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Pathophysiology of Heart Failure

Rukma juslim
Bagian Kardiologi FK. UHT /
RSAL Dr. Ramelan Surabaya
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
Progression Further damage
Excessive wall stress
Neurohormonal activation
Patients surviving %

Mechanism of death Myocardial ischemia


Sudden death 40%
Worsening CHF 40%
Other 20%

Annual mortality
<5% 10% 20 to 30% 30 to 80%
0
Asymptomatic Mild Moderate Severe

Left ventricular dysfunction and symptoms

(Massie & Shah, 1997)


FRAMINGHAM HEART STUDY
100

90 Males
80
Females

70

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 Hemodynamic Neurohormonal

Digitalis and Vasodilators or ACE-I, β-blockers


Diuretic to Perfuse positive inotropes to and other agents to
kidneys relieve ventricular block neurohormonal
wall stress activation

1940s 1960s 1970s 1990s - 2000


Electrical Mechanical
• substrate • cell death
• dennervation • fibrosis
• chemical milieu Heart

Coronary

LV Dysfunction Vascular tone/structure

Peripheral

Neuroendocrine

• Autonomic NS • Hepatic
• Metabolic • Skeletal muscle
• Renal • Other

The multiple effects of left ventricular (LV) dysfunction


Activation of Neurohormonal Pathways in HF
Coronary Disease Cardiomyopathy Cardiac Overload

Left Ventricular Dysfunction

Neurohormonal Activation
• Cathecholamines
Vasoconstriction • RAS
• AVP
• Endothelin

Peripheral Organ Cardiac Remodelling


Blood Flow

skeletal RBF LV dilatation LV hypertrophy


muscle flow Na+ retention
Arrhythmias

Exercise Intolerance Edema, Congestion Sudden Death Pump Failure

Ruffolo, J Cardiovasc, Pharmachol, 1998


NEUROHUMORAL EFFECTS OF HEART FAILURE

BACKWARD FAILURE Poor organ FORWARD FAILURE


INTO LUNGS & RV perfusion LOW BLOOD PRESSURE

Low BP Baroreflexes
JVP  kidney
Adrenergic stimulation
RV failure RV ANP
 
LA RENIN 
EXCESS
back Angiotensin AFTERLOAD
big liver
edema ward Aldosterone

Left pressure
ventricle 
Increasing
Na+ loss Na+ retension
forward
Edema
failure
INCREASING heart
BACKWARD 
FAILURE 
Increasing EXCESS
BLOOD VOLUME
low renal
preload blood flow

(Opie, 1994)
MYOCARDIAL LV DYSFUNCTION CONGESTIVE
DAMAGE HEART FAILURE

ASYMPTOMATIC SYMPTOMATIC

Myocyte loss Ventricular remodeling


or depression Peripheral
abnormalitas
R Pressure
h overload
P Volume
overload  LVEDP
Further myocyte loss?
 Cardiac output  NE
r • Energy limitation
 Ang II
• Myoc. damage
Decr. myocyte vasoconstriction
T = Pxr Contractility? Decreased
2h
LV reserve
Hypertrophy
NE LV dilation
Dilation
Ang II & hypertrophy
• Myocyte slippage Increased
afterload Increased
blood
 LVEDP volume
Impaired
Vascular Decreased
T normal = P x r  T increase =  P x r  Smooth muscle Renal Na+
2h  2h  Edema
relaxation perfusion retention

Adequate Inadequate Abnormal


hypertrophy hypertrophy Endothelial Abnormal skeletal
function Muscle blood Decreased
Flow & exercise
metabolism capacity
“Betablocker and beta adrenergic
receptor in heart failure”
Adrenergic Renin-angiotensin
?

Vasoconstriction
Direct
cardiotoxicity Increased Volume
heart rate and overloaded
contractility

Increased Increased
MVO2 wall stress

Myocyte
damage Hypertrophy

Decreased contractility
(Bristow, 1993)
Adaptive Mal-
Myocyte adaptive
slippage Increased
Remodeling O2 demand

Ischemia
Increased Increased
myocardial stroke volume
volume (Starling)
Myocyte
Stretch hypertrophy Increased
myocardial Decreased
Humoral mass Wall stress Impaired
(Laplace) Contractility
RAAS
Epinephrine Interstitial
Arrhythmo-
Endothelin fibrosis genesis
Growth factors

Factors influencing myocardial remodelling in HF


Left Ventricular Remodeling Following
Myocardial Infarction

Acute Infarction
(hours)

Infarct Expansion
(hours to days)

Global Remodeling
(days to months)
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)
Main events in the progression of heart failure

Myocardial injury
• Myocardial infarction
• Hemodynamic overload
• Inflammation

Secondary mediators
• Norepinephrine
• Angiotensin  Aldosterone
• Endothelin
• Cytokines
• Oxidative stress
• Mechanical stress

Ventricular Remodeling
• Myocyte hypertrophy
• Myocyte apoptosis
• Fetal phenotype
• Extracellular matrix changes
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

 Angiotensin II Vascular and cardiac


Vasoconstriction hypertrophy
Aldosterone release
Peripheral organ blood flow Cardiac remodelling

Na+ and water retention


 Skeletal muscle  Renal Left ventricular
Blood flow blood flow dilation & hypertrophy

Exercise intolerance Pump failure

Edema
Angiotensinogen
Bradykinin
Renin
Angiotensin I
ACE Degradation
Chymase
Angiotensin II

AT1 receptor AT2 receptor B1/B2 receptor

NO

Reactive oxygen species


Pro-inflammatory processes Vasodilation
Vasoconstriction Growth inhibition
Cellular growth/proliferation Apoptosis
Apoptosis
Neurohumoral activation

The renin-angiotensin system.


Pathophysiology of CHF
Injury to myocytes
and EC matrix

Neurohumoral activation Oxidative stress


Increased cytokines Apoptosis
Immune and Ventricular
Altered gene
inflammatory changes remodelling Expression
altered fibrinolysis Energy starvation

Electrical, vascular, renal,


pulmonary, muscle effects

CHF

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


OXIDATIVE STRESS : A CONTINUUM FROM
REVERSIBLE LV DYSFUNCTION TO CHF
ISCHEMIA
INDUCED
LIPID INFARCTION
PEROXIDATION

OXIDATIVE REVERSIBLE LV OXIDATIVE


STRESS ON DYSFUNCTION STRESS DURING REMODELING
REPERFUSION STUNNING HYPERTROPHY

OXIDIZED LDL ATHERO- TNF- INDUCED


SCLEROSIS OXIDATIVE
STRESS CHF
ENDOTHELIAL HYPERTENSION TRIGGERS
OXIDATION APOPTOSIS

(Ferrari et al, 1999)


Heart failure
Cardiac output

Neurohumoral Cytokine Peripheral


activation activation Blood flow
Angiotensin II TNF- Shear stress
Norepinephrine

SOD

Vasoconstriction
Oxydative
Endothelial dysfunction Vascular remodeling
stress

Exercise
capacity
(Drexter, 1998)

Hypothesized role of vascular endothelial dysfunction


in the pathogenesis of chronic HF.
NADPH: nicotamide adenine denocleotide phosphate
Effects of Inflammatory Mediators on Left
Ventricular Remodeling
Alterations in the biology of the myocyte
Myocyte hypertrophy
Contractile abnormalities
Fetal gene expression
Alteration in the extracellular matrix
MMP activation
Degradation of the matrix
Fibrosis
Progressive myocyte loss
Necrosis
Apoptosis

(Mann, 2004)
Epinephrine Aldosterone
Angiotensin II
Beta-blocker Aldosterone receptor
Angiotensin Beta-receptor antagonist
receptor blocker Aldosterone receptor
Angiotensinreceptor

?? receptor
Endothelin receptor ?? antagonist
Endothelin receptor
antagonist
TNF-alpha-receptor
TNF-alpha-receptor
Endothelin antagonist
??
TNF-alpha

Schematic figure of cardiomyocyte showing the multiple


Neurohormonal receptors that are activated in chronic heart failure
( deBoer & van Veldhulsen, 2002 )
New therapeutic options in the treatment
of heart failure

• Cardiac resynchronization therapy (CRT).


• CRT + implantable cardioverter
defibrillator (ICD).
• Cardiac reparation : “rebuilding” the failing
heart with new cells, genes, or blood
vessels.
• Heart transplantation
TATALAKSANA
GAGAL JANTUNG KONGESTIF
(Fokus pada disfungsi sistolik)

Rukma juslim

Subbagian Kardiologi Bagian Ilmu Penyakit Dalam


FK UHT/RSAL Dr. Ramelan Surabaya
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
Progression Further damage
Excessive wall stress
Neurohormonal activation
Patients surviving %

Mechanism of death Myocardial ischemia


Sudden death 40%
Worsening CHF 40%
Other 20%

Annual mortality
<5% 10% 20 to 30% 30 to 80%
0
Asymptomatic Mild Moderate Severe

Left ventricular dysfunction and symptoms

(Massie & Shah, 1997)


Activation of Neurohormonal Pathways in HF
Coronary Disease Cardiomyopathy Cardiac Overload

Left Ventricular Dysfunction

Neurohormonal Activation
• Cathecholamines
Vasoconstriction • RAS
• AVP
• Endothelin

Peripheral Organ Cardiac Remodelling


Blood Flow

skeletal RBF LV dilatation LV hypertrophy


muscle flow Na+ retention
Arrhythmias

Exercise Intolerance Edema, Congestion Sudden Death Pump Failure

Ruffolo, J Cardiovasc, Pharmachol, 1998


Wall stress

Wall stress  O demand O2 demand


2
 Subendo Coronary perfusion
perfusion Systemic
vasoconstriction
Cardiac
dilation Ischemia Coronary
vasoconstriction
(stenosis)
Wall motion
abnormality
Myocardial Neurohormonal
dysfunction activation
( Relaxation/ contractility) (Catecholamines, RAS)

Myocardial ischemia - a self-propagating process.


