5Its also a gland Myocardial injury Fall in LV performance Activation of RAAS, SNS, ET,and othersANPBNPPeripheral vasoconstrictionHemodynamic alterationsMyocardial toxicitySlide 10Left ventricular dysfunction results from myocardial injury. Changes occur in the peripheral circulation that also affect cardiac function and contribute to the symptoms of HF.Vasoconstrictors – those in the sympathetic nervous system and the Renin Angiotensin Aldostrerone (RAA) System, as well as arginine vasopressin and endothelin – become activated to increase afterload and preload by conserving Na+ ions and water. Vasodilators – hormones in the natriuretic peptide system, as well as endothelin – derived relaxing factor and prostaglandins – help to unload the left ventricle and promote natriuretic action. In other words the actions of ANP and BNP counteract the activation of the RAAS and sympathetic nervous system.Remodeling andprogressiveworsening ofLV functionMorbidity and mortalityHeart failure symptoms
6Epidemiology of CHD in the US Single most frequent cause of death656,000 deaths in 20021 of every 5 deathsIncidenceEach year, 1.2 million Americans will have a new or recurrent coronary event, and >40% will die as a result700,000 events will be first attacks; 500,000 will be recurrencesPrevalence13 million Americans have a history of CHD (acute MI, other acute ischemic (coronary) heart disease, angina pectoris, atherosclerotic cardiovascular disease, and all other forms of heart disease)CHD = coronary heart disease; MI = myocardial infarction. American Heart Association. Heart Disease and Stroke Statistics—2005 Update; 2005.
7Epidemiology of CHD Scotland Single most frequent cause of deathIncidencePrevalenceCHD = coronary heart disease; MI = myocardial infarction. American Heart Association. Heart Disease and Stroke Statistics—2005 Update; 2005.
8Risk for CHD Increases With Additional Risk Factors: INTERHEART Study 5122561286432168421Odds ratio (99% Cl)Smk(1)DM(2)HTN(3)ApoB/A1(4)1+2+3All 4+Obes+PSAll RFsPS = psychosocialYusuf S, et al. Lancet. 2004;364:
9Odds Ratio for 1st MI (99% CI) INTERHEART: Impact on CV Risk of Multiple Risk Factors (Smoking, Lipids, Hypertension, Diabetes, Abdominal Obesity, Diet, ↓Physical Activity, Alcohol, Psychosocial*)512– Large int’l case-control study – 15,152 cases – 14,820 controls – 52 countries – Follow-up: 4 years2561286432Odds Ratio for 1st MI (99% CI)16Smk = smokingDM = diabetesHTN = hypertensionObes = abdominal obesityPs = psychosocial factors84Design Large international case-control studyParticipants 15,152 cases; 14,820 controls; 52 countriesObjective To determine association of first MI with: Smoking Lipids Hypertension Diabetes Abdom.Obes. Diet Physical Alcohol Psychosocial activity consumption factors (eg, stress, depression)Follow-up 4 years, February 1999–March 2003Clinical Implications9 simple and modifiable risk factors are strongly associated with acute MI worldwide• These 9 risk factors account for >90% of the population attributable risk globally and in most regions• Implementing preventive strategies based on our current knowledge would prevent the majority of premature CHD worldwide21Smk (1)DM (2)HTN (3)ApoB- ApoA1 (4)1+2+3All 4All 4 + ObesAll 4 + PsAll risk factors*eg, stress, depressionNote: odds ratio plotted on a doubling scale..Yusuf S, et al. Lancet. 2004;364:Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet. 2005;366:
11Symptoms of CAD NONE…….. Sudden Cardiac Death Chest Pain Usually a pressureNot secondsAnginal equivalentsJaw or shoulder painNausea & vomitingShortness of breathWeak & dizzyDiaphoresis
12Symptoms of Heart Attack Anginal equivalentsJaw/shoulder painNausea & vomitingShortness of breathWeak & dizzyDiaphoresisClassic presentationChest pressureElephantSweatingNausea/vomitingRadiation of painShortness of breath
