PATHOPHYSIOLOGY OF PATHOPHYSIOLOGY OF HEART FAILUREHEART FAILURE

Prof. J. HanProf. J. Hanacacekek

Technical co-operation: L. ŠurinováTechnical co-operation: L. Šurinová

Notes to heart physiologyNotes to heart physiology

• Essential functions of the heartEssential functions of the heart

• to cover metabolic needs of body tissueto cover metabolic needs of body tissue (oxygen, substrates) by adequate blood supply(oxygen, substrates) by adequate blood supply

• to receive all blood comming back from the tissue to receive all blood comming back from the tissue to the heartto the heart

• Essential conditions for fulfilling these functionsEssential conditions for fulfilling these functions

• normal structure and functions of the heartnormal structure and functions of the heart

• adequate filling of the heart by bloodadequate filling of the heart by blood

Essential functions of the heart are secured Essential functions of the heart are secured by integration of electrical and mechanicalby integration of electrical and mechanical

functions of the heartfunctions of the heart

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

- - changes of the heart ratechanges of the heart rate

- changes of stroke volume- changes of stroke volume

• Control of HR:Control of HR:- autonomic nervous system- autonomic nervous system

- - hormonal(humoral) controlhormonal(humoral) control

• Control of SVControl of SV:: - preload- preload

- contractility- contractility

- afterload- afterload

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

PreloadPreload

Stretching the myocardial fibers during diastole by increasing end-Stretching the myocardial fibers during diastole by increasing end-

diastolic volume diastolic volume →→ ↑↑ force of contraction during systole = force of contraction during systole = StarlingStarling

´s law´s law

preloadpreload = = diastolic muscle sarcomere length leading to increased diastolic muscle sarcomere length leading to increased tension in muscle before its contraction tension in muscle before its contraction (Fig.2,3)(Fig.2,3)

- venous return to the heart is important venous return to the heart is important →→ end-diastolic end-diastolic volume is influenced

- stretching of the sarcomere maximises the number stretching of the sarcomere maximises the number of actin-myosin bridges responsible for development of forceof actin-myosin bridges responsible for development of force

- - optimal sarcomere length optimal sarcomere length ∼∼ 2.2 2.2 µµmm

Myocardial contractilityMyocardial contractility

Contractility of myocardiumContractility of myocardium CChanges in hanges in ability of myocardium to ability of myocardium to developdevelop the the force force by contraction that occurby contraction that occur independently onindependently on the the changes in myocardial fibchanges in myocardial fibrre lengthe length

Mechanisms involved in changes of contractilityMechanisms involved in changes of contractility

• ↑↑ amount of created cross-bridges in the sarcomereamount of created cross-bridges in the sarcomere by by ↑↑ of of [[Ca Ca ++++]] ii concentration concentration

-- catecholamines catecholamines →→ ↑[↑[ CaCa++++]] ii→→ ↑↑ contractility contractility

- - inotropic drugs inotropic drugs →→ ↑[↑[ CaCa++++]] ii→→ ↑↑ contractility contractility

↑↑ contractilitycontractility →→ shifting the entire ventricular function shifting the entire ventricular function curve upward and to the leftcurve upward and to the left

↓↓ contractilitycontractility →→ shiffting the entire ventricular functionshiffting the entire ventricular function curve (hypoxia, acidosis) downward and to the righcurve (hypoxia, acidosis) downward and to the rightt

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

It It is expressed as tension which must be developedis expressed as tension which must be developed in the wall in the wall of ventricles during systole to open the semilunar valveof ventricles during systole to open the semilunar valvess and and eject blood toeject blood to aorta/pulmunary artery aorta/pulmunary artery

Laplace law:Laplace law:

intraventricular pressure x radius of ventricleintraventricular pressure x radius of ventriclewall tension = --------------------------------------------------------wall tension = -------------------------------------------------------- 2 x2 x ventricular wall thickness ventricular wall thickness

↑↑ afterloadafterload:: due to - elevation of arterialdue to - elevation of arterial resistance resistance - - ↑↑ ventricular size ventricular size - myocardial hypotrophy- myocardial hypotrophy

