OEDEMA

Sutikno Tanuwidjaja Subbagian Kardiologi Bagian Ilmu Penyakit Dalam FK UNDIP/RS Dr. Kariadi Semarang

LUNGS

RIGHT HEART

LEFT HEART

BODY ORGANS

CAPILLARIES

CELLS

Circulating plasma -3L

Interstitial space (internal environment - 12 L

Intracellular space - 30 L

Major body fluid compartments with average volumes indicated for a 70-kg human. Total body water is about 60% of body weight.

BERAT BADAN TOTAL (70 KG)

AIR TUBUH TOTAL (42L) ICV (28L) SDM

ECV (14L)
PV (3 L)

Vol darah 5 L IF = ECV - PV

Volume distribusi air mencakup volume intraselular (ICV) dan ekstraselular (ECV).

Arterial end

BLOOD CAPILLARY

Venous end

LYMPHATIC CAPILLARY

Diffusion of fluid and dissolved substances between the capillary and interstitial space

Epithelial Alveolar basement epithelium membrane

Capillary Capillary basement membrane endothelium

Interstitial space

RED BLOOD CELL

Diffusion of oxygen

The structures of the alveolar-capillary membrane over which reciprocal diffusion of oxygen and carbon dioxide occurs

Diffusion of carbon dioxide

ALVEOLUS

CAPILLARY

100%
LUNGS

RIGHT HEART PUMP

LEFT HEART PUMP

100% 3%
HEART MUSCLE

100%

14%
BRAIN

15%
SKELETAL MUSCLE

BONE

5% 21% ARTERIES

VEINS
GASTROINTESTINAL SYSTEM, SPLEEN

6%
LIVER

22%
KIDNEY

6%
SKIN

8%
OTHER

Definition of Heart Failure

Heart failure is the pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure. Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of ventricle to fill with or eject blood.

100 Patients surviving %

Progression Mechanism of death Sudden death 40% Worsening CHF 40% Other 20%

Further damage Excessive wall stress Neurohormonal activation Myocardial ischemia

Annual mortality

<5%
Asymptomatic

10%
Mild

20 to 30%
Moderate

30 to 80%
Severe

Left ventricular dysfunction and symptoms

(Massie & Shah, 1997)

FRAMINGHAM HEART STUDY

100 90 80 70

Males Females

Rate per 1000

60 50 40 30 20

10
0 45-54 55-64 65-74 75-84 85-94

Age (yr)

Incidence of heart failure by age and sex

(Kannel & Belanger, 1981)

EVOLVING MODELS OF HEART FAILURE

Cardiorenal
Digitalis and Diuretic to Perfuse kidneys

Hemodynamic
Vasodilators or

Neurohormonal
ACE-I, -blockers

positive inotropes to
relieve ventricular wall stress

and other agents to

block neurohormonal activation

1940s

1960s

1970s

1990s - 2000

Activation of Neurohormonal Pathways in HF

Coronary Disease Cardiomyopathy Cardiac Overload

Left Ventricular Dysfunction

Neurohormonal Activation Cathecholamines RAS AVP Endothelin

Vasoconstriction

Peripheral Organ Blood Flow skeletal muscle flow RBF retention

Cardiac Remodelling LV hypertrophy

Na+

LV dilatation

Arrhythmias

Exercise Intolerance

Edema, Congestion

Sudden Death

Pump Failure

Ruffolo, J Cardiovasc, Pharmachol, 1998

Electrical substrate dennervation chemical milieu

Heart

Mechanical cell death fibrosis

Coronary

LV Dysfunction

Vascular tone/structure Peripheral

Neuroendocrine

Autonomic NS Metabolic Renal

Hepatic Skeletal muscle Other

The multiple effects of left ventricular (LV) dysfunction

The Role of Angiotensin II in the progression of Heart Failure

Coronary artery disease Pressure overload Cardiomyopathy Left ventricular dysfunction

Arterial blood pressure

Renin release

Vasoconstriction
Peripheral organ blood flow
Skeletal muscle Blood flow Exercise intolerance