(Remme, 2000)
Myocyte Death

Neutrophil Decreased CO TGF-1


infiltration release

Enhanced NE release Juxtaglomerular


Activation Increased Macrophage & fibroblast chemotaxis
from adrenal medulla Apparatus ANP
of MMPs and sympathetic nerve Fibroblast proliferation
Activation of BNP Macrophage transformation
in ECM terminals RAAS

Increased ACE TGF-1


Elevated
Elevated Plasma Na+ expression release from
Degradation of Water macrophages
inter-myocyte plasma NE AII
collagen excretion
struts
ET-1
release Decreased Local AII & Fibroblast
Myocyte Volume Aldosterone transformation into
slippage SVR production myofibroblast

Myocyte Hypertrophy Transient


TGF-1 expression
Improvement
LV function Activation of TIMPs
Wall thinning
Type I & III collagen
synthesis
Ventricular Increased
Dilatation wall stress Local AII release
Mechanical Activation of fetal gene program
stretch Increased contractile proteins Fibrosis

Early Remodeling (<72 hours) Late Remodeling

Diagrammatic representation of the many factors involved in


the pathophysiology of ventricular remodeling. (Sutton & Sharpe, 2000)
Pathophysiology of CHF
Injury to myocytes
and EC matrix

Neurohumoral activation Oxidative stress


Increased cytokines Apoptosis
Immune and Ventricular
Altered gene
inflammatory changes remodelling Expression
altered fibrinolysis Energy starvation

Electrical, vascular, renal,


pulmonary, muscle effects

CHF

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


Progression of Cardiovascular Disease
Coronary
artery Hypertension
Arrhythmia
disease

Left ventricular Low ejection


Remodeling Death
remodeling fraction

Valvular Pump
Cardiomyopathy failure
disease

• Neurohormonal stimulation
• Endothelial dysfunction Symptoms: Chronic
Noncardiac Dyspnea
• Vasoconstriction heart
factors Fatigue
Edema failure
• Renal sodium retention

(Abraham, 2000)
Risk
Factors HEART FAILURE SPECTRUM

Heart disease
Asymptomatic
LV Dysfunction
Symptoms
NYHA II-III Symptoms
NYHA - IV

Symptoms
ECHO / LV dysfunction
? BNP
Stages of Heart Failure
Stages Examples
Stage A: At high risk for HF but HTN, CAD, DM, cardiotoxins,
without structural heart disease FHx of CM
or symptoms of HF

Stage B: Structural heart disease Previous MI, LV systolic dysfunction,


but without symptoms of HF asymptomatic valvular disease

Stage C: Structural heart disease Known structural heart disease,


with prior or current symptoms SOB and fatigue, reduced exercise
of HF tolerance

Stage D: Refractory HF requiring Marked symptoms at rest


specialized interventions despite maximal medical therapy

ACC/AHA Heart Failure Practice Guidelines 2001


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
Management outline (ESC)
1. Establish that the patient has heart failure (in accordance
with the definition presented on page 1528 diagnosis
section)
2. Ascertain presenting features: pulmonary oedema,
exertional breathlessness, fatigue, peripheral oedema
3. Assess severity of symptoms
4. Determine aetiology of heart failure
5. Identify precipitating and exacerbating factors
6. Identify concomitant diseases relevant to heart failure and
its management
7. Estimate prognosis
8. Anticipate complications
9. Counsel patient and relatives
10. Choose appropriate management
11. Monitor progress and manage accordingly
(Remme & Swedberg, 2001)
Stages in the evolution of HF and recommended therapy by stage

Stage A Stage B Stage C Stage D

Pts with: Pts with: Pts with:


• Hypertension • Previous MI Pts who have
• Struct. HD
• CAD Struct. • LV systolic Develop. marked symptoms
• Shortness of Refract.
• DM
Heart
dysfunction Symp. of Symp. of at rest despite
Disease breath and fatigue,
• Cardiotoxins • Asymptomatic HF HF at rest maximal medical
reduce exercise
• FHx CM Valvular disease therapy
tolerance

THERAPY THERAPY THERAPY THERAPY


• Treat Hypertension • All measures under • All measures under • All measures under
• Stop smoking stage A stage A stage A, B and C
cessation • ACE inhibitor • Drugs for routine use: • Mechanical assist
• Treat lipid disorders • Beta-blockers • diuretic device
• Encourage regular • ACE inhibitor • Heart transplantation
exercise • Beta-blockers • Continuous IV
• Stop alcohol & • digitalis inotrophic infusions
drug use for palliation
• ACE inhibition
ACC/AHA Guidelines for the
Evaluation and Management of Chronic Heart Failure in the Adult 2001
INITIAL EVENT LV REMODELING CLINICAL
SYNDROME
Myocardial Insult AII
and/or
Excessive Load M.R.
PATHOPHYSIOLOGY

LV Dilation Myocyte Loss,


and Elongation or
Hypertrophy Slippage
Diastolic Wall
Stress
Energy Supply Decreased
LV Reserve

CHF
Increased
Afterload

GISSI-3 SAVE V-HeFT-1


TRIALS

CONSENSUS-2 SOLVD (prev.) V-HeFT-2


SMILE TRACE SOLVD (treat.)
ISIS-4 CONSENSUS-1
AIRE
The pathophysiology of heart failure progressing
with time from the initial event. (Lejemtel et al, 2001)
ACE inhibitors for congestive heart failure
NEUROHUMORAL EFFECTS OF HEART FAILURE

BACKWARD FAILURE Poor organ FORWARD FAILURE


INTO LUNGS & RV perfusion LOW BLOOD PRESSURE

Low BP Baroreflexes
JVP  kidney
Adrenergic stimulation
RV failure RV ANP
 
LA RENIN 
EXCESS
back Angiotensin AFTERLOAD
big liver
edema ward Aldosterone

Left pressure
ventricle 
Increasing
Na+ loss Na+ retension
forward
Edema
failure
INCREASING heart
BACKWARD 
FAILURE 
Increasing EXCESS
BLOOD VOLUME
low renal
preload blood flow

(Opie, 1994)
Chronic Congestive Heart Failure

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

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

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

Loop of Henle
Collecting tubule
LOW VS HIGH CEILING DIURETICS
High-ceiling
Dose for Loop diuretics
oliguria

Dose for
severe CHF
EFFICACY

Dose for
mild CHF
Low-ceiling
Dose for Thiazides
hypertension
K+ -sparing

Opie (2001)

DOSE
Inotropic agent Congestive
+ vasodilator symptoms
Inotropic agent
+ vasodilator Inotropic
Vasodilator agent only
+ diuretic only
Stroke volume

Diuretic
only

Congestive
and low-
Low-output output
symptoms symptoms

Left ventricular filling pressure

(Smith & Kelly, 1991)


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 1 2 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)


Trial or Number Odds Ratio Red n (%)
group of trials of patients & 95% CL ± SD
Vasodilator beta-blocker trials
Carvedilol trials
ANZ 415 25±27
US ‘Dose ranging’ 345 80±24
US ‘Moderate’ 278 41±39
US ‘Severe’ 105 54±75
US ‘Mild’ 366 78±41
Three smaller trials 149 -3±92
Subtotal vasodilator beta-blocker trials (1658) 49±15
Other vasodilator beta-blocker trials
Six small trials 250 4±86

Subtotal all vasodilator (1908) 47±15


beta-blocker trials
Non-vasodilator beta-blocker trials
CIBIS 641 25±18 An overview of
MDC 383 -8±33 all available
Eight smaller trials 209 32±40 randomized
trials of beta-
Subtotal non-vasodilator (1233) 18±15 blocking therapy
beta-blocker trials
in heart failure
TOTAL 3141 31±11 involving a total
of 3141 patients.
(Sharpe & Doughty, 1998)
OR=0.69, 95% Cl 0.54 to 0.89 0 0.5 1.0 1.5 2.0
CIBIS II
All-cause mortality
Not diabetic
Diabetic
CrCl < 60 ml/min
CrCl  60 ml/min
Age  71 years
Age < 71 years
Ald. antagonist no
Ald. antagonist yes
Digitalis no
Digitalis yes
Amiodarone no
Amiodarone yes
NYHA III
NYHA IV

Total

.4 .5 .6 .7 .8 .9 1 1.1 1.2 1.3


Relative Risk
Relative risk of treatment effect on mortality by predefined subgroups
according to characteristics at baseline. Horizontal bars represent 95% Cls;
the size of the boxes which mark the centres of the lines are inversely related
to confidence intervals, i.e. small boxes represent wide Cls.
E. Erdmann et al./European Journal of Heart Failure 3 (2001) 469 - 479
INOTROPIC, VAGAL & SYMPATHOLYTIC EFFECTS OF DIGOXIN