↓↓ afterloadafterload:: due to - due to - ↓↓ arterial arterial resistance resistance - myocardial hypertrophy- myocardial hypertrophy - - ↓↓ ventricular size ventricular size

AfterloadAfterload

Heart failureHeart failure

DefinitionDefinition

It is the pathophysiological process in whichIt is the pathophysiological process in which

the heart as a pump is unable to meetthe heart as a pump is unable to meet

the metabolic requirements of the tissue for the metabolic requirements of the tissue for

oxygen and substrates despite the venousoxygen and substrates despite the venous

returnreturn to heart to heart is either normal or increased is either normal or increased

Explanation of the termsExplanation of the terms

• Myocardial failureMyocardial failure == abnormalities reside in the abnormalities reside in the myocardiummyocardium and lead and lead

to to inability of inability of myocardium myocardium to fulfilling its to fulfilling its function function

• Circulatory failureCirculatory failure = = any abnormality of the circulationany abnormality of the circulation responsible for the inadequacy in bodyresponsible for the inadequacy in body tissuetissue perfusion, e.g. decreased blood volume, changesperfusion, e.g. decreased blood volume, changes of vascular tone, heart of vascular tone, heart functiones functiones disordersdisorders

• Congestive heart failureCongestive heart failure = clinical syndrome which is developed = clinical syndrome which is developed due to due to accumulation of the blood inaccumulation of the blood in frontfront of the left or right parts of the heartof the left or right parts of the heart

General pathomechanisms involved in heart General pathomechanisms involved in heart failure developmentfailure development

Cardiac mechanical dysfunction can developCardiac mechanical dysfunction can develop as as a a consequence in preload, contractility and afterload consequence in preload, contractility and afterload disordersdisorders

Disorders of preloadDisorders of preload

↑↑↑↑ preloadpreload →→ length of sarcomere is more than optimal length of sarcomere is more than optimal →→ →→ ↓↓ strength of contractionstrength of contraction

↓↓↓↓ preloadpreload →→ length of sarcomere is well below thelength of sarcomere is well below the optioptimalmal →→ →→ ↓↓ strength of contractionstrength of contraction

Important:Important: failing ventricle requires higher end-diastolicfailing ventricle requires higher end-diastolic volume volume

to achieve the same improvement of CO that normalto achieve the same improvement of CO that normal

ventricle achievesventricle achieves with lower ventricular volumeswith lower ventricular volumes

Disorders of contractilityDisorders of contractility

In In the the most forms of heart failure the contractility ofmost forms of heart failure the contractility of myocardium myocardium

is decreased (ischemia, hypoxiais decreased (ischemia, hypoxia,, acidosis, acidosis, inflammation, toxins, inflammation, toxins,

metabolic disordersmetabolic disorders...... ) )

Disorders of afterloadDisorders of afterload due to: due to:• fluid retentionfluid retention in the body in the body

• ↑↑ arterial resistancearterial resistance

• valvular heart diseases ( stenosisvalvular 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 – les 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 small

• 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 failureCauses of heart pump failure

A. MECHANICAL ABNORMALITIESA. MECHANICAL ABNORMALITIES

1. Increased pressure load1. Increased pressure load– – ccentral (aortic stenosisentral (aortic stenosis, aortic coarctation..., aortic coarctation...))

–– pperipheral (systemic hypertension)eripheral (systemic hypertension)

2. Increased volume load2. Increased volume load– – valvular regurgitationvalvular regurgitation

– hypervolemia

3. Obstruction to ventricular filling3. Obstruction to ventricular filling –– valvular stenosisvalvular stenosis

–– pericardial restrictionpericardial restriction

B. MYOCARDIAL DAMAGEB. MYOCARDIAL DAMAGE

1. Primary1. Primarya) a) ccardiomyopathyardiomyopathy

b) b) mmyocarditisyocarditis

c) c) ttoxicity (oxicity (e.g. e.g. alcohol)alcohol)

d) d) mmetabolic abnormalities (etabolic abnormalities (e.g. e.g. hyperthyreoidismhyperthyreoidism))

