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Gatot S. Lawrence
Consultant, Cardiovascular Pathology
Kedokteran Keluarga
Kedokteran Forensik-Medikolegal
Vascular Research Unit
Department of Pathology
RSUP Dr. Wahidin Sudirohusodo
Faculty of Medicine Universitas Hasanuddin
Makassar - Indonesia
Lahir
Genotype
Molecular - Microenviroment
MED
Genotype
Cellular - Microenvironment
Pre-Morbus
Genotype
Organs - Microenvironment
Morbus
Morbus + Complication
Endotel Vaskuler
Membran semipermeabel
Non-thrombogenic interface
Modulasi tonus vaskuler dan aliran darah
Metabolisme hormon
Regulasi reaksi imun dan radang
Modifikasi lipoprotein pada dinding arteri
Regulasi pertubuhan tipe sel lain : tu sel
otot polos
Vascular Endothelium
Continues
Single-cell-thick membrane
Virchow R (1856) Wien Med Wochenschr :
Ross R (1973) --- Nature
Modern cellular & molecular biology
Working concept
dramatic evolution
Lawrence GS
Regional Specialization
Lawrence GS
PRO-THROMBOTIC
ANTI-THROMBOTIC
Prostacyclin
Nitric Oxide
Ecto-ADPase
Thrombomodulin
Heparin-like Molecule
Alpha2- macroglobulin
Tissue Plasminogen
Activator
Urokinase
CONSTRICTOR
Endothelin - 1
Angiotensin - II
Vasoconstrictor
Prostaglandins
DILATOR
Prostacyclin
Nitric Oxide
Other EDRF
Substances
Platelet
Lymphocytes
RBC
Monocytes
Leukocytes
Lawrence GS
Endothelial Stimulation
Rapid (within minutes)
Reversible responses
Independent of new protein
synthesis
Example: EC changes induced by
histamine, serotonin,
vasoactive mediators
Pober J, Contran RS: Cytokines and endothelial cell biology.
Physiol Rev 70:427,1990.
Endothelial Activation
Reflect alterations in gene
expression and protein
synthesis
Sialyl-Lewis X
Selectin
ELAM- 1
Activated
Integrin
(LFA-1)
Integrin
ICAM-1
Endothelial Dysfunction
Lawrence GS
Endothelial Dysfunction
The term is often used to describe
several types of potentially
reversible changes in the
functional state of endothelial cells
that occur in response to
environmental stimuli.
Pober J, Contran RS: Cytokines and endothelial cell biology.
Physiol Rev 70:427,1990.
IMPORTANT IN HYPERTENSIVE
PATIENTS ?
Circulating
*kiren
eg: Alleskiren
Renin inhibitors
*pril
eg: Captopril; enalapril;
Peridonpril; ramipril
ACE inhibitor
*pril
eg: Captopril; enalapril;
Peridonpril; ramipril
Tissue
Angiotensinogen
Renin
Angiotensin I
Converting enzyme
Angiotensin II
Angiotensin
receptors
Non-ACE pathways
- Chymase
- CAGE
- Cathepsin G
Remodeling
Stimulation of matrix glycoproteins and
matrix metalloproteinase production
Stimulation of VSMC hypertrophy,
migration, and proliferation
Increased expression of growth factors
Increase fibrosis
Inflammation
Increased expression of MCP-1, TNF-,
IL-6, VCAM and ICAM
Activation of NADH/ NADPH oxidase
Production of superoxide anions
Activation of monocyte and
macrophage cytokine production
Thrombosis
Increased platelet activation,
aggregation, and adhesion
Stimulation of PAI-1 synthesis
Reduced Plasminogen Activator
Alteration of the tPA/ PAI-1 ratio
Increased inflammation
Vasoconstriction
Stimulation of AT1 receptors
Increase destruction of NO
Enhanced release of norepinephrine
and endothelin
Decreased baroreceptor sensitivity
Reduced vasodilatory prostaglandins
Thrombin
Shear Stress
Homocysteine
Altered Permeability
Hypoxia
Cytokines
Vasoactive Substances
Leukocytes Adhesion
Growth Factors
Chemoattractans
Procoagulant Activity
DiCorleto PE, Soyombo AA.: Curr Opin Lipiddol 1993;4:364-372
GSL Lao
Dyslipidemia
Hypertension
Hypoxia/ischemia/
reperfusion
Smoking
Diabetes
Oxidative stress
Endothelial dysfunction
NO
PAI-1
Thrombosis
Local mediators
VCAM,
ICAM
Inflammation
Tissue ACE
PAI-1
Vasoconstriction
Angiotensin II
Growth Factor
matrix
Proteolysis
Vascular lesion
Plaque rupture
Monocytes
Platelet
Lymphocytes
Leukocytes
RBC
Lawrence GS
MCP-1
GS Lawrence 2005
Sub-endothelium
1. Nichols WW, ORourke MF. McDonalds Blood Flow in Arteries: Theoretical, Experimental and Clincal Principles. 5th edition.
London: A Hodder Arnold Publication; 2005.
