OBESITAS

DISLIPIDEMI
SINDROMA METABOLIK
Dr. M a h a t m a SpPD
SMF Penyakit Dalam F.K. UMS
SURAKARTA
 INTRODUCTION

• OBESITY NOT A NEW FENOMENA

– THE VENOUS OF WILLENDORF (25OOO YEARS AGO)

• PREVALENCE OF OBESITY INCREASE

– Di Amerika 20%(1991)40%(2001) (CARO 2002)
– Di koja, Jkt 4,2%(1982) 10,9%(1992)48,6%(2001)(SOEGONDO 2003)
– Di Sembiran 19,8%(2002), Sangsit 21,1%(2003), Denpasar
56,1%(2003)(obesitas sentral) (ARYANA 2002;SUASTIKA 2003)

• CENTRAL OBESITY HYPERTENSION, DM, DYSLIPIDEMIA,

HYPERINSULINEMIA, SOME RISK FACTORS CHD (METABOLIC
SYNDROME)
– DYSMETABOLIC CARDIOVASKULAR SYNDROM (McFarlane 2001)
Digestion and metabolism of dietary fat

1/9/2018
Lipemia is normal , however dyslipidemia is abnormal. We need lipid for
normal body metabolism . There are several kinds of lipids. Lipids are
hydrophobic therefore its must be tranferred in a hydrophilic form as
lipoprotein 11
Bile Acids
Dietary + LIVER
Cholesterol 7 LDL
Fat
2 Apo, B-100
1
Endogenous
Cholesterol

INTESTINES EXTRAHEPATIC
10 TISSUES

3 5

NASCENT HDL

LPL LPL
4 6
HDL3
LDL
REMNANTS VLDL 8 9
CHYLOMICRONS Apo E, B-100
Apo E, B-48 Apo E, C-II, LCAT HTGL
Apo E, C-II, B-48 B-100

Exogenous Endogenous CETP

HDL2
Pathway Pathway
1/9/2018
Diagrammatic representation of lipoprotein metabolism. (Oberman, 1992)
 Triglyceride-rich lipoproteins:
size, structure and composition

1/9/2018
HDL metabolism and reverse cholesterol transport

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 Inhibits oxidation Inhibits endothelial
of LDLs HDL adhesion molecules

Inhibits Stimulates
tissue factor endothelial NO
production

Enhances reverse
cholesterol transport

Opposes atherothrombosis

Potential mechanisms by which HDLs oppose atherothrombosis.

1/9/2018 (Barter. EMCNA (2004):398)
LDL metabolism and reverse cholesterol transport

1/9/2018
 Obesitas
Eropa Asia

IMT > 30 kg/m2 > 25 kg/m2

♀ > 90 ♀ > 80 cm
Waist Circumference
♂ > 102 ♂ > 90 cm

1/9/2018
 Obesity is caused by imbalance of high
Food intake and or low energy expenditure

1/9/2018
 PATOGENESIS OBESITAS
 Faktor genetik
 Parental fatness
 7 gen penyebab : - Leptin receptor
- Melanocortin receptor – 4
- Alpha-melanocyte stimulating hormone
- Prohormone convertase – 1
- Leptin
- Bardert-Biedl
- Dunnigan partial lypodystrophy
 Faktor lingkungan : - Nutrisional - Medikasi
- Aktifitas fisik - Sosial ekonomi
- Trauma
1/9/2018
 Mengapa Orang Jadi Gemuk?

SlametS 12
 EVOLUSI MANUSIA
Makanan yang
diproses

Hidup santai
Banyak gerak

25 tahun 50 tahun

SlametS 13
 Kegemukan (Obesitas)

Android Ginekoid
Gemuk tidak sehat Gemuk “sehat”
SlametS 14
 Penurunan Berat
Sindrom Badan 5-10%
Metabolik

Diabetes Hipertensi

Trigliserid Kolesterol HDL

Jantung
koroner

SlametS 15
 “Overweight and Obesity widespread, serious
But treatable”

1/9/2018
 Low Calorie Balance Diets Very Low Calorie Diets
( LCD ) ( LCD )