14Options for Transport of Patients With STEMI and Initial Reperfusion Treatment Hospital fibrinolysis:door-to-needlewithin 30 minNot PCIcapableCall 9-1-1Call fastEMS on-sceneEncourage 12-lead ECGsConsider prehospital fibrinolytic if capable and EMS-to-needle within 30 minOnset of symptoms of STEMI9-1-1EMSdispatchEMS triage planInter-hospitaltransferPCIcapableGOALS5min8minEMS TransportPatientEMSPrehospital fibrinolysisEMS-to-needlewithin 30 minEMS transportEMS-to-balloon within 90 minPatient self-transportHospital door-to-balloonwithin 90 minThis slide summarizes the essential concept of a triage plan for patients with chest pain and underscores the importance of time-to-treatment. Effective treatment delivered within the “Golden Hour” following symptom onset and reducing the total ischemic time to less than 2 hours preserves myocardium and is associated with reduced mortality.For patients with STEMI, reperfusion may be accomplished by fibrinolysis or primary angioplasty. The choice of specific strategy depends on how the patient is being transported and the capabilities of the receiving hospital. The objective is to keep the total ischemic time to 120 minutes or less:Prehospital fibrinolysis should be started within 30 minutes of the arrival of EMS if EMS has fibrinolytic capability and the patient meets the criteria for fibrinolysis;Door-to-needle time should be 30 minutes or less for patients who are fibrinolysis candidates when EMS does not have fibrinolytic capability;Door-to-balloon time should be 90 minutes or less when fibrinolysis is not an option and transport to a PCI-capable hospital is an option..Dispatch1 minGolden hr = 1st 60 minTotal ischemic time: within 120 minAdapted with permission from Antman EM, et al. Available at:Accessed November 1, 2005.Antman EM, Anbe DT, Armstrong PW, et al, American College of Cardiology, American Heart Association, Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:
15What happens in the Ambulance? Paramedics take your history and perform a brief examIVOxygenPut on the monitorMay receive nitroglycerin under the tongue. (tingle, get a H/A)Maybe: ECG, thrombolytic (clot dissolver)
17ED Visits - US 130,000,000 annually 10.4 M chest pain (8.0%) 6.24 M suspected or actualcardiac4.1 Msent home non-cardiac50,000 MIs3.1 Mnon-cardiac(50%)1.2 MAMI(20%)1.5 MUA(24%)374,400sudden death(6%)
18Spectrum of Acute Coronary Syndromes PresentationIschemic Discomfort at RestNo ST-segmentElevationST-segmentElevationEmergencyDepartmentCardiacMarkers–+++In-hospital6-24 hoursUnstable Angina (UA)Non-Q-wave MI(NSTEMI)Q-wave MI(STEMI)Adapted from Braunwald E, et al. Available at:
19STEMI: Brief Physical Exam in the Emergency Department Airway, Breathing, Circulation (ABC)Vital signs, general observationPresence or absence of jugular venous distensionPulmonary auscultation for ralesCardiac auscultation for murmurs or gallopsPresence or absence of strokePresence or absence of pulsesPresence or absence of systemic hypoperfusion (cool, clammy, pale/ashen)Antman EM, et al. Available at: Accessed November 1, 2005.
20STEMI: Acute Medical Therapy General treatmentmeasuresAnalgesicsNitratesOxygenβ-blockers (decrease heart rate)Primary PCI or coronary thrombolysis (primary PCI preferred after 3 hours)Aspirin ( mg, acute dose)HeparinIf PCI:– Clopidogrel– GP IIb/IIIa inhibitorsInfarct sizelimitationReperfusionAntithrombotic and antiplatelet therapyAntman EM, et al. Available at: Accessed November 1, 2005.
21Chest Pain on a Saturday morning While the physician was examining the ECG, the patient became unconscious and the rhythm on the monitor changed…
22Chest Pain on a Saturday morning 12:01 100J DC cardioversion, patient immediately in NSR12:03 Clot box brought to room and catheterization lab team notified12:04 IV line started, 325 mg aspirin chewed and metoprolol given12:10 Open cath table and staff available, heparin iv and clopidogrel po given12:19 Patient’s stretcher rolls
23Goals of Reperfusion Therapy PatientTransportIn-hospitalReperfusionD-N ≤ 30 min5 min< 30 minD-B ≤ 90 minMethods of Speeding Time to ReperfusionMedia campaignPatient educationGreater use of 9-1-1MI protocolCritical pathwayQuality improvement programBolus lyticsDedicated PCI teamPrehospital ECG and Prehospital Rx, if possibleAdapted with permission from: Antman EM, et al. Available at: Accessed November 1, 2005.