Adrenergic CHF
activation
in CHF
Positive inotropic effect
Baroreceptors
Vagomimetic 3 Na+
effect – Digoxin Na+
2K+
Sympatho-
inhibitor +
effects NE
SA AV Ca2+
– Na+ rises

E + Toxic arrhythmias

Diuresis
RAS
inhibition Vasodilation

Digitalis has both neural and myocardial cellular effects. Opie (2001)
DIG STUDY
Mortality from Any Cause (%) 50

40

30

20
Placebo

10
P = 0.80
Digoxin
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Months

Mortality in the Digoxin and Placebo Groups


DIG STUDY
50
Death or Hospitalization Due to
Worsening Heart Failure (%)

40

30
Placebo

20

10
Digoxin P < 0.001
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52

Months

Incidence of Death or Hospitalization Due to Worsening Heart Failure


in the Digoxin and Placebo Groups
1.00
0.95
0.90

Probability of Survival
0.85
0.80
0.75
0.70 Spironolactone
0.65
0.60
0.55 Placebo
0.50
0.45 p<0.001
0.00
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
No. At Risk
Placebo 841 775 723 678 628 592 565 483 379 280 179 92 36
Spironolactone 822 766 739 698 669 639 608 526 419 316 193 122 43

Kaplan-Meier Analysis of the Probability of Survival among Patients


in the Placebo Group and Patients in the Spironolactone Group
(Pitt et al, 1999)
HF: Mortality Remains High
• ACEI
– Risk reduction 35% (mortality and hospitalization)1
• -blockers
– Risk reduction 38% (mortality amd hospitalization)2
• Spironolactone
– Mortality reduction 23%
• Oral nitrates and hydralazine
– Benefit vs placebo; inferior enalapril (mortality)

However: 4-year mortality remains ~40%


1 Davies MK et al. BMJ. 2000. 320: 428-431. (meta-analysis: 32 trials. N=7105)
2 Gibbs CR et al. BMJ. 2000. 320: 495-498. (meta-analysis: 18 trials. N=3023)
COMBINED ALL CAUSE MORTALITY AND MORBIDITY
SUB-GROUP WITHOUT ACEI BACKGROUND THERAPY
Val-HeFT
1.0
44.5%
RISK REDUCTION
EVENT-FREE PROBABILITY

P = 0.0002
0.8

0.6

VALSARTAN (N = 185) PLACEBO (N = 181)


0.4
0 3 6 9 12 15 18 21 24 27
TI
TIME SINCE RANDOMIZATION (MONTHS)
Combined Morbidity/Mortality in Subgroups
Val-HeFT
% Patients FAVORS VALSARTAN FAVORS PLACEBO

All Patients 100


< 65 47
 65 53
Male 80
Female 20
EF < 27 50
EF  27 50
ACEI (Yes) 93
ACEI (No) 7
BB (Yes) 35
BB (No) 65
IHD (Yes) 57
IHD (No) 43

0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4
-Receptor
Na+/H2O retention signaling pathway Sympathetic
Vasoconstriction ACE/AII
Vascular remodelling Aldosterone

Sympathetic Sympathetic
RAAS activation
Neurohormonal
activation Wound healing fibrosis
hypertrophy
Neurohormonal
activation

Remodelling
Ca2+ homeostasis
Metabolism
Remodelling
Vasoconstriction
SR/Mitochondrial
abnormalities LV dysfunction
Stunning Endothelin

Cytokines
Ischaemia TNF
Injury

Contractile
depression iNOS/NO-O•
radicals
Neurohormonal
O• radicals AII?
Apoptosis

Ischaemia
Reperfusion Remme, 1998
HEMODYNAMICS OF VASODILATORS IN CHF

+ Inotropic
Increased cardiac output
Decreased fatigue

Normal

AFTERLOAD
REDUCTION

PRELOAD REDUCTION
Decreased pulmonary wedge pressure
Decreased dyspnea
Theoretical Frank-Starling curves in CHF. (Opie, 2001)
THE STRATEGY IN THE MANAGEMENT
OF HEART FAILURE
• Prevention and early intervention
before the disease progresses to
a later stage.
• Prevention should include detection
and treatment of aetiological factors
and risk factors
• Early intervention is directed towards
treatment of acute coronary syndrome
DIASTOLIC HEART FAILURE
( Definition, Pathofisiology, Diagnosis and Treatment)

Rukma Juslim
Bagian Kardiologi, Sub Bagian Kardiologi Ilmu Penyakit
Dalam
FK. UHT / RSAL. Dr. Ramelan Surabaya
SCOPE OF THE PROBLEM
• Epidemiological studies of HF have
suggested that 30-50% of cases of HF
have preserved LV systolic function.
• It is assumed that these cases represent
DHF, this suggests that DHF contributes
significant to the huge burden of disease
caused by HF.
• If the epidemiology evidence is accurate,
a large proportion of the HF population is
left with no proven, effective treatment.
PULMONARY VENOUS
PRESSURE

Input

Filling Emptying
Stroke
ED volume x EF effective = volume
LV Distensibility Contractility x
Relaxation Afterload Heart
Left atrium Preload
Mitral valve rate
Structure
Pericardium
Diastolic function Systolic function

Output

CARDIAC OUTPUT

Block diagram of left ventricular pump performance


(Little, 2001)
Defining Diastolic Heart Failure

• Diastolic dysfunction refers to a condition in which


abnormalities in mechanical function are presenting
during diastole.
• Diastolic dysfunction is a condition in which higher
than normal LV filling pressure are needed to maintain
a normal cardiac output.
• Diastolic heart failure is a clinical syndrome
characterized by the symptoms and signs of heart
failure, a preserved EF and abnormal diastolic
function.
A B
cardiac cycle C D
phase

R
P T
lead II electrocardiogram
atrial ventricular
muscle contraction

systolic pressure incisura


120
pulse pressure
aortic pressure

80 diastolic pressure
pressure, mmHg
left ventricular pressure
40 left atrial
pressure

closed open closed


aortic valve

mitral valve open closed open


S3 S4 S1 S2 S3
heart sounds

120 end-diastolic volume


stroke volume
left ventricular volume, mL

60 end-systolic volume

0 0.2 0.4 0.6 0.8


time(s)

CARDIAC CYCLE-LEFT HEART.


Cardiac cycle phases: A, diastole; B, systole; C, isovolumetric contraction; and D, isovolumetric relaxation
LV Diastolic Pressure-Volume Relation
B A

A : Normal
LV Pressure

B : Diastolic Dysfunction

P
V

P
V
LV Volume
( Little & Downes, 1990 )
Fibrosis
Passive
Cellular disarray chamber
stiffness
Hypertrophy Diastolic
pressure
Asynchrony

Abnormal loading Relaxation

Ischemia

Abnormal Ca++ flux

( Suga et al, 1989 )


Abnormal Pericardial
relaxation restraint

Left ventricular pressure

A B
Increased Chamber
chamber stiffness dilation

C D
Left ventricular volume

Mechanisms that cause diastolic dysfunction. (Zile, 1990)


CAUSES OF PRIMARY DIASTOLIC
DYSFUNCTION
Obstruction to filling (mitral stenosis, cor triatriaotrium,
pulmonary venous stenosis).
External compression (cardiac tamponade, constrictive
pericarditis)
Reduced left ventricular distensibility
Left ventricular hypertrophy
Hypertension
Aging
Ischemia
Restrictive cardiomyopathies
Transplant rejection
Diabetes
( Little & Cheng, 1998)
PRESSURE – VOLUME CURVE OF SYSTOLIC AND DIASTOLIC FAILURE

SYSTOLIC FAILURE DIASTOLIC FAILURE

Decreased
Normal diastolic
diastolic chamber
Normal
chamber
Left Ventricular Pressure

Left Ventricular Pressure


distensibility
distensibility

Left Ventricular Volume Left Ventricular Volume


Clinical Clues to the Differential Diagnosis of
Congestive Heart Failure
Systolic CHF Diastolic CHF
History
Myocardial infarction XX X
Hypertension X XX
Physical examination
Displaced PMI X
S3 gallop X
S4 gallop X
Chest radiograph
Cardiomegaly XX X
Pulmonary congestion XX XX
Electrocardiogram
Q waves XX X
Left ventricular hypertrophy X XX
(Goldsmith & Dick, 1993)
Prevalence of Specific Symptoms and
Signs in Systolic vs Diastolic Heart
FailureDiastolic Systolic
Heart Failure Heart Failure
(EF>50%) (EF<50%)
Symptoms
Dyspnea on exertion 85 96
Paroxysmal nocturnal dyspnea 55 50
Orthopnea 60 73
Physical examination
Jugular venous distension 35 46
Rales 72 70
Displaced apical impulse 50 60
S3 45 65
S4 45 66
Hepatomegaly 15 16
Edema 30 40
Chest radiograph
Cardiomegaly 90 96
Pulmonary venous hypertension 75 80
( Zile & Brutsaert, 2002 )
Diagnostic Criteria for Diastolic Heart Failure
Signs or symptoms of congestive heart failure
Exertional dyspnoea [eventually objective evidence by reduced peak exercise oxygen consumption
(<25 ml.kg-1.min-1)], orthopnea, gallop sounds, lung crepitations, pulmonary oedema
and
Normal or mildly reduced left ventricular systolic function:
LVEF45% and LVEDIDI<3.2 cm.m-2 or LVEDVI<102 ml.m-2
and
Evidence of abnormal left ventricular relaxation, filling, diastolic distensibility and diastolic stiffness:
Slow isovolumic left ventricular relaxation:
LVdP/dtmin <1100 mmHg.s-1
and/or IVRT<30y>92 ms, IVRT30-50y>100 ms, IVRT>50y>105 ms
and/or >48 ms
and/or slow early left ventricular filling:
PFR<160 ml.s-1.m-2
and/or PFR<30y<2.0 EDV.s-1, PFR30-50y<1.8 EDV.s-1, PFR>50y<1.6 EDV.s-1
and/or E/A<50y<1.0 and DT<50y>220 ms, E/A>50y<0.5 and DT>50y>280 ms
and/or S/D<50y>1.5, S/D>50y>2.5
and/or reduced left ventricular diastolic distensibility:
LVEDP>16 mmHg or mean PCW>12 mmHg
and/or PV A Flow > 35 cm.s-1
and/or PV A t>MV A t+ 30 ms
and/or A/H>0.20
and/or increased left ventricular chamber or muscle stiffness:
b>0.27
and/or b’>16
( European Study Group on DHF, 1998 )
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 )
Sensitivity and specificity of clinical
features in the diagnosis of CHF
Sensitivity Specificity
Symptom

