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Transcript
Mechanisms linking obesity
with cardiovascular disease
Luc F. Van Gaal, Ilse L. Mertens & Christophe
E. De Block
Obesity and cardiovascular disease
 Obesity is a fast growing problem that is reaching
epidemic proportions worldwide, and is associated
with an increased risk of premature death.
 Individuals with a central deposition of adipose
tissue can experience elevated cardiovascular
morbidity and mortality, including stroke,
congestive heart failure, myocardial infarction and
cardiovascular death.
Obesity and Dyslipidaemia
 Dyslipidaemia in obesity is characterized by
increased levels of very low-density lipoprotein
(VLDL) cholesterol, triacylglycerols and total
cholesterol, an increase in small dense LDL
particles, and lower high density lipoprotein (HDL)
cholesterol levels.
 It is not clear whether hypercholesterolaemia
further increases the risk of cardiovascular disease
in obese individuals.
Obesity and Dyslipidaemia
 The insulin-resistant state of abdominal obesity
adds substantially to the CHD risk of patients with
familial hypercholesterolaemia.
 Aggressive reduction of lipids with the use of
statins can have a beneficial effect on coronary
plaque development in obese individuals.
Obesity and Dyslipidaemia
 Hepatic overproduction of VLDL seems to be the
primary and crucial defect in obesity — a
consequence of hepatic steatosis.
 In addition to increased synthesis, there is also
decreased clearance of triacylglycerol-rich
lipoproteins (TRLs) induced by a decrease in
lipoprotein lipase activity
Obesity and Dyslipidaemia
LDL particle
hepatic lipase
smaller, denser
LDL particles
cholesteryl ester transfer
protein (CETP)
(Oxidation)
Obesity and Dyslipidaemia
 Increased levels of non-esterified fatty acids
(NEFAs) linking obesity to cardiovascular disease.
 Facors involved in NEFA increase:
- increased lipolysis and the release of NEFAs in
hypertrophic dipocytes
- decreased fatty acid oxidation
- low levels of adiponectin
- the inflammatory state associated with obesity
Obesity and Dyslipidaemia
 High NEFA concentrations may increase ROS
generation in mononuclear cells, and induce insulin
resistance in myocytes and hepatocytes.
 Increased levels of NEFAs might affect endothelial
nitric oxide production, thereby impairing
endothelium-dependent vasodilation.
 They may also increase myocardial oxygen
requirements — and therefore ischaemia —
decrease myocardial contractility and induce
cardiac arrhythmias.
Obesity and Oxidative stress
 Oxidative stress has been proposed to be a
potential pathogenic mechanism linking obesity
and insulin resistance with endothelial dysfunction.
 However, it is not clear whether obesity itself or
obesity-associated conditions lead to oxidative
stress.
 Decrease in oxidative stress after dietary restriction
and weight loss has been reported in obese
individuals.
Pro-coagulation and hypofibrinolysis
 In obesity and metabolic syndrome, fibrinogen,
von Willebrand factor (vWF) and PAI-1 have been
most extensively studied as markers of the
haemostatic and fibrinolytic system and as possible
predictors for the development of cardiovascular
disease and type 2 diabetes.
Pro-coagulation and hypofibrinolysis
 In obese individuals, only PAI-1 levels were
increased in those with metabolic syndrome.
 It is mainly expressed in stromal cells, including
monocytes (liver cells), smooth muscle cells and
pre-adipocytes.
 Visceral adipose tissue seems to have up to five
times the number of PAI-1-producing stromal cells
compared with subcutaneous adipose tissue.
Pro-coagulation and hypofibrinolysis
 Plasma PAI-1 levels are more closely related to fat
accumulation and PAI-1 expression in the liver
than in adipose tissue, suggesting that in insulinresistant individuals the fatty liver is an important
site of PAI-1 production.
 CRP increases PAI-1 expression and activity in
human aortic endothelial cells.
Obesity and Visceral fat
 In addition to total body fatness, the accumulation
of abdominal fat independently increases
cardiovascular risk.
 The waist-to-hip ratio reflects abdominal fat in
predicting type 2 diabetes, stroke, myocardial
infarction and cardiovascular mortality in middleaged individuals.
Obesity and Visceral fat
 Adipose tissue is an active endocrine and paracrine
organ that releases a large number of cytokines and
bioactive mediators, such as leptin, adiponectin,
interleukin-6 (IL-6) and tumour necrosis factor-α
(TNF-α), that influence not only body weight
homeostasis but also insulin resistance, diabetes,
lipid levels, tension, coagulation, fibrinolysis,
inflammation and atherosclerosis.
IL-6 and TNF-α
 IL-6 and TNF-α are inflammatory cytokines and
the main inducers of CRP secretion in the liver.
 CRP is a marker of low-grade inflammation, and
studies suggest that this protein has a role in the
pathogenesis of atherosclerotic lesions in humans.
