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İSCHAEMİC HEART DİSEASE

İSCHAEMİC HEART DİSEASE. Prof Dr. Rasim ENAR Istanbul University Cerrahpasa Medical Faculty Department Cardiology.

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İSCHAEMİC HEART DİSEASE

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  1. İSCHAEMİC HEART DİSEASE Prof Dr. Rasim ENAR IstanbulUniversity CerrahpasaMedicalFaculty DepartmentCardiology

  2. Myocardialischaemiaresult of acuteorpersistently (chronic) decreasemyocardialbloodflowduetonarrowedcoronarylumendiameter, mainlycausedbycoronaryAtherosclerosis. Mechanisms: 1. Whilepatient has stablecoronayobstructıonduetosinificantplaquestenosis ( ≥ %50 lumendiameternarrowing) mostlyremainasyptomatic in therestingconditıons. At thissituatıoncoronaryflowneverrespond (augmented) toincreasedmyocardialoxygendemand (strenousexertıon, emotıonalstress); somyocardialischaemiaoccurred, as a result of demand – supplydismatch; clinicallytermedChronicCoronaryarterydisease (CAD) orstableanginapectoris. 2. On theotherhand, patientwho has previouslynear normal coronaryflowwithinsignificantobstructiveplaque (<%50 luminalnarrowing); whencoronaryflowsuddendecreasebelowthecritcallevel ( supply not matchingrestingdemand ) fromresult of abrupttrhrombosısuperimposedoverplaquedisruptıon, ultimatelyacutemyocardialischeamiadeveloped, İn clinicalpracticecalledAcutecoronarysyndromes (ACS). • Mainclinicalpresentatıons of ACS are;regardlessamount of myocardialinjuryaresuddencardiacdeath, symptomaticorasymptomaticacutemyocardialischaemia.

  3. ATHEROSCLEROSIS: Atherosclerosos İs inflamatory disease of the arterial wall that underlies many of the common causes of cardiovascular morbidity and mortality; including myocardial infarction (MI), peripheral vascular disease (and cerebrovascular disease). Coronary artery disease (CAD) causes severe disability and more death than any other disease (includingcancer). Atherosclerosısdevelops over the course of 50 years, beginning in the early teenage years. Risk Factorsfor (atherosclerotic) CAD: Majorindependent RF: • Advancedage; malegender, postmenopausalwomen. • Tobaccosmoking, • Diabetesmellitus, • Elevated total andlow-densitylipoproteincholesterol (LDL), • Lowhighdensitylipoproteincholesterol (HDL), • Hypertensıon. • METs (hypertensıon, abdominalobesity, dislipidemia, insülinresistan/diabetes). Predisposing RF: • Abdominalobesity; • Ethniccharacteristics; • Familyhistory of prematureCoronaryheartdisease ( firstdegreerealatives; <55 yearsfor men, <65 yearsforwomen). • Obesity; physicalinactivity; psychosocialfactors.

  4. Pathophysıology of Atherosclerosıs: The normal vessel wall and endothelial function: A normal, healthy artery comprises: 1- Endothelium – a monolayer of endothelial cells and its basement membrane cover inner surface of vessel lumen. 2- Media – concentric layers of smooth muscle cells, elastin fibres and extracellular matrix. 3- Surrounding Adventitia of connective tissue. • The endothelial cell layer maintaining vascular homeostasis. Endothelial cells provide a functional link between blood in the lumen and the vessel wall. They transduce many physiological stimuli, that have effects on blood cells, endothelium itself and on neighbouring smooth muscle cells. Nitric oxide (NO) is one of the most important signalling molecules produced by the endothelium. NO was originally identified as ‘endothelium-derived relaxing factor’. • In normal blood vessels, NO is generated by the enzyme endothelial nitric oxide synthase (eNOS), which is present in endothelial cells.

  5. Endothelialdysfunction in Atherosclerosis: The overall effects of NO on the vessel wall are to inhibit the processes that contribute to early atherosclerosis . • İn diseasedartery, early and characteristic feature of is abnormal function of the endothelium (endotelialdysfunctıon); characterized by loss of endothelial NO bioactivity and associated activation of the endothelium; resulting in predisposition to thrombosis and inflammatory cell adhesion and recruitment . * İn thefollowingconditions,endothelial dysfunction can be detected before macroscopic atherosclerosis is visible: • Hypercholesterolaemia • Smoking • Hypertension • Heartfailure. *Keypoint: İn allthesepatients with atherosclerosis, arteriesaretructurallynormal. Clinically, endothelial dysfunction manifests as abnormalities in NO-mediated vascular responses: (for example: lack of dilatation, or paradoxical constriction of coronary artery segments in response to intracoronary infusion of acetylcholine).

