Patofisiologi Sistem Kardiovaskular
Patofisiologi Sistem Kardiovaskular
Patofisiologi Sistem Kardiovaskular
PATHOFISIOLOGI KARDIOVASKULAR
Lahir:
Pendidikan:
*Dokter umum : FK USU
*Spesialis Peny.Dalam: FK USU
*Konsultan Kardiovaskular
(Cardiologist):FK UI Jakarta.
Pekerjaan:
Tel: 62-61
8469960; HP:08126040589
PATHOFISIOLOGI
SISTEM KARDIOVASKULAR
HIPERTENSI
PENYAKIT JANTUNG KORONER
KELAINAN KATUP JANTUNG
ARITMIA
GAGAL JANTUNG
SHOCK
DISFUNGSI ENDOTEL
DLL
THE
PATHOPHYSIOLOGY
OF HYPERTENSION
Dr.Abdul Majid
Bagian Fisiologi FK USU Medan
Hypertension practice
Guidelines
JNC 7
2003
W H O 1999
I S H 1999
2003 Canadian
ESC 2003
Recommendations
for the Management of
Hypertension
British Society of
Hypertension
2003/2004
Kaplan`s
Clinical
Hypertension
2002
Hypertension Syndrome
Arterial
Compliance Endothelial
Obesity
Dysfunction
Abnormal
Abnormal
Glucose
Lipid
Metabolis
Metabolism
m
Hypertension
Accelerated
Neurohormona
Atherogenesi
l
s
Dysfunction
RenalLV Hypertrophy
Function
Bloodand Dysfunction
Abnormal
Clotting Changes
Insulin
Mechanism
Metabolism
Changes
Kannel WB. JAMA. 1996;275:1571-1576. Weber MA et al. J Hum Hypertens. 1991;5:417-423. Dzau
VJ et al. J Cardiovasc Pharmacol. 1993;21(suppl 1):S1-S5.
ESC 2003
ESH-ESC 2003
BP Classification
JNC 7
2003
BP
BP
Optimal
<120 / <80
<120/<80
Normal
120-129 / 80-84
120-129 /80-84
Prehypertension
High normal
130-139 / 85-89
130-139 / 85-89
Prehypertension
Grade 1
Hypertension (mild)
140-159 / 90-99
140-159 / 90-99
Stage 1
Hypertension
Grade 2
Hypertension
(moderate)
Grade 3
Hypertension
(severe)
Isolated Systolic
Hypertension
160-179 /100109
>160 / >100
JNC VII(2003)
Bp
Classification
Normal
Stage 2
Hypertension
> 140
< 90
Isolated Systolic
Hypertension
Types of hypertension
Essential Hypertension
hypertension with no apparent cause
Secondary Hypertension
hypertension of known cause
2.5-5%
0.5-4%
0.2-1%
0.1-1%
0.1-0.5%
0.1-0.2%
90-95%
Risk Factors
Age
Gender (18- 70)
Race
Genetic factors
.Other:
obesity
high alcohol intake
high Na intake
abnormal renin values
high stress level
low birth weight
drugs
Patho-physiology of Hypertension
HTN develop gradually over a long period of time.
The development of HTN requires the adjustment of several
compensatory mechanisms over time.
