RESPIRATORY FAILURE Miklós Molnár Semmelweis University Institute of Pathophysiology 2005.
Etiopathogenesis of heart failure and pathophysiology of ...
Transcript of Etiopathogenesis of heart failure and pathophysiology of ...
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Etiopathogenesis of heart failure
and pathophysiology of therapy
Fedor Šimko
ÚPF LFUK, Bratislava
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Disclimer slide –prednáška je určená len na
výučbové potreby medikov LFUK v Bratislave
Fedor Šimko
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Heart failure –
the cardiovascular problem No. 1
Frequent (above 70 years - 10 % prevalence)
Poor prognosis – 5-year mortality - 50%
Economic burden
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Factors regulating the
pumping function of the heart
preload
contractility
afterload
heart rate
synergism of individual heart parts
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Preload
Is the load present in the left
ventricle before starting the
contraction – systole
//
- end-diastolic volume
- end diastolic pressure
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Preload is associated with Frank-
Starling mechanism:
The force of contraction during
systole depends on the initial
length of muscular fibres
(up to 2,2 um sarcomer size) – in
this point the maximal number of
act-myosin bridges can be
formed
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ContractilityIs a factor modifying the contractile
ability independently from end-diastolic
length of fibres (sarcomeres)
but depending from positive or negative
inotropic factors
(Positive inotropic substances increase
the speed of actino-myosine bridges
formation)
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Afterload- wall tension during
systole
depending from:
– Aortic compliance
- Peripheral arteriolar resistance
- Blood volume in arterial bed
T= P x r/2h – La-Place law
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Heart rate increases minute volume
by more frequent emptying the
ventricles
- Frequency effect
-critical value of heart rate
- Unfavorable in aortic or mitral valve
stenosis
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Synergism of heart
parts
Base, middle part, apex
Right and left ventricles
Atrias and chambers
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Heart failure is the state, when
the heart is not able to maintain
the adequate perfusion of the
periphery
despite normal or increased
filling pressure
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Heart failure:
Systolic vs. Diastolic
Acute vs. Chronic
Left HF vs. right HF
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Etiology of HF
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1. Myocardial damage
Ischemic heart disease
cardiomyopathies
myocarditis
toxic damage
heart damage in endocrinopathies
2. Chronic hemodynamic overload
presure
volume
3. Heart rythm disorders
4. Restricted filling of the ventricles
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Most frequent reasons of HF
HYPERTENSION
ISCHEMIC
HEART
DISEASE
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Forward failure -hypoperfusion of the periphery
Backward failure - blood
congestion in front of the
failing ventricle
2 types of HF manifestations
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Forward failure - hypoperfusion
of the periphery (muscles!!!, skin,
kidney, other organs)
Backward failure - congestion (LV,
LA, lungs!!!)
Dyspnea
Fatigue, weekness,
renal failure, cold extremities, cachexia
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Compensatory mechanisms of
HF
1. Frank- Starling mechanism
2. Neurohumoral activation
(SNS, RAAS, ADH)
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Physiologic myocardium Concentric hypertrophyin pressure oveload
Excentric hypertrophy in volume overload
Primary dilatation Secondary dilatation
Hypertrophy of the heart
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Oedema model of HF
• Impaired pumping
function
• Reduction of renal
flow
• Impaired water
secretion
• Oedema
• Increased ventricular
pressure
• Increase in venous
pressure
• Impaired venous return
from kidney
• oedema
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Prognosis predictors in CHHF
Norepinephrine level
Renin level
Ejection faction
Size of the LV in diastole
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Obrázok noradrenalínovej
závislosti
