors.

In arteries of the upper body, SMCs In arteries of the upper body, SMCs can actually derive from a can actually derive from a completely different germ layer, completely different germ layer, neurectoderm rather than neurectoderm rather than mesodermmesoderm

SMCs in the coronary arteries derive SMCs in the coronary arteries derive from mesoderm, but in a special from mesoderm, but in a special way[from pro epicardial organ].way[from pro epicardial organ].

SMCs show molecular heterogeneity SMCs show molecular heterogeneity early during development.early during development.

the promoter of a characteristic the promoter of a characteristic smooth muscle gene, known as smooth muscle gene, known as SM22, drives gene expression in SM22, drives gene expression in venous, but not arterial.venous, but not arterial.

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

Normal ArteryNormal Artery

Response to injury Response to injury hypothesishypothesis

* Injury to the endothelium* Injury to the endothelium(dysfunctional endothelium)(dysfunctional endothelium)

* Chronic imflammatory response* Chronic imflammatory response* Migration of SMC from media to * Migration of SMC from media to

intimaintima* Proliferation of SMC in intima* Proliferation of SMC in intima• Excess production of ECMExcess production of ECM• Enhanced lipid accumulationEnhanced lipid accumulation

Response to injury Response to injury hypothesis (I)hypothesis (I)

1. Chronic EC injury (subtle?)1. Chronic EC injury (subtle?) EC dysfunctionEC dysfunction Increased permeabilityIncreased permeability Leukocyte adhesion (via VCAM-1)Leukocyte adhesion (via VCAM-1) Thrombotic potentialThrombotic potential

Response to injury Response to injury hypothesis (II)hypothesis (II)

2.2. Accumulation of LDL (cholesterol)Accumulation of LDL (cholesterol)3.3. Oxidation of lesional LDLOxidation of lesional LDL4.4. Adhesion & migration of blood Adhesion & migration of blood

monocytes; transformation into monocytes; transformation into macrophages and foam cellsmacrophages and foam cells

5.5. Adhesion of plateletsAdhesion of platelets6.6. Release of factors from platelets, Release of factors from platelets,

macrophages and ECsmacrophages and ECs

Response to injury Response to injury hypothesis (III)hypothesis (III)

7.7. Migration of SMC from media to Migration of SMC from media to intimaintima

8.8. Proliferation of SMCProliferation of SMC9.9. ECM production by SMCECM production by SMC10.10. Enhanced lipid accumulationEnhanced lipid accumulation

Intracellular (SMC and macrophages)Intracellular (SMC and macrophages)ExtracellularExtracellular

Response to InjuryResponse to Injury

ATHEROSCLEROSIS INITIATIONATHEROSCLEROSIS INITIATION

Endothelial Endothelial DysfunctionDysfunction

Initiation of Fatty StreakInitiation of Fatty Streak

Fatty StreakFatty Streak

Fatty Streak-AortaFatty Streak-Aorta

Fibro-fatty AtheromaFibro-fatty Atheroma

Evolution of atheromaEvolution of atheroma

Smooth Muscle Cell Death During Smooth Muscle Cell Death During Atherogenesis.Atherogenesis.

The Arterial Extracellular Matrix.The Arterial Extracellular Matrix. Angiogenesis in Plaques.Angiogenesis in Plaques. Plaque MineralizationPlaque Mineralization

The Focality of Lesion The Focality of Lesion FormationFormation

Lesion progressionLesion progression

COMPLICATIONS OF ATHEROSCLEROSISCOMPLICATIONS OF ATHEROSCLEROSIS

Plaque Rupture and Thrombosis. Plaque Rupture and Thrombosis.

Thrombosis Caused by Thrombosis Caused by Superficial Erosion of Plaques.Superficial Erosion of Plaques.

Plaque Rupture and Plaque Rupture and ThrombosisThrombosis

Thrombosis Caused by Superficial Erosion of Thrombosis Caused by Superficial Erosion of PlaquesPlaques

Fibrous Plaques Complicated Lesions

? small atheroma cause most ? small atheroma cause most myocardial infarctions . myocardial infarctions .

