Metabolic Syndrome & CVD

8/3/2019 Metabolic Syndrome & CVD

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Multiple comorbidities: additive and

predictive of cardiovascular risk

Peter M. Nilsson

Lund University

University Hospital

Malm, Sweden


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Clinical outcomes: majorClinical outcomes: major

complications of CVDcomplications of CVD

Heart Attack/ACS Stroke/TIA

ACS=acute coronary syndrome; CVD=cardiovascular disease; TIA=transient ischaemic attack


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Chain of events leading toChain of events leading to

cardiovascular mortalitycardiovascular mortality

Dzau, Braunwald. Am Heart J. 1991

Risk factors Hyperlipidaemia Hypertension Diabetes Smoking

Psychosocial stress

AtherosclerosisLV hypertrophy

Coronary artery disease

Myocardialischaemia Neurohormonal

activation

Loss ofmuscle Suddendeath

Remodeling

Ventriculardilation

Heart failure

Death

Coronarythrombosis

Myocardialinfarction

Arrhythmias

Stroke

Renal failure


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Genetic influences on CVD risk andGenetic influences on CVD risk and

Type 2 diabetesType 2 diabetes


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Secular trends in CVD in the UKSecular trends in CVD in the UK

Secular trends in age-standardised mortality per 100,000 population from

coronary heart disease for men and women, 1921-1998, England and WalesLawlor et al. BMJ. 2001

600

500

400

300

200

100

0

Coronaryhea

rtdiseasemortality

per100,

000population

Men

Women

1924

1930

1936

1942

1948

1954

1960

1966

1972

1978

1984

1990

1996

Year


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The challenge: the clustering ofThe challenge: the clustering of

related risk factorsrelated risk factors

HDL=high-density lipoprotein; LDL=low-density lipoproteinDeedwania. Am J Med. 1998

AtherosclerosisAtherosclerosis

Type 2 diabetesType 2 diabetes

Hypertension

Obesity

Hyperinsulinaemia

Type 2 diabetes Hypertriglyceridaemia

Small, dense LDL

Low HDL


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(1886-1975)

Kylin E. Studien

ber dasHypertonie-

Hyperurikemie-

syndrom.

Zentralblatt fr

Innere Medizin

1923;7:105

Es kil Kylin


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MetabolicMetabolic syndrome: does it exist?syndrome: does it exist?

argumentsarguments PROPRO

Historical observations of the syndrome; it has been

around for a long time!

Logical clustering of risk factors for the metabolic

syndrome is based on evolutionary selection and brain

reward systems Risk prediction of CVD is possible based on the

metabolic syndrome

Treatment of metabolic syndrome/insulin resistance andassociated risk factors is beneficial


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Fasting plasma glucose 6.1 mmol/l

Abdominal obesity: waist circumference>88 cm (women) or >102 cm (men)

Triglycerides 1.7 mmol/l

HDL cholesterol


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Third National Health and Nutrition Examination Survey (NHANES IThird National Health and Nutrition Examination Survey (NHANES III)II)

20-29 30-39 40-49 50-59 60-69 70

Prevalence

(%)

Men

Women

50

40

30

20

10

0

Ford et al. JAMA. 2002

AgeAge--specific prevalence of the metabolicspecific prevalence of the metabolic

syndrome among 8814 US adultssyndrome among 8814 US adults


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Adverse prognostic implications ofAdverse prognostic implications of

cardiovascular metabolic syndromecardiovascular metabolic syndrome

Lakka et al. JAMA. 2002

PopulationPopulation--based observational study in 1209 Finnish menbased observational study in 1209 Finnish men

Metabolic syndrome presentMetabolic syndrome present Metabolic syndrome absentMetabolic syndrome absent

234234

834834

100100

292292

279279288288NoNo

852852866866YesYes

FollowFollow--up (years)up (years)

Cumulative

Cumulative

hazard(%)

hazard(%)

Coronary heart

disease mortality

234234

834834

100100

292292

279279288288

852852866866


All-cause mortality

00

55

1010

1515

2020


CVD mortality

RR (95% CI):RR (95% CI):

3.55 (1.963.55 (1.96--6.43)6.43)

234234

834834

100100

292292

279279288288

852852866866

No. at risk of metabolic syndrome

88 1010 121266442200

00

55

1010

1515

2020 RR (95% CI):RR (95% CI):3.77 (1.743.77 (1.74--8.17)8.17)

88 1010 121266442200

00

55

1010

1515

2020

88 1010 121266442200

RR (95% CI):RR (95% CI):

2.43 (1.642.43 (1.64--3.61)3.61)


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Incidence of cardiovascular events in nonIncidence of cardiovascular events in non--

diabetic subjects with the metabolic syndromediabetic subjects with the metabolic syndrome

1.02

(0.73-1.42)

1.36

(0.98-1.90)

1.47

(1.04-1.88)

