Transcript Guidelines for the diagnosis and treatment of

CHRONIC HEART
FAILURE
Faculty of Medicine
University of Brawijaya
Introduction
Definition : Heart Failure
“The situation when the heart is incapable of
maintaining a cardiac output adequate to
accommodate metabolic requirements and the
venous return.“ E. Braunwald
“Pathophysiological state in which an
abnormality of cardiac function is responsible
for the failure of the heart to pump blood at a
rate commensurate with the requirements of
the metabolizing tissues.” Euro Heart J; 2001. 22: 1527-1560
DEFINITION OF HEART FAILURE.
Criteria 1 and 2 should be fulfilled in all cases
1. Symptoms of heart failure
(at rest or during exercise)
And
2. Objective evidence of cardiac dysfunction
(at rest)
And
(in cases where the diagnosis is in doubt)
3. Response to treatment directed towards heart
failure
Task Force Report. Guidelines for the diagnosis and treatment of chronic heart failure.
European Society of Cardiology.2001
EPIDEMIOLOGY
Europe
The prevalence of symptomatic HF range from 0.4-2%.
10 million HF pts in 900 million total population
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
USA
nearly 5 million HF pts.
± 500,000 pts are D/ HF for the 1st time each year.
Last 10 years  number of hospitalizations has increased.
Nearly 300,000 patients die of HF each year.
ACC/AHA Guidelines for the
Evaluation and Management of Chronic Heart Failure in the Adult 2001
DESCRIPTIVE TERMS in HEART FAILURE
 Acute vs Chronic Heart Failure
 Systolic vs Diastolic Heart Failure
 Right vs Left Heart Failure
 Mild , Moderate, Severe Heart Failure
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1528
New York Heart Association (NYHA)
Classification of Heart Failure
Class – I
No limitation : ordinary physical exercise does
not cause undue fatigue, dyspnoea or palpitations.
Class – II
Slight limitation of physical activity : comfortable at rest but ordinary activity results in
fatigue, dyspnoea, or palpitation.
Class - III
Marked limitation of physical activity : comfortable at rest but less than ordinary activity
results in symptoms.
Class - IV
Unable to carry out any physical activity without discomfort : symptoms of heart failure are
present even at rest with increased discomfort
with any physical activity.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1531
(Adapted from Williams JF et al., Circulation. 1995; 92 : 2764-2784)
ACC/AHA – A New Approach To The Classification of HF
Stage
Descriptions
Examples
A
Patient who is at high risk for
developing HF but has no
structural disorder of the heart.
Hypertension; CAD; DM;
rheumatic fever; cardiomyopathy.
B
Patient with a structural disorder
of the heart but who has never
developed symptoms of HF.
LV hypertrophy or fibrosis;
LV dilatation; asymptomatic VHD;
MI.
C
Patient with past or current
symptoms of HF associated with
underlying structural heart
disease.
Dyspnea or fatigue ec LV systolic
dysfunction; asymptomatic
patients with HF.
D
Patient with end-stage disease
Frequently hospitalized pts ; pts
awaiting heart transplantation etc
ACC/AHA Guidelines for the
Evaluation and Management of Chronic Heart Failure in the Adult 2001
Stages in the evolution of HF and recommended therapy by stage
•
•
•
•
•
•
Stage A
Stage B
Pts with :
• Hypertension
• CAD
• DM
• Cardiotoxins
• FHx CM
Pts with :
• Previous MI
• LV systolic
dysfunction
• Asymptomatic
Valvular disease
Struct.
Heart
Disease
THERAPY
Treat Hypertension
Stop smoking
Treat lipid disorders
Encourage regular
exercise
Stop alcohol
& drug use
ACE inhibition
THERAPY
• All measures under
stage A
• ACE inhibitor
• Beta-blockers
Stage C
Stage D
Pts with :
Develop
Symp.of
HF
• Struct. HD
Refract.
• Shortness of
Symp.of
breath and fatigue,
HF at rest
reduce exercise
tolerance
THERAPY
• All measures under
stage A
• Drugs for routine use:
• diuretic
• ACE inhibitor
• Beta-blockers
• digitalis
•
•
•
•
Pts who have
marked symptoms
at rest despite
maximal medical
therapy.
THERAPY
All measures under
stage A,B and C
Mechanical assist
device
Heart transplantation
Continuous IV
inotrphic infusions for
palliation
ACC/AHA Guidelines for the
Evaluation and Management of Chronic Heart Failure in the Adult 2001
EVOLUTION OF
CLINICAL STAGES
NORMAL
Asymptomatic
LV Dysfunction
No symptoms
Compensated
Normal exercise
CHF
Abnormal LV fxn
No symptoms
Decompensated
Exercise
CHF
Abnormal LV fxn
Symptoms
Refractory
Exercise
CHF
Abnormal LV fxn
No symptoms
Normal exercise
Normal LV fxn
Symptoms not controlled
with treatment
Evolution of the Concept of Heart Failure
1950 to 2000
1950
2000
Aetiology
Hypertension
Valvular heart dis
CHD
Hypertension
Dilated CMP
Natural Course
Slowly progressive
Understanding
Hemodynamic model
Slowly progressive (remodelling)
or unpredictable and rapid
( coronary event )
Neurohormonal model
Common cause
of death
Pulmonary infection
Sudden death
Pump failure
Arrhythmia
Atrial
Ventricular
Treatment goal
Control edema
Slowing Heart Rate
Improve quality of life
+ reduce mortality + reduce
hospitalization
Patophysiology of C H F
g
a
b
c
d
e
g
f
a
AO
Aortic
closure
Aortic
pressure
Ventricular
pressure
Crossover
Heart
sounds
A2
P2 S
3
M1
T1
S4
MO
Atrial
pressure
Cardiologic
systole
a
c
v
Opie (2001)
JVP
T
P
P
ECG
Q
S
0
800 msec
The Wiggers cycle
g
f
e
a
b
iso
c
d
iso
PULMONARY VENOUS
PRESSURE
Input
Filling
Emptying
Stroke
EF
ED volume x
effective = volume
LV Distensibility
x
Contractility
Relaxation
Afterload
Heart
Left atrium
Preload
rate
Mitral valve
Pericardium
Structure
Diastolic function Systolic function
Output
CARDIAC OUTPUT
Block diagram of left ventricular pump performance
(Little, 2001)
PRESSURE – VOLUME CURVE OF SYSTOLIC AND DIASTOLIC FAILURE
DIASTOLIC FAILURE
Normal
Normal
diastolic
chamber
distensibility
Left Ventricular Volume
Left Ventricular Pressure
Left Ventricular Pressure
SYSTOLIC FAILURE
Decreased
diastolic
chamber
distensibility
Left Ventricular Volume
(Zile & Brutsaert 2002)
Left ventricular pressure
Abnormal
relaxation
Pericardial
restraint
B
A
Chamber
dilation
Increased
chamber stiffness
C
D
Left ventricular volume
Mechanisms that cause diastolic dysfunction. (Zile, 1990)
DETERMINANTS OF
VENTRICULAR FUNCTION
CONTRACTILITY
PRELOAD
AFTERLOAD
STROKE
VOLUME
- Synergistic LV contraction
- LV wall integrity
- Valvular competence
CARDIAC OUTPUT
HEART
RATE
Frank-Starling Law
Normal
Cardiac Output
Compensated
Normal C.O.
CHF
LVEDP
Ventricular Function Curve:
Frank-Starlings
Normal
SV
LVEDV
Congestion
The Pathophysiology of Heart Failure
Hurst. The Heart. Diagnosis and Management of Heart Failure.10th ed. 688
Pathophysiological Sequence of
CHF
Heart Failure
Inadequate Cardiac Output
( ) O2 Delivery (rest and/or exercise)
Systemic Vasoconstriction
SAS (NE))
RAAS (A-II)
() Flow to Skin, Gut,
and Renal Circulations
Neurohormonal Activation
Activation of
RAS and ANS
Hurst. The Heart. Diagnosis and Management of Heart Failure.10th ed. 688
Frank-Starling Effect
Ventricular dilatation
Wall stress
O2 consumption
Coronary
perfusion
SNS
Preload
Afterload
Renin release
Angiotensin II
Growth
factors
ALDO
Vasoconstriction
Hypertrophy
Apoptosis
Fluid
accumulation
Collagen
deposition
SNS: sympathetic nervous system
Myofibril
necrosis
Sympathetic nervous system up-regulation
Increased
Norepinephrine levels
Activation of the
RAA system
Increased
Angiotensin II &
Aldosteron
Na+
& water
retention
Vasoconstriction
Direct
Myocardial toxicity
Decreased
Renal blood
flow
Myocyte dysfunction
Increased HR, PVR &
arteriolar vasoconstriction
Increased myocardial
oxygen demand
Cardiac remodeling
Myocyte
necrosis
Intracellular
Ca2+ overload/
Energy depletion
Apoptosis
Cesario et.al; Reviews in cardiovascular medicine, vol 3, no.1, 2002
Causes of Heart Failure
Myocardial Damage or Disease
Infarction (Acute) / Ischemia
 Myocarditis
 Hypertrophic Cardiomyopathy