Several hypothesis exists for the original pathogenesis of HTN:
Excess Na intake
Renal Na retention
Renal Angiotensin System (RAS)
Stress & sympathetic over activity
Peripheral resistance
cell membrane and endothelial dysfunction
Obesity
insulin resistance
Reduced
Excess Na Nephron
intake
Numbers
Stress
Genetic
Alterations Obesity
Endothelium
derived
factors
Decreased
Renal Na
Sympatheic RAS Cell-membrane
Hyper
filtration
retention
Over activity Excess alterations insulinemia
surface
Fluid
Volume
Venous
constriction
Preload
Functional
Contractibility
constriction
Structural
hypertrophy
Pathophysiology of blood
pressure changes
BLOOD
PRESSURE
CARDIAC
OUTPUT
BLOOD VOLUME
PERIPHERAL
RESISTANCE
FUNCTIONAL
VASOCONSTRICTION
CONTRACTILITY
Normal Remodeling
PULSE RATE
STRUCTURAL HYPERTROPHY
IMPACT OF
HYPERTENSION
ON
TARGET ORGANS
Complications of HTN
CNS
Cardiac
Renal
Stroke or TIA
Sequelae of
Hypertension
Heart diseases
Retinal
Retinopathy
Nephropathy,
Proteinuria, CrCl
Vascular
Peripheral arterial
Disease (atherosclerotic
plaque iliac,carotid,
femoral artery, aorta)
Renal Complications
Benign arteriolar
Nephrosclerosis
Malignant arteriolar
Nephrosclerosis
Chronic Renal
Failure
GLOMERULAR
HYPERPRESSURE
RENAL ISCHEMIA
Tubulo-interstitial
changes
Glomerular
changes
CNS Complications
Hypertensive
encephalopathy
Cerebral
hemorrhage
Ischemic stroke
TIAs
Small vessels
Charcot
Loss of
Hyaline Sclerosis microaneurysms Self-regulation
ISCHEMIA
Dementia
HEMORRHAGE
Stroke
EDEMA
Encephalopathy
Retinal complications
Hypertensive retinopathy
Venous
tapering
Increased
light reflexes
from
arterioles
Blurred
optic disc
Punctate
hard
exudate
Normal
hemorrhag
e
Vascular Complications
Artherioscelorosis
wall:lumen ratio
remodeling
Atherosclerosis
Plaque
Fibrous cap
necrotic center
Fibrinoid necrosis.
Aortic dissection.
Normal Remodeling
Cardiac Damage in
Hypertension
Cardiac Sequelae of
Hypertension
Left Ventricle Hypertrophy
Arrhythmias
Heart failure
LVH
Diastolic
dysfunction
CHF
Hypertension
Smoking
Dyslipidemia
DM
Normal LV
structure and function
MI
LV remodelling
Time
(decades)
Death
Systolic
dysfunction
Subclinical
LV dysfunction
Overt
heart failure
Time
(months)
Arch Intern Med 1996;156
PATHOFISIOLOGI
GAGAL JANTUNG
(Heart Failure)
Heart Failure
a major public health problem and
its prevalence is rising, with a
projected 2- to 3-fold increase over
the next decade.
Heart failure is primarily a disease of
the elderly
6% to 10% of people older than 65
years have HF ,and 80% of patients
hospitalized with HF are more than
65 years old ..
HF is often associated with poor
outcome; the 5-year mortality rate is
50%. (despite advances in treatment).
Oxygen
Carbon dioxide
Coronary
Thrombosis
Myocardial
Ischemia
Stroke CAD
Myocardial
Infarction
Silent
Angina
Hibernation
PVD
Atherosclerosis
LVH
End
stage
Risk factors
Heart
Hypertension, High Cholesterol, D M, Disease
Smoking, Platelets, fibrinogen
Arrhythmia
and Loss of
Muscle
Sudden
Death
Remodeling
Ventricular
Dilation
Congestive
Heart Failure
Denyut jantung
"heart failure"
Others:
Idiopathic cardiomyopathy
Myocarditis
Valvular heart disease
Familial
toxic, metabolic
200
180
160
140
120
100
120
110
100
90
80
70
Stage A
At high risk for
heart failure but
without
structural heart
disease or
symptoms of HF
Stage B
Structural heart
disease but without
symptoms of HF
Stage D
Refractory HF requiring
specialized interventions
Stage A
At high risk for
heart failure
but
without
structural
heart disease
or
symptoms of
HF
St
ru
disheactur
ea rt al
se
eg,Patients with:
Hypertension
Coronary artery disease
Diabetes mellitus
or
Patients
using cardiotoxin
with FHxCM
Stage B
Structural heart
disease but without
symptoms of HF
Stage C
Structural heart
disease with prior or
current symptoms of HF
Stage D
Refractory HF requiring
specialized interventions
ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult
A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995
Guidelines for the Evaluation and Management of Heart Failure)
Mekanik kompensasi
Gagal Jantung
Hipertophi
konsentrik
(dilatasi )
sel otot >
Serat otot
jantung
memanjang /
dilatasi
Frank
Starling law
Peningkatan
aktifitas
simpatis
&
neurohormo
nal
Angiotensinogen
SNS
Aldosterone
Angiotensin I
NEP
ACE
Natriuresis
ANP
AT II
relaxation
Myocardial
hypertrophy
fbrosis
Cardiovascular System
constriction
Pening
katan
aktifitas
simpatis
&
neuro
hormonal
Heart Failure
Hemodynamic
effect
Cardiac output
Pre Load
Sympathetic activity
Na& Fluid
retention
Hypo Renal
Perfusion
Reflex
Arteriolar
vasocons
triction
After Load
SVR
Neurohormonal hyperactivity
Ventricular Failure
_
Cardiac Output
Systemic
Vascular
Resistance
Arterial
Pressure
Symphatetic
Angiotensin II
Aldosterone
Vasopressin
_
-
Atrial
Natriuretic
Peptide
Blood
Volume
Venous
pressure
Venous
Tone
Pulmonary
Edema
Systemic
Edema
Hipertropi jantung
Tekanan atrium
Dilatasi ventrikel
Peningkatan daya kontraksi
vs
kronis
vs
diastolik
Definisi
Gagal Jantung yang disebabkan oleh meningkatnya
resistensi terhadap pengisian pada satu atau kedua
ventrikel
EF NORMAL ( > 40 %)
Common etiology:
CAD
Hypertension
Common etiology:
:Aritmia , MCI.
