Download Pathogenesis of heart failure

Heart Failure
Department of Pathophysiology
Zhang Xiao-ming
Clinical example
病史：患者，女，40岁，风湿性心脏病
史10余年。近3月来出现劳累后心慌、
闷气，伴浮肿、腹胀，不能平卧。
体查：重病容, 半坐卧位, 颈静脉怒张, 呼
吸36次/分, 两肺底可闻湿性罗音。心界
向左右两侧扩大, 心率130次/分, 血压
(110/80mmHg) 。
心尖部可闻IV级收缩期吹风样及舒张期
雷鸣样杂音。肝脏在右肋下6cm可触及，
有压痛，腹部有移动性浊音，骶部及下
肢明显凹陷性水肿。
1. Basic Concepts
2. Causes
3. Classification of heart failure
4. Pathogenesis of heart failure
5. Compensatory mechanisms in heart
failure
6. Functional and metabolic alterations
7. Treatment principles
1. Basic Concepts
(1) Heart failure
(2) Cardiac insufficiency
(3) Congestive heart failure
Heart failure is the pathological process
in which the systolic or/and diastolic
function of the heart is impaired, and as a
result, cardiac output decreases and is
unable to meet the metabolic demands of
the body.
(2) cardiac insufficiency include
compensatory stage and decompensatory
stage.
(3) Congestive heart failure is a kind
of chronic HF with expansion of blood
volume.
HF with increased volume and fluid
accumulated in the lungs, abdominal
organs (especially the liver) and
peripheral tissues.
Prevalance
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
2. Causes
(1) Etiological causes
(2) The precipitating causes
Determinants of cardiac function
contractility
preload
afterload
Stroke Volume
Heart rate
Cardiac output
(1) Etiological causes
1) Dysfunction of myocardium
(A) Myocardial damage:
myocardial infarction;
Cardiomyopathy;
Myocarditis
(B) Metabolic disturbance
ischemia and hypoxia;
beriberi
2) Overload for myocardium
(A)Pressure overload (increased afterload):
(Afterload is the resistance to shortening that
the muscle must overcome during contraction.)




systemic hypertension
aortic stenosis,
pulmonary hypertension,
pulmonary artery stenosis.
Aortic semilunar valve stenosis
aortic narrow
Pulmonary semilunar valve stenosis
pulmonary artery stenosis
(B) Volume overload (increased
preload):
Preload is the stretch exerted on the
muscle in the resting state. (diastolic phase.)
Reasons of increased
volume overload for
left ventricle:
(a) mitral regurgitation
(b) aortic regurgitation
Reasons of the volume
overload for right
ventricle:
(a) tricuspid regurgitation
(b) pulmonary regurgitation
(c) interatrial septal defect, if the direction of
blood shunt in atrial septal is from left to
right.
(d) Interventricular septal defect, if the direction
of blood shunt in interventricular septal is from
left to right.
(e) high cardiac output states secondary to
hyperthyroidism, anemia, arterivenous
fistula, and hepatic cirrhosis may also be
responsible for volume overload of the
ventricles.
(2) The precipitating causes
1) Infection
left heart failure
↓
pulmonary vascular congestion
pulmonary edema
↓
susceptible to pulmonary infection.
Infection of airway
↙
fever
↓
↓
tachycardia
↓
↑ ATP consumption
↓
need more cardiac
output
↓
↘
hypoxia
↓
↓ATP production
↓
aggravate myocardial
injury
↓
aggravate heart failure
2) Acid-Base disturbance
 Acidosis
 Hyperkalemia
3) Arrhythmias
(A) Tachycardia
tachycardia →O2 consumption ↑
↓
short diastolic phase
↙
↘
less ventricular filling
less coronary filling
↓
↓
reduced CO/stroke
reduced O2 supply to
myocardium
↓
reduced contractile
force
↙
aggravate heart failure
(B) Brachycardia
Brachycardia leads to the reduction of
CO/min.
