1. Cardiovascular Risk Factor Overview and Management
Nathan D. Wong, PhD, FACC
Associate Professor and Director,
Heart Disease Prevention Program, University of California, Irvine

2. Cardiovascular Disease: The Leading Cause of Death in US Women in 1995
Heart disease
375
Cerebrovascular disease
96.4
Lung cancer
60.6
COPD*
48.9
Pneumonia/Influenza
45.1
Breast cancer
43.8
Accidents
31.9
Diabetes
33.1
Ovarian cancer
9.9 50
100
150
200
250
300
350
400
Deaths (1,000)
*COPD=chronic obstructive pulmonary disease.
Adapted from Anderson RN et al. Monthly Vital Statistics Report. Vol 45(suppl 2):June 12, 1997.

3. CHD in the United States
CHD is the single largest killer of men and women
~13.9 million have history of MI and/or angina
Each year 1.1 million people have MI
370,000 die of MI, 250,000 die within 1 hr
By age 60, every 5th man and 17th woman develops CHD
1998 estimated direct and indirect costs of heart disease are $95.6 billion
53.3 million adults have elevated LDL-C and warrant intervention (1994 NHANES data)
22.3 million qualify for drug therapy, 5.5 million receive therapy
AHA Heart and Stroke Statistical Update; 1997.
National Center for Health Statistics. National Health and Nutrition Examination Survey (III); (Data collected )

4. CVD Mortality Trends for Males and Females*
520
500
480
Deaths in thousands
460
440
420 20
1979 81 83 85 87 89 91 93 95
1996
Years
Males
Females
*United States: mortality.
AHA Heart and Stroke Statistical Update; 1998.

5. PDAY: Percentage of Right Coronary Artery Intimal Surface Affected With Early Atherosclerosis
Raised lesions 30
Men 30
Women
Fatty streaks 20 20 10 10
Intimal surface (%)
15-19
20-24
25-29
30-34
15-19
20-24
25-29
30-34
15-19
20-24
25-29
30-34 10 20 30
White
White 30 20 10
15-19
20-24
25-29
30-34
Black
Black
Age (y)
PDAY= Pathobiological Determinants of Atherosclerosis in Youth.
Strong JP, et al. JAMA. 1999;281:

6. Beyond Cholesterol: Predicting Cardiovascular Risk In the 21st Century
Lipids HTN Diabetes
Behavioral
Hemostatic Thrombotic
Inflammatory
Genetic
Slide 2. Beyond cholesterol: predicting cardiovascular risk in the 21st century
As we understand more about the biology of atherothrombosis, we need to move beyond standard cholesterol screening if we are to appreciate the promise of preventive early intervention therapies. While hyperlipidemia, hypertension, and diabetes, as well as the behavioral risk factors of smoking and diet, remain major critical modifiable risk factors for vascular disease, we have learned over the years that many hemostatic and thrombotic markers such as lipoprotein(a), D-dimer, and homocysteine, inflammatory markers such as C-reactive protein (CRP), fibrinogen, and interleukin-6, and genetic markers are all part of the evolving understanding of cardiovascular risk.
Keywords: markers, risk factors
Slide type: figure (chart)

7. Continuum of Patients at Risk for a CHD Event
Post MI/Angina
Secondary
Prevention
Other Atherosclerotic Manifestations
Subclinical Atherosclerosis
Primary Prevention
Multiple Risk Factors
Low Risk
Courtesy of CD Furberg.

8. Total Cholesterol Distribution: CHD vs Non-CHD Population
Framingham Heart Study—26-Year Follow-up
No CHD
35% of CHD Occurs in People with TC<200 mg/dL
CHD
Slide 3. Total cholesterol distribution: CHD vs non-CHD population
In the Framingham Heart Study, as many as one third of all coronary heart disease (CHD) events occurred in individuals with total cholesterol <200 mg/dL. Considering that the average U.S. cholesterol level is approximately 210 to 220 mg/dL, almost half of all heart attack events and all stroke events that will occur in the United States next year will in fact occur among individuals with below-average lipid levels. For this reason, our research group has sought in our large-scale prospective epidemiologic studies to understand better other markers associated with cardiovascular risk.
Reference:
Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis 1996;124(Suppl):S1-9.
Keywords: cholesterol distribution, Framingham Heart Study
Slide type: graph
150
200
250
300
Total Cholesterol (mg/dL)
Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.
1996 Reprinted with permission from Elsevier Science.

