PATHOPHYSIOLOGY

OF HEART FAILURE
Prof. J. Hanacek
 Notes to heart physiology

• Essential functions of the heart

• to cover metabolic needs of body tissue

(oxygen, substrates) by adequate blood supply

• to receive all blood comming back from

the tissue

• Essential conditions for fulfilling these functions

• normal structure and functions of the heart
 normal structure and function of tissue
surrounding heart
• adequate filling of the heart by blood
 Essential functions of the heart are secured
by integration of its electrical and mechanical
functions

Cardiac output (CO) = heart rate (HR) x stroke vol.(SV)

- changes of the heart rate

- changes of stroke volume

• Control of HR:
- autonomic nervous system

- hormonal (humoral) control

• Control of SV:
- preload, contractility, afterload, number and size of myocytes,
heart architecture, synchronisation of function of the atrias and
ventricles
 Adaptive mechanisms of the heart
to increased load

• Frank - Starling mechanism

• Ventricular hypertrophy
– increased mass of contractile elements  strength
of contraction

• Increased sympathetic adrenergic activity

– increased HR, increased contractility

• Incresed activity of R–A–A system

Causes leading to changes of number and size
of cardiomyocytes
Preload
Stretching the myocardial fibers during diastole by increasing end-
diastolic volume  force of contraction during systole =
Starling´s law

preload = diastolic muscle sarcomere length leading to increased

tension in muscle before its contraction (Fig.2,3)

- venous return to the heart is important  end-diastolic

volume is influenced

- stretching of the sarcomere maximises the number

of actin-myosin bridges responsible for development of force

- optimal sarcomere length  2.2 m

 Myocardial contractility

Contractility of myocardium
Changes in ability of myocardium to develop force
by contraction that occurs independently on changes
in myocardial fibre length

Mechanisms involved in changes of contractility

•  amount of created cross-bridges in the sarcomere
by  of Ca ++i
- catecholamines  Ca++i  contractility

- inotropic drugs  Ca++i  contractility

 contractility  shifting the entire ventricular function
curve upward and to the left
 contractility  shifting the entire ventricular function
curve (hypoxia, acidosis) downward and
to the right
 The pressure – volume loop

• It is the relation between ventricular volume and pressure

• This loop provides a convenient framework for understanding

the response of individual left ventricular contractions
to alterations in preload, afterload, and contractility

• It is composed of 4 phases:
- filling of the ventricle
- isovolumic contraction of ventricle
- isotonic contraction of ventricle (ejection of blood)
- isovolumic relaxation of ventricle
Pressure – volume loops recorded under different
conditions
Afterload

It is expressed as tension which must be developed in the wall

of ventricles during systole to open the semilunar valves and
eject blood to aorta/pulmunary artery

Laplace law:

intraventricular pressure x radius of ventricle

wall tension = --------------------------------------------------------
2 x ventricular wall thickness

 afterload: due to - elevation of arterial resistance

-  ventricular size
-  intrathoracic pressure (loss of myocard)

 afterload: due to -  arterial resistance

- myocardial hypertrophy
-  ventricular size
 Heart failure

Definition

It is the pathophysiological process in which

the heart as a pump is unable to meet
the metabolic requirements of the tissue for
oxygen and substrates despite the venous
return to heart is either normal or increased
Definition of the terms

• Myocardial failure = abnormalities reside in the myocardium and lead

to inability of myocardium to fulfill its function

• Circulatory failure = any abnormality of the circulation

responsible for the inadequacy in body tissue
perfusion, e.g. decreased blood volume, changes
of vascular tone, heart function disorders

• Congestive heart failure = clinical syndrome which is developed

due to accumulation of the blood in front
of the left or right parts of the heart
 General pathomechanisms involved in heart
failure development

Cardiac mechanical dysfunction can develop as

a consequence in preload, contractility and afterload
disorders

Disorders of preload
 preload  length of sarcomere is more than optimal 
  strength of contraction

 preload  length of sarcomere is well below the optimal 

  strength of contraction
Important: failing ventricle requires higher end-diastolic volume
to achieve the same CO that normal ventricle
achieves with lower ventricular volumes

Disorders of contractility
In the most forms of heart failure the contractility of myocardium
is decreased (ischemia, hypoxia, acidosis, inflammation, toxins,
metabolic disorders... )

Disorders of afterload due to:

• fluid retention in the body  increased blood volume
•  arterial resistance

• valvular heart diseases ( stenosis )

Characteristic features of systolic dysfunction
(systolic failure)
• ventricular dilatation

• reducing ventricular contractility (either generalized

or localized)

• diminished ejection fraction (i.e. that fraction of end-diastolic

blood volume ejected from the ventricle during each systolic
contraction – less then 45%)

• in failing hearts, the LV end-diastolic volume (or pressure)

may increse as the stroke volume (or CO) decreases
Characteristic features of diastolic dysfunctions
(diastolic failure)

