RAAS Hormones, Cardio-Vasular Remodeling, and Aldosterone Antagonists

RAAS Hormones, Cardio-Vasular Remodeling, and Aldosterone Antagonists

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Description: Hormones du SRAA et remodelage cardio-vasculaire, RAAS hormones and cardio-vascular remodeling, Cardiac remodeling, Heart failure is a serious disease, Inter-relations between triggers of HF, Le remodelage cardiaque, Signal-transduction pathways of cardiac hypertrophy, The changes of myosin, Structural alterations in heart failure. .

 
Author: Claude Delcayre (Fellow) | Visits: 1354 | Page Views: 5102
Domain:  Medicine Category: Biotech/Pharma Subcategory: Cardiology 
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Contents:
Hormones du SRAA et remodelage cardio-vasculaire.
Claude Delcayre
U942 INSERM Hop Lariboisi�re

RAAS hormones and cardio-vascular remodeling
� When and why is there a remodeling in CV system? � Why are RAAS hormones involved in this process? � What are the effects of RAAS hormones? � Which interest to block RAAS in HF, in HTN, in DN?

Cardiac remodeling

Normal heart

Hypertrophy

Heart failure

Heart failure is a serious disease X

EPICAL
Zannad et al. JACC 1999

Increase in aged population In France, >30 000 deaths/ year ; frequent and long hospitalisations In France, cost for society >10 MF (1,9% total medical expenses).

Inter-relations between triggers of HF

Remodeling

Contractile dysfunction

Heart Failure

Arrhythmias

Le remodelage cardiaque
Surcharge de travail cardiaque
M�canismes adaptatifs
Quantitatifs: Hypertrophie myocytaire Qualitatifs : Changements d 'expression g�nique

Hypertrophie Compens�e

Signal-transduction pathways of cardiac hypertrophy.

Heineke & Molkentin, 2006

The changes of myosin

Normal
Alpha myosin heavy chain High ATPase activity High contraction speed

Hypertrophied
Beta myosin heavy chain Low ATPase activity Low contraction speed

Le remodelage cardiaque
Surcharge de travail cardiaque
M�canismes adaptatifs
Quantitatifs: Hypertrophie myocytaire Qualitatifs : Changements d 'expression g�nique

Hypertrophie Compens�e

M�canismes d�l�t�res
Fibrose myocardique Dysr�gulations neurohormonales Alt�rations en production du NO Stress Oxydant

Insuffisance Cardiaque

Structural alterations in heart failure
muscle LIM protein (MLP)-null mouse heart

Wilding JR, Joubert F,... Ventura-Clapier R, J Physiol 2006.

Bla... bla... Swedberg et al (Circulation 1990) made the important observation that the renin-angiotensinaldosterone system becomes activated in patients with heart failure as well. Bla...bla...

A reliable marker of neuroendocrine response?

Ceconi, Dialogues in Cardiovascular Medicine 1999.

Clinical studies: the role of hormones in HF.

� HOPE: 26% decreased cardiovascular mortality in patients with coronary disease treated by ramipril 1 � CIBIS II: 34% decreased mortality in HF patients (class III-IV) with standard treatment + bisoprolol 2 � RALES: 30% decreased mortality in HF patients (class III-IV) with standard treatment + spironolactone 3
1. The HOPE Study Investigators, N Engl J Med 2000. 2. CIBIS-II Investigators and Committee, Lancet 1999. 3. Pitt et al, N Engl J Med 1999.

Post-MI LV dysfunction

Mild CHF

Moderate CHF

Severe CHF

AIRE/SAVE (ramipril/captopril)

SOLVD Treatment (enalapril)

CONSENSUS (enalapril)

CAPRICORN (carvedilol)

US Carvedilol/MERIT (carvedilol/metoprolol)
-----?----TOPCAT EMPHASISE-HF

COPERNICUS (carvedilol)

EPHESUS (eplerenone)

RALES (spironolactone)

OPTIMAAL (Losartan) VALIANT (Valsartan)

ELITE (Losartan) Valheft / CHARM (Valsartan/Candesartan)

-----?------

Effect of triple therapy with an ACE inhibitor, betablocker and aldosterone antagonist.
0: Placebo

0 1 0 1 2 3 4 4 2 3

1: ACEI 2: ACEI + BB 3: ACEI + BB + AA

4: Total lives saved over 2 years

Update of clinical trials from the Am. College of Cardiology 2003. Based on SOLVD, MERIT and EPHESUS (for NYHA II) and CONSENSUS, COPERNICUS and RALES (for NYHA III/IV).
(Cleland JGF, et al. Eur J Heart Fail. 2003)

Progression of heart failure

Cardiac function
(Hypertrophy, changes of gene expression..)

ACE inhibitors Beta-blockers Aldo Antagonists ...

Remodeling

Fibrosis, Ionic changes..

Failure
Time

HF invokes compensatory SNS and RAAS activation,
which increases blood FFAs and thereby inhibits the uptake of glucose by muscle and damages the pancreas.

Ashrafian et al, Circulation 2007

Neurohormonal activation in HF is a vicious circle

I am vicious !

The vicious circle of aldosterone in H.F.
Cardiac flow rate
Kidney perfusion Ang II (plasma/heart) Overload Aldo (heart) Aldo (plasma) Na, H2O Retention K+, Mg2+ Loss Plasma volume Arrythmias

Cardiac function

?
Cardiac catecholamines Cardiac & vascular fibrosis Coronary dysfunction

Tissue compliance

?

