Evidence Based Cardiovascular Disease

Manju B. Reddy, PhD.

Iowa State University

Food Science and Human Nutrition

Global Causes of Death

http://www.who.int/cardiovascular_diseases

# 1cause

Projected global deaths by cause

: Beaglehole and Bonita, 2008

Prevalence and Incidence

• The United States ranks 13th and 17th, among industrialized nations for the prevalence of CVD in women and men, respectively.

• More than 71 million Americans have at least one form of CVD.

Forms of CVD

• Hypertension

• Coronary Heart Disease (CHD)

• Stroke

• Rheumatic heart disease

• Congestive heart failure

Percentage breakdown of deaths from CVD (United States:2004)

52

17

76 4 14

Coronary HeartDisease

Stroke

HF*

High Blood Pressure

Diseases of theArteries

Other

52

17

76 4 14

Coronary HeartDisease

Stroke

HF*

High Blood Pressure

Diseases of theArteries

Other

Source: NCHS and NHLBISource: NCHS and NHLBI *Not a true underlying cause.

NCHS and NHLBINCHS and NHLBI

0

100

200

300

400

500

600

700

800

900

00 10 20 30 40 50 60 70 80 90 00 05

Years

Death

s i

n T

ho

usan

ds

Deaths from Diseases of the HeartDeaths from Diseases of the Heart (United States: 1900–2005)(United States: 1900–2005)

Pathology - Atherosclerosis

Atherosclerosis is a major underlying cause of CVD

•Fatty streaks: Earliest lesion (children)

•Fibrous plaques: more complex lesion that can occlude the artery (extends into lumen)

•Complicated lesion: Hemorrhage in the plaque

Progression of Atherosclerosis

(From Harkreader H. Fundamentals. Philadelphia: W.B. Saunders, 2000)(From Harkreader H. Fundamentals. Philadelphia: W.B. Saunders, 2000)

(From Harkreader H. Fundamentals. Philadelphia: W.B. Saunders, 2000)(From Harkreader H. Fundamentals. Philadelphia: W.B. Saunders, 2000)

Plaque Formation

1. Proliferation of smooth muscle cells 2. Accumulation of smooth muscle cells in to

connective tissue matrix3. Accumulation of lipid and cholesterol around the

cells4. Plaque or atheromas:

lipid deposits that develop in the innermost layer. Plaque forms in response to injuries of endothelium in artery wall (hypercholesterolemia, oxidized LDL, hypertension, smoking, obesity, diabetes, homocysteine, high cholesterol or high saturated fat diets)

Structure of Plaque

Risk FactorsNon modifiable risk factors:

– Age– Gender– Family history

Modifiable risk factors:– Hyperlipidemia– Adiposity (BMI and Waist circumference)– Inactivity– Cigarette smoking– Hypertension– Diabetes– Atherogenic diet

10.1

21.4

34.6

59.2

4.28.9

40.2

74.4

20.0

65.2

010

2030

4050

6070

80

45-54 55-64 65-74 75-84 85-94

Age

Pe

r 1

,00

0 P

ers

on

Ye

ars

Men Women

10.1

21.4

34.6

59.2

4.28.9

40.2

74.4

20.0

65.2

010

2030

4050

6070

80

45-54 55-64 65-74 75-84 85-94

Age

Pe

r 1

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0 P

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ars

Men Women

Includes CHD, HF, stroke or cerebral hemorrhage. Does not include hypertension alone.