Dyspnoea 66 % 52 %
Orthopnoea 21 % 81 %
Paroxysmal nocturnal dyspnoea 33 % 76 %
Oedema (by history) 23 % 80 %

Sign

Resting heart rate > 100 beats/min 7% 99 %


Rales 13 % 91 %
Oedema (on examination) 10 % 93 %
Third heart sound 31 % 95 %
Neck vein distension 10 % 2%
( Luscher, 2000 )
Echo-Doppler and Diastolic Dysfunction
Normal diastolic Mild diastolic Pseudonormal Restrictive-
function dysfunction stage filling stage
Left ventricular relaxation Normal   

Left ventricular stiffness Normal   

Left atrial contractility Normal  Normal 

Preload Normal Normal  

QRS
T P
Electrocardiogram
E wave
A wave
Mitral flow
Diastole

Systole
Pulmonary venous
flow
Atrial reversal
( Garcia, 2000 )
Echocardiographic Left Ventricular (LV) Function*
Mean (SE) P Value
Controls Patients with Patients with SHF vs DHF vs SHF vs
(n=28) SHF (n=60) DHF (n=59) Control Controls DHF
LVEDV, mL 102 (12) 192 (10) 87 (10) .001 .32 .001
LVESV,mL 46 (11) 137 (9) 37 (9) .001 .51 .001
LVSV, mL 56 (4) 55 (3) 50 (3) .95 .15 .14
LVEF, % 54 (2) 31 (2) 60 (2) .001 .007 .001
Septal thickness, mm 0.85 (0.03) 0.89 (0.02) 1.31 (0.04) .34 .001 .001
Posterior wall thickness, mm 0.91 (0.03) 0.97 (0.02) 1.20 (0.03) .10 .001 .001
LV mass, g 125 (12) 232 (9) 160 (9) .001 .03 .001
LV mass/volume ratio 1.49 (0.17) 1.22 (0.14) 2.12 (0.14) .23 .002 .001
Mitral early velocity, cm/s 70 (6) 85 (5) 77 (4) .02 .26 .18
Mitral atrial velocity, cm/s 71 (5) 91 (4) 91 (4) <.001 .001 .91
Early/atrial ratio 1.05 (0.10) 1.09 (0.08) 0.92 (0.08) .75 .23 .12
Early deceleration time, ms 230 (11) 179 (10) 239 (9) .001 .46 .001
IVRT, ms 106 (5) 111 (4) 104 (4) .42 .84 .27
* All comparisons adjusted for sex of patients. Left ventricular volume and mass also adjusted for body
surface area. SHF indicates systolic heart failure; DHF, diastolic heart failure; LVEDV, left ventricular
and-diastolic volume; LVESV, left ventricular end-systolic volume; LVSV, left ventricular stroke
volume; LVEF, left ventricular ejection fraction; and IVRT, isovolume relaxation. (Kitzman et al, 2002)
Criteria for Definite DHF
Criterion Objective Evidence
Definite evidence of CHF Includes clinical symptoms and signs, supporting
laboratory tests (such as chest X-ray), and a typical
clinical response to treatment with diuretics, with or
without documentation of elevated LV filling pressure
AND
(at rest, on exercise, or in response to a volume load)
or a low cardiac index
Objective evidence of normal LV LV EF > 0.50 within 72 h of event
systolic function in proximity to
the CHF event

AND

Objective evidence of LV diastolic Abnormal LV relaxation /filling/distensibility indices on


dysfunction cardiac catheterization

( Vasan & Levy, 2000 )


Criteria for Probable DHF
Criterion Objective Evidence
Definitive evidence of CHF Includes clinical symptoms and signs, supporting laboratory tests
(such as chest X-ray), and a typical clinical response to treatment
with diuretics, with or without documentation of elevated LV filling
AND pressure (at rest, on exercise, or in response to a volume load) or a
low cardiac index
Objective evidence of normal LV systolic LV EF > 0.50 within 72 h of CHF event
function in proximity to the CHF event
BUT
Objective evidence of LV diastolic No conclusive information on LV diastolic function
dysfunction is lacking

Criteria for Possible DHF


Criterion Objective Evidence

Definitive evidence of CHF Includes clinical symptoms and signs, supporting laboratory test (such
as chest X-ray), and a typical clinical response to treatment with
AND diuretics, with or without documentation of elevated LV filling pressure
(at rest, on exercise, or in response to a volume load) or a low cardiac index
Objective evidence of normal LV systolic LV EF > 0.50
function, but not at the time of the CHF event
AND
Objective evidence of LV diastolic dysfunction No conclusive information on LV diastolic function
is lacking
( Vasan & Levy, 2000 )
Treatment of Diastolic Heart Failure

The guidelines are based on


- clinical investigations in relatively small groups of
patients
- clinical experience
- concepts based on pathophysiolgical mechanisms
Treatment of Diastolic Heart failure

• symptom targeted treatment


• disease / pathological targeted treatment
• the underlying mechanism targeted
treatment

( Zile & Brutsaert, 2002 )


Diastolic Heart Failure: Treatment

Symptom targeted treatment


Decrease pulmonary venous pressure
Reduce LV volume
Maintain atrial contraction
Prevent tachycardia
Improve exercise tolerance
Use positive inotropic agents with caution
Diastolic Heart Failure: Treatment
Symptom targeted treatment

Nonpharmacological treatment
Restrict sodium to prevent volume overload
Restrict fluid to prevent volume overload
Perform moderate aerobic exercise to improve cardiovascular
conditioning, decrease heart rate and maintain skeletal muscle
function
Pharmacological treatment
Diuretics including loop diuretics thiazides, spironolactone
Long-acting nitrates, -Adrenergic blockers
Calcium channel blockers
Renin angiotensin-aldosterone antagonists including ACE
inhibitors, angiotensin II receptor blockers and aldosterone
antagonists
Diuretics reduce stroke volume more in diastolic than in
systolic dysfunction
Systolic dysfunction Diastolic dysfunction
Without Without
diuretics diuretics
Left ventricular pressure

With With
diuretics Systole diuretics
Steeper slope
indicates increased
stiffness of
left ventricle

Diastole End-diastolic
End-diastolic
pressure pressure

Stroke volume Stroke volume

Left ventricular volume Left ventricular volume


Diastolic Heart Failure

Disease-targeted treatment
Prevent/treat myocardial ischemia

Prevent/regress ventricular hypertrophy

Mechanisms targeted treatment


Modify myocardial and extramyocardial mechanisms

Modify intracellular and extracellular mechanisms


Diastolic Heart Failure : Effects of
Age on Prevalence and Prognosis

Age, y

<50 50-70 >70

Prevalence 15 33 50

Mortality 15 33 50

Morbidity 25 50 50

( Zile & Brutsaert, 2002 )


Trials of Diastolic Heart Failure

Trial Comparison Follow-up (n) Diagnostic Criteria Other Important Main Outcomes
for DHF Inclusion/ Exclusion
Criteria

PEP-CHF Placebo 1.000 3 of 9 clinical and Age > 70 years Death or HF-related
Perindopril Minimum 18 months 2 of 4 echocardiographic Diuretics hospitalization
criteria
Hospital admission in last
3 months
CHARM-2 Placebo 2.500 EF > 40% None Death or hospitalization
Candesartan Minimum 24 months for HF
I-PRESERVE Placebo 3.600 EF > 45% Clinical diagnosis of HF Death and hospitalization
Irbesartan Approx 48 months cardiovascular disease
SENIORS Placebo 2.000 EF > 35% and a cardiac Aged > 70 years
(diastolic subset) Nebivolol (% DHF uncertain) abnormality Hospital admission within
last 12 months
Hong Kong Placebo 450 Doppler criteria Diuretics Death or hospitalization
Ramipril Minimum 12 months for HF
Irbesartan Quality of life 6-minute
walk test
SWEDIC Placebo 140 Doppler criteria AF excluded Regression of diastolic
Carvedilol 9 months dysfunction

( Banerjee, et.al, 2002)


g a b c d e f g a

AO
Aortic
Aortic closure
pressure
Ventricular
pressure
Cross- MO
over Atrial
pressure

M1 A2
Heart S4 T1 P2 S
3
sounds
Cardiologic
systole

a c
v

JVP
Opie (2001)