Kehamilan, dll
(
A
C
S
)
Coronary Ischemic
Syndromes
2002
ACC/AHA GUIDELINES
Eugene Braunwald, MD, Chair
Pathophysiology
Acute Coronary
Syndrome
(ACS)
Heart
attack
Acute Coronary Syndrome ???
Unstable
angina
Non-Q wave
MI (NSTEMI)
Q-wave MI
(STEMI)
(UAP)
characterized by
the common pathophysiology of
a disrupted atheroslerotic plaque
ACS: physiopathology
Ruptured Plaque
Thrombu
s
Inflammatory
Cells
Few
SMCs
Activated
Macropha
ges
Lipid
Core
Atherosclerotic
Vessel
Plaque
Rupture
Platelet Adhesion,
Activation, and
Aggregation
Thrombus
Formation
Thrombotic
Occlusion
MI
Stroke
Vascular
Death
Koroner normal
Pasokan seimbang dengan kebutuhan
(aliran darah koroner)
(kebutuhan miokard)
PJK Pasokan ,
tetap
kebutuhan
Risk Factors
of
ACS
Assessment of
cardiovascular risk
Predisposing Risk Factors
Obesity
Abdominal Obesity
Physical inactivity
Family history of premature CHD
Ethnic characteristics
Psychosocial factors
Heart Failure
Thrombosis
Coagulopathy
Diabetic
Diabetic
Angiopathy
Angiopathy
Hypertension
Reperfusion
Injury
Endothelial
Dysfunction
Peripheral Artery
Disease
Hyperlipidemia
Inflammatory
Disease
Immune Reaction
Atherosclerosis
Atherosclerosis
Carotid
Arteries
Coronary
Arteries
Peripheral
Vasculature
Stroke
Heart Attack
Angina
Intermittent
Claudication
Patofisiologi SKA
Agregasi trombosit,
akumulasi lipid & makrofag
Plak stabil
Plak tak
stabil
Injury &
disfungsi endotel
Hipertensi
Merokok
DM
Dislipidemia
Zat vasoaktif
dll
Disfungsi endotel
disrupsi
Trombosis akut
APTS
Oklusi koroner
IMA
Vasokonstriksi
Fatty
Streak
Fibrous
Plaque
Occlusive
Atherosclerotic
Plaque
Plaque
Rupture/
Fissure &
Thrombosis
Unstable
Angina
MI
Coronary
Death
Stroke
Effort Angina
Claudication
Clinically Silent
Increasing Age
Courtesy of P Ganz.
Critical Leg
Ischemia
UA/NSTEMI
PATHOGENESIS (NONEXCLUSIVE)
Nonocclusive thrombus on
pre-existing plaque
CAUSES OF UA/NSTEMI
Mechanical
Obstruction
Thrombosis
Dynamic
Obstruction
Dynamic obstruction
(coronary spasm or
vasoconstriction)
MVO2
Inflammation/
Infection
Mechanical
Obstruction
Thrombosis
Progressive mechanical
obstruction
Inflammation and/or
infection
Secondary UA
.
