Coronary Artery Disease

1. Coronary Artery Disease

2. Coronary Arteries

3. Coronary Artery Disease • AKA Ischemic Heart Disease or Coronary Heart Disease • 82.6 million American adults have CVD • 16.3 million have CHD or CAD • 7.9 million have had an AMI • 7 million have had a stroke • CHD caused 1 of 6 deaths in the US 2007 • CHD is the single largest killer of US adults • Every 25 secs someone has a coronary event • Every minute someone will die from a coronary event AHA stats 2011

4. Cause • Ischemia - Imbalance between mycocardial oxygen supply and demand results in hypoxia • Mostly due to atherosclerotic plaques

5. Risk Factors • Obesity/Inactivity • Hyperlipidemia • LDL • Smoking • Hypertension (≥ 140/90 or on meds) • Low HDL (<40) • Diabetes mellitus • Type A personality (stress) • Age • Men ≥ 45 or women ≥ 55 • Family history of CHD • Before 55 for male or before 65 for female

6. New Problem?

7. Clinical Presentation • Silent Ischemia • Angina pectoris (chest pain) • Description – heavy pressure • Location – over the sternum, left arm, jaw • Radiation – left shoulder, jaw • Duration – 0.5-30 minutes • Nitroglycerin relief • Stable or Unstable • Myocardial Infarction

8. Diagnosis • Electrocardiogram (ECG) • Echocardiogram • Stress test • Angiogram • CT scan • Magnetic resonance angiography (MRA) • Bloodwork • Cholesterol • C-reactive protein • MPO

9. Development of Atheroscleosis

10. Stages of Atherosclerosis

11. Intervention • Many of these therapeutics can not reverse the atherosclerotic scarring. • Pharmacological and Lifestyle • Treatment of Angina • Prevent thrombosis • Reduce further plaque formation/progression • Dissolve blood clots • Invasive procedures • Angioplasty • Stent • Bypass

12. Nature Medicine 17,1410–1422 (2011) Established Therapies Thrombolytics

13. Organic Nitrates • Prodrugs – source of nitric oxide (NO) • Nitroglycerine • Isosorbidedinitrate, Isosorbide-5-mononitrate • Taken during angina attack • Dose and freqdependent tolerance

14. Statins • Competitive inhibitors of HMG-CoA reductase • Decreased cholesterol synthesis • Increased expression of the LDL receptor gene • Reduce LDL levels • Documented in reducing fatal and nonfatal CHD events, strokes, and total mortality • Adverse effects were similar in placebo and drug groups

15. Statins Zocor Lipitor Crestor

16. Effects on Triglycerides & Lipoprotein Levels • Decrease triglycerides in hypertriglyceridemia • 35-45% • Increase HDL-C • Normal patients: 5-10% • Low patients: 15-20% • Decrease LDL-C • 20-55% • Non-lipid lowering effects • Endothelial function (Enhances production of nitric oxide) • Anti-inflammatory • Reduce venous thromboembolic events • 43% • Adverse Effects • Hepatotoxicity • Elevated hepatic transaminase values • One case of liver failure per million person-years of use • Myopathy • One death per million prescriptions caused by rhabdomyolysis

17. Niacin (Nicotinic Acid) • Inhibits the lipolysis by hormone-sensitive lipase • Reduces transport of free fatty acids to the liver • Decreases hepatic triglyceride synthesis • May inhibit diacylglycerol acyltransferase-2 • Rate-limiting in triglyceride synthesis • Reducing triglyceride synthesis reduces hepatic VLDL production • Raises HDL levels by decreasing the fractional clearance of apoA-I in HDL

18. Effects on Lipoprotein Levels & Adverse Effects • Increases HDL: 30-40% • Lowers triglycerides by 35-45% • Reduces LDL: 20-30% • Half-life: 60 minutes • Requires 2-3 doses/day • Therapeutic Use • Hypertriglyceridemia and low HDL levels • Adverse Effects • Flushing • Dyspepsia • Hepatotoxicity • Hyperglycemia

19. Renin Angiotensin Pathway Blockers

20. Beta Blockers • Effects • Reduce heart contractility and rate • Reduce Renin secretion by kidneys • Antihypertensive

21. Propranolol (Inderal) • First β-blocker discovered • Nonselective • Prototypical drug • Competitive antagonist • Equal affinity for β1 and β2 • Pure antagonist • Pharmacokinetics • Oral absorption: 95-98% • Metabolized by the liver • Renal excretion • Half-life: 3-6 hours • Clinical Use • Hypertension • Angina • Management of life-threatening arrhythmias • Prevention of myocardial infarction, migraine and anxiety disorders • Adverse Effects • Bradycardia • Hypotension

22. Metoprolol (Lopressor) • Second leading prescription drug in 2007 • β1 selective • First one • Equipotent to propranolol in inhibiting β1 but 50-100 fold less potent at β2 • Pure antagonist • Pharmacokinetics • Oral absorption: 50% • Metabolized by the liver • Renal excretion • Some in feces • Half-life: 3-5 hours • Clinical Use • Hypertension • Angina • Tachycardia • Heart failure • Prevention of migraines • Adverse Effects • Hypotension • Depression • Vision problems

23. Calcium channel blockers • Relax blood vessels • Increase the supply of blood and oxygen to the heart while • Reduce the heart's workload • Norvasc (amlodipine) • Plendil (felodipine) • Cardizem, Cardizem CD, Cardizem SR, Dilacor XR, Diltia XT, Tiazac (diltiazem) • Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM (verapamil) • Adalat, Adalat CC, Procardia, Procardia XL (nifedipine) • Cardene, Cardene SR (nicardipine) • Sular (nisoldipine) • Vascor (bepridil) • Caduet is a combination of a statin cholesterol drug and amlodipine (above).

24. Antiplatelet Drugs

25. Antiplatelet Drugs

26. Emerging Therapies Nature Medicine 17,1410–1422 (2011)

27. Novel Experimental Strategies Vaccines targeting LDL or and apoB

28. Novel Experimental Strategies