 Awal program : kalori  600 – 1000 kcal/hari  Formula pabrik

- Asupan lemak 
 Sering sebabkan gangguan
- Asupan KH 
metabolisme
 Kalori : 1200 – 1600 kcal/hari
 Perlu pengawasan di RS
 Protein : 1 g/Kg BB aktual
 Utk persiapan operasi
 KH : sisanya

1/9/2018
 Berbagai macam obat
Penurun Berat Badan

1. Bekerja di saluran cerna ( penghambat ensim

lipase pankreas ) : orlistat
2. Bekerja menekan pusat nafsu makan di otak :
 Lewat jalur serotoninergik : fenfluramine & dexfenfluramine
 Lewat jalur noradrenergik : phentermine
 lewat jalur serotoninergik & jalur noradrenergik : sibutramine

1/9/2018
 Complication
• Cancer
• Cardiovascular
• Diabetes Mellitus
• Gallstones
• Hiperlipidemia
• Obstructive Sleep Apneu
• Obesity Hypoventilation Syndrome
• Osteoarthritis
•1/9/2018
Polycystic Ovarian Syndrome
 DISLIPIDEMIA
Kelainan metabolisme lipid, ditandai
dengan peningkatan serta penurunan
fraksi lipid plasma.

TRIAD LIPID
 Kol-total/ kol-LDL
 Trigliserid (TG)
 Kol-HDL.
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 KLASIFIKASI DISLIPIDEMIA

• DISLIPIDEMIA PRIMER
- kelainan pada ensim atau apoprotein
- bersifat genetik
• DISLIPIDEMIA SEKUNDER
- akibat penyakit: DM, Peny.ginjal, Tiroid
- akibat obat: diuretika, penyekat beta,
kontrasepsi oral, kortikosteroid.
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 Secondary Dyslipidemia
• Pathological states
– Diabetes
– Hypothyroidism
– Cushing’s syndrome
– Nephrotic syndrome
– Chronic renal failure
– Monoclonal gammapathy
– Obstructive liver disease
• Lifestyle habits
– Obesity
– Alcohol
– Stress
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• Drugs that raise LDL-C and/or
lower HDL-C
– Oral estrogens
– Progestins
– Anabolic steroids
– Corticosteroids
– Retinoids, such as isotretinoin
– Sertraline hydrochloride
– Human immunodeficiency virus (HIV)
– protease inhibitors
– Non-selective -adrenergic
antagonists
– Cyclosporine
– Thiazide diuretics
 PENATALAKSANAAN DISLIPIDEMIA

Target : menormalkan fraksi lipid sesuai

faktor risiko PJK yang ada.

• Non-farmakologik :
- Life style  obesitas
- Terapi nutrisi
- Batasi minuman beralkohol
- Hindari merokok
• Farmakologik :
1/9/2018
- Non farmakologik + obat hipolipidemik
 Target Lipid

Kolesterol Total
 < 200 yg diinginkan
 200 – 239 batas tinggi
  240 tinggi
Kolesterol LDL
 < 100 optimal
 100 – 129 di atas optimal
 130 – 159 batas tinggi
 160 – 189 tinggi
  190 sangat tinggi
Kolesterol HDL
 < 40 rendah
 > 60 tinggi
Trigliserida
 < 150 normal
 150 – 199 batas tinggi
 200 – 499 tinggi
  500 sangat tinggi
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 OBAT HIPOLIPIDEMIK ORAL

1. Penghambat HMG-CoA reduktase

(statin)
2. Sequestran asam empedu (resin)
3. Asam fibrat
4. Asam nikotinat (niacin)
5. Penghambat absorbsi kolesterol
(ezetimibe)
6. Probucol
1/9/2018
 Penghambat HMG-CoA reduktase

• Menurunkan produksi kolesterol hepar

• Mengaktifasi Sterol Regulatory Binding
Protein (SREBP)--- ekspresi reseptor
LDL .
• Katabolisme LDL meningkat
• Uptake VLDL & IDL oleh reseptor LDL , TG plasma .
• Kombinasi dgn NIACIN atau FIBRAT-----
miopati atau gangguan fungsi hepar.
• Pd hiperkolesterolemia berat, kombinasi dg RESIN.
• Efek pleiotropik---- cegah aterosklerosis.

