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oedeme aigu des poumons est un etat pathologique où le coeur est incapable de
pomper le sang à une vitesse adequate pour repondre aux besoins des tissus
Insuffisance cardiaque : Physiopathologie
L ’insuffisance cardiaque
droite peut être isolée ou
s ’ajouter à l ’insuffisance
cardiaque gauche
(insuffisance cardiaque
globale)
Un coeur insuffisant ne
parvient plus à éliminer
Ankle edema
l'eau et le sel: la diurèse
baisse et il y a une
surcharge hydrosodée.
COMPENSATORY RESPONSES DURING
HEART FAILURE:
CARDIAC OUTPUT
FORCE REMODELING
RATE PRELOAD AFTERLOAD CARDIOMEGALY
A compensatory
ALDOSTERONE structural
response
EDEMA
CARDIAC OUTPUT
EDEMA : Compensatory response
TACHYCARDIA: An early mediated by the renin angiotensin
compensatory response mediated by aldosterone system & by
increased sympathetic tone increased sympathetic outflow
Pathophysiology : compensatory responses
10
Increased
preload
Edemas
↓ Cardiac output
Ventricular remodeling
Water and sodium retention
↑ sympathetic activity
How ?
Improving pumping action
Reduce cardiac workload
Diuretics
Ventricular remodeling ↓ Cardiac output
↑ sympathetic activity
Activation of RAAS
Thiazide diuretics :
Monotherapy with thiazide diuretics has a limited role in CHF.
Combination therapy with loop diuretics is often effective in those refractory to loop diuretics alone
K+ sparing diuretics:
Weak diuretics, but achieve volume reduction with limited K+ and Mg2+ wasting
Aldosterone antagonists:
LV systolic decreases renal flow→overactivation of RAA axis and → aldosterone
levels in CHF
Spironolactone induces 30% reduction in mortality ( progressive heart failure,
sudden cardiac death)
Gynecomastia: 10% men
Severe hyperkalemia 2% all patient
The pathophysiologic effects of hyperaldosteronemia
are diverse and extend beyond Na+ and fluid retention
Objective
:Reduction in preload through venodilatation or
reduction in afterload through arteriolar dilation or both
Remember that :
Vasodilation = increase in peripheral perfusion ??
Reflex tachycardia !
Only ACEI, ARBs & (hydralazine + isosorbide dinitrate) demonstrably improve survival
Nitrovasodilators
Advantages LV filling pressure ; pulmonary and systemic vascular resistance &
coronary blood flow (improve systolic and diastolic ventricular function )
Disadvantages no effect on systemic vascular resistance & tolerance
ARBs
Advantages over ACEI : no AngII "escape“ & bradykinin-mediated side effects
Excellent alternative in CHF patients intolerant of ACE inhibitors
ARB + aldosterone antagonist : in LV ejection fraction and quality of life scores in
patients with CHF due to systolic dysfunction
Beta receptor antagonists
CHF is fundamentally a disorder of impaired stroke volume and cardiac output
CHF symptom relief from short-term sympathomimetics e.g. dobutamine
Studies :
Long-term sympathomimetic use is associated with increased CHF mortality rates
-Blockers in CHF mortality
Mainly metoprolol & carvedilol
Explanation : -Blockers
Prevent myocardial ischemia without significantly influencing serum electrolytes
Decrease the frequency of unstable tachyarrhythmias to which CHF patients are
particularly prone
Prevent or delay progression of myocardial contractile dysfunction by inhibiting
maladaptive proliferative cell signaling in the myocardium, reducing catecholamine-
induced cardiomyocyte toxicity, and decreasing myocyte apoptosis
May induce positive LV remodeling by decreasing oxidative stress in the myocardium
Therapy is initiated at very low doses, generally less than one-tenth of the final
target dose, and titrated cautiously upward
Positive inotropic drugs
Cardiac glycosides
27
• Myocte depolarisationshift of Na
and Ca in the cell
• Ca2+ enter via Ltype channel,and
by Na +Ca2+ exchanger and
facilitate Ca2+ release from SR via
Ryanodine Receptors (RyR)Ca2+
intracellularmyocardial
contraction
• During repolarisation , Ca2+ is re-
sequestered in SR by Ca2+ -ATPase
SERCA2, removed from the cell by
Na +Ca2+ exchanger and to a lesser
extent by Ca2+ -ATPase
• The electrochemical potential of Na
+ is maintained by active transport
out of Na by Na+,K+,ATPase
Cardiac action potential
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Non nodal
tissues
Rapid
Repolarization Plateau
Rapid
Depolarization
Delayed
Diastolic Repolarization
Potential
Cardiac excitation-contraction coupling
1 2
4
3
6
6 5
Depolarisation cardiomyocytaire : Repolarisation cardiomyocytaire :
le calcium intracellulaire est sequestré à
nouveau dans le réticulum sarcoplasmique par
La dépolarisation est initiée par une Ca2+‐ ATPase (SERCA2) et par un
l’ouverture des canaux Na voltage antiporteur Na+/Ca2+.
dependants et l’entrée des ions Na La capacité d’échange Na+/Ca2+ de cet
La dépolarisation rapide inactive les cx antiporteur dépend étroitement de la
sodiques et ouvre les cx K et les canaux concentration intracellulaire de sodium:
calciques voltage dépendants de type L
favorisant l’entrée des ions Ca2+ d’une part l’antiporteur utilise le gradient
extracellulaire sodique pour déplacer du calcium vers
L’augmentation modérée de la l’espace extracellulaire contre son propre
concentration calcique intracellulaire gradient de concentration.
induit la libération du Ca2+ stocké dans D’autre part, les concentrations
le réticulum cytoplasmique (via le extracellulaires de Na+ et Ca2+ sont
récepteur à la ryanodine RYR), c’est « la
libération de calcium induite par le bien moins variables que les concentrations
calcium » intracellulaires dans des conditions
physiologiques.