24Time from Symptom Onset to Treatment Predicts 1 Year Mortality—Primary PCI The relative risk of 1 year mortality increases by 7.5% for each 30 minute delay.Roughly 1% every 3 minutesY=2.86 (± 1.45) X X2 P<.001De Luca G, et al. Circulation. 2004;109:
25Meta-analysis of 50,246 Patients in Lytic Trials (Juice to squeeze) per 1000 treated patientsAbsolute benefit204060803691215182124Time to TreatmentBoersma E, et al. Lancet.1996;348:771
26Primary PCI vs Thrombolysis in STEMI: Meta-analysis (23 RCTs, N=7739) 25Short-term Outcomes(4-6 weeks)P<.0001Bonferroni correction6 variables: p <0.008320P<.000115P=.0002P<.0001Frequency (%)PCIP=.03210Thrombolytic therapy5P<.0001This meta-analysis encompassed 23 trials in which 3872 patients with STEMI were randomized to primary percutaneous transluminal coronary angioplasty (PTCA) and 3867 patients were randomized to thrombolytic therapy. Stents were used in 12 of the 23 trials and in 8 trials GP IIb/IIIa inhibitors were used.Results indicated that the incidence of every short-term clinical outcome of interest was significantly higher in patients receiving thrombolytic agents than it was in those who underwent primary PTCA.Results with PTCA continued to be superior to those with thrombolysis during long-term follow-up and were independent of the type of thrombolytic agent used (76% received a fibrin-specific agent rather than streptokinase) and whether or not the patient was transferred to primary PTCA.DeathNonfatalMIRecurrentIschemiaHemor-rhagicStrokeMajorBleedDeath, NonfatalReinfarction,or StrokeAdapted with permission from Keeley EC, et al. Lancet. 2003;361:13-20.Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13-20.
27What if the ECG is not diagnostic? (As it is in >95%)
28Blood Markers Necrosis Something has to die Strain Natriuretic peptidesOtherInflammationPlaque ruptureIschemia changes the blood
29ACS Sequence and Timing All IschemiaSome Ischemia, Some NecrosisAll NecrosisPlaque RuptureOnset of PainED PresentationDischarge-12 to 0 hrs12 to 24 hrsAmount of TissueTimeIMAcTnIschemiaMuscle deathVentricular OverloadBNP<> means click the mouse to advance to next in animationWe start with a time line of events in an ACS presentation <>A plaque ruptures, which leads to chest pain, which provokes a patient to present to the hospital emergency room, and we label presentation as time zero <>Looking at the amount of tissue involved <>, we can see that the tissue starts ischemic, and prolonged ischemia leads to necrosis, or infarct. <>IMA rises rapidly with the onset of ischemia, and we believe starts to fall as more of the muscle converts from ischemic to necrotic <>Troponin, on the other hand, starts to rise slowly with the onset of necrosis, peaks at about 24 hours after presentation (6 hours or so after all the tissue is necrotic and no more is ischemia), and falls slowly over several days. <>BNP rises once the remaining healthy muscle is required to compensate for the lost pump function of the heart, and therefore may be elevated at the time of discharge. <>Therefore, there is a progression from ischemia (IMA), to necrosis (troponin) to muscle overload (BNP). These three markers together reveal what is happening during the ACS event.BNP
30Appearance of necrosis markers 10203040506070802468121824324872Hours After Onset of MICKMBMyoglobinTnIHospital arrivalEstablished release kinetics of necrosis markers have consistently demonstrated the sequential release of myoglobin, CKMB and Troponin, respectively. The early rise of myoglobin is also met with an early decline (within 12 hours), making this an important, dynamic surveillance marker in the initial hours post event. It’s dynamic nature also documents the potential value of rapid sequential testing of myoglobin as a way of confirming an acute event vs a pre-existing non cardiac necrotic source. CKMB has greater specificity, is a standardized and trusted immunoassay, and is released within a few hours post AMI. Finally, cardiac Troponin is a highly specific marker but lacks good sensitivity in the first few hours post event.It is clear that these markers complement each other in providing early sensitivity Myoglobin/CKMB with better specificity Troponin I & T. Studies have examined the potential role of using these markers in a panel approach vs any single marker in isolation.
31Disease vs Events? Oxygen supply diminishes with disease progression TimeOxygenOxygen supply diminishes with disease progressionOxygen demand changes daily and during lifeIschemia occurs when O2 demand exceeds supply
33What is IMA?Human Serum Albumin (HSA) is a circulating protein in blood with a metal binding site at the N-terminus.The N-terminus is altered during an ischemic event, resulting in Ischemia Modified Albumin (IMA™). IMA is unable to bind metals at the N-terminus.Ischemia Modified Albumin = IMAHSA is the most common protein in blood.There is a metal binding site at the N-terminus of IMA – for transition metals copper, cobalt and nickel.It was discovered that exposure to ischemic tissue alters the end terminus of HSA in such a way that it can no longer bind metals.The conversion of HSA to IMA is mediated by free radical production (see later slides). The organ specificity (ie: to myocardial ischemia) is not well understood.Bar Or et al, European Journal of Biochemistry, 2001
34Chest Pain at Presentation 12% ACS13% Rule Out75% Grey ZoneCurrent EP ProtocolEP Protocol with good NPV ischemia marker25% ACS35% Rule Out40% Grey ZoneWithout IMA, the chest pain challenge is what to do with 75% of chest pain patients for whom a diagnosis can not be made at presentation, and therefore are subjected to serial blood draws, and other time consuming and expensive procedures such as provocative testing, myocardial perfusion imaging, echocardiography, angiography, and so on.With IMA, the number of patients who can be discharged early is almost three times as many (the test presently only has indications for use as a rule out).The potential value of a positive IMA test is to expedite diagnostic evaluation or suggesting more rapid or intensive therapy in higher risk patients.Therefore number of patients in the “Grey Zone” is considerably reduced.Excellent clinical data exists to show the value of IMA as a rule out, and additional clinical studies are under way to investigate the value of IMA as a rule in.