Excess Load on Ventricle

Volume/ Pressure Overload
Resistance to Flow into Ventricle
Cardiac Arrhythmias
Primary Changes in CHF
Site of
Failure
Backward
Failure
Right Heart () Systemic
Failure
Venous
Pressure
Left Heart
Failure
Forward
Failure
() ejection
into
Pulmonary
Artery
() Pulmonary () ejection
Venous
into aorta
Pressure
MI-INDUCED HEART FAILURE
Myocardial Damage
Contractility
Pump Performance
() Systolic Work Load
Vasoconstriction
RAAS SYSTEM
FLUID RETENTION
() SAS Drive
Diagnosis of C H F
IDENTIFICATIONS OF HF PATIENTS

With a Syndrome of Decrease Exercise
Tolerance

With a Syndrome of Fluid Retention

With No Symptoms or Symptoms of
Another Cardiac or Non Cardiac
Disorder
(MI, Arrythmias, Pulmonary or
Systemic Thromboembolic Events)
SYMPTOMS AND SIGN

Breathlessness, Ankle Swelling, Fatique
→ Characteristic Symptoms

Peripheral Oedema, JVP ↑, Hepatomegaly
→ Signs of Congestion of Systemic Veins

S3  , Pulmonary Rales , Cardiac Murmur 
ECG
A low Predictive Value
 LAH and LVH May Be Associated wit LV Dysfunction
 Anterior Q-wave and LBBB a good predictors of EF ↓↓
 Detecting Arrhytmias as Causative of HF

CHEST X-RAY
 A Part of Initial Diagnosis of HF
→ Cardiomegaly, Pulmonary Congestion
 Relationship Between Radiological Signs and
Haemodynamic Findings may Depend on the Duration
and Severity HF
HAEMATOLOGY & BIOCHEMISTRY