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 Sequestran asam empedu (resin)
• Efektif  kol-LDL
• Mengikat as.empedu di usus ---- ekskresi garam
empedu feces .
• Memotong siklus enterohepatik
Asam nikotinat (niacin)
• Hambat mobilisasi as.lemak bebas jar. perifer ke
hepar.
• Sintesis TG & VLDL di hepar 
• Hambat konversi VLDL menjadi IDL
• Meningkatkan GLUKOSA & asam urat plasma
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 NICOTINIC PERIPHERAL
ADIPOCYTE TISSUES
ACID
* Cholesterol
TG
 HDL
HSL

FFA Acyl  Acetyl 

CoA CoA

DGAT2
TG DG
HDL
Cholesterol
VLDL
PL HEPATOCYTE
Cholesterol
B100

Mechanisms of action of NA Nicotinic acid inhibits hepatic TG synthesis at the level of FA synthesis and
esterification of DG. NA also blocks apoAI-containing HDL holoparticle uptake at the liver without altering
transport of cholesterol from HDL to the liver by SRB1. Finally, NA acutely inhibits adipocyte lipolysis, but the
1/9/2018 significance of this effect on lipoprotein physiology is unclear.
Meyers EMCNA 33 (2004):561)
Fibrat (derivat asam fibrat)
- Sangat tepat untuk hipertrigliseridemia.
- Dapat untuk hiperlipidemia kombinasi
- Dapat dikombinasi dengan RESIN & NIACIN, kom
binasi dengan statin dapat timbul miopati, Gemfi-
brosil jangan dikombinasi dengan statin.
- Bekerja pada peroxisome proliferator-activated re
ceptor- (ppar-)
- Jarang: transaminase hepar naik, batu empedu,
kreatin kinase otot naik, libido turun.
- Efek potensiasi dg Obat Hipoglikemik Oral dan an-
ti-koagulan oral.
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 FIBRATES
gemfibrozil, fenofibrates

Glitazones

Eicosanoids

PPAR
PPAR

- Activated PPAR
Nucleus - Retinoid R
PPAR

AGGTCA N AGGTCA

Target Genes Regulating 5

PPRE Lipoprotein Metabolism
(Peroxysome Proliferator Responsive Elements)

Mechanism
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of action of fibrates on lipoprotein metabolism.
Peroxisome Proliferator-Activated Receptor- a transcription factor
 Penghambat absorbsi kolesterol
(ezetimibe)

• Hambat kol. makanan & kol. Cairan empedu di

usus halus. (NPC1L1).
• Timbunan kol. di hepar .
• Klirens kol. plasma .
• Utk  kol-total, kol-LDL dan Apo-B pd
hiperkolesterolemia primer.
• Efektif sbg mono terapi maupun kombinasi dg
statin.

1/9/2018
 Primary Lipid Goal Drugs of Choice

LDL-C (or non-HDL-C) 1st : Statin, Resin, Ezetimibe

per NCEP calculations 2nd : Nicotinic Acid
3rd : Combination

1st : Nicotinic Acid

Secondary Lipid Goals (TG 150-400)
TG < 150 mg/dl Fibrate / fenofibrate
(TG >400)
2nd : Statin, Fish Oil
3rd : Combination

1st : Nicotinic Acid

HDL-C > 40 (men)
2nd : Fibrate, Statin
> 50 (women)
3rd : Combination

The role of nicotinic acid in the treatment of the metabolic syndrome. Nicotinic acid is an effective agent
in the attainment of both primary and secondary goals set by the NCEP. (Meyers. EMCNA 33 (2004):570)
1/9/2018
 Cholesterol balance in man

Extrahepatic Dietary
Organs LDL IDL VLDL Cholesterol
300 mg/day
25%
Cholesterol
Synthesis
900 mg/day Biliary
Cholesterol Cholesterol
Synthesis 75%

Transport
via HDL & LDL Chylomicron transport
50% intestinal Faecal sterols
Cholesterol absorbed 50% cholesterol
excreted
Cholesterol lowering drugs
1/9/2018 Statins Ezetimibe Plant stanols Resins
Summary of the major drugs used for the treatment of hyperlipidemias
(Rader 2004)