35What if the markers are all negative? (And they are in >90%)
36If It Moves, Even Below Your Hospital’s Cutpoint, It Is Bad MarkerComparatorOR for 30 day MACE95% CIing Tnvs. stable Troponin2.25ing Tn3.04ing CKMBvs. stable CKMB0.67ing CKMB0.96Logistic regression models showing the odds ratios for predicting ACSMACE: MI, revascularization (PCI or CABG), or positive testing (>70% stenosis atcatheterization, [+] MPI or non-invasive stress testing) within 30 days of index visit.
37All this testing… What’s the end result? Most (88%) of the time, its negativeYou go home18% of the time, something is positiveECG IMMEDIATE Cath labMarker URGENT Cath labStress test Semi-elective Cath lab
38What happens in the Cath Lab? Define the anatomyAcutely closed vessel fix itChronically closed vessel nothingStenotic vessel: have options~50%; either medicine or angioplasty works>70%; most get angioplasty
40Prevalence of coronary heart disease in Scotland: Scottish Heart Health Study. 10,359 men and women aged years from 22 districts in the Scottish Heart Health StudyDescribed the prevalence rates of coronary heart disease in Scotland in and their relation to the geographical variation in mortality in these districts.Coronary heart disease in Scotland was the highest reported to the WHO fromAngina was more common in men (5.5%) than in women (3.9%)A history of MI was 3 times more common in men than womenAngina correlated well with mortality from coronary heart diseaseBr Heart J Nov;64(5):295-8
412001: The good newsThe Cardiovascular Epidemiology Unit at the University of Dundee celebrated its 20th anniversary with a 40 % decline in coronary mortality rateThe steep decline in coronary mortality in Scotland mirrors the pattern in the rest of Britain.Improvement is a combination of:Heightened awareness of health issuesImproved diet and more exerciseImprovement in treatments.Scotland's record on heart disease is much improvedRussia now has the highest coronary mortality rate.
422003 British Women's Heart and Health Study 20% MI, angina, HF, CVA, PVD.50% HTN, 12% smoked, 25% obese50% w/ total cholesterol > 6.5 mmol/l, only 3% had low HDLAge adjusted CVD prevalencehighest in Scotland: 25.0% (21.5% to 28.8%)lowest in S. England: 15.4% (13.5% to 17.6%).Woman in Scotland are 1.53 times more likely to have CVDOf women with CVD12% are smokers, 1/3 had uncontrolled HTN, 1/3 were obese90% had a cholesterol > 5 mmol/l.Only 41% were taking antiplatelet drugs and 22% were taking a statin.Journal of Epidemiology and Community Health 2003;57:
43In Scotland Coronary Heart Disease one of the leading causes of death 10,331 deaths in 2005Scotland has one of the highest death rates from CHD in the western worldDue tohigh rates of smokingpoor dietdeprivation
44In the year ending March 31 2006 Scottish hospitals48,962 hospital discharges for CHD16,320 were for AMI(heart attack)CHD discharges represented around 4% of all acute hospital discharges.NHSScotland carried out2,319 Coronary Artery Bypass Grafts 5,803 angioplasties17,065 angiographies
45http://www.isdscotland CHD mortality is strongly related to age. 0-44 year olds is 4.1 per 100,00075+, the rate is per 100,000The incidence of CHD is higher in men, elderly and deprived areas of ScotlandSmokingbeing overweightraised blood pressureraised level of cholesterol
46Cost of Cardiovascular Disease in the UK CVD cost the UK £29.1 billion in 2004(exceeds the GDP of Kuwait)29% (£8.5 billion) was due to Coronary Heart Disease27% (£8.0 billion) Cerebrovascular DiseaseCVD Cost break down60% health care23% productivity losses17% informal care-related costsConclusions:CVD is a leading public health problem in the UK measured by the economic burden of disease.Heart 2006;92:
47Small changes in UK cardiovascular risk factors could halve CHD mortality The UK called for a 40% reduction in CVD mortality by 2010.Potential reductions from the year 2000, were calculated for:Continuation of recent risk factor trends~10,685 fewer CAD deaths in 2010 than in 2000Modest additional reductions in cholesterol and smoking~51,270 fewer deathsOptimistic changes in obesity, DM, and physical activity, would have relatively small effects.Journal of Clinical Epidemiology 58 (2005) 733–740