Transcript Systolic heart failure

Heart Failure
Learning Objectives
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Discuss the definition
Discuss the etiology
Discuss the classification
Discuss main mechanisms
Discuss the response of body to heart failure
Discuss the clinical manifestations
Discuss the treat principles
Introduction
Determinants of cardiac function
contractility
preload
afterload
Stroke Volume
Heart rate
Cardiac output
Definition
Heart failure is the inability
of the heart to supply
adequate blood flow and
generate a cardiac output
sufficient to meet the
metabolic demands of the
body .
Shock
Pericarditis
Prevalence
1996 WHO survey:
Incidence rate 1.9% men>women
2-year mortality rate 37%
6-year mortality rate 82%
American:
2 to 3 million
400,000 new cases
Etiology
direct impairment of myocardial
contractility and diastolic
function
ischemic heart disease,
myocarditis, cardiomyopathy
Primary myocardial
dysfunction
Ventricular
overload
result of excess pressure,
volume or high-output states
hypertension, aortic stenosis, pulmonary embolism
aortic or mitral regurgitation
thyrotoxicosis, anemia, pregnancy or infection
Predisposing cause
Systemic Infection
Acid-base & Electrolyte Disturbance
Arrhythmia
Pregnancy & Labour
Classification
Degree of cardiac function
Low vs High Output
Left vs Right Ventricular
Systolic vs Diastolic
NYHA Classification
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary
physical activity does not cause undue fatigue,
palpitation, or dyspnea (shortness of breath).
Class II (Mild) Slight limitation of physical activity. Comfortable
at rest, but ordinary physical activity results in
fatigue, palpitation, or dyspnea.
Class III
Marked limitation of physical activity.
(Moderate)
Comfortable at rest, but less than ordinary activity
causes fatigue, palpitation, or dyspnea.
Class IV
(Severe)
Unable to carry out any physical activity without
discomfort. Symptoms of cardiac insufficiency at
rest. If any physical activity is undertaken,
discomfort is increased.
Low vs High Output
Most
CO<4 L/min, cardiac index < 2.5 L/min/m2
CO may be normal at rest but may simply fail to rise
sufficiently on exertion
Abnormally elevated demands
cardiac output may be within normal range or even
elevated, such as hyperthyroidism, anemia, Paget's
disease, AV fistula or beriberi.
Part initially involved in the pathological changes
In the early stages Left ventricular
right ventricular
pulmonary congestion
fluid build-up in the veins
shortness of breath, fatigue and swelling in the legs
and coughing
and ankles
As heart failure progresses
both ventricles failure
whole heart failure
Rheumatic myocarditis
Very serious anemia
Systolic heart failureInability of the heart to contract with enough force to
pump adequate amounts of blood through the body.
Diastolic heart failureInability of the heart to relax properly and fill with
blood as a result of stiffening of the heart muscle.
Cardiac Muscle
Molecular Basis of Contraction
Mechanisms for heart failure
•Weaken of contractility
•Abnormity of diastolic properties
of ventricle
•Asynergia of ventricular
contraction and relaxation
weaken of contractility
Force
Velocity
Weaken of cardiac contractility
(1) Damage of myocardial cells
(2) Myocardial metabolic dysfunction
(3) Dysfunction of EC coupling
(4) Hypertrophy
 Necrosis
Cell swells and ruptures.
Cell contents spill out.
Myocardial ischemia
Hypoxia
Virus or bacterial infection
Atherosclerosis of the
larger coronary arteries
Myocardial Infarction
• It once was thought that most heart attacks were
caused from the closure of an artery.
• It is now clear that this process can occur in even
minor blockages.
• There is rupture of the cholesterol plaque .
• The heart muscle that is injured in this way can cause
irregular rhythms that can be fatal, even when there
is enough muscle left to pump plenty of blood.
The relationship between ventricular
dysfunction and prognosis
Myocardial
infarcted size
5-10%
10-20%
20-40%
>40%
Cardiac
index
Mortality
Normal
2%
Slightly decreased 10%
Decreased
22%
Markedly decreased 60%
 Apoptosis
•Active
•Signal-dependent
•Gene-directed
•Energy-requiring
Cellular self-destruction process
DNA 'ladder'
Detection of DNA
fragmentation
Apoptosis index 35.5%
More and more studies have proposed that
apoptosis has been shown to contribute to loss
of
cardiomyocytes
in
cardiomyopathy,
progressive decline in ventricular function, and
congestive heart failure.
