Beta-Blocker For Reducing

Cardiovascular Disease

Dr Suryono, SpJP. FIHA

Elevated HR Predicts Excessive Male

CV Mortality
Heart Rate

Age-adjusted incidence
of CV mortality/1000

30

30-67
68-75
76-83
84-91
> 92

20

10

35-64 (p < 0.001)

65-94 (p < 0.01)

Men initially free of CV disease

Adapted from Kannel, Am. Heart. J., 1987

Elevated HR is an Important Risk Factor

Elevated HR is linked to or predicts :
Higher hypertensive risk
Ischaemia in coronary disease
Coronary heart disease
Cardiovascular mortality

Palatini & Julius; J. Hypertens., 1997

Increased Heart Rate Means Increased

Hypertensive Risk
(Data adjusted for standard risk factors)
HR quintiles
0.5

Relative Risk
1.0
1.5
2.0

2.5

Low 1
1.04

1.34

1.57

4
1.66

High 5

p = 0.014

Adapted from Selby et al., Am. J. Epidemiol., 1990

Coronary Disease : Ischaemia is Closely

Linked to HR

Likelihood of Ischaemia (%)

60
Magnitute of
HR increase

50

> 8 bpm
> 10 bpm
> 15 bpm
> 20 bpm

40
30

n = 50

20
10
0

<10

10-19

20-29

30-39

40-49

Duration of period of HR increase (min)

Andrews et al., Circulation, 1993

Elevated Heart Rate Increased Likelihood

of CHD
2.00

MEN

WOMEN

Relative Risk

1.75
1.50

1.49
1.40

1.25

1.25
1.10

1.00
0.75

< 74

74-84

> 84

< 74

74-84

> 84

Heart Rate
Adapted from Gillum, Am. Heart. J., 1991

Elevated HR Predicts Male Sudden Death

2-year age-adjusted mortality rate

MEN

5
4
3
2

WOMEN

1
0

< 65

66-73

74-79

80-87

> 88

Quintile of heart rate

Adapted from Kannel et al., Am Heart J., 1985

Elevated HR : Connection With

Insulin Resistance
Heart Rate

SNS tone

Beta-receptors
Acute effects

Alpha-receptors

Chronic effect

Vasoconstriction
Low nutritional flow

Fast twitch fibers

Muscle glucose uptake

Insulin resistance

Dyslipidemia

HR is a Marker for Coronary Risk

Cholest Glucose

HDL-Ch

Insulin
p < 0.0001

Heart Rate
Blood
pressure

Triglycer
Haematocrit

p < 0.01

p < 0.05

B.M.I.

Palatini & Julius; J. Hypertens., 1997

Correlation between heart rate and

males death

Singh AHJ suppl. 2003;5(G);G3-G9

Lower HR can Prolong Life

Adjusted Odds Ratio

1.8

MEN

1.6

1.4

1.39

1.39

1.38

(n = 747)

1.2

1.0

HR

Smoking

SBP
Adapted from Gillum, Am. Heart. J., 1991

Why does heart rate increase ?

Causes of Sympathetic Nervous

System (SNS) Activation
Genetic
Factors

Diet

SNS
Activation
Psychosocial
Stress

Acute
Physical
Stressors

Catecholamine levels
Heart
rate

Cardiac
output

Blood
pressure

Platelet
aggregation

Awareness of the Sympathetic

Nervous System
Cardiovascular risks associated with elevated
levels of plasma catecholamines
Left Ventricular Hypertrophy
Vascular Hypertrophy
Arteriosclerosis
Platelet Aggregability
Sudden Cardiac Death
Myocardial Infarction

Role of BB

Cardiovascular Continuum

BB are equally effective?

NO
ISA(+) lessen anti-HT action
B2 blockade properties lessen anti-HT
action
Non selective < selective

Effect of Beta-Blockers on Haemodynamic

Response to an Acute Stressor
Without ISA

With ISA

Heart

Heart

STRESS

HR controlled

HR

CO
BP

BP controlled
Catecholamines

Catecholamines

Vessels

Vessels

TPR reduced

TPR
Blood Platelets

Blood Platelets

Coagulation

Coagulation ?

Hypothesis for the Action of Bisoprolol

Sympathetic Nervous System
Higher
Centers

Sympathetic
Ganglia
Synaptic
Transmission
Neuromuscular
Synapse
NE Release

SA node
HR
Cardiac Muscle

Adrenal Medulla

Vascular Muscle

NE Storage

Catecholamine Production

Vasodilation BP

Adapted from Kailasam et al., Hypertension, 1995; 26: 14

The use of BB in clinical practice

1. Anti Hypertensive Properties

Established
since 2006 : CONTROVERSIAL

British Hypertension Society

Guidelines2004; based on renin
levels
Younger (< 55
years)
and non-black
Step
1

Older ( 55 years)
and black

C or
D

A or
B

Step
2
Step
3
Step 4
(Resistant
hypertension)

A or B plus C or
D
A or B + C +
D

Add either blocker or

spironolactone or other
diuretic

A = ACE inhibitor or angiotensin receptor blocker, B = Beta-blocker, C =

Calcium channel blocker, D = Duiretic (thiazide or thiazide like)