Drugs Major Mechanism Common side effects

indications
↓ cholesterol
Statins Elevated LDL synthesis, LDL Myalgia, arthralgia, dyspepsia,
hepatic receptor ↑ transient transaminase elevation
VLDL production ↓
Bile acid ↑ bile excretion ↑LDL Bloating, constipation, elevated
sequestrant Elevated LDL receptors TG
(BAS)
Nicotinic acid Elevated TG, low ↓ VLDL hepatic Cutaneous flushing, elevated
(NA) HDL, elevated TG synthesis glucose and UA, and LFT
Fibric acid Elevated TG, and ↑ LPL, ↓ VLDL Dyspepsia, myalgia, gallstones,
derivatives remnants synthesis OT/PT ↑
Severely elevated ↓ VLDL and
Fish oil TG chylomicron Dyspepsia, fish odor, diarrhoea
production
Specific
Cholesterol ↓Intestinal cholesterol
absorption Elevated LDL absorbtion Elevated transaminase
inhibitors
(SCAI)
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 Tabel 7. Obat Hipolipidemik
Obat Dosis

Gol. Resin Pengikat Asam Empedu

- Kolestiramin 4 – 24 gr/hari
- Kolestipol 5 – 30 gr/hari
Gol. Asam Nikotinat
- Asam Nikotinat 100 mg/ 2 x sehari ditingkatkan
sampai 1,5 – 3 gr/hari
- Acipimox 250 mg 2 x sehari
- Niacin ER 1000 – 2000 mg 1 x sehari
Gol. Statin
- Fluvastatin 40 – 80 mg malam hari
- Lovastatin 5 – 40 mg malam hari
- Pravastatin 5 – 40 mg malam hari
- Simvastatin 5 – 40 mg malam hari
- Atorvastatin 10 – 80 mg malam hari
- Rosuvastatin 10 – 40 mg malam hari

1/9/2018
 Lanjutan

Obat Dosis

Gol. Asam fibrat

Bezafibrat 200 mg 3 x sehari atau
400 mg sekali sehari (retard)
Fenofibrat 100 mg 3 x sehari atau
300 mg sekali sehari
Gemfibrozil 600 mg 2 x sehari atau
900 mg sekali sehari
Golongan lain
Probukol 500 mg 2 x sehari

Penghambat absorbsi lemak

Ezetimibe 10 mg sekali sehari

1/9/2018
 Leptin

Adiponectin

Resistin

Adipsin (ASP)

Angiotensinogen/AT-II

Cytokines
(TNF-, IL-6)

Insulin kurang baik kerjanya

Decreased Acanthosis
fibrinolytic activity nigricans

Hyperuricemia NASH

EAGLE FLIES ALONE, MHT

 Dasar
Cardioprotective

Adiponectin and Clinical Consequences

Type 2 diabetes and

Atherosclerosis
glycemic disorders

Dyslipidemia
– Low HDL
– Small, dense LDL
Visceral – Hypertriglyceridemia
Obesity Hypertension

Endothelial dysfunction/
inflammation (hsCRP)

Impaired thrombolysis
 PAI-1
Insulin resistance and -cell dysfunction are linked

Increased
lipolysis and Elevated
release of circulating FFA
free fatty
acids
High insulin
Insulin
demand -cell
resistance dysfunction

Decreased glucose
uptake into muscle
and adipose tissue Hyperglycemia
and raised hepatic
glucose output
Pathogenesis ? Even suggested pathogenesis is useful for prevention program.
a. Genetic abnormality b. Fetal malnutrition c.Visceral obesity

Food intake Genetic Physic

excess background inacting

Adipo Genesis Overweight

Obesity

Insulin Resistance

Pancreatic Hyperinsulinemia
-cell stress &
damage
*
“Inadequate” Compensatory
Insulin Response Hyperinsulinemia

Type 2 Diabetes Insulin Resistance

Syndrome

CVD
Retinopathy Hypertension
Nephropathy Stroke
Neuropathy PCOS
NAFLD
*ACE position statement (2003)

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Differentiation between the Insulin Resistance Syndrome and type 2 diabetes.
Modified from ACE (2003) & Tenenbaum (2003) (Djokomoeljanto, 2004) DM-BR- 2004
 Autocrine
Endocrine
Paracrine