A Part of Routine Diagnostic
 Hb, Leucocyte, Platelets
 Electrolytes, Creatinine, Glucose, Hepatic Enzyme,
Urinalysis
 TSH, C-RP, Uric Acid
ECHOCARDIOGRAPHY
 The Preferred Methods
 Helpful in Determining the Aetiology
 Follow Up of Patients Heart Failure
PULMONARY FUNCTIONS


A Little Value in Diagnosis Heart Failure
Usefull in Excluding Respiratory Diseases
EXERCISE TESTING
 Focused on Functional, Treatment Assessment and
Prognostic
STRESS ECHOCARDIOGRAPHY


For Detecting Ischaemia
Viability Study
NUCLEAR CARDIOLOGY
 Not Recommended as a Routine Use
CMR
( CARDIAC MAGNETIC RESONANCE IMAGING)
 Recommended if Other Imaging Techniques not
Provided Diagnostic Answer
INVASIVE INVESTIGATION
 Elucidating the Cause and Prognostic Informations
 Coronary Angiography :
in CAD’s Patients
 Haemodynamic Monitoring :
To Assess Diagnostic and Treatment of HF
 Endomyocardial Biopsy :
in Patients with Unexplained HF
NATRIURETIC PEPTIDES

Cardiac Function ↓↓ (LV Function ↓↓) →
↑↑ Plasma Natriuretic Peptide Concentration
(Diagnostic Blood Use for HF)

Natriuretic Peptide ↑↑ :
Greatest Risk of CV Events
Natriuretic Peptide ↓↓ :
Improve Outcome in Patients with
Treatment