CO/min=CO/stroke × heart rate (strokes /min)
4) Pregnancy
5) others
3. Classification of heart failure
(1) According to the course of disease
1) Acute HF
2) Chronic HF
(2)According to the severity
1) mild HF or complete compensation
2) middle HF or incomplete compensation
3) severe HF or decompensation
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.
(3)According to the cardiac output (CO)
1) Low-output HF
2) High-output HF
The cardiac output will decrease from “high
output state” , but the absolute value is still
greater than the normal value of healthy person.
正常心
输出量
正常人
低输出量
型心衰
高输出量
型心衰前
高输出量
型心衰
The situation of “high output state” occurs
in the patients with:
 hyperthyroidism,
 anemia,
 arterio-venous fistulas,
 beriberi.
(4) According to the location of heart failure
1) Left -side heart failure (LHF)
2) Right-side heart failure (RHF)
3) Biventricular failure (whole heart failure)
(5)According to the function impaired
1) systolic failure
2) Diastolic failure
Case of HF
A 60-year-old man sustained an extensive acute
myocardial infarction in left ventricle 4 years before
his recent admission. Since that time, he has
become progressively more breathless on exertion.
The questions are:
(a) What is the etiological cause?
(b) What type of HF the patient is according to the disease
process?
(c) What type of HF the patient is according to the
position of lesion?
(d) Was he the high -output HF?
(e) What type of HF the patient is according to the function
impaired?
4. Pathogenesis of heart failure
(1) Depressed myocardial contractility
(systolic phase)
(2) Altered diastolic properties of ventricles
(diastolic phase)
(3) Asymmetry and asynchronism in
ventricular contraction and relaxation
(both)
The molecular basis for myocardial
contraction:
Contraction protein:
thin filament (actin)
myofibril←sarcomere
thick filament (myosin)
regulation protein:
Tropomyosin
troponin
Cardiac Muscle
Molecular Basis of Contraction
(1) Decreased myocardial contractility
1) Myocardial cellular injuries
2) Myocardial metabolic dysfunction
3) Dysfunction of excitation-contraction
coupling
4) Excessive myocardial hypertrophy
1) Myocardial cellular injuries
morphologic changes: necrosis,
apoptosis
reasons: myocardial ischemia
(myocardial infarction)
myocarditis
cardiomyopathy
Atherosclerosis of
the larger
coronary arteries
Myocardial Infarction
The quantitative relationship
---------------------------------------------------------size of myocardial
cardiac
prognosis
infarction
output
(mortality)
----------------------------------------------------------5~10%
normal
2%
10~20%
slightly decreased
10%
20~40%
decreased
22%
>40%
markedly decreased
60%
----------------------------------------------------------
2) Myocardial metabolic dysfunction
(A) Disorders in energy production and
liberation
Deficiency of blood supply or oxygen supply
(shock, ischemic heart disease, severe anemia)
→ aerobic metabolism is impaired
→ less production of ATP.
results of the ATP decrease:
 The activity of myosin ATPase decreases
 Ca2+ transportation disturbance
 disfunction of mitochondria
 quantity of the functional proteins
decrease
(B) Disorders in energy utilization
 There are three kinds (myosin isozymes) of
ATPase:
V1(α\αpeptide chain)
V2(α\β)
V3(β\β)
 While the V3 type of myosin ATPase is increased
in hypertrophic myocardium.
3) Dysfunction of excitation-contraction
coupling
 Excitation-contraction coupling
(A) Reduced uptake, storing and release
of Ca2+ by sarcoplasmic reticulum(SR)
 Handling of calcium by SR
Release
M
SR
Re-uptake
Storing
Plays a critical role in the onset of early heart failure.
Level of SR calcium binding proteins (calsequestrin and
calreticulin) has not been changed.
uptake↓
ATP-dependent pump
Phospholamban(PLB)
In heart failure :
•Expression of PLB
•NE , Beta-adrenoceptor activation
•ATP supply
storing ↓
Level of SR calcium binding proteins
(calsequestrin and calreticulin) has not
been changed.
release ↓
Ryanodine receptor
(RyR)
Ca2+-induced Ca 2+
release
• SR Ca2+ content decrease
• RyR mRNA and protein level decrease
• in acidosis, affinity of calcium and its binding
protein increase, so the calcium is difficult to be released.