Angiotensin II
Aldosterone release

Vascular and cardiac hypertrophy

Cardiac remodelling

Na+ and water retention

Renal blood flow

Left ventricular dilation & hypertrophy Pump failure

Edema

Diuresis

Vasodilatation
Prostaglandins

Antimitogenic Natriuretic peptides

No

Myocardial dysfunction
AVP Renin All Aldosterone

Free radicals Cytokines

Growth hormone

Endothelins Catecholamines

Apoptosis Hypertrophy

Salt and water retention

Vasoconstriction

Many different neurohormonal pathways are stimulated following myocardial dysfunction

Adaptive

Myocyte slippage

Maladaptive Increased O2 demand

Remodeling
Increased myocardial volume Increased myocardial mass Increased stroke volume (Starling)

Ischemia

Stretch
Humoral RAAS Epinephrine Endothelin Growth factors

Myocyte hypertrophy

Decreased Wall stress (Laplace)

Impaired Contractility Arrhythmogenesis

Interstitial fibrosis

Factors influencing myocardial remodelling in HF

CARDIAC REMODELING
Cardiac remodeling may be defined as genome expression,

molecular, cellular and interstitial changes that are

manifested clinically as changes in size, shape and function of the heart after cardiac injury. Remodeling encompasses cellular changes including myocyte hypertrophy, necrosis, apoptosis, fibrosis, increased fibrillar collagen and fibroblast proliferation.

(Cohn et al, 2000)

Index Event (myocardial injury) 0.60 LV Ejection Fraction 0.20 Asymptomatic Symptomatic

Disease progression in heart failure. LV = left ventricular.

( Elchorn & Young , 2001)

ACE inhibitors for congestive heart failure

NEUROHUMORAL EFFECTS OF HEART FAILURE

BACKWARD FAILURE INTO LUNGS & RV

Poor organ perfusion

FORWARD FAILURE LOW BLOOD PRESSURE

JVP RV failure ANP

Low BP
kidney

Baroreflexes
Adrenergic stimulation

RV

LA

RENIN

EXCESS AFTERLOAD

big liver edema Left ventricle

back ward pressure

Na+ loss

Angiotensin Aldosterone

Na+ retension Edema

INCREASING BACKWARD FAILURE

heart

Increasing forward failure

Increasing preload

EXCESS BLOOD VOLUME

low renal blood flow (Opie, 1994)

DETERMINANTS OF VENTRICULAR FUNCTION

CONTRACTILITY PRELOAD
STROKE VOLUME
Synergistic LV contraction LV wall integrity Valvular competence HEART RATE

AFTERLOAD

CARDIAC OUTPUT

FRAMINGHAM CRITERIA FOR CONGESTIVE HEART FAILURE

Major Criteria Paroxysmal nocturnal dyspnea Neck vein distention Rales Radiographic cardiomegaly Acute pulmonary edema S3 gallop Central venous pressure > 16 cm H2O Circulation time > 25 sec Hepatojugular reflux Pulmonary edema, visceral congestion, or cardiomegaly at autopsy Weight loss > 4.5 kg in 5 days in response to treatment of congestive heart failure
Minor Criteria Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion Decrease in vital capacity by one third from maximal value recorded Tachycardia (rate > 120 beats min)
The diagnosis of CHF in this study required that two major or one major and two minor criteria be present concurrently, Minor Criteria were acceptable only if they could not be attributed to another medical condition. ( Ho KL, et al., 1993 )

Clinical Clues to the Differential Diagnosis of Congestive Heart Failure

Systolic CHF History Myocardial infarction Hypertension Physical examination Displaced PMI S3 gallop S4 gallop Chest radiograph Cardiomegaly Pulmonary congestion Electrocardiogram Q waves Left ventricular hypertrophy Diastolic CHF

XX X
X X

X XX

X XX XX XX X X XX X XX
(Goldsmith & Dick, 1993)