2. Slager CJ, Wentzel JJ, Gijsen FJ, et al. The role of shear stress in the generation of rupture-prone vulnerable plaques Nat Clin Pract
Cardiovasc Med 2005;2:401-407
3. Chatzizisis YS et al: J Am Coll Cardiol 2007;49:237993
Early Plaques
Advance Plaques
Lawrence GS
Unstable Plaque
stable Plaque
Lawrence GS
Cytokines , Proteases
Coagulation factor
MMP-1, MMP-3, MMP-9
MMP-2 + MMP-9
PDGF
IL-1
TNF-
TGF-
Lawrence GS
Jantung Normal
ANGINA PECTORIS
Suatu symptom dari IHD yang ditandai
dengan paroxysmal dan biasanya
serangan berulang substernal atau
precordial yang tidak enak (constricting,
squeezing, choking, atau knifelike) yang
disebabkan oleh ischemia miokard
transient (15 detik-15 menit), sehingga
terjadi nekrosis selluler.
STABLE ANGINA
Paling sering ditemukan
Disebabkan oleh penurunan perfusi koroner
hingga stenosis coroner kronis
Sehingga jantung rentan terhadap iskemia
yang berikutnya, yang dapat dicetuskan oleh:
Aktivitas fisik yang meningkat
Rangsangan emosional
Atau keadaan apa saja yang meningkatkan
beban jantung
PRINZMETAL ANGINA
Variant dari angina
Bentuk yang tidak umum
Angina episodik yang terjadi pada
waktu istirahat
Dilaporkan sebagai akibat vasospasm
arteri koroner
Biasanya terdapat elevasi ST (EKG),
yang merupakan tanda iskemia
transmural
UNSTABLE ANGINA
Unstable atau crescendo angina
Peningkatan serangan nyeri biasanya
lebih sering dan sangat progresif
Biasanya terjadi pada waktu istirahat
Serangan nyeri lebih lama
Disebabkan oleh kerusakan plak
atherosklerotik yang disertai dengan
thrombosis mural partial dan mungkin
embolisasi atau vasospasm (atau
keduanya)
MYOCARDIAL INFARCTION
Dikenal sebagai Serangan Jantung
Paling sedikit 250.000 pasien mati
sebelum sempat tiba di RS
Bentuk Infarck :
Transmural infarction : Nekrosis iskemia
pada ketebalan penuh dinding ventrikel
Subendocardial infarction: Nekrosis
iskemia 1/3-1/2 lapisan dalam dari ventrikel
Infarction
Dysfungsi kontraktil
Arrhytmia
Ruptur miokardium
Perikarditis
Thrombus mural
Aneurysma Ventrikuler
Disfungsi Muskulus Papiler
Gagal Jantung Progresif
Healed Infarct
Infarction
Thrombus
Rupture
Infarction
Cardiac Tamponade
Gagal Jantung
Sering disebut sebagai : gagal jantung
kongestif (congestive heart failure)
Kejadian yang sering ditemukan
Prognosis jelek
Sistem kardiovaskuler berfungsi
mempertahankan tekanan arterial dan
perfusi organ vital
Ascites
Edema
Systolic Dysfunction
Diastolic Dysfunction
Akibat ketidakmampuan ruang jantung
untuk relaksasi, ekspansi, mengisi
volume darah ventrikel yang cukup
Dapat sebagai akibat dari :
Massive left ventricular hypertrphy
Myocardial fibrosis
Deposition of amyloid
Constrictive pericarditis
Hypertension
Pressure overload
Valvular disease
Pressure and/or
volume overload
Myocardial Infarction
Regional dysfunction
With volume overload
CARDIAC DYSFUNCTION
Heart failure
(systolic / diastolic)
arrhythmias
neurohumoral stimulation
Epidemiologi IHD
Penyebab utama kematian
500.000 kematian /thn di AS
Sejak 1980 angka tersebut menurun, sbg jasa:
Pencegahan / modifikasi gaya hidup: merokok,
hipertensi, kolesterol tinggi, kerja kantor
(sedentary life style)
Kemajuan bidang terapi: obat baru, thrombolisis
untuk MJ, percutaneous transluminal coronary
angio[lasty (PTCA), intravascular stents,
coronary by pass, pengontrolan diabetes, HRT,
obat penurun lemak
Patogenesis IHD
Kekurangan perfusi koroner
Interaksi kompleks antara:
Penyempitan o/k fixed atherosclerosis dari
arteri epikardial
Intramural thrombosis pada plak
atherosklerosis yang rusak
Aggregasi platelet
vasospasm
Reference
Robin-Contran: Pathologic Basis of Diseases. 2005
Deepak L Bhatt & Marcus D Flather : Handbook of Acute Coronary
Syndrome. 2004
Morteza Naghavi. Asymptomatic Atherosclerosis. Pathophysiology,
Detection and Treatment. 2010
Peter P. Toth, Christopher P. Cannon. Comprehensive Cardiovascular
Medicine in the Primary Care Setting. 2010