2. Secondary2. Secondary

a) a) ooxygen deprivation (xygen deprivation (e.g. e.g. coronary heart disease)coronary heart disease)

b) b) iinflammation (nflammation (e.g. e.g. increased metabolic demands)increased metabolic demands)

c) c) cchronic obstructive lung diseasehronic obstructive lung disease

C. ALTERED CARDIAC RHYTHMC. ALTERED CARDIAC RHYTHM

1. 1. vventricular entricular flutter and flutter and fibrilationfibrilation

2. 2. eextreme tachycardiasxtreme tachycardias

3. 3. eextreme bradycardiasxtreme bradycardias

Pathomechanisms involved in heart failurePathomechanisms involved in heart failure

A. Pathomechanisms involved in myocardial failureA. Pathomechanisms involved in myocardial failure

• Damage of cardiomyocytesDamage of cardiomyocytes →→ ↓↓ contractility, contractility, ↑↑ ↓↓ compliancecompliance

Consequences:Consequences:•• defect in ATP production and utilisationdefect in ATP production and utilisation

•• changes in contractile proteinschanges in contractile proteins

•• uncoupling of excitation – contraction processuncoupling of excitation – contraction process

•• ↓↓ number of cardiomyocytesnumber of cardiomyocytes

• impairment of relaxation of cardiomyocytes withimpairment of relaxation of cardiomyocytes with decrease decrease compliance of myocardiumcompliance of myocardium

• impaired of sympato-adrenal system (SAS) impaired of sympato-adrenal system (SAS) →→ ↓↓ number number of of ββ 11-adrenergic receptors on the surface of cardiomycytes-adrenergic receptors on the surface of cardiomycytes

2. Changes of neurohumoral control of the heart 2. Changes of neurohumoral control of the heart functionfunction

• Physiology:Physiology: •• SNSSNS →→ ↑↑ contractili contractilityty

↑↑ HRHR ↑↑ activactivity of ity of physiologic physiologic pacemakerspacemakers

Mechanism:Mechanism: •• ↑↑ sympathetic activity sympathetic activity →↑→↑ cAMP cAMP →→ →↑[→↑[ Ca Ca ++++]] ii →→ ↑↑ contractilitycontractility

•• ↑↑ sympathetic activity sympathetic activity →→ ↓↓ influenceinfluence of parasympathetic system onof parasympathetic system on thethe heartheart

•• Pathophysiology:Pathophysiology: normal neurohumoral control isnormal neurohumoral control is

changed and creationchanged and creation of pathologic of pathologic

neurohumoral mechanismsneurohumoral mechanisms are present are present

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

Catecholamines :Catecholamines : - concentration in blood :- concentration in blood :

- norepinephrin – 2-3x norepinephrin – 2-3x higher at the rest than in healthy subjectshigher at the rest than in healthy subjects

- - circulating norepinephrin is increased much more circulating norepinephrin is increased much more during equal load in patients suffering from CHF than during equal load in patients suffering from CHF than in in healthy subjecthealthy subject

- ↓↓ number of beta 1 – adrenergic receptors number of beta 1 – adrenergic receptors →→ →→ ↓↓ sensitivity ofsensitivity of cardiomyocytes to catecholamines cardiomyocytes to catecholamines →→ →→ ↓↓ contractilitycontractility

System rennin – angiotensin – aldosteronSystem rennin – angiotensin – aldosteron

hheart failureeart failure →↓→↓ CO CO →↓→↓ kidney perfusion kidney perfusion →→ stim stim.. Of Of RAA RAA systemsystem

Important:Important:

Catecholamines and system RAA = compensatory mechanisms

↑↑ heart function and arterialheart function and arterial BPBP

The role of angiotensin II in development of heart The role of angiotensin II in development of heart failurefailure

•• vasoconstriction ( in resistant vesels)vasoconstriction ( in resistant vesels)

•• retention of Na retention of Na →↑→↑ blood volume blood volume

• ↑↑ releasing of arginin – vasopresin peptide (AVP ) releasing of arginin – vasopresin peptide (AVP ) fromfrom neurohypophysisneurohypophysis

