metabolic syndrome & cvd
TRANSCRIPT
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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
FollowFollow--up (years)up (years)
All-cause mortality
00
55
1010
1515
2020
FollowFollow--up (years)up (years)
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