PAI-1 Leptin

TGF-β ?TNFα
?IL-6
TF
Adipsin/ASP Sex steroids
Glucocorticoids
?TNF-α /IL-6/Leptin
?Angiotensin
Renin-Angiotensin
system ?PAI-1

Steroid hormones ?Adiponectin

Adipose tissue
?AdipoQ

Factors FFA, TNF and PAI-1 can affect peripheral tissues

1/9/2018
 PROTEIN YANG DISEKRESI ADIPOSIT

1. ESTROGEN 16. VISFATIN 31. RBP

2. LEPTIN 17. HSL 32. APO-E
3. AGOUTI RELATED PROTEIN 18. LIPOTRANSIN 33. ICAL
4. TNF α 19. PERILIPINS 34. LPL
5. IL1B 20. FFAs 35. CETP
6. IL-6 21. TGF-β 36. PLTP
7. ANGITENSINOGEN 22. VEGF 37. NO
8. ASP 23. IGF-1 38. PC-1
9. ADIPSIN 24. PGE2 39. AQUAPORINS
10. FACTORS B,C3 25. PGI1 40. FIAF
11. ADHESIVE PROTEIN 26. GLUCOCORTICOID 41. LACTATE
12. PAI-1 27. 11βHSD 42. MONOBUTYRIN
13. TF 28. AROMATASE 43. GALACTIN-12
14. RESISTIN 29. METALLOTHIONIEN 44. ESM-1
15. ADIPONECTIN 30. MIF 45. APELIN

(TJOKROPRAWIRO 2003)
AUGUST 3-7TH 2006 INTERNATIONAL SYMPOSIUM SHOCK AND CRITICAL CARE
Definitions of the metabolic syndrome
(Bloomgarden 2004, 1st Conggress on Insulin Resistance Syndrome)

ATP III WHO AACE (IRS) EGIR (IRS)

IGT/HOMA-IR, One of ** Fasting hyperin-
IFG/DM and sulinemia( highest
2 of 4 below quartile) and
At least 3 of 5 And 2 of 4 2 of 4
Uirinary alb exc > 20 g / m
WHR male 90 in men
female 85 in women
Waist CF male >102 cm  94 cm
female > 88 cm  80 cm
Triglycerides  150 mg/dl 150 mg/dl or 150 mg/dl or 2.0 mmol/l or
HDL chol male 40 mg/dl 35 mg/dl 40 mg/dl  1.0 mmol/l
female 50 mg/dl 39 mg/dl 50 mg/dl
Blood pressure 130/8 5mmHg  140/90 mmHg 130/85 mmHg 140/90 mmHg or
treated for Hyp.
Blood glucose  110 mg/dl FBG 110-125 or FPG 6,1 mmol/l
2hpc 140-200 (exc.DM)

** CVD, hypertension, PCOS, NAFLD, family history of T2DM / hypertension / CVD, history of
gestational
1/9/2018 diabetes, non Caucasian, sedentary lifestyle, BMI>125 or WC>40 male, >35 female,
age>40yrs
 S U M M A R Y
Definisi Dx Drug Komplikasi
Cancer
Akumulasi Cardiovascular
jaringan lemak Diabetes Mellitus
berlebihan, baik Orlistat Gallstones
IMT
Obesity besar maupun Sibutramine Hiperlipidemia
WC Obstructive Sleep Apneu
jumlahnya
Obesity Hypoventilation Syndrome
Osteoarthritis
Polycystic Ovarian Syndrome

Kelainan TG Statin
metabolisme CH Niacin Aterosklerosis accelareted
Dislipidemi Ezetimibe C H D
lipid LDL
HDL Nicoitinic SNH

WC Dislipidemia
Kumpulan Ht C H D, SNH
gejala yang DM Hipertensi
Metabolic disebabkan oleh TG Metformin Diabetes Mellitus
Syndrome karena obesitas CH Glitazone NAFLD
sentral ---- ------ LDL PCOS
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Insulin resisten HDL Hperuricemia
Alb Microalbuminuria
 ↓ AMPK 51 1 ↓ INSULIN RESISTANCE 2 ↓ 1 h PP (↓ PmH)
β-Endorphin 50 3 ↓ FPG
↓ ADMA 49 4 ↓ VAT