  6. ProgressivemolecularpathologyandClinicalevent: ATHEROSCLEROSİS.The causes ofthis process appear to beLipid retention, oxidation, and modification, which provoke chronic inflammationat susceptible sites in the walls of all major conduit arteries. Initial visiblelesionFatty streaks evolve into fibrous plaques,some of develop into forms vulnerable pronetorupture, causing thrombosis or stenosis. CAD is almost always due to atheromatousnarrowing and subsequent occlusion of the vessel. Earlyatheroma ispresent from young andprogresslifelong. • A mature plaque iscomposed of two constituents, each associated with a particularcell population: 1) The lipid core is (“lipidgruels”) formedmainly released from necrotic“foam cells”( monocyte derived macrophages), which migrateinto the intima and ingest lipids. 2) The connective tissue matrix isderived from smooth muscle cells, which migrate from themedia into the intima, where they proliferate and change theirphenotype to form a fibrous capsule around the lipid core. When a plaqueproduces a > 50% diameterstenosis (or> 75% reduction in cross sectional area), reducedblood flowthrough the coronary artery during exertion may lead toAngina. • Acute coronary events usually arise when acutethrombusformation follows disruption of a plaque. • In Acute myocardial infarction,occlusion is more complete than in Unstable anginapectoris (USAP), wherearterial occlusion is usually subtotal. Downstream embolism ofthrombus may also produce microinfarcts in UAP.

  7. Progression of atheromatous plaque from initial lesion to complex andrupturedplaque■ (Left): Schematic representation of normal coronary artery wall (top) anddevelopment of atheroma (bottom).

  8. ATHEROTHOMBOSISandHigh Risk Plaque: • Atherothrombosis is a complex disease in which cholesterol deposition, inflammation, andthrombus formation play a major role. • The atheroscleroticdisease is asymptomatic during a long period and dramaticallychanges its course when complicated by thrombosis. • Rupture of high-risk vulnerable plaques is responsiblefor coronary thrombosis;which it is thethe main cause of unstable angina, acute myocardial infarction, andsudden cardiac death. In addition to rupture, plaque erosion may also lead to occlusivethrombosis and acute coronaryevents. • Exposure of thrombogenicsubstrate as resultant of plaquerupture (Virchowtriad) is a keyfactor in determiningthrombogenicity at thelocalarterial site.

  9. THE VİRCHOW TRİAD OF THROMBOGENİCİTY: 1) Localvesselwallsubstrates Atherosclerosis: • Degree of plaque disruption (i.e., erosion, ulceration) Vesselwallinflammation: • Components of plaque (i.e., lipid core) • Macrophages and generation of microparticles (i.e., tissue factorcontent) Post-interventionalvesselwallinjury: • Plaquedisruptionafterpercutaneoustransluminalcoronaryangioplasty, atherectomy, orstenting • Injury of smooth-muscle cells (i.e., rich in thrombin) 2) Rheology Highshearstress: • Severe stenosis (i.e., change in geometry with plaque disruption,residualthrombus) • Vasoconstriction (i.e., serotonine, thromboxane A2, thrombin,dyfunctionalendothelium) Oscillatoryshearstress: • Bifurcation of arteries, plaque irregularities Post-intervention slow blood flow/local stasis (i.e., dissectinganeurysm). 3) Systemic factors of the circulating blood Metabolicorhormonalfactors • Dyslipoproteinemia [triglycerides, increasedlow-densitylipoproteinor oxidized low-density lipoprotein cholesterol, decreased highdensity • lipoproteincholesterol, lipoprotein(a)] • Diabetesmellitus (i.e., glycosylation) • Catecholamines (i.e., smoking, stress, cocaine use) • Renin-angiotensinsystem (i.e., high-reninhypertension) Plasmavariables of hemostasis: • Tissue factor, factor VII, factor VII, fibrinogen, thrombingeneration (fragments 1 and 2), thrombin activity (fibrinopeptide A), plasminogenactivatorinhibitor-1, tissueplasminogenactivator. • Infectious (i.e., Chlamydiapneumoniae, cytomegalovirus, Helicobacterpylori) and cellular blood elements (i.e., monocytes and whitebloodcells)

  10. Cross-sectioned coronary artery containing a ruptured plaque with a non-occlusive platelet-rich thrombus superimposed: The actual defect in thefibrous cap is not seen in this section but is located nearby, documented by the presence of extravasated radiographic contrast medium (postmortem coronaryangiography) in the soft, lipid-rich core just beneath the thin, inflamed fibrous cap. ■Trichrome stain, rendering thrombus red, collagen blue, and lipidcolorless.*Threemajordeterminants of plaque’svulnerabilitytorupture: (1) The size andconsistency of theatheromatouscore;(2) Thicknessthefibrouscapcoveringthecore;(3) İnflamatıonandrepairwithinthecap.

  11. Plaque vulnerability, disruption, and thrombosis: Anatomicalchanges leading to acute coronary syndrome and subsequent plaqueremodeling. An element of vasoconstriction is usually present.

  12. ACUTE CORONARY SYNDROMES:

  13. Definitıon: ACS, termed; symptomsresultingfromAcutemyocardialischaemiaduetoacuteatherothromboticevents. • Presentatıon of ACS includeswiderange of clinicalcondition; fromasymptomaticmyocardialinfarctıontosuddencardiacdeath, andalsotypicallyunstableangina, ST segmentelevatıon , non-ST segmentelevatıon Mİ. Thecurrentnomeclaturedivide ACS into 2 mainsubgroupsby ECG findings (ST- segment, T- wave). Thisclasificatıonalsoguidedtheprimarytherapy.