•• ↑↑ sensitivity of vessel wall to norepinephrinesensitivity of vessel wall to norepinephrine

• mitogenic effect on smooth muscles in vessels and mitogenic effect on smooth muscles in vessels and

onon cardiomyocytes cardiomyocytes →→ hypertrophy hypertrophy

•• constriction of vas efferens ( in glomerulus )constriction of vas efferens ( in glomerulus )

•• ↑↑ sensation of thirstsensation of thirst

•• ↑↑ secretion of aldosteron from adrenal glandsecretion of aldosteron from adrenal gland

•• mesangial conctraction mesangial conctraction →→ ↓↓ glomerular filtration rateglomerular filtration rate

• facilitation of norepinephrine releasing from facilitation of norepinephrine releasing from sympatheticsympathetic nerve endingsnerve endings

Pathophysiology of diastolic heart failurePathophysiology of diastolic heart failure

• systolic heart failuresystolic heart failure = = failure of ejecting function of the heartfailure of ejecting function of the heart

• diastolic heart failurediastolic heart failure = = failure of filling the ventricles,failure of filling the ventricles,

↑↑ resistanceresistance to filling to filling of ventricles of ventricles

But,But, wwhich of the cardiac cycle ishich of the cardiac cycle is real real diastole ? diastole ?

Diastolic failure is a widely recognized clinical entity

Definition of diastolic heart failureDefinition of diastolic heart failure

It is pathophysiological process characterized by symptoms and It is pathophysiological process characterized by symptoms and signs of congestive heart failure, which is caused bysigns of congestive heart failure, which is caused by increased increased filling resistance of ventricles and filling resistance of ventricles and iincreasedncreased intraventricular intraventricular diastolic pressurediastolic pressure

Primary diastolic heart failurePrimary diastolic heart failure

- no signs and symptoms of systolic dysfunctionno signs and symptoms of systolic dysfunction is present is present

-- ! up to 40% ! up to 40% of of patients suffering from heart failure!patients suffering from heart failure!

Secondary diastolic heart failureSecondary diastolic heart failure

- diastolic dysfunction is the consequence of- diastolic dysfunction is the consequence of primary primary systolic systolic dysfunctiondysfunction

Main causes and pathomechanisms of diastolicMain causes and pathomechanisms of diastolic heart failureheart failure

1.1. structural disordersstructural disorders →↑→↑passive chamber stiffnesspassive chamber stiffness

• intramyocardialintramyocardial

– – e.g. myocardial fibrosis, amyloidosis,e.g. myocardial fibrosis, amyloidosis, hypertrophy, hypertrophy, myocardial ischemiamyocardial ischemia......

b) extramyocardialb) extramyocardial – e.g. constrictive pericarditis – e.g. constrictive pericarditis

2. functional disorders2. functional disorders →→ ↓↓ relaxation of chambers relaxation of chambers e. g. myocardial e. g. myocardial

ischemia, advanced hypertrophy of ventricles,ischemia, advanced hypertrophy of ventricles,

failing myocardium, asynchronyfailing myocardium, asynchrony in heart in heart

functionsfunctions

Causes and mechanism participating on impairedCauses and mechanism participating on impaired ventricular relaxationventricular relaxation

a)a) physiological changesphysiological changes in chamber relaxation in chamber relaxation due todue to: :

– – prolonged ventricular contraction prolonged ventricular contraction

Relaxation of ventricles is not impairedRelaxation of ventricles is not impaired !

b) pathological changesb) pathological changes inin chamber relaxation chamber relaxation due todue to: : IImpaired relaxation processmpaired relaxation process

•• delayed relaxation (retarded)delayed relaxation (retarded)

•• incomplete (slowed) relaxationincomplete (slowed) relaxation

•• Consequences of impaired ventricular relaxationConsequences of impaired ventricular relaxation

- filling of ventricles isfilling of ventricles is more dependent on diastasis more dependent on diastasis and onand on thethe systolesystole of atrias than in healthy subjects of atrias than in healthy subjects

SSymptoms and signs:ymptoms and signs:

•• exercise intoleranceexercise intolerance = = early sign of diastolic failureearly sign of diastolic failure

