Pumps & Pipes 1

Christie M. Ballantyne, M.D.Christie M. Ballantyne, M.D.

Center for Cardiovascular Disease PreventionCenter for Cardiovascular Disease PreventionMethodist DeBakey Heart CenterMethodist DeBakey Heart Center

Baylor College of MedicineBaylor College of MedicineHouston, TexasHouston, Texas

Atherosclerosis

Key Clinical Issues

1. What causes the development of atherosclerosis?

2. Why do some atherosclerotic plaques develop a thrombus leading to vessel occlusion and clinical symptoms (MI, stroke)

3. How do we identify early atherosclerosis which does not limit flow and does not cause symptoms?

4. How do we stop or reverse atherosclerosis?

5. How do we monitor whether therapy is successful?

How do you know if you are at risk for a heart attack?

Case

A 58-year-old former CEO, recently retired, concerned about his risk for heart disease because of a family history of heart disease. He exercises on a regular basis; diet and weight have fluctuated over the years with his stress and workload. His only medical problem is high blood pressure, which is controlled with medication.

Case

Physical examination: Blood pressure 142/80Height 6'2", Weight 210 lb

Labs: Total cholesterol 233Triglycerides 100HDL cholesterol 36LDL cholesterol 177

What is his risk for coronary heart disease?

Major Risk Factors That Modify LDL-C Goals

• Cigarette smoking• Hypertension: 140/90 mm Hg or on

antihypertensive medication• Low HDL-C: <40 mg/dL*• Family Hx of premature CHD: male first-degree

relative <55 years, female first-degree relative <65 years

• Age: men 45 years, women 55 years*High HDL-C (60 mg/dL) is a negative risk factor and

decreases by 1 the total number of risk factors

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Assessing CHD Risk in MenStep 1: Age

Years Points20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 13

Step 2: Total Cholesterol

HDL-C(mg/dL) Points

60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-Cholesterol

Systolic BP Points Points(mm Hg) if Untreated if Treated

<120 0 0120-129 0 1130-139 1 2140-159 1 2160 2 3

Step 4: Systolic Blood Pressure

Step 5: Smoking Status

Points at Points at Points at Points at Points at Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79

Nonsmoker 0 0 0 0 0Smoker 8 5 3 1 1

Age

Total cholesterol

HDL-cholesterol

Systolic blood pressure

Smoking status

Point total

Step 6: Adding Up the Points

Point Total 10-Year Risk Point Total 10-Year Risk<0 <1% 11 8%0 1% 12 10%1 1% 13 12%2 1% 14 16%3 1% 15 20%4 1% 16 25%5 2% 17 30%6 2%7 3%8 4%9 5%10 6%

Step 7: CHD Risk

ATP III Framingham Risk Scoring

TC Points at Points at Points at Points at Points at(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79

<160 0 0 0 0 0160-199 4 3 2 1 0200-239 7 5 3 1 0240-279 9 6 4 2 1280 11 8 5 3 1

What is his Framingham Risk Score?

Age

Total cholesterol

HDL cholesterol

Systolic blood pressure

Smoking

Total:

8

3

2

2

0

15

PointsPoints

Risk of CHD event (MI or death): 20%Risk of CHD event (MI or death): 20%

High risk for CHD event: >20% over 10 years

Intermediate risk: 10–20%

Low risk: <10%

Current Approaches to "Risk Assessment" (Predicting Heart

Attack and Stroke)

1. Count risk factors

2. Equations to quantitate absolute 10-year risk or lifetime risk

What causes a heart attack?

Endothelial Dysfunction in Atherosclerosis

Ross R. N Engl J Med 1999; 340:115–126.

Fatty-Streak Formation in Atherosclerosis

Ross R. N Engl J Med 1999; 340:115–126.

Formation of an Advanced, Complicated Lesion in Atherosclerosis

Ross R. N Engl J Med 1999; 340:115–126.

Unstable Fibrous Plaques in Atherosclerosis

Ross R. N Engl J Med 1999; 340:115–126.

Are there other tests to identify better who might have a heart

attack or stroke?

New Tests for Risk Assessment

• Blood tests related to inflammation

– High-sensitivity C-reactive protein (CRP)

– Lipoprotein-associated phospholipase A2 (Lp-PLA2)

LUMEN

MEDIA

INTIMA

LDL

The Role of Lp-PLA2 in CVD

Lp-PLA2

Adhesion Molecules

LUMEN

MEDIA

INTIMA

Lp-PLA2

The Role of Lp-PLA2 in CVD

Oxidized LDL

Cytokines

Lyso-PC+

OxFA

LDL

LUMEN

MEDIA

INTIMA Lyso-PC+

OxFA

Lp-PLA2

Adhesion Molecules

CytokinesPlaque Formation

Foam Cell

Monocytes

Macrophage

The Role of Lp-PLA2 in CVD

Oxidized LDL

LDL

11.38

6.02 5.52

5.844.03

1.000.00

2.00

4.00

6.00

8.00

10.00

12.00

High Medium Low

Low

Medium

High

5.52

CRP, mg/L Lp-PLA 2

, g/L

Isch

emic

Str

oke

Haz

ard

Rat

io

95% CI 3.13–41.41,p<0.001

(>3) (1–3) (<1)

(422)

(310–422)

(<310)

6.02

2.854.27

Association of Lp-PLA2 and CRP with Incident Ischemic Stroke

4.36

Ballantyne CM et al. Arch Intern Med 2005;165:2479-2484.

• Ankle-brachial index (ABI)

• B-mode ultrasound of carotids (intima-media thickness)

• Electron beam computed tomography (EBCT)

• Exercise and nuclear stress tests

Noninvasive Assessments for Subclinical Atherosclerosis

• ARIC study – 16,000 individuals with 20 years of follow up

• 1.2 million SNPs per individual by end of year• Multiple imaging and blood tests on each

individual (100s to 1000s of data points per patient

• How to analyze and “mine” the data?

Biomarkers, Genes, Imaging and Prediction of MI and Stroke

ABCs of Prevention

A. Aspirin, ACE inhibitor

B. Blood pressure, beta-blocker

C. Cholesterol

D. Diet

E. Exercise

Intensity of lipid-modifying

therapy is dependent upon the

absolute risk for CHD events

Assessment of Therapeutic Efficacy

Prostate Cancer

Symptoms: urine flow

Blood tests: PSA

Imaging: ultrasound, MRI, CT

Invasive: biopsy

CAD

Symptoms: blood flow

"Stress" tests: to assess blood flow

Invasive: cath

Barriers to New Drug Development

• Lack of blood tests (biomarkers) to quantitate atherosclerosis

• No imaging tests to track progression/ regression in routine clinical practice