  14. Theclassification of ACS (based on theelectrocardiogram): • Patientswithprolongedacutechestpainandpersistent (>20 min) ST-segmentelevation is termed ST-elevation ACS (STE-ACS) andgenerallyreflects an acute total coronaryocclusion. Ultimately, most of thesepatientswilldevelop an ST-elevation MI (STEMI). • Because of majorluminalpathologyaretotal occlusıonby fibrin-richthrombus, thisgroup of patientsshould be undergonereperfusıontherapy, as soon as possible. • Thetherapeuticobjective is toachieverapid, complete, andsustainedreperfusionbyprimarypercutaneouscoronaryinterventıon (PCI) orfibrinolytictherapy(FLT). 2. Patientswithacuteprolongedchestpainwithratherthanpersistent ST-segmentelevation; transient ST-segmentdepressionor T-waveinversion, flat T waves, pseudo-normalization of T waves, or no ECG changes at presentation . • Theinitialstrategy in thesepatients is toalleviateischaemia, symptoms,and stop ongoing Mİ. At thisgroup of patients, because of thrombusnon-occlusiveandplatelet- rich, İntensiveantithrombotics (particularlyantiplatelets, antithrombinsandcombinatıon) mainstay of therapy, not treatedwithfibrinolytictherapy. • At presentation, theworkingdiagnosis of non-ST-elevation ACS (NSTE-ACS), based on themeasurement of troponins, will be furtherqualified as non-ST-elevation MI (NSTEMI) orunstableangina (USAP). İn Patientswithnon-ST-segmentelevatıon at presentıon ECG; İfthere is biochemicalevidence of myocardialinjury (elevatedbtroponinand CK- MB) termedNSTEMİ, and in theabsence of myocardialinjurybiomaker is termed USAP. However, slightcTnelevatıonwasfoundsome in USAP patientswhoseearlyrecurrence of ischaemicevents risk wasincreased ( termedHigh- risk USAP).

  15. AcuteCoronarySyndromes Superfıcıal erosıon RupturedFibrouscap Total occlusıon Nonocclusıve Criticalstenosıs Platelet- rich Thrombus Fibrin- rich Thrombus Non-ST- Elevatıon ST- Elevatıon cTn↑ CK/MB↑ CK-MB- cTn↑ CK-MB- cTn - MYOCARDİAL İNFARCTION NSTEMI NQMI QMI USAP + High- RİSK

  16. Clinical Features of Myocardial IschaemiaandInfarction: Onset of myocardial ischaemia is the initial step in thedevelopment of MI ,results from an imbalance betweenoxygen supply and demand. • Myocardial ischaemia in clinical setting can usually be identified from the patient’shistory and the ECG. • Suggestedischaemic symptomsinclude various combinations of chest, upper extremity,mandibularpainor epigastric discomfort (with exertion or at rest) b) ischaemia equivalent symptomsarenot rare; such as dyspnoea or fatigue, dizziness, lightheadedness. c) Thediscomfort associated with acute MI usually lasts >20 min. d) Often, the discomfort is diffuse— (not localized, not positional,andnot affected by movement of the region)—and it maybe accompanied by diaphoresis, nausea or syncope. However,these symptoms are not specific for myocardial ischaemia.Accordingly, they may be misdiagnosed and attributed togastrointestinal, neurological, pulmonaryormusculoskeletaldisorders. e) MI may occur with atypical symptoms—suchaspalpitations or cardiac arrest— or even without symptoms (silent).Forexample in women, the elderly, diabetics, or post-operativeand critically ill patients. Careful evaluation of these patientsis advised.

  17. CHEST PAİN / DİSCOMFORT İN AMİ PATİENT: Usually lasts more than 20 minutes and often persists for several hours. The pain of Mİ however can last in 15 minutes; occasionally fatal infarction isdevelopedin by only a few minutes of severe pain or even unheralded cardiac arrest. Quality: Patientswithprioranginapectorısusuallydescribetheirdiscomfort of AMİ is beingsimilar in quality, but more severe. • Whilesubsternalpressure is unlikelyto be of superficialorigin, Most of thepatientsaid: ”Elephantsitting on mychest” (orpressure, heaviness) ortheclenchedfistsign”. Commonlocatıon: Smilarthat of describedforanginapectoris. Thepain is usuallylocated in retrosternalarea, it oftenradiatestotheneck, jaw, leftshoulderandinneraspect of leftarm. Uncommonlocatıon: Aresimiliartothatdescribedforanginapectoris.Thepainmayfeltonly in thelowerjaw,leftorrightshoulder, innerorouteraspect of theleftorrightupperarm, leftorrightelbow, leftorrightwrist. Size of painfularea: The size painfularea on thechest is theclenchedfistorlarger. Duratıon of thepain: Thepain of AMİ usuallylastlongerthan 30 minutes. Afterresolutıon of themostintensepain, patientdescribelessintenseheavinessorachethatmaylastfor 12- 24 hours. • Pain of AMİ; painonset is withlowİntensityand in following 30-60 minutesgraduallyincreaseandreachingpeak in a hourandpersistedseveralhoursuntilreperfused. Usually not respondsublingual NTG. Patientfilingdoom.