↑ Apn 48 5 ↓ WC

↓ Resistin 47 6 ↓ Glucose Absorption

↓ Leptin 46 56↓ FOXO1/ ↓FABP4 7 ↑ Glycogenesis
↓ NFKB 45 8 ↑ Insulin Rec. Binding
↓Cytosolic Ca++ 44 9 ↑ GUT : GLUT-5 Expression
↓SMC Fibroblast 43 10↑ Post-Receptor Effect
↑ Plaque Regression 42 11↓ Glucolipotoxicity
↑ NO (↑ HSP-90, ↑ eNOS) 41 METFORMIN 12↓ Oxidative Stress
↓ Capillary Permeability 40 MIRACLE 13 ↓ Inflammation
↓MMP-9 39 ↓ FFA
14
↑ Peripheral A. Blood Flow 38 ↓TG, ↑ HDL-C, ↓Tot-C, ↓ LDL-C
15
56
↑ PTEN 37 16 Synthesis & Secretion of GLP-1
EFFECTS
↓HT-29 36 17 ↓ AGE
↓ LNCaP 35 18 ↓ Fibrinogen
↓ PC-3 34 19↓ Factor-VII (TF)
↓DU 145 33 20 ↓ PAI-1
↓ cyclin D1 32 21 ↓ Factor-XVIIIA
↑ TSC2 31 22 ↓ TSH
↑ TSC1 30 23 ↓ Respiratory Complexl
↓ mTORC1 29 24 ↑ Erythrocyte Deformability
↑ LBK1 28 25↓ Platelet Aggregation
↑ p53 27 26↓ Hyperinsulinemia

FIGURE-4 MET with 56Metabolic-Cardiovascular-Carner (MMC) Protective Effects

(MMC : Metabolic Cardiovascular Cancer protector IIIustrated : Tjokroprawiro 1994-2011

1/9/2018
VasokonstriktorVasodilator Proinflamasi AntiInflamasi

-PDGF, Tissue factor -Prostacyclin

-Prostacyclin
-Von willebrand factor -Thrombomodulin
-Endothelium-1 -Nitric oxide -PAI-1 -Ecto-ADPase
-Angiotensin-II -Other “EDRF-Like” - Coagulation factor -TPA
-Thromboxane A2 Substances -ILGF, ROS -Urokinase
-Prostaglandin -Acethylcholine -Interleukin -Heparin sulfat
Thrombomodulin -Angiotensin II - Nitric Oxid
 overview
Atherothrombosis:
A Generalized & Progressive Disease
Atherosclerosis Atherothrombosis
Foam Cells Intermediate Lession Plaque
Fatty Streak ATHEROMA Rupture

ACS

Dekade ke I - III Dekade IV Dekade V

ATHEROSCLEROSIS DIMULAI UMUR 5 TAHUN

1/9/2018
gejala
 overview

RISKMODIFIABLE
NON FACTOR:
AGE, GENDER, FAMILY
MODIFIABLE
RESIKO TRADISIONAL : :
OVERWEIGHT, HIPERTENSI, SMOKING
NONPHISICAL INACTIVITY, DISLIPIDEMIA,
MODIFIABLE DM
RESIKO INFLAMASI :
HIPERURICEMIA, STRES PSIKIS
MODIFIABLE
FAKTOR RESIKO INFLAMASI :
BAKTERI CHLAMIDIA
,
FAKTOR RESIKO TROMBOGENIK:
FAKTOR RESIKO
FIBRINOGEN RENDAH,TROMBOGENIK
ESTROGEN RENDAH
HOMOSISTEIN TINGGI, PAI-1, D DIMER, Tpa
VON WILLEBRAND
Modifiable risk factors
Vasculotoxic consequences of
postprandial plasma glucose increase

Postprandial
plasma glucose 
Endothelin Generation of
release free radicals

 Endothelial  Endothelial
function  Glycosylation Expression function 
 Vasoconstriction of functional of adhesion  More aggressive
proteins molecules lipids

 HDL activity   Xanthoma cell generation  Cholesterin

 NO release   Growth factors  adhesion
 Vasodilation   Proliferation of vascular
 Collagen  smooth muscle cells 

