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 increa

sed 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 add

s 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 p

rimary 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

smaller, denser LDL particles

hepatic lipase

LDL particle

cholesteryl ester transfer protein (CETP)

(Oxidation)

Obesity and Dyslipidaemia Increased levels of non-esterified fatty acids (NEF

As) 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 gen

eration 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 insulin-resistant 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 middle-aged 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 arteri

al 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, antidia

betic and antiinflammatory properties, and is expressed abundantly in adipocytes.

Unlike most other adipokines, adiponectin is decreased in obesity, diabetes and other insulin-resistant 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 mo

lecules, 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 pro

bably involved in the development of obesity-related diseases.

Visfatin levels correlate strongly with an individual’s amount of visceral fat, exert insulin-mimetic 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 ele

vated 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 non-

adipose 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 con

sidered 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 findin

gs 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 eccen

tric 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 importan

t 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 byimprov

ing non-insulin-dependent glucose uptake. It improves the ratio between HDL and LDL cholester

ol because it increases the activity of lipoprotein lipase. it decreases triacylglycerols, increases fibrinolysis, dec

reases 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

Thank you for your attention!