Heart Failure

Department of Pathophysiology

Zhang Xiao-ming

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) 。

Clinical example

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.

PrevalancePrevalance

2 to 3 million

400,000 new cases

1996 WHO survey:

Incidence rate 1.9% men>women

2-year mortality rate 37%

6-year mortality rate 82%

American:

2. Causes(1) Etiological causes

(2) The precipitating causes

contractility

afterloadpreload

Stroke Volume

Cardiac output

Heart rate

Determinants of cardiac function Determinants of cardiac function

(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 stenosisaortic 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.

1) Infection left heart failure ↓ pulmonary vascular congestion pulmonary edema ↓ susceptible to pulmonary infection.

(2) The precipitating causes

Infection of airway

fever tachycardia hypoxia↙ ↓ ↘

↑ ATP consumption ↓ATP production

↓ ↓ ↓

↓ ↓

need more cardiacoutput

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

(1) According to the course of disease

1) Acute HF

2) Chronic HF

3. Classification of heart failure

(2)According to the severity 1) mild HF or complete compensation

2) middle HF or incomplete compensation

3) severe HF or decompensation

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 (Moderate)

Marked limitation of physical activity. 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.

NYHA Classification

(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.

低输出量型心衰

低输出量型心衰

高输出量型心衰前高输出量型心衰前

高输出量型心衰

高输出量型心衰

正常心输出量

正常人正常人

The situation of “high output state” occurs in the patients with:

hyperthyroidism, anemia, arterio-venous fistulas, beriberi.

(5)According to the function impaired

1) systolic failure

2) Diastolic failure

(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)

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)

Contraction protein:

thin filament (actin) myofibril←sarcomere thick filament (myosin)

regulation protein: Tropomyosin troponin

The molecular basis for myocardial contraction:

Cardiac Muscle

Molecular Basis of Contraction Molecular Basis of Contraction 

1) Myocardial cellular injuries

2) Myocardial metabolic dysfunction

3) Dysfunction of excitation-contraction coupling

4) Excessive myocardial hypertrophy

(1) Decreased myocardial contractility

1) Myocardial cellular injuries

morphologic changes: necrosis, apoptosis

reasons: myocardial ischemia (myocardial infarction) myocarditis cardiomyopathy

Myocardial Infarction

Atherosclerosis of the larger

coronary arteries

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.

Excitation-contraction coupling

3) Dysfunction of excitation-contraction coupling

(A) Reduced uptake, storing and release of Ca2+ by sarcoplasmic reticulum(SR)

Re-uptake Storing

Release

M

SR

Handling of calcium by SR

Plays a critical role in the onset of early heart failure. Level of SR calcium binding proteins (calsequestrin and calreticulin) has not been changed.

ATP-dependent pump

Phospholamban(PLB)

In heart failure :

•Expression of PLB •NE , Beta-adrenoceptor activation •ATP supply

uptake↓

storing ↓

Level of SR calcium binding proteins (calsequestrin and calreticulin) has not been changed.

Ca2+-induced Ca 2+ release

Ryanodine receptor(RyR)

• 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.

release ↓

How is the process of calcium influx changed in heart failure? 

Two main pathways

Calcium channel Na+-Ca2+ exchanger

(B) Reduced influx of extracellular Ca2+

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.

The quantity of myoplasmic Ca2+ is inadequate The combinative activity between Ca2+ and

troponin decreases

e.g. ischemia, hypoxia, acidosis

(C) dysfunction of Ca2+ binding to troponin

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

Decreased myocardial contractility

1) Myocardial cellular injuries 2) Myocardial metabolic dysfunction 3) Dysfunction of excitation-contraction

coupling 4) Excessive myocardial hypertrophy

Summary

(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 actin-myosin 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.

diminished contractionnormal

absent contraction

Asymmetry means: regional abnormal contraction; diminished contraction ; absent contraction.

(3) Asymmetry and asynchronism in ventricular contraction and relaxation

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 contractilitymechanism: circulating catecholamines and

sympathetic tone ↑

CO/min=CO/stroke × HR (strokes /min)

When HR higher than 180/min→decompensation

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.

2) Cardiac dilatation (The Frank-Starling mechanism)

If the length of sarcomere is over 2.25 μm,

↓ the number of force-

generating cross bridges will decrease,

↓ the contraction force will

reduce, ↓ decompensation.

Types of myocardial hypertrophy

------------------------------------------------------------------ type concentric hypertrophy eccentric hypertrophy------------------------------------------------------------------- cause pressure overload volume overload------------------------------------------------------------------- cardiac chamber no yesdilation--------------------------------------------------------------------pattern ofincreased in parallel. in seriessarcomeres (stand side by side)--------------------------------------------------------------------

3) Myocardial hypertrophy

正常压力负荷

过重容量负荷

过重

向心性肥大

离心性肥大

Concentric hypertrophy Eccentric hypertrophy

Compensatory mechanism : overall myocardial contractility ↑ tension↓; Oxygen consumption↓

(2) Systemic compensation1) Increase of the blood volumeA. 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

↙ ↓ ↘ ↓ .

tachycardia

↑ demand of O2 of heart muscle

↑peripheral resistance

↓ filling time for ventricles ↑ afterload of

ventricles

↓filling time forcoronary artery

↓CO/stroke

contraction of blood vessel

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

left heart failure (increased LVEDP)increased pulmonary venous pressure

↓

pulmonary congestion and pulmonary edema

↓ ↓

increased airway resistance

reduced compliance of lung

↓↓

decreased O2 inhalation

more work of breathing to distend the stiff lungs

↓

increased O2 consumption

hypoxemia+ metabolic acidosis

dyspnea

↓

↓

1) 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

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) 。

Clinical example

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。