Cardiovascular risk of

metabolic diseases
Cardiovascular risk of metabolic
diseases
CARDIOVASCULAR DISEASE is the main
cause of populational death and 2/3 of these
events are attributed to coronary artery disease
Cardiovascular risk of metabolic
diseases

3 of the major CV risk factors:

Diabetes Mellitus
Hypertension
Insuline
Dyslipidemia
resistance
 CONCEPT OF METABOLIC SYNDROME

Reaven in 1988 described

"syndrome X - patients presented with glucose

intolerance, systemic hypertension, dyslipidemia
and CV disease, all linked by insulin resistance,
defined as a genetic or acquired condition
characterized by reduced tissue uptake of glucose
in response to insulin stimulation
Alternative names to Metabolic
syndrome

Syndrome X

Insulin resistance syndrome

Deadly quartet

Reavens syndrome
 Metabolic diseases
Constellation of metabolic abnormalities that
confer increased risk of cardiovascular
disease(CVD) and diabetes mellitus.
Cardiovascular risk of metabolic
diseases
The concept of the syndrome was expanded and its
denomination changed to metabolic syndrome (MS)

hypertension
dyslipidemia (hypertriglyceridemia and low hdl-cholesterol),
central obesity
postprandial hyperlipemia,
microalbuminuria
hyperuricemia
hypofibrinolysis
hyperandrogenism

also described as part of metabolic diseases

The World Health Organization has suggested that this
diagnosis should be established when, in addition to
disturbance of glucose metabolism (insulin resistance
and/or glucose intolerance), the patient shows at least
two of the following components:

(a) Blood pressure >140/90 mmhg,

(b) Hypertriglyceridemia (>150 mg/dl) and/or low levels
of hdl-cholesterol (<35 mg/dl for men and <40 mg/dl
for women);
(c) Central obesity (waist-to-hip ratio >0.90 for men and
>0.85 for women) and/or body mass index >30
kg/m2 and
(d) Microalbuminuria (urinary albumin excretion >20
g/min or albumin-to-creatinine ratio >30 mg/g).
The major features of metabolic
syndrome include

Central obesity
Hypertriglyceridemia
Low high density lipoprotein (HDL)
Hyperglycemia
hypertension
 EPIDEMIOLOGY
Prevalence increases with age
Greater industrialization and urbanization

Increase in waist circumference is found

predominantly in women.

Fasting TG>150 mg/dl and hypertension more

likely in men.
 Risk factors
Overweight/ obesity- central (key feature)

Sedentary lifestyle
Predictor of CVD events and associted mortality
Associated with central obesity, TGs, HDL, BP , glucose
intolerance

Aging- prevalence increases with age

Diabetes mellitus- approx. 75% of T2DM or IGT have metabolic
syndrome
Coronary heart disease- 50% of CHD patients have metabolic
syndrome
About 1/3rd of MS patients have premature CAD
Lipodystrophy- both genetic or acquired have severe insulin resistance
Cardiovascular risk of metabolic
diseases
Hemodynamic: Metabolic effects:
angiotensin II and elevated High levels of plasma
blood pressure glucose and small dense
LDL particles

Oxidative stress endothelial cell injury and

reduction in nitric oxide levels (potent vasodilator). As a
consequence, deficient vasodilation and fibrinolysis will
occur which have a negative prognostic impact on CV
risk.
Systemic hypertension and
lipoprotein metabolism disturbances
hypertension frequently found in subjects with obesity
and type 2 DM - insulin resistance and lipid profile
disturbances is a common metabolic abnormality
among these diseases

Insuline exagerated action - renal sodium reabsorption,

sympathetic activity and trophic effects on the smooth
muscle tissue blood pressure elevation

insulin resistance at vascular level reduces nitric

oxide, important vasodilator blood pressure
elevation, endothelial dysfunction, micro and macro
vascular lesions
 Systemic hypertension and
lipoprotein metabolism disturbances

Hypertriglyceridemia and low levels of HDL-cholesterol

are the most characteristic lipid profile changes found in
the insulin resistance

Free fatty acids originated from visceral adipose tissue

induce increased hepatic production of VLDL -
hypertriglyceridemia and hyperglycemia are typical
manifestations of MS

Triglyceride synthesis is stimulated even further by

hyperinsulinemia
 Systemic hypertension and
lipoprotein metabolism disturbances

low HDL-cholesterol concentration in MS, activation of

the cholesterol ester transferase protein (CETP), which
increases cholesterol esters transfer from the
chylomicron to the HDL-cholesterol

Small dense particles of LDL-cholesterol - highly

atherogenic. - able to pass through the endothelium
and, in the intima, trigger the formation of foam cells,
the initial step in the atherogenic process
Glucose metabolism disturbances
Hyperinsulinemia might increase CV risk by
inducing a pro-thrombotic state, dependent on
PAI-1 activation

Insulin may determine structural changes in

LDL-cholesterol particles and stimulate muscle
cells proliferation from the vascular walls
favoring atherogenesis
PATHOPHYSIOLOGY OF DIABETIC VASCULAR
DISEASE