Fig. 11.7

                                                                         

                                               

AHA Classification of AHA Classification of atherosclerosisatherosclerosis

Novel Invasive Imaging ModalitiesNovel Invasive Imaging Modalities

OPTICAL COHERENCE TOMOGRAPHYOPTICAL COHERENCE TOMOGRAPHY

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

INTRACORONARY THERMOGRAPHY.INTRACORONARY THERMOGRAPHY.

PALPOGRAPHY.PALPOGRAPHY.

COMPUTATIONAL FLOW DYNAMICSCOMPUTATIONAL FLOW DYNAMICS..

SPECIAL CASES OF ARTERIOSCLEROSISSPECIAL CASES OF ARTERIOSCLEROSIS

Restenosis After Arterial Restenosis After Arterial Intervention.Intervention.

Accelerated Arteriosclerosis Accelerated Arteriosclerosis Following Transplantation.Following Transplantation.

Restenosis After Arterial Restenosis After Arterial InterventionIntervention

After balloon angioplasty, luminal After balloon angioplasty, luminal narrowing recurs in approximately narrowing recurs in approximately one-third of cases within 6 months.one-third of cases within 6 months.

These observations renewed interest These observations renewed interest in adventitial inflammation with scar in adventitial inflammation with scar formation and wound contraction as formation and wound contraction as a mechanism of arterial constriction a mechanism of arterial constriction following balloon following balloon angioplasty[angioplasty[negative remodeling].negative remodeling].

Restenosis After Arterial Restenosis After Arterial InterventionIntervention

The widespread introduction of The widespread introduction of stents has changed the face of stents has changed the face of the restenosis problem.the restenosis problem.

The process of in-stent stenosis, The process of in-stent stenosis, in contrast with restenosis after in contrast with restenosis after balloon angioplasty, depends balloon angioplasty, depends uniquely on intimal thickening.uniquely on intimal thickening.

Histological analyses reveal that Histological analyses reveal that a great deal of the volume of the a great deal of the volume of the in-stent restenotic lesion is made in-stent restenotic lesion is made up of myxomatous tissue.up of myxomatous tissue.

It comprises occasional stellate It comprises occasional stellate SMCs embedded in a loose and SMCs embedded in a loose and highly hydrated extracellular highly hydrated extracellular matrix.matrix.

The introduction of stents has The introduction of stents has reduced the clinical impact of reduced the clinical impact of restenosis because of the very restenosis because of the very effective increase in luminal diameter effective increase in luminal diameter achieved by this technique.achieved by this technique.

stents that elaborate antiproliferative stents that elaborate antiproliferative and antiinflammatory substances and antiinflammatory substances have shown great benefit in terms of have shown great benefit in terms of preventing in-stent stenosis.preventing in-stent stenosis.

Accelerated Arteriosclerosis Accelerated Arteriosclerosis Following TransplantationFollowing Transplantation

Aneurysmal DiseaseAneurysmal Disease Atherosclerosis produces not only Atherosclerosis produces not only

stenoses but also aneurysmal stenoses but also aneurysmal disease .disease .

Data from the Pathobiological Data from the Pathobiological Determinants of Atherosclerosis Determinants of Atherosclerosis in Youth Study (PDAY) show that in Youth Study (PDAY) show that the dorsal surface of the the dorsal surface of the infrarenal abdominal aorta has a infrarenal abdominal aorta has a particular predilection .particular predilection .

Absence of vasa vasorum.Absence of vasa vasorum.

The relative lack of blood supply to The relative lack of blood supply to the tunica media in this portion of the tunica media in this portion of the abdominal aorta.the abdominal aorta.

the lumbar lordosis of the biped the lumbar lordosis of the biped human may alter the human may alter the hydrodynamics of blood flow in the hydrodynamics of blood flow in the distal aorta, yielding flow distal aorta, yielding flow disturbancesdisturbances

Transmural destruction of the arterial architecture occurs Transmural destruction of the arterial architecture occurs in aneurysmal disease.in aneurysmal disease.

Many studies have documented overexpression of matrix-Many studies have documented overexpression of matrix-

degrading proteinases, including matrix metalloproteinases degrading proteinases, including matrix metalloproteinases in human aortic aneurysm specimens.in human aortic aneurysm specimens.