Identify Pts. With Asymptomatic LV
Dysfunction (MI, CAD)
ALGORITHM FOR THE DIAGNOSIS OF THE HF
(ESC, 2001)
Suspected Heart Failure Because
of symptoms and signs
Assess Presence of Cardiac Disease by ECG, X-Ray
or NatriureticPeptides (Where Available)
If Normal
Heart Failure
Unlikely
Tests Abnormal
Imaging by Echocardiography (Nuclear
Angiography or MRI Where Available)
If Normal
Heart Failure
Unlikely
Tests Abnormal
Assess Etiology, Degree, Precipitating
Factors and Type of Cardiac Dysfunction
Choose Therapy
Additional Diagnosis Tests
Where Appropriate (e.g.
Coronary Angiography)
Treatment of C H F
Aims of Treatment
1. 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
2. Morbidity
Maintenance or improvement in quality of life
3. Mortality
Increased duration of life
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
ACC/AHA & EUROPE (ESC) 2001
GUIDELINES FOR THE MANAGEMENT
OF HEART FAILURE
 ACE-inhibitor
→ Use as first line therapy
→ Should be up titrated to the dosages shown in the large
clinical trial, and not titrated based on symptomatic
improvement
 DIURETIC → to control fluid overload
 Β-BLOCKER
→ For all patients with stable mild-severe HF on
standard treatment
ACC/AHA & EUROPE (ESC) 2001
GUIDELINES FOR THE MANAGEMENT
OF HEART FAILURE
 Aldosteron Receptor Antagonis
→ in advance HF ( NYHA III-IV )
 DIGOXIN
→ in AF (atrial fibrillation)
→ May be added for symptom relief
 ARB
→ Considered in patients not tolerate ACEinhibitors and not on β - blocker
Management Outline
Establish that the patient has HF.
Ascertain presenting features: pulmonary oedema, exertional
breathlessness, fatigue, peripheral oedema
Assess severity of symptoms
Determine aetiology of heart failure
Identify precipitating and exacerbating factors
Identify concomitant diseases
Estimate prognosis
Anticipate complications
Counsel patient and relatives
Choose appropriate management
Monitor progress and manage accordingly
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
TREATMENT
Correction of aggravating factors
Pregnancy
Arrhythmias (AF)
Infections
Hyperthyroidism
Thromboembolism
Endocarditis
Obesity
Hypertension
Physical activity
Dietary excess
MEDICATIONS
Treatment options
Non-pharmacological management
General advice and measures
Exercise and exercise training
Pharmacological therapy
Angiotensin-converting enzyme (ACE) inhibitors
Diuretics
Beta-adrenoceptor antagonists
Aldosterone receptor antagonists
Angiotensin receptor antagonists
Cardiac glycosides
Vasodilator agents (nitrates/hydralazine)
Positive inotropic agents
Anticoagulation
Antiarrhythmic agents
Oxygen
Devices and surgery
Revascularization (catheter interventions and surgery), other forms of surgery
Pacemakers
Implantable cardioverter defibrillators (ICD)
Heart transplantation, ventricular assist devices, artificial heart
Ultrafiltration, haemodialysis
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
PHARMACOLOGIC THERAPY
Improved Decreased Prevention Neurohumoral
Control
symptoms mortality
of CHF
DIURETICS
yes
?
?
NO
DIGOXIN
yes
=
minimal
yes
INOTROPES
yes
?
no
Vasodil.(Nitrates)
yes
yes
?
no
yes
YES
yes
YES
yes
+/-
?
YES
ACEI
Other neurohormonal
control drugs
mort.
TREATMENT
Normal
Asymptomatic
LV dysfunction
EF <40%
Symptomatic CHF
ACEI
NYHA II Symptomatic CHF
NYHA - III
Diuretics mild
Neurohormonal
Symptomatic CHF
Loop
inhibitors
NYHA - IV
Diuretics
Digoxin?
Inotropes
Specialized therapy
Transplant
Secondary prevention
Modification of physical activity
Pharmacological therapy
Stages in the evolution of HF and recommended therapy by stage
•
•
•
•
•
•
Stage A
Stage B
Pts with :
• Hypertension
• CAD
• DM
• Cardiotoxins
• FHx CM
Pts with :
• Previous MI
• LV systolic
dysfunction
• Asymptomatic
Valvular disease
Struct.
Heart
Disease
THERAPY
Treat Hypertension
Stop smoking
Treat lipid disorders
Encourage regular
exercise
Stop alcohol
& drug use
ACE inhibition
THERAPY
• All measures under
stage A
• ACE inhibitor
• Beta-blockers
Stage C
Stage D
Pts with :
Develop
Symp.of
HF
• Struct. HD
Refract.
• Shortness of
Symp.of
breath and fatigue,
HF at rest
reduce exercise
tolerance
THERAPY
• All measures under
stage A
• Drugs for routine use:
• diuretic
• ACE inhibitor
• Beta-blockers
• digitalis
•
•
•
•
Pts who have
marked symptoms
at rest despite
maximal medical
therapy.
THERAPY
All measures under
stage A,B and C
Mechanical assist
device
Heart transplantation
Continuous IV
inotrphic infusions for
palliation
ACC/AHA Guidelines for the
Evaluation and Management of Chronic Heart Failure in the Adult 2001
1. ACE INHIBITOR
Angiotensin-converting enzyme inhibitors
Recommended as first-line therapy.
Should be uptitrated to the dosages shown to be
effective in the large, controlled trials, and not
titrated based on symptomatic improvement.
Moderate renal insufficiency and a relatively low blood
pressure (serum creatinine  250 µmol.l-1 and systolic
BP  90 mmHg) are not contraindications.
Absolute contraindications: bilateral renal artery
stenosis and angioedema.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
VASODILATORS
CLASSIFICATION
VENOUS
Nitrates
Molsidomine
Venous
Vasodilatation
MIXED
Calcium antagonists
a-adrenergic Blockers
ACEI
Angiotensin II inhibitors