Progression of Cardiovascular Disease

Coronary artery Hypertension disease Arrhythmia

Left ventricular remodeling

Remodeling

Low ejection fraction

Death

Cardiomyopathy

Valvular disease

Pump failure

Neurohormonal stimulation Endothelial dysfunction Vasoconstriction Renal sodium retention

Noncardiac factors Symptoms: Dyspnea Fatigue Edema

Chronic heart failure

(Abraham, 2000)

Risk Factors Heart disease

HEART FAILURE SPECTRUM

Asymptomatic LV Dysfunction

Symptoms NYHA II-III

Symptoms NYHA - IV

Symptoms

ECHO / LV dysfunction BNP

Aims of treatment
Prevention
a) Prevention and/or controlling of diseases leading to cardiac dysfunction and heart failure b) Prevention of progression to heart failure once cardiac dysfunction is established

Morbidity
Maintenance or improvement in quality of life

Mortality
Increased duration of life
Guidelines for the diagnosis and treatment of chronic heart failure European Heart Journal (2001) 22, 1527-1560

Chronic Congestive Heart Failure

DIURETICS
Thiazides

Cortex

Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle

K-sparing
Inhibit reabsorption of Na in the distal convoluted and collecting tubule

Medulla
Loop of Henle

Loop diuretics
Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle

Collecting tubule

LOW VS HIGH CEILING DIURETICS

Dose for oliguria Dose for severe CHF EFFICACY Dose for mild CHF Dose for hypertension High-ceiling Loop diuretics

Low-ceiling Thiazides K+ -sparing

Opie (2001)

DOSE

Inotropic agent + vasodilator Inotropic agent + vasodilator + diuretic Stroke volume

Congestive symptoms Inotropic agent only

Vasodilator only

Diuretic only

Low-output symptoms
Left ventricular filling pressure

Congestive and lowoutput symptoms

(Smith & Kelly, 1991)

INITIAL EVENT
Myocardial Insult and/or Excessive Load

LV REMODELING AII M.R.

LV Dilation and Hypertrophy Myocyte Loss, Elongation or Slippage

CLINICAL SYNDROME

PATHOPHYSIOLOGY

Diastolic Wall Stress Energy Supply

Decreased LV Reserve

CHF
Increased Afterload

GISSI-3 CONSENSUS-2 SMILE ISIS-4

TRIALS

SAVE SOLVD (prev.) TRACE

V-HeFT-1 V-HeFT-2 SOLVD (treat.) CONSENSUS-1 AIRE

The pathophysiology of heart failure progressing with time from the initial event. (Lejemtel et al, 2001)

INOTROPIC, VAGAL & SYMPATHOLYTIC EFFECTS OF DIGOXIN

Adrenergic activation in CHF Vagomimetic effect Sympathoinhibitor effects Baroreceptors

CHF
Positive inotropic effect
3 Na+ 2K+

Digoxin

Na+

NE

+
SA

AV

Na+ rises

Ca2+

Toxic arrhythmias

Diuresis RAS inhibition Vasodilation

Digitalis has both neural and myocardial cellular effects. Opie (2001)

Bisoprolol pooled (2 trials) Bucindolol pooled (4 trials) Carvedilol pooled (5 trials) Metoprolol pooled (9 trials) 5 small trials Overall (25 trials)

0.1

0.2

0.5

10

Pooled odds ratios (and 95% confidence intervals) describing the effect of blockers on mortality in patients with heart failure (fixed effects model)
(Cleland et al, 1999)

Betablocker and beta adrenergic receptor in heart failure

Adrenergic
? Direct cardiotoxicity Renin-angiotensin

Vasoconstriction
Increased heart rate and contractility Volume overloaded

Increased MVO2

Increased wall stress

Myocyte damage Hypertrophy Decreased contractility (Bristow, 1993)

Endothelial cell of intramyocardial coronary artery

Vascular smooth muscle cells

Cardiac fibrolast of interstitial space

Tissue fluid of interstitium Myocyte Fibrillar collagen Endothelial cell of capillary

Myocyte and nonmyocyte constituents of the heart.