Adipose tissue and Leptin
 a bioactive substance found in adipose tissue
 Controls food intake and energy expenditure
 Human obesity is associated with elevated leptin
levels, which have been proposed to have a role in
insulin resistance and metabolic syndrome.
 There may be a direct link between
hyperleptinaemia and increased cardiovascular
disease risk.
Adipose tissue and Leptin
 Leptin may enhance platelet aggregation and
arterial thrombosis, promote angiogenesis, impair
arterial distensibility and induce proliferation and
migration of VSMCs.
 leptin seems to enhance the calcification of
vascular cells, making the arterial wall a target of
leptin.
Adipose tissue and Adiponectin
 Adiponectin has important anti-atherogenic,
antidiabetic and antiinflammatory properties, and is
expressed abundantly in adipocytes.
 Unlike most other adipokines, adiponectin is
decreased in obesity, diabetes and other insulinresistant states.
Adipose tissue and Adiponectin
 The mechanism by which plasma levels are
reduced in individuals with visceral fat
accumulation has not yet been clarified, but an
increase in TNF-α secretion from accumulated
visceral fat seems to have inhibiting effect.
Adipose tissue and Adiponectin
 Adiponectin increases the expression of messenger
RNA and protein production of tissue inhibitor of
metalloproteinase in macrophages through the
induction of IL-10 synthesis, and selectively
suppresses endothelial cell apoptosis.
 This suggests that adiponectin protects plaque
rupture by the inhibition of matrix
metalloproteinase function.
Adipose tissue and Adiponectin
 Adiponectin inhibits the expression of adhesion
molecules, such as vascular cell adhesion
molecule-1 (VCAM-1), ICAM-1 and E-selectin,
through the inhibition of nuclear factor-κB (NF-κB)
activation.
 It also suppresses foam-cell formation.
Adipose tissue and Visfatin
 Visfatin is a visceral-fat-specific protein that is
probably involved in the development of obesityrelated diseases.
 Visfatin levels correlate strongly with an
individual’s amount of visceral fat, exert insulinmimetic effects in culture cells, and have a potent
insulin-like activity of adipogenesis.
Adipose tissue and Retinol-binding
protein 4, RBP4
 RBP4 is an adipocyte-secreted molecule that is
elevated in the serum before the development of
diabetes and seems to signal the presence of insulin
resistance and associated cardiovascular risk
factors.
 RBP4 seems to be involved in impairing insulin
signalling in muscles and inducing the expression
of gluconeogenic enzymes in the liver, contributing
to insulin resistance.
Non-Adipose tissue and Adipokines
 A number of adipokines might originate from nonadipose cells in adipose tissue — macrophages in
particular — and these include atherogenic
cytokines.
 Different factors could induce macrophage
infiltration and activation in white adipose tissue
such as adipocyte hypertrophy and hyperplasia,
secretion of monocyte chemoattractant protein-1
(MCP-1) or local actions of leptin or adiponectin.
Ectopic fat
 It is not yet clear whether visceral fat should be
considered to be a variant of ectopic fat, such as
liver or muscle fat, or an incapacity of the body to
store fat in predesigned subcutaneous and/or
gluteal areas.
 Liver fat has been directly associated with
mortality risk.
Ectopic fat
 This idea about fat topography is in line with
findings that peripheral, particularly gluteal, fat
might even have a protective effect.
 Ectopic fat storage in the heart, blood vessels and
kidneys can impair their function, contributing to
the increased cardiovascular risk in obesity.
Ectopic fat
 In animal models, cardiac lipotoxicity causes
eccentric left ventricular remodelling, increased
left ventricular pressure and decreased systolic
performance, leading, ultimately, to dilated
cardiomyopathy.
 In peripheral vessels, high amounts of perivascular
fat cells could contribute mechanically to the
increased vascular stiffness seen in obesity.
Insulin resistance, obesity, and
cardiovascular disease
 Insulin resistance may be one of the most
important factors linking abdominal visceral
adiposity to cardiovascular risk.
 Several of the possible mechanisms linking obesity
to cardiovascular disease, such as increased levels
of NEFAs, lipotoxicity and disturbances in
adipokine secretion, are believed to be related to
insulin resistance.
Insulin resistance, obesity, and
cardiovascular disease
 Oxidative stress is considered to be the common
factor underlying insulin resistance.
Obesity and smoking
Fitness versus fatness
 In general, for each unit of BMI increment, the risk
of CHD increases by 8%.
 being physically active moderately attenuated but
did not eliminate the adverse effect of obesity on
coronary health, and being lean did not counteract
the increased risk associated with physical
inactivity.
Fitness versus fatness
Increase physical activity:
 It improves glucose tolerance and sensitivity
byimproving non-insulin-dependent glucose uptake.
 It improves the ratio between HDL and LDL
cholesterol because it increases the activity of
lipoprotein lipase.
 it decreases triacylglycerols, increases fibrinolysis,
decreases platelet aggregation, improves oxygen
uptake in the heart as well as in peripheral tissues,
lowers the resting heart rate by increasing vagal tone,
and lowers blood pressure.
Summary
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