•• ↓↓ coronary blood flow during diastolecoronary blood flow during diastole

•• Causes and mechanisms involved in developmentCauses and mechanisms involved in development of ventricular stiffnessof ventricular stiffness

•• ventricular complianceventricular compliance = passive property of ventricle= passive property of ventricle

Source of compliance: Source of compliance: cardiomyocytes and other heart cardiomyocytes and other heart

tissue to stretching tissue to stretching

↓↓ VVentricular compliance is caused by structuralentricular compliance is caused by structural abnormalities abnormalities

localized in myocardium and in extramyocardial tissuelocalized in myocardium and in extramyocardial tissue

a) a) Intramyocardial causesIntramyocardial causes : myocardial fibrosis, hypertrophy of : myocardial fibrosis, hypertrophy of ventricular wall,restrictive cardiomyopathyventricular wall,restrictive cardiomyopathy

b. Extramyocardial causesb. Extramyocardial causes :: constrictive pericarditis constrictive pericarditis

The role of myocardial remodelling in genesis ofThe role of myocardial remodelling in genesis of heart failureheart failure

•• adaptive remodelling of the heartadaptive remodelling of the heart

•• pathologic remodelling of the heartpathologic remodelling of the heart

Main causes and mechanisms involved in Main causes and mechanisms involved in pathological remodelation of the heartpathological remodelation of the heart

1.Increased amount and size1.Increased amount and size of myocytesof myocytes == hypertrophyhypertrophy

Due to:Due to: - - ↑↑ volume and/or pressure load volume and/or pressure load (excentric, concentric hypertrophy(excentric, concentric hypertrophy))

- hormonal stimulation of cardiomyocytes by - hormonal stimulation of cardiomyocytes by norepinephrine, angiotenzine IInorepinephrine, angiotenzine II

2. Increased 2. Increased % % ofof non-myocytnon-myocyticic cells cells iin myocardiumn myocardium and and their their influenceinfluence on structure and function of heart on structure and function of heart

a.a. endothelial cellsendothelial cells – – endothelins :endothelins : mitogenic ability mitogenic ability →→ →→ stimulation growth of smooth muscle cells of vessels, fibroblastsstimulation growth of smooth muscle cells of vessels, fibroblasts

b.b. fibroblastsfibroblasts - - ↑↑ production of kolagens production of kolagens

Symptoms and signs of heart failureSymptoms and signs of heart failure

• forward failure:forward failure: symptoms result from inability of the heart to pump enough symptoms result from inability of the heart to pump enough

blood to the peripheryblood to the periphery (from(from left heart), or to the lungs (from left heart), or to the lungs (from

the right heart)the right heart)

a) forward failure of left heart:a) forward failure of left heart:-- muscle weakness, fatigue, muscle weakness, fatigue, dyspepsia, oliguriadyspepsia, oliguria........

•• generalgeneral mechanism mechanism:: tissue hypoperfusiontissue hypoperfusion

b) forward failure of right heartb) forward failure of right heart:: - hypoperfusion of the - hypoperfusion of the lungs lungs →→ disorders of gas disorders of gas exchangeexchange

- decreased blood supply decreased blood supply to the left heartto the left heart

2. backward failure:2. backward failure: – symptoms result from inability of the heart to accept symptoms result from inability of the heart to accept

the blood comthe blood commming from periphery and from lungsing from periphery and from lungs

• backward failure of left heart:backward failure of left heart:

– – increased pulmonary capillary pressureincreased pulmonary capillary pressure →→ dyspnoea dyspnoea and tachypnoea, pulmonary edema (cardiac asthma) and tachypnoea, pulmonary edema (cardiac asthma) →→

→→ arterial arterial hypoxhypoxemiaemia and hypercapnia and hypercapnia........

b. backward failure of right heart:b. backward failure of right heart:

– increased pressure in increased pressure in systemic systemic venous systemvenous system →→ →→ peripheral edemas, hepatomegaly, ascites peripheral edemas, hepatomegaly, ascites →↑→↑nocturnalnocturnal diuresisdiuresis........