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Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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Demography Prevalence of symptomatic HF %, 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
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Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University
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Page 1: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Heart failure

Laszlo L. TornociInst. Pathophysiology

Semmelweis University

Page 2: Heart failure Laszlo L. Tornoci Inst. 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.

Page 3: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 4: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Classification

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

Page 5: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Complaints

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

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

Page 6: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Physical findings

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

– Left heart, backward failure• pulmonary rales

– Miscellaneous• cyanosis• S3 gallop

Page 7: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Causes of heart failure

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

clinical condition worse, ‘decompensate’ the patient)

Page 8: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Underlying causes

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

Page 9: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 10: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Precipitating causes 2.

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

Same workload, but weaker heart

Page 11: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Terms

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

Page 12: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 13: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 14: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 15: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 16: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 17: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 18: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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]

Page 19: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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]

Page 20: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Some of the factors affecting contractility

• sympathetic stimulation• hypertrophy

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

increase decrease

Page 21: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 22: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

]

Page 23: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 24: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 25: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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]

Page 26: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

]

Page 27: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Neurohormonal response to HF

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

• Inflammatory reaction• Hypertrophic response

Overview

Page 28: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Neurohormonal response

• Systemic• Organ• Cellular

Effects by levels

Fluid retention, fatigue, cachexia

Hypertrophy, remodeling

Change of myosin isoforms, Ca++

torlasz:

more examples are needed

Page 29: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Neurohormonal response to HF

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

• Inflammatory reaction• Hypertrophic response

Overview

Page 30: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

++

+++

+++

Page 31: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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:

Page 32: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Hemodynamic defense reactionAdaptive (beneficial), short term responses

salt and water retention preload cardiac output

vasoconstriction afterload BP

cardiac stimulationcontractility relaxation

HR

cardiac output

Page 33: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 34: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Neurohormonal response to HF

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

• Inflammatory reaction• Hypertrophic response

Overview

Page 35: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Inflammatory reaction

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

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

Page 36: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Neurohormonal response to HF

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

• Inflammatory reaction• Hypertrophic response

Overview

Page 37: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 38: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 39: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 40: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Therapy

• Emergency setting– keep the patient alive!

• Usual setting– alleviate symptoms (improve QOL)

– prolong survivalcontradiction is possible!

Goals of therapy in general

Page 41: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Classical approaches in drug therapy

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

• Heart– positive inotropic agents (digitalis)

Page 42: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 43: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Maladaptive features of the vasoconstrictor response

vasoconstriction

afterload

cardiac output

myocardial energyexpenditure

myocardial cell death

arrhythmias,sudden death

survivalworsesymptoms

Page 44: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Expected response to vasodilators

vasoconstriction

afterload

cardiac output

myocardial energyexpenditure

myocardial cell death

arrhythmias,sudden death

survivalbettersymptoms

Page 45: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

Actual response to vasodilators

vasoconstriction

afterload

cardiac output

myocardial energyexpenditure

myocardial cell death

arrhythmias,sudden death

survival bettersymptoms

BP

hemodynamicdefense reaction

hypertrophy

Page 46: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 47: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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.

Page 48: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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

Page 49: Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University.

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:


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