patofisiologi sistem kardiovaskular
DESCRIPTION
Bahan Kuliah PatofisiologiTRANSCRIPT
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PATHOFISIOLOGI KARDIOVASKULAR
Dr.Abdul Majid SpPD-KKV
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Dr.Abdul Majid SpPD-KKV
Lahir: Rantau Prapat, 29 Juli 1945.
Pendidikan:
*Dokter umum : FK USU
*Spesialis Peny.Dalam: FK USU
*Konsultan Kardiovaskular
(Cardiologist):FK UI Jakarta.
Alamat: Jln KIWI Taman Kuswari Indah II/M37, Medan
Tel: 62-61 8469960; HP:08126040589
Pekerjaan:
Bagian Fisiologi FK USU
Konsultan Peny.Dalam & Jantung RS Permata Bunda Medan
3.bin4.bin5.bin -
PATHOFISIOLOGI SISTEM KARDIOVASKULAR
HIPERTENSIPENYAKIT JANTUNG KORONERKELAINAN KATUP JANTUNGARITMIAGAGAL JANTUNGSHOCKDISFUNGSI ENDOTELDLL -
Bagian Fisiologi FK USU Medan
Dr.Abdul Majid
THE PATHOPHYSIOLOGY OF HYPERTENSION
-
W H O 1999
I S H 1999
Hypertension practice
Guidelines
2003 Canadian Recommendations
for the Management of HypertensionJNC 7 2003
British Society of Hypertension 2003/2004
Kaplan`s Clinical Hypertension 2002
ESC 2003
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Hypertension Syndrome
Its More Than Just Blood PressureDecreased
Arterial ComplianceEndothelial Dysfunction
Abnormal Glucose Metabolism
Neurohormonal Dysfunction
Renal-Function Changes
Blood-Clotting Mechanism Changes
Obesity
Abnormal Insulin Metabolism
LV Hypertrophy
and DysfunctionAccelerated Atherogenesis
Abnormal Lipid Metabolism
Hypertension
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.
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ESH 2003 & JNC VII(2003)
> 140
< 90
JNC 7 2003
ESH-ESC 2003BP ClassificationBP BPJNC VII(2003)Bp ClassificationOptimal110Isolated Systolic HypertensionIsolated Systolic HypertensionESC 2003
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Types of hypertension
Essential Hypertensionhypertension with no apparent cause 90-95%
Secondary Hypertensionhypertension of known cause
chronic renal diseases2.5-5%Renovascular diseases0.5-4%Oral contraceptive pills 0.2-1%Coarctation of the Aorta0.1-1%Primary aldosteronism0.1-0.5%Pheochromocytoma0.1-0.2% -
Risk Factors
AgeGender (18- 70)RaceGenetic factors.Other:
obesityhigh alcohol intakehigh Na intakeabnormal renin valueshigh stress levellow birth weightdrugs -
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 intakeRenal Na retentionRenal Angiotensin System (RAS)Stress & sympathetic over activityPeripheral resistancecell membrane and endothelial dysfunctionObesityinsulin resistance -
Excess Na
intake
Reduced
Nephron
Numbers
Stress
Genetic
Alterations
Obesity
Endothelium
derived
factors
Renal Na
retention
Decreased
filtration
surface
Sympatheic
Over activity
RAS
Excess
Cell-membrane
alterations
Hyper
insulinemia
Fluid
Volume
Venous
constriction
Preload
Contractibility
Functional
constriction
Structural
hypertrophy
Blood pressure=
HTN
Cardiac Output
Peripheral Resistance
X
and/or
-
Pathophysiology of blood pressure changes
BLOOD
PRESSURE
CARDIAC
OUTPUT
PERIPHERAL
RESISTANCE
BLOOD VOLUME
CONTRACTILITY
PULSE RATE
STRUCTURAL HYPERTROPHY
FUNCTIONAL
VASOCONSTRICTION
Normal
Remodeling
*
Blood pressure results from the interaction between cardiac output and peripheral arterial resistance. Cardiac output depends on diverse factors like blood volume, myocardial contractility and heart rate. An increase of peripheral arterial resistance is caused by functional or structural vasoconstriction of medium-sized arteries, which are commonly called resistance arteries.
The increase in arterial resistance is produced in all arterial beds, but it is in the kidney that the relative increase of resistance is highest. Even though the increase in renal resistance does not contribute greatly to global resistance, this increase is particularly important, given the role of the kidney to keep the hemostasis of the total sodium content of the body.
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RAAS
SNS
Cardiovascular System
Aldosterone
Natriuresis
NEP
Myocardial hypertrophy fbrosis
relaxation
constriction
AT II
ANP
Angiotensin I
ACE
Neurohumoral Control of the Cardiovascular System
Angiotensinogen
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IMPACT OF HYPERTENSION
ON
TARGET ORGANS -
Factors Involved in Organ Lesions in Hypertension
TIME
HEMODYNAMIC
FACTORS
NON-HEMODYNAMIC
FACTORS
BP figures
Circadian persistence
Increased variability
Sudden changes
Hormones
Cellular programming
OTHER CV RISK
FACTORS
*
The slide shows the structural and functional damage to the target organs caused by HT, and also the clinical manifestations of that damage.
HT produces changes in the elasticity of great vessels and increases atheroma formation, with a subsequent risk of vessel wall rupture or occlusion.
In the heart, HT also produces diastolic dysfunction and left ventricular hypertrophy. It may lead to cardiac heart failure, ischemic cardiomyopathy and sudden death due to coronary occlusion or arrhythmias.
In the kidney, HT produces a decrease in renal flow, glomerular hyperpressure, thus favouring the development of nephroangiosclerosis and renal insufficiency.
In the central nervous system, HT disturbs the autoregulation curve, favours vascular hyaline sclerosis, microaneurysms and the development of stroke and dementia.
EFFECTS
of
HT
Arteries
Arteries
Heart
Heart
Kidney
Kidney
CNS
CNS
Heart
failure
Isc
.
Cardiomyopathy
Sudden
Death
Renal
failure
atheromas
Nephroangio
-
sclerosis
LV
Hypertrophy
Stroke
Dementia
microaneurysms
hyaline
sclerosis
compliance
functional
reserve
Occlusion
Disection
diastolic
dysfunction
flow
flow
reduction
reduction
self
self
-
-
regulation
regulation
curve
curve
FUNCT. CHANGES
STRUCTURAL CHANGES
CLINICAL MANIFESTATIONS
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Retinopathy
Heart diseases
Stroke or TIA
Nephropathy,Proteinuria, CrCl
Peripheral arterial Disease (atherosclerotic plaque iliac,carotid, femoral artery, aorta)
Sequelae of Hypertension
Complications of HTN
Cardiac
CNS
Vascular
Retinal
Renal
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Renal Complications
Benign arteriolar NephrosclerosisMalignant arteriolar NephrosclerosisChronic Renal Failure -
How does HT damage the kidney?