Mechanisms
Oxidative stress
Cytokines
Imbalance in cellular calcium
Dysfunction of mitochondria
liberation
storing
utilization
Actinmyosine
citric acid
α-ketoglutaric acid
acetyl
oxaloacetic acid
succinic acid
Free Ca2+
Combined Ca2+
H2 O
Energy metabolism of cardiac myocyte
pump
 Disorders in liberation of energy
Occurs in ischemic heart disease, shock,
severe anemia and hypoxia.
The reduced contractility is mainly because
of the decreased level of ATP.
• Mechanical energy decrease
• Calcium
imbalance in the head of myosin hydrolyzes
The actomyosin-ATPase
ATP and
generates
energy
needed
by
filaments
sliding.
Normal
transport
and
distribution
of
calcium
depend
on the
• mitochondria Dysfunction
channel andthere
calcium
When ATP level decreased,
is notpump
enough substrate for
• Protein
synthesis
decrease for contraction is reduced.
ATPase
so
the
mechanical
The pump
needs
energy toenergy
transport calcium out of the cell
against the concentration gradient.
The calcium overload will directly lead contracture and
rupture of myocardium and so damage the contractility.
 Disorders in utilization of energy
Key problem is how much the efficiency of
actomyosin-ATPase is.
This enzyme reduces its activity in heart failure.
Myosin isozyme V3 is increased especially during
hypertrophy.
 Excitation-contraction coupling
Intracellular calcium concentrations of cardiac
muscle cells range from 10-7 to 10-5 M.
Extracellular concentration of calcium is about
2 × 10-3M.
There is a chemical gradient for calcium to diffuse
into the cell.
Because cells have a negative resting membrane
potential , there is also an electrical force driving
calcium into the cell.
 Dysfunction of excitation-contraction coupling
The change of intracellular calcium concentration
and the reaction of contractile protein to this
change determine Calcium
the contractility
of cardiac
influx
myocyte.
Dysfunction of
Calcium handling by SR
Ca2+ binding to troponin
How is the process of calcium influx changed
in heart failure?
Two main pathways
Calcium channel
Na+-Ca2+ exchanger
Calcium
Channel
What happened to the channel in heart failure?
• The density of beta-adrenoceptor is relatively
decreased. Generation of norepinephrine is decreased
while consuming is fasted.
• Acidosis caused by hypoxia or ischemia will blunt the
sensitivity of myocyte to beta-adrenoceptor.
• Hyperkalemia will inhibit the calcium influx because
extracellular potassium and calcium compete with
each other in entry into cells.
Na+-Ca2+exchanger
Molecular Components:
•Electrogenic exchange of 3Na for 1Ca
•Forward mode = Ca removal, inward current
•Reverse mode = Ca influx, outward current
•Modulated by Ca, PIP2, ATP
•Three isoforms (NCX1, NCX2, NCX3) + splice
variant n 970 AAs, ~120kD
Increased expression and function of the exchanger in
human heart failure as well as in animal models.
This increase is the consequence of defective SR Ca2+
uptake and depends on [Ca2+]i in the failing heart.
It may play a key role for altered contractile function
and arrhythmogenesis in hypertrophy and heart failure.
Cardiovascular Research
Volume: 57, Issue: 4
March 15, 2003
 Dysfunction of excitation-contraction coupling
Calcium influx
Dysfunction of
Calcium handling by SR
Ca2+ binding to Troponin
 Handling of calcium by SR
Release
M
SR
Re-uptake
Storing
ATP-dependent pump
Phospholamban
In heart failure
•Expression of pump
•Beta-adrenoceptor activation
•ATP supply
Ryanodine receptor
Ca2+-induced Ca 2+ release
•SR Ca2+ content decrease
•mRNA and protein level are both found to reduce in
heart failure
•Hydrogen increases affinity of calcium and its binding
protein, so the calcium is difficult to be released.
Concentration of cytosolic calcium
Normal affinity of troponin to calcium
 Dysfunction of excitation-contraction coupling
Calcium influx
Dysfunction of
Handling the calcium by SR
Ca2+ binding to troponin
How does the myocyte maintain the calcium homeostasis?
1. Ca2+ entry via L-type Ca2+ channels.
2. Ca2+-induced-Ca2+-release (CICR) from SR through
Ryanodine receptors.
3. Reuptakeinto SR via ATPdependent pump (stimulated
by phosphorylation of phospholamban). Bound in the
SR to calsequestrin
4. Extrusion from the myocyte
• – Na+/Ca2+ exchange 3:1
• Ca2+ pump of sarcolemma
Diastolic properties of ventricle
―Myocardial relaxation is an active process, not merely
an intermittent rest period between systolic periods.