MVO2
Dynamic
Obstruction
Inflammation/
Infection
Worldwide Statistics
Each year:
> 4 million patients are admitted with
unstable angina and acute MI
> 900,000 patients undergo PTCA
with or without stent
CABG
STElevation
Elevation
ST
Non ST Elevation MI
UnstableAngina
Angina
Unstable
Myocardial Infarction
Infarction
Myocardial
NonQw
QwMI
MI
QwMI
MI
Non
Qw
(NSTEMI)
(NSTEMI)
(STEMI)
(STEMI)
Diagnosis ACS
Chest pain
( typical)
ECG
changes
Cardiac
serum
marker
Myocardial Ischemia
silent ischemia
Spectrum
of
presentation
exertion-induced
angina
unstable angina
acute myocardial
infarction
evaluation
Based on the patients
history / physical exam
ECG
UA/NSTEMI
EMERGENCY ROOM TRIAGE
sensation
Unexplained indigestion, belching, epigastric pain
Radiating pain to neck, jaw, shoulders, back or to
one or both arms
UA/NSTEMI
THREE PRINCIPAL PRESENTATIONS
Rest Angina*
Increasing Angina
UAP
ST depression,
deep T inverted
Non Q MCI
(NSTEMI)
hyper acute T (0-1 hrs),
ST elevation (hours),
Q wave
MCI(STEMI)
Q wave (8-48 hrs),
Non-Q-Wave MI:
diagnosis
Prolonged chest pain
Associated symptoms
from the autonomic
nervous system
nausea, vomiting,
diaphoresis
Persistent ST-segment
depression after
resolution of chest pain
Clues to
Q-Wave MI:
Prolonged chest pain
Associated symptoms
from the autonomic
nervous system
nausea, vomiting,
diaphoresis
ST-segment elevation/
Q wave
Clues to diagnosis
MCI non Q
(Non ST
Elevation MI)
Subendokard
Subepikard
ST depression
T inverted
Q wave (-)
MCI Q wave
(ST Elevation MI)
ST elevation
T inverted
Q wave(+)
II
III
aVR
aVL
aVF
NEJM 1997;337:1648-1653
FEATURE
HIGH OR INTERMEDIATE
LIKELIHOOD THAT
UA/NSTEMI IS CAUSED BY
HIGH LIKELIHOOD
INTERMEDIATE LIKELIHOOD
OBSTRUCTIVE
CAD
Absence of high-likelihood features
and presence of any of the following:
History
Examination
Transient MR,
hypotension,
diaphoresis,
pulmonary edema,
Extracardiac
vascular disease
HIGH LIKELIHOOD
INTERMEDIATE LIKELIHOOD
Absence of high-likelihood features
and presence of any of the following:
ECG
Fixed Q waves
Abnormal ST segments
or T waves not
documented to be new
Cardiac
markers
Normal
Acute Coronary
Syndrome
Ischemic Discomfort
Unstable Symptoms
No ST-segment
elevation
Unstable
angina
History
Physical Exam
ST-segment
elevation
Non-Q
AMI
Q-Wave
AMI
ECG
Acute
Reperfusion
Fibrous cap
1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
Suspected Cardiac
Pain
ECG
No ECG
ST
ECG ST
Or LBBB
Acute
MI
Normal ECG,
ECG ischemic or
CK-MB,& cTn
CK-MB or cTn
Suspected
ACS
Confirmed
ACS
Let it
beat!
Pathophysiology
arrhythmias
. ECG Rhythm Abnormalities
Topics for Study:
Supraventricular Arrhythmias
Regular atrial activity with a "clean" saw-tooth appearance in leads II, III, aVF,
and usually discrete 'P' waves in lead V1. The atrial rate is usually about 300/min,
but may be as slow as 150-200/min or as fast as 400-450/min.
PVCs may be unifocal (see above), multifocal (see below) or multiformed. Multifocal PVCs
have different sites of origin, which means their coupling intervals (measured from the previous
QRS complexes) are usually different. Multiformed PVCs usually have the same coupling
intervals (because they originate in the same ectopic site but their conduction through the
ventricles differ. Multiformed PVCs are common in digitalis intoxication.
PVCs may occur early in the cycle (R-on-T phenomenon), after the T wave
(as seen above), or late in the cycle - often fusing with the next QRS (fusion
beat). R-on-T PVCs may be especially dangerous in an acute ischemic
situation, because the ventricles may be more vulnerable to ventricular
tachycardia or fibrillation. Examples are seen below.
In the above example, "late" (end-diastolic) PVCs are illustrated with varying degrees of fusion. For
fusion to occur the sinus P wave must have made it to the ventricles to start the activation sequence,
but before ventricular activation is completed the "late" PVC occurs. The resultant QRS looks a bit
like the normal QRS, and a bit like the PVC; i.e., a fusion QRS.