RENAL ISCHEMIA
GLOMERULAR
HYPERPRESSURE
Atherosclerosis
Vasoconstriction of
preglomerular vessels
Tubulo-interstitial
changes
Glomerular
changes
Decrease of
the number of
nephrons
Imbalance
of afferent and efferent
arteriolar tone
*
Renal lesions are produced through two mechanisms. First, renal ischemia, due either to renal artery damage or to vasoconstriction of preglomerular vessels. Second, due to glomerular hyperpressure, as a result of an imbalance between afferent and efferent tone of the arteriole.
Both mechanisms eventually lead to nephosclerotic glomerular disorders and tubulo-interstitial disorders.
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CNS Complications
Hypertensive encephalopathyCerebral hemorrhageIschemic strokeTIAs -
Development of Central Nervous System Lesions due to Hypertension
ISCHEMIA
HEMORRHAGE
Atherosclerosis
Small vessels
Hyaline Sclerosis
Dementia
Stroke
Charcot
microaneurysms
Loss of
Self-regulation
EDEMA
Encephalopathy
*
The pathogenesis of CNS lesions can be:
ischemia, which is favoured by atherosclerosis or microvascular lesions. Ischemia may lead either to stroke or to dementia. hemorrhage, as a result of Charcots microaneurysms. sudden edema, if the self-regulation ability of cerebral vessels is surpassed. As a result, blood flow increases abruptly and edema is produced. This situation occurs in hypertensive encephalopathy. -
Retinal complications
Hypertensive retinopathyBlurred optic disc
Increased light reflexes from arterioles
Venous tapering
Punctate hard exudate
hemorrhage
Normal
-
Vascular Complications
Artherioscelorosis wall:lumen ratioremodelingAtherosclerosis PlaqueFibrous capnecrotic centerFibrinoid necrosis.Aortic dissection.Normal
Remodeling
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Cardiac Damage in
HypertensionHT is the main risk factor for heart failure and one of the main risk factors for ischemic cardiomyopathy
CHF prevalence is increasing, whereas the incidence of ischemic cardiomyopathy is decreasing
Antihypertensive treatment reduces ischemic heart disease risk by 16% at 10 years and up to 25% after a longer period
*
Hypertension is one of the main risk factors for the development of heart failure and one of the main predictors of ischemic cardiomyopathy.
Even though antihypertensive treatment allows an initial reduction of heart failure, the incidence of this disease is on the rise. This is due to higher survival figures, which enables a greater number of subjects at risk to live longer. However, the incidence of ischemic cardiomyopathy is gradually declining.
It is estimated that antihypertensive treatment reduces risk by 16%, according to data from the most important intervention studies. This figure is lower than the expected 25% reduction rate suggested by population studies. The longer the treament, the more the benefits (data from the Framinghan study).
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Cardiac Sequelae of Hypertension
Left Ventricle Hypertrophy
Heart failure
Arrhythmias
Coronary Heart Disease
-
Development of Cardiac Lesions
due to HypertensionLEFT VENTRICULAR
HYPERTROPHY
ISCHEMIA
Myocardial fibers
hypertrophy
Greater collagen
content
Heart
failure
Arrhythmias
Atherosclerosis of
epicardiac coronary
arteries
Microvascular
damage
Ischemic
cardiomyopathy
*
The factors involved in the development of these heart diseases are: left ventricular hypertrophy and remodeling, which lead to heart failure and more frequent arrhythmias, and coronary ischemia, which is produced either by lesions of the epicardial coronary arteries and/or by microvascular damage coupled with a decrease in coronary reserve.
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Pathogenesis of LVH
Pressure Volume Overload
Age
Gender
Genetics
Race
Obesity
Neurohormonal Factors
Angiotensin IIAldosteroneACE -
Pathogenesis of LVH
Pressure Volume Overload
Age
Gender
Genetics
Race
Obesity
Neurohormonal Factors
Angiotensin IIAldosteroneACEMyocardial
Ischemia
Impaired
contractility
Impaired
LV Filling
Ventricular
Arrhythmias
Infarction
Congestive Heart Failure
Sudden Death
-
Obesity
DM
Hypertension
Smoking
Dyslipidemia
DM
LVH
MI
Systolic dysfunction
Diastolic dysfunction
Death
CHF
Normal LV Subclinical Overt
structure and functionLV remodellingLV dysfunction heart failure
Time Time
(decades) (months)
Progression from hypertension to heart failure
Arch Intern Med 1996;156
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PATHOFISIOLOGI
GAGAL JANTUNG
(Heart Failure) -
Pathophysiologic mechanisms of hypertension.(2).
Oparil S et al. Ann Intern Med 2003;139:761-776
2003 by American College of Physicians
Pathophysiologic mechanisms of hypertension.(2)
- 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).
Heart Failure
-
Oxygen Carbon dioxide
-
End stage Heart Disease
Hypertension, High Cholesterol, D M,
Smoking, Platelets, fibrinogen
Atherosclerosis
CAD
Congestive Heart Failure
Ventricular Dilation
Remodeling
Arrhythmia and Loss of Muscle
Sudden Death
Myocardial Infarction
Coronary Thrombosis
Myocardial Ischemia
Heart 2000;84(Suppl I):i20-i22
LVH
Stroke
PVD
Silent
Angina
Hibernation
Risk factors
Chain of events leading to end stage heart disease
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Kemampuan Pompa Jantung
( Cardiac Performance)
KontraktilitasDenyut jantungPreload ( beban awal)dipengaruhi oleh end diastolic volume (EDV)Afterload (beban susulan ) ditentukan oleh resistensi perifer -
Preload
Kontraktilitas
Afterload
Ukuran ventrikel kiri
Pemendekan serabut miokard
Stroke volume
Heart rate
Cardiac output
Tekanan Darah
Resistensi perifer
-
Kesanggupan intrinsik jantung untuk penyesuaian diri terhadap beban yang berbeda
Dalam batas fisiologis jantung akan memompakan semua darah yang masuk kedalam jantung tanpa menimbulkan penumpukan darah berlebihan. Ini disebabkan oleh peregangan yang ditimbulkan volume darah yang masuk menyebabkan kekuatan kontraksi bertambah.
Dengan perkataan lain:
Kontraksi jantung sewaktu sistolis akan bertambah kuat bila pengisian darah lebih banyak pada masa diastolik.Frank StarlingS LAW
-
Kurva Frank Starling
Stroke volume
End Diastolic Volume
Pada kurva dapat dilihat
Bila pengisian ventrikel bertambah ,
darah yang dipompakan >>
( EDVSTROKE VOLUME )
-
Kurva Frank Starling
Stroke volume
End Diastolic Volume
STRETCHING OF MYOCARD
Total blood volume
Body position
Intrathoracic pressure
Atrial contribution to ventr.filling
Pumping action of skletal muscle
Venous tone
Intrapericardial pressure
-
Kurva Frank Starling
Stroke volume
End Diastolic Volume
Normal
Stimulasi Adrenergik
Fungsi jantung
Syok Kardiogenik
-
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)
Page last updated 03/04/2002
Heart failure is.
a complex clinical syndrome that can result from any
structural or functional cardiac disorder
that impairs the ability of the ventricle
to fill with or eject blood.
