Atherosclerosis

Degenerativ ilness of vessel wall.

Chronic process, change of function
and structure of vessel wall (intima,
mediaformation of atheroma plques,
rupture, trombosis) oclusion of the
vessel and ischemia
CVD (IHD, stoke, PAD)
Time course of AS
 Risc factors

Metabolic syndrome
Hyperinzulinemia
Obesity
Dyslipidemia (cholesterol, triglicerides)
Hypertension
Diabetes mellitus
Smoking .
Age, heredity, diet, exercise
 Why insulin resistance matters?

Genetic factors Insulin Environmental

resistance effects

hyperinsulinemia

Increased Lowered HDL Small dense

Glucose tolerance
triglycerides cholesterol LDL

Endothelial Hypercoagulable
hypertension state
dysfunction

Cardiovascular
disorders

Modified from Reaven G. In: LeRoith D, et al, eds. Diabetes Mellitus: A Fundamental and Clinical Text.
2000;Philadelphia, PA: LWW pp604-614.
 Metabolic syndrome:
Definition according to IDF

women men
Europe 80 94

Waist circumference South Asia 80 90

China 80 90
Japan 90 85
Plus 2 or more other categories

high triglycerides (>1.7 mmol/l)

low HDL cholesterol ( < 0.9/1.1 mmol/l)
Arterial hypertension ( >130/85 mmHg)
Higher fasting glycemia (> 5.6 mmol/l)

Berlin, April 2005

 Waist circumference is an auxiliary
marker of visceral fat amount

Women cm Men
>88 cm = considerably increased risk 1 >102 cm = considerably increased risk1
>80 cm = increased risk1 >94 cm = increased risk1

1Lean MEJ, et al. Lancet;1998:351:8536

Clinic manifestations of insulin resistance

Central obesity

Visceral fat
MetS increases cardiovascular mortality
3.6fold

Kuopio Ischaemic Heart

15 CV mortality Disease Risk Factor
RR (95% CI) Study
3.55 (1.986.43)
Cumulative risk, %

10
Metabolic
syndrome

5
Without
metabolic
syndrome

0 2 4 6 8 10 12 years

Lakka HM et al. JAMA 2002;288:2709-2716.

Obesity

orlistat
GLP-1
Adipose tissue
hormonal activ organ

Leptin (1990)
FFA

Peptidy

Steroidy

TNF-

IGF-1

Angiotenzinogen

Resistin
 Physiology

Lipid are insoluble in water thus they are transported in bloodstream as

macromolucular complex

The complexes are surrounded by a stabilizing coat of pospholipids.

Protiens (apoprotiens) embeded into the surface of lipoprotien particles &

allows the particles to be recognized by receptors in the liver and periphral
tissues.
 Biochemistry of blood lipids

Cholesterol 3.5 6.5 mmol/L

Male: 0.95 2.15 mmol/L
HDL Cholesterol
Females: 0.7 2.0 mmol/L
LDL 1.55 4.4 mmol/L

VLDL 0.128 0.645 mmol/L

Male: 0.7 2.1 mmol/L
Triglyceride
Female: 0.5 1.7 mmol/L
 LIPOPROTEIN SUBCLASSES

Cholesterol Triglycerides Chylo-

0.95
microns

1.006 IDL
Chylomicron
Density (g/mL)

VLDL Remnants
1.02 LDL
Phenotype A
Phenotype B

1.06 HDL2
1.13 HDL
3
Apo B
1.20

5 10 20 40 60 80 1,000
Diameter (nm)
Adapted from Freedman DS, et al. Arterioscler Thromb Vasc Biol. 1998;18:1046-1053.
http://www.med.unibs.it/~marchesi/lipoprot.html
 DM - hypertension

50 70 % of DM 2 have hypertension
Recomendation: Blood presure< 130/85

ACEI MIA, proteinuria, retinopathy

Sartans
 The lipid lowering diet
The main aim of lipid loweing diet are:

-Reduce the total fat intake: dairy products and meat are the principal sources
of saturated fat in the diet,intake of these products should be reduced and
substituted with fish and poultry.sausages, fried food, pastries and cakes
contain large quantities of fat and should be avoided.

-Substitution with monounsaturates and polyunsaturates: monounsaturated oils

like olive oil,and polyunsaturated oils such as sunflower,corn and soya oil
should be used un cooking instead of saturated fat.

-Reduce the dietary cholesterol intake: liver,offal, and fish roes should be
avoided.

-Increase the intake of fibre: food high in soluble fibre,such as pulses, legumes
and root vegetables help reduce circulating lipid concentrations.

-Reduce alcohol consumption and achieve an ideal bodyweight.

 Pharmacology

Mainly we have 3 groups of drugs that are used for lowering lipid levels:

1-Fibrates: -They raise HDL concentration and reduce LDL cholesterol by

10-15 %.

-Useful in patients with modest hypercholesterlaemia.

-Gemfibrozil has been demonstrated to reduce the incidence of

cardiovascular events.

-Clofibrate is rarely used and is associated with an increased

incidence of gallstones.
 Pharmacology

2- Bile acid binding resins: -They produce an 8-15% reduction in LDL cholesterol
concentration.

-Cholestyramine has been shown to reduce the

incedence of cardiovascular events in
hypercholesterolaemic patients.

-They have a synergistic effect when given with

statins.
this combination can reduce LDL cholesterol
concentration by 50-60%.
 Pharmacology

3- Statins: -The most potent cholesterol-lowering agents available and They can
reduce LDL cholesterol concentrations by 30-40%.