1st Degree AV Block: PR interval > 0.20 sec; all P waves conduct to the
ventricles.
Type II AV block is almost always located in the bundle branches, which means that the
QRS duration is wide indicating complete block of one bundle; the nonconducted P wave is blocked in the
other bundle. In Type II block several consecutive P waves may be blocked as illustrated below:
node.
Wolff-Parkinson-White Preexcitation
Pathophysiologi
Endothelial dysfunction:
References
OCTOBER 1997
VOLUME 18 No 10
PP 1530-1535
The
Endotheliu
m in
Clinical
Practice
edited by
THE ENDOTHELIUM:
A PIVOTAL ROLE IN
HEALTH AND
CARDIOVASCULAR
DISEASE
DO ACE
INHIBITORS
MODULATE
ATHEROSCLEROSIS?
Gabor M.Rubanyi
Victor J.Dzau
European Heart
Journal
Journal of the European
Society of Cardiology
Heart
Evolving Strategies in
Cardiovascular Care:
The Renin-Angiotensin
System and the Future
BMJ
Oxygen
Carbon dioxide
Blood vessels
All have endothelial lining
A New Principle
Nitric Oxide, NO, is a short-lived, endogenously produced gas that acts as a signalling
molecule in the body. Signal transmission by a gas, produced by one cell, which penetrates
membranes and regulates the function of other cells is an entirely new principle for signalling
in the human organism.
Contents
:Introduction Furchgott's sandwich Ignarro's spectral analyis Murad's enzyme activation Nitroglycerine, a 100 year old explosive and heart
medicine NO has many Clinical Applications
These pages are based on material from the 1998 Physiology or Medicine Nobel Poster.
Credits and references for the poster
Physiolo
gy
of the
Endothel
The
endothelium
is the largest
organ in
the body
In a 70 kg man,
its total surface
area is 6 tennis
courts
The Healthy Endothelium
In a 70 kg man,
its total weight is
1,800 g (> the
liver, -- 5 hearts
LDL-cholesterol
Endothelium
Subendothelial
matrix
Smooth muscle
The
endothelium
is not only a selective barrier ,
it also has metabolic and
secretory activity.
In 1980 , it was discovered that
the endothelium released
a)Vasodilator substance(s)
EDRF (endothelium derived
relaxing factor)
b)Vasoconstrictor substances
Endothelial cells
Aggregating platelets
Bradykinin
Ach Histamine AVP
M2
H2
VP1
A,
NA
AA
B2
EDRF(s)
Relaxation
ADP
5-HT
P2
5-HTI
Thrombin Endothelin
T
ET
Vascular
Endothelium
Recognized
Recognizedas
asaamajor
majorregulator
regulatorofof
vasculartone
toneand
andhemostasis
hemostasis
vascular
Provides
Providesaasmooth,
smooth,non-thrombogenic
non-thrombogenic
surfaceand
andaapermeability
permeabilitybarrier
barrier
surface
Synthesizes
Synthesizesand
andreleases
releasesaanumber
numberofof
vasoactivesubstances
substancesthat
thatcontrol
control
vasoactive
relaxationand
andcontraction,
contraction,
relaxation
thrombogenesisand
andfibrinolysis,
fibrinolysis,and
and
thrombogenesis
plateletactivation
activationand
andinhibition
inhibition
platelet
Contributes
Contributestotoblood
bloodpressure
pressurecontrol,
control,
bloodflow,
flow,vessel
vesselpatency
patency
blood
Pepine, C., et. al., Vascular Health as as Therapeutic Target in Cardiovascular Disease, Vascular Biology
Working Group, University of Florida, 1998.
Vasodilators
Nitric
EDHF
Prostacycline
Endothelin
Angiotensin
(PGI2)
Bradykinin
Acetylcholine,
serotonine, histamine,
substance P, etc
II
Thomboxane
A2,
Acetylcholine,
arichdonic acid,
prostaglandin H2, etc
Inflammatory modulators /
mediators
Adhesion molecules: ELAM, ICAM
Antigens : MHC-II
Luscher, T., Barton, M., Biology of the Endothelium, Clinical Cardiology, vol. 20 (Suppl. II0, II-3 -II-10 (1997).
Cells
Blood
P MNS
Monocytes
Platelets
Endothelium
Endothelium Derived
Factors
Vascular
Proliferation
Smooth Muscle
Relaxation
Contraction
Modulation of the tone and structure of vascular smooth muscle by the vascular
endothelium.
