Advances in the Science of Cholesterol Management

A Clinical Overview

Normal Arterial Wall

Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cells Elastic/collagen fibers External elastic membrane

Development of Atherosclerotic Plaques

Fatty streak Normal Lipid-rich plaque Foam cells Fibrous cap

Thrombus

Lipid core

Vulnerable vs Stable Atherosclerotic Plaques

Lumen
Fibrous Cap
Lipid Core

Vulnerable Plaque Thin fibrous cap Inflammatory cell infiltrates: proteolytic activity Lipid-rich plaque Stable Plaque

Lumen

Lipid Core

Fibrous Cap

Thick fibrous cap Smooth muscle cells: more extracellular matrix Lipid-poor plaque

Libby P. Circulation. 1995;91:2844-2850.

Plaque Stabilization
Unstable plaque
Fibrous cap Fibrous cap

Stable plaque

Inflammatory cells

Fewer inflammatory cells Lipid core Lipid core

Toschi V et al. Circulation. 1997;95:594-599; Libby P. Circulation. 1995;91:2844-2850.

Thrombosis Influences the Severity of a Cardiovascular Event

Nonocclusive thrombus
Unstable angina NonQ-wave MI

Occlusive thrombus
Q-wave MI Sudden death

Factors limiting thrombosis: Minor plaque disruption High flow Low thrombotic tendency

Factors favoring thrombosis: Major plaque disruption Low flow or vasospasm Thrombotic tendency

Kullo IJ, et al. Ann Intern Med. 1998;129:1050-1060.

Clinical Manifestations of Atherosclerosis

Coronary heart disease
Stable angina, acute myocardial infarction, sudden death, unstable angina

Cerebrovascular disease
Stroke, TIAs

Peripheral arterial disease

Intermittent claudication, increased risk of death from heart attack and stroke

American Heart Association, 2000.

Risk Factors for CHD

Modifiable
Dyslipidemia
Raised LDL Low HDL Raised TGs

Nonmodifiable
Age : male 45 years female 55 years Sex Family history of premature CHD

Smoking Hypertension Diabetes mellitus Obesity Dietary factors Thrombogenic factors Sedentary lifestyle

CHD in male first-degree relative <55 years CHD in female first-degree relative <65 years

Wood D, et al. Atherosclerosis. 1998;140:199-270.

Lower Cholesterol Levels Associated With Lower CHD Risk

150

CHD Incidence per 1000

The Framingham Heart Study

125 100 75 50 25 0 204 205-234 235-264 265-294 295

Serum Cholesterol (mg/100 mL)

Castelli WP. Am J Med. 1984;76:4-12.

Relation of Serum Cholesterol to CHD Mortality

4

The MRFIT Study

3.42

Mortality Relative Risk

2
1.73

2.21

1.29

n = 356,222 (35-57 yrs)

0 < 182 182-202 203-220 221-244 > 244

Serum Cholesterol (mg/dL)

Stamler J, et al. JAMA. 1986;256:2823-2828.

LDL Cholesterol
Remains the cornerstone of dyslipidemia therapy1 Strongly associated with atherosclerosis and CHD events1 10% increase results in a 20% increase in CHD risk1 Most patients with elevated LDL untreated
Only 4.5 million out of 28.4 million treated 2,3
1. Wood D et al. Atherosclerosis. 1998;140:199-270. 2. National Centre for Health Statistics. National Health and Nutrition Examination Survey (III), 1994. 3. Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369.

HDL Cholesterol
Low HDL cholesterol is a strong independent predictor of CHD1 The lower the HDL cholesterol level the higher the risk for atherosclerosis and CHD2 Low HDL is defined categorically as a level < 40 mg/dL (a change from < 35 mg/dL in ATP II)1 HDL cholesterol tends to be low when triglycerides are high2

1. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497. 2. Wood D, et al. Atherosclerosis. 1998;140:199-270.

Triglycerides
Recent data suggest that elevated triglycerides are an independent risk factor for CHD Normal triglyceride levels: < 150 mg/dL Borderline-high triglycerides: 150 to 199 mg/dL High triglycerides: 200 to 499 mg/dL Very high triglycerides: ( 500 mg/dL) increase pancreatitis risk
Initial aim of therapy is prevention of acute pancreatitis

NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

Non-HDL Cholesterol

Non-HDL Cholesterol = TC HDL Cholesterol1 Secondary target of therapy when serum TG 200 mg/dL1 New non-HDL-C goal for patients with elevated TG is LDL-C goal + 30 mg/dL1 Non-HDL-C includes all atherogenic lipoprotein particles including LDL-C, Lp(a), IDL-C, and VLDL-C2
1. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497. 2. Cui Y, et al. Arch Intern Med. 2001;161:1413-1419.

New Concepts for ATP III

Modified Risk Factor Assessment
Inclusion of more patients in the high-risk category (greater focus on diabetes, noncoronary atherosclerosis, multiple risk factors) Incorporation of global risk assessment in the guidelines Complete fasting lipoprotein profile recommended Definition of low HDL-C is now < 40 mg/dL for males and females Triglyceride cut points lowered from 200 mg/dL to 150 mg/dL

NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

New Concepts for ATP III (cont)

Modified Treatment Guidelines
LDL-C < 100 mg/dL identified as optimal LDL-C goal of < 100 mg/dL expanded to include CHD patients and those with CHD risk equivalent

NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

New Concepts for ATP III (cont)

More Intensive Lifestyle Intervention: Therapeutic Lifestyle Changes (TLC)
Therapeutic diet lowers saturated fat (< 7% of total calories) and cholesterol (< 200 mg/d) intakes to levels of previous Step II diet Adds dietary options to enhance LDL-C lowering
Plant stanols/sterols (2 g/d) Viscous (soluble) fiber (10-25 g/d)

Increased emphasis on weight management and physical activity

NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

LDL Cholesterol Goals for Therapeutic Lifestyle Changes (TLC) and Drug Therapy According to NCEP ATP III
LDL-C Goal (mg/dL) < 100 LDL-C Level for Initiation of TLC (mg/dL) 100 LDL-C Level for Consideration of Drug Therapy (mg/dL)

Risk Category CHD or CHD Risk Equivalents (10-y risk > 20%)

130 (100-129: drug optional)

2 + Risk Factors (10-y risk 20%)

< 130

130

10-y risk 10%-20%: 130 10-y risk < 10%: 160 190 (160-189: LDL-C-lowering drug optional)

0-1 Risk Factor

< 160

160

NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.