  18. AMİ Associated Symptoms : • Diaphoresis, cold clammy skin, and apprehension (however, all of these symptoms may be absent). • Shortness of breath, nausea, vomiting, dizziness. • Women with acute MI often reveal atypical symptoms with low levels of chest pain orabsence of pain. Shortness of breath (57.9%), weakness (54.8%), and fatigue (42.9%). • Presyncope and rarely syncope may occur owing to bradyarrhythmias, especially inferior MI. • Because of bradyarrithmiasduetoatrioventricular , sinoatrialconductıonblocksandexcessivevagalstimulatıonnausea, presyncope, syncopevomiting, dizzinessmorecharacteristicforinferior AMİ. • Painless infarcts (in about 10% of patients), especially in diabetics or the elderly. PhysicalSigns • •Patient appears apprehensive (feelingdoom), restless, anxious, cold, clammy. • Area of chest pain may be indicated with a clenched fist (Levinesign). • Chestpainneverlocatedandprecipitatedbytwofingers.

  19. Common locations of cardiac pain:■ Language of hands.■ “Levine sign”.

  20. ECG Manifestatıon of Acute Myocardial ischemia:

  21. 50 20 10 5 2 1 Use of Cardiac Markers in ACS URL = 99th %tile of Reference Control Group Cardiac troponin after “classical” AMICK-MB after AMICardiac troponin after “microinfarction” Multiples of the URL Upper reference limit 0 1 2 3 4 5 6 7 8 Days After Onset of AMI • Myocardial injury is detected when blood levels of sensitiveand specific biomarkers such as cTn or the MB fraction ofcreatinekinase (CKMB) are increased. Blood samples for the measurement of cTn should bedrawn on first assessment (after >6-8h of AMİ onset).

  22. ACUTE ST- SEGMENT ELEVATION Mİ (STEMİ): ST-segmentelevatıonornew LBBB in thesetting of symptomsconsistentwithacutemyocardialischemiaanddetectedevidence of myocardialnecrosis. Practical Formula: (“ECG, + Symptoms, + BioNecrosis = Mİ”). İmportance of Mİ: • Worldwide, coronaryarterydisease (CAD) is thesinglemostfrequentcause of death. Over seven millionpeopleeveryyeardiefrom CAD, accountingfor 12.8% of alldeaths. • Everysixthmanandeveryseventhwoman in Europewilldiefrommyocardialinfarction. Themortalityof STEMI is influencedbymanyfactors: (age, Killipclass, time delaytotreatment, mode of treatment, Mİ locatıonhistory of priormyocardialinfarction, diabetesmellitus, renalfailure,andnumber of diseasedcoronaryarteries, LV ejectionfraction). • The in-hospitalmortalityvariesbetween 6% and 14%. • Declineacuteandlong-termmortalityfollowing STEMI in parallelwithgreateruse of reperfusiontherapy, primary PCI, modern antithrombotictherapyandsecondarypreventiontreatments. Still, mortalityremainssubstantialwithapproximately 12% of patientsdeadwithin 6 months,

  23. Pathological characteristics of AMİ: • MI is defined in pathology as myocardial cell death due to prolonged ischaemia. After the onset of myocardial ischaemia, histological cell death is not develop, immediately, takes a defifinite period of time to cell-death (as little as 20 min, or less). It takes several hours before myocardial necrosis can be identified by macroscopic or microscopic post-mortem examination. • Complete necrosis of myocardial cells at risk requires at least 2–4 h, or longer; depending on the presence of collateral circulation to the ischaemic zone, persistent or intermittent coronary occlusion, the sensitivity of the myocytes to ischaemia, • The entire process leading to a healed infarction usually takes at least 5–6 weeks. Definitıon of Myocardial İnfarctıon: The term of Mİ should be used when there is evidence of myocardial necrosis in a clinical setting onsistent with acute myocardial ischemia. Under this conditıon one of the following critera meet the diagnosis of Mİ: • Detectıon of a rise an/or fall of cardiac biomarkers (cTn) with at least one value above 99th percantile of URL and with at least one of the following: -+ ST-T changes or new LBB. -+ Development pathological Q wave . -+İmaqging new loss of viable myocardium or regional wall motıon abnormality. -+ İdentificatıon of intracoronary thrombus by angiography.