Predictive Role of Aldosterone and Cortisol in Patients with Chronic Heart Failure

Guder et al. Circulation 2007

ANP / BNP inhibit the RAAS

Mair J et al, Scand J Clin Lab Invest 1999

Hormones du SRAA et remodelage cardio-vasculaire

1. L'activation hormonale dans l'insuffisance cardiaque 2. Matrice extracellulaire et fibrose 3. Actions de l'aldosterone 4. Effets b�n�fiques des � anti-aldost�rones � 5. Synth�se locale d'aldosterone

Le remodelage cardiaque
Surcharge de travail cardiaque
M�canismes adaptatifs
Quantitatifs: Hypertrophie myocytaire Qualitatifs : Changements d 'expression g�nique

Hypertrophie Compens�e

M�canismes d�l�t�res
Fibrose myocardique Dysr�gulations neurohormonales Alt�rations en production du NO Stress Oxydant

Insuffisance Cardiaque

La matrice extra-cellulaire
Membrane Basal lamina Collagene

MEC
Basal lamina Membrane

Int�grine Sarcoglycane/ dystroglycane

Laminine Collag�ne IV

Collag�ne Fibronectine

Fibronectine

Myocardial infarction in rat (1 mo.)

Non infarcted zone

Infarcted zone

L.V. hypertrophy

LV

Fibrosis, Necrosis

Remodeling in HF involves cardiac fibrosis

Perivascular Scar

Interstitial

Detrimental consequences:
Decreases diastolic, then systolic, compliance. Favors arrythmias.

Cardiac fibrosis in senescence.

Young rat (3 mo.)

Senescent rat (24 mo.)

Hemalun-eosin stain

Ventricular Remodeling (in humans)

Coronary occlusion Myocardial infarction Myocardial expansion Ventricular dilatation Cardiac failure

Hours Days Weeks Months ............

Cardiac fibrosis: consequences

Fibrosis
Stiffness Heterogeneity

Diastolic dysfunction

Systolic dysfunction

Arrythmia

Heart failure

Sudden death
Zannad F 2001

Prevention / regression of fibrosis by A.C.E. Inhibitors
Species (1) Model rat 5m. rat 6m. rat 5m. man 54y. rat 14m. rat 6m. rat 6m. rat 5m. 2K-1C SA Infarct. I.C.M. SHR SHR SHR SHR Treatment Enalapril Captopril Perindopril Captopril Enalapril 5 w. 12 s. 8 w. Effect on fibrosis dim 46% perivasc. diminution normalisation Authors
Veniant & al. 93 Jalil & al. 91 Michel & al. 88 Mukherjee & Sen 91 Pahor & al. 91 Brilla & al. 91 Brilla & al. 91 Albaladejo & al. 94

6-26 m. norm. coll tot. & I/III 11 m. diminution 59% normalisation normalisation Aorta: prevention

Lisinopril Lo. 12 w. Lisinopril Hi. 12 w. Quinapril 16 s.

(1) : age at end of treatment

Hormone and cytokines antagonists

Prevents remodeling

Francis G., 2000

Inhibiteurs des r�cepteurs AT1

� Etudes ELITE : Comparaison losartan/ captopril � Etude RESOLVD : Comparaison candesartan/ placebo � Etude Val-HEFT: Comparaison valsartan/ placebo , tous les patients recevant un IEC (stratification en fonction du traitement beta-bloquant) � Etude CHARM avec le candesartan � Etude VALIANT avec le valsartan (post IDM)

Nakamura, Cardiovasc Res. 2003

Therapies of HF

Inotropic agents

Vasodilators, ACEI, Aldo antag.

Beta-blockers Ivabradine?

Transplantation

Assist. devices

New targets ??
Katz A. Heart Failure 2000

Benefits of Heart Rate Reduction

Beneficial Effects of Ivabradine on Cardiac Remodelling and RAAS Expression in Rat Severe Chronic HF

Screening

Drug treatment

0 0 Myocardial infarction

1

2 2 Echo, Holter, Randomization

3

4

5 m.

Echo, Holter, Sacrifice

70

LVEF (%)

50 40

LVEDP (mm Hg)

50 30 30

*
MI MI+Iva 0 1 2 3 4 5

20 10 0 0 1 2 3 4 5

*
MI MI+Iva

10 0

Time (months)

Time (months)

Milliez P, Samuel JL, Delcayre C. Am J Physiol, 2008.

ECG parameters after treatment

RR interval (ms)
200 150 100 50 0 Sham MI MI+Iva * 8 6 4 2 0

SDRR (ms)
6000 4000 * 2000

VPCs /24h
*



0 Sham MI MI+Iva Sham MI MI+Iva

PR (ms)
60 60

QRS (ms)
* 120

QT (ms)

40

40

80

20

20 0 Sham MI MI+Iva Sham MI MI+Iva

40

0

0 Sham MI MI+Iva

Left ventricular collagen
Peri-vascular Sham-operated Interstitial Sham-operated
Collagen volume fraction (%)

5 4 3 2 1 0 Sham

*


MI

MI

MI

MI + Iva

Collagen volume fraction (%)

7 6 5 4 3 2 1 0 10 20 30 40 LVEDP (mmHg) 50 MI MI+IVA SHAM R= 0,77133 P
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