K+ channel activators
Nitroprusside
Arterial
Vasodilatation
ARTERIAL
Minoxidil
Hydralazine
ACEI
MECHANISM OF ACTION
VASOCONSTRICTION
ALDOSTERONE
VASOPRESSIN
SYMPATHETIC
VASODILATATION
PROSTAGLANDINS
Kininogen
tPA
Kallikrein
Angiotensinogen
RENIN
Angiotensin I
A.C.E.
ANGIOTENSIN II
Inhibitor
BRADYKININ
Kininase II
Inactive Fragments
ACEI
HEMODYNAMIC EFFECTS
Arteriovenous Vasodilatation
-
PAD, PCWP and LVEDP
SVR and BP
CO and exercise tolerance
No change in HR / contractility
MVO2
Renal, coronary and cerebral flow
Diuresis and natriuresis
ACEI
ADVANTAGES
Inhibit LV remodeling post-MI
Modify the progression of chronic CHF
Survival
Hospitalizations
- Improve the quality of life
In contrast to others vasodilators,
do not produce neurohormonal activation
or reflex tachycardia
Tolerance to its effects does not develop
ACEI
UNDESIRABLE EFFECTS
Inherent in their mechanism of action
- Hypotension
- Hyperkalemia
- Angioneurotic edema
- Dry cough
- Renal Insuff.
Due to their chemical structure
- Cutaneous eruptions
- Neutropenia,
thrombocytopenia
- Digestive upset
- Dysgeusia
- Proteinuria
ACEI
CONTRAINDICATIONS
Renal artery stenosis
Renal insufficiency
Hyperkalemia
Arterial hypotension
Intolerance (due to side effects)
ACE-Inhibitors in Asymptomatic Heart Failure
 Development of symptomatic HF
 Hospitalization of HF
SAVE & TRACE Study
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
ACE-Inhibitors in Symptomatic Heart Failure
All patients symptomatic Heart Failure should receive ACE-I.
A) No fluid retention, ACE-I should be given first.
B) With fluid retention, ACE-I + Diuretic
ACE-I : A) improves survival and symptoms.
B) reduces hospitalization.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
ACE INHIBITORS USED TO TREAT HEART FAILURE
DRUG
DOSE RANGE
(mg)FREQUENCY
TARGET DOSE FOR
SURVIVAL BENEFIT*
Captopril
6.25 – 150
Three times daily 50 mg three times daily
Enalapril
2.5 – 20 Twice daily
10 mg twice daily
Lisinopril
2.5 – 40 Daily
Ramipril2.5 – 10 Once or twice daily 5 mg twice daily
Quinapril
5 – 20
Twice daily
Zofenopril†
30 mg twice daily
Trandolapril†
4 mg daily
Imidapril HCl 5 – 10
Once daily
10 mg daily
* Target doses are those associated with increased survival in clinical trials
† This drug is not approved in the United States
2. DIURETICS
Diuretics
Essential for symptomatic treatment when
fluid overload is present and manifest.
Always be administered in combination
with ACE inhibitors if possible.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
DIURETICS
Thiazides
Inhibit active exchange of Cl-Na
in the cortical diluting segment of the
ascending loop of Henle
Cortex
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
LOOP DIURETICS
MECHANISM OF ACTION
Excrete 15 - 20% of filtered Na+
Elimination of K+, Ca+ and Mg++
Resistance of afferent arterioles
-
Cortical flow and GFR
-
Release renal PGs
-
NSAIDs may antagonize diuresis
K-SPARING DIURETICS
MECHANISM OF ACTION
Eliminate < 5% of filtered Na+
Inhibit exchange of Na+ for K+ or H+
Spironolactone = competitive
antagonist for the aldosterone receptor
Amiloride and triamterene block
Na+ channels controlled by aldosterone
DIURETIC EFFECTS
Volume and preload
Improve symptoms of congestion
No direct effect on CO, but
excessive preload reduction may
Improves arterial distensibility
Neurohormonal activation
Levels of NA, Ang II and ARP
Exception: with spironolactone
DIURETICS
ADVERSE REACTIONS
Thiazide and Loop Diuretics
Changes in electrolytes:
Volume
Na+, K+, Ca++, Mg++
metabolic alkalosis
Metabolic changes:
glycemia, uremia, gout
LDL-C and TG
Cutaneous allergic reactions
DIURETICS
ADVERSE REACTIONS
Thiazide and Loop Diuretics
Idiosyncratic effects:
Blood dyscrasia, cholestatic jaundice and
acute pancreatitis
Gastrointestinal effects
Genitourinary effects:
Impotence and menstrual cramps
Deafness, nephrotoxicity
(Loop diuretics)
DIURETICS
ADVERSE REACTIONS
K-SPARING DIURETICS
Changes in electrolytes:
Na+,
K+, acidosis
Musculoskeletal:
Cramps, weakness
Cutaneous allergic reactions :
Rash, pruritis
3. ALDOSTERONE
INHIBITORS
ALDOSTERONE INHIBITORS
Spironolactone
ALDOSTERONE
Competitive antagonist of the
aldosterone receptor
(myocardium, arterial walls, kidney)
Retention Na+
Retention H2O
Edema
Excretion K+
Arrhythmias
Excretion Mg2+
Collagen
deposition
Fibrosis
- myocardium
- vessels
ALDOSTERONE INHIBITORS
INDICATIONS
FOR DIURETIC EFFECT
• Pulmonary congestion (dyspnea)
• Systemic congestion (edema)
FOR ELECTROLYTE EFFECTS
• Hypo K+, Hypo Mg+
• Arrhythmias
• Better than K+ supplements
FOR NEUROHORMONAL EFFECTS
• Please see RALES results,
N Engl J Med 1999:341:709-717
Aldosterone receptor antagonists - spironolactone
Recommended in advanced HF (NYHA III-IV),
in addition to ACE inhibition and diuretics to
improve survival and morbidity
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
Aldosterone receptor antagonists - spironolactone
The RALES mortality trial
Low dose spironolactone (12.5–50 mg) on top
of an ACE inhibitor and a loop diuretic 
improved survival of patients in advanced
heart failure (NYHA class III or IV).
4. ß-Blockers
Start Low Go Slow
Activation and Blockade of Neurohumoral
System in CHF
RAA System
SNS System