-
The cardinal manifestations of HF are :
dyspnea and fatigue, which may limit exercise tolerance,
fluid retention, which may lead to pulmonary congestion and peripheral edema.
Because not all patients have volume overload at the time of initial or subsequent evaluation, the term
"heart failure"
is preferred over the older term
"congestive heart failure."
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)
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Etiology of Heart Failure
Idiopathic cardiomyopathy Myocarditis Valvular heart disease Familial toxic, metabolic200
180
160
140
120
100
120
110
100
90
80
70
Coronary artery disease
Hypertension
Others:
*
Faktor Penyebab Gagal Jantung
1.Kelainan miokard intrinsk
Penyakit jantung koroner (PJK)
Kardiomiopathi
Penyakit infiltratif: hemokromatosis,amiloidosis,
sarkoidosis, miokarditis.
2.Beban kerja berlebih
a) Peningkatan resistensi terhadap ejeksi ( pressure overload):
hipertensi, stenosis katup Aorta / Pulmonal, kardiomiopathi hipertropik
b)Peningkatan stroke volume (volume load):
b)Peningkatan stroke volume (volume load):
Aorta insufisiensi( AI), Mitral insufisiens (MI),Trikuspid insufisiensi ( TI), shunts left to right kongenital
c) Kebutuhan tubuh yang meningkat (high output failure):
Tirotoksikosis, anemia, kehamilan, A-V fistula.
3.Kerusakan miokard iatrogenik:
a) 0bat: doxorubricine ( Adriamycin), disopyramide.
b) Terapi radiasi untuk tumor mediastinum atau peny. Hodgkins
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Classification of Heart Failure
NYHA = New York Heart Association
NYHA Class I
NYHA Class II
NYHA Class III
NYHA Class IV
No limitation. Ordinary physical exercise does not
cause fatigue, dyspnea, or palpitation
Slight limitation of physical activity.
Comfortable at rest, but ordinary activity results in
fatigue, dyspnea, or palpitation
Marked limitation of physical activity, but less than
ordinary activity results in symptom
Unable to carry any physical activity. Symptoms
of HF are present even at rest, with increased
discomfort upon any level of physical activity
-
Stages in the evolution of heart failure and recommended therapy by stage.
ACC/AHA Guidelines 2002
for the Evaluation and Management of
Chronic Heart Failure in the Adult
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 C
Structural heart disease with prior or current 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
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
eg,Patients with:
HypertensionCoronary artery diseaseDiabetes mellitusor
Patients
using cardiotoxinwith FHxCMeg, Patients with:
previous MI LV systolic dysfunctionasymptomatic valvular diseaseeg, Patients with:
known structural heart diseaseshortness of breath and fatigue, reduced exercise toleranceeg ,Patients who have:
marked symptoms at rest despite maximal medical therapy ( eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)
Structural heart disease
Stages in the evolution of heart failure and recommended therapy by stage. FHx CM indicates family history of cardiomyopathy; MI, myocardial infarction; LV, left ventricular; and IV, intravenous.
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)
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Mekanik kompensasi
Gagal Jantung
-
Hipertophi konsentrik
(dilatasi )
sel otot >
Mekanik kompensasi Gagal Jantung
Respon jantung terhadap beban yang meningkat:
Serat otot jantung memanjang / dilatasi Frank Starling law
Peningkatan aktifitas simpatis & neurohormonal
-
RAAS
SNS
Cardiovascular System
Aldosterone
Natriuresis
NEP
Myocardial hypertrophy fbrosis
relaxation
constriction
AT II
ANP
Angiotensin I
ACE
Neurohumoral Control of the Cardiovascular System
Angiotensinogen
-
Mekanik kompensasi Gagal Jantung
* daya kontraksi serabut otot yang memanjang tanpa penigkatan tekanan pengisian
*stimulasi Renin-Angiotensin-Aldosterone system
* H.R dan resistensi vaskular sistemik untuk mempertahankan tekanan darah
*tonus vena
*ADH(vasopressin)
*Oleh adanya regangan & tekanan atrium kiri dan kanan, pelepasan Atrial Natriuretic factor natriuresis dan diuresis.
Pening
katan
aktifitas simpatis
&
neuro hormonal
-
Sympathetic activity
Hypo Renal Perfusion
Cardiac output
Reflex Arteriolar vasocons
triction
SVR
After Load
Pre Load
Na& Fluid retention
Hemodynamic effect
Neurohormonal hyperactivity
Renin, Angiotensin, Aldosterone, Vasopressin ,
ANP , BNP , Nor Epinephrine
Heart Failure
-
Ventricular Failure
Cardiac Output
Arterial Pressure
Symphatetic
Angiotensin II
Aldosterone
Vasopressin
Atrial Natriuretic Peptide
Venous pressure
Systemic Vascular Resistance
_
+
Blood Volume
Venous Tone
-
_
_
Pulmonary Edema
Systemic Edema
_
-
Dekompensasi ( Gagal Jantung )
Mekanik kompensasi berlebihan:
*Retensi Na & H2O >>
* resistensi vaskular sistemik
Hipertropi jantung
Tekanan atrium
Dilatasi ventrikel
Peningkatan daya kontraksi
Beban kerja fungsi tidak dapat dipertahankan secara adekuat
-
Gejala gejala Gagal Jantung
Sesak nafas bila aktifitas fisikMudah capekDenyut jantung cepat Kedua tungkai bengkakTimbunan cairan ditubuh Batuk-batuk ( malam hari)dll -
Jenis-jenis Gagal Jantung (Heart Failure)
Forward vs Backward Heart FailureGagal jantung kanan vs jantung kiri Gagal jantung akut vs kronis Low output vs High output failure Gagal jantung sistolik vs diastolik -
Gagal Jantung Diastolik
Definisi
Gagal Jantung yang disebabkan oleh meningkatnya resistensi terhadap pengisian pada satu atau kedua ventrikel
EF NORMAL ( > 40 %)
-
Common etiology:
CAD
Common etiology:
Hypertension
Systolic Heart Failure
Diastolic Heart Failure
EDV 175.6 ml, EF 37%
EDV 70 ml, EF 65%
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Faktor Presipitasi Gagal Jantung
Kardiak :Aritmia , MCI.
Non kardiak : anemia, emboli paru, pneumonia, tirotoksikosis, asupan garam>>,penghentian obat, penggunaan cairan parenteral yang cepat atau berlebihan, obat NSAID, obat steroid, demam .
Kehamilan, dll
-
A Major Medical Problem
Acute Coronary Syndromes
( A C S )Acute Coronary Ischemic Syndromes
-
UNSTABLE ANGINA & NONST-SEGMENT
ELEVATION MYOCARDIAL INFARCTION
ACC/AHA GUIDELINES
Eugene Braunwald, MD, Chair
Feb.2001 British Cardiac Society
2002
*
-
Pathophysiology
Acute Coronary Syndrome
( A C S )
Dr Abdul Majid SpPD-KKV
-
Heart
attack
Acute Coronary Syndrome ???
-
Acute Coronary Syndrome
Pasien dengan spektrum klinis rasa tidak enak didada
atau gejala lainnya yang disebabkan oleh iskemia miokardcharacterized by
the common pathophysiology of
a disrupted atheroslerotic plaque
The spectrum of clinical conditions ranging from:Unstable angina
(UAP)
Non-Q wave MI (NSTEMI)
Q-wave MI (STEMI)
-
ACS: physiopathology
-
Thin Fibrous Cap
Lipid Core
Unstable Plaque
Thrombus
Inflammatory
CellsFew
SMCsActivated
MacrophagesRuptured Plaque
Plaque Rupture Leads to Thrombus Formation
-
Plaque Rupture Leads to Thrombus Formation
Yeghiazarians Y et al. N Engl J Med. 2000;342:101-114.
*
1
-
Role of Platelets in Thrombus Formation
in Acute Ischemic EventsAtherosclerotic
VesselPlaque
RupturePlatelet Adhesion,
Activation, and Aggregation
Thrombus
FormationThrombotic
OcclusionLipid
CoreSchafer AI. Am J Med. 1996;101:199209.
Vessel wall injury Plaque rupture
Exposure of subendothelial collagen and
other platelet-adhering ligandsMI
Stroke
Vascular
Death
-
a cross-section of the coronary artery. Most of its wall is filled with smooth muscle cells that can contract and relax.
atherosclerotic plaque( consists of cholesterol, inflammatory cells, and fibrosis, and it reduces the space for blood flow in the artery.)
Nitroglycerin dilates constricted arteries.
A spasm can suddenly develop in an atherosclerotic coronary artery ( angina pectoris)
-
The anterior surface of the heart demonstrates an opened left anterior descending coronary artery. Within the lumen of the coronary can be seen a dark red recent coronary thrombosis. The dull red color to the myocardium as seen below the glistening epicardium to the lower right of the thrombus is consistent with underlying myocardial infarction.
At high magnification, the dark red thrombus is apparent in the lumen of the coronary. The yellow tan plaques of atheroma narrow this coronary significantly, and the thrombus occludes it completely.
- Koroner normal
Pasokan seimbang dengan kebutuhan
(aliran darah koroner)(kebutuhan miokard)
PJK Pasokan , kebutuhan tetap
Pasokan tetap, kebutuhan
-
Risk Factors of
ACS
- Cigarette smoking Elevated Blood PressureElevated serum LDL
cholesterol Low serum HDL cholesterolDiabetes Mellitus Advancing
Age
Predisposing Risk Factors
Risk parallels Endothelial
Dysfunction !! !!
Major independent Risk Factors
Obesity Abdominal Obesity Physical inactivityFamily history of premature CHDEthnic characteristicsPsychosocial factorsConditional risk factors
Elevated serum triglyceridesSmall LDL particles Elevated serum homocysteineElevated serum lipoprotein(a) Prothrombotic factors(eg, fibrinogen)
Inflammatory markers(eg, C-reactive protein)
Assessment of
cardiovascular risk
Grundy et al, J Am Coll Cardiol 1999;34:1348-59
-
Endothelial Dysfunction
Diabetic Angiopathy
Endothelial Dysfunction and Cardiovascular Disease
Peripheral Artery Disease
Atherosclerosis
Thrombosis Coagulopathy
Hyperlipidemia
Diabetic
Angiopathy
Vasospasm
Coronary, Cerebral
Heart Failure
Reocclusion
Reperfusion Injury
Hypertension
Inflammatory
Disease
Immune Reaction
Adapted from Rubanyi GM: J Cardiovasc Pharmacol.1993;22(suppl 4) S1-S14
-
Carotid
Arteries
Coronary
Arteries
Peripheral
Vasculature
Atherosclerosis
Stroke
Heart Attack
Angina
Intermittent
Claudication
-
Patofisiologi SKA
Injury &
disfungsi endotel
Plak tak stabil
Hipertensi
Merokok
DM
Dislipidemia
Zat vasoaktif dll
Vasokonstriksi
Disfungsi endotel
Platelet & thrombin
dependent vasoconstriction
Agregasi trombosit, akumulasi lipid & makrofag
disrupsi
Oklusi koroner
Trombosis akut
APTS
IMA
Plak stabil
-
Normal
Fatty
StreakFibrous
PlaqueOcclusive
Atherosclerotic
PlaquePlaque
Rupture/
Fissure &
ThrombosisMI
Stroke
Critical Leg Ischemia
Clinically Silent
Coronary
Death
Increasing Age
Effort Angina
Claudication
Unstable
Angina
Atherosclerosis: A Progressive Process
Courtesy of P Ganz.
-
UA/NSTEMI
Nonocclusive thrombus on pre-existing plaqueDynamic obstruction (coronary spasm or vasoconstriction)Progressive mechanical obstructionInflammation and/or infectionSecondary UA
PATHOGENESIS (NON-EXCLUSIVE)Braunwald Circulation 98:2219, 1998
Thrombosis
Thrombosis
Mechanical Obstruction
Mechanical Obstruction
Dynamic
Obstruction
Dynamic
Obstruction
Inflammation/
Infection
Inflammation/
Infection
MVO2
MVO2
.
.
CAUSES OF UA/NSTEMI
*
-
Worldwide Statistics
Each year:
> 4 million patients are admitted with unstable angina and acute MI > 900,000 patients undergo PTCA with or without stent -
Traditional Coronary Artery Bypass Grafts. One vein graft is sutured to the aorta, then to the LAD .
C A B G (Coronary Artery Bypass Grafts)
-
Spectrum of Acute coronary syndromes
Acute Coronary Syndrome
No ST Elevation
ST Elevation
Unstable Angina
Myocardial Infarction
Non Qw MI Qw MI
(NSTEMI) (STEMI)
Non ST Elevation MI
Braunwald E et al. J Am Coll Cardiol 2000;36:9701062.
*
Slide 2The spectrum of clinical conditions that range from unstable angina to nonQ-wave acute myocardial infarction (MI) and Q-wave MI is referred to as acute coronary syndromes. ST-segment elevation may or may not be present in patients presenting with ischemia. A minority of patients with ST-elevation (small arrow) have a nonQ-wave MI (nonQw MI), whereas most of these patients (large arrows) eventually develop a Q-wave MI (Qw MI). Unstable angina or a nonST-elevation MI is the likely cause in patients presenting without ST-elevation. The majority of patients with nonST-elevation MI do not evolve a Q-wave; these patients are defined as having a nonQw MI. Only a minority of patients with nonST-elevation MI have a Q-wave. These patients are later diagnosed as having Q-wave MI [1].