(B) Reduced influx of extracellular Ca2+
How is the process of calcium influx changed
in heart failure?
Two main pathways
Calcium channel
Na+-Ca2+ exchanger
Calcium
Channel
In failing myocardium
↓ norepinephrine (NE)
concentration
↓ β-receptor
density
↓ open of Ca2+ channel
↓ inward
movement of Ca2+
 In addition, H+ may prevent Ca2+ from moving
inward by depressing the sensitivity of beta
receptor to norepinephrine.
 K+ can also impair influx of Ca2+ by competing
effect.
(C) dysfunction of Ca2+ binding to troponin
 The quantity of myoplasmic Ca2+ is inadequate
 The combinative activity between Ca2+ and
troponin decreases
e.g. ischemia, hypoxia, acidosis
4) Excessive myocardial hypertrophy
Mechanism:
 The concentration of norepinephrine in
hypertrophic myocardium is reduced
→ myocardial contractility decreased
 The proliferation of mitochondria number can not
keep pace with the proliferation of myocardial
filaments. In addition, oxidative-phosphorylation
in mitochondria is also impaired.
→ Energy generation decreased
 The proliferation of the capillaries number can
not match with the proliferation of the
myocardial filament. In addition, oxygen
consumption of hypertrophic myocardium
increases.
→oxygen and blood supply to hypertrophic
myocardium is inadequate.
 The activity of myosin ATPase decreases
→defect in utilization of energy
 The function of calcium pump in SR is decreased
→calcium ion release reduced
→excitation-contraction coupling impaired
Summary
Decreased myocardial contractility
 1) Myocardial cellular injuries
 2) Myocardial metabolic dysfunction
 3) Dysfunction of excitation-contraction
coupling
 4) Excessive myocardial hypertrophy
(2) Altered diastolic properties of
ventricles
1) Inadequate reduction of myoplasmic
[Ca2+]
2) Impaired dissociation of the actin-myosin
complex
3) Decreased ventricular diastolic potential
4) Reduced ventricular compliance
1) Inadequate reduction of myoplasmic
[Ca2+]
When the ATP is decreased:
(a) the uptake of Ca2+ by sarcoplasmic
reticulum is reduced
(b) the outward flow of Ca2+ is reduced
2) Impaired dissociation of the actinmyosin complex
inadequate ATP supply
3) Decreased ventricular diastolic potential
4) Reduced ventricular compliance
Concept :
Ventricular
compliance indicates
the ratio of the
change in volume to
the change in
pressure
“dV/dP”.
Reasons :
myocardial hypertrophy; inflammation;
edema; fibrosis.
Effects :
 ventricular filling is reduced, the CO/stroke is
reduced.
 the myocardial tension is increased. It will
elevates the myocardial oxygen requirement;
 compresses the coronary arterioles and reduce
the blood supply to the myocardium.
(3) Asymmetry and asynchronism in
ventricular contraction and relaxation
Asymmetry means:
regional abnormal contraction;
diminished contraction ;
absent contraction.
normal
diminished
contraction
absent
contraction
Asynchronism means the contraction of
ventricle is not at the same time.
Pathogenesis of heart failure
(1) Depressed myocardial contractility
(systolic phase)
(2) Altered diastolic properties of ventricles
(diastolic phase)
(3) Asymmetry and asynchronism in
ventricular contraction and relaxation
(both)
Case of HF
A 60-year-old man sustained an
extensive acute myocardial infarction 4
years before his recent admission. Since
that time, he has become progressively
more breathless on exertion.
The question is:
what are the pathogenesis of HF in this
patient?