Angiotensin II
Noradrenalin
ACE-I
β-Blocker
Hypertrophy, apoptosis, ischaemia,
arrhytmia, remodeling, fibrosis
ADRENERGIC ACTIVATION
↑ CNS Sympathetic
Outflow
↑ Sympathetic
activity to kidneys
& blood vessels
↑ Cardiac
Sympathetic activity
β1-receptors
β2-receptors
a1-receptors
Mycocyte hypertrophy & death,
dilatation, ischaemia & arrhytmia’s
Vasoconstriction
Sodium Retention
Packer, AHA 2000
Why add-on β-blocker,
if HF patient is already stable
on standard therapy with
ACE-I, diuretics ± digoxin
?
Benefits of “Add-on” β-Blocker
Short-term :
1. Improvement of symptoms (LVEF ↑)
2. Improvement of NYHA class
3. Improvement of daily activities
4. Reduction of hospitalization rate & length of
hospital stay (financial & psychological burden)
Long-term :
1. Slowing the progression of CHF
2. Increase of survival rate
Beta-adrenoceptor antagonists
Recommended for the treatment of all pts
with stable, mild, moderate and severe heart
failure on standard treatment, unless there is
a contraindication.
Patients with LV systolic dysfunction, with or
without symptomatic HF, following an AMI
long-term betablockade is recommended
in addition to ACE inhibitor.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
PHARMACOLOGICAL PROPERTIES OF
β-BLOCKING AGENT FOR HF
a-
β1BLOKADE
β2BLOKADE
BLOKADE
ISA
ANCILLARY
EFFECTS
Carvedilol
+++
+++
+++
-
+++
Metoprolol
+++
-
-
-
-
Bisoprolol
+++
-
-
-
-
AGENT
ISA: intrinsic sympathetic activity
THE RECOMMENDED PROCEDURE FOR
STARTING β-BLOCKER
1. Patient should be on standard therapy
(ACE inhibitor +/- diuretic)
2. Patient in stable conditions
 No iv inotropic therapy
 Without signs of marked fluid retention
3. Start initial low doses and titrate to maintenance dose
(the dose may be doubled every 1 – 2 weeks)
(ESC.Guidelines for HF, 2001)
DOSES OF β-BLOCKER
β BLOCKER
FIRST DOSE
TARGET DOSE
TITRATION
PERIOD
Bisoprolol
1.25 mg
10 mg
Weeks – Month
Metoprolol
Tartrate
5 mg
150 mg
Weeks – Month
Metoprolol
Succinate
12.5 mg
200 mg
Weeks – Month
Carvedilol
2 x 3.125 mg
2 x 25 mg
Weeks – Month
(European Heart Journal, vol. 22, Sept. 2001)
CONTRAINDICATIONS OF
β-BLOCKER IN PATIENT H F
 Asthma Bronchial
 Severe Bronchial Desease
 Symptomatic Bradycardia and
Hypotension
INTOLERANCE OF β-BLOCKER
Symptomatic
Bradycardia
Worsening HF
Hypotension
How to Handle Intolerance
SYMPTOMATIC BRADYCARDIA
Check Blood Digoxin and/or reduce
other AV nodus inhibiting drugs
Reduces β-Blocker dose
or if necessary stop it
Consider implantation of
pacemaker
How to Handle Intolerance
WORSENING HF
Increase dose of Diuretics
Reduces β-Blocker dose
or if necessary stop it
If indicated, give inotropic drugs or
nitroprusside or nitroglycerin
How to Handle Intolerance
HYPOTENSION
Reduces ACE-I or
vasodilator
 Take β-Blocker :
 After meal
 At different time than ACE-I
 Reduces dose or if necessary stop it
5. Angiotensin II receptor
antagonists
ANGIOTENSIN II INHIBITORS
MECHANISM OF ACTION
RENIN
Angiotensinogen
Other paths
AT1
RECEPTOR
BLOCKERS
AT1
Vasoconstriction
Angiotensin I
ACE
ANGIOTENSIN II
RECEPTORS
Proliferative
Action
AT2
Vasodilatation
Antiproliferative
Action
AT1 RECEPTOR BLOCKERS
DRUGS
Losartan
Valsartan
Irbersartan
Candesartan
Competitive and selective
blocking of AT1 receptors
Angiotensin II receptor antagonists
ARBs could be considered in patients who do not
tolerate ACE inhibitors for symptomatic
treatment.
It is unclear whether ARBs are as effective as
ACE inhibitors for mortality reduction.
In combination with ACE inhibition, ARBs may
improve heart failure symptoms and reduce
hospitalizations for worsening heart failure.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
6. Cardiac glycosides
DIGOXIN
Na-K ATPase
Na+
K+
K+ Na+
Na-Ca Exchange
Na+
Myofilaments
Ca++
Ca++
CONTRACTILITY
DIGOXIN
PHARMACOKINETIC PROPERTIES
Oral absorption (%)
Protein binding (%)
Volume of distribution (l/Kg)
Half life
Elimination
Onset (min)
i.v.
oral
Maximal effect (h)
i.v.
oral
Duration
Therapeutic level (ng/ml)
60 - 75
25
6 (3-9)
36 (26-46) h
Renal
5 - 30
30 - 90
2-4
3-6
2 - 6 days
0.5 - 2
DIGOXIN
DIGITALIZATION STRATEGIES
Loading dose (mg)
i.v
0.5 + 0.25 / 4 h
ILD: 0.75-1
oral 12-24 h
oral 2-5 d
0.75 + 0.25 / 6 h 0.25 / 6-12 h
1.25-1.5
1.5-1.75
Maintenance
Dose
(mg)
0.125-0.5 / d
0.25 / d
ILD = average INITIAL dose required for
digoxin loading
DIGOXIN
HEMODYNAMIC EFFECTS
Cardiac output
LV ejection fraction
LVEDP
Exercise tolerance
Natriuresis
Neurohormonal activation
DIGOXIN
NEUROHORMONAL EFFECTS
Plasma Noradrenaline
Peripheral nervous system activity
RAAS activity
Vagal tone
Normalizes arterial baroreceptors
DIGOXIN
EFFECT ON CHF PROGRESSION
30
Placebo n=93
DIGOXIN
Withdrawal
%
WORSENING
OF CHF
20
p = 0.001
DIGOXIN: 0.125 - 0.5 mg /d
(0.7 - 2.0 ng/ml)
10
EF < 35%
Class I-III (digoxin+diuretic+ACEI)
Also significantly decreased exercise
time and LVEF.
0
RADIANCE
N Engl J Med 1993;329:1
DIGOXIN n=85
0
20
40
60
Days
80 100
DIGOXIN
LONG TERM EFFECTS
Survival similar to placebo
Fewer hospital admissions
More serious arrhythmias
More myocardial infarctions
DIGOXIN
CLINICAL USES
AF with rapid ventricular response
CHF refractory to other drugs
Other indications?
Can be combined with other drugs
DIGOXIN
CONTRAINDICATIONS
ABSOLUTE:
- Digoxin toxicity
RELATIVE
- Advanced A-V block without pacemaker
- Bradycardia or sick sinus without PM
- PVC’s and TV
- Marked hypokalemia
- W-P-W with atrial fibrillation
DIGOXIN TOXICITY
CARDIAC MANIFESTATIONS
ARRHYTHMIAS :
- Ventricular (PVCs, TV, VF)
- Supraventricular (PACs, SVT)
BLOCKS:
- S-A and A-V blocks
CHF EXACERBATION
DIGOXIN TOXICITY
EXTRACARDIAC MANIFESTATIONS
GASTROINTESTINAL:
- Nausea, vomiting, diarrhea
NERVOUS:
- Depression, disorientation, paresthesias
VISUAL:
- Blurred vision, scotomas and yellow-green
vision
HYPERESTROGENISM:
- Gynecomastia, galactorrhea
Cardiac glycosides
indicated in atrial fibrillation and any degree of
symptomatic heart failure.
A combination of digoxin and beta-blockade
appears superior than either agent alone.
In sinus rhythm, digoxin is recommended to
improve the clinical status of patients with
persisting heart failure despite ACE inhibitor and
diuretic treatment.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
Cardiac glycosides
DIG trial
Long-term digoxin did not improve survival.
The primary benefit and indication for digoxin
in heart failure is to reduce symptoms and
improve clinical status  decrease the risk of
hospitalization for heart failure without an
impact on survival.
7. Vasodilator agents
Vasodilator agents in chronic heart failure
No specific role for vasodilators in the treatment of HF
Used as adjunctive therapy for angina or concomitant
hypertension.
In case of intolerance to ACE inhibitors ARBs are
preferred to the combination hydralazine–nitrates.
HYDRALAZINE-ISOSORBIDE DINITRATE
Hydralazine (up to 300 mg) in combination with ISDN (up to 160
mg) without ACE inhibition may have some beneficial effect on
mortality, but not on hospitalization for HF.
Nitrates may be used for the treatment of concomitant angina or
relief of acute dyspnoea.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
8. Positive inotropic therapy
POSITIVE INOTROPES
CARDIAC GLYCOSIDES
SYMPATHOMIMETICS
Catecholamines
ß-adrenergic agonists
PHOSPHODIESTERASE INHIBITORS
Amrinone
Enoximone
Others
Milrinone
Piroximone
ß-ADRENERGIC STIMULANTS
CLASSIFICATION
B1 Stimulants
Increase contractility
Dobutamine Doxaminol Xamoterol
Butopamine Prenalterol Tazolol
B2 Stimulants
Produce arterial vasodilatation and reduce SVR
Pirbuterol Rimiterol Tretoquinol Terbutaline Soterenol
CarbuterolFenoterol Salbutamol SalmefamolQuinterenol
Mixed
Dopamine
DOPAMINE AND DOBUTAMINE
EFFECTS
DA (µg / Kg / min)
Dobutamine
<2
DA1 / DA2
2-5
ß1
>5
ß1 + a
ß1
Contractility
±
++
++
++
Heart Rate
±
+
++
±
Arterial Press.
±
+
++
++
++
+
±
+
-
±
++
±
Receptors
Renal perfusion
Arrhythmia
POSITIVE INOTROPES
CONCLUSIONS
May increase mortality
Safer in lower doses
Use only in refractory CHF
NOT for use as chronic therapy
Positive inotropic therapy
Commonly used to limit severe episodes of
HF or as a bridge to heart transplantation
in end-stage HF.
Repeated or prolonged treatment with oral
inotropic agents increases mortality.
Currently, insuffcient data are available to
recommend dopaminergic agents for heart
failure treatment.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
Positive inotropic therapy
POSITIVE INOTROPHIC AGENTS
Dobutamin
Milrinone
Levosimendan
DOPAMINERGIC AGENTS
Ibopamine is not recommended for the treatment of
chronic HF due to systolic LV dysfunction.
Intravenous dopamine is used for the sort-term
correction of haemodynamic disturbances of severe
episodes of worsening HF.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
9. Antiarrhythmics
ANTIARRHYTHMICS
Sustained VT, with/without symptoms
- ß Blockers
- Amiodarone
Sudden death from VF
- Consider
implantable
defibrillator
ANTIARRHYTHMICS
MORTALITY
15
13.6
ns
13.7
MORTALITY
AT 2 YEARS
10
%
n=1486
5-21d post MI
Amiodarone
5
200 mg/d
Follow up 1 - 4 years
EMIAT
Am Coll Cardiol 1996
0
101 / 743
102 / 743
Placebo
Amiodarone
Antiarrhythmics
No indication for the use of antiarrhythmic agents in HF
Indications for antiarrhythmic drug therapy include AF
(rarely flutter), non-sustained or sustained VT.
CLASS I ANTIARRHYTHMICS
should be avoided
CLASS II ANTIARRHYTHMICS
Beta-blockers reduce sudden death in heart failure
CLASS III ANTIARRHYTHMICS
Amiodarone is the only antiarrhythmic drug without
clinically relevant negative inotropic effects.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
10. Anticoagulation
11. Antiplatelet Drugs
ANTICOAGULANTS
PREVIOUS EMBOLIC EPISODE
ATRIAL FIBRILLATION
Identified thrombus
LV Aneurysm (3-6 mo post MI)
Class III-IV in the presence of:
- EF < 30
- Aneurysm or very dilated LV
Phlebitis
Prolonged bed rest
Anticoagulation
Recommendation
1. All pts with HF and AF should be treated with
warfarin unless contraindicated.
2. Patients with LVEF 35% or less.
HFSA Guidelines for Management of Patients With Heart Failure Caused by Left
Ventricular Systolic Dysfunction - Pharmacological Approaches 2000
Antiplatelet Drugs
Recommendation
There is insufficient evidence concerning the
potential negative therapeutic interaction
between ASA and ACE inhibitors.
Antiplatelet agent for pts with HF who have
underlying CAD.
HFSA Guidelines for Management of Patients With Heart Failure Caused by Left