T P
P
ECG
Q S
0 800 msec

The Wiggers cycle


g
f

e iso
a b c d
iso
Aortic valve
170 opening
LV pressure (mmHg) LV ESPVR

End
systole

Mitral valve
End
opening diastole
0
0 45
LV Volume (ml)

A left ventricular (LV) pressure-volume loop describing one cardiac cycle.


increased
contractility normal
contractility
LV pressure, mmHg

120

increased
afterload

80

40 increased
preload

60 120

LV volume, mL
The effect of increased contractility upon the left ventricular end-systolic pressure-volume relationship
Diuresis Antimitogenic
Vasodilatation

Prostaglandins Natriuretic
NO
peptides

Myocardial
dysfunction Free radicals
Cytokines

Growth
AVP Renin
hormone
Endothelins
All
Catecholamines
Aldosterone Apoptosis
Hypertrophy
Vasoconstriction
Salt and water
retention

Many different neurohormonal pathways are stimulated


following myocardial dysfunction
Angiotensin II  PAI-1
 NADH/NADPH oxidase

 Superoxide anion production


( oxidative stress)
 Fibrinolysis
 Inactivation of NO

 VCAM-1, MCP1 & cytokines  LDL oxidation 


 Deposition of cholesterol
 Phospolipase C
 Monocyte & leucocyte
 Protein kinase C Adhesion  cytokine release Inflammatory state

 Protein phosphorylation  Expression of Vulnerable plaque


growth factors
 Intracellular Ca++

 Fibroblast  Plateled-derived  Transforming


growth factors growth factors growth factors 1
Receptor-operated
Ca++ channels
CV events

Vascular SM cell proliferation & migration


Processes Occuring in Ventricular
Remodeling
Cardiomyocyte lengthening
Ventricular wall thins
Infarct expansion rather than extension occurs
Inflammation and reabsorption of necrotic tissue.
Scar formation
Continued expansion of infarct zone
Dilation and reshaping of the left ventricle
Myocyte hypertrophy
Ongoing myocyte loss
Excassive accumulation of collagen in the cardiac
intersitium

(Cohn et al, 2000)


Ischemia/Reperfusion
ENZYMATIC O2
ANTIOXIDANTS
e.g, SOD, Catalase,
Glutathione O .2 - ANTIOXIDANTS
Peroxidase e.g, Vitamin E, C, β-carotene
Flavonoids, cardiovascular drugs
H2O2 (TMZ, carvedilol, captopril etc)
histidine

-OH/1O2

Lipid peroxidation/Protein damage


DNA damage (Apoptosis)

Myocardial Dysfunction
Heart Failure
Schematic presentation of antioxidant protective strategies in heart failure. Ischemia followed by reperfusion generates superoxide anion (-O2-), which rapidly
dismutates to hydrogen peroxide (H2O2). In the presence of iron, -OH radical or possibly 1O2 may be formed via iron-catalyzed. Haber weiss reaction. These
highly destructive species initiate lipid peroxidation in the cell membranes, damage proteins and cause DNA fragmentation resulting in the apoptotic
(programmed) cell death of myocly. Traditional enzymatic antioxidants that scavenge oxyradicals or prevent their formation are not always effective because of
their limited accessibility to the free radical generation. However, a large number of netural orsynthetic compaunds have the ability to inhibit the oxidative
Damage either by scavenging free radicals or inhibiting lipid peroxidation. TMZ=trimetazidine.
Proinflammatory cytokines involved with heart failure
and dilated cardiomyopathy

Source
Cytokine
Macrophages
Interleukin-1 alpha (IL-1)
Macrophages
Interleukin-1 beta (IL-1β)
T lymphocytes and endothelial cells
Interleukin-2 (IL-2)
Membrane of T cells
Soluble interleukin-2 receptor
(sIL-2R)
Macrophages, endothelial cells,
Tumor necrosis factor  (TNF )
myocytes (in certain conditions)
T lymphocytes
Interferon  (INF)
Myocytes (atrial myocytes)
Atrial natriuretic factor (ANF)
Myocytes, endothelial cells,
Interleukin 6 (IL-6)
T lymphocytes

(
Two Minute Assessment of Hemodynamic Profile
Congestion at rest?

NO YES Evidence for


Warm & Dry Warm & Wet Congestion

A B Orthopnea
NO Elevated JVP
Low perfusion
YES Edema (25%)
at rest? Cold & Wet Pulsatile hepatomegaly
Cold & Dry
Ascites
L C Rales (rare in chronic
HF)
Louder S3
Evidence for low perfusion
Narrow pulse pressure8 P2 radiation leftward
Cool extremities* Abdomino-jugular reflex
May be sleepy, obtunded Valsalva square wave
Suspect from ACEI hypotension
And low serum Sodium
One cause of worsening renal fn

* Most helpful
Treating Hemodynamic profiles
DRY WET
WARM
A B Vasodilators
Natriuretic peptides
Nitroprusside
COLD L C nitroglycerin

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].
CARDIAC STRESS

Free Radiacals &


 Antioxidants

Exogeneous Antioxidants

 Oxidative Stress

Lipids, DNA & Activation of


Apoptosis Cytokines
Protein
Damage e.g. TNF-α, IL-6,
ANF & IL-1α
Cardiac
Dysfunction

Heart Failure

Events linking oxidative stress and heart failure in Cardiac stress


conditions
(peroxinitrous acid) OH
NO ONOOH
L-arginine Citrulline
 Singlet oxygen
NO synthase NADPH O 
2 1O
NADPH 2 MYOCYTE
OXIDASE
H2O2  HOCl
NADP+

Cl MPO monochloramine O  1O


2 2
NEUTROPHIL NH2Cl
Lipid peroxidation
MPO HOCL

-OH

CHEMOATTRACTANT ADHERENCE FACTORS


H2O2
ONOOH
(peroxinitrous acid)
ACTIVATOR OH
O 
2  NO
HO
Fe 2 2
NO SOD
Xanthine oxidase O2 L-arginine Citrulline
?
PGG2 PGH2 ? catecholamine NO synthase
cyclooxygenase
ENDOTHELIAL CELL
BASEMENT MEMBRANE

Schematic representation of the relationship of free radicals, neutrophils and endothelial in ischemic reperfusion injury of the myocyte. Superoxide anion is
generated from the endothelial cells via one or more pathways (xanthine oxidase, cyclo-oxygenase Catecholamine oxidation or mitochondria). Nitric oxide isproduced
from L-arginine by means of a reduced nicotinamide adenine dinucleotide phosphate (NADPH) –dependent cytosolic enzyme, nitric oxide oxide. The superoxide
derived oxidants such as H2O2, 1O2 or OH radical (formed either by reaction of O 2-, H2O2 and iron, or interaction of O2- and NO) interact with membrane
components of endothelial cells to from potent granulocyte chemoattractants. During ischemia and reperfusion, neutrophils adhere to the vessel wall at sites of
inflammation and release a variety of toxic products such as .O2-, H2O2, .OH radical, monochloramines, and the proteolytic enzyme elastase. The generation of the
cytotoxic metabolites within the microenvironment formed between the adherent activated neurorophils and the altered endotheliel cells leads to an increase in
vascular permeability and myocyte damage. [From reference 107].
O2 NO ONOO Vascular wall
Adhesion molecules
cytokines e NOS
 I NOS
Mito
O22
NFkB
OH' Impaired Vasodil.
Vasc. Dysfunction
Oxidases
(e.G.NADPH) SOD
Cytosolic Myocardium
Enzymes Lipidperoxidation
Respiratory Protein/DNA-damage
Apoptosis/necrosis
chain
Contractive dys-
function
CatalaseO2
(2)H2O2 H2O

 Glutathione peroxidase xx Glutathione reductase

Major pro-and antioxidant metabolic pathways in the intracellular redox network. A preponderant production of
oxygen derived radicals favours vascular and myocardial dysfunction through altered gene expression andlor by damaging
biomolecules with subsequent necrosis/apoptosis
 CD (%)  CF (ml/min)

4 60


2 30

0 0
Control (pre-pacing) Failure (4 weeks)

Fig. 2. Impairment of endothelium-dependent dilator responses presented as changes in flow


dependent dilation (FDD) during peak reactive hyperemia (RH max) in experimental
Congestive heart failure estimated in instrumented conscious dogs (mean values + SEM, n =
4, *p < 0.05 compared to prepacing controls).
Inadequate Ischemic events Neurohormonal
Wall stress stimulation
Cytokines/Growth factors
[TNFα, IL-1/6, LPS] / [ALL, PDGF, thrombin]

Oxygen radicals

SAPK NFk B
Kinase Kinase
activation activation

Antioxidants
Activation of
Transcription
p42/44 MAPK [ERK ½] p38 MAPK H2O2,O2 ‘
JNK-1, ATF-1

Kinase, transkription factors Antioxidant enzymes Oxidases


Growth factors cylokines iNOS
Matrix proteins Adhesion molecules
MCP-1, hypertrophy