  24. MANAGEMENT OF STEMİ: Theaim of therapy: Reperfusiontherapy (RPT) is indicated in all patients withsymptoms of <12 h durationandpersistent ST-segmentelevationor (presumed) new LBBB. Primaryprincipal of RPT: Reperfusıon (openoccludedartery)should be performed as soon as possibleanwithmaintainpatency of openartery at least 1year. • 2 Typies of RP therapiesareindicated; Percutaneousinterventıon (PCI) andFibrinolyticTherapy (FLT). • Time-to- threatment ( delay of RP) is thekey of sucess. When RP perform in patientwithin 1h of symptomonset, Mİ could be aborted . Rule of Reperfusıon : RPT Should be introduced “timely” toallpatientwithpersistent STE within 12h of symptomonset. Timely RP (delay of therapy): Time frompresentatıon in Firstmedicalcontact (FMC), orHospitalemergencyroom (door) to -needle (FLT) or/ -balooninflatıon (PCI). Recomendeddelays: Door- needle: <30 minutesanddoor- balon <90 min (PCI capableHxt) or <120 min (Non-PCI capableHxt).Patientpresentingearlywithlarge Mİ PCI delayshould be <60min. Adjunctiveantithrombotictherapyto RP therapies : Antitromboticstherapy is thecornerstone of RPT toestablıshacutereperfusıonandmaintainsustainpatency. • FLT: withconcurrently; aspirin, ClopidegrolandLowMolecularweightHeparin (Enoxaparin). • PCI : At thetable; Aspirin Prasugrel/clopidogrel, Bivaluridinorheparins.

  25. Summary of important delays andtreatment goals in the management of acute ST-segmentelevationmyocardialinfarction: • FMC- ECG andDiagnosıs: ≤ 10 min. • PCI- Hospital: Door-tobaloon: ≤90 min. • (Earlypresentatıonwithlarge Mİ): ≤60 min). • Not-PCI-Hospital: FMC-Baloon: ≤120 min. • FLT: Door (FMC)- Needle: ≤30 min. • SELECTION OF RP THERAPİES : • Primary PCI is therecommendedreperfusiontherapyoverfibrinolysis, ifperformedby an experiencedteam within120 min of FMC. • Primary PCI is indicatedforpatientswith severe acuteheartfailureorcardiogenicshock, unlesstheexpected PCI relateddelay is not excessiveandthepatientpresentsearlyaftersymptomonset. • FLTis recommendedwithin 12 h of symptomonset in patientswithoutcontraindications, ifprimary PCI cannot be performedby an experiencedteamwithin 120 min of FMC.Fibrin-specificfibrinolyticsprefered (Alteplase, Tenecteplase PA)

  26. İNDİCATIONS AND STRATEGY OF REPERFUSION THERAPY: 1- Reperfusiontherapy is indicated in allpatientspresentwithsymptoms of <12 h durationandpersistent ST-segmentelevationor (presumed) new LBBB. • Prefered RPT is PPCI (ifperformedtimely). FLT is alternative of PPCI. 2- If FMC is EMS or at a non-PCI-capablecentre, patientimmediately transfer tothecatheterizationlaboratoryfor PCI. 3-Insettingswhereprimary PCI cannot be performedwithin 120 min of FMC by an experiencedteam, fibrinolysisshould be considered, particularlyif it can be givenpre-hospital (e.g. in theambulance) andwithinthefirst 120 min of symptomonset . • Afteradministratıon of FLT, patientsshould be transfer to PCI-centerforearlyanggıography. • Primary PCI (— defined as an emergentpercutaneouscatheterintervention in thesetting of STEMI, withoutpreviousfibrinolytictreatment —) is thepreferredreperfusionstrategy in patientswith STEMI; whenprovided it can be performedrapidly (i.e. withinguideline-mandatedtimes), by an experiencedteam, regardless of whetherthepatientpresentsto a PCI-capablehospital.

  27. İnitial therapy: • Aspirin, should be diagnosed with given as soon as posible to patient with symptoms of high likelihood ACS. • Clopidegrol, should be combined to ASA after STEMİ diagnosed by ECG and rapidly evaluate for Emergent RP strategy . • Nitrates, sublingual Nitroglycerin for testing ischaemia or relieve for chest discomfort. • Oxygen, with nasal canul is traditional aproach, high concantratıon O2 inhalatıon should be avoided in for COPD patients . • Morphin, use for control anxiety in patients unresponsive to nitrates therapy. Therapies in first 24h: • Oral Beta bloker: Oral should be given all patients unless has symptoms and sign of heart failure, complete heart block and severe bradycardia. • ACEİ: Should be given partıcularly nonreperfused, unseccesful RP and large Mİ with systolic LV dysfunctıon. • Statin regardless the cholesterol levels. • Aldasteron antagonist: İn patients dysfunctıon on ACEİ and beta blocker therapy with large Mİ and systolic LV dysfunctıonshould be combined untill hyperkalemia and moderate renal dyfunctıon. Discharged therapies: These drugs should be included to patient’s therapy: • ASA, Clopidegrol ( for PCI Prasugrel), BB, ACEİ, aldosteron antagonist ( given in first 2 weeks) and statin.