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Hemodynamic overload /loss of myocytes
Stroke volume Proliferative effect
AdrenalinNoradrenalin
Ang IIEndothelin
Arg.-vasopressin
Aldosterone
Retention ofNa+, H2O
Tension in LV wall
endothelial dysfunction,
atherosclerosis
O2 demands O2 supply
Myocardial ischaemia,LV remodelling, LV dysfunction
Myocardial hypertrophy and fibrosis
frequency
contractility
Neurohumo-
ral model of
HF
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Pathophysiology of HF
therapy
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Original approach:
Increased contractility: positive
inotropic drugs
Reduction of volume retention –
diuretics
Reduction of heart burden -decrease of preload/afterload
vasodilatation
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Positive effect –
Enhancement of contractility
and heart rate
MV = SV x P
Neurohumoral activation -
acute
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Positive effect
Increased
contractility and HR
Neurohumorl activation –
chronic HF
Negative effect
Pathologic
remodeling
ATP
devastation
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Angiotensin II
Aldosterone
Catecholamines
Endothelin
Bradykinin
NO – nitric oxide
Prostacycline
Natriuretic peptide
Pathologic heart remodeling
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Trial ACE I % mortality
SAVE captopril from 25 to 20%
TRACE trandolapril from 42 to 35%
AIRE ramipril from 23 to 17%
SOLVD enalapril from 40 to 35%
ACE inhibitors
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Trial AT1 blocker % mortality
ELITE losartan from 9 % to 5%
ELITE II losartan from 16 % to 17.7%
Angiotensin receptor blockers
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Trial ACEI + AldB % mortality
RALES spironolactone reduction by 30%
Ephesus eplerenone reduction by 16%
Aldosterone receptor blocker
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Trial ACEI + Drug % mortality -
increased
PROMISE Milrinone from 24 % to 30 %
XAMOTEROL Xamoterol from 4 % to 9 %
VEST Vesnarinone from 19 % to 23 %
PRIME - II Ibopamine from 20 % to 25 %
Inotropic trials
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Trial ACEI + inotr.drug % mortality
-
increased
DIG digoxin from 35,1% to 34,8%
+ sympt. improvement
Inotropic trialsInotropic trials
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Trial ACEI + BB % mortality
CIBIS II bisoprolol from 17 to 12%
Merit HF metoprolol from 11 to 7%
COPERNICUS carvedilol from 20 to 12%
N. America carvedilol from 7.8 to 3.2%
Beta blockers
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Hemodynamic overload /loss of myocytes
Stroke volume Proliferative effect
AdrenalinNoradrenalin
Ang IIEndothelin
Arg.-vasopressin
Aldosterone
Retention ofNa+, H2O
Tension in LV wall
endothelial dysfunction,
atherosclerosis
O2 demands O2 supply
Myocardial ischaemia,LV remodelling, LV dysfunction
Myocardial hypertrophy and fibrosis
frequency
contractility
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SHIFT:
Primary endpoint : combined CV death + hospit. HF
Ivabradine – reduction of HR by 10/min
and of prim. endpoint by 18%
5.Elevated HR as a risk: beside BB
Ivabradine (If channel blocker
in SA node
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Neprilisin inhibitor AT1 blocker+
ANPAdrenomeduline
Bradykinin
Antiremodeling
vasodilatation
Angiotensin II
effect
Antiremodeling
vasodilatation
Additive mortality reduction in HF
compared to ACEI
SACUBITRIL VALSARTAN
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Pathomechanisms of HF therapy
Reduction of neurohumoral activation
(ACEI, ARB, BB, AldB, sacub.+ARB)
Reduction of fibrosis
(ACEI,ARB, AldB, sacub.+ARB
Reduction of hemodynamic load
(ACEI, ARB, sacub.+ARB)
Reduction of catecholamine danger
-BB (reduction of uncoupling + reduction of HR+
reduction of dysrrhytmias)
HR reduction
(ivabradine)
remodeling
ATP
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first choice – positive
inotropic drugs
betablockers- contraindicated
in HF
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Why did pathophysiological
considerations fail?Calcium is not decisive in heart failure
Calcium is decisive, but not the amount but the compartmentalisation
ATP is more decisive than calcium
Neurohormonal activation is decisive, but not through inotropy but through remodeling or
everything is different
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Recent 30 years – great advance in HF treatment
still -
we are at the beginning