4 Endothelial Dysfunction Pathophysiology of CAD: AtherosclerosisComplicatedLesion/RuptureFoamCellsFattyStreakIntermediateLesionAtheromaFibrousPlaqueAtherosclerosis is a progressive disease involving the development of arterial wall lesions. As they grow, these lesions may narrow or occlude the arterial lumen. Complex lesions may also become unstable and rupture, leading to acute coronary events, such as UA, myocardial infarction, and stroke.Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998; 82(suppl 10A):Endothelial DysfunctionFrom FirstDecadeFrom ThirdDecadeFrom FourthDecade9
5 Hemostatic Thrombotic Cardiovascular RisksCardiovascular RisksSlide 2. Beyond cholesterol: predicting cardiovascular risk in the 21st centuryAs we understand more about the biology of atherothrombosis, we need to move beyond standard cholesterol screening if we are to appreciate the promise of preventive early intervention therapies. While hyperlipidemia, hypertension, and diabetes, as well as the behavioral risk factors of smoking and diet, remain major critical modifiable risk factors for vascular disease, we have learned over the years that many hemostatic and thrombotic markers such as lipoprotein(a), D-dimer, and homocysteine, inflammatory markers such as C-reactive protein (CRP), fibrinogen, and interleukin-6, and genetic markers are all part of the evolving understanding of cardiovascular risk.Keywords: markers, risk factorsSlide type: figure (chart)Lipids HTN DiabetesBehavioralHemostatic ThromboticInflammatoryGenetic
6 Atherosclerosis is a Diffuse Process 10%: ManifestedClaimECGOther lab data90%: HiddenPhysician judgmentCareful history taking
7 Clinical Manifestations Of IHD Myocardial IschemiaTransient LV DysfunctionProgressive LV DysfunctionAngina & ACSBreathlessnessArrhythmiaMost myocardial ischemia is painless (“silent”) …Sudden Death
10 Clinical Classification of CP (Chronic Stable Angina) Probability Definite (typical) angina:Substernal discomfort, with a characteristic quality and duration and radiationProvoked by exertion or emotional stressRelieved by rest or nitroglycerin in less than 10 minutes.Atypical angina meets 2 of the of characteristicsNoncardiac CP meets 1 of the typical angina characteristics.“Definitely not” angina: ? CP is unrelated to activity, appears to be clearly non-cardiac origin and is not relieved by nitroglycerin.
11 Grading of Angina of Effort by the Canadian Cardiovascular Society CommentDefinitionCanadian ClassAngina only with extraordinary exertion at work or recreationOrdinary physical activity does not cause anginaIAngina with walking more that two blocks on a level surface or climbing more that one flight of stairs at a normal paceSlight limitation of ordinary activityIIWalking 1-2 blocks on a level surface or climbing 1 flight of stairs at a normal paceMarked limitation of ordinary physical activityIIIAngina at rest or with minimal activity or stressInability to carry out any activity without discomfortIV
12 Types of Stressors Exercise Pharmacologic Treadmill Bicycle, upright or supinePharmacologicVasodilatorsDipyridamolAdenosinePositive inotropes/chronotropesDobutamine
14 Anti-ischemic and preventive drugs for IHD The treatment of angina is aimed at decreasing oxygen demand and/or increasing oxygen supply.Antiischemic and anti-anginal drugs (most commonly, a combination of these agents is used for management.A = Anti-platelet (aspirin) and anti-thrombotic therapy and antianginal therapy (nitrates) and ACE inhibitorsB = Beta-blocker and BPC = Cigarette smoking and Cholesterol lowering agents and Calcium antagonistsD = Diet and DiabetesE = Education and Exercise
15 Effects of Treatment of Chronic Stable Angina Angina ControlImproved Prognosis/ Prevention Of MINitratesYesNoBBCCBsDihydropyridines:Short actingLong actingNondihydropyridines:Diltiazem, VerapamilPoorNo (prognosis ↓)??NoAspirinStatins?yesACEIsPTCACABG