PULMONARY CAPILLARY FLUID DYNAMICS

Arteriole

Hydrostatic forces at either end of the pulmonary capillary favor a driving pressure through the capillary bed of approximately 4 mm Hg. The normal mean forces acting at the pulmonary capillary are as follows : AVERAGE FORCES TENDING TO PUSH FLUID OUT OF THE PULMONARY VASCULAR SPACE
Mean pulmonary capillary hydrostatic pressure Subatmospheric pulmonary interstitial hydrostatic pressure (drawing fluid into the lung) Interstitial oncotic pressure Net Forces Directing Fluid Outward 8.0 mm Hg -10.0 mm Hg +12.0 mm Hg 30.0 mm Hg

Laterstitial space

Alveolus

AVERAGE FORCES TENDING TO PUSH FLUID INTO THE PULMONARY VASCULAR SPACE Plasma oncotic pressure Net Forces Dircted Inward Net forces : Outward Inward Venule AVERAGE FORCES DIRECTING FLUID INTO THE PULMONARY TISSUE SPACE 28.0 mm Hg 28.0 mm Hg 30.0 mm Hg -28.0 mm Hg

2.0 mm Hg

Pulmonary capillary fluid dynamics (Adapted from Wilson RF: Cardiovascular physiology. In Critical care manual, ed 2, Philadelphia, 1992, Davis)

PRESSURES CAUSING FLUID MOVEMENT

Capillary Alveolus

Hydrostatic pressure Osmotic pressure Net pressure

+7

-8

-8 -5000 -8 -4 (0)

-8

( Surface tension at pore ) ( Evaporation )

-28 -14 (+1)

-5000

Lymphatic pump
Hydrostatic and osmotic forces at the capillary (left) and alveolar membrane (right) of the lungs. Also shown is a lymphatic (center) that pumps fluid from the pulmonary interstitial spaces. (Modified from Guyton, Taylor, and Granger : Dynamics of the Body Fluids. Philadelphia, W. B. Saunders Company, 1975)

Various causes of edema

Pathophysiology of CHF
Injury to myocytes and EC matrix Neurohumoral activation Increased cytokines Immune and inflammatory changes altered fibrinolysis

Ventricular remodelling

Oxidative stress Apoptosis Altered gene Expression Energy starvation

Electrical, vascular, renal, pulmonary, muscle effects CHF

McMurray J, Pfeffer M. Circulation. 2002 (in press)

VEIN

Venules

Capillary (nutrient) bed Metarterioles

Arterioles

ARTERY

CAPILLARY (NUTRIENT) BED

HEART RATE

PRELOAD

CARDIAC OUTPUT

AFTERLOAD STROKE VOLUME

CONTRACTILITY

MUSCULAR SYNCHRONY

Determinants of stroke volume and cardiac output

stroke volume Ventricular end-diastolic volume

Starlings law of the heart

mmHg 120

LV
Aorta LV Pressure LA

80
40 0 ml 120

80
40 0

sv LV Volume RV

R
P Q S Relaxation Passive stiffness Elastic recoil Atrial reserve Factors influencing LV diastole M-mode achocardiography T P ECG

AO
cm/s 80 40 0

MI

Dopplerecho

Cardiac Cycle

(Stork et al, 1995)

Maximal activity
Ventricular performance

2 C Normal-exercise 1

Normal-rest Contractile state of myocardium

Walking Rest

B D A

3 Exercise 3 Heart failure Rest E Fatal 4 myocardial depression Pul. edema

Dyspnea Ventricular EDV

Stretching of myocardium
Diagram showing the interrelationship of influences on ventricular end-diastolic Volume (EDV) through stretching of the myocardium and the contractile stase Of the myocardium.

Treating Hemodynamic profiles

DRY WARM WET B C
Vasodilators Natriuretic peptides Nitroprusside nitroglycerin

A L

COLD

Inotropic drugs Dobutamine Milrinone (levosimendan) (enoxinune)

Suggestions for how the hemodynamic profiles may be used to conceptualize initial therapy for patients with advanced heart failure, patients who are wet and warm (profile B) generally can be dried out without complex intervention. patients who are cold and wet (profile C) often require addition of other therapy to Warm up before they can dry out.Concepts are further discussed in text and in Ref [30].