Vascular damage with generation of atherosclerotic plaques

TEORI ATHEROSCLEROTHROMBOSIS patofisiologi

ATHEROSCLEROSIS THROMBOSIS PENYAKIT

 Disfungsi Endotel
 Infiltrasi L D L - PJK
 Radikal bebas Inflamasi - SNH
 Imunologi
 patofisiologi

tissue factor PAI-1

S S S i i i i i

Permeabel

Hiperinsulin

S = selectin

i = imunoglobulin( VCAM dll)

INTIMA

SS
 patofisiologi
MONOSIT
LDL
DM
tissue factor PAI-1
S S S i i i i i

LDL
kecil LDL
ox SEL BUSA

Radikal
Bebas.
AGEs

Makrofag
INTIMA

MEDIA SEL OTOT POLOS

SS
 MONOSIT LUMEN
Glukose fibrinolisis
LDL agregasi tr.

DM
tissue factor PAI-1
S S S i i i i i
PLAQUE
LDL PLAQUE
kecil LDL
ox Hiperinsulin
SEL BUSA

Radikal
Bebas. Migrasi
AGEs

Makrofag
INTIMA

Sitokin+ f. pertumbuhan

Proliferasi
MEDIA SEL OTOT POLOS SS
 Mo von Willebrand
P,E-selectins EC
Mo
PSGL-1
VLA-4
VCAM-1
Mac-1, LFA-1
Native LDL ICAM-1
Foam cell

Cytokines
Mo
MCP-1
M-CSF
Proteo- Mo M + HSP-60
glycans
CD40
+ CD40L
MM-LDL LysoPC Oxygen CD36
radicals + T
+
+ SR-A1 CD14
Cell mediated oxidation TLR4 LPS
Oxidized LDL

SMC

Foam cell formation in the intima. LDL can pass into / out intima. If excess it is trapped in the matrix by proteoglycans
binding. At antioxidants lack, lipids and LDL proteins are oxydized by oxidating products from cells in the vessel wall. LDL
proteins are also glycated. Extensive uptake of m-LDL via scavenger receptors (CD36 and SR-A)  macrophages are turned into
1/9/2018
foam cells. This process is accelerated by (1) MCSF, (2) LPS via receptor CD14 with toll-like receptor 4 (TLR4), (3) by heat shock
protein (HSP-60) via CD14, (4) by PAF and cytokines released from macrophages in an autocrine loop.(Mehrabian 2003)
 Progression to advanced atherosclerotic lesions (3rd step)
Lumen MC
Native Monocytes
LDL
5LO MCP-1 Platelets
LTA4 LTB4
Chemotaxis BLTR
EC
Matrix

MM-LDL
ROS TC Advanced
M-CSF GM-CSF plaque

5LO
Lipid DC IL-1/TNF
Cell ROS
oxidation proliferation
SMC cell proliferation
Cytokine 5LO
oxLDL uptake induction
by SRA GM-CSF NC
5LO
Intima TNF-
Macrophage
IL-1 Procoagulants SMC
adhesion
NF-B, cytokines

Media

5LO (5 –Lipoxyoxygenase) and (LTB4) (leukotriene B4) plays very important role in
1st, 2ndand
the1/9/2018 3rdstep of atherogenesis besides LDL oxidation and oxidized LDL
(Mehrabian, 2003)
patofisiologi
 ATEROSKLEROSIS menjadi PLAK VULNERABLE
(LIPID DAN MAKROFAG MENINGKAT)
(SEL MAST DAN OTOT POLOS MENURUN)

PEMICU INFLAMASI :
INFEKSI, STRES, MEKANIK
HEMODINAMIK

PLAQUE RUPTUR/ PENIPISAN PENURUNAN ISI

DISRUPSI PLAQUE CAP KOLAGEN

PLATELET PHOSPOLIPID
VWF ACTIVITY

Adhesion
FIBRIN
FORMATION OKLUSI KORONER/
TROMBUS SINDROM KORONER AKUT
ADP Agregation
TXA2
 CRP, inflammation, and endothelial activation