References
1. Braunwald E et al. J Am Coll Cardiol 2000;36:9701062.
-
Diagnosis ACS
Chest pain
( typical)
ECG changes
Cardiac serum marker
-
exertion-induced angina
silent ischemia
unstable angina
acute myocardial infarction
Spectrum
of
presentation
Myocardial Ischemia
-
Ischemic Heart Disease evaluation
Based on the patients
history / physical exam E C Gnon-cardiac chest pain
Stable angina
Unstable angina
myocardial infarction
Patients are categorized into :
cardiac chest pain
-
UA/NSTEMI
Chest pain or severe epigastric pain, typical of myocardial ischemia or MI:Substernal compression or crushing chest painPressure, tightness, heaviness, cramping, aching sensationUnexplained indigestion, belching, epigastric painRadiating pain to neck, jaw, shoulders, back or to one or both armsAssociated dyspnea, nausea and/or vomiting, diaphoresis
EMERGENCY ROOM TRIAGEIF THESE SYMPTOMS ARE PRESENT, OBTAIN STAT ECG
*
-
Ischemic chest pain
-
Pleuritic pain (i.e., sharp or knife-like pain brought on by respiratory movements or cough)
Primary or sole location of discomfort in the middle or lower abdominal region
Pain that may be localized at the tip of 1 finger, particularly over the LV apex
Pain reproduced with movement or palpation of the chest wall or armsVery brief episodes of pain that last a few seconds or lessPain that radiates into the lower extremitiesFEATURES NOT CHARACTERISTIC
OF MYOCARDIAL ISCHEMIA*
Meeting Comments
- Modified and reviewed - possible changes
-
UA/NSTEMI
THREE PRINCIPAL PRESENTATIONS
Rest Angina* Angina occurring at rest and prolonged, usually > 20 minutes, occurring within 1 week of presentation
New-onset AnginaNew-onset angina of at least CCS Class III severity ( marked limitation of ordinary physical activity) severity with onset within 2 mo of initial presentation
Increasing AnginaPreviously diagnosed angina that has
become distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by > 1 CCS) class to at least CCS Class III severity.
Braunwald Circulation 80:410; 1989
* Pts with NSTEMI usually present with angina at rest.
*
-
hyper acute T (0-1 hrs), ST elevation (hours),
Q wave (8-48 hrs), T inverted (1-2 days)
ECG changes in Acute Coronary Syndrome
ST depression with/ without T inverted, Q wave (-)
ST depression, deep T inverted
Q wave MCI(STEMI)
Non Q MCI (NSTEMI)
UAP
-
Unstable Angina : Likelihood of CAD
Previous history of CADpresence of risk factorsolder ageST-T wave ischemic ECG changesAgency for Health Care Policy Research - 1994
Chest pain (-)
Chest pain (+)
-
Non-Q-Wave MI: Clues to diagnosis
Prolonged chest painAssociated symptoms from the autonomic nervous systemnausea, vomiting, diaphoresisPersistent ST-segment depression after resolution of chest pain -
Q-Wave MI: Clues to diagnosis
Prolonged chest painAssociated symptoms from the autonomic nervous systemnausea, vomiting, diaphoresisST-segment elevation/ Q wave -
I
II
III
aVR
aVL
aVF
MCI non Q (Non ST Elevation MI)
Subendokard
Subepikard
ST depression
T inverted
Q wave (-)
ST elevation
T inverted
Q wave(+)
MCI Q wave
(ST Elevation MI)
-
Cardiac serum marker in Acute Myocardial Infarction
-
Troponin as Predictor of Ischemic Events
Death or MI at 30 days (n = 773)NEJM 1997;337:1648-1653
-
FEATURE
HIGH LIKELIHOOD
INTERMEDIATE LIKELIHOOD
Absence of high-likelihood features
and presence of any of the following:
HIGH OR INTERMEDIATE LIKELIHOOD THAT
UA/NSTEMI IS CAUSED BY OBSTRUCTIVE CAD
Chest or left arm pain reproducing prior documented angina. Known history of CAD, including MI
Transient MR, hypotension, diaphoresis, pulmonary edema, or rales
History
Examination
Chest or left arm pain or discomfort
Age > 70
Male sex
Diabetes mellitus
Extracardiac vascular disease
*
-
FEATURE
HIGH LIKELIHOOD
INTERMEDIATE LIKELIHOOD
Absence of high-likelihood features
and presence of any of the following:
HIGH OR INTERMEDIATE LIKELIHOOD THAT
UA/NSTEMI IS CAUSED BY OBSTRUCTIVE CAD
New transient ST-
segment deviation or
T-wave inversion
(0.2 mV) with symptomsElevated cardiac Tnl, TnT,
or CK-MBECG
Cardiac
markersFixed Q waves
Abnormal ST segments or T waves not documented to be new
Normal
*
-
Acute Coronary Syndrome
Ischemic Discomfort
Unstable SymptomsNo ST-segment
elevationST-segment
elevationUnstable Non-QQ-Wave
angina AMI AMIECG
Acute
ReperfusionHistory
Physical Exam -
Plaque Rupture with Thrombosis
Thrombus
Fibrous cap
1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
-
Acute Coronary Syndrome
Process of resolutionspontaneous thrombolysisvasoconstriction resolutionpresence of collateral circulationDelayed or absence of resolution may lead tonon-Q-wave or Q-wave myocardial infarction
-
To exclude an acute coronary syndrome:
If at 12 h after onset of symptoms
Symptoms have not recured
ECG is normal
CK-MB is normal
Troponin is normal
The patient can be mobilized and discharge
Their risk should be assessed with a stress test
Feb.2001 British Cardiac Society
-
Suspected Cardiac Pain
ECG
No ECG ST
Normal ECG,
CK-MB,& cTn
ECG ischemic or
CK-MB or cTn
Suspected ACS
Confirmed ACS
Feb.2001 British Cardiac Society
ECG ST Or LBBB
Acute MI
-
Let it beat!
-
. ECG Rhythm Abnormalities
Topics for Study:1. Introduction to rhythm analysis
2. Supraventricular arrhythmias
3. Ventricular arrhythmias
Pathophysiology arrhythmias
-
.