9. 14-y incidence rates (%) for CHD
Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal (Framingham)
12.50
11.91
11.91 14
9.05
10.7 12
11.24 10
6.6
5.53
14-y incidence rates (%) for CHD 8
6.56
3.83
4.85 6
4.67
2.06
 260
4.15 4
3.77
2.78
230–259
Speaker’s Notes/Talking Points:
Low high-density lipoprotein cholesterol (HDL-C) levels (< 40 mg/dL) are associated with an increased risk of coronary heart disease (CHD) even if the total cholesterol (Total-C) level is < 200 mg/dL. This slide shows the CHD incidence over 14 years among Framingham Study subjects who were aged 48–83 years at baseline.1 Among those with HDL-C levels < 40 mg/dL and Total-C < 200 mg/dL, 11.24% experienced a CHD event. This incidence was virtually the same as that (11.91%) for subjects with HDL-C levels between 40–49 mg/dL and Total-C  260 mg/dL.
References
1. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA. 1986;256:2835–2838. 2
200–229
Total-C (mg/dL)
< 200
< 40
40–49
50–59
 60
HDL-C (mg/dL)
Risk of CHD by HDL-C and Total-C levels; aged 48–83 y
Castelli WP et al. JAMA 1986;256:2835–2838

10. CHD Incidence Related to HDL-C Levels in Various Trials
Men
Women -2
% change in risk per 1 mg/dL increment in HDL-C -4 -6 -8
-10
FHS = Framingham Heart Study; LRCF = Lipid Research Clinics Prevalence Mortality Follow-up Study; CPPT = Lipid Research Clinics Coronary Primary Prevention Trial; MRFIT = Multiple Risk Factor Intervention Trial
Speaker’s Notes/Talking Points:
To determine whether the relationship between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) is independent of the influence of other risk factors, Gordon et al analyzed the relation between HDL-C and CHD incidence (adjusting for age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol) in four American cardiovascular studies: the Framingham Heart Study (FHS), the Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF), the Lipid Research Clinics Coronary Primary Prevention Trial (CPPT), and the Multiple Risk Factor Intervention Trial (MRFIT).1 A 1-mg/dL increase in HDL-C was associated with a significant 2% decrease in CHD risk in men (FHS, CPPT, and MRFIT) and a 3% decrease in women (FHS). The regression coefficients for LRCF in this slide are based on CHD mortality because only fatal outcomes were documented in that study.
Reference
1. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989;79:8–15.
FHS
CPPT
LRCF
LRCF
MRFIT
FHS
95% confidence intervals (CIs) for adjusted proportional hazards regression coefficients. Gordon DJ et al. Circulation 1989;79:8–15

11. Clinical Benefits of Cholesterol Reduction
A recent meta-analysis of 38 trials demonstrated that for every 10% reduction in TC
CHD mortality decreased by 15% (P<0.001)
total mortality decreased by 11% (P<0.001)
Decreases were similar for all treatment modalities
Cholesterol reduction did not increase non-CHD mortality
Gould AL et al. Circulation. 1998;97: 1

12. Major CHD Risk Factors Other Than LDL-C According to NCEP ATP-III
Positive risk factors
Age
male ³45
female ³55
Family Hx of CHD: 1st-degree relative with MI or sudden cardiac death - male relative: <age 55
female relative: <age 65
Current cigarette smoking
Hypertension: BP ³140/90 mm Hg or on antihypertensive meds
Low HDL-C: <40 mg/dL
Diabetes IS A CHD QUIVALENT IDENTIFYING PT AS HIGH RISK
Negative risk factor
High HDL-C: 60 mg/dL

13. Other Recognized Risk Factors
Obesity: traditionally determined by body mass index >30 kg/m2 with overweighted defined as 25-<30 kg/m 2.
Abdominal obesity involves waist circumference >40 in. in men, >35 in. in women
Physical inactivity: various definitions

14. JNC VI: Risk Stratification and Treatment*
Group A Group B Group C
Uncomplicated HTN HTN w/Risk Factors TOD/ CCD/ Diabetes
High-normal Lifestyle Lifestyle Drug therapy‡ ( /85-89) modification modification
Stage 1 Lifestyle Lifestyle Drug therapy ( /90-99) modification modification† (up to 12 mo) (up to 6 mo)
Stages 2 and 3 Drug therapy Drug therapy Drug therapy (160/ 100)
* Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy.
† For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modifications.
‡ For those with heart failure, renal insufficiency, or diabetes.
TOD/CCD = target organ disease/clinical cardiovascular disease.
JNC VI. November 1997:chapter 2. NIH publication