+C-reactive protein

(adjusted**hazard

ratio)

1.06

(0.78-1.44)

1.46

(1.09-1.97)

1.66

(1.22-2.25)

Risk factors (adjusted

* hazard ratio)

1.27

(0.96-1.67)

1.62

(1.23-2.12)

1.95

(1.48-2.58)

Age + sex (adjusted

hazard ratio)

70 / 67

4.4 / 1000

35 / 38

7.7 / 1000

38 / 40

9.8 / 1000

33 / 38

10.9 / 1000

Incident

MI / stroke (n/n)

1105949774Number (N)

No

metabolic

syndrome

IDFEGIRNCEP ATP III

EGIR=European Group for the Study of Insulin Resistance

IDF=International Diabetes Federation

MI=myocardial infarctionNilsson P. et al. Diabetic Med. 2006, in press


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Key neurochemical systemsKey neurochemical systems

comprising the brain reward circuitrycomprising the brain reward circuitry

Gardner. In: Lowinson et al, eds. Substance Abuse. 4th ed. Lippincott Williams andWilkins; 2005. Kruger et al. Photographic Atlas of the Rat Brain. Cambridge Press; 1995


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Brain reward system triggered


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but also by these things!


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Prevalence of obesity in the USA,Prevalence of obesity in the USA,

19911991--20002000

Mokdad et al. JAMA. 2001


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Life expectancy at age 40: impact ofLife expectancy at age 40: impact of

excess body weightexcess body weight

43.4

46.3

40.3

43.0

37.5

39.2

35

40

45

50

Female non-smoker Male non-smoker

L

ife

expectancy

(years)

Normal 18.5-24.9 kg/m2

Overweight 25-29.9 kg/m2

Obese 30 kg/m2

Framingham Heart Study

3.3 y 7.1 y

3.1 y 5.8 y

Peeters et al. Ann Intern Med. 2003


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IR?IL-6

TNF-

Thin fibrous cap

Unstable plaque

Impaired fibrinolysis

Increased collagen

Endothelial dysfunction

Subcutaneous AT

Skeletal Muscle

Insulin resistance (IR)syndrome of atherogenic

dyslipidaemia

Expanded

Visceral

AT

PAI-1

NEFAs

Glucose

NEFAs

Apo B Glucose Insulin

XX

IRLPL

Liver

Triglycerides HLHL

Potential contribution of expanded visceral adiposePotential contribution of expanded visceral adipose

tissue to the atherothrombotic protissue to the atherothrombotic pro--inflammatoryinflammatory

profile of abdominally obese patientsprofile of abdominally obese patients

Desprs et al. Ann Endocrinol. 2001

Adiponectin

AdiponectinAdiponectin


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Neaton et al. Arch Intern Med. 1992

142+

125-131


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INTERHEART: importance ofINTERHEART: importance of

APO B and AIAPO B and AI levelslevels

LargeVLDL1

Large

LDL

SmallLDL

Large

LDL

LargeHDL2

SmallHDL3

SmallHDL3

LargeHDL2

Healthy profileMetabolic syndrome

and

Type 2 diabetes

SmallVLDL2

Low apo B High apo B

High apo AI

Low apo AI

VLDL=very low-density lipoproteinYusuf et al. Lancet. 2004


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Fetal growth, retardation,

and risk:

- Arterial hypertension?

- Type 2 diabetes?

- Cardiovascular

disease?- Insulin resistance

syndrome?

The BarkerFetal Origin Hypothesis


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Future Fo rumDEFINING G LOBAL STANDARDS IN VASCULAR DISEASE

Conroy et al. Eur Heart J. 2003

TenTen--year risk of fatal CVD in highyear risk of fatal CVD in high--risk regions of Europe byrisk regions of Europe by

gender, age, SBP, total cholesterol, and smoking statusgender, age, SBP, total cholesterol, and smoking status


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Sverige


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Butler et al. Eur Heart J. 1998

Vascular ageing: atherosclerosis andVascular ageing: atherosclerosis and

arterial stiffeningarterial stiffening

From first decade

Intermediate

lesion

Foam

cells

Fatty

streak Atheroma

Fibrous

plaque

Complicated

lesion/rupture

Endothelial dysfunction

From third decade From fourth decade

Growth of the lipid coreSmooth

muscle and

collagen

Thrombosis


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ConclusionsConclusions

Evolutionary biology and evolutionary medicine can

provide new perspectives on the metabolic syndromeand clusters of CVD risk factors

Survival genes do not match with modern lifestyle,

resulting in abdominal obesity, chronic inflammation, and

insulin resistance

A life course approach takes into account the early

programming (fetal life, catch-up post-natal growth) for

prediction of cardiovascular risk and Type 2 diabetes

Lifestyle programmes have to be tailored to brain reward

systems and may prevent vascular ageing

Metabolic Syndrome & CVD

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