18 ACSs ACS UA NSTEMI STEMI The ACSs consist of acute myocardial infarction, which is subdivided into Q wave and non-Q infarctions, and a related condition referred to as UA.As their name implies, Q wave MI (QMI) and non-Q wave MI (NQMI) are differentiated by the presence or absence of a pathological Q wave on the 12-lead ECG. Both produce tissue necrosis, QWMI tends to produce more necrosis and, therefore, may be a larger infarct.UA (USA) does not produce infarction, that is does not show evidence of tissue necrosis, but is included in ACS because of its common pathophysiology.UANSTEMISTEMI
19 What is ACS?All have sudden ischemia due to sudden occlusion of one or more of the coronary arteries, resulting in decreased oxygen supply to the heart muscle.Thrombosis with sub-total (UA, NSTMI) or total coronary artery occlusion (STEMI)Can not be differentiated in the first hoursAll have the same initiating events:Plaque ruptureThrombus formationVasoconstriction
22 Pathophysiology of Acute Coronary Syndrome UAST depression, T Wave inversion or normalNo enzyme releaseNSTEMIUsually no Q waves at presentationCPK, LDH + Troponin releaseSTEMIST elevation+ Q waves at discharge
23 The Three I 1. IschemiaEpicardial Coronary ArteryLateral Wall of LVSeptumLeftVentricularCavityThe vessel lumen is now narrowed by a clot. If the clot is incomplete or collateral circulation is good, only the hardworking, poorly perfused sub-endocardial tissue will become ischemic.This is represented on the ECG by ST depression or T wave inversion.Positive ElectrodeInterior Wall of LV
24 The Three I 2. InjuryThrombusIf the clot is complete or the collateral circulation is poor, the ischemia will be transmural (through to wall). This is seen on the ECG as ST segment elevation.Most often this occurs due to a complete and persistent clot. Spontaneous lysis at this point is rare and the tissue is expected to infarct unless acute reperfusion therapy can be rapidly initiated.ST segment elevation is presumptive evidence of ACUTE MI.Ischemia
25 The Three I 3. InfarctionThrombusInfarcted AreaElectrically SilentDuring the evolution of an infarct, Q waves, ST elevation, and T inversion may occur together.ST elevation is the most important finding to the emergency care provider. It is presumptive evidence of acute myocardial infarction.IschemiaDepolarization
26 UA Syndromes New onset angina (1 month) Crescendo angina Increased frequency, severity, or duration (prolonged episodes (>10-15min))Decrease in exertion required to provokeAcute coronary syndrome (ACS)Ischemic chest pain >20 minutesOnset at rest or awakening from sleepFailure to abate with >2-3 S.L. NTGPost infarction anginaPrinzmetal’s (variant) angina
27 Unstable AnginaUp to 70% patients sustain MI over the ensuing 3 months>90% of AMI result from an acute thrombus obstructing a coronary artery with resultant prolonged ischemia and tissue necrosis
28 SYMPTOMS SUGGESTIVE OF ACS Definite ACSNoncardiac DiagnosisChronic Stable AnginaPossible ACSNo ST-ElevationST-ElevationTreatment as indicated by alternative diagnosisACC/AHA Chronic Stable Angina GuidelinesST and/or T wave changesOngoing painPositive cardiac biomarkersHemodynamic abnormalitiesNondiagnostic ECG Normal initial serum cardiac biomarkersObserve≥ 12 h from symptom onsetEvaluate for reperfusion therapyNo recurrent pain; negative follow-up studiesRecurrent ischemic pain or positive follow-up studiesDiagnosis of ACS confirmedStress study to provoke ischemiaConsider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient)ACC/AHA STEMI GuidelinesNegativePotential diagnoses: nonischemic discomfort; low-risk ACSPositiveDiagnosis of ACS confirmed or highly likelyAdmit to hospitalManage via acute ischemia pathwayAlgorithm for evaluation and management of patients suspected of having ACS.Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 2.Arrangements for outpatient follow-up
29 Risk Scores TIMI GRACE History Age Hypertension DM Smoking ↑ CholesterolFamily historyHistory of CADPresentationSevere anginaAspirin within 7 daysElevated markersST-segment deviation HR SBPElevated creatinineHeart failureCardiac arrestAntman EM, et al. JAMA 2000;284:835–42. Eagle KA, et al. JAMA 2004;291:2727–33.GRACE = Global Registry of Acute Coronary Events; TIMI = Thrombolysis in Myocardial Infarction.