Two Minute Assessment of Hemodynamic Profile

Congestion at rest? NO Warm & Dry YES Warm & Wet
Evidence for Congestion Orthopnea Elevated JVP Edema (25%) Pulsatile hepatomegaly Ascites Rales (rare in chronic HF) Louder S3

NO
Low perfusion at rest? YES

A
Cold & Dry L

B
Cold & Wet C

Evidence for low perfusion Narrow pulse pressure8 Cool extremities* May be sleepy, obtunded Suspect from ACEI hypotension And low serum Sodium One cause of worsening renal fn

P2 radiation leftward Abdomino-jugular reflex Valsalva square wave

* Most helpful

HEMODYNAMICS OF VASODILATORS IN CHF

+ Inotropic
Decreased fatigue Increased cardiac output

Normal

AFTERLOAD REDUCTION PRELOAD REDUCTION

Decreased pulmonary wedge pressure Decreased dyspnea

Theoretical Frank-Starling curves in CHF. (Opie, 2001)

Pathophysiology of CHF
Injury to myocytes and EC matrix Neurohumoral activation Increased cytokines Immune and inflammatory changes altered fibrinolysis

Ventricular remodelling

Oxidative stress Apoptosis Altered gene Expression Energy starvation

Electrical, vascular, renal, pulmonary, muscle effects CHF

McMurray J, Pfeffer M. Circulation. 2002 (in press)

HIPOTESA STARLING

Arteriole

AVERAGE FORCES TENDING TO PUSH FLUID OUT OF THE SYSTEMIC VASCULAR SPACE
Interstitial space Mean capillary hydrostatic pressure Subatmospheric interstitial hydrostatic pressure (acting as a vacuum drawing fluid into the interstitium) Interstitial oncotic pressure Systemic cell Net Forces Directing Fluid Outward -6.0 mm Hg +5.3 mm Hg 28.3 mm Hg 17.0 mm Hg

Capillary AVERAGE FORCES TENDING TO PUSH FLUID INTO THE SYSTEMIC VASCULAR SPACE
Plasma oncotic pressure Net Forces Dircted Inward Net forces : Outward Inward 28.0 mm Hg 28.0 mm Hg 28.3 mm Hg -28.0 mm Hg

Venule

AVERAGE FORCE DIRECTING FLUID INTO THE BODY TISSUE SPACE

0.3 mm Hg

Systemic capillary fluid dynamics (Adapted from Wilson RF: Cardiovascular physiology. In Critical care manual, ed 2, Philadelphia, 1992, Davis)

 Preload

Overload/ Myocyte loss

Energy supply: demand ratio

Cellular hypertropy Afterload

Altered collagen matrix

Remodelling Cardiac output

Neurohormonal activation

Inotropy

Baroreflex response
Natriuretic peptides Prostaglandins Bradykinin Response to stress Fluid & salt retention

Renin-angiotensinaldosterone Sympathetic nervous system Endothelin Arginine vasopressin

Ca2-

Arrhythmias Sudden death

Vasoconstriction, vascular remodelling, endothelial dysfunction Peripheral resistance

Altered skeletal muscle blood flow and metabolism

Dyspnea, edema, fatigue

maintains blood pressure redistributes cardiac output

perfusion of vital organs

The pathophysiology of heart failure involves the interaction of intrinsic cardiac function wit neurohormonal activation, peripheral vasoconstriction and volume expansion. Neurohormonal activation may increase vasoconstriction and lead to a vicious cycle of worsening cardiac function. Natriuretic peptides and other hormones with vasodilating properties may have potentially beneficial effects on vasoconstriction and volume expansion. This complex model is influenced by numerous factors, including age of patient, drugs, presence of coronary artery disease and the constant feedback of the various regulatory systems. Demonstrated effect; Possible effect; + Positive feedback; - Negative feedback; Decrease; Increase; Ca2+ Intracellular calcium concentrations