L’augmentation massive de la
concentration calcique intracellulaire est Le sodium entré dans la cellule est ensuite
disponible pour interagir avec les externalisé par la Na+/K+ ATPase.
protéines contractiles, augmentant la
force de contraction.
Ca2+ is Ca 2+ entry via L
removed by channel triggers the
re-capture release of Ca2+
in SR by from SR (2)
Ca2+ - 2
ATPase 1 Ca2+
SERCA2
intracellular
4
myocardial
contraction
4 3
Ca2
removed
Na balance is from the
5 instored by cell by
NA+K+ Na+Ca2+
ATPase exchanger
Mecanism of action
Glycosides bind & inhibit the phosphorylates subunit Na
+/K + ATPase pump ↓Na+ extrusion .
Increased
intracellular (Na+)
slows extrusion of Ca
2+ via the Na + /Ca
2
2+ exchange
transporter.
At higher concentrations:
increase in sympathetic nervous system activity that influences
cardiac tissue automaticity, the genesis of atrial and ventricular
arrhythmias.
Cardiac glycosides : PK
Treatment of intoxication
Oral KCl or SLOW KCl infusion (with frequent monitoring of ECG and kalemia)
Anti-arrhythmic agents : lidocaine, propranolol, and phenytoin
Atropine if severe sinus bradycardia
Glycosides antibodies : Purified Fab fragments from anti-digoxin antisera (DIGIBIND)
Cardiac glycosides : Indications
Systolic heart failure : clinical experience
Digoxin reduces symptoms and the need for hospitalization
and improves quality of life of patients with heart failure
Digoxin does not prolong survival !!
Patients who have been withdrawn from digoxin have
experienced a worsening of heart failure
Dopamine
Low doses 2 g/kg : renal blood flow maintain an adequate GFR
in hospitalized CHF patients with impaired renal function refractory to
diuretics
Intermediate doses 2-5 g/kg : myocardial contractility
Tachycardia may actually provoke ischemia (and ischemia-induced malignant
arrhythmias) in patients with coronary artery disease
Dobutamine
-agonist of choice for the management of CHF patients with systolic
dysfunction
Pharmacologic tolerance may limit infusion efficacy beyond 4 days
addition or substitution with a class III PDE inhibitor may be necessary to
maintain adequate circulatory support.
Other inotropic positive medication
Phosphodiesterase inhibitors : Inamrinone &
milrinone : PDE3 I
Pharmacological effects (inodilators)
Stimulate myocardial contractility
Cause balanced arterial and venous
dilation
Consequent fall in systemic and pulmonary
vascular resistances and left and right-heart
filling pressure
Indications :
Coronary artery diseases
Chronic heart failure
Metabolized by CYP3A4
Natriuretic peptides (NP): hormones that help maintain sodium and fluid balance.
Elimination by:
• Receptor mediated degradation
• Breakdown by extracellular
proteases i.e. neprilysin
Neurohormonal system : neprilysin
46
Neprilysin
Other names : metalloendopeptidase, enkephalinase, neutral
endopeptidase 24.11 (NEP), vasopeptidase, an atriopeptidase.
Expressed in several tissues but most commonly in the kidney.
Catalyzes the degradation of numerous endogenous peptides,
such as
ANP, BNP, CNP
Bradykinin
Substance P
Adrenomedullin
Glucagon Nesiritide
Vasoactive intestinal peptide Neprilysin inhibitors
Calcitonin gene-related peptide :Candoxatri
Omapatrilat :
Enkephalins
Angiotensin II
Neurohormonal system: modulators
47
Neurohormonal system: modulators
48
Nesiritide :
IV administration
Associated with significant hypotension
No proof of morbidity & mortality
Neurohormonal system: modulators
49
Candoxatril :
• Oral drug
• Dose-dependent ANP and
natriuresis & Angiotensin II
• Failed to show reduction in systemic
vascular or pulmonary resistance in
patients with HF
Neurohormonal system: modulators
50
Omapatrilat :
• First dual neprilysin / ACE I /
aminopeptidase P
• Promising results : BP &
hemodynamic improvement in HF
patients
• Failed to show substantial benefit in
comparison with enalapril
• High occurrence and severity of
angioedema !!
Angiotensin receptor neprilysin inhibitor
51
ARNI
Angiotensin receptor neprilysin inhibitor
52
ARNI
LCZ696 = complex of sacubitril + valsartan ENTRESTO
Dual-acting crystalline complex composed of sacubitril and valsartan in their
anionic forms, sodium cations, and water molecules
Excretion
Sacubitril: 52-68% (primarily as LBQ657) in urine; 37-48% (primarily as
LBQ657) in feces
Valsartan: 13% in urine; 86% in feces
Angiotensin receptor neprilysin inhibitor
53
ARNI
Indications : patients with CHF (NYHA class II-IV) and
reduced ejection fraction
Adverse effects:
Most frequent (>10%) : hypotension, hyperkalemia
1-10%: cough, dizziness, orthostatic hypotension
<1% : angioedema