Cylokinel growth factor dependent signaling cascades In congestive heart failure cardiovascular dysfunction
in the pathogenesis of congestive heart failure imply the activa- is associated with enkanced oxidant stress stimulating gene ex-
tion of specifce protein kinases that are in part activated by oxy- pression via reox-sensitive kinases and transcription factors
gen-derived radicals originating from different cellular oxi- (NFkB:nuclear factor kappa B; SAPK: stress-activated pro-
dases and locations (e.g. mithokondria, cytosol, membranes), tein kinases; JNK-1: e-Jun NH2-terminal kinases 1). Antioxi-
LPS: lipopolysaccharide; AII: angiotensis II; PDGF: platelet dant therapy may beneficially affect te oxygen radical-driven
derived growth factor; MAPK; mitogen activated protein ki- excessive axpression of growth factors, adkesion molecules ete..
nases; ERK: extracellular signal-regulated kinase.
• Neurormonal
activation (SNS,
• Collagen • Ventricular
RAAS, vasopressin)
• Cytokine activation deposition remodelling
(ET, TNF-α, IL’S, Y-IFN)
MYOCARDIAL • MMP activation •  LV systolic
INFLAMMATN/ • Growth factor activat”
INJURY (TGF-β, bFGF, IGF) • Myocylte function
• Pro-oxidant stress • Clinical
hypertrophy
• Mechanical strethc
symptoms and
• Disordered calcium •  Apoptosis
regulation signs
• Skeletal muscle
• Altered NO activity
•  Mortality
• Altered β-adrenoceptor alterations
pathway

Mechanisme of disease progression in CHF (SNS=sympathetic nervaus system; RAAS=renin-angiotensin-aldosterone


system; ET=endothelin;TNFX=tumor-necrosis factor α; IL=interleukin γ-IFN= γ-interveron, TGFβ=transforming
growth factor Β; bFGF=basic fobroblast growth factor; IGF=insulin-like growth factor; NO=nitric oxide;
MMP=matrix metalloproteinase; LV=left ventricular).
Impaired ventricular Ventricular conduction Abnormal breakthrough
function delay Time and site

RV-LV asynchrony
(activation and contraction)

RV asynchrony LV asynchrony

Septum Free wall

Activation/contraction No contraction
(early low load) (early high load)

Relaxation Contraction
(high late load) (overstretched segmens)

Perfusion mismatch

Cellular volumetric changes

Extracellular/cellular matrix
modifications

Schematic representation of possible electrical and mechanical effects determined by ventricular conduction
delay, and more specifically left bundle branch block. LV=left ventricle/left ventricular; RV=right ventricle/right
Ventricular.
OXYGEN FREE RADICALS PRODUCTION
IN THE CARDIOVASCULAR SYSTEM

HEART ENDOTHELIUM BLOOD COMPONENT

MITOCHONDRIAL/ NITRIC OXIDE LEUKOCYTES


ELECTRON PATHWAY ACTIVATION
TRANSPORT CHAIN

CELL MEMBRANEI MACROPHAGES/


ACTIVATION OF
ARACHIDONIC CASCADE TNF α-INDUCED
VARIOUS
AND CATECHOLAMINE iNOS EXPRESSION
OXIDASES…
AUTO-OXIDATION
TNF-α

DEATH MACROPHAGES OXIDATIVE


RECEPTOR iNOS STRESS
MITOCHONDRIA

OXIDATIVE
STRESS

CASPASES
ACTIVATION

APOPTOSIS
Acute Compensatory Cardiac
Normal load hypertrophy failure
h h

LV systolic pressure N + + +
LV radius N + + +
LV
+ wall thickness N N + +
LV
N diastolic volume N + + ++
Systolic
N wall stress N + N +
Diastolic wall stress N + N +

The normal (N) relationship between left ventricular wall thickness (h) and
chamber radius (r) is shown (first panel).
Remodeling stimuli Increased wall stress
Wall stress
Cytokines
Neurohormones
Oxidative stress

Myocyte hypertrophy
Ventricular
enlargement
Altered intestinal matrix

Fetal gene expression

Altered calcium-handling Systolic or diastolic


proteins dysfunction

-Myocyte death

Overview of the pathoghysiology of myocardialremodeling


2 C
Maximal
activity Normal-exercise
1
Normal-rest
Ventricular performance

Contractile state
of myocardium
B 3’
Walking
Exercise
D 3 Heart failure
Rest
A Rest
E Fatal
4 myocardial
Dyspnea Pul. edema depression
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.
Endothelial cell of
intramyocardial
coronary artery

Vascular
smooth
muscle Cardiac
cells fibrolast
of
interstitial
space
Tissue fluid
of interstitium

Endothelial
Myocyte cell of
capillary
Fibrillar
collagen

Myocyte and nonmyocyte constituents of the heart.


Overload

Increased Growth stimuli


Energy
utilization Maladaptive Myocyte
hypertrophy elongation

Decreased Progressive
Energy supply Dilatioon
(remodeling)
Apoptosis

Energy starvation Necrosis

Some of the viciouscircles that operate in the overloaded heart.


Overload both increases energy utilization and stimulates growth. The former
Systemic (circulatory) Tissue (local)
Liver Tissue (heart, brain,
Vasculature)
Angiotensinogen
Tissue renin +
Renal renin
Renal renin
Angiotensin I
Other
Lung ACE Tissue Proteases
ACE E,g.,
Angiotensin II chymase
Protease Protease
Inactive “Active” fragments
fragments Ang III, Ang IV,
Angiotensin II Ang 1-7

Angiotensin Extracellular
receptors intracellular
Intemalization Gene Regulation
Inactivation Angiotensinogen
Cellular Response Renin
Contraction ACE
Secretion Angiotensin
Receptor
The systemic and tissue components of the renin-angiotensin system. Several tissues, including
myocardium, vasculature, kidney, and brain, have the capacity to generate angiotensin II independent of
the circulating renin-angiotensin system. Angiotensin II produced at the tissue level may
Play an important role in the pathophysiology of heart failure. ACE = angiotensin-converting enzyme.
(Modified from timmermans PB, Wong PC, Chiu AT, et al : Angiotensin II receptors and angiotensin II
Receptor antagonists. Pharmacol Rev 45:205, 1993).
Angiotensin II
TNF alpha
Endothesin β1-adrenergic
α 1-adrenergic Mechanical strain Angiotensin II
Low High

NADPH
Cocidase

ROS Cytochrome c
ROS release

Kinase cascades Caspase cascades


+SERCA2
Myocyte hypertrophy NA/Ca2 Ext Myocyte apoptosis
RAAS
Impairment in
stimulation
Renal perfusion
+

Myocardial Sodium
failure reabsorption

-
Atrial or ventricular NAP
Distention, or both release

Heart failure Compensated Decompensated


Impairment in
Mild to moderate Moderate to severe
Renal perfusion
Urinary sodium:
Potassium ratio > 1.0 < 1.0
Cardioregulatory
center

Glossopharryngeal
And vagal afferents
From high-pressure
baroreceptors
Sympathetic
trunk
Sympathetic
ganglion AVP
Aldosterone
Sympathetic
nerves

Angiotensin II
release

Peripheral Solute-free water axcretion


vasoconstriction  Sodium excretion
Afferents NORMAL Efferents

+ CNS Heart
Ach
Arterial rate
chemoreceptors
-
Arterial NE
barorecaptors Parasympatetic
NE
- Contraction
Cardiopulmonary
sympathetic
baroreceptores Na+reabsorption
-
E Renin
NE Renal vascular
Muscle NE resistance
mataboreceptors
Peripheral
NE Vascular
resistance

Afferents HEART FAILURE Efferents

+ CNS Heart
Arterial rate
cemoreceptors Ach
-
Arterial
NE
barorecaptors Parasympatetic
NE Adverse
-
Cardiopulmonary Cardiac effects
sympathetic
baroreceptores
- Na+reabsorption
E Renin
NE Renal vascular
Muscle NE resistance
mataboreceptors
+ Peripheral
NE Vascular
resistance
Overload/
 Energy supply:
 Preload Myocyte loss
demand ratio

Cellular Altered collagen


hypertropy matrix

 Afterload
Remodelling

  Inotropy
 Cardiac output

Baroreflex Neurohormonal
response activation

• Natriuretic • Renin-angiotensin-
peptides aldosterone
• Prostaglandins • Sympathetic Arrhythmias
• Bradykinin  Ca2-
nervous system Sudden death
 • Endothelin
 Response • Arginine vasopressin
to stress

Fluid & salt
retention
Vasoconstriction, vascular remodelling, endothelial dysfunction

Peripheral
maintains blood pressure perfusion
resistance
Altered skeletal muscle redistributes cardiac output of vital
blood flow and metabolism organs

Dyspnea, edema, fatigue

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
Diuresis
Vasodilatation Antimitogenic

Natriuretic
Prostaglandins peptides No

Myocardial
Free radicals
dysfunction
Cytokines

Renin Growth
AVP
Endothelins hormone
All
Catecholamines Apoptosis
Aldosterone
Hypertrophy
Vasoconstriction
Salt and water
retention

Many different neurohormonal pathways are stimulated following myocardial dysfunction


Myocyte Death

Neutrophil Decreased CO TGF-1


infiltration release

Enhanced NE release Juxtaglomerular


Activation Increased Macrophage & fibroblast chemotaxis
from adrenal medulla Apparatus ANP
of MMPs and sympathetic nerve Fibroblast proliferation
Activation of BNP Macrophage transformation
in ECM terminals RAAS

Increased ACE TGF-1


Elevated
Elevated Plasma Na+ expression release from
Degradation of Water macrophages
inter-myocyte plasma NE AII
collagen excretion
struts
ET-1
release Decreased Local AII & Fibroblast
Myocyte Volume Aldosterone transformation into
slippage SVR production myofibroblast