―Up to 15% of myocardial energy may be expended for that
relaxation.
―Diastolic stage is important to blood supply for heart itself
and it is also necessary for the venous return.
Abnormity of diastolic properties of ventricle
(1) Delayed calcium decrease
(2) Impaired dissociation of the actin-myosin complex
(3) Decreased diastolic potential energy of ventricles
(4) Reduced compliance of myocardium
 Delayed calcium decrease
•After each systole, the concentration of myoplasmic Ca2+
need to decrease from 10-5mol/L to 10-7mol/L, allowing
decoupling of the actin-myosin cross-bridges.
•Without adequate ATP seen in myocardial ischemia and
severe anemia, Ca2+ is delayed uptaked by sarcoplasmic
reticulum and delayed efflux from the myocyte.
•Thus, Ca 2+ still combines with troponin and myocardium
can not relax fully.
 Impaired dissociation of the actin-myosin
•Myocardial relaxation is not a passive, but rather is an energyrequiring activity.
•ATP is needed for the actin-myosin complex to dissociate, so
inadequate ATP supply may lead to impairment of actin-myosin
decoupling.
•Obviously, any pathologic factor with disorders in energy
metabolism may result in heart failure through diastolic
dysfunction.
 Decreased diastolic potential energy of ventricles
•Early diastolic recoil of the ventricular walls in conjunction
with release of elastic potential energy stored during systole
deformation, generating suction and thus contributing to
diastolic filling.
•Many pathologic factors accounted for depressed myocardial
contractility may lead a limited loading of ventricle as well as
diastolic potential energy.
•In addition, ventricular relaxation may be depressed when
coronary blood flow reduces due to coronary artery disease,
systemic hypertension, and cardiomyopathy.
 Reduced compliance of myocardium
The ability of a blood vessel or a cardiac chamber to
change its volume in response to changes in pressure has
important physiological implications.
C=
V/
P
Compliance is determined by :
1. Physical properties of the tissues making up
the ventricular wall
2. State of ventricular relaxation
ventricular hypertrophy
low cardiac output,
pulmonary venous
hypertension, and
pulmonary edema.
Asynergia of ventricular contraction and relaxation
The heart cannot contract simultaneously.
Hypokinesis (impaired wall with diminished or
absent contraction);
Dyskinesis ( impaired wall demonstrating
paradoxical outward motion during systole);
Contraction asynchronism or dysynchrony.
Dysynchrony occurs when the electrical
impulses that coordinate the ventricles misfire
such as arrhythmia, so that the different parts of
the heart cannot contract at the same time.
1.
2.
3.
4.
Reduces the forward flow of blood through the heart
Abnormal interventricular septal wall motion
Reduced diastolic filling time
Prolonged mitral regurgitation duration
Normal
Dyskinesis
Hypokinesis
Dysynchrony
The Progressive Development of
Cardiovascular Disease
This progression of heart failure follows the
developmental rule which is from slight to severe,
from compensation to decompensation.
The reactions to the initiating event, such as
increased preload, afterload, do not change
through the whole period from early stage to late
stage.
vasoconstriction
Response of the body
Cardiac compensation
Systemic compensation
Neurohormonal compensation
Cardiac compensation
Increase of heart rate
Expansion of the heart
Hypertrophy
 Expansion of the heart
When venous return is increased to the heart or heart
can not eject enough blood to artery, ventricular filling
and preload increase.
This stretching of the myocytes causes an increase in
force generation which enables the heart to eject the
additional venous return, thereby increasing SV.
Frank-Starling Law of the Heart
Cardiac Output increases as LV
End-Diastolic Volume increases
What is the basis for this mechanism?
1.Length-tension relationships for cardiac myocytes.
2.Length-dependent activation
Systemic compensation
Increase in blood volume
Redistribution of blood flow
Increase of erythrocyte
Increased ability of tissues to utilize oxygen
Neurohormonal compensation
Arterial baroreceptors
Cardiopulmonary baroreceptors
Sympathetic nerves
Renin-angiotensin system
Antidiuretic hormone
Atrial natriuretic peptide
Arterial constriction
Venous constriction
Increased blood volume
Maintain arterial pressure
Increased venous pressure
Catecholamines
Down regulation of adrenergic R
Vasoconstriction of p eripheral vasculature
RAS system
Retains Na/water,↑ preload
Stimulates fibrosis
Potent vasoconstrictor ,↑ afterload
Antidiuretic hormone
Water retention
Vasoconstriction
Endothelin – 1
Vasoconstriction
Stimluates cardiac
fibrosis
 Deleterious effects
Overload of heart
Oxygen consuming increase
Arrhythmia
Injury by cytokines
Myocardial remodeling
Retention of water and sodium
Myocardial remodeling
-Changes in shape and size of the chamber
involves changes in the structure, function, and
gene expression of the myocardial cell
Processes Occurring in ventricular remodeling
•Cardiomyocyte lengthening
•Ventricular wall stress increases
•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
•Excessive accumulation of collagen in interstitium
•Gene makeup
Why ventricular remodeling occurs?