• ventricular cavity size is normal or smaller than normal

• myocardial contractility is normal or hyperdynamic

• ejection fraction is normal (>50%) or supranormal

• ventricle is usually hypertrophied

• ventricle is filling slowly in early diastole (during the period

of passive filling)
 end-diastolic ventricular pressure is increased
 Causes of heart pump failure

A. MECHANICAL ABNORMALITIES

1. Increased pressure load

– central (aortic stenosis, aortic coarctation...)
– peripheral (systemic hypertension)

2. Increased volume load

– valvular regurgitation
– hypervolemia

3. Obstruction to ventricular filling

– valvular stenosis
– pericardial restriction
 B. MYOCARDIAL DAMAGE

1. Primary
a) cardiomyopathy
b) myocarditis

c) toxicity (e.g. alcohol)

d) metabolic abnormalities (e.g. hyperthyreoidism)

2. Secondary
a) oxygen deprivation (e.g. coronary heart disease)

b) inflammation (e.g. due to increased metabolic demands)

c) chronic obstructive lung disease

 C. ALTERED CARDIAC RHYTHM

1. ventricular flutter and fibrilation

2. extreme tachycardias

3. extreme bradycardias
Pathomechanisms involved in heart failure
A. Pathomechanisms involved in myocardial failure

1. Damage of cardiomyocytes   contractility,

 compliance
Consequences:
 defect in ATP production and utilisation
 changes in contractile proteins
 uncoupling of excitation – contraction process
  number of cardiomyocytes

 impairment relaxation of cardiomyocytes with decrease

compliance of myocardium

 impaired of sympato-adrenal system (SAS)   number of

1-adrenergic receptors on the surface of cardiomycytes
In normal conditions, the ryanoid channel in SR is stabilized, but in heart
failure abnormal calcium leak is induced. In heart failure, channel gating is
hypersensitized to calcium: at a lower concentration of calcium, the channel
is more activated.
2. Changes of neurohumoral control of the heart
function

• Physiology: • SNS   contractility

 HR
 activity of physiologic pacemakers

Mechanism:   sympathetic activity  cAMP 

Ca ++i  contractility

  sympathetic activity  influence

of parasympathetic system on the heart

• Pathophysiology: normal neurohumoral control is

changed and creation of pathologic
neurohumoral mechanisms are present
 Nitric oxyde
Bradykinin

Endothelin

Pro-proliferative effects Anti-proliferative effects

Chronic heart failure (CHF) is characterized by an imbalance of
neurohumoral adaptive mechanisms with a net results of excessive
vasoconstriction and salt and water retention

Catecholamines : - concentration in blood :

- norepinephrin – 2-3x higher at the rest than in healthy subjects
- circulating norepinephrin is increased much more
during equal load in patients suffering from CHF than
in healthy subject

-  number of beta 1 – adrenergic receptors 

 sensitivity of cardiomyocytes to catecholamines 
  contractility

System rennin – angiotensin – aldosteron

heart failure  CO  kidney perfusion  stim. of RAA system
Important:

Catecholamines and system RAA = compensatory mechanisms

 heart function and arterial BP

The role of angiotensin II in development of heart

failure
 vasoconstriction (mainly in resistant vesels)

 retention of Na  blood volume

  releasing of arginin – vasopresin peptide (AVP –antidiuretic

hormon) from neurohypophysis
 facilitation of norepinephrine release from sympathetic nerve
endings

  sensitivity of vessel wall to norepinephrine

 mitogenic effect on smooth muscles in vessels and on

cardiomyocytes in the heart  hypertrophy

 mitogenic effect on fibrocytes in vessel wall and in

myocardium

 constriction of vas efferens (in glomerulus)

  sensation of thirst

  secretion of aldosteron from adrenal gland

 mesangial conctraction  glomerular filtration rate

 Pathogenesis of heart failure

Index event – primary

cause of heart damage

Secondary damage –
remodeling

Adrenergic, RAA,
cytokine systems are
involved in the remodeling

Douglas L. Mann, 2004

 Pathophysiology of diastolic heart failure

 systolic heart failure = failure of ejecting function of the heart

 diastolic heart failure = failure of filling the ventricles,

 resistance to filling of ventricles

Diastolic failure is a widely recognized clinical entity

But, which of the cardiac cycle is real diastole ?

Definition of diastolic heart failure

It is pathophysiological process characterized by symptoms and

signs of congestive heart failure, which is caused by increased filling
resistance of ventricles and increased intraventricular diastolic
pressure

Primary diastolic heart failure

- no signs and symptoms of systolic dysfunction is present
- ! up to 40% of patients suffering from heart failure!

