1. PATHOPHYSIOLOGY ANDCLASSIFICATION OFCARDIOVASCULARDISEASES CAUSED BYATHEROSCLEROSIS

Prof. Željko Reiner, MD, Ph.D.

Department of Internal Medicine,University Hospital Rebro, Zagreb,Croatia

Cardiovascular diseases are the leading cause of mortalityin the developed world and are becoming more and moreimportant as the cause of mortality in the developingcounties as well. Most of them are caused by atherosclero-sis.

The terms atherosclerosis and atheroma are derived fromGreek words athera meaning gruel, skleros meaning hardand oma meaning a mass. They accurately describe thenature of advanced lesions which characterize thisdegenerative and inflammatory disease of the arteries.

The past decade has witnessed enormous progress in ourunderstanding of the pathophysiological nature ofatherosclerosis which begins with endothelial dysfunction,the trigger for which are risk factors such ashypercholesterolemia, smoking, hypertension,hyperhomocysteinemia, impaired glucose metabolism andpossibly infectious agents such as Cytomegalovirus,Helicobacter pylori and especially Chlamydia pneumoniae.Particularly important is increased concentration ofplasma low-density lipoproteins (LDL) rich in cholesterol,and oxidant stress since they play a major role in impair-ing endothelial function. They achieve this by activatingproinflammatory signalling pathways such as nuclearfactor kappa B (NFkB) and by reducing the bioavailabilityof nitric oxide (NO). Biomechanical forces on theendothelium caused by hypertension including low shearstress from disturbed blood flow also activate the endothe-lium. Hypertension also increases the formation ofhydrogen peroxide and free radicals such as thesuperoxide anion and hydroxyl radicals in plasma andthese substances reduce the formation of NO by theendothelium and increase leukocyte adhesion.

NFkB signal transduction pathway is an importantregulator of the transcription of a number ofproinflammatory genes, including those that lead to theexpression of adhesion molecules, e.g. vascular celladhesion molecule-1 VCAM-1, ICAM-1, and selectins.High-density lipoproteins (HDL) and the cholesterol theycontain are, however, a protective factor for atherosclero-sis, and have opposing effects on the endothelium. HDL

prevents endothelial vasomotor dysfunction and reducesthe expression of adhesion molecules. In response tolipoprotein oxidation, monocytes and lymphocytes arerecruited to the artery wall. This involves the expression ofadhesion molecules, chemotactic proteins, and growthfactors for monocyte–macrophages. After subsequentlypenetrating beneath the endothelium, monocytes,transformed into macrophages, accumulate oxidizedlipoproteins and turn into foam cells. This process ismediated by cell-surface receptors that recognize oxida-tively modified LDL. Foam cells are the hallmark of earlyatherosclerosis. The collections of foam cells together withT lymphocytes on vessel surface could be visible to thenaked eye as fatty streaks - flat yellow-gray areas.

Undamaged endothelium has an established capacity toprevent platelets aggregating into microthrombi and toregulate lipid entry into vessel walls. However, oncedamaged, its capacities in these respects are reduced, soaggregation of platelets occurs. Aggregation of plateletsleads to release of platelet-derived growth factor (PDGF)which stimulates the migration and proliferation ofsmooth muscle cells (SMC). Macrophages and endothe-lium, as well as T lymphocytes, also release growth factorsand cytokines (eg. PDGF, TGF–beta etc.) and are alsoresponsible for migration of SMC from the arterial mediainto the intima. This migration is followed by intenseproliferation of SMC with loss of their normal contractilefunction and an increase in synthetic function. Increasedlipid uptake occurs simultaneously with an increase inSMC number, so that formation of foam cells from SMC isalso common. SMC start to synthesize and secretecollagens, elastin and complex proteoglycans thustransforming a lipid lesion into a fibro-lipid atheromatousplaque. Fibroblast proliferation, which is also enhancendunder these circumstances, leads to the synthesis andsecretion of collagens, and related macromolecules aswell, participating therefore in the genesis of the plaque.

Fibro-lipid plaque is the characteristic lesion of advancedatherosclerosis. It consists of a cap of fibrous tissue andSMC which confer mechanical stability of the plaque andseparate the lipid rich thrombogenic core from the vessellumen and circulating blood. The plaques expand at theirshoulders by means of continued leukocyte adhesion andentry caused by the same factors as those mentionedearlier. Influx of leukocytes and activation of macrophagesat the plaque shoulders which then releasemetalloproteases and other proteolytic enzymes causesfibrous cap fissuring. Recurrent fissuring of plaques withthin caps and large lipid-rich cores causes a step-wiseincrease in plaque size, with platelet aggregation at thesespots, resealing of plaques, and partial incorporation ofthrombus within complicated lesions. This transient non-occlusive thrombus formation in coronary arteries usually

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presents clinically as unstable angina pectoris. However,deep ruptures resulting in occlusive thrombus formationin coronary arteries are the usual cause of acute myocar-dial infarction.

Whether a plaque will remain intact and therefore stable,or rupture and lead to occlusive thrombus formation in acoronary artery causing an acute coronary syndrome dueto ischemia, depends upon a number of factors, the mostimportant of which is its composition. Stable plaques havea thick fibrous cap, a small lipid core, and few inflamma-tory cells. In contrast, unstable vulnerable plaques havehigh lipid content, numerous inflammatory cells, and athin fibrous cap containing reduced collagen and vascularSMC. Although unstable plaques are believed to accountfor only a small number of all atheromata in coronaryarteries, they are responsible for most acute coronaryevents.

Anyhow, atherosclerosis of coronary arteries causes severalmajor clinical categories largely determined by clinicalhistory, physical examination and laboratory findings.These major clinical categories include angina pectoris(stable angina, unstable angina, silent ischemia, syndromeX, and Prinzmetal’s variant angina), myocardial infarction(MI), ischaemic cardiomyopathy and sudden cardiacdeath due to coronary heart disease (CHD). Unstableangina pectoris and MI together with sudden ischaemicdeath are the mean features of so-called acute coronarysyndrome.

Angina pectoris is a clinical syndrome caused by thedelivery of insufficient oxygen to the heart muscle via thecoronary arteries, leading to ischemia. Angina is character-ized by episodic chest (precordial) discomfort, pressureor pain lasting up to 15 minutes. It is typically precipitatedby exertion or strong emotions and relieved by rest orsublingual nitroglycerin. An angina attack may beprecipitated by the first contact with cold air on leaving awarm room during cold weather. In unstable angina, ascompared with stable angina, the chest pain is generallymore intense, lasts longer, is brought on by less effort oreven occurs spontaneously at rest (e.g. when the patient issedentary); it is progressive in nature, or involves anycombination of these changes. Unstable angina is causedby an acute but reversible increase in coronary obstructiondue to rupture or fissuring of the fibrous cap of theatheromatous plaque with consequent thrombus forma-tion.

Silent ischemia is myocardial ischemia detected onambulatory ECG monitoring (characterized by transient STsegment depression of at least one mm. persisting for atleast one minute) or during exercise stress testing,echocardiography or nuclear stress scintigraphy in theabsence of chest pain or any other symptoms. It may becategorized into 3 types: type 1 patients are totallyasymptomatic, type 2 are those who are symptomatic aftera prior documented MI and type 3 patients who manifestsilent ischemia but also may have symptomatic ischemia.At least 75% of the ischemia occurring in patients withstable angina is clinically silent.

Syndrome X is angina, or angina - like chest pain relievedby rest or sublingual nitroglycerin in patients who have anabnormal ECG in exercise test and myocardial lactateproduction during ischemia but no coronary atheroscle-rotic lesion proved on coronary angiography. The exactaetiology of this syndrome is unclear but most likely itrepresents a heterogeneous group of changes bestcharacterized by a reduced capacity of the coronarycirculation to augment blood flow in the face of anincrease in oxygen demand.

Prinzmental’s (or variant) angina is angina caused by aspasm occurring within 1 cm. of an obstruction of theproximal portion of a major coronary artery. It is charac-terized by chest discomfort at rest which is relieved aftersublingual nitroglycerin and by ST segment elevation inECG during the attack. However, between anginal attacks,which tend to occur with regularity at certain times of theday, the ECG may be normal. The changes are usuallyconfined to a single epicardial coronary artery, butmultivessel spasm can also occur as well as the spasm atdifferent levels within the same vessel.