Current clinical trials are testing the hypothesis that MMP Current clinical trials are testing the hypothesis that MMP inhibitors can reduce the expansion of aneurysmsinhibitors can reduce the expansion of aneurysms

Consequences of Consequences of AtherosclerosisAtherosclerosis

Altered Vessel FunctionAltered Vessel Function

Vessel changeVessel change Plaque narrows Plaque narrows

lumenlumen Wall weakenedWall weakened

ThrombosisThrombosis

Breaking loose of Breaking loose of plaqueplaque

Loss of elasticityLoss of elasticity

ConsequenceConsequence Ischemia, turbulenceIschemia, turbulence Aneurysms, vessel Aneurysms, vessel

rupturerupture Narrowing, ischemia, Narrowing, ischemia,

embolizationembolization Athero-embolizationAthero-embolization

Increase systolic Increase systolic blood pressureblood pressure

Common Consequences Common Consequences of Atherosclerosis in of Atherosclerosis in

Specific VesselsSpecific Vessels

AortaAorta

AneurysmAneurysm Pulsatile abdominal massPulsatile abdominal mass Abdominal painAbdominal pain BleedingBleeding

AtheroembolizationAtheroembolization Narrowing of lumenNarrowing of lumen

Usually not a problemUsually not a problem

Aortic Aneurysm

Carotids and Cerebral Carotids and Cerebral CirculationCirculation

Atherosclerosis with thrombosis can Atherosclerosis with thrombosis can lead to brain infarctionlead to brain infarction

Red or whiteRed or white Coagulative or liquefactiveCoagulative or liquefactive Can lead to transient ischemic Can lead to transient ischemic

attacks (TIA), if narrowing is attacks (TIA), if narrowing is aggravated by mural thrombus or aggravated by mural thrombus or vasospasmvasospasm

Celiac and Mesenteric Celiac and Mesenteric ArteriesArteries

Narrowing primarily at aorta Narrowing primarily at aorta bifurcationbifurcation

Ischemia uncommon because of Ischemia uncommon because of collateral circulationcollateral circulation

Ischemia can occur if more than 1 Ischemia can occur if more than 1 artery severely affected - ischemic artery severely affected - ischemic entercolitisentercolitis

Renal ArteryRenal Artery

Progressive ischemic atrophy of Progressive ischemic atrophy of kidney leads to gradual kidney kidney leads to gradual kidney failure (nephrosclerosis)failure (nephrosclerosis)

Renal hypertension due to Renal hypertension due to decreased perfusiondecreased perfusion

Iliac and Femoral Iliac and Femoral ArteriesArteries

AneurysmsAneurysms Vessel occlusion by plaque and Vessel occlusion by plaque and

thrombusthrombus Ischemia of leg muscles, especially Ischemia of leg muscles, especially

during exercise (intermittent during exercise (intermittent claudication)claudication)

Ulcers of skin of legs and feetUlcers of skin of legs and feet Gangrene of feetGangrene of feet

Non-Modifiable Risk Non-Modifiable Risk FactorsFactors

AgeAge A dominant influenceA dominant influence Atherosclerosis begins in the young, but does Atherosclerosis begins in the young, but does

not precipitate organ injury until later in lifenot precipitate organ injury until later in life GenderGender

Men more prone than women, but by age 60-Men more prone than women, but by age 60-70 about equal frequency70 about equal frequency

Family HistoryFamily History Familial cluster of risk factorsFamilial cluster of risk factors Genetic differencesGenetic differences

Modifiable Risk FactorsModifiable Risk Factors(potentially controllable)(potentially controllable) HyperlipidemiaHyperlipidemia HypertensionHypertension Cigarette smokingCigarette smoking Diabetes MellitusDiabetes Mellitus Elevated HomocysteineElevated Homocysteine Factors that affect hemostasis and Factors that affect hemostasis and

thrombosisthrombosis Infections: Herpes virus; Chlamydia Infections: Herpes virus; Chlamydia

pneumoniaepneumoniae Obesity, sedentary lifestyle, stressObesity, sedentary lifestyle, stress

NOVEL ATHEROSCLEROTIC RISK NOVEL ATHEROSCLEROTIC RISK FACTORSFACTORS..

SmokingSmoking Other than advanced age, smoking is Other than advanced age, smoking is

the single most important risk factor the single most important risk factor for coronary artery disease.for coronary artery disease.