FHS, 1980-2003. NHLBI

Incidence of CVD by Age and Sex

Risk is higher in males

Less difference at older age

Lipids and Lipoprotein Risk Factors• Total cholesterol: amount in all lipoprotein fractions (High)

• Total triglyceride: amount in all lipoprotein fractions (High)

• Chylomicrons: transport dietary fat and cholesterol from small intestine to liver and periphery

• VLDL: transport endogenous triglyceride and cholesterol

• LDL (bad cholesterol): major cholesterol transport lipoprotein (High)

• HDL (good cholesterol): reverse cholesterol transport (Low)

Optimal Desirable Borderline High Risk

Total Cholesterol Below 200 200-239240 or higher

LDL Cholesterol <100 Below 130 130-159160 or higher

HDL Cholesterol Above 60 35-45 Below 40

Ratio Total cholesterol/HDLs

Below 4.5 4.5-5.5 Above 5.5

Cholesterol* Levels and Their Meanings

NCEP STEPIII – NHLBI

*mg/dL

Corvol et al. Arch Intern Med. 2003:163:669

Lipid lowering therapy and stroke

RR= probability of the event : exposed /non exposed Example: Developing lung cancer is 10% in smokers vs 1% non-smokers

RR = (10/100)/1/100 = 10Smokers have 10% higher risk for developing cancer compared to non-smokers

Associations of physical activity and waist circumference with CHD*

Tricia et al. Circulation. 2006;113:499-506

*Nurses’ health study 1986-2000 (n=88,393; 20-y follow up). RR= Relative Risk adjusted for age, parental history of CHD, postmenopausal status and hormone use, aspirin use, BMI and alcohol consumption

Abdominal adiposity

Associations of BMI and waist circumference with CHD*

*Nurses’ Health Study 1986-2000 (n=88,393; 20-y follow up). RR= Relative Risk adjusted for age, parental history of CHD, postmenopausal status and hormone use. aspirin use, and alcohol consumption

Tricia et al. Circulation. 2006;113:499-506

CHD and Physical Activity

* Adjusted for age; n=44,452; US Men, Health Professional Follow-up Study

Mahael et al. JAMA. 2002;288 (data collected 1994-2000)

No training0.83 0.65

Physical Activity, Smoking and CHD

Lee et al. JAMA 2001, 285:1447-1454

N=39,372, healthy female professionals <45y

Hypertension

• Antihypertensive drug use was more protective than lipid lowering drugs (RR=1.6 vs 1.1) in a Prospective Epidemiological study of Myocardial Infarction (PRIME) with 2,500 men with 5-y follow up (50-59 y) (Blacher et al. J Hyperten

2004;22:415-23)• Follow up report with 10-y follow up with 9,649

men showed similar results with CHD, CVD death and stroke (Blacher et al. 2009. J Human Hyperten)

CVD Mortality and DiabetesHazard ratio = How often the event happens in one group compared to other group; Example: Cancer survival at any point of time in treatment group vs control group

Zeymer, U. Int J Cardiol. 2006, 11–20

Hazard ratio

Diet CVD

Replacement of total, unsaturated, and even possibly saturated fats with refined, high-glycemic index carbohydrates is unlikely to reduce CHD risk and may increase risk in persons predisposed to insulin resistanceDiet that will likely reduce the risk of CHD1. rich in whole grains and other minimally processed carbohydrates 2. includes moderate amounts of fats (approximately 30%–40% of total energy), particularly unsaturated fats and omega-3 polyunsaturated fats from seafood and plant sources3. lower in refined grains and carbohydrates4. less packaged foods, baked goods, and fast foods containing trans fatty acids

Mozaffarian, D. Current Atherosclerosis Reports 2005, 7:435–445

Percentage Change in Consumption by Kilocalories per Capita per Day in Selected Countries from 1980 to 2003, FAOSTAT Food

Consumption Data

Food Type China Egypt India Mexico South Africa

Total Kilocalories

26.3 16.2 25.7 1.5 5.7

Meat 247 48.3 40.0 18.3 6.9

Cereals −13.9 17.6 13.8 −1.4 4.7

Sugar and Sweeteners

51.9 8.8 27.2 2.4 −18.3

Fruits 600 103 60.0 19.4 33.3

Vegetables 367 10.3 37.5 40.7 0.0

Palm Oil 640 No Data 730 2100 2400

Soybean Oil 635 35.5 48.2 50.0 189

Vegetable Oil 259 −47.8 84.6 14.7 75.4

Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health.Institute of Medicine (US) Committee on Preventing the Global Epidemic of Cardiovascular Disease: Meeting the Challenges in Developing Countries; Fuster V, Kelly BB, editors.Washington (DC): Academic Press, 2010

Diet and Lipoproteins

• Saturated fat: LDL receptor LDL uptake from blood LDL in circulation

• Fiber: Fiber binds bile acids and re-absorption of cholesterol and excretion in the feces.