  28. NON ST ELEVATION ACS (NSTE): Patientswithpresentwithischaemicchestpain >20 minutesduratıon, with ECG changiesratherthanpersistent STE ; diagnosed is NSTE- ACS. • Biomarkers (troponins) furtherdistinguish NSTEMI andunstableangina. ItsPathological, imaginghavedemonstratedatheroscleroticplaqueruptureorerosion, withdifferingdegrees of superimposedplateletthrombosisandvasospasmwithnon-total lumenocclusıonanddistalembolization. • Whencompared STEMİ, because of less severe thrombogenicburden but moresustainprothromboticactivity, thispatients has higher rate of subsequentlateischemicevents risk (recurrentischemia, Mİ andischemiarequiredrehospitalisatıon ) evenlowerinhospitalmortalityandmorbidity . Clinicalpresentation Theclinicalpresentation of NSTE-ACS encompasses a widevariety of symptoms. Traditionally, severalclinicalpresentationshavebeendistinguished: †Prolonged (.20 min) anginalpain at rest. † New onset (de novo) angina (Class II or III of theClassification of the CCS. † Recentdestabilization of previouslystableanginawith at leastCanadian CCS Class III anginacharacteristics. (crescendo angina); or † Post-MI angina.

  29. MANAGEMENT STRATEGY: Inpatientswith a suspected NSTE-ACS, diagnosisandshort-termischaemicandbleedingrisksstratificationshould be evaluatebased on a combination of clinicalhistory, symptoms, physicalfindings, ECG (repeatedorcontinuous ST monitoring), andbiomarkers. • 12-leadECGshould be obtainedwithin 10 minafterfirstmedicalcontactandimmediatelyread. • NSTE- ACS patientsshould be admittedpreferablytochestpainunitsorcoronarycareunits. • It is recommendedtouseestablishedrisk scoresforprognosisandbleeding (e.g. TIMI, GRACE and CRUSADE risk scoresystems). • Blood has to be drawnpromptlyfortroponin (cardiactroponin T or I) measurement. Theresultshould be availablewithin 60 min. The test should be repeated 6–9 h afterinitialassessmentifthefirstmeasurement is not conclusive. Initialtherapeuticmeasures: Aspirin, Oxygen, Nitrates, Morphine (!). Treatmentswhen an NSTE- ACS diagnosisappearslikely: P2Y12 inhibitor (TicagrelororClopidegrol) andAnticoagulatıon (FondaparinuxorEnoxaparin) should be combined Aspirin (Preferablyinhospitaladmısıon) and oral Beta blockergiven in 24h of hospitaladmisionif not contraindicated . • Ticagrelorforhigh risk NSTE- ACS patiensproceedto PCI. • Becausehighfrequency of reccurenceischaemicevent rate; İnvasivestrategy is themainstay of therapy, NSTE- ACS patientwithİntermediateandhigh risk shouldreferredtoinvasivestrategyinhospitalcourse.

  30. TIMIRisk score: • İndicators of 35 dayscompositeeventsrisks (Mortality, ornew, reMİ, or severe recurrentischemiareguiringurgentrevascularizastıonthrough 14 dayafteradmision). • Age ≥65 years At least 3 risk factors, • Priorcoronarystenosis ≥50% • ST- segmentdeviation on ECG presentatıon, • At least>2 anginal events in the proceeding 24 hours, • Aspirin treatment in the prior 7 days, • Increasedcardiacbiomarkers, • Prior congestive heart failure, MI, CABG or PCI. Each characteristic qualifies for one point in the risk score • 0-1: %4.7; 3: %%13.2; • 6-7: %40.9. GRACE Risk score – - (Allcausemortality risk in hospitaland at 6 months). • Killipclass (heartfailure) • Arterialbloodpressure • ST deviation on ECG • Cardiacarrest • Increasedcreatinineconcentration • Increased CK-MB or troponinconcentration • Heart rate. • Risk score: >140- (İn hospitaldeath >%3); • Risk score >118: - (at 6 monthdeath %8).

  31. Risk Calculator for 6-Month Postdischarge Mortality After Hospitalization for Acute Coronary Syndrome Record the points for each variable at the bottom left and sum the points to calculate the total risk score

  32. İNVASİVE STRATEGY: Cardiac catheterization followed by revascularization has been shown to prevent recurrent ischaemia and/or improve short and long-term outcomes. • İnvasive approach in higher risk NSTE- ACS patients showed approximately %20-30 reductıon risk of 2 years mortality, non-fatal Mİ and reccurent USAP. • Several risk factors (troponin elevation, diabetes, ST-segment depression, renal insufficiency, etc.) have been identified to predict the long-term benefit of an invasive strategy. Depending on the acuteness of risk, the timing of angiography can be tailored, according to four categories: _ invasive (,72 h); – urgent invasive (,120 min); – early invasive (,24 h); _ primarily conservative. The optimal timing depends on the risk profile of the individualpatient and can be assessed by several variables

  33. Urgent invasive strategy (<120 min after first medicalcontact): • This should be undertaken for very high risk patients. Thesepatientsarecharacterizedby: - Refractory angina (indicating evolving MI without STabnormalities). - Recurrent angina despite intense antianginal treatment, associatedwith ST depression (2 mm) or deep negative T waves. - Clinical symptoms of heart failure or haemodynamic instability (‘shock’). - Life-threatening arrhythmias (ventricular fibrillation or ventricular tachycardia). Earlyinvasivestrategy (<24 h afterfirstmedicalcontact) Mostpatientsinitiallyrespondtotheantianginaltreatment, but are at increased risk andneedangiographyfollowedbyrevascularization: - High risk patients as identifiedby a GRACE risk score >140 and/orthe presence of at leastone (following) primaryhigh risk criterionshouldundergoinvasiveevaluationwithin 24 h. • Relevantriseand /orfallcTn. • Dynamic ST-Twavechanges(silentorsymptomatic).