Ventricular Systolic Dysfunction - Pharmacological Approaches 2000
A
Chronic heart failure — choice of
pharmacological therapy
LV systolic dysfunction
ACE inhibitor
Diuretic
Beta-blocker
Aldosterone
Antagonist
Asymptomatic LV
dysfunction
Indicated
Not indicated
Post MI
Not indicated
Symptomatic HF (NYHA II)
Indicated
Indicated if
Fluid retention
Indicated
Not indicated
Worsening HF (NYHA III-IV)
Indicated
Indicated
comb. diuretic
Indicated
End-stage HF (NYHA IV)
Indicated
Indicated
comb. diuretic
Indicated
Indicated
Indicated
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
B
Chronic heart failure — choice of
pharmacological therapy
LV systolic dysfunction
Angiotensin
II receptor
antagonists
Asymptomatic LV
dysfunction
Not indicated
Symptomatic HF (NYHA II)
Worsening HF (NYHA III-IV)
End-stage HF (NYHA IV)
Vasodilator
(hydralazine/ Potassium -sparing
Cardiac glycosides
isosorbide
diuretic
dinitrate)
With AF
Not indicated
(a) when AF
If ACE inhibitors
If ACE inhibitors
and angiotensin
are not tolerated (b) when improved
from more severe II antagonists
and not on betaare not
HF in sinus
blockade
tolerated
rhythm
If ACE inhibitors
If ACE inhibitors
and angiotensin
are not tolerated
indicated
II antagonists
and not on betaare not
blockade
tolerated
If ACE inhibitors
If ACE inhibitors
and angiotensin
are not tolerated
indicated
II antagonists
and not on betaare not
blockade
tolerated
Not indicated
If persisting
hypokalaemia
If persisting
hypokalaemia
If persisting
hypokalaemia
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
Intervention
Surgical
Revascularization
Non Surgical
Pts with heart failure of ischaemic origin revascularization 
symtomatic improvement.
A strong negative correlation of operative mortality and LVEF,
a low LVEF (<25%) was associated with increased
operative mortality. Advance HF symptoms (NYHA IV)
resulted in a greater mortality rate.
Off pump coronary revascularization may lower the surgical
risk for HF.
Heart Transplantation is an accepted mode of treatment for
end-stage HF.
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
Care and Follow-up
Recommended components of programs
use a team approach
vigilant follow-up, first follow-up within 10 days of
discharge
discharge planning
increased access to health care
optimizing medical therapy with guidelines
intense education and counselling inpatient and
outpatient
strategies address barriers to compliance
early attention to signs and symptoms
flexible diuretic regimen
Guidelines for the diagnosis and treatment of chronic heart failure
European Heart Journal (2001) 22, 1527-1560
Future treatment
Neurohormonal modulation
1.
2.
3.
4.
5.
6.
7.
Sympathetic nervous system
The RAA system
Atrial and brain natriuretic peptides
Arginin vasopressin
Endothelin
Growth hormone
Calcitonin gene related peptide
Cardiac reparation: fixing the heart
with cells, new vessels and genes (1)
Cell based
interventions
Aims: to repopulate fibrous scars with new
contractile cells
1. Multiplication of residual myocytes
(forcing the cells to enter mytotic cycle)
2. Transforming fibrablasts in the scar
3. Implanting exogenous contractiles cells
(foetal cardiomyocites, skeletal
myoblasts, stem cells)
Eur Heart J 2002;4: D73-81
CON’T (2)
Angiogenesis
Aims: to provides new blood supply to
the diseased heart
1. Administration of angiogenic growth factors
VEGF, basic FGF
2. Problems: nature of compound , dose,
route, and adverse events (abnormal blood
vessels, proliferative retinopathy, etc)
Eur Heart J 2002;4: D73-81
CON’T(3)
Gene therapy
Aims: to improve the function of the failing
heart
1. Gene manipulation of 3 majors areas: Ca
handling, beta-adenergic signalling and
apoptosis
2. Inducing expression of silent genes
Safety problems: control of targeted protein
expression, inflammation, autoimmunity
and oncogenesis (basically irreversible)
Eur Heart J 2002;4: D73-81
Resume
Pharmacological Treatment :
I.
Asymptomatic Systolic LV dysfunction :
•
•
II.
ACE Inhibitor
-Blocker (in CAD)
Symptomatic Systolic LV dysfunction
A.
No fluid retention
ACE Inhibitor
-Blocker
If ischaemia (+)  nitrate / revascularization
B.
Fluid retention
Diuretic
ACE Inhibitor (ARBs if not tolerated)
-Blocker
± Digitalis
Resume
III.
Worsening HF
Standard treatment : ACE Inhibitor, -Blocker
Diuretic : doses  + loop diuretic
Low dose spironolactone
Digitalis
Consider :
» Revascularization
» Valve surgery
» Heart transplant
IV.
End-stage HF
Intermittent inotrophic support
Circulatory support (IABP, Ventr.Assist Devices)
Haemofiltration on dialysis
 briddging to heart transplantation
Conclusion
Management of HF must be starting from
the earlier stage (AHA/ACC stage A).
Treatment at each stage can reduce
morbidity and mortality.
Before initiating therapy :
Established the correct diagnose.
Consider management outline.
Conclusion
Non pharmacolgical intervention are helpfull in :
improving quality of life
reducing readmission
lowering cost.
Organize multi-disciplinary care :
HF clinic, HF nurse specialist, pts telemonitoring.
Health care system.
To optimize HF management
Treatment should be according to the Guidelines,
intensive education, and behavioral change efforts.
THANK YOU
Have a nice study !!!