31 Likelihood That S&S Represent an ACS Secondary to CAD LOW LIKELIHOODINTERMEDIATE LIKELIHOODHIGH LIKELIHOODFEATUREAbsence Of High- Or Intermediate Likelihood Features But May Have:Absence Of High-likelihood Features And Presence Of Any Of The Following:Any Of The FollowingProbable ischemic symptoms in absence of any of the intermediate-likelihood characteristicsRecent cocaine useChest or left arm pain or discomfort as chief symptomAge >70 yearsMale sexDiabetes mellitusChest or left arm pain or discomfort as chief symptom reproducing prior documented anginaKnown history of CAD, including MIHistoryChest discomfort reproduced by palpationExtracardiac vascular diseaseTransient MR murmur, hypotension, diaphoresis, pulmonary edema, or ralesExaminationT wave flattening or inversion less than 1 mm in leads with dominant R wavesNormal ECGFixed Q wavesST depression 0.5 to 1 mm or T wave inversion greater than 1 mmNew, or presumably new, transient ST-segment deviation (≥1 mm) or T wave inversion in multiple precordial leadsECGNormalElevated cardiac TnI, TnT, or CK-MBCardiac markers
32 ACC/AHA System for Risk Stratification of Patients with UA LOW RISK (30 DAYS DEATH/MI RISK: <3%)INTERMEDIATE RISK (30 DAYS DEATH/MI RISK: 3-8%)HIGH RISK (30 DAYS DEATH/MI RISK: 8-15%)FEATURENo High- Or Intermediate-risk Feature But May Have One Of The Following Features:No High-risk Feature But Must Have One Of The Following:At Least One Of The Following:Prior MI, peripheral or cerebrovascular disease, or CABG; prior aspirin useAccelerating tempo of ischemic symptoms in preceding 48 hrHistoryNew-onset or progressive CCS class III or IV angina the past 2 wk without prolonged rest pain but with moderate or high likelihood of CADProlonged rest angina, now resolved, with moderate or high likelihood of CADRest angina <20 min or relieved with rest or sublingual NTGProlonged ongoing (>20 min) rest painCharacter of painAge >70Pulmonary edema, most likely caused by ischemiaNew or worsening MR murmurS3 or worsening ralesHypotension, bradycardia,tachycardiaAge >75Clinical findingsNormal or unchanged ECG during an episode of chest discomfortT wave inversion >0.2 mVPathologic Q wavesAngina at rest with transient ST-segment changes >0.05 mVBBB, new or presumed newSustained VTECGnormalSlightly elevatedelevatedCardiac markers
33 Selection of Initial Treatment Strategy: Initial Invasive Versus Conservative Strategy Recurrent angina/ischemia at rest with low-level activities despite intensive medical therapyElevated cardiac biomarkers (TnT or TnI)New/presumably new ST-segment depressionSigns/symptoms of heart failure or new/worsening mitral regurgitationHigh-risk findings from noninvasive testingHemodynamic instabilitySustained ventricular tachycardiaPCI within 6 monthsPrior CABGHigh risk score (e.g., TIMI, GRACE)Reduced left ventricular function (LVEF < 40%)ConservativeLow risk score (e.g., TIMI, GRACE)Patient/physician presence in the absence of high-risk features
34 Angina: Prognosis LV function Number of coronary arteries with significant stenosisExtent of jeoporized myocardium
35 Unstable Angina / NTMI Pharmacologic Therapy ASA and Heparin beneficial for ACSs (UA, NSTEMI, STEMI)Decrease MVO2 with nitrates, BBs, CCBs, and ACE inhibitorsconsider platelet glycoprotein IIb / IIIa inhibitor and / or LMWH
36 Preparation for Discharge After UA/NSTEMI Antiplatelet RxASA mg/dayClopidogrel 75 mg/dayBeta blockerACEI/ARBEspecially if DM, HF, EF <40%, HTNStatinLDL <100 mg/dL (ideally <70 mg/dL)Secondary prevention measures (control of RF)
37 Pharmacological Therapy for Musculoskeletal Symptoms With Known CVD or Risk Factors for IHD NewAcetaminophen, ASA, tramadol,narcotic analgesics (short term)Nonacetylated salicylatesNon COX-2 selective NSAIDsNSAIDs with some COX-2 selectivityCOX-2 selective NSAIDsSelect pts at low risk of thrombotic eventsPrescribe lowest dose required to control symptomsAdd ASA 81 mg and PPI to pts at ↑ risk of thrombotic events*Regular monitoring for sustained hypertension (or worsening of prior BP control), edema, worsening renal function, or GI bleedingIf these occur, consider reduction of the dose or discontinuation of the offending drug, a different drug, or alternative therapeutic modalities, as dictated by clinical circumstances*Addition of ASA may not be sufficient protection against thrombotic events.Reproduced with permission from Antman EM, et al. Circulation 2007;115:1634–42.PPI = proton-pump inhibitor.
40 Definition of MIDeath of part of the heart muscle due to its sudden loss of blood supply.Often causes chest pain and electrical instability of the heart muscle tissue.