15. Probability of Death From CHD in Patients With NIDDM and in Nondiabetic Patients, With and Without Prior MI
100 80 60
Survival (%) 40
Nondiabetic subjects without prior MI
Diabetic subjects without prior MI
Nondiabetic subjects with prior MI
Diabetic subjects with prior MI
Speaker’s Notes/Talking Points:
The treatment of cardiovascular risk factors in patients with diabetes is controversial, with some investigators suggesting that such patients should be treated as though they had established coronary heart disease (CHD).1 To determine whether diabetic patients who have not had myocardial infarctions (MIs) should be treated as aggressively for cardiovascular risk factors as diabetic patients who have had MIs, Haffner and colleagues compared the 7-year incidence of MI (both fatal and nonfatal) among 1,378 nondiabetic subjects with the MI incidence among 1,059 subjects with non-insulin-dependent diabetes mellitus (NIDDM) in a Finnish population-based study.2 The probability of death from CHD was estimated among diabetic and nondiabetic subjects, with and without prior MI. As this slide shows, the probability of death from CHD was highest among diabetic subjects with prior MI and was lowest among nondiabetic subjects without prior MI. Diabetic subjects without prior MI and nondiabetic subjects with prior MI had intermediate survival rates as well as similar outcomes. These findings suggest that cardiovascular risk factors should be treated in diabetic patients as aggressively as in nondiabetic patients with prior MI.
References
1. Haffner SM. The Scandinavian Simvastatin Survival Study (4S) subgroup analysis of diabetic subjects: implications for the prevention of coronary heart disease. Diabetes Care. 1997;20:469–471.
2. Haffner SM, Lehto S, Ronnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–234. 20 1 2 3 4 5 6 7 8
Years
Kaplan-Meier estimates
Haffner SM et al. N Engl J Med 1998;339:229–234

16. Definitions of Diabetes and Impaired Fasting Glucose
New ADA definition (1998) defines fasting blood sugar of > 126 mg/dl as diabetes, casual blood glucose > 200 mg/dl. Impaired fasting glucose is mg/dl
Diabetic control generally defined as HgbA1c <8%.
BP recommended <130/80 mmHg, LDL-C goal <100 mg/dl

17. Secondary CHD Prevention in Women: Results from the CARE Trial
CARE was a secondary prevention trial of pravastatin versus placebo treatment in 4159 men and women with average lipid levels over 5 years
576 post-menopausal women were randomized; average age 61; 10% on HRT
Average baseline lipids: TC 215 mg/dL, LDL-C 140 mg/dL, HDL 45 mg/dL
5 year treatment results: 46% reduction in all coronary events, 48% reduction in PTCA, 40% reduction in CABG, 56% reduction in stroke
Slide 10. Secondary CHD prevention in women: results from the CARE trial
The CARE trial included 576 (14%) women, whose mean HDL-C at baseline was 45 mg/dl, which is borderline low for women. Pravastatin significantly reduced combined coronary events (coronary death, nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty [PTCA], and coronary artery bypass grafting [CABG]) by 45% and PTCA by 48%; reductions in CABG and stroke were substantial but were not statistically significant.
Reference:
Lewis SJ, Sacks FM, Mitchell JS, East C, Glasser S, Kell S, Letterer R, Limacher M, Moye LA, Rouleau JL, Pfeffer MA, Braunwald E, for the CARE investigators. Effect of pravastatin on cardiovascular events in women after myocardial infarction: the Cholesterol and Recurrent Events (CARE) trial. J Am Coll Cardiol 1998;32:
JACC 1998;32:

18. Primary endpoint: nonfatal MI and CHD death
Heart and Estrogen/Progestin Replacement Study (HERS): Secondary Prevention of CHD in Women
Randomized, placebo-controlled trial of E/P therapy vs. placebo in 2763 women with CHD; average age 67 years
Treatment was mg CEE mg medroxyprogesterone daily for 4 years
Primary endpoint: nonfatal MI and CHD death
Secondary endpoints: CABG, PTCA, unstable angina, CHF, PVD, TIA
Slide 11. Heart and Estrogen/Progestin Replacement Study (HERS): secondary prevention of CHD in women
HERS examined the observational association between estrogen replacement and CHD risk reduction in a randomized prospective trial of estrogen plus MPA at fixed dosages in women with CHD.
Reference:
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:
JAMA 1998;280:

19. HERS Results
Non-fatal MI HRT 116 Placebo 129 CHD death HRT 71 Placebo 58
End of Year 1 CHD events (HRT) 42.5/1000 women-years CHD events (Plac) 28/1000 women-years
Year 4-5: CHD events (HRT) 23/1000 women-years CHD events (Plac) 34.3/1000 women-years
DVT/PE HRT 6.3 vs. Plac 2.2
Cholelithiasis HRT 84 vs. Plac 62
Slide 12. HERS results
Although hormone-replacement therapy decreased LDL-C by 11% and increased HDL-C by 10% compared with placebo, at a mean follow-up of 4 years neither the primary endpoint nor any of the secondary endpoints were significantly different between treatment groups. Relative hazard of nonfatal myocardial infarction was slightly decreased and relative hazard of CHD death was slightly increased with hormone treatment, but the differences were not statistically significant. However, there was a statistically significant trend for more CHD events with hormone treatment in year 1 and fewer events in years 4 and 5. Hormone treatment also increased risk for venous thromboembolic events (deep vein thrombosis [DVT] or pulmonary embolism [PE]) and gall bladder disease.
Reference:
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:
JAMA 1998;280:

20. HERS Results
No statistically significant difference between HRT and placebo in both primary and secondary endpoints after 4 years.
Within first year, greater incidence in CHD events in HRT group. In years 3 and 4, lower CHD events in HRT group compared to placebo.
HRT lowered LDL 11% and increased HDL 10% compared to placebo.
Approximately 50% of randomized women were on lipid-lowering drugs.
Higher incidence of VTE and cholelithiasis in HRT group.
Slide 13. HERS results: summary
On the basis of the HERS results, the investigators concluded that a woman with CHD who is already on hormone-replacement therapy should not discontinue therapy, because hormone treatment reduced CHD risk at later time points during the study. However, with the lack of overall CHD benefit combined with a trend toward increased CHD risk, the authors did not recommend initiating hormone-replacement therapy as secondary prevention in a woman not currently on therapy.
Reference:
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:
JAMA 1998;280:

21. Is there clinical evidence that inflammatory markers predict future coronary events and provide additional predictive information beyond traditional risk factors?
Slide 5. Is there clinical evidence that inflammatory markers predict future coronary events and provide additional predictive information?
In this discussion, we are going to focus on the clinical question of whether there is clinical evidence that inflammatory markers can be used to predict future coronary events, and if so, whether they provide additional predictive information to that obtained from traditional risk factors.
Keywords: inflammation, inflammatory markers
Slide type: text

22. hs-CRP and Risk of Future MI in Apparently Healthy Men
P Trend <0.001
P < 0.001
P < 0.001
P = 0.03
Relative Risk of MI
Slide 6. hs-CRP and risk of future MI in apparently healthy men
In the prospective Physicians' Health Study, a cohort of almost 22,000 healthy, middle-aged men were tracked over an 8- to 10-year period for first ever occurrence of myocardial infarction (MI). As shown in the slide, the relative risk of a future MI increases in a direct linear fashion as the level of hs-CRP goes from low-normal to high-normal. This effect was highly statistically significant, and in fact, hs-CRP was as strong a predictor in this cohort as was cholesterol level. It is important to point that these data were derived from a high-sensitivity CRP assay; that is, all the levels of inflammation detected here are well within normal limits; none of these individuals have chronic inflammatory disorders.
Reference:
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:
Keywords: C-reactive protein, Physicians' Health Study
Slide type: graph
1 <0.055
– 0.114
– 0.210
4 >0.211
Quartile of hs-CRP (range, mg/dL)
Ridker PM et al. N Engl J Med 1997;336:

23. Quartile of hs-CRP (range, mg/dL)
hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women
P Trend <0.002
Any Event
MI or Stroke
Relative Risk
Slide 11. hs-CRP and risk of future cardiovascular events in apparently healthy women
An important clinical consideration is the generalizability of these data, particularly to women. In the Women's Health Study, a prospective cohort of some 38,000 middle-aged, predominantly postmenopausal American women who were free of cardiovascular disease at study entry, the relative risk of future vascular events increased as the level of C-reactive protein went from low-normal to high-normal. This was true for all vascular events as well as for the specific combined endpoint of MI or stroke.
Reference:
Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:
Keywords: C-reactive protein, Women's Health Study
Slide type: graph
1 <0.15
–0.37
–0.73
4 >0.73
Quartile of hs-CRP (range, mg/dL)
Ridker PM et al. Circulation 1998;98:

24. Lp(a) in Atherogenesis: Another Culprit?
Identical to LDL particle except for addition of apo(a)
Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all
Accumulates in atherosclerotic plaque
Binds apo B-containing lipoproteins and proteoglycans
Taken up by foam cell precursors
May interfere with thrombolysis
Maher VMG et al. JAMA. 1995;274:
Stein JH, Rosenson RS. Arch Intern Med. 1997;157:

25. Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort10 5
3.6
2.7 2
1.9
1.8
1.8
1.2 1 RR
0.5
Lp(a) TC HDL-C HT GI Smoking
0.2
0.1
RR=relative risk; HT=hypertension; GI=glucose intolerance.
Bostom AG et al. JAMA. 1996;276:

26. Homocysteine: Role in Atherogenesis
Linked to pathophysiology of arteriosclerosis in 1969
CVD patients have elevated levels of plasma homocysteine
May cause vascular damage to intimal cells
Elevated levels linked to:
genetic defects
exposure to toxins
diet
Increased dietary intake of folate and vitamin B6 may reduce CVD morbidity and mortality
McCully KS. Am J Pathol. 1969;56:
McCully KS. JAMA. 1998;279:
Rimm EB et al. JAMA. 1998;279:

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