The endothelial cell has the ability to sensechanges in hemodynamic (physical) forces, and
respond to vasoactive substances (circulating or locally produced), and mediators released from blood cells (e.g.
polymorphonuclear neutrophils,PMNs )and platelets. These stimuli then trigger the synthesis/ release of biologycally active
substances from the endothelium (endothelium-derived ( vasoactive ) factors) that modulate the tone (relaxation or
contraction) and structure of underlying vascular smooth muscle. By virtue of these recently discovered properties, the
vascular endothelium contributes to cardiovascular homeostasis in a significant way. SP, substance P, VP, vasopressin, Bk,
bradykinin, 5-HT, serotonin, ATP, adenosine triphosphat, ADP, adenosine diphosphate, LCT 4, leukotriene C4..
Proteins :
Endothelin ( ET 1 )
Growth Factors (PDGF)
Adhesion Molecules ( ELAM, ICAM, VCAM )
Matrix Proteins ( Heparine SO 4 )
Coagulation Factors( TF, tPA, PAI, TM, VWF )
Antigens ( MHC III )
Enzymes ( ACE )
Receptors
Biologycally active substances produced by the endothelial cell, which contribute to the physiologic and pathophyisiologic
functions of the vascular endothelium. EDRF, endothelium-derived relaxing factor; PGI 2, prostacyclin; NO, notric oxide; RNO, nitroso compound; PDGF, platelet-derived growth factor; PAF, platelet-activating factor; ET-1, endothelin 1; ELAM,
endothelial leukocyte adhesion molecule; ICAM,intrcellular adhesion molecule ; VCAM, vascular adhesion molecule TF,
tissue factor; t-PA, tissue plasminogen activator inhibitor; TM, thrombomodulin; VWF, von Willebrand factor; MHC-II, major
histocompatibility antigen II; ACE, angiotensin-converting enzyme.
Adapted from Rubanyi GM: J Cardiovasc Pharmacol.1993;22(suppl 4)
S1-S14
Permeability
Lipid
Transport
Vascular
Tone/Structure
Metabolic
Activity
Thrombosis
Hemostasis
Immune
Respons
Angiogenesis
Inflammation
Tumor
growth/metastasis
Some of the important physiologic and pathophysiologic functions
of the vascular endothelium.
Adapted from Rubanyi GM: J Cardiovasc Pharmacol.1993;22(suppl 4) S1-S14
Vasoactive Substances
Effects of Endothelin
Effects of NO
Vasodilator (via relaxation of
smooth muscle cells)
Growth inhibitor (via actions
on smooth muscle cells and
endothelial and mononuclear
cells)
Inhibitor of platelet
adherence/aggregation
Inhibitor of
endothelial/leukocyte
interactions
Powerful vasoconstriction
Release from endothelium
stimulated by Ang II
Effects of Bradykinin
Activates L-arginine-NO
pathway, promoting dilation
and inhibiting smooth muscle
cell proliferation
Activates release of
prostacyclin and EDHF,
inhibiting platelet
adherence/aggregation and
VSM contraction
Induces increase in t-PA
activity, promoting
fibrinolysis
B2
Endothelial
cell
L-citruline
L-Arg
NO-synthase
Nitric Oxide
(NO) Synthesis
NO
NO
Smooth
muscle
cell
NO
Peripheral
Renin Secretion
vasoconstriction
Renal
resistance
Glomerulo-tubular
Feedback
NO
Sodium
Reabsorption
Pressurenatriuresis
Angiotensin II
Nitric Oxide
Vasodilation
Antiproliferatio
n
Antithrombotic
Antioxidant
Antiinflammatory
Vasoconstriction
Proliferation
Thrombotic
Pro-oxidant
Pro-inflammatory
Angiotensin I
Bradykinin
(active)
Inactive
peptide
Angiotensin II
A
A
Converting
enzyme
Endothelial cells
5-Hydroxytryptamine
Norepinephrine
Inactive metabolites
B
MAO
ATII
COMT
Basal membrane
Figure:
The handling of bioactive substances by the endothelium
A. Substances such as Angiotensin I and Bradykinin are transformed by converting enzyme located on the endothelial cell
membrane with resulting formation of active and inactive components, respectively.