Myocyte Hypertrophy Transient


TGF-1 expression
Improvement
LV function Activation of TIMPs
Wall thinning
Type I & III collagen
synthesis
Ventricular Increased
Dilatation wall stress Local AII release
Mechanical Activation of fetal gene program
stretch Increased contractile proteins Fibrosis

Early Remodeling (<72 hours) Late Remodeling

Diagrammatic representation of the many factors involved in


the pathophysiology of ventricular remodeling. (Sutton & Sharpe, 2000)
ACE inhibitors for congestive heart failure
NEUROHUMORAL EFFECTS OF HEART FAILURE

BACKWARD FAILURE Poor organ FORWARD FAILURE


INTO LUNGS & RV perfusion LOW BLOOD PRESSURE

Low BP Baroreflexes
JVP  kidney
Adrenergic stimulation
RV failure RV ANP
 
LA RENIN 
EXCESS
back Angiotensin AFTERLOAD
big liver
edema ward Aldosterone

Left pressure
ventricle 
Increasing
Na+ loss Na+ retension
forward
Edema
failure
INCREASING heart
BACKWARD 
FAILURE 
Increasing EXCESS
BLOOD VOLUME
low renal
preload blood flow

(Opie, 1994)
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 1 2 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)


1.00
0.95
0.90

Probability of Survival
0.85
0.80
0.75
0.70 Spironolactone
0.65
0.60
0.55 Placebo
0.50
0.45 p<0.001
0.00
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
No. At Risk
Placebo 841 775 723 678 628 592 565 483 379 280 179 92 36
Spironolactone 822 766 739 698 669 639 608 526 419 316 193 122 43

Kaplan-Meier Analysis of the Probability of Survival among Patients


in the Placebo Group and Patients in the Spironolactone Group
(Pitt et al, 1999)
HF: Mortality Remains High
• ACEI
– Risk reduction 35% (mortality and hospitalization)1
• -blockers
– Risk reduction 38% (mortality amd hospitalization)2
• Spironolactone
– Mortality reduction 23%
• Oral nitrates and hydralazine
– Benefit vs placebo; inferior enalapril (mortality)

However: 4-year mortality remains ~40%


1 Davies MK et al. BMJ. 2000. 320: 428-431. (meta-analysis: 32 trials. N=7105)
2 Gibbs CR et al. BMJ. 2000. 320: 495-498. (meta-analysis: 18 trials. N=3023)
AF
Atrial ATP/DC

Preventive
Pacing therapies
VT/VF
Ventricular
ATP/DC

DDDR-pacing
Brady

Resynchronization therapy
CHF

(a) The coexistence of heart failure and arrhythmias (bradycardias [Brady], atrial fibrillation [AF],
ventricular tachycardia [IVT] and ventricular fibrillation [VF]) is mirrored by (b) the coexistence of
various treatment modalities in a single electrical device. ATP=antitachycardia pacing;
CHF=congestive heart failure; DC=direct-current cardioversion defibrillation.
Hormones Abnormal External
Inflammatory Oxygen
(catecholamines, Nitric oxide Genetic factors baroceptor factors
cytokines free radicals
ET-1, steroids) reflexes

Metabolic status
(Global/local factors)

Energy Resting energy Skeletal muscle Skeletal muscle Cardiac muscle Cardiac muscle Endothelial
reserves expenditure function apoptosis function apoptosis function

Energy status Skeletal muscle Cardiac muscle Vasculature

Deterioration of CHF

Complex interactions between different body systems in the pathogenesis of chronic heart failure.
CHF=chronic heart failure; ET=endothelin.
Overload /  Energy supply :
 Preload Myocyte loss demand ratio

Cellular Altered collagen


hypertrophy matrix

 Afterload Remodelling


 Cardiac output  Inotropy

 Baroreflex Neurohormonal
response activation

• Natriuretic • Renin-angiotensin-
peptides aldosterone Arrhythmias
• Prostaglandins • Sympathetic nervous  Ca2+
• Bradykinin system
• Endothelin Sudden death
 Response to  • Arginine vasopressin
stress

Fluid & salt
retention
Vasoconstriction, vascular remodelling, endothelial dysfunction

 Peripheral maintains blood pressure Perfusion


resistance redistributes cardiac output of vital
Altered skeletal muscle
organs
blood flow and metabolism

Dyspnea, edema, fatigue


Val-Heft : Combined
Neurohormonal systems activated in chronic heart failure
COMBINED ALL CAUSE MORTALITY AND MORBIDITY
SUB-GROUP WITHOUT ACEI BACKGROUND THERAPY
Val-HeFT
1.0
44.5%
RISK REDUCTION
EVENT-FREE PROBABILITY

P = 0.0002
0.8

0.6

VALSARTAN (N = 185) PLACEBO (N = 181)


0.4
0 3 6 9 12 15 18 21 24 27
TI
TIME SINCE RANDOMIZATION (MONTHS)
THE STRATEGY IN THE MANAGEMENT
OF HEART FAILURE
• Prevention and early intervention
before the disease progresses to
a later stage.
• Prevention should include detection
and treatment of aetiological factors
and risk factors
• Early intervention is directed towards
treatment of acute coronary syndrome
Risk
Factors HEART FAILURE SPECTRUM

Heart disease
Asymptomatic
LV Dysfunction
Symptoms
NYHA II-III Symptoms
NYHA - IV

Symptoms
ECHO / LV dysfunction
? BNP
100
Progression Further damage
Excessive wall stress
Neurohormonal activation
Patients surviving %

Mechanism of death Myocardial ischemia


Sudden death 40%
Worsening CHF 40%
Other 20%

Annual mortality
<5% 10% 20 to 30% 30 to 80%
0
Asymptomatic Mild Moderate Severe

Left ventricular dysfunction and symptoms

(Massie & Shah, 1997)


mmHg LV
120 Aorta
80 LV Pressure
40
LA
0

ml
120
sv
80 LV Volume
40
RV
0
R
T ECG
P P

Q S

Relaxation
Passive stiffness Factors
influencing
Elastic recoil
LV diastole
Atrial reserve

M-mode
AO MI achocardio-
cm/s graphy
80

40
Dopplerecho
E A
0

Cardiac Cycle (Stork et al, 1995)


Clinical Clues to the Differential Diagnosis of
Congestive Heart Failure
Systolic CHF Diastolic CHF
History
Myocardial infarction XX X
Hypertension X XX
Physical examination
Displaced PMI X
S3 gallop X
S4 gallop X
Chest radiograph
Cardiomegaly XX X
Pulmonary congestion XX XX
Electrocardiogram
Q waves XX X
Left ventricular hypertrophy X XX
(Goldsmith & Dick, 1993)
Diastolic Heart Failure: Treatment
Symptom targeted treatment
Decrease pulmonary venous pressure
Maintain atrial contraction
Prevent tachycardia
Reduce LV volume
Improve exercise tolerance
Pharmacological treatment
Renin angiotensin-aldosterone antagonists including ACEI, ARB and
aldosterone antagonists
Calcium channel blockers
-Adrenergic blockers
Diuretics, nitrates, and positive inotropic agents with caution
Myocyte Death

Neutrophil Decreased CO TGF-1


infiltration release

Enhanced NE release Juxtaglomerular


Activation Increased Macrophage & fibroblast chemotaxis
from adrenal medulla Apparatus ANP
of MMPs and sympathetic nerve Fibroblast proliferation
Activation of BNP Macrophage transformation
in ECM terminals RAAS

Increased ACE TGF-1


Elevated
Elevated Plasma Na+ expression release from
Degradation of Water macrophages
inter-myocyte plasma NE AII
collagen excretion
struts
ET-1
release Decreased Local AII & Fibroblast
Myocyte Volume Aldosterone transformation into
slippage SVR production myofibroblast

Myocyte Hypertrophy Transient


TGF-1 expression
Improvement
LV function Activation of TIMPs
Wall thinning
Type I & III collagen
synthesis
Ventricular Increased
Dilatation wall stress Local AII release
Mechanical Activation of fetal gene program
stretch Increased contractile proteins Fibrosis

Early Remodeling (<72 hours) Late Remodeling

Diagrammatic representation of the many factors involved in


the pathophysiology of ventricular remodeling. (Sutton & Sharpe, 2000)
Activation of Neurohormonal Pathways in HF

Coronary Disease Cardiomyopathy Cardiac Overload

Left Ventricular Dysfunction

Neurohormonal Activation
• Cathecholamines
Vasoconstriction • RAS
• AVP
• Endothelin

 Peripheral Organ
Cardiac Remodelling
Blood Flow

 skeletal  RBF LV dilatation LV hypertrophy


muscle flow Na+ retention
Arrhythmias

Exercise Intolerance Edema, Congestion Sudden Death Pump Failure

Ruffolo, J Cardiovasc, Pharmacol, 1998


DETERMINANTS OF
VENTRICULAR FUNCTION

CONTRACTILITY

PRELOAD AFTERLOAD

STROKE
VOLUME

• Synergistic LV contraction
HEART
• LV wall integrity
RATE
• Valvular competence