-Simvastatin and pravastatin reduce both mortality and cardiovascular

morbidity in hypercholesterolaemic patients.Pravastatin reduce the risk
of another heart attack in patients with cholesterol concentrations in
upper half of the normal range (4.0 6.0 mmol/L).

-Other functions of statins include: Improving endothelial function.

Modulate inflammatory responses.
Maintain plaque stability.
Prevent thrombus formation.

-statins may have some side effects like: myalgia and muscle cramps.
 Atheroma plaque stabilisation

Regular exercise
TK, supression of neurohumorl activation (beta-
blockers, ACE inhibitors)
Acetylosalicylic acid - 25% reduction of MI, cerebral
ischemias and mortality
hypertriglyceridenemia - Insulin, Fibrates
Hypercholesterolemia - Statins Cl: CCH=4,5-5 mmol/l,

Targets: LDL=2,5-3, HDL 1, TG < 2 mmol/l

 Secondary hyperlipidaemia

-Diabetes mellitus

-0besity

-Renal impairment

-Hypothyroidism

-Nephrotic syndrome

-Hepatic dysfunction

-Drug: like oral contraceptive, thiazides diuretics,

corticosteroids.
 Osteoporosis - definition

Disorder of body structure with reduced rigidity of bones

with predisposition to increased risc for fractures
Consistence of bones consist of bones density and bone
quality.

Health bone Osteoporosis

NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

Bone metabolism
Osteoporosis without treatment

10 rok 20 rok
 Osteoporosis
Reduced rigidity of bones
Increased risk of fracture

Bone
rigidity
Bone quolity + Bone density

1. Architecture
2. Bone turnover
3. Accumulation of microtraumas
4. mineralisation
5. Infuence of osteoclasts and osteoblasts
NIH Consensus Development Panel on Osteoporosis. JAMA 2001
Inbalance between new bone production
and bone resorption
 Risk factors

Age
History od fracture with small injury
Low BMI
Corticosteroids
Familly history of fractures
Smoking
Regular alkohol drinking
Patological densitometry examination

Kanis JA et al, Bone, 2002;30:251-258

Kanis JA et al, Osteoporos Int, 2005;16:581-589
 Regulation of Ca metabolism

Ca2+ Ca2+ reabsorption

PO43 excretion
kidney

PTH calcitriol normal Ca2+

parathyroid
gland
Ca2+
PO43
kost release

Brown EM. In: The Parathyroids Basic and Clinical Concepts 2nd ed. 2001. Bilezikian JP et al. (eds)
PTH, parathyroid hormone
 Vitamin D
7-dehydrocholesterol
UV light

Vitamin D3 - cholecalciferol Muscle strength

25-hydroxylase

Calcidiol 25(OH)D3
parathyroids
Calcitriol hypercalcemia
1,25(OH)2D3 hypercalciuria
1alpha-hydroxylase

osteoblast RANK-L
corticoids, inflammation (-)
resorption
 Beta cells
Imunomodulation Psoriasis

Vit. D receptors Increases

muscle strength
Calcitriol
Hematopoetic sys.
Reduces proliferation Reduces
Increases differentiation PTH synthesis

Reduces tumor cell

proliferation of
a prostate and bowels
Influence of Ca on nonvertebral bone fractures

Cumulative incidence (%) 15

Placebo
Calcium and vitamin D
p=0.02
10

5
0 6 12 18 24 30 36
month

0
Dawson-Hughes B, et al. N Engl J Med 1997;337:6706
Senile osteoporosis
Low active
vitamin D

hypokalcemia

PTH
Calcium a vitamin D are basic treatment for
senile osteoporosis + other treatment
modalities

Calcium = 500 - 1000 mg / day

Vitamin D 3 = 800 IU/ day
 Womens Health Initiative

6700 old women with 5.2 years of follow-up

Vertebral fracture
Intestinal cancer
Differences % vs. placebo

Disadvantages

Hip fracture
160
120 +112%
80
40 +29% +41% +26%
0
Tromb. venous

Breast cancer
Cardiovascular
diseases

Stroke

-40 -37% -34% -34%

-80

Advantages

Manson JE at al, N Engl J Med, 2003;349:523-534

 Bisfosfonty

N-obsahujc bisfosfonty N-neobsahujc bisfosfonty

inhibice prenylace (inkorporovny do intracelulrnch
analog ATP apoptza)
Seazeny podle schopnosti
inhibice kostn resorpce Etidront - CH3

Pamidront - 100x Clodront - Cl

Alendront - 100-1000x
Tiludront - SC6H5Cl

Risedront - 1000-10000x
Ibandront

Zoledront - >10000x
 kalcitonin
(-)

(-)
Kalcidiol
(+)

Ca
P
Hyperkalcemie Na

Kalcitriol
hyperkalciurie
hyperfosfaturie
hypernatriurie
Stroncium ranelat
 PROTELOS

Bone production Bone resorption

PROTELOS + Pre-OB Replikace Pre-OC

Diferenciace - PROTELOS

OC
OB
Aktivita kostn tvorby +

- PROTELOS

Kost. resorpn aktivita -

Pre-OB: preosteoblast; OB: osteoblast
Pre-OC: preosteoklast; OC: osteoklast

Marie PJ et al. Calcif Tissue Int. 2001;69:121-129.

Preventing osteoporosis

C alcium
Vitamin D
E xercise
Prevent F alls
G ain weight
Stop S moking