Coronary Artery Disease

Coronary Arteries

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

Cause

• Ischemia - Imbalance between mycocardial oxygen supply and demand results in hypoxia

• Mostly due to atherosclerotic plaques

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

New Problem?

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

Diagnosis

• Electrocardiogram (ECG)• Echocardiogram• Stress test• Angiogram• CT scan• Magnetic resonance

angiography (MRA)• Bloodwork

– Cholesterol– C-reactive protein– MPO

Development of Atheroscleosis

Stages of Atherosclerosis

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

Established TherapiesNature Medicine 17,1410–1422 (2011)

Thrombolytics

Organic Nitrates

• Prodrugs – source of nitric oxide (NO)– Nitroglycerine– Isosorbide dinitrate, Isosorbide-5-mononitrate– Taken during angina

attack– Dose and freq

dependent tolerance

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

Statins

Lipitor

Zocor

Crestor

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

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

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

Renin Angiotensin Pathway Blockers

Beta Blockers

• Effects– Reduce heart contractility and rate– Reduce Renin secretion by kidneys

• Antihypertensive

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

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

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).

Antiplatelet Drugs

Antiplatelet Drugs

Emerging Therapies

Nature Medicine 17,1410–1422 (2011)

Novel Experimental Strategies

Vaccines targeting LDL or and apoB

Novel Experimental Strategies