Bile acids

Cholesterol

X

Absorption

Fiber

Bile acidsFeces

Important qualities of carbohydrates in reducing CVD risk

Mozaffarian D. Current Atherosclerosis Reports 2005,7:435–445

Adjusted Relative Risk of CHD according to the whole-grain foods

N=75,521 female nurses

*Adjusted for BMI, smoking, alcohol, family history, hypertension/hypercholesterolemia, menopausal status, asiprin and multiple vitamin , activity, and energy intake use,

Simin et al. Am J Clin Nutr 1999;70:412–9.

.77.86

.89

.45

.72.82

.76

Antioxidants• Protect from oxidative damage to LDL (oxidized LDL

atherosclerosis)• Protective effect of antioxidants (vit E, β carotene and C)

Diet and Heart Diseases

Beta carotene supplementation and CHD risk

Tornwall et al. European Heart Journal. 2004, 25, 1171–1178

alpha-tocopherol, beta-carotene cancer prevention (ATBC) study.

Fish Consumption on CHD

Whelton , SP. Am J Cardiol 2004;93:1119–1123 – Meta analysis

Omega-3 fatty acidsPrecursors of eicosanoid synthesis blood clotting blood pressure blood lipids

Fish Consumption and CVD

Wennberg, et al AJCN 2012

Other Risk Factors

Homocysteine

• High levels may promote atherosclerosis by damaging the inner lining of arteries and promoting blood clots

homocysteine and folate intake – risk!

• B6, B12 are also important

Hyperhomocysteinemia is not a major risk factor for cardiovascular disease (AHA)

Metabolism of Homocysteine

*THF= tetrahydrofolate (folate containing co-enzyme)

Protein synthesis

*THF-CH3

THF

Vitamin B12

Cysteine

Methionine

-CH3

Serine

B6

Homocysteine

X

X

Homocysteine and CVDParameter Active group Placebo group

Homocysteine (mmol/l) Baseline 15.9 ± 7.3 15.7 ± 5.7 2 years 12.7 ± 5.0 16.1 ± 5.2 5 years 11.9 ± 3.3 15.5 ± 4.5

Folate (nmol/l) Baseline 27.8 ± 12.3 28.7 ± 11.0 2 years 41.4 ± 9.2 26.1 ± 9.3

Vitamin B6 (nmol/l) Baseline 87.4 ± 128.8 64.5 ± 82.0 2 years 275.8 ± 175.3 80.3 ± 111.6

Vitamin B12 (pmol/l) Baseline 332.3 ± 161.7 323.2 ± 166.6 2 years 768.0 ± 196.9 320.9 ± 181.7

Mann et al. Nephrol Dial Transplant. 2008, 23: 645–653

C-Reactive Protein• Inflammation: Process by which the body

responds to injury or an infection• Inflammation is involved with atherosclerosis• C-reactive protein (CRP) is one of the acute

phase proteins that increase during systemic inflammation

• hs-CRP and CVD risk

< 1.0 mg/L Low risk

1.0 and 3.0 mg/L Moderate risk

3.0 mg/L High risk

CDC and AHA recommend to measure CRP

Framingham Heart Study – CVD Risk

• Population of interest - Individuals 30 to 74 y old and without CVD at the baseline examination – 10 y risk

Predictors• Age • Diabetes • Smoking • Treated and untreated Systolic Blood Pressure • Total cholesterol • HDL cholesterol