Young Hypertensive

Diastolic HT ~ BMI>
Central obesity
Stimulate sympathomimetic activity

Mech of action BB in young

hypertensive
ISA (-)
Depends on renin
level
High renin or
normal renin :
effective
Low renin: not
effective

ISA (+)
Fall of systemic
vascular
resistance (b2)
through NO
release
Fall in Plasma
Nor-adr
Renin little effect

GOOD
GOOD ANTIHYPERTENSIVE
ANTIHYPERTENSIVE EFFECT
EFFECT
Sinus
Sinus rate
rate

Renin
Renin inhibiton
inhibiton

Bradycardia
Bradycardia
Negative
Negative inotropy
inotropy

11-SELECTIVE
-SELECTIVE
Less
Less
bronchopasm
bronchopasm
Metabolic
Metabolic
Fewer
Fewer peripheral
peripheral effects
effects
Circulatory
Circulatory
NONSELECTIVE
NONSELECTIVE
(
(11-
-22))

Similar
Similar cardiac
cardiac and
and antihypertensive
antihypertensive effects
effects
More
More marked
marked pulmonary
pulmonary and
and peripheral
peripheral effects
effects

-Antagonist may be either 11-cardioselective or noncardioselective ( 11- 22 antagonism).

2. Anti Heart Failure Properties

New
NOT all beta blockers are EQUAL
NON-ISA is vital component
Xamoterol

Mortality >25%

Bucindolol

Mortality n.n. <10%

Nevibolol

Mortality n.s.<12% (elderly)

ISA +

Bisoprolol, Carvedilol, Metoprolol: Mort

<35%

Mechanism of anti heart failure

Bradycardia-prolonged
diastolic coronary
filling time
Anti-ischaemiadecreased oxyg.
requirement
Antiarrhythmic( sudden
death)
Inhibition of
catecholamineinduced necrosis and
apoptosis (beta-1)

Up-regulation of B1 receptors
Inhibition of reninangiotensinaldosterone system
Increase in atrial
natriuretic factor

CIBIS III
Dose titration
week week week week week week week
12
0
2
4
6
8
10

6 months

week week week week week

28
30
32
34
36

24 months

20

1.25

2.5 3.75

Random
-isation

7.5

10

10

10

enalapril (mg/d)

bisoprolol (mg/d)
3.75
1.25 2.5

20
5

7.5

10

bisoprolol (mg/d)

enalapril (mg/d)

Monotherapy

Combination therapy

6 months

6 to 18 months

3. BB and metabolic changes

B2-blockage: HbA1-c, BS, FFA, insulin
sensitivity, TG, VLDL, HDL
Non selective (propranolol, timolol, nadolol)
or partially selective (atenolol, metoprolol) :
the offenders
Highly B1-selective(bisoprolol), a-b1
(carvedilol)
Non selective may also block B3 receptor:
increased obesity and diabesity

1-blockade benefits in central

obesity/insulin resistance/DM2 with
hypertension
:1-blockade

DM2/obe
se
Insulin
resistance
Insulin/leptin
Noradrenaline
Release
PRA

Ventricular
arrhythmias
B1 stimulation-induced
cardiac and coronary artery
damage (atheroma)

BP + nondipping at
night

Angiotensin
II
Intraglomerular
pressure +
nephropathy

4. UNSTABLE ANGINA AT REST

HEPARIN
HEPARIN
or
or LMWH
LMWH
Aspirin
Aspirin

PLATELET
PLATELET
AGGREGATION
Gp
Gp IIb/IIIa
IIb/IIIa
blockers
blockers
IfIf troponin
troponin
High
High risk
risk group
Diltiazem
Diltiazem in
in
selectec
selectec cases
cases

NITRATES
(intravenous)
Increased
Increased
O
O22 demand
demand

-BLOCKADE
-BLOCKADE
Hypertension
Hypertension
tachycardia
tachycardia
O
O22 wastage

Subendocardial
Subendocardial LV
LV end-diastolic
end-diastolic
ischemia
pressure
ischemia
pressure

Increased
Increased
sympathetic
sympathetic
Increasing
Increasing
drive
drive
ischemic
ischemic
damage
damage
LV
LV failure
pain
pain
Regional
Regional
ischemia
ischemia

Reduction ofmortality

Secondary prevention of myocardial

infarction with different types of blockers
1 - selective

-30

without ISA
non-selective
without ISA

-20

1 - selective
with ISA
non-selective
with ISA

-10

- blockers
without ISA

- blockers
with ISA

Yusuf S et al. Progress Cardiovasc. Diseases 1985; 5: 335-371

Beta1 and Beta2

Selectivity Ratios
100
75/
1

75
50

B1/B2
Selectivity
Ratios

20/
1

25
0
1/25
1/
50

1/
300

35/
1

35/
1

1/
2
Propranolol
Atenolol
Bisoprolol
Metoprolol
Betaxolol

1/300
ICI 118,551

Wellstein et al Europ Heart J 1987

Efektif, Aman, Terjangkau

Lodoz

2,5 &

Lodoz

(Bisoprolol 2,5 & 5 mg + HCT 6,25)

Concor 2,5 &

Concor 5
(Bisoprolol 2,5 & 5 mg)

Thank You