1/9/2018
 LOKASI NYERI ANGINA GAMBARAN KHAS
NYERI ANGINA

Infark : 2 dari 3
(Angina, EKG khas, Enzim )
Lansia dan atau DM sering
tak terasa nyeri
Diagnosa
Diagnosa
Diagnosa
Diagnosa
TEORI ATHEROSCLEROTHROMBOSIS patofisiologi

ATHEROSCLEROSIS THROMBOSIS PENYAKIT

 Disfungsi Endotel
 Infiltrasi L D L - PJK
 Radikal bebas Inflamasi - SNH
 Imunologi
 ATEROSKLEROSIS menjadi PLAK VULNERABLE
(LIPID DAN MAKROFAG MENINGKAT)
(SEL MAST DAN OTOT POLOS MENURUN)

PEMICU INFLAMASI :
INFEKSI, STRES, MEKANIK
HEMODINAMIK

PLAQUE RUPTUR/ PENIPISAN PENURUNAN ISI

DISRUPSI PLAQUE CAP KOLAGEN

PLATELET PHOSPOLIPID
VWF ACTIVITY

Adhesion
FIBRIN
FORMATION OKLUSI KORONER/
TROMBUS SINDROM KORONER AKUT
ADP Agregation
TXA2
 patofisiologi
AGGREGATION
ADHESION
Platelet
cAMP
VWF GPIIb-IIIa
Fosfodiesterase(-) Fibrinogen
ATP

PKC ADP, Ca2+

Thromboxane A2 serotonin
Epinephrine DAG

ADP PGG2, PGH2 PF4, TG

Thrombin PIP2 PLC
COX PDGF
Fibrinogen
PAF Arachidonic Acid vWF
Thromboxan IP3 phospolipase
e
Collagen phospolipid

Kanal CALSIUM
PLATELET
COAGULATION
ACTIVITIES
 AGGREGATION
ADHESION Platelet

cAMP
VWF GPIIb-IIIa
Fosfodiesterase(-) Fibrinogen
ATP

PKC ADP, Ca2+

Thromboxane A2 serotonin
Epinephrine DAG

ADP PGG2, PGH2 PF4, TG

Thrombin PIP2 PLC
COX PDGF
Fibrinogen
PAF Arachidonic Acid vWF
Thromboxan IP3 phospolipase
e
Collagen phospolipid
PLATELET
Kanal CALSIUM
COAGULATION
ACTIVITIES

Antiplatelet Drugs Mechanism of Action

Antiplatelet Drugs Mechanism of Action

Clopidogrel

ADP
Ticlopidin
Dipiridamol
ADP

GPllb/llla
Inhibitor
Collagen thrombin
Beta blocker TXA2
Calcium Chanel
Blocker ASA
COX

FOR INTERNAL USE ONLY

 Mekanisme Hemostasis
Extrinsik Intrinsik
Anti koagulan/ Proses lisis Fibrin
Coagulasi

D dimer,FDP
IX Heparin + AT3

VIII +
Fibrinogen Fibrin
F Fibrin Polimer
Protein C XII Monomer
V+X i
Protrombin Trombin b
r
i Antiplasmin
n
Plasminogen Plasmin
Agregasi trombosit
PAI 1

Fibrin Clot
tPA
Urokinase
Streptokinase

EAGLE FLIES ALONE, MHT

ATHEROSCLEROTHROMBOSIS THERAPHY

• DIET : tinggi L Arginin, Rendah Lemak

• POLA HIDUP :olah raga, menghindari ROKOK
• ACE INHIBITOR
• ANTI OKSIDAN
• OBAT PENURUN LEMAK
• ANTAGONIS KALSIUM
• BETA BLOKER
• METFORMIN
• ASPIRIN, TICLOPIDIN
• CLOPIDOGREL
• PIOGLITAZONE
• PENTOXYFILLINE
• C ILOSTASOL
 Atherosclerothrombosis therapy

Dislipidemia Hypertension

Statins ACE Inhibitors

Fibric Acid Derivatives ARB
ATHEROSCLEROSIS Β-Blocker
THROMBOSIS Calcium Channel Blockers
Diuretics

Anti Platelet Activation

Insulin Resistance
and Aggregation
Metformin Aspirin
Thiazolidinediones Clopidogrel
Ticlopidine