Points Age HDLTotal Cholesterol

SBP Not Treated

SBP Treated Smoker Diabetic

-2 60+ <120

-1 50-59 0

0 30-34 45-49 <160 120-129 <120 No No

1 35-44 160-199 130-139

2 35-39 <35 200-239 140-159 120-129

3 240-279 160+ 130-139 Yes

4 280+ 140-159 Yes

5 40-44 160+

6 45-49

7

8 50-54

9

10 55-59

11 60-64

12 65-69

13

14 70-74

15 75+

Estimate of CVD in men – CVD Points

Calculating CVD Risk

Points Risk Points Risk Points Risk

-3 or less Below 1% 5 3.9% 13 15.6%

-2 1.1% 6 4.7% 14 18.4%

-1 1.4% 7 5.6% 15 21.6%

0 1.6% 8 6.7% 16 25.3%

1 1.9% 9 7.9% 17 29.4%

2 2.3% 10 9.4% 18+ Above 30%

3 2.8% 11 11.2%

4 3.3% 12 13.2%

Evidence Based Information

• Selection of expert panel

• Selection of topic and systemic search

• Evidence rating and recommendation

• Clinical recommendations

• Research needs and future directions

Risk Status Criteria

High risk Established coronary heart diseaseCerebrovascular diseasePeripheral arterial diseaseAbdominal aortic aneurysmEnd-stage or chronic renal diseaseDiabetes mellitus10-Year Framingham global risk 20%

Classification of CVD Risk in Women

Mosca et al. Circulation, Evidence-Based Guidelines for CardiovascularDisease Prevention in Women: 2007 Update.

Risk Status Criteria

At risk >1 major risk factors for CVD, including:

Cigarette smokingPoor dietPhysical inactivityObesity, especially central adiposityFamily history of premature CVD (CVD at 55 yearsof age in male relative and 65 years of age in female relative)HypertensionDyslipidemia

Evidence of subclinical vascular disease (eg, coronary calcification)Metabolic syndromePoor exercise capacity on treadmill test and/or abnormal heart rate recovery after stopping exercise

Classification of CVD Risk in Women

Mosca et al. Circulation, Evidence-Based Guidelines for CardiovascularDisease Prevention in Women: 2007 Update.

Risk Status Criteria

Classification of CVD Risk in Women

Mosca et al. Circulation, Evidence-Based Guidelines for CardiovascularDisease Prevention in Women: 2007 Update.

Optimal risk Framingham global risk <10% and a healthy lifestyle, with no risk factors

Optimal risk

Class I

Conditions for which there is evidence for and/or general agreement that the procedure or treatment is useful and effective.

Class II

Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment.

IIa The weight of evidence or opinion is in favor of the procedure or treatment.

IIb Usefulness/efficacy is less well established by evidence or opinion.

Class III

Conditions for which there is evidence and/or general agreement that the procedure or treatment is not useful/effective and in some cases may be harmful.

Classification Levels

Level of Evidence

A Data derived from multiple randomized clinical trials.

B Data derived from a single randomized trial or nonrandomized studies.

C Consensus opinion of experts.

Guidelines for prevention of CVD in Women: Clinical Recommendations

A few examples….

1. Life Style Interventions Cigarette Smoking - should not smoke and

should avoid environmental smoke (class I, level B)

Physical activity – minimum of 30 min brisk walking every day (class I, level

B)

Loose weight or sustain weight loss. 60- 90 min brisk walking every day (class I, level C)

Life Style interventions… Dietary intake – Fruits and vegetable-rich

diet, whole grain, high-fiber foods, fish (2x/wk), Saturated fat intake <10% of energy (<7%, if possible), cholesterol <300 mg/d, alcohol not more than 1 drink/d, sodium <2.3 g/d (1 tsp), and trans fatty acids <1% energy (class I, level B)

2. Major Risk Factor Interventions

A few examples…..

