Cardiovascular diseasesCardiovascular diseases

John C. Stevenson

Risk factors forRisk factors forcoronary heart disease (CHD)coronary heart disease (CHD)

• Genetic– Family history– Ethnic origin

• Metabolic– Diabetes mellitus– Hypertension– Obesity

• Lifestyle– Diet– Exercise– Smoking

• Socioeconomic status

• Menopause status

Prevalence of coronary vascular Prevalence of coronary vascular disease (CVD) and some risk factorsdisease (CVD) and some risk factors

USA females 2004USA females 2004

0

25

50

75

Total

CVD

CHD

Stroke

Hyper

tens

ion

Smok

ers

Hyper

chole

ster

olem

ia

Ove

rwei

ght

Obe

se

Diabe

tes

% o

f P

op

ula

tio

n

www.americanheart.org

CVD and menopausal statusCVD and menopausal status

0

1

2

3

4

5

6

7

40 40–44 45–49 50–54

Age (years)

CV

D in

cid

en

ce

pe

r 1

00

0 w

om

en

Premenopausal

Postmenopausal

Adapted from the Framingham Study, DHEW No 74, 1974

CVD risk factorsCVD risk factors

• Lipids and lipoproteins

• Glucose and insulin metabolism

• Body fat distribution

• Coagulation and fibrinolysis

• Homocysteine

• Inflammatory markers

• Blood pressure

• Arterial function

Metabolic syndromeMetabolic syndrome

Insulin resistance

Central obesity

Impaired GTDyslipidemia

CoagulationHypertension

CHD

CHD: metabolic changesCHD: metabolic changes

• Lower HDL and HDL2

• Lower apolipoprotein AI

• Higher triglycerides

• Higher insulin response

• Lower insulin sensitivity

• Lower tissue plasminogen activator (tPA)

• Higher PAI-1

• Higher systolic blood pressure

• Greater android fat Ley et al. J Am Coll Cardiol 1994;23:377–83

Lipoproteins and CHDLipoproteins and CHD

• Increased total cholesterol

• Increased LDL cholesterol

• Decreased HDL and HDL2 cholesterol

• Increased triglycerides

• Increased lipoprotein(a)

• Increased small dense LDL cholesterol

• Decreased postprandial lipid clearance

• Increased LDL oxidation

Menopause and lipidsMenopause and lipids

-30 -20 -10 0 10 20 30

% Change

Cholesterol

Triglycerides

LDL

HDL

HDL2

HDL3

Apo B

Apo AI

Lipoprotein(a)

Stevenson et al. Atherosclerosis 1993;98:83–90

Glucose/insulin and CHDGlucose/insulin and CHD

• Impaired glucose tolerance

• Hyperinsulinemia

• Increased insulin response to glucose

• Increased insulin resistance

• Increased uric acid

Insulin metabolismInsulin metabolism

*

*

Menopause Menopause

*p < 0.001

Incremental pancreatic Insulin secretion

Insulin half-life

Walton, et al. Eur J Clin Invest 1993;23:466–73

0

0.5

1

1.5

2

2.5

Pre Post

nm

ol/m

l.min

0

2

4

6

8

10

12

Pre Post

min

Glucose Insulin C-peptide

r = 0.20 r = 0.49 r = 0.28

Menopausal age ns p < 0.05 ns

Chronological age ns ns ns

Body mass index ns p < 0.001 ns

Insulin metabolismInsulin metabolism

0

1

2

3

4

5

< 50 < 55 > 55

Age range (years)

Si (

μU

.ml-

1)

Insulin sensitivity

IVGTT incremental areas

Walton, et al. Eur J Clin Invest 1993;23:466–73; Proudler, et al. Clin Sci 1992;83:489–94

Seige K, et al. 6th Symposium of the German Endocrinological Society: Modern Developments in Progestagenic Hormones in Veterinary Medicine; 1959, 1960; Kiel: Springer Verlag; 1959. p. 274–9

