Heart failure

Laszlo L. TornociInst. Pathophysiology

Semmelweis University

Definition

A clinical syndrome characterized by progressive weakening of the heart as a pump, causing complex changes in processes at systemic, organ and cellular levels, finally leading to premature myocardial cell death.

Demography

• Prevalence of symptomatic HF 0.4-2.0%, 6-10% in people over 65 years

• Disease of the elderly (mean age > 70 years)• Prevalence is rising• Bad prognosis: 5-year survival rate < 50%• Mortality (even if age adjusted) is increasing

Classification

• Acute/chronic HF• Forward/backward failure• Systolic/diastolic dysfunction• Left/right sided HF

Complaints

• Left heart, backward failure– dyspnea– orthopnea– paroxysmal nocturnal dyspnea

• Left heart, forward failure– weakness, fatigue– nycturia

Physical findings

– Right heart, backward failure• edema, hydrothorax• congestive hepatomegaly• distension of neck veins

– Left heart, backward failure• pulmonary rales

– Miscellaneous• cyanosis• S3 gallop

Causes of heart failure

• Underlying (true) causes• Precipitating causes (which make the

clinical condition worse, ‘decompensate’ the patient)

Underlying causes

• Ischemic heart disease• Hypertension• Valvular heart disease• Cardiomyopathies• Other

Precipitating causes 1.

• Increased cardiac output – metabolic need

(fever, infection, hyperthyroidism)– volume overload

(renal failure, high sodium intake)

• Pressure overload – high BP– pulmonary embolism

Increased workload

Precipitating causes 2.

• Cardiac ischemia• Decreased efficiency (arrhythmias)• Drug effect• Endocarditis, myocarditis

Same workload, but weaker heart

Terms

• Inotropy (contractility)• Lusitropy (capability to relax or be filled)• Preload• Afterload

Frank-Starling law

isometric contractions

0 4 0 8 0v o lu m e [m l]

1 2 0

4 0

8 0

pres

sure

[mm

Hg]

1 2 0

Contractility (inotropy)

0 4 0 8 0v o lu m e [m l]

1 2 0

4 0

8 0

pres

sure

[mm

Hg]

1 2 0

d e c rea sed

in c re ased

n o rm a l

Pressure-volume (PV) loop

0 4 0 8 0v o lu m e [m l]

1 2 0

4 0

8 0

pres

sure

[mm

Hg]

1 2 0

E D V

en d d ia s to licP V re la tio n sh ip

d ias to le

sy s to le

en d sy s to licP V re la tio n sh ip

E S V

Increasing inotropy

0 4 0 8 0v o lu m e [m l]

1 2 0

pres

sure

[mm

Hg]

4 0

8 0

1 2 0

1 4 0

Decreasing inotropy(systolic dysfunction)

0 4 0 8 0v o lu m e [m l]

1 2 0

pres

sure

[mm

Hg]

4 0

8 0

1 2 0

1 4 0

Decreasing lusitropy (diastolic dysfunction)

0 4 0 8 0v o lu m e [m l]

1 2 0

pres

sure

[mm

Hg]

4 0

8 0

1 2 0

1 4 0

Cardiac output vs. right atrial pressure

00

-4 4 8rig h t a tria l p re ssu re [m m H g ]

5

1 0

1 5ca

rdia

c ou

tput

[l/m

in]

Effect of contractility on cardiac output

00

-4 4

n o rm al

in c reased

d ec reased

8rig h t a tr ia l p ressu re [m m H g ]

5

1 0

1 5

2 0

2 5ca

rdia

c ou

tput

[l/m

in]

Some of the factors affecting contractility

• sympathetic stimulation• hypertrophy

• ischemia, AMI• valvular heart disease• high BP• parasympathetic stimulation• sympathetic inhibition• myocarditis

increase decrease

Venous return curve

00

-4

5

1 0

4 8rig h t a tria l p re ssu re [m m H g ]

veno

us re

turn

[l/m

in]

m ean c irc u la to ry fillin g p re ssu re

Venous return curves

00

-4 4 1 2 1 6

n o rm al m e an c irc u la to ryfillin g p re ssu red ec rease d

in c re a sed

8rig h t a tria l p re ssu re [m m H g ]

5

1 0

1 5

card

iac

outp

ut [

l/min

]

Determinants of MCFP

s tre ssed v o lu m e

b lo o d v o lu m e

sy m p a th e tics tim u la tio n

sy m p a th e ticin h ib itio n

c ro ss sec tio n o f v e in s

u n stre ssed v o lu m e

mea

n ci

rcul

ator

y fil

ling

pres

sure

Cardiac output – venous return

eq u ilib r iu m p o in t

00

-4

5

1 0

1 5

4 8rig h t a tria l p re ssu re [m m H g ]

card

iac

outp

ut a

nd v

enou

s ret

urn

[l/m

in]

M C F P

Effect of sympathetic stimulation

00

-4 4 1 2 1 6

ca rd iac o u tp u t in th e re stin g s ta te

ca rd ia c o u tp u t du rin gsy m p a th e tic s tim u la tio n

8rig h t a tria l p re ssu re [m m H g ]

5

1 0

1 5

2 0

2 5ca

rdia

c ou

tput

[l/m

in]

Fluid retention in chronic HF

00

-4 4

AB C

1 2 1 68rig h t a tria l p re ssu re [m m H g ]

5

1 0

1 5

card

iac

outp

ut [

l/min

]

