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Treatment of Myocardial Infarction • Epidemiology • Pathogenesis – Where do lesions form – How lesions grow • Treatment of the sequelae of myocardial infarction (MI) – Ventricular arrhythmias – Congestive heart failure (CHF) – Stem cells Myocardial infarction • 700,000 new and 500,000 recurrent heart attacks in U.S. in 2007. • 653,000 deaths/yr in U.S. due to coronary artery disease • Estimated cost (2007): $150 billion. – Cholesterol-lowering medications: $14 billion. – 1.28 million PTCA/coronary angioplasties/stents – 427,000 coronary artery bypass surgeries Circulation. 2007;115:e69-e171. Economic costs of heart disease Circulation. 2007;115:e69-e171. http://www.who.int/cardiovascular_diseases/en/cvd_atlas_14_deathHD.pdf Crude Death Rates for Leading Causes of Death in the United States from 1900 to 1950 Braunwald, E. N Engl J Med 1997;337:1360-1369 Changes in Age-Adjusted Death Rates from Coronary Heart Disease (CHD), Stroke, and Noncardiovascular Disease (Non-CVD) in the United States from 1950 to 1995 Hypertension and hypercholesterolemia linked to CHD ….. x Surgeon General’s report on smoking. Braunwald, E. N Engl J Med 1997;337:1360-1369 Traditional risk factors for MI • Hypertension (Borderline 120-139/80-89) • Hypercholesterolemia – LDL (Borderline 100-159 mg/dl) – HDL (Borderline 40-59 mg/dl) • Diabetes mellitus (Borderline fasting glucose 110- 125 mg/dl) • Cigarette smoking ~ only 10% of all patients with CAD will not have any of these known risk factors. Ann Intern Med 142:393-402, 2005 Proposed Mechanism for Fatty Streak Formation Andrew Watson, M.D., Ph.D. Where do lesions form? Predilection sites occur at areas of low shear stress and oscillatory flow. Circ Res 53:502-514, 1983 How do lesions grow? * 40% Outward remodeling Inward remodeling • Plaques initially grow outward within the vessel wall (“outward remodeling”) instead of inward toward the lumen • Inward remodeling* is associated with vulnerability to rupture. Naghavi, M. et al. Circulation 2003;108:1664-1672; NEJM 316:1371-5, 1987 Episodic plaque growth by intraplaque hemorrhage from vasa vasorum RBC Arterioscl Thromb Vasc Biol 25:2054-2061, 2005; N Engl J Med 349:2316-25, 2003 Modeling to calculate effect of calcification on plaque stress distribution J Am Coll Cardiol 46;1507-15, 2005 The clinical event: Myocardial infarction • Formation of plaque (decades, no symptoms) • Plaque rupture (60-70%) or erosion (30-40%) Lusis, A. J. et al. Circulation 2004;110:1868-1873 Animation of thrombus Acute sequelae of MI • Unstable cardiac rhythms (Ventricular tachycardia or fibrillation: VT/VF) • Loss of pump function (Congestive heart failure: CHF) Immediate Sequelae of MI Unstable electrical rhythm (ventricular tachycardia and fibrillation – VT or VF) Approximately 1/3 of patients with MI die before reaching the hospital or in the ER, probably from VF. Immediate Sequelae of AMI Poor pump function or congestive heart failure (CHF) can result if too much of the myocardium is damaged. Therefore the focus of treatment of AMI is restoration of blood flow within the first six hrs. Acute Treatment of MI • Plaque rupture or erosion Aspirin Heparin ADP receptor blockers Inhibit further GP IIb/IIIa inhibitors clot formation Restore blood Thrombolytic agents Angioplasty Surgery flow. • Sequelae of MI – Loss of pump function: CHF ACEI – Loss of stable electrical rhythm Beta blockers Antiarrhythmics • Cholesterol and Inflammation Statins ACEI = angiotensin converting enzyme inhibitors Estimated Short-Term Mortality from Acute Myocardial Infarction in the United States in Different Eras Braunwald, E. N Engl J Med 1997;337:1360-1369 Long-term treatment of MI • Plaque rupture or erosion Aspirin Heparin ADP receptor blockers Inhibit further GP IIb/IIIa inhibitors clot formation • Sequelae of MI – Loss of pump function: CHF ACEI, b-blockers, aldosterone antag. – Loss of stable electrical rhythm Antiarrhythmics Defibrillators b -blockers • Cholesterol and Inflammation Statins What if the patient continues to have CHF despite medications? • Biventricular pacemakers to synchronize contraction • Heart transplantation • Assist devices 6000-8000 patients each yr are added to the transplant waiting list. 2, 125 in 2005 ~ 17% of patients on the waiting list die before a new heart is available. Cardiac Support Devices (CSD) Prevents dilatation. Improves collagen content. Unpublished reports indicate that CSD decreases need for transplant or assist devices. www.paracorsurgical.com Components of the Left Ventricular Assist Device Survival 50% at 1 yr (cf. 50% 10 yr survival with transplantation). Death due to infection (41%), device failure (17%). 