Menopause and diabetesMenopause and diabetes

Nu

mb

er o

f w

om

en n

ewly

d

iag

no

sed

wit

h d

iab

etes

Years from menopause

Premenopause Postmenopause120

100

80

60

40

20

0 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16

Body compositionBody composition

30

40

50

60

Pre Post

% A

nd

roid

fa

t

30

40

50

60

Pre Post

% G

yn

oid

fa

t

Menopause Menopause

* *

*p < 0.001Ley, et al. Am J Clin Nutr 1992;55:950–54

Menopause and hemostasisMenopause and hemostasis

• Increased fibrinogen

• Increased factor VII

• Increased plasminogen activator inhibitor-1 (PAI-1)

• Increased antithrombin

• ? Increased protein C

• Increased tissue plasminogen activator (tPA)

Bonithon-Kopp, et al. Int J Epidemiol 1990;19:42–8; Heinrich, et al. Clin Chem 1991;37:1950–4

Endothelial functionEndothelial function

Menopausal

Flow-mediated dilatation (FMD)

*p < 0.01Arrowood, et al. Circulation 2000;A514

0

2

4

6

8

10

12

Pre Post

%In

cre

as

e in

FM

D

*

CHD assessmentsCHD assessments

• Ischemia– Exercise ECG– Stress thallium scan

• Imaging– Coronary angiography– Multi-slice CT scanning– MRI scanning– Ultrasound IMT

• Risk factors– Fasting lipids/lipoproteins– Fasting glucose/insulin– C-reactive protein– Homocysteine

CHD preventionCHD prevention

• Lipid-lowering drugs

• Antihypertensives

• Weight reduction

• Physical activity

• Smoking cessation

• ? HRT

HRT and CHDHRT and CHD

• Lipids and lipoproteins

• Glucose and insulin metabolism

• Body fat distribution

• Coagulation and fibrinolysis

• Homocysteine

• Inflammatory markers

• Blood pressure

• Arterial function

Epidemiology: CHD and HRT Epidemiology: CHD and HRT

21.510.50

RR

Hospital case-control

Population case-control

Prospective internal control

Cross-sectional

Prospective external control

All studies combined

Prospective internal control

and cross-sectional

Stampfer and Grodstein. Raven Press, 1994

HRT and CHDHRT and CHD

• HRT is beneficial to CVS– Primary prevention– Secondary prevention

• Women start HRT around menopause

• Studies are not randomized– Healthy user bias (applies

to other outcomes, e.g. osteoporosis)

– Data can be adjusted for potential biases

• HRT is not beneficial to CVS– Primary prevention– Secondary prevention

• Women start HRT at later ages

• Problem lies with HRT– Dose and type of

estrogen– Dose and type of

progestogen– Harm is due to increased

thrombogenesis– Harm is due to adverse

vascular remodelling

Observational studies Randomized trials

Adapted from Grodstein F, et al. J Women’s Health 2006;15:35–44

Postmenopausal hormone use and CHDPostmenopausal hormone use and CHDNurses Health Study 1976-2000Nurses Health Study 1976-2000

Timing of hormone initiation with respect to ageTiming of hormone initiation with respect to age

Adjusted for age, body mass index, hypercholesterolemia, hypertension, parental coronary heart disease, diabetes, cigarette smoking, dietary data, husband’s education, alcohol intake, physical activity, vitamin E or multivitamin supplementation, aspirin use

50–59 years

60+ years

RR (95% CI)

0 0.2 0.4 0.6 0.6 1.0 1.2 1.2

Excluding postmenopausal women with prevalent CHDExcluding postmenopausal women with prevalent CHD

IMS Position Statement, Climacteric 2004;7:333–7

Effect of HRT-ERT on CHD in PMWEffect of HRT-ERT on CHD in PMWTiming of initiation, data from WHITiming of initiation, data from WHI

CEE

CEE + MPA

Haz

ard

ra

tio

s

Yea

rs s

ince

men

op

aus

e

< 10

10–19

> 20

< 10

10–19

> 20

0.56

0.92

1.04

0.89

1.22

1.71

0 0.5 1.0 1.5 2.0 2.5

0 0.5 1.0 1.5 2.0 2.5

Hazard ratio(95% CI)