Electrocardiogram (ECG; EKG)
the chart recording of the electrical activity of the heart as measured from the body surface potentials
Systole period of myocardial contraction
Diastole period of cardiac muscle relaxation
P wave corresponds to atrial depolarization
PR interval a measure of the conduction time required for an impulse to be conducted from the atria to the ventricles (normal: 0.12 0.20 sec)
QRS complex represents depolarization of the ventricles
S-T segment interval between ventricular depolarization and repolarization
T wave reflects ventricular repolarization
-
V. ECG Rhythm Abnormalities
Introduction to rhythm analysis
Topics for Study:2. Supraventricular arrhythmias
Premature atrial complexes
Premature junctional complexes
Atrial fibrillation
Atrial flutter
Ectopic atrial tachycardia and rythm
Multifocal atrial tachycardia
Paroxysmal supraventricular tachycardia
Junctional rhythms and tachycardias -
V. ECG Rhythm Abnormalities
Topics for Study:3. Ventricular arrhythmias
Premature ventricular complexes (PVCs)
Aberrancy vs. ventricular ectopy
Ventricular tachycardia
Differential diagnosis of wide QRS tachycardias
Accelerated ventricular rhythms
Idioventricular rhythm
Ventricular parasystole
-
Lesson V (cont) Supraventricular Arrhythmias
1.Premature atrial complexes
2.Premature junctional complexes
3.Atrial fibrillation
4.Atrial flutter
5.Ectopic atrial tachycardia and rhythm
6.Multifocal atrial tachycardia
7.Paroxysmal supraventricular tachycardia
8.Junctional rhythms and tachycardias
-
1.Premature atrial complexes
Occur as single or repetitive events and have unifocal or multifocal origins.
The ectopic P wave (called P') is often hidden in the ST-T wave of the preceding beat. (Dr. Marriott, master ECG teacher and author, likes to say: "Cherchez le P on let T" which in French means: "Search for the P on the T wave", but it's more sexy in French!)
The P'R interval is normal or prolonged because the AV junction is often partially refractory when the premature impulse enters it.
Supraventricular Arrhythmias
-
The pause after a PAC is usually incomplete; i.e., the PAC usually enters the sinus node and resets its timing, causing the next sinus P to appear earlier than expected. (PVCs, on the other hand, are usually followed by a complete pause because the PVC does not usually perturb the sinus node; see ECG below.)
-
3.Atrial Fibrillation (A-fib)
-
4.Atrial Flutter (A-flutter):
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.
-
Junctional Escape Rhythm: This is a sequence of 3 or more junctional escapes occurring by default at a rate of 40-60 bpm. There may be AV dissociation or the atria may be captured retrogradely by the junctional pacemaker. In the ECG example below the retrograde P waves are not seen and must be hidden in the QRS's; the significant "Q" wave with ST elevation in the bottom strip suggests an acute MI.
8.Junctional Rhythms and Tachycardias
-
Lesson V (cont ) Ventricular arrhythmias
1.Premature ventricular complexes (PVCs)
2.Aberrancy vs. ventricular ectopy
3.Ventricular tachycardia
4.Differential diagnosis of wide QRS tachycardias
5.Accelerated ventricular rhythms
6.Idioventricular rhythm
7.Ventricular parasystole -
1. Premature Ventricular Complexes (PVCs)
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 as isolated single events or as couplets, triplets, and salvos (4-6 PVCs in a row), also called brief ventricular tachycardias.
-
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.
-
3.Atrio-Ventricular (AV) Block
Possible sites of AV block:
AV node (most common)
His bundle (uncommon)
Bundle branch and fascicular divisions (in presence of already existing complete bundle branch block)
1st Degree AV Block: PR interval > 0.20 sec; all P waves conduct to the ventricles.
-
Type I (Wenckebach) AV block (note the RR intervals in ms duration):
Type II (Mobitz) AV block(note there are two consecutive constant PR intervals before the blocked P wave):
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:
Type I AV block is almost always located in the AV node, which means that the QRS duration is usually narrow, unless there is preexisting bundle branch disease.
-
Complete (3rd Degree) AV Block
Usually see complete AV dissociation because the atria and ventricles are each controlled by separate pacemakers.
Narrow QRS rhythm suggests a junctional escape focus for the ventricles with block above the pacemaker focus, usually in the AV node.
Wide QRS rhythm suggests a ventricular escape focus (i.e., idioventricular rhythm). This is seen in ECG 'A' below; ECG 'B' shows the treatment for 3rd degree AV block; i.e., a ventricular pacemaker. The location of the block may be in the AV junction or bilaterally in the bundle branches.
-
Left Bundle Branch Block (LBBB)
"Complete" LBBB" has a QRS duration >0.12s
Close examination of QRS complex in various leads reveals that the terminal forces (i.e., 2nd half of QRS) are oriented leftward and posteriorly because the left ventricle is depolarized after the right ventricle.Terminal S waves in lead V1 indicating late posterior forces
Terminal R waves in lead I, aVL, V6 indicating late leftward forces; usually broad, monophasic R waves are seen in these leads as illustrated in the ECG below; in addition, poor R progression from V1 to V3 is common.
-
Wolff-Parkinson-White Preexcitation
-
Pathophysiologi
Endothelial dysfunction:
Dr Abdul Majid SpPD-KKV
Dept. of Physiology FK USU
Consultant Internist and Cardiologist Permata Bunda Hospital
Medan
-
Ten to 20 years ago .
the cardiovascular was thought to be controlled by
circulating factors such as
the renin- angiotensin system
and
the sympathetic nervous system
which were able to regulate the heart, kidney , and the blood vessels
Heart 2000;84(Suppl I):i20-i22
-
More recently, however, it has become evident that the blood vessels itself plays an important role that involves many factors including
nitric oxide, which is vasodilator,
and endothelin, a vasoconstrictor.
In fact, the endothelium is altered morphologically as a result of coronary artery disease.
Heart 2000;84(Suppl I):i20-i22
-
Heart
SEPTEMBER 2000 VOLUME 84 SUPPLEMENT I
Evolving Strategies in Cardiovascular Care:
The Renin-Angiotensin System and the Future
BMJ
THE ENDOTHELIUM: A PIVOTAL ROLE IN HEALTH AND CARDIOVASCULAR DISEASE
C.M. BOULANGER P.M. VANHOUTTE
British Cardiac Society
European Heart Journal
Journal of the European Society of Cardiology
DO ACE
INHIBITORS
MODULATE
ATHEROSCLEROSIS?
OCTOBER 1997
VOLUME 18 No 10
PP 1530-1535
References
The Role of Endothelium in Cardiovascular Homeostasis and Disease
Gabor M.Rubanyi
Cardivascular Research, Berlex Bioscience, Richmond. California, USA
Journal of Cardiovascular Pharmacology
22(Suppl, 4);SI-S14@1993 Raven Press, Ltd, New York
The Endothelium in Clinical Practice
edited by
Gabor M.Rubanyi
Victor J.Dzau
Source and Target of Novel Therapies
The Relevance of Tissue
Angiotensin- Converting Enzymes:
Manifestations in Mechanistic and Endpoint Data.
Victor J.Dzau,Kenneth Bernstein, David Celermajer , et al.
Am J Cardiol 2001;88(suppl):I L-20L
Clinical Assessment of Endothelial Function
Hiroaki Shimokawa, M.D., Ph.D.