• Blood Pressure Optimal level and life style - <120/80 mm Hg

through life style approaches (weight control, physical activity, alcohol, sodium, other healthy diet (class I, level B)

Pharmacotherapy – If >140/90 mm Hg or even lower with kidney disease or diabetes (class I, level A)

• Lipids and lipoprotein levels– Optimal levels and life style approaches –

LDL-C <100 mg/dL; HDL-C >50 mg/dL; TG <150 mg/dL; and non HDL-C <130 mg/dL (class I, level B)

– Pharmacotherapy (high risk women) – drug therapy + life style approach in women with CHD (class I, level A) or atherosclerotic CVD or diabetes or 10 y absolute risk (class I, level B). Low HDL or elevated non-HDL – Niacin or fibrate therapy after LDL-C goal is reached (class IIa, level B)

– Diabetes - Life style and pharmacotherapy (class I, level B) to achieve an HbA1c <7%

3. Preventive Drug Interventions

• Aspirin (75 -325 mg/d) in high risk women unless contraindicated (class I, level A). Other risk and healthy women, >65y age (81-100 mg/d) if BP is controlled (class IIa, level B)

Class III Interventions for CVD or MI prevention

Menopausal therapy - Hormone therapy and SERMs should not be used for primary or secondary prevention (class III, level A)

Antioxidant supplements (Vitamin E, C and carotene) for primary or secondary prevention (class III, level A)

Folic acid + B6 and B12 should not be used for primary or secondary prevention (class III, level A)

Aspirin for MI in women <65 y: routine use is not recommended to prevent MI (class III, level A)

Mortality in Younger and Older womenAssociated with Hormone Therapy

CHD mortalityMean age, less than 65 years 0.98 (0.75, 1.30)Mean age, 65 years or over 1.00 (0.77, 1.31)

All strokeMean age, less than 65 years 1.35 (1.14, 1.60)Mean age, 65 years or over 1.20 (0.95, 1.51)

Non-fatal AMIMean age, less than 65 years 1.04 (0.79, 1.38)Mean age, 65 years or over 0.94 (0.75, 1.17)

All-cause mortalityMean age, less than 65 years 1.02 (0.90, 1.15)Mean age, 65 years or over 1.03 (0.86, 1.24)

Magliano et al. Int.Journal of Obst Gyn 2006; 113:5–14. Meta analysis

Diet and CVD –Evidence Based Assessment

• Dietary advice regarding cardiovascular disease (CVD) prevention is complex• American Heart Association (AHA) recommendation

for low-fat diet of: 55% of total calories from carbohydrates30% from fat15% from proteincholesterol restricted to 300 mg/day

Low fat recommendations lead to refined CHO intake

Popular Dietary Approaches for Cardiovascular Health

• Low CHO diets (5-30% CHO)• Very-low-fat diets (< 15% total calories from fat,

70% CHO)• Low glycemic diets (lower postprandial glucose

response)• The Mediterranean Diet (plant foods, minimally

processed, seasonally fresh, olive oil, dairy, fish/poultry, etc)

• DASH diet (similar to Med. Diet with high K, Ca, Mg, fiber to control hypertension)

Summary of Diets

• Very-Low-Fat Diet

Possible decrease in cardiac events

Concerns about universal applicability and sustainability

• Mediterranean Diet

Secondary prevention

Prevention of sudden cardiac death

Healthy overall approach to dieting

Long-term sustainability

• DASHDecreased hypertension

Similar to Mediterranean Diet

Optimal Diet Recommendations

None of the diets are independently perfect for cardiovascular health but the recommendations are:1.Low CHO intake, especially high GI foods

2.Increased consumption of fruits and vegetables, whole grains

3.Increased intake of PUFA (plant oils and fish)

4.Low fat dairy products and nuts

Parikh et al. J Am Coll Cardiology 2005

Suggested Readings

• Mozaffarin. Effects of dietary fats versus carbohydrates on coronary heart disease: A review of the evidence. Curr Athero reports 2005;7:435.

• http://circ.ahajournals.org/cgi/content/full/109/5/672

• http://www.framinghamheartstudy.org/risk/gencardio.html

• http://content.onlinejacc.org/cgi/content/full/45/9/1379

Suggested Readings

• http://circ.ahajournals.org/cgi/content/full/109/5/672

• http://www.framinghamheartstudy.org/risk/gencardio.html

• http://content.onlinejacc.org/cgi/content/full/45/9/1379