PATHOFISIOLOGI KARDIOVASKULAR

Dr.Abdul Majid SpPD-KKV

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 Hypertension

JNC 7 2003

British Society of Hypertension 2003/2004

Kaplan`s Clinical Hypertension 2002

ESC 2003

Hypertension Syndrome
Its More Than Just Blood Pressure

Decreased
Arterial Compliance

Endothelial Dysfunction

Abnormal Glucose Metabolism

Neurohormonal Dysfunction

Renal-Function Changes

Blood-Clotting Mechanism Changes

Obesity

Abnormal Insulin Metabolism

LV Hypertrophy
and Dysfunction

Accelerated 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.

ESH 2003 & JNC VII(2003)

> 140

< 90

JNC 7 2003

ESH-ESC 2003BP ClassificationBP BPJNC VII(2003)Bp ClassificationOptimal110Isolated Systolic HypertensionIsolated Systolic Hypertension

ESC 2003

Types of hypertension

Essential Hypertension

hypertension with no apparent cause 90-95%

Secondary Hypertension

hypertension 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.

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

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

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

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.

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 retinopathy

Blurred 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

Cardiac Damage in
Hypertension

HT 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).

Cardiac Sequelae of Hypertension

Left Ventricle Hypertrophy

Heart failure

Arrhythmias

Coronary Heart Disease

Development of Cardiac Lesions
due to Hypertension

LEFT 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.

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 IIAldosteroneACE

Myocardial

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

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

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)

Etiology of Heart Failure

Idiopathic cardiomyopathy Myocarditis Valvular heart disease Familial toxic, metabolic

200

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

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 mellitus

or

Patients

using cardiotoxinwith FHxCM

eg, Patients with:

previous MI LV systolic dysfunctionasymptomatic valvular disease

eg, Patients with:

known structural heart diseaseshortness of breath and fatigue, reduced exercise tolerance

eg ,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)

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%

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 miokard

characterized 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
Cells

Few
SMCs

Activated
Macrophages

Ruptured 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 Events

Atherosclerotic
Vessel

Plaque
Rupture

Platelet Adhesion,

Activation, and Aggregation

Thrombus
Formation

Thrombotic
Occlusion

Lipid
Core

Schafer AI. Am J Med. 1996;101:199209.

Vessel wall injury Plaque rupture
Exposure of subendothelial collagen and
other platelet-adhering ligands

MI

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 factors

Conditional 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
Streak

Fibrous
Plaque

Occlusive

Atherosclerotic
Plaque

Plaque
Rupture/
Fissure &
Thrombosis

MI

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
PATHOGENESIS (NON-EXCLUSIVE)

Nonocclusive thrombus on pre-existing plaqueDynamic obstruction (coronary spasm or vasoconstriction)Progressive mechanical obstructionInflammation and/or infectionSecondary UA

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 2

The 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 G

non-cardiac chest pain

Stable angina

Unstable angina

myocardial infarction

Patients are categorized into :

cardiac chest pain

UA/NSTEMI
EMERGENCY ROOM TRIAGE

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

IF 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 extremities

FEATURES 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 changes

Agency 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 symptoms

Elevated cardiac Tnl, TnT,
or CK-MB

ECG

Cardiac
markers

Fixed Q waves

Abnormal ST segments or T waves not documented to be new

Normal

*

Acute Coronary Syndrome

Ischemic Discomfort
Unstable Symptoms

No ST-segment
elevation

ST-segment
elevation

Unstable Non-QQ-Wave
angina AMI AMI

ECG

Acute
Reperfusion

History
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 to

non-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
Topics for Study:

Introduction to rhythm analysis

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 lining

High 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 poster

Murad, born 1936
Dept. of Integrative Biology
Pharmacology and Physiology
University of Texas Medical School, Houston

Robert F Furchgott, born 1916
Dept. of Pharmacology,
SUNY Health Science Center
New YorkLouis

J 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, etc

Vasoconstrictors

EndothelinAngiotensin IIThomboxane A2, Acetylcholine, arichdonic acid, prostaglandin H2, etc

Substances 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-II

Inflammatory 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 Platelets

Physical Forces

Shear StressPressure

Vasoactive 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 vasoconstriction

Release 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
Streak

Fibrous
Plaque

Occlusive

Atherosclerotic
Plaque

Plaque
Rupture/
Fissure &
Thrombosis

MI

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 Tubing

Inability 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 Shock

Obstructive shock

Outflow obstruction ->pulmonary embolus Inflow obstruction -> Cardiac tamponade

Hypovolaemic shock

Exogenous loss from haemorrhage Endogenous loss -> third space loss & capillary leak syndrome

Let it beat!

CLASSIFICATION OF BLOOD PRESSURE
FOR ADULTS AGE 18 AND OLDER

CategorySBP 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

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On Prevention, Detection,

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