Landmark studies in the early 1950s Landmark studies in the early 1950s first reported strong positive first reported strong positive associations between cigarette smoke associations between cigarette smoke exposure and coronary heart disease. exposure and coronary heart disease.

smoking may enhance oxidation of smoking may enhance oxidation of low-density lipoprotein (LDL) low-density lipoprotein (LDL) cholesterol and impair endothelium-cholesterol and impair endothelium-dependent coronary artery dependent coronary artery vasodilation.vasodilation.

Smoking has adverse hemostatic and Smoking has adverse hemostatic and inflammatory effects, including increased levels inflammatory effects, including increased levels of CRP, soluble ICAM-1, fibrinogen, and of CRP, soluble ICAM-1, fibrinogen, and homocysteine.homocysteine.

Cessation of cigarette consumption Cessation of cigarette consumption overwhelmingly remains the single most overwhelmingly remains the single most important intervention in preventive cardiology. important intervention in preventive cardiology.

Smoking predicts better outcome following Smoking predicts better outcome following various reperfusion strategies (the so-called various reperfusion strategies (the so-called “smoker's paradox”) --- smokers are likely to “smoker's paradox”) --- smokers are likely to undergo such procedures at a much younger age undergo such procedures at a much younger age and hence have on average lower comorbidityand hence have on average lower comorbidity

HypertensionHypertension Most epidemiological studies now Most epidemiological studies now

recognize the joint contributions of recognize the joint contributions of SBP&DBP to the development of CV SBP&DBP to the development of CV risk.risk.

ISH has at least as much importance ISH has at least as much importance as DBP for the outcomes of total CV as DBP for the outcomes of total CV &CVA .&CVA .

Treatment of systolic hypertension Treatment of systolic hypertension is well supported, even in the is well supported, even in the elderly.elderly.

Isolated systolic hypertension thus Isolated systolic hypertension thus appears to represent a distinct appears to represent a distinct pathophysiological state.pathophysiological state.

In ISH elevated blood pressure In ISH elevated blood pressure reflects reduced arterial elasticity reflects reduced arterial elasticity not necessarily associated with not necessarily associated with increased peripheral resistance or increased peripheral resistance or an elevation in mean arterial an elevation in mean arterial pressure.pressure.

Hyperlipidemia and Elevated Low-Hyperlipidemia and Elevated Low-Density Lipoprotein CholesterolDensity Lipoprotein Cholesterol

In the 1850s, the German pathologist In the 1850s, the German pathologist Virchow recognized in human atheromata Virchow recognized in human atheromata “numerous plates of cholesterine…which “numerous plates of cholesterine…which display themselves even to the naked eye display themselves even to the naked eye as glistening lamellae. as glistening lamellae.

Multiple Risk Factor Intervention Trial Multiple Risk Factor Intervention Trial (MRFIT).(MRFIT).

Northwick Park Study and the Northwick Park Study and the Prospective Cardiovascular Munster Prospective Cardiovascular Munster (PROCAM) Cohort .(PROCAM) Cohort .

the Atherosclerosis Risk in Communities the Atherosclerosis Risk in Communities (ARIC) study.(ARIC) study.

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

Metabolic Syndrome, Metabolic Syndrome, Insulin Resistance, and Insulin Resistance, and

Diabetes.Diabetes.

Exercise, Weight Loss, Exercise, Weight Loss, and Obesity.and Obesity.

Physical exercise reduces myocardial Physical exercise reduces myocardial oxygen demand and increases exercise oxygen demand and increases exercise capacity, both of which correlate with capacity, both of which correlate with lower levels of coronary risk.lower levels of coronary risk.

The cardioprotective effects of The cardioprotective effects of exercise include reduced adiposity and exercise include reduced adiposity and diabetes incidence, lowered blood diabetes incidence, lowered blood pressure, and improvement of pressure, and improvement of dyslipidemia, as well as vascular dyslipidemia, as well as vascular inflammation.inflammation.

Exercise also enhances endothelial Exercise also enhances endothelial dysfunction, insulin sensitivity, dysfunction, insulin sensitivity, and endogenous fibrinolysis. and endogenous fibrinolysis.

In the Women's Health Initiative, In the Women's Health Initiative, walking briskly for 30 minutes five walking briskly for 30 minutes five times/week was associated with a times/week was associated with a 30 percent reduction in vascular 30 percent reduction in vascular events over a 3.5-year follow-up. events over a 3.5-year follow-up.