B. Substances such as Norepinephrine and 5-Hydroxytryptamine (serotonin) are actively taken up and degraded
enzymatically by MAO and catechol-O-methyltransferase(COMT)
CM Boulanger, PM Vanhoutte: The Endothelium, 1994
Angiotensin I
Angiotensin II
AT
Renin
Prepro ET
Big ET
ACE
ECE
Endothelin I
AI
Contraction
AT1
Inactive
products
ACE
B2
L-Arginine
NOS2
Cyg
ATII
ATG
Angiotensin II
ETA
Bradykinin
(active)
NO
cGMP
AA
PGI2
cAMP
Relaxation
Figure: The endothelium plays an important role in the control of the vascular system.
Luscher TF, Heart 2000:84(Suppl I): i20-i22
Endothelial
dysfunction
The Endothelium
Endothelial Dysfunction
Any Alteration in normal endothelial
function
Results in imbalance between :
This scanning electron micrograph of coronary
artery endothelium. illustrates the fragility of
the endothelial monolayer. A few intact
endothelial cells can be seen in the upper left
corner, but the remainder of the vessel wall is
denuded of endothelium due to mechanical
injury by catheter manipulation. This results in
exposure of underlying smooth muscle and
connective tissue as well as platelet
aggregation.
Oxidative stress
Angiotensin II
Nitric Oxide
Activity
Redox state : normal oxidative metabolism in arterial wall
( balanced superoxide anion and NO )
Oxidative stress : superoxide anion production and
breakdown of NO stimulate adhesion molecule expression and
promote leukocyte adhesion to endothelium, leading to
inflammatory response
Risk factors
DM
Smoking
Oxidative stress
Endothelial Dysfunction
NO . Local mediators . Tissue ACE leading to Angiotensin II
PAI-I
Thrombosis
Thrombosis
VCAM
ICAM cytokines
Endothelin
Inflammation Vasoconstriction
Vasoconstriction
Inflammation
Growth
factors marks
Vascularlesion
lesion
Vascular
andremodeling
remodeling
and
Proteolysis
Plaquerupture
rupture
Plaque
Clinical Sequelae
Gibbons GH, Dzau VJ. N Engl J Med. 1994;330: 1431-38
Fatty
Streak
Fibrous
Plaque
Occlusive
Atherosclerotic
Plaque
Plaque
Rupture/
Fissure &
Thrombosis
Unstable
Angina
MI
Coronary
Death
Stroke
Effort Angina
Claudication
Clinically Silent
Increasing Age
Courtesy of P Ganz.
Critical Leg
Ischemia
Impact of
Endothelial Dysfunction
Arteriosclerosis
Atheromas
and
Thrombosis
ENDOTHELIAL
DYSFUNCTION
Vascular Spasm
Arterial
resistances
Heart Failure
Thrombosis
Coagulopathy
Diabetic
Diabetic
Angiopathy
Angiopathy
Hypertension
Endothelial
Dysfunction
Reperfusion
Injury
Peripheral Artery
Disease
Hyperlipidemia
Immune Reaction
Atherosclerosis
Adapted from Rubanyi GM: J Cardiovasc Pharmacol.1993;22(suppl 4) S1-S14
Inflammatory
Disease
Shock:
the manifestation of cardiovascular failure.
"Acute circulatory failure with inadequate or
inappropriately distributed tissue perfusion
resulting in generalized cellular hypoxia.
Types of shock:
Cardiogenic shock
Obstructive shock
Acute myocardial infarction
Outflow obstruction ->pulmonary embolus
Acute aortic incompetence
Inflow obstruction -> Cardiac tamponade
Ischaemic mitral regurgitation
LV aneurysm
Myocardial contusion
~ 40% of myocardium damaged leading to
Shock
Hypovolaemic shock
Exogenous loss from haemorrhage
Endogenous loss -> third space loss & capillary leak syndrome
Distributive shock
A state of relative hypovolaemia (eg. loss blood oncotic pressure).
Impaired distribution and oxygen utilisation.
Classic examples: septic shock, spinal shock, anaphylactic shock, AV
shunting.
Let it
beat!
Normal
Category
SBP
(mmHg)
Hypertension
DBP
Category
DBP
(mmHg) ( mmHg)
( mmHg)
SBP
Stage 1/
Grade1
140-159 or 90-99
Stage 2/
Grade 2
160-179 or 100-109
Stage 3/
Grade 3
180
140 and
140-149 and
or
< 90
< 90
110