  34. Invasivestrategy (<72 h afterfirstmedicalcontact) • Inpatientswithlessacute risk andwithoutrecurrence of symptoms, angiographymay be performedwithin a time window of 72 h. Thus, suchpatientsshouldundergoelectiveinvasiveevaluation at thefirstopportunitydepending on thelocalcircumstances. Conservative strategy (no or elective angiography) • Patients that fulfil all of the following criteria may be regarded aslow risk and should not routinely be submitted to early invasiveevaluation: † No recurrence of chest pain. † No signs of heart failure. † No abnormalities in the initial ECG or a second ECG (at 6–9 h). † No rise in troponin level (at arrival and at 6–9 h). † No inducibleischaemia. Therapy: ASA, Clopidegrol, Enoxaparin, Beta blocker, Statin.

  35. STABLE ANGİNA: Stable angina is defined as short duration chest and/or arm discomfort that shows no change in the past 60 days in frequency, duration, or precipitating causes. • Most often pain duration is less than 10 minutes, and rarely up to 15 minutes; the mild-to-moderate discomfort is relieved within 1 to 10 minutes by cessation of the precipitating activity or use of sublingual nitroglycerin. • In more than 90% of patients, stable angina is caused by a greater than 70% obstruction in at least one coronary artery. In less than 10% of patient wit5h lesser degree of atheromatous obstruction, coronary artery spasm, or small vessel disease is present.

  36. Pathophysiology: Myocardialischaemia is a dynamicprocess. It is nowclearthatthree, not two, determinantsplay a major role in thepathogenesis of myocardialischaemia, whichmaymanifest as thechestpain of anginaorremainpainless ( termedsilentischaemia). Thethreedeterminants of myocardialischaemiaare as follows: •1. Concentricoreccentriccoronaryatheromacausinggreaterthanabout 70% stenosis. • Concentricplaquesareobservedmainlywithstableanginaandthere is a tendencyforthemto be eccentric in patientswithfrequent rest painand in thosewithunstableangina. • 2. Increasedmyocardialoxygendemand. • 3. Release of catecholaminesoccurring at theonset of anginaandduringtheepisode in mostpatientswithstableangina. Release of catecholaminesmayactuallyinitiateischemia, whichstimulatesfurthercatecholaminerelease, and a viciouscircleperpetuatestheoxygenlack

  37. ThemajorSymptoms of chronicischaemicheartdisease is anginapectoris, with a clinicaldiagnosisbased on fivefeatures: 1) Thecharacter of pain is deepvisceralpressureorsqueezingsensatıon, ratherthansharporstabbingorpinbrick-likepain. • İt is qualitydeepvisceralandintense it makethepatients pay atentıon, but not excruciating. • Area of painnot locatedandprecipitatedwith 2 fingertips 2) Thepainalmostalways has somesubsternalcomponent, althoughsomepatientcomplain of painonly on therightorleftside of thechest, upperback, orepigastrium. 3) Thepainmayradiatefromthethoraxtothejaw, neckorarm (usuallyulnarsurface of leftarm). 4) Anginausuallyprecipitatedexertıon, emotionalupset, orothereventsthatincreasedmyocardialoxygendemand (tachyarrhythmias, extremeelevatıons in bloodpressure). 5) Anginapectoris is transient, lastingbetween 2- 30 minutes.It is relieved (within 1- 5 minutes) bysessatıon of theprecipitatingevents (exercise) ortakingsublingualnitroglycerin(within 1-2 minutes). • Chestpainthatlastlongerthan 30 minutes it is moreconsistentwith Mİ pain; pain < 2 minutes is unlikelyduetomyocardialischaemia.

  38. DİAGNOSIS: • Diagnosis is based on a careful relevant history. Distinctive characteristics: The pain of angina has certain distinctive characteristics; Aaretrosternal discomfort precipitated by a particular activity, especially walking quickly up an incline or against the wind. • The discomfort is a tightness, constriction, squeezing, heaviness, pressure, strangulation, burning, nausea, or an indigestion-like feeling of gradual onset that disappears at rest. • Occasionally, the pain is described as sharp, and at times discomfort is replaced by shortness of breath on exertion. • The area of pain is usually at least the size of a clenched fist, often occupying most of the central chest area. The patient uses two or more fingers, the entire palm of the hand, or the fist to indicate the pain site. A finger or pencil point area of pain is rarely caused by myocardial ischaemia. •Relief of pain in an individual with stable angina always occurs within minutes of cessation of the precipitating exertional or emotional activity. Relief with sublingual nitroglycerin occurs promptly within 1–2 minutes. • Pain or discomfort disappears within 1 to 5 minutes of stopping the precipitating activity. • Discomfort may start in the lower, middle, or upper substernal area, the lower jaw, or the arm