Hazard ratio(95% CI)

LEVEL 1

Hsia J, et al. Arch Intern Med 2006;166:357–65

WHI: coronary events withWHI: coronary events withET or placebo by age at baselineET or placebo by age at baseline

Hazard ratio (95% CI)

Coronary event

CHD (MI or coronary death)

CABG or PCI

MI, coronary death CABG, and PCI

MI, coronary death CABG, PCI and

confirmed angina

0 0.5 1 1.5 2

p = 0.07

p = 0.09

p = 0.09

p = 0.11

50–5960–6970–79

WHI: coronary heart diseaseWHI: coronary heart diseaseHRT and CHD: absolute risk by ageHRT and CHD: absolute risk by age

p-value for trend = 0.16n = 27,347

Taken from Rossouw, et al. J Am Med Assoc 2007;297:1465–77

-2-1

19

-10-8-6-4-202468

101214161820

Age at randomisation (years)

Ab

so

lute

ex

ce

ss

ris

k o

f C

HD

pe

r 1

00

00

pe

rso

n-y

ea

rs

50–59 60–69 70–79

Adapted from Rossouw, et al. J Am Med Assoc 2007;297:1465–77

WHI: HT and WHI: HT and absolute riskabsolute risk of cardiovascular of cardiovascular disease by disease by years since menopauseyears since menopause

Years since menopause Hazard ratio CI Absolute excess risk

(per 10,000person-years)

< 10 0.76 0.50–1.16 –6

10–19 1.10 0.84–1.45 4

> 20 1.28 1.03–1.58 17

p for trend = 0.02

ERT and atheroma preventionERT and atheroma prevention

• 222 healthy postmenopausal women

• 17β-estradiol 1 mg daily vs. placebo

• Study duration 2 years

• Carotid artery intima-media thickness by ultrasound scan

0

0.002

0.004

mm

/ye

ar

Placebo

ERT

I/M thickness

Progression

Hodis, et al. Ann Intern Med 2001;135:939–53

ERA studyERA study

-0.12

-0.07

Ch

an

ge

in M

LD

(m

m)

Placebo

CEE

CE-MPA

Progression

p = NSHerrington DM, et al. N Engl J Med 2000

HRT and CHD eventsHRT and CHD events

• Increased CHD events in elderly women– ? Increased

thrombogenesis/adverse remodelling

– ? Estrogen dose too high

MI / death

CABG / PCI

0 21

50–59 years

70–79 years

HR

composite

Hsai, et al. Arch Intern Med 2006;166:357–65

Estradiol and myocardial ichemiaEstradiol and myocardial ichemia

0

200

400

600

800

0

200

400

600

800

Tim

e (s

ec)

Time to 1 mm ST depression

Total exercise time

Placebo Estradiol Placebo Estradiol

*p = 0.01; **p < 0.01 Rosano, et al. Lancet 1993;342:133–6

*

**

Tim

e (s

ec)

CHD treatmentCHD treatment

• Anti-anginal drugs

• Statins

• Angioplasty + stenting

• CABG

• ? HRT

HERS trialHERS trial

• 2763 women

• Mean age 66.7 years

• > 6 months from cardiac event

• Conjugated equine estrogens 0.625 mg + MPA 2.5 mg

• Event rate 3.3%(estimated 5%)

• Mean follow-up 4.1 years (estimated 4.75 years)

• No overall benefit seen

0

0.4

0.8

1.2

1.6

0 1 2 3 4

Years

RH

CHD events

Trend p = 0.009

Hulley, et al. J Am Med Assoc 1998;260:605–13

HERS trialHERS trial

2

2.5

3

3.5

4

4.5

5

1 2 3 4

Ca

rdio

va

sc

ula

r e

ve

nts

(%

)

Placebo

HRT

Hulley, et al. J Am Med Assoc 1998;260:605–13

WHISPWHISP

• 100 postmenopausal women followed up to 12 months

• Acute coronary syndrome (majority MI)

• Randomized to placebo or HRT 2–28 days post-event

• 17β-estradiol 1 mg/NETA 0.5 mg daily

• Efficacy– Lipid parameters– (Clinical events)