Acute myocardial infarction is ischaemic necrosis of themyocardium usually resulting from an occlusion by anacute thrombus of a coronary artery that supplies thedamaged area, often after an atheromatous plaquerupture. The patients suffer from a deep chest pain orpressure often with radiation to the left arm or jaw whichis similar to the discomfort of angina pectoris. However itis usually more severe, long-lasting, and is not relieved byrest or sublingual nitroglycerin. Some patients, particularlywomen, can have silent MI or only atypical chest discom-fort. MI is also characterized by ECG changes: the classicpresentation includes ST segment elevation, inversion of Twaves and development of pathological Q waves or loss ofR waves. The diagnosis of MI is aided by laboratory testsincluding increased creatine kinase activity, particularlyMB izoenzime, and increased troponin and myosin.

Ischaemic cardiomyopathy is predominantly caused bydiffuse coronary artery atherosclerotic disease. It is causedby chronic coronary artery stenosis myocardial fibrosiswith diffuse loss of myocytes and results in impairedventricular systolic function reflected by low ejectionfraction (EF). The main symptoms of this chronic diseaseare effort dyspnoea and fatigue.

Sudden cardiac death is witnessed death that occurssuddenly, i.e. within one hour of the onset of symptoms inan apparently healthy person, where death could not beascribed to other causes. The main reason is cardiacarrest, i.e. absent or inadequate ventricular contractionsthat immediately result in systemic circulatory failure. Itresults primarily from electrical dysfunction, particularlyventricular fibrillation, asystole or electromechanicaldissociation very often caused by MI. However it is not onlyatherosclerosis of the coronary arteries that is important.

Cerebrovascular disease is the first cause of death inCroatia and the third most common cause of death indeveloped countries. Cerebrovascular disease presentseither as transient ischaemic attacks (TIAs) and/or asischaemic stroke. Thrombi or emboli from ulceratedatheromatous plaques can interrupt intracranial or

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extracranial arterial blood supply causing brain ischemiaand consequent neurological symptoms. If the bloodsupply is promptly restored, brain tissue recovers andneurological symptoms disappear. However, if vesselocclusion lasts longer than 1 hour, the result is ischaemicnecrosis and permanent neurologic damage.

Transient ischaemic attacks are episodes of sudden, focalneurological dysfunction from a vascular cause, i.e.internal carotid-middle cerebral or the vertebrobasilararterial system. They last several minutes or, much lessoften, hours but resolve within 24 hours. Symptoms areidentical to those of stroke but are transient.

Stroke can be caused by cerebral ischemia and infarction(85% of all cases), cerebral haemorrhage (10%) orsubarachnoid haemorrhage (5%). The hallmark ofischaemic stroke is the sudden onset of focal neurologicaldeficit. The symptoms of ischaemic stroke are related tothe location and the volume of brain tissue damaged aswell as to the mechanism of injury. For example if thecarotid blood supply is compromised and thereforemiddle cerebral artery becomes occluded, monocularblindness, contralateral hemiparesis and aphasia occur.

Peripheral artery disease (PAD) caused by atherosclerosisis also increasing as the population ages and as patientssurvive their myocardial infarctions. The pathophysiologi-cal basis of PAD is identical to that which occurs incoronary artery atherosclerosis and the same risk factorsare associated. PAD can be present as chronic ischaemiathat is caused by gradual enlargement of an atheromatousplaque and therefore insufficient blood supply, forexample to a limb. The symptom of this entity is intermit-tent claudication, i.e. pain or cramps that occur onwalking and are usually relieved in 1 to 5 minutes by restafter which the patient can walk as far again before painrecurs. Disease progression is marked by a reduction inthe distance the patient can walk without pain. Acuteischaemia due to acute artery occlusion is characterized bysudden onset of severe pain, coldness and pallor in anextremity with absent pulses distal to the obstruction.

Recommended literature:

1 Braunwald E. Unstable angina: A classification.Circulation 1989; 80:410-14.

2 Cannon RO. Chest pain with normal coronaryangiograms. NEJM 1993; 328:1706-8.

3 Libby P. Molecular basis of the acute coronarysyndromes. Circulation 1995; 91:2844-50.

4 Reiner Ž, Tedeschi-Reiner E. Novije spoznaje opatofiziologiji atheroskleroze.Lijec Vjesn 2001;123:26-31.

5 Ross R. Atherosclerosis – an inflamatory disease. NEJM1999; 340:115-26.

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