Secondary diastolic heart failure

- diastolic dysfunction is the consequence of primary
systolic dysfunction
Main causes and pathomechanisms of diastolic
heart failure

1. structural disorders passive chamber stiffness

a) intramyocardial
– e.g. myocardial fibrosis, amyloidosis, hypertrophy,
myocardial ischemia...

b) extramyocardial – e.g. constrictive pericarditis

2. functional disorders   relaxation of chambers e. g.

myocardial ischemia, advanced hypertrophy of ventricles, failing
myocardium, asynchrony in heart ventricle functions
Causes and mechanism participating on impaired
ventricular relaxation

a) physiological changes in chamber relaxation due to:

– prolonged ventricular contraction
Relaxation of ventricles is not impaired !

b) pathological changes in chamber relaxation due to:

Impaired relaxation process

 delayed relaxation (retarded)

 incomplete (slowed) relaxation

 Consequences of impaired ventricular relaxation
- filling of ventricles is more dependent on diastasis
and on the systole of atrias than in healthy subjects

Symptoms and signs:

 exercise intolerance = early sign of diastolic failure
  coronary blood flow during diastole

 Causes and mechanisms involved in development

of ventricular stiffness

 ventricular compliance = passive property of ventricle

Source of compliance: cardiomyocytes and other types of cells in

the heart tissue to stretching
  Ventricular compliance is caused by structural abnormalities
localized in myocardium and in extramyocardial tissue

a) Intramyocardial causes : myocardial fibrosis, hypertrophy of

ventricular wall, restrictive cardiomyopathy

b. Extramyocardial causes : constrictive pericarditis

The role of myocardial remodelling in genesis of

heart failure
 adaptive remodelling of the heart

 pathologic remodelling of the heart

 Main causes and mechanisms involved in
pathological remodelation of the heart

1.Increased amount and size of myocytes = hypertrophy

Due to: -  volume and/or pressure load

(excentric, concentric hypertrophy)
- hormonal stimulation of cardiomyocytes by
norepinephrine, angiotenzine II, endothelin...

2. Increased % of non-myocytic cells in myocardium

and their influence on structure and function of heart

a. endothelial cells – endothelins : mitogenic ability 

 stimulation growth of smooth muscle cells of vessels, fibroblasts

b. fibroblasts -  production of kolagens

 Symptoms and signs of heart failure

1. forward failure:
symptoms result from inability of the heart to pump enough
blood to the periphery (from left heart), or to the lungs (from
the right heart)

a) forward failure of left heart:- muscle weakness, fatigue,

dyspepsia, oliguria....

 general mechanism: tissue hypoperfusion

b) forward failure of right heart: - hypoperfusion of the

lungs  disorders of gas
exchange
- decreased blood supply
to the left heart
2. backward failure:
– symptoms result from inability of the heart to accept
the blood comming from periphery and from lungs

a. backward failure of left heart:

– increased pulmonary capillary pressure  dyspnoea
and tachypnoea, pulmonary edema (cardiac asthma) 
 arterial hypoxemia and hypercapnia....

b. backward failure of right heart:

– increased pressure in systemic venous system 
 peripheral edemas, hepatomegaly, ascites nocturnal diuresis....
 Processes involved in the picture of left ventricular
remodeling
Alterations in myocyte biology
Excitation contraction coupling
Myosin heavy chain (fetal) gene expression
Adrenergic desensitization
Hypertrophy with loss of myofilaments
Cytoskeletal proteins
Myocardial changes
Myocyte loss
Necrosis
Apoptosis
Alterations in extracellular matrix
Matrix degradation
Replacement Fibrosis
Alterations in left ventricular chamber geometry
Spherical shape
Wall thinning
Mitral valve incompetence
Mechanical disadvantages created by LV remodeling
Increased wall stress (afterload)
Afterload mismatch
Episodic subendocardial hypoperfusion
Increased oxygen utilization
Functional mitral regurgitation
Worsening hemodynamic overloading
Worsening activation of compensatory mechanisms
Activation of maladaptive gene expression
Activation of maladaptive signal transduction pathways
 Characteristics of pathological and physiological cardiac hypertrophy
Pathologic cardiac hypertrophy Physiologic cardiac hypertrophy

Stimuli Pressure load in a disease setting
(e.g. hypertension, aortic coarction)
or volume load (e.g. valvular disease)
Cardiomyopathy (familial, viral, toxic,
metabolic)
Regular physical activity or chronic exercise training
Volume load (e.g. running, walking, swimming)
Pressure load (e.g. strength training: weight lifting

Cardiac
morphology Increased myocyte volume Increased myocyte volume
Formation of new sarcomeres Formation of new sarcomeres
Interstitial fibrosis
Myocyte necrosis and apoptosis
Fetal gene
expression Usually upregulated* Relatively normal*

Cardiac
function Depressed over time Normal or enhanced
Completely
reversible Not usually Usually
Association with
heart failure
and increased Yes No
mortality
McMullen and Jennings, 2007