Adipocyte Biology and Inflammation

the role of inflammation in the pathogenesis of

diabetes and the metabolic syndrome.
 Glucose metabolism disturbances

The adipocyte, long regarded as a storage depot for

triglycerides, actually can generate substantial
quantities of proinflammatory mediators, such as tumor
necrosis factor-alpha (TNF-)
TNF- can cause insulin resistance and can thus
causally link adiposity to diabetes.
TNF- and allied proinflammatory cytokines derived
from the adipocyte can activate vascular endothelial
and smooth muscle cells to provoke aspects of vascular
dysfunction.
In this manner, adipocyte products can directly promote
vascular dysfunction and hasten atherogenesis
Orasanu G, Plutzky J: The pathologic continuum of diabetic
vascular disease. J Am Coll Cardiol 53:S35, 2009
 Type 2 diabetes and its associated metabolic
abnormalities favor an imbalance in the coagulation
and fibrinolytic systems that support clot formation
and stability.

Type 2 diabetes increases plasminogen activator

inhibitor type 1 (PAI-1) levels, impairing fibrinolytic
capacity in atherosclerotic lesions.

Diabetes increases the expression of tissue factor

and levels of plasma coagulation factors, and
decreases levels of endogenous anticoagulant.
Central obesity and metabolic
syndrome
Abdominal adiposity - adipose tissue distribution is
mainly dependent on the accumulation of visceral fat,
which has been implicated in the pathogenesis of
insulin resistance

Visceral adipose tissue is characterized by intense

lipolytic activity (receptors with high affinity for
catecholamines and cortisol) and less effective
antilipolytic activity (less insulin receptor binding),
which results in free fatty acids production
Central obesity and metabolic
syndrome
visceral fat might be an exaggerated release of free fatty
acids into general and portal circulation

plasma triglyceride concentration - increased hepatic

secretion of VLDL.

increased fatty acid oxidation in liver promotes the

pathway of gluconeogenesis and promotes
hyperglicemia, which in turn stimulates beta cell
secretion, favoring hyperinsulinemia
Central obesity and metabolic
syndrome
Fatty acids oxidation in muscle determined decreased
glucose transport and insulin effectiveness, long-term
hyperinsulinemia provokes down-regulation of muscle
insulin receptors, characterizing the insulin resistance
state

lipotoxic effect on the pancreas - deteriorate insulin

production progressively
Other disturbances of metabolic
syndrome Microalbuminuria 1

Microalbuminuria 20 and 200 g/min independent

risk factor for CVD, interpreted as indicative of
endothelial dysfunction at glomerular level in DM

Endothelial dysfunction - increased frequency of

microalbuminuria among patients with MS

microalbuminuria and other CV risk factors, such as

increased blood pressure, triglyceride and fibrinogen
levels, suggesting it also has a role in the prediction of
CV disease
 Other disturbances of metabolic
syndrome Microalbuminuria 2
Hyperglycemia-dependent glomerular hyperfiltration,
together with elevated blood pressure, increase
intracapillary glomerular pressure, basement membrane
permeability disturbance and glomerular capillar injury.

chronic hyperglycemic - glycosilation of structural

proteins, advanced glycosilation end products (AGEs)
accumulation and loss of the glomerular basement
membrane negative potential, which aggravates its
permeability to plasma macromolecules. Increased
production of cytokines such as TGFb, which induces
mesangial expansion, also has been involved in the
microalbuminuria determinants of diabetic patients
Abnormalities of Blood
Coagulation - Fibrinolytic System
Patients with MS - defect in coagulation-fibrinolysis system,
atherothrombosis

Activation of factor viii and von willebrand factor, elevation of

fibrinogen and plasminogen activator inhibitor 1 (pai-1), which
facilitate thrombus formation, are consequences of the insulin
resistance state

Recently, another potent fibrinolysis inhibitor has been isolated from

human plasma, the thrombin activable fibrinolysis inhibitor (taf-1).
Higher levels of TAF-1 were observed in obese diabetic patients as
compared to healthy subjects (49). TAF-1 has shown to be
independently associated with markers of obesity
Others
Hyperuricemia - associated with obesity, DM,
hypertension and dyslipidemia

Homocysteine association with atherogenesis (high

concentration in patients DM)

Markers of Inflammation (adiponectin, C-reactive

protein), relation with insuline resistence

Endothelin-1- peptide vasoconstrictor, reflecting

endothelial damage caused by the insulin resistance
syndrome
Que1- Metabolic syndrome comprises of all except

A. Hypertension
B. Dyslipidemia
C. Type 1 diabetes mellitus
D. Central/upper body obesity

Que2- All of the following parameters are included in the

diagnostic criteria of metabolic syndrome except

A. Serum HDL levels

B. Serum triglyceride levels
C. Serum LDL levels
D. Fasting plasma glucose
Que3- Various risk factors for metabolic syndrome
includes all except

A. Increasing Age
B. Obesity
C. Congenital heart disease
D. Sedentary life style
Que4- Metabolic syndrome is associated with increased
risk of all except

A. Cardiovascular disease
B. Type 2 diabetes mellitus
C. Hypothyroidism
D. Non-alcoholic fatty liver disease

Que5- Basic pathophysiology associated with the

pathogenesis of metabolic syndrome is

A. Hypertension
B. Hyperlipidemia
C. Insulin Resistance
D. Hyperglycemia