-
Oxygen Carbon dioxide
-
Blood vessels
All have endothelial liningHigh power view of endothelial cells lining a small blood vessel cut in cross-section. (You see just the nuclei - the cytoplasm between them is extremely flat.) Endothelium = the simple squamous epithelium lining blood vessels.
Low power view of larger vessels, showing endothelial nuclei lining the lumen. The yellowish cells filling each vessel's lumen are blood cells.
-
The Nobel Prize in Physiology or Medicine 1998
The Nobel Assembly at the Karolinska Institute in Stockholm, Sweden, has awarded the Nobel Prize in Physiology or Medicine for 1998 to Robert F Furchgott, Louis J Ignarro and Ferid Murad for their discoveries concerning "the nitric oxide as a signalling molecule in the cardiovascular system".
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 posterMurad, born 1936
Dept. of Integrative Biology
Pharmacology and Physiology
University of Texas Medical School, HoustonRobert F Furchgott, born 1916
Dept. of Pharmacology,
SUNY Health Science Center
New YorkLouisJ Ignarro, born 1941
Dept. of Molecular and Medical Pharmacology
UCLA School of Medicine
Los AngelesFerid -
Physiology
of the
Endothelium
ENDOTHELIAL CELLS(ARE)MORE THAN A SHEAT OF NUCLEATED CELLPHANE
LORD FLOREY,1966
-
The Endothelium : A Living Organ
The Healthy Endothelium
In a 70 kg man, the total of endothelial cells is 1 trillion
In a 70 kg man, its total surface area is 6 tennis courts
The
endothelium
is the largest
organ in
the body
In a 70 kg man, its total weight is 1,800 g (> the liver, -- 5 hearts
*
Slide Objective
Recently, endothelial dysfunction has become a target of therapy to reduce or slow the outcomes associated with certain disease states (eg, atherosclerosis).Narrative
Some of the characteristics of a dysfunctional endothelium are:decreases in EDRF, which promotes platelet adhesion, vasoconstriction, and leukocyte adhesion.
decreases in tPA and PAI-1, which promote thrombosis
increases in adhesion molecules, which promote monocyte or macrophage retention
These changes impair blood flow and place a patient at higher risk of atherosclerotic events.Recently, endothelial dysfunction has become a target of therapy to reduce or slow the outcomes associated with certain disease states (eg, atherosclerosis) (Celermajer. J Am Coll Cardiol 1997;30:325). -
The Endothelium and Surrounding Elements
Blood cells
Endothelium
Smooth muscle
Subendothelial
matrix
LDL-cholesterol
Coagulation elements
*
The elements found around the endothelial cells play a central role in vascular homeostasis. Blood cells, coagulation and fibrinolysis elements, lipid particles, the subendothelial matrix and the vascular smooth muscle cells are in close connection with the epithelium.
-
is not only a selective barrier ,
it also has metabolic and secretory activity.
In 1980 , it was discovered that the endothelium released
Vasodilator substance(s) EDRF (endothelium derived relaxing factor)Vasoconstrictor substances EDCF (endothelium derived contrcting factor)The endothelium
-
M2
5-HTI
H2
VP1
2
B2
P2
T
ET
Ach
Histamine
AVP
A,NA
Bradykinin
AA
ADP
5-HT
Thrombin
Endothelin
Aggregating platelets
Endothelial cells
EDRF(s)
Smooth muscle cells
Relaxation
-
Vascular Endothelium
Recognized as a major regulator of vascular tone and hemostasis
Provides a smooth, non-thrombogenic surface and a permeability barrier
Synthesizes and releases a number of vasoactive substances that control relaxation and contraction, thrombogenesis and fibrinolysis, and platelet activation and inhibition
Contributes to blood pressure control, blood flow, vessel patency
Pepine, C., et. al., Vascular Health as as Therapeutic Target in Cardiovascular Disease, Vascular Biology Working Group, University of Florida, 1998.
a cross-section of the coronary artery. Most of its wall is filled with smooth muscle cells that can contract and relax.
-
Vasoactive Substances
Vasodilators
Nitric oxide (N0) / EDRFEDHFProstacycline (PGI2)BradykininAcetylcholine, serotonine, histamine, substance P, etcVasoconstrictors
EndothelinAngiotensin IIThomboxane A2, Acetylcholine, arichdonic acid, prostaglandin H2, etcSubstances Released by Endothelium
-
Substances Released by Endothelium
Growth promototrs : VEGF, FGF
Growth inhibitors : tGFbeta, NO, prostacycline
Hemostasis and Thrombosis
Anti-thrombogenic factors: t-PA (tissue plasminogen activator),
TM (thrombomodulin), heparin sulfate
Thrombogenic factors:VWF ( von Willebrand factor),
PA-I (plasminogen activator inhibitor),
adhesive glycoproteins
Growth Mediators/Modulators
Luscher, T., Barton, M., Biology of the Endothelium, Clinical Cardiology, vol. 20 (Suppl. II0, II-3 -II-10 (1997).
Adhesion molecules: ELAM, ICAMAntigens : MHC-IIInflammatory modulators / mediators
-
Endothelium Endothelium Derived Factors
Vascular Relaxation Contraction Proliferation
Smooth Muscle
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..
Adapted from Rubanyi GM: J Cardiovasc Pharmacol.1993;22(suppl 4) S1-S14
Blood
Cells
P MNSMonocytes PlateletsPhysical Forces
Shear StressPressureVasoactive Substances
Peptides (thrombin, SP, VP)Kinins(Bk)Amines ( 5 HT ) Nucleotides ( ATP, ADP ) AA metabolites ( LTC 4 ) -
Endothelium derived mediators
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; R-NO, 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
Small Molecules : Histamine Free Radicals EDRF ( NO, R NO )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 ) ReceptorsLipids : Prostaglandin ( PGL 2 ) Leukotrienes PAF -
Thrombosis Hemostasis
Permeability
Metabolic Activity
Angiogenesis
Lipid Transport
Vascular Tone/Structure
Immune Respons
Tumor growth/metastasis
Inflammation
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 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
Pepine, C., et. al., Vascular Health as as Therapeutic Target in Cardiovascular Disease, Vascular Biology Working Group, University of Florida, 1998.