41 Etiology Formation of a blood clot on a cholesterol plaque Occasionally: rupture of the surface of the cholesterol plaque
42 AMI Clinical FeaturesTypical: intense, oppressive chest pressure radiating to left armAtypical – 25% of all AMIsPleuritic or sharp/stabbing CPPalpable CP (10-33% AMI)Arm pain onlyIndigestionSOB only (40% in elderly)“Dizziness” (5% AMI)NauseaSyncope
43 Diagnosis of AMI: ECGDefines location, extent, and prognosis of infarctionST elevation diagnostic of coronary occlusionQ-waves do NOT signify completed infarctionST depression or T inversion: unlikely total coronary occlusionST elevation in V4R for RV infarctionObserve up to 24 hrs for non-diagnostic ECGDifferentiate from early repolarization
44 Acute Myocardial Infarction Wavefront phenomenon of ischemic evolution - endocardium to epicardiumIf limited area of infarction homeostasis achievedIf large area of infarction (>20% LV) congestive heart failureIf larger area of infarction (>40% LV) hemodynamic collapse
52 Timing of Release of Various Biomarkers After Acute Myocardial Infarction Shapiro BP, Jaffe AS. Cardiac biomarkers. In: Murphy JG, Lloyd MA, editors. Mayo Clinic Cardiology: Concise Textbook. 3rd ed. Rochester, MN: Mayo Clinic Scientific Press and New York: Informa Healthcare USA, 2007:773–80.Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 5.
54 Sample Admitting Orders IV access: NS or D5W to KVOVital signs: Q 1/2 hr until stable, then q 4 hr and PRN. Notify if HR <60 or >110; BP <90 or >150; RR <8 or >22.Pulse oximetry x 24 hrsActivity: CBR for 12 hrs, with bedside commode and progress as tolerated after 12 hrsMonitor: 24 hoursDiet: heart-healthy dietMedications: MONA:MorphineOxygen nasal: 2L/min x 3 hrsNitrates: IV NTG for hrs if no / HR or BPAspirin: mg QDβ-blocker: IV→po (if no contraindications): metoprolol 12.5 mg po q6No prophylactic antiarrhythmicsHeparinIV: large anterior MI, PCI, LV thrombus, alteplase/reteplase use (for ~48 hours)SQ: for all other MIClopidogrelGP IIb/IIIa inhibitors (Eptifibatide)ACEi in all MI if no hypotension: captopril 6.25 mg po q8Statin: atorvastatin 80 mg po
55 Indications For Reperfusion ST elevation >0.2 in 2 adjacent chest leadsST elevation >0.1 in 2 adjacent limb leadsDominant R waves and ST depression in V1-V3 (posterior infarct)New LBBB
56 Absolute Contraindications Patients >75 years may get less overall benefit than younger patients but advanced age is no longer considered a major contraindication for TTPrevious hemorrhagic stroke at any time; other strokes or cerebrovascular events within one yearKnown intracranial neoplasm or AVMActive internal bleeding (does not include menses)Suspected aortic dissection
57 Relative Contraindications and Cautions for Fibrinolytics in AMI Severe uncontrolled HTN on presentation (BP >180/110 mm Hg)History of severe poorly controlled chronic hypertensionHistory of prior nonhemorrhagic CVA beyond 1 yr or known intra-cerebral pathology not covered in contraindicationsCurrent use of anticoagulants in therapeutic doses (INR 2-3); no bleeding diathesisRecent trauma (within 2-4 weeks) including head injuryRecent (within 2-4 weeks) internal bleedingActive peptic ulcerKnown bleeding diathesis (e.g., from significant liver dysfunction, or neoplasm)PregnancyFor SK, APSAC, anistreplase: prior exposure (especially within 5 d-2 yrs) or prior allergic reactionPrior central venous or noncompressible vascular puncture Prolonged cardiopulmonary resuscitation (>10 minutes)Recent surgery (<2 weeks) excluding intracranial or spinal surgery which may require a longer interval
58 RisksBleeding is the primary complication of TT and stroke is the greatest concern (1.8%)Stroke: 1.4%. Predictors:Patients with a previous TIA or stroke were at particularly high riskOlder ageSBP >140 mm HgDBP >100 mm HgLower body weightAllergic reactions can be seen in patients treated with SK
59 Complications of AMI Extension / Ischemia Arrhythmia Pericarditis Expansion / AneurysmAMIRV InfarctHeart FailureMechanicalMural Thrombus
60 AMI Management Pharmacologic Therapy on Hospital Discharge Aspirin indefinitely (ticlopidine or clopidogrel for aspirin allergy or intolerance)Beta blockers for at least 2-3 yearsACE inhibitors for CHF, LVEF <40%, or large infarction (even with preserved LVEF)Lipid lowering agentsWarfarin for mural thrombus, extensive anterior infarct, DVT, AF