In the Women's Health Study, high In the Women's Health Study, high BMI was more strongly associated BMI was more strongly associated with adverse cardiovascular with adverse cardiovascular biomarkers than physical activitybiomarkers than physical activity

Mental Stress, Depression, and Mental Stress, Depression, and Cardiovascular Risk.Cardiovascular Risk.

In the INTERHEART study,psychosocial In the INTERHEART study,psychosocial stress was found to be associated with stress was found to be associated with vascular risk, with a magnitude of vascular risk, with a magnitude of effect similar to that of the major effect similar to that of the major coronary risk factors.coronary risk factors.

In the Enhancing Recovery in Coronary In the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Heart Disease Patients (ENRICHD) trial, formal psychosocial intervention trial, formal psychosocial intervention modestly improved measures of clinical modestly improved measures of clinical depression but did not significantly depression but did not significantly improve event-free survivalimprove event-free survival

High-Sensitivity C-Reactive High-Sensitivity C-Reactive ProteinProtein

Composed of five 23-kDa subunits, Composed of five 23-kDa subunits, CRP is a circulating member of the CRP is a circulating member of the pentraxin family that plays a major pentraxin family that plays a major role in the human innate immune role in the human innate immune response.response.

Although derived primarily from the Although derived primarily from the liver, studies have found that cells liver, studies have found that cells within human coronary arteries, within human coronary arteries, particularly in the atherosclerotic particularly in the atherosclerotic intima, can also elaborate CRP.intima, can also elaborate CRP.

hsCRP levels less than 1, 1 to 3, and hsCRP levels less than 1, 1 to 3, and higher than 3 mg/liter should be higher than 3 mg/liter should be interpreted as lower, moderate, and interpreted as lower, moderate, and higher relative vascular risk.higher relative vascular risk.

Values of hsCRP in excess of 8 mg/liter Values of hsCRP in excess of 8 mg/liter may represent an acute-phase may represent an acute-phase response caused by an underlying response caused by an underlying inflammatory disease or intercurrent inflammatory disease or intercurrent infection and should lead to repeat infection and should lead to repeat testing in approximately 2 to 3 weeks.testing in approximately 2 to 3 weeks.

consistently high values, however, consistently high values, however, represent very high risk of future represent very high risk of future cardiovascular disease.cardiovascular disease.

Fibrinogen and Fibrin D-Fibrinogen and Fibrin D-DimerDimer

fibrinogen associates positively fibrinogen associates positively with age, obesity, smoking, with age, obesity, smoking, diabetes, and LDL cholesterol diabetes, and LDL cholesterol level, and inversely with HDL level, and inversely with HDL cholesterol level, alcohol use, cholesterol level, alcohol use, physical activity, and exercise physical activity, and exercise level. level.

Fibrinogen, like CRP, is an acute-Fibrinogen, like CRP, is an acute-phase reactant and increases phase reactant and increases during inflammatory responses.during inflammatory responses.

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

Lipoprotein(a)Lipoprotein(a) Lipoprotein(a) (Lp[a]) consists of an Lipoprotein(a) (Lp[a]) consists of an

LDL particle with its apolipoprotein LDL particle with its apolipoprotein B-100 (apo B-100) component B-100 (apo B-100) component linked by a disulfide bridge to linked by a disulfide bridge to apolipoprotein(a) (apo[a]).apolipoprotein(a) (apo[a]).

The close homology between Lp(a) The close homology between Lp(a) and plasminogen has raised the and plasminogen has raised the possibility that this lipoprotein may possibility that this lipoprotein may inhibit endogenous fibrinolysis.inhibit endogenous fibrinolysis.

Many but not all prospective cohort Many but not all prospective cohort studies have supported a role for studies have supported a role for Lp(a) as a determinant of vascular Lp(a) as a determinant of vascular risk.risk.

Standardization of commercial Standardization of commercial Lp(a) assays remains problematic Lp(a) assays remains problematic and inaccuracy of commercial Lp(a) and inaccuracy of commercial Lp(a) assays has resulted from the use of assays has resulted from the use of techniques sensitive to apo(a) size.techniques sensitive to apo(a) size.

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