Title: Adrenergic blockade critical success factors for stopping disease progression within the cardiovascu
1Adrenergic blockade critical success factors
for stopping disease progression within the
cardiovascular continuum
- Lars Rydén
- Stockholm, Sweden
2Antiadrenergic Therapy in the Cardiovascular
Continuum - State of the Art
Objectives
Review data on the CV-continuum with emphasis
on peripheral vascular resistance
and LV-dysfunction post myocardial
infarction antiadrenergic therapy in heart
failure the potential of different
antiadrenergic pharmaceuticals
3The Cardiovascular Continuum
Myocardialinfarction
Coronarythrombosis
Arrhythmia loss of muscle
Myocardialischaemia
Remodelling
Ventriculardilatation
CAD
AtherosclerosisLVH
Congestiveheart failure
Death
Risk factorssmoking,hypertension cholesterol,
diabetes
4Relationship between plasma norepinephrine and
mortality
Cumulative mortality ()
100 80 60 40 20 0
PNE gt900 pg/ml
PNE 600-900 pg/ml
PNE lt600 pg/ml
Overall plt0.0001
6
12
24
36
48
54
0
18
30
42
60
Months
(Francis et al from V-HeFT II Circulation 1993
87 V140-48)
5Biological responses mediated byadrenergic
receptors in the heart
Response Receptor mediation Cardiac myocyte
growth b1, b2, a1 Positive inotropic
response b1, b2, (a1) Positive chronotropic
response b1, b2 Myocyte toxicity b1, b2 Myocyte
apoptosis b1, ?b2
6Role of the adrenergic system in heart failure
Norepinephrine
a-adrenoreceptor
b-adrenoreceptor
Myocardial remodelling Myocyte hypertrophy Abnorma
l contractile function Myocyte apoptosis
Myocardial failure
7Role of the adrenergic system in heart failure
Norepinephrine
a-adrenoreceptor
b-adrenoreceptor
Myocardial remodelling Myocyte hypertrophy Abnorma
l contractile function Myocyte apoptosis
Myocardial failure
8The Cardiovascular Continuum
Different times for antiadrenergic therapy
Risk factor
NYHA Class
LV-dysfunction
0 I II III IV
Overt Heart Failure
Prevention
Mild
Moderate
Therapy
Severe
Time
9The discovery of adrenaline
Extract of adrenal glands from sheep causes
arterial vasoconstriction (Oliver 1893)
Water and alcohol extract a substance from the
adrenal gland with powerful action on the heart
and blood vessels (Oliver Schäter 1894)
Isolation of adrenaline
(Abel 1900)
10The use of adrenergic antagonists
1500 Ergot fungus (Claviceps purpourea) used
to stimulate labour 1900 The alkaloid,
ergotamine, found to inhibit adrenaline-induced
increase in blood pressure
11The discovery of adrenoreceptors Two types of
receptors a and b
(Ahlquist 1948)
12The synthesis of adrenergic antagonists
Synthesis of the nitrogen mustard analogue,
dibenamine. Exerts strong antiadrenergic
activity (Goodman Nickerson 1945)
Dichloroisoprenaline (DCI) - partial
b-antagonist (Slater Moran 1950) 1960 DCI
modified to first b-blocker (Pronethalol) -
toxic
13The launching of b blockers
1964 propranolol - the first b blocker
successfully launched Shortly thereafter
followed by alprenolol... .and
several others
14The Nobel Prize 1988
In medicine or physiology to Sir James
Black for the discovery of important principles
of drug treatment
15The use of b blockade in heart failure
1975
First report (Waagstein et al) Indications of
improved survival (Swedberg et al) Confirme
d in large clinical trials with carvedilol,
bisoprolol and metoprolol
1979
?
!
1996
1999
16Pharmacological differences between some b
blockers
Sympathetic activation
b1 receptors
b2 receptors
a1 receptors
Bisoprolol
Metoprolol
Bucindolol
Propranolol
Carvedilol
Cardiotoxicity
17The Cardiovascular Continuum
Myocardialinfarction
Coronarythrombosis
Arrhythmia loss of muscle
Myocardialischaemia
Remodelling
Adrenergic blockade
Ventriculardilatation
CAD
AtherosclerosisLVH
Congestiveheart failure
Death
Risk factorssmoking,hypertension cholesterol,
diabetes