  39. TheCanadianCardiovascularSociety (CCS) grading of angina is widelyusedtodifferentiatemild, moderate, or severe stableangina: • Class 1 Angina: Pain is precipitatedonlybysevere andusuallyprolongedexertion. • Class 2 Angina: Pain on moderateeffort, forexample, precipitatedbywalkinguphillorbywalkingbrisklyformorethanthreeblocks on thelevel in thecold, against a wind, orprovokedbyemotionalstress. There is “slightlimitation of ordinaryactivity.” • Class 3 Angina: Markedlimitation of ordinaryactivity; painoccurs on mildexertion, *usuallyrestrictingdailychores. Unabletowalktwoblocks on thelevel at comfortabletemperaturesand at a normal pace. • Class 4 Angina: Chestdiscomfort on almostanyphysicalactivity, forexample, dressing, shaving, walkinglessthan 100 feetindoors. Painmay be present at rest.

  40. THERAPY: Patients suitable for medical management usually have two of the following characteristics: • Stable, functional class 1 or 2 angina. • Good effort tolerance, negative or weakly positive treadmill exercise test . Patients who are unable to exercise because of intermittentclaudication or arthritis cannot be graded as class 1 or 2. • Good ventricular function( EF), or estimate greaterthan 50%. • Absence of left main coronaryarterydisease. • Presence of double vessel disease in the absence of severe proximal stenosis of the LADarterywith normal EF. • Concomitant comorbiddisease and contraindications to bypass surgery. • Age over 80 and not in good general health. • Lesions not ideal for intervention. ►Most patients with stable class 1 and 2 angina are managed with sublingual nitroglycerinand a one-a-day β-blocker plus aspirin and a statin to keep the LDL less than 2 mmol/L (80 mg/dL), fortargetedebloodpressure <135/85 mmHgwithcalcıum antagonist, ACEİ/ARB orcombinatıons. Duidlinesrecomended d secondarypreventıonmeasuresshould be implemented .

  41. Q’s of the İHD forMedicalstudents:??. • 1- Earliestcharacteristics of atherosclerosıs?. • Fattystreaks • endotelialdysfunctıon, • Lipidaccumulatıon, • Thrombosıs. 2- Sıgn of Subclinicalatherosclerosıs? • a) Fattystreak • b) fibrousplaquewith <%50 luminaldiameternarrowing. • c) Macroscopic Normal coronaryarteries. 3- Mechanism of stableangina? • Decreasedcoronaryflowwithdecreasedoxygendemand • İncreasedmyocardialoxygendemand not matchingaugmentedcoronaryflow, • Acuteplaquedisruptıon • Vazospasm. 4- Modifiable CAD risk factors? • a) Age, genetics, gender • b) tobaccosmoking, diabetes, hypertensıon • ECG changes, partıcularly Q wave. 5- What is thebestPrimarytherapyfortheseischemicsyndromes ?. • Syndromes: a) NSTE ACS b) STEMİ, stableangina • SelectedTherapy: i) Fibrinolytics; ii) Primary PCI; iii) Nitroglycerinand beta blocker;i) combinatıon of antiplateletandanticoagulandrugs. • 6- What is yourfırstorder?: Patientpresentationwithishemicsymptoms of <6 h duratıonand ST elevatıon on ECG. • a) Measuredtroponinlevelemergently; b) give Aspirin; c) referredtothe general hospital; d) Givesublingual nitrogliserin; e) Transport tothe PCI-centerif (----------------------- minutes) orgive (---) in (----minutes).

  42. 2- Inflammatorycellrecruitment: 1) Endothelial dysfunction in atherosclerosis is accompanied by endothelial cell activation, which results in expression of cell surface adhesion molecules (the selectins and VCAM-1). 2) These molecules mediate recruitment of inflammatory cells (monocytes and T cells). Inflammatory cell accumulation is also increased bysmoothmusclecellsandaccumulation of modified lipid (e.g. oxidized low-density lipoprotein, LDL). • Localrheologicalfactoreffects(differences in blood flow, shear stress and endothelial cell biology ) determineside of thevascularsusceptibilty. 3) Monocytes recruited into the vessel wall ingest modified lipids and become activated foam cells. Necrotic foam cells contribute to the lipid core of developing plaques. • In addition, activated macrophages and T cells express pro-inflammatory cytokines and growth factors, which maintain inflammatory cell recruitment and stimulate endothelial activation and smooth muscle cell proliferation. 3- Vascularsmoothmusclecells Vascular smooth muscle cells in the vascular media are normally quiescent and contractile. 4) In response to vascular injury, cytokines and growth factors (e.g interleukins, interferon-γ, tumour necrosis factor α), smooth muscle cells can change to an activated phenotype that allows them to migrate, proliferate and synthesize extracellular matrix proteins (collagen and elastin). These factors contribute to the growth of the plaque. 5) Smooth muscle cell migration and proliferation with extracellular matrix synthesis may contribute to luminal narrowing. • However, formation of a strong fibrous cap by smooth muscle cells, is important in maintaining plaque stability by isolating the lipid core and inflammatory cells from circulating blood

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