10-30% may have a stroke or cerebral bleed. Rose, E. A. et al. N Engl J Med 2001;345:1435-1443; Circulation 2005:112:e111-115. MicroMed Debakey VAD 1” Only moving part at 10000 rpm. Treatment of Myocardial Infarction (MI) • Scope of the problem • Pathogenesis • Treatment of the sequelae of myocardial infarction (MI) – Ventricular arrhythmias – Congestive heart failure (CHF) • Newer concepts – Identifying “vulnerable” lesions – Role of inflammation – Stem cells Cotran 6th ed. Identifying the vulnerable plaque • Not size • Neovascularization • Thin cap with large lipid core – Intravascular ultrasound+elastography – Optical coherence tomography – MRI • Active inflammation Circulation 106:804-8, 2002 Detecting only flow-limiting lesions will miss future heart attacks 2/3 of plaque rupture occur in vessels with <50% stenosis J Am Coll Cardiol 22;1141-1154, 1993 Imaging of neovascularization by contrast-enhanced ultrasound [bubbles coated with echistatin (binds avb1 a5b1)] Circulation 111:3248-54, 2005 Targeting of neovascularization with nanoparticles (MRI) Magn. Reson. Med. Vol.53, 3 Pages: 621-627 IVUS elastography: High strain areas correlate with high lipid content Circulation 102:617-23, 2000 Thin cap with large lipid core as seen by Optical Coherence Tomography JACC 37:1277-83, 2001; Circulation 107:113-9, 2003 Plaque characterization by MRI Circulation 101:2503-9, 2000 Active inflammation/macrophage infiltration • Thermography: Increased temperature was prognostic for recurrent angina, MI or death (41 vs 7%) in patients who are undergoing PTCA. • Diffuse near-infrared reflectance spectroscopy (based on the abs of light by organic molecules) JACC 37:1277-83, 2001; Circulation 107:113-9, 2003; Circulation 105:923-7. 2002 Once we identify the vulnerable plaque, can we prevent MI? Maybe not. • In patients with plaque rupture leading to symptoms, 80% were shown to have 1-5 other plaque ruptures that did not cause symptoms. • There is widespread inflammation throughout the coronary vascular bed Circulation 106:804-8, 2002; NEJM 347:5-12, 2002 Traditional modifiable risk factors for MI • Diabetes mellitus • Cigarette smoking • Hypertension • Hypercholesterolemia The most effective drugs in lowering cholesterol levels are Statins Statins • Block HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis • In patients with a history of angina or MI who start statins, it takes about 2 years before a decrease in cardiac events is seen. • In patients with acute MI, it takes only 4 mo of statins to decrease the number of recurrent ischemic events. • In addition to its cholesterol-lowering properties, statins have been shown to be anti-inflammatory. Lancet 344:1383-9, 1994; JAMA 285:1711-18, 2001; Circ 108:1560-6, 2003 Identifying the vulnerable plaque: Can we prevent MI? Yes, with statins. • In patients with plaque rupture leading to symptoms, 80% were shown to have 1-5 other plaque ruptures that did not cause symptoms. • There is widespread inflammation throughout the coronary vascular bed Circulation 106:804-8, 2002; NEJM 347:5-12, 2002 Relationship Between Mean Low-Density Lipoprotein Cholesterol Levels and Median Change in Percent Atheroma Volume for Several Intravascular Ultrasound Trials: The lower the LDL, the better Nissen, S. E. et al. JAMA 2006;295:1556-1565. News Return to article Nature Published online: 4 January 2006; | doi:10.1038/43900 8a Blow follows blow for stem-cell work Your cells help you back to health Coronary artery disease (CAD) is the most common form of heart disease or cardiovascular disease, affecting almost 1.3 million Americans. CAD and its complications, such as heart attack and angina pectoris, are the leading causes of death in the United States in both men and women. While standard treatment can help most, the rest still live in pain with little or no hope. Contact Us http://www.vescell.com/ Chaophya Hospital, Bangkok $ 35,000 (including airfare, hotel) Contact Us Mount Elizabeth Hospital, Singapore Phyathai Hospital, Bangkok Bangkok Heart Hospital, Bangkok Gleneagles Hospital, Singapore Cardiac cell dogma • Human cardiac tissue cannot regenerate. • Cardiac cells respond to stress or injury by hypertrophy, not hyperplasia • ? Loss of regenerative capacity related to an advanced immune system Lancet 364:183-92, 2004 Cardiac cell dogma Cardiac cell biology • Human cardiac tissue • Cardiac cells can cannot regenerate. regenerate, albeit • Cardiac cells respond limited potential. to stress or injury by • Stem cells present in hypertrophy, not the bone marrow and hyperplasia heart can help improve • ? Loss of regenerative cardiac function after capacity related to an myocardial infarction. advanced immune system Lancet 364:183-92, 2004 Mechanism: Controversial/unknown Circ 114:339-352, 2006 Randomized controlled trials of stem cell therapy in patients with MI N=67 N=60 N=100 N=204 (2006) (2004) (2006) (2006) Infusion 1 d Infusion ~ 6 Infusion 5-8 Infusion 3-7 after MI days after days after days after MI/stent MI/stent MI/stent No change in LVEF No change in LVEF contractility. (52% to 57%) contractility. (50% to 54%) Increased glucose metabolism after stenting and stem cell infusion post-MI Before and after stenting and stem cell infusion European J Nuc Med and Mol Imaging 31:1146-51,2004 Molecular imaging of stem cell survival, proliferation and migration using bioluminescence and PET Circulation 113:1005-14, 2006 Summary • Hypertension, LDL, HDL, diabetes and smoking account for 90% of cardiac events. • Myocardial infarctions occur when plaques rupture or erode, leading to clot – Vulnerable plaques are characterized by new vessels, large lipid core, thin cap and inflammation. – Therapies are focuses to inhibit clot formation, restoration of blood flow (angioplasty, bypass surgery), preventing unstable heart rhythms and negative remodeling, and decreasing inflammation. • Current and future biophysical research focused on identifying vulnerable plaques, tracing fate of stem cells, building drug delivery systems.
"Treatment of Coronary Artery Disease"