Hemodynamic
Sympathetic nervous system
Hormonal alterations
Beta blockers and ACEI have a direct
antagonistic effect on the remodeling process.
The heart is composed of
Cardiac myocytes
Nonmyocyte cells
Extracellular matrix
ECM is defined as a network surrounding and
supporting the cells which make up the myocardium.
Structural proteins
collagen types I and III and elastin
laminin, fibronectin and
Adhesive proteins
collagen types IV and VI
Anti-adhesive proteins tenascin, thrombospondin and
osteopontin
Enzymes
metalloproteinases
The main consequences of fibrosis:
– Reduction in the early filling of the ventricle
– Systolic function is altered by both the alterations in
the ventricular filling and by fibrosis disturbing
the mechanical coupling between the sarcomeres
– fibrosis causes myocardial electrical dysfunction
and leads to the occurrence of ventricular arrhythmias
Matrix metalloproteinases
Responsible for extracellular collagen degradation and
remodeling is the matrix metalloproteinases.
MMP has high selectivity and affinity for components
of the extracellular matrix.
MMP activity is inhibited in progressive chronic heart
failure. This inhibition leads to the collagen
aggradations in the cell.
 Hypertrophy
It means the enlargement or overgrowth of heart
due to an increase in size of its constituent cells.
Depending on the type of hemodynamic load producing the
failure, sarcomeres develop either in parallel or in series.
overload
chamber radius
wall thickness
Concentric hypertrophy
Eccentric hypertrophy
Mechanisms underlying the induction of myocardial
hypertrophy in response to haemodynamic stress
What is the effect of hypertrophy?
-Physiological
-Increase the contractile force of heart
-Reduce ventricular wall tension towards normal and
then reduce oxygen consuming of heart
-Pathological
Associated with a high risk of cardiac mortality
How hypertrophy turns into decompensation?
Intrinsic defect
Change of phenotype
Remodeling of extracellular matrix
Lopsided growth
Clinical Manifestations
Pulmonary edema
Dyspnea
Congestion of Pulmonary Circulation
Congestion of Systemic Circulation
venous congestion
Edema
Hepatomegaly
Low Cardiac Output state
Paleness
Fatigue
limb weakness
urine reduces
shock
 Pulmonary edema
Pulmonary edema is a condition associated
with increased loss of fluid from the
pulmonary capillaries into the pulmonary
interstitium and alveoli.
Plasma oncotic pressure higher
than pulmonary capillary
pressure
Connective tissue and cellular
barriers are relatively
impermeable to plasma proteins
Extensive lymphatic system
 Dyspnea
Exertional dyspnea
Orthopnea
Paroxysmal nocturnal dyspnea
Paroxysmal nocturnal dyspnea is a sudden
onset of severe shortness of breath and
coughing, awakening the patient.
1 Depression of respiratory center during sleep
2 Decrease of ventricular function due to decreased
sympathetic tone
3 Redistribution of fluid to the chest
Cardiac asthma is characterized by wheezing due to
bronchospasm.
Treatment principles
1. Treating the primary disease
2. Improve Cardiac Function
3. Physical and emotional rest
4. Dietary fluid and sodium restrictions
5. Heart transplant
6. Surgical procedure
Cardiomyoplasty technique: the left latissimus dorsi muscle
(LDM) is transposed into the chest through a window created by
resecting the anterior segment of the 2nd rib (5 cm). The LDM is
then wrapped arround both ventricles. Sensing and pacing
electrodes are connected to an implantable cardiomyostimulator.
Left Ventricular Volume Reduction Surgery
—The surgery involves resecting a wedge- shaped portion
of heart muscle extending from the left ventricular apex
to the base of the mitral valve.
—The heart muscle between the heads of the papillary
muscle is removed so that the mitral valve is preserved
and the wound subsequently sutured.
—The procedure may be combined with valve repair of
replacement if these valves are incompetent.
—The basic concept is the heart improves because its wall
tension is improved .
Patients with heart failure also should:
Control their weight;
Watch what they eat;
Not smoke cigarettes or use other tobacco products;
Abstain from or strictly limit alcohol consumption
Modest exercise
Thank you very much!