CARDIAC OUTPUT
Processes Occuring
in Ventricular Remodeling
Cardiomyocyte lengthening
Ventricular wall thins
Infarct expansion rather than extension occurs
Inflammation and reabsorption of necrotic tissue
Scar formation
Caontinued expansion of infarct zone
Dilation and reshaping of the left ventricle
Myocyte hypertrophy
Ongoing myocyte loss
Excessive accumulation of collagen in the
cardiac interstitium
(Cohn et al, 2000)
Epidemiology
Epidemiology of CHF in the community
Age Prevalence Incidence
(years) (%) (new cases per 1000 per year)

50 1 2
80 9 14

Epidemiology of CHF: hospital admissions

Survey Admissions
USA hospital admissions
per year
Gillum (1985) 585 000
Yancy and Firth (1988) 900 000
UK Hillingdon survey
Parameshwar (1990) 4.9% of medical hospital admissions
Injury to myocytes and extracellular matrix

• neurohumoral
activation • oxidative stress
• increased cytokine • apoptosis
expression Ventricular • altered gene
• immune and remodeling
expression
inflammatory
• energy starvation
changes
• altered fibrinolysis

Electrical, vascular, renal, pulmonary muscle


and other effects

CHF

Current neurohumoral paradigm of CHF,


emphasizing central role of heart.
(McMurray & Pfeffer, 2000)
VASCULAR REMODELING AND
ATHEROSCLEROSIS IN THE ELDERLY

Rukma Juslim
Division of Cardiology, Department of Internal Medicine
Hang Tuah University, Dr. Ramelan Hospital
Semarang
Aging: The Major Risk Factor for
Cardiovascular Morbidity and Mortality
STROKE STROKE
Disease

Increasing Age
Increasing Age

Clinical
Practice  LV RESERVE
Threshold
“normal” Aging
Prevention
Stage

ARTERIAL
STIFFENING
AND
THICKENING

(Lakatta et al, 1994)


RELATIONSHIP OF CARDIOVASCULAR HUMAN AGING
IN HEALTH TO CARDIOVASCULAR DISEASE
Age-Associated Changes Plausible Mechanisms Possible Relation to Human Disease
Cardiovascular structural remodeling
 Vascular intimal thickness  Migration of and  matrix Early stages of atherosclerosis
production by VSMC
Possible derivation of intimal
cells from other sources
 Vascular stiffness Elastin fragmentation Systolic hypertension
 Elastase activity
 Collagen production Stroke
by VSMC and
 cross-linking of collagen
Altered growth factor Atherosclerosis
regulation/tissue repair
mechanisms
 LV wall thickness  LV myocyte size Retarded early diastolic
cardiac filling
 Myocyte number (necrotic  Cardiac filling pressure
and apoptotic death)
Altered growth factor Lower threshold for dyspnea
regulation
Focal collagen deposition
 Left atrial size  Left atrial pressure/volume  Prevalence of lone atrial fibrillation
(Lakatta et al, 2001)
RELATIONSHIP OF CARDIOVASCULAR HUMAN AGING
IN HEALTH TO CARDIOVASCULAR DISEASE
Age-Associated Changes Plausible Mechanisms Possible Relation to Human Disease
Cardiovascular functional changes
Altered regulation of vascular  NO production/effects Vascular stiffening; hypertension
tone  AR responses
 Cardiovascular reserve  Vascular load Lower threshold for, and increased
 Intrinsic myocardial severity of, heart failure
contractility
 -Adrenergic modulation of
heart rate, myocardial
contractility, and vascular
tone
Reduced physical activity Learned lifestyle Exaggerated age s in some aspects
of cardiovascular structure and
function; negative impact on
atherosclerotic vascular disease,
hypertension, and heart failure

(Lakatta et al, 2001)


Atherosclerosis Timeline
Foam Fatty Intermediate Fibrous Complicated
Cells Streak Lesion Atheroma Plaque Lesion/Rupture

Endothelial dysfunction
From first decade From third decade From fourth decade
Smooth muscle Thrombosis,
Growth mainly by lipid accumulation and collagen haematoma

Adapted from Stary HC et al. Circulation 1995;92:1355-1374.


Thrombin LDL
Signals Flow or shear Angiotensin II Inflammatory Adhesion Oxidized LDL
stress Stretch ATP mediators molecules Lipoprotein (a)

Ligand receptors ELAMs Lipoprotein


Sensors Potassium Ion channel Integrins receptors
channel

Vascular transducer cell


Nucleus

Mediators Gap junctions


Vasoactive Matrix modulators Extracellular-matrix
substances Growth regulators receptors

Agents of Vascular Remodeling (Signals, Sensors, and Mediators)


(Gibbons & Dzau, 1994)
The components biologic process
of vascular remodeling
• Detection of signals (sensors)
• The relay of signals within the cell and
adjacent cells (transducers)
• The synthesis and release or activation
of substances (mediators)
• The resultant structural changes in the
vessel wall
Pressure Flow Injury

A B C D E F
The Spectrum of Vascular Remodeling
Vessel A represents hypertensive vascular disease with vascular hypertrophy, in which the
medial layer is thickened and the luminal diameter is reduced; vessel B, hypertensive vascular
disease without medial hypertrophy, in which the luminal diameter is reduced; vessel C,
decreased vessel dimensions is response to a long-term decrease in flow; vessel D, increased
vessel dimentions in response to a long-term increase in flow; vessel E, neointimal hyperplasia
(migration and proliferation of vascular smooth-muscle cells) in response to vascular injury; and
vessel F, atherosclerosis in response to vascular injury of conduit vessels.
(Gibbons & Dzau, 1994)
VASCULAR REMODELING
 Vascular remodeling is an active process of
structural alteration that involves changes
in at least four cellular process – cell growth, cell
death, cell migration, and production or
degradation of ECM – and is dependent on a
dynamic interaction between locally generated
growth factors, vasoactive substances, and
hemodynamic stimuli.
 Remodeling is usually an adaptive process that
occurs in response to long-term changes in
hemodynamic conditions, but it may subsequently
contribute to the pathophysiology to vascular
diseases and circulatory disorders.
(Gibbons & Dzau, 1994)
Endothelial dysfunction leads to imbalance
of factors resulting in vascular disease
Normal endothelium Abnormal endothelium
Hypertension Diabetes

LDL cholesterol Family history

Triglycerides
Oxidative
damage

Upregulation of
Endothel Dysfunction angiotensin II
Vascular Retard Inhibit SMC Barrier to receptors
tone platelet & migration & LDL cholesterol.
leukocyte proliferation Degrade VLDL &
adhesion chylotriglyceride
(lipase) Vasoconstriction Increased SMC Increased lipid
platelet & migration deposition.
leukocyte & growth Reduced
adhesion clearance

Adapted from Omoigui and Dzau. Am J Hypertens. 1993:6(3 pt 2):30S-39S


Monocyte

Adherence
BLOOD

LDL

Entry

+
MCP-1 Endothelial Foam Cells
+ Damage
M-CSF Oxidation
Growth and + MM-LDL
change of
phenotype Oxidation
Accumulation
+ OX-LDL
of cholesterol-
loaded
Macrophage macrophage

Receptor-mediated
Uptake of Ox-LDL
ARTERY WALL
(Steinberg, 1991)
Characteristics of the
stable atherosclerotic plaque
Fibrous cap
(VSMCs and matrix) Intimal VSMCs
Endothelial (repair phenotype)
cells

Lipid core

Adventitia

Medial VSMCs
(contractile phenotype)
Advanced Atherosclerosis
Activated macrophages
induce intimal VSMC
apoptosis and degrade the
Intimal VSMCs matrix in the fibrous cap
become senescent

lipid
Lipidcore
core

Adventitia
VSMC–inflammatory cell interactions
in atherosclerosis
MMPs secreted by
macrophages degrade
the extracellular matrix

Macrophages
induce
VSMC
apoptosis
TNF-
IL-1
Fibrous
Macrophage
cap
T-lymphocyte IFN-g
PDGF Inflammatory
cytokines
inhibit matrix
protein
production
Macrophages secrete growth factors that by VSMCs
promote VSMC recruitment and proliferation
MMPs and Arterial Remodelling

plaque Rupture
plaque
Lumen
Intimal MMP-9
Hyperplasia MMP-1,2,3,8,9,14 (Definitely “ugly”)
MMPs ?
MMP-2,9

Constrictive remodeling (“bad”?) Expansive remodeling (“good”?)


Stable plaque
Aneurysm

MPP-9

Ghalis & Khatri, 2002


The complexity of atherosclerosis:
beyond cholesterol lowering – conclusions
Statin therapy

Non-lipid
Lipid mechanisms mechanisms

Measurable Measurable
indicators indicators

Lower Plaque stabilisation


LDL-C Net
clinical Inflammation
Raise HDL-C benefit
Platelet thrombus
Lower triglycerides formation
Coagulation

Endothelial NOS

Modified from Rosenson et al (1998)


SUMMARY
 Cardiovascular changes in the elderly must be considered as risk
factors for CV diseases.
 With advancing age, the intima becomes thickened due to
increase of migration, proliferation and matrix production by
VSMCs.
 The endothelium appears to have central role in the initiation of
atherosclerosis.
 Endothelial cells participate directly in vascular remodeling or
activating substance that influence the cell migration, growth,
death, and production or degradation of extracellular matrix.
 The intrinsic capacity of the vessel to alter its geometry is termed
vascular remodeling.
 The current concept of atherosclerosis which places emphasis on
the remodeling of the arterial wall, provides a framework for
understanding how, through weakening and destabilization,
angiographically undetectable moderate lesions could become
culprits for ACS.