5. Compensatory mechanisms in
heart failure
The Progressive Development of
Cardiovascular Disease
(1) Cardiac compensation
–
–
–
increased HR and cardiac contractility
Cardiac dilatation (The Frank-Starling mechanism)
Myocardial hypertrophy
(2) Systemic compensation
–
–
–
–
Increase the blood volume
Redistribution of blood flow
Increase of erythrocytes
Increased ability of tissues to utilize oxygen
(3) neurohormonal compensation
–
–
–
Sympathetic nervous system
Renin-angiotensin system
Atrial natriuretic peptide; endothelin
(1) Cardiac compensation
1) Increased HR and cardiac contractility
mechanism: circulating catecholamines and
sympathetic tone ↑
CO/min=CO/stroke × HR (strokes /min)
When HR higher than 180/min→decompensation
2) Cardiac dilatation (The Frank-Starling
mechanism)
Normally the length of sarcomere is 1.65~ 2.25μm.
When cardiac output is reduced
↓
the end-diastolic pressure is increased
↓
the force-generating cross bridges are increased
↓
the contractility will increase
↓
the cardiac output will increasing.
If the length of sarcomere
is over 2.25 μm,
↓
the number of forcegenerating cross bridges
will decrease,
↓
the contraction force will
reduce,
↓
decompensation.
3) Myocardial hypertrophy
Types of myocardial hypertrophy
-----------------------------------------------------------------type concentric hypertrophy eccentric hypertrophy
------------------------------------------------------------------cause
pressure overload
volume overload
------------------------------------------------------------------cardiac
chamber
no
yes
dilation
-------------------------------------------------------------------pattern of
increased
in parallel.
in series
sarcomeres (stand side by side)
--------------------------------------------------------------------
离心性肥
大
向心性肥
大
压力负荷
过重
正常
容量负荷
过重
Concentric hypertrophy
Eccentric hypertrophy
Compensatory mechanism :
 overall myocardial contractility ↑
 tension↓; Oxygen consumption↓
(2) Systemic compensation
1) Increase of the blood volume
A. GFR ↓
decreased cardiac output
↓
reduced renal blood flow
↓
↓
stimulate the R-A-A system ← stimulate sympathetic system
↓
↓
GFR ↓
B. Reabsorption of water and sodium↑
 Redistribution of blood flow in kidney
 EF ↑
 R-A-A-S ↑ , ADH ↑
 PGE2 ↓, ANP ↓
2) Redistribution of blood flow
reduced cardiac output
↓
increased activity of
sympathetic nervous system
↓
increased secretion of catecholamine
↓
contraction of the renal, muscular,
skin arteries (more α-receptor)
↓
more blood supply to heart
↓
increase the contractility of myocardium
3) Increase of erythrocytes (EPO)
decreased cardiac output
↓
reduced renal blood flow
↓
Stimulate the synthesis and release of EPO
↓
Stimulate the bone marrow and regulate the
production of EPO
↓
Increases oxygen supply to the tissues
4) Increased ability of tissues to utilize
oxygen
HF → chronic hypoxia →
 The quantity of mitochondria and their surface
area ↑
 The amount and the activities of many
enzymes in the respiratory chain ↑
 phosphofructokinase is activated → anaerobic
glycolysis ↑ → ATP ↑
 myoglobin ↑ → a compensatory mechanism of
oxygen storage
(3) Neurohormonal compensation
1) sympathetic nervous system
(A) Cause :
reduced cardiac output
↓
reduced baroreceptor activity.
( in carotid sinus and aortic arch)
↓
increased sympathetic excitability
↓
increased release of catecholamine
(adrenaline + noradrenalin) from adrenal medullary
(B) Effect of increased catecholamine
(a) open the channel of Ca2+
↓
increase [Ca2+] in
myoplasm
↓
increased myocardial
contractility (the positive
inotropic effect)
↓
increased CO/ stroke.
(b) Increase the heart rate (the positive chronotropic
effect) to increase CO/min.
(c) Constrict the capacity of veins to increase the
venous return. The contractility will increase by
the Frank-Starling mechanism.