• Safety– Hemostatic parameters

0

5

10

15

20

25

30

35

40

45

CVA

Death M

I

CVA/dea

th/M

I

CV adm

issio

n

Ev

en

t ra

te (

%)

HRT

Placebo

RH 0.68 (CI 0.32–1.46)

Collins, et al. Eur Heart J 2006;27:2046–53

Time

Premenopausal years Postmenopausal years

OvariectomyPlaque area

(% of placebo)

Healthy diet CEE + atherogenic diet1.1. 70%1,2

Atherogenic diet CEE + atherogenic diet2.2. 50%3

Healthy diet Atherogenic diet

Healthy diet+ CEE3.3. 0%4

~ 6-year human equivalent

Timing of HRT interventionTiming of HRT interventionEffect of estrogens on atherogenesis

in non-human primates

1Clarkson, et al. J Clin Endocrinol Metab 1998;83:721; 2Adams, et al. Arterioscler Thromb Vase Biol 1997;17:217; 3Clarkson, et al. J Clin Endocrinol Metab 2001;86:41; 4Williams, et al. Arterioscler Thromb

Vase Biol 1995;15:827

The window of opportunity: The window of opportunity: hypothetical pathogenetic sequencehypothetical pathogenetic sequence

Age distribution in WHI population and Age distribution in WHI population and stage of atherosclerosis progressionstage of atherosclerosis progression

0% 10% 20% 45% 25%

< 50 yrs 50–54 yrs 55–59 yrs 60–69 yrs 70–79 yrs

Endothelial dysfunction

Foam Fatty Intermendiate Atheroma Fibrous Complicatedcells streak lesion plaque lesion/rupture

HRTObs. Studies

Clinical practice HT

RCT

WHIMS

35–45 yrs 45–55 yrs 55–65yrs > 65 yrs

Endothelial injury Lipid accumulation Inflammation

Estrogens’ preventive action requires healthy tissue

Conclusions: generalConclusions: general

• CVD is major cause of death in women

• Similar risk factors for males and females

• Menopause gives additional risk

• Prevention and treatment similar for males and females

• HRT potentially gives additional benefit

Conclusions: HRTConclusions: HRT• Biological plausibility for beneficial CVD effects of HRT

– Metabolic processes– Arterial function

• Clinical studies– Benefit for myocardial ischemia– Benefit for atheroma prevention in healthy women

• Population studies– Concordance of benefit in primary prevention– Event studies suggest benefit for secondary prevention

• Randomized clinical trials– Early harm followed by later benefit– More benefit seen in younger women – ? therapeutic window

of opportunity– More benefit seen with lower dose ± different/no progestogen

HRT and CHD:HRT and CHD:MisperceptionsMisperceptions

• HRT increases CHD risk throughout the whole postmenopausal period

• HRT causes an increase in coronary events in the first 1–2 years in all women

IMS Global Summit 2008. Climacteric 2008;11:267–72

HRT and CHD:HRT and CHD:EvidenceEvidence

• HRT in women aged 50–59 years does not increase CHD risk in healthy women and may even decrease the risk in this age group

• Estrogen-alone therapy in the age group 50–59 years was associated with significantly less coronary calcification (equivalent to a smaller plaque burden), which is consistent with findings of a lower coronary intervention score in women of this age in the WHI study

IMS Global Summit 2008. Climacteric 2008;11:267–72

HRT and CHD:HRT and CHD:EvidenceEvidence

• Early harm (more coronary events during the first 2 years of HRT) was not observed in the early postmenopausal period. The number of CHD events decreased with duration of HRT in both WHI clinical trials

• Data derived from randomized controlled trials in the age group 50–59 years are similar to the older observational data, suggesting a protective effect of HRT on coronary disease

IMS Global Summit 2008. Climacteric 2008;11:267–72

HRT and CHD:HRT and CHD:EvidenceEvidence

• Late starters of standard-dose HRT may have a transient, slightly increased risk for coronary events

IMS Global Summit 2008. Climacteric 2008;11:267–72