Effects of Endothelin
Powerful vasoconstrictionRelease from endothelium stimulated by Ang II
Effects of Bradykinin
Activates L-arginine-NO pathway, promoting dilation and inhibiting smooth muscle cell proliferationActivates release of prostacyclin and EDHF, inhibiting platelet adherence/aggregation and VSM contractionInduces increase in t-PA activity, promoting fibrinolysis -
B2
Nitric Oxide (NO) Synthesis
NO
Peripheral
vasoconstriction
Renal
resistance
Glomerulo-tubular
Feedback
Renin Secretion
Sodium
Reabsorption
Pressure-
natriuresis
Endothelial cell
Smooth muscle cell
L-Arg
NO
NO-synthase
L-citruline
NO
NO
-
Endothelial health: A balancing act
Angiotensin II
Nitric Oxide
-
Endothelial Function Balance
Vasodilation
Antiproliferation
Antithrombotic
Antioxidant
Anti-inflammatory
Vasoconstriction
Proliferation
Thrombotic
Pro-oxidant
Pro-inflammatory
Maintenance Vascular Health
*
(Empty)
-
ATII
Angiotensin I
Angiotensin II
Bradykinin
(active)
Inactive
peptide
Converting enzyme
Endothelial cells
Basal membrane
5-Hydroxytryptamine
Norepinephrine
COMT
MAO
Inactive metabolites
A
A
B
Figure: The handling of bioactive substances by the endothelium
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.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
*
The interaction of the renin-angiotensin system and bradykinins with the endothelium is shown on the slide. The ACE of the endothelium generates angiotensin II and deactivates bradykinin. The effects of angiotensin II are mediated by specific AT1 receptors, whereas bradykinin triggers the release of NO and PGI2 via specific receptors.
The effects of angiotensin II and bradykinin are antagonistic.
-
ATII
Angiotensin I
Angiotensin II
Bradykinin
(active)
Inactive
products
AT
AT1
ETA
Contraction
Relaxation
Endothelin I
Angiotensin II
Prepro ET Big ET
ECE
Renin
AI ATG
ACE
B2
ACE
L-Arginine NOS2
NO
Cyg AA
PGI2
cGMP
cAMP
Figure: The endothelium plays an important role in the control of the vascular system.
Luscher TF, Heart 2000:84(Suppl I): i20-i22
*
The interaction of the renin-angiotensin system and bradykinins with the endothelium is shown on the slide. The ACE of the endothelium generates angiotensin II and deactivates bradykinin. The effects of angiotensin II are mediated by specific AT1 receptors, whereas bradykinin triggers the release of NO and PGI2 via specific receptors.
The effects of angiotensin II and bradykinin are antagonistic.
-
Endothelial dysfunction
-
The Endothelium
Any Alteration in normal endothelial function Results in imbalance between :- relaxing and contracting factors.
- anticoagulant and procoagulant properties
- growth-inhibiting and promoting factors
Endothelial Dysfunction
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 -
Unifying model :Endothelial Dysfunction to Cardiovascular Disease
Risk factors
Hyperlipidemia
Hypertension
D M
Smoking
Hypoxia/ ischemia/ reperfusion
Oxidative stress
Endothelial Dysfunction
NO . Local mediators . Tissue ACE leading to Angiotensin II
Thrombosis
Inflammation
Vasoconstriction
Vascular lesion and remodeling
Plaque rupture
Gibbons GH, Dzau VJ. N Engl J Med. 1994;330: 1431-38
Clinical Sequelae
PAI-I
VCAM
ICAM cytokines
Endothelin
Growth
factors marks
Proteolysis
-
Normal
Fatty
StreakFibrous
PlaqueOcclusive
Atherosclerotic
PlaquePlaque
Rupture/
Fissure &
ThrombosisMI
Stroke
Critical Leg Ischemia
Clinically Silent
Coronary
Death
Increasing Age
Effort Angina
Claudication
Unstable
Angina
Atherosclerosis: A Progressive Process
Courtesy of P Ganz.
-
Impact of Endothelial Dysfunction
ENDOTHELIAL
DYSFUNCTION
Arterial
resistances
Vascular Spasm
Arteriosclerosis
Atheromas
and
Thrombosis
*
Endothelial dysfunction is at the root of
- the progressive increase in resistance and decrease in reserves in areas like the coronary or the kidney;
- the vascular spasm which triggers clinical events of ischemic heart disease;
- the development of arteriosclerosis and the formation of atherome plaques; and
- arterial thrombosis as the final event which leads to the occurrence of cardiovascular accidents.
-
Endothelial Dysfunction
Diabetic Angiopathy
Endothelial Dysfunction and Cardiovascular Disease
Peripheral Artery Disease
Atherosclerosis
Thrombosis Coagulopathy
Hyperlipidemia
Diabetic
Angiopathy
Vasospasm
Coronary, Cerebral
Heart Failure
Reocclusion
Reperfusion Injury
Hypertension
Inflammatory
Disease
Immune Reaction
Adapted from Rubanyi GM: J Cardiovasc Pharmacol.1993;22(suppl 4) S1-S14
-
Acute circulatory failure
Pump Fluid TubingInability to supply adequate oxygen to match tissue demand
Shock:
the manifestation of cardiovascular failure.
"Acute circulatory failure with inadequate or inappropriately distributed tissue perfusion resulting in generalized cellular hypoxia.
-
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.
Types of shock:
Cardiogenic shock
Acute myocardial infarction Acute aortic incompetence Ischaemic mitral regurgitation LV aneurysm Myocardial contusion ~ 40% of myocardium damaged leading to ShockObstructive shock
Outflow obstruction ->pulmonary embolus Inflow obstruction -> Cardiac tamponadeHypovolaemic shock
Exogenous loss from haemorrhage Endogenous loss -> third space loss & capillary leak syndrome -
Let it beat!
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CLASSIFICATION OF BLOOD PRESSURE
FOR ADULTS AGE 18 AND OLDERCategorySBP DBP (mmHg) ( mmHg)
Optimal -
National High Blood Pressure Education Program
The Sixth Report of the
JOINT NATIONAL COMMITTEE
On Prevention, Detection,
Evaluation, and Treatment of
High Blood Pressure
NATIONAL INSTITUTES OF HEALTH
Slide 2
The spectrum of clinical conditions that range from unstable angina to
non
Q-wave acute myocardial infarction (MI) and Q-wave MI is referred to as
acute coronary syndromes. ST-segment elevation may or may not be
present in patients presenting with
ischemia.
A minority of patients with ST-
elevation (small arrow) have a nonQ-wave MI (nonQw MI), whereas most
of these patients (large arrows) eventually develop a Q-wave MI (
Qw MI).
Unstable angina or a
nonST-elevation MI is the likely cause in patients
presenting without ST-elevation. The majority of patients with
nonST-
elevation MI do not evolve a Q-wave; these patients are defined as having a
nonQw MI. Only a minority of patients with
nonST-elevation MI have a Q-
wave. These patients are later diagnosed as having Q-wave MI [1].
References
1
.
Braunwald E
et al
.
J Am
Coll Cardiol
2000
;
36
:9701062.
22.0
19.0
1.0
0.3
0.0
5.0
10.0
15.0
20.0
25.0
Patient with Cardiac
Events (%)
Troponin positiveTroponin negative
Troponin TTroponin I
National High Blood Pressure Education Program
The Sixth Report of the
JOINT NATIONAL COMMITTEE
On Prevention, Detection,
Evaluation, and Treatment of
High Blood
Pressure
NATIONAL INSTITUTES OF HEALTH