(C) Injury effect of excessive sympathetic
nervous activity
↙
↑ demand
of
. O2 of
heart
muscle
tachycardia
↓
↘
↓filling
time for
coronary
artery
↓ filling
time for
ventricles
↓CO/stroke
contraction of
blood vessel
↓
↑peripheral
resistance
↑ afterload of
ventricles
2) Renin-angiotensin system
decreased cardiac output
↓
reduced renal blood flow and GFR
↓
stimulate the R-A-A system
↓
renin↑ , AngⅡ↑, aldosterone ↑
↓
↓
GFR ↓
increased reabsorption of sodium
increased ADH release
↓
↓
increased water retention
6. Functional and metabolic
alterations in HF
 low CO → poor perfusion of organs
(forward failure)
 blood damming in the vein →
pulmonary or systemic edema
(backward failure)
(1) Congestion of pulmonary
circulation
In LHF, the left ventricular pressure ↑
→left atrium pressure ↑
→pulmonary veins, capillaries
→pulmonary congestion and pulmonary
edema
1) dyspnea
left heart failure (increased LVEDP)
increased pulmonary venous pressure
↓
pulmonary congestion and pulmonary edema
↓
increased airway
resistance
↓
decreased O2
inhalation
↓
reduced compliance
of lung
↓
more work of breathing
to distend the stiff lungs
↓
increased O2 consumption
↓
hypoxemia+ metabolic acidosis
↓
dyspnea
A. Exertional dyspnea
Concept: The patient with exertional dyspnea
has no dyspnea at rest, but will feel breathless if
he had a exercise.
Mechanism:
 the need for oxygen in exercise↑
 HR↑，diastolic phase ↓
 blood back to heart ↑, pulmonary congestion↑,
Pulmonary compliance↓
B. Orthopnea
 Orthopnea indicates
the situation that the
dyspnea will be
relieved by sitting or
standing, and will
aggravate in the
recumbent position.
.
mechanism:
 In the position of sitting, more blood stay in
lower extremities.
 In the position of sitting, the volume of the
thoracic cavity ↑
 In the recumbent position, more fluid will be
absorbed into the blood and will aggravate the
pulmonary congestion.
C. Paroxysmal nocturnal dyspnea
The patients awakens suddenly with a feeling of
extreme dyspnea, and sits upright, gasps for a
while. Then he feels better and sleep again at
night.
Mechanism:
(a)When the patient lies down at night, more
blood move back to heart. The volume load is
increased.
(b) The respiratory center is depressed at
night. It is not sensitive to the stimulation of
hypoxia, so the attack occurs suddenly.
(c) During sleeping, the sympathetic activity
is reduced, the caliber of airway reduce, the
airway resistance increase.
2) Pulmonary edema
 In LHF, CO↓, left atrial and left ventricular
end-diastolic pressure↑, the pulmonary
capillary filtration pressure ↑
 Permiability of the capillary ↑
(2) Congestion of systemic circulation
 In RHF,
the right atrial pressure ↑
→systemic veins
→systemic congestion
Manifestation:
 Engorgement of neck veins
 Congestion of liver
 edema
(3) Decreased cardiac output (CO)
Manifestation:
– Pale or cyanosis
– Fatigue and limb weakness
– mental confusion and disturbed behavior
(impairment of memory, anxiety, restlessness
and insomnia)
– Oliguria
– Cardiac shock
(4) Blood pressure(BP)
1) Arterial BP
 In chronic HF, BP is in normal range due to
the compensation (increased blood volume
and sympathetic excitability).
 In acute HF, BP is decreased due to low
cardiac output.
2) Venous BP
(A) In left HF, the pulmonary venous
pressure will increase, pulmonary congestion
and edema will occur.
(B) In right HF, the systemic venous
pressure will increase .
7. Treatment principles
(1) Correct the underlying causes of HF
(2) Improve the cardiac function
(3) Reducing afterload and preload
(4) Maintain the normal fluid volume
Clinical example
病史：患风湿性心脏病10余年。近3月来
出现劳累后心慌、闷气，伴浮肿、腹胀，
不能平卧。
体查：重病容, 半坐卧位, 颈静脉怒张, 呼
吸36次/分, 两肺底可闻湿性罗音。心界向
左右两侧扩大, 心率130次/分, 血压
(110/80mmHg) 。
心尖部可闻IV级收缩期吹风样及舒张期雷
鸣样杂音。肝脏在右肋下6cm可触及，有
压痛，腹部有移动性浊音，骶部及下肢
明显凹陷性水肿。