Neurohormonal response to HF

• Hemodynamic defense reaction– Salt and water retention – Vasoconstriction– Cardiac stimulation

• Inflammatory reaction• Hypertrophic response

Overview

Neurohormonal response

• Systemic• Organ• Cellular

Effects by levels

Fluid retention, fatigue, cachexia

Hypertrophy, remodeling

Change of myosin isoforms, Ca++

torlasz:

more examples are needed

Neurohormonal response to HF

• Hemodynamic defense reaction– Salt and water retention – Vasoconstriction– Cardiac stimulation

• Inflammatory reaction• Hypertrophic response

Overview

Hemodynamic defense reaction

Exercise Shock HF

Durationminutes to hours

hours lifetime

Challengeneed more

cardiac output blood volume pump failure

Response fluid retention vasoconstriction cardiac stimulation

++

+++

+++

Hemodynamic defense reaction

– Salt and water retention

– Vasoconstriction

– Cardiac stimulation: contractility , faster relaxation, HR

– Cell growth and proliferation

Effects:

Stimulatorycatecholamines (per. eff.)angiotensin IIADHendothelin

InhibitoryANPNObradykinindopaminecathecolamines (central eff.)

Mediators:

Hemodynamic defense reactionAdaptive (beneficial), short term responses

salt and water retention preload cardiac output

vasoconstriction afterload BP

cardiac stimulationcontractility relaxation

HR

cardiac output

Hemodynamic defense reactionMaladaptive (not beneficial), long term responses

salt and water retention preload edema

pulmonary edema

vasoconstriction afterload cardiac output energy demand

cardiac stimulationcontractility relaxation

HR

energy demand arrhythmiassudden death

Neurohormonal response to HF

• Hemodynamic defense reaction– Salt and water retention – Vasoconstriction– Cardiac stimulation

• Inflammatory reaction• Hypertrophic response

Overview

Inflammatory reaction

• Adaptive (beneficial), short term results– not known (heat shock proteins?)

• Maladaptive (not beneficial), long term results– cardiac cachexia– apoptosis– necrosis

Neurohormonal response to HF

• Hemodynamic defense reaction– Salt and water retention – Vasoconstriction– Cardiac stimulation

• Inflammatory reaction• Hypertrophic response

Overview

Hypertrophic responseGene expression in myocardial cells will change as a result of:

• cell stress• hemodynamic defense reaction• inflammatory reaction

adaptive hypertrophy maladaptive hypertrophy

• sarcomere number• cardiac output

• remodeling• energy demand• cell death

Changes of growth factor expressions: TGF- , IGF-1 , FGF

Concentric hypertrophy

0 4 0 8 0v o lu m e [m l]

1 2 0

pres

sure

[mm

Hg]

4 0

8 0

1 2 0n o rm a lco n ce n tr ic

h y p e rtro p h y

Eccentric hypertrophy

0 4 0 8 0v o lu m e [m l]

1 2 0 1 6 0 2 0 0 2 4 0 2 8 0

pres

sure

[mm

Hg]

4 0

8 0

1 2 0

n o rm al ecce n trich y p e rtro p h y

Therapy

• Emergency setting– keep the patient alive!

• Usual setting– alleviate symptoms (improve QOL)

– prolong survivalcontradiction is possible!

Goals of therapy in general

Classical approaches in drug therapy

• Circulation– decrease fluid retention (diuretics)– decrease afterload, preload (vasodilators)

• Heart– positive inotropic agents (digitalis)

Diuretic therapy

flu id re ten tio n

b ack w ard fa ilu reim p ro v es

fo rw ard fa ilu rew o rsen s

v o lu m e d ep le tio nca rd ia c o u tp u t

e jec tio n p re lo ad

n eu ro h o rm o n a lre sp o n se

ad m in is tra tio n o fa d iu re tic

Maladaptive features of the vasoconstrictor response

vasoconstriction

afterload

cardiac output

myocardial energyexpenditure

myocardial cell death

arrhythmias,sudden death

survivalworsesymptoms

Expected response to vasodilators

vasoconstriction

afterload

cardiac output

myocardial energyexpenditure

myocardial cell death

arrhythmias,sudden death

survivalbettersymptoms

Actual response to vasodilators

vasoconstriction

afterload

cardiac output

myocardial energyexpenditure

myocardial cell death

arrhythmias,sudden death

survival bettersymptoms

BP

hemodynamicdefense reaction

hypertrophy

Renin-angiotensin systemangiotensinogen (1-14)

angiotensin I (1-10)

angiotensin II (1-8)

angiotensin III (2-8)

angiotensin IV (3-8)

renin

ACE, chymase

kallikrein,cathepsin G

peptidase

peptidase

ACE: angiotensin converting enzyme

Actions of ACE

• Converts angiotensin I to angiotensin II• Breaks down kinins (bradykinin)

So ACE inhibitors not only decrease angiotensin II levels, butincrease bradykinin concentration. This is beneficial, but may cause coughing as a side effect.

Summary of drug therapy

drug control fluid retention

alleviate symptoms

prolong survival

diuretic ++ + ?

ACE inhibitor + + ++

-blocker* (0) (+) ++

digitalis + ++ 0

*: long term effects are in parentheses

Availability

http://xenia.sote.hu/depts/pathophysiology

The heart failure lectures (in .ppt file format) can be downloaded from inside the university local area network (e.g. Students’ Center) at this address: