Beta-Blocker For Reducing Cardiovascular Disease

Beta-Blocker For Reducing Cardiovascular Disease

Dr Suryono, SpJP. FIHA

Elevated HR Predicts Excessive Male CV Mortality

Elevated HR Predicts Excessive Male CV Mortality

35-64 (p < 0.001)

Age

-adj

uste

d in

cide

nce

of C

V m

orta

lity/

1000

30

20

10

0

30-6768-7576-8384-91> 92

65-94 (p < 0.01)

Men initially free of CV disease

Heart Rate

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

Elevated HR is an Important Risk FactorElevated 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

Increased Heart Rate Means Increased Hypertensive Risk

(Data adjusted for standard risk factors)(Data adjusted for standard risk factors)

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

0.5 1.0 1.5 2.0 2.5

p = 0.014

Relative RiskHR quintiles

Low 1

2

3

4

High 5

1.04

1.34

1.57

1.66

Coronary Disease : Ischaemia is Closely Linked to HR

Coronary Disease : Ischaemia is Closely Linked to HR

Andrews et al., Circulation, 1993

<10 10-19 20-29 30-39 40-49

Duration of period of HR increase (min)

60

50

40

30

20

10

0

Like

lihoo

d of

Isc

haem

ia (

%)

Magnitute of HR increase

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

n = 50

Elevated Heart Rate Increased Likelihood of CHD

Elevated Heart Rate Increased Likelihood of CHD

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

< 74 74-84 > 84 < 74 74-84 > 84

Rel

ativ

e R

isk

Heart Rate

2.00

1.75

1.50

1.25

1.00

0.75

1.25

1.40

1.10

1.49

WOMENMEN

Elevated HR Predicts Male Sudden DeathElevated HR Predicts Male Sudden Death

6

5

4

3

2

1

0

2-ye

ar a

ge-a

djus

ted

mor

talit

y ra

te

< 65 66-73 74-79 80-87 > 88

Quintile of heart rate

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

WOMEN

MEN

Elevated HR : Connection With Insulin Resistance

Elevated HR : Connection With Insulin Resistance

Heart Rate SNS tone

Beta-receptors Alpha-receptors

Acute effects Chronic effect Vasoconstriction

Low nutritional flow

Fast twitch fibers Muscle glucose uptake

Insulin resistance Dyslipidemia

HR is a Marker for Coronary RiskHR is a Marker for Coronary Risk

Palatini & Julius; J. Hypertens., 1997

Cholest Glucose

Insulin

Bloodpressure

B.M.I. Haemato-

crit

Triglycer

HDL-Ch

Heart Rate p < 0.0001

p < 0.01

p < 0.05

Correlation between heart rate and male’s death

Correlation between heart rate and male’s death

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

Lower HR can Prolong LifeLower HR can Prolong Life

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

HR Smoking SBP

Ad

just

ed

Odd

s R

atio

1.8

1.6

1.4

1.2

1.0

1.39 1.39 1.38

MEN

(n = 747)

Why does heart rate increase ?Why does heart rate increase ?

Causes of Sympathetic Nervous System (SNS) Activation

Causes of Sympathetic Nervous System (SNS) Activation

SNSActivation

GeneticFactors

AcutePhysicalStressors

Diet

PsychosocialStress

Heartrate

Cardiacoutput

Bloodpressure

Plateletaggregation

Catecholamine levels

Awareness of the Sympathetic Nervous System

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 BBRole of BB

Cardiovascular ContinuumCardiovascular Continuum

BB are equally effective?BB are equally effective?

· ISA(+) lessen anti-HT action· B2 blockade properties lessen anti-HT

action· Non selective < selective

NO

Effect of Beta-Blockers on Haemodynamic Response to an Acute Stressor

Effect of Beta-Blockers on Haemodynamic Response to an Acute Stressor

Without ISAWithout ISA With ISAWith ISA

BP controlled

Vessels

TPR reduced

Heart

HR controlled

CO

BP

Blood Platelets

Coagulation

Blood Platelets

Vessels

TPR

Heart

HR

CatecholaminesCatecholamines CatecholaminesCatecholamines

STRESS

Coagulation ?

Hypothesis for the Action of BisoprololHypothesis for the Action of Bisoprolol

Sympathetic Nervous SystemSympathetic Nervous System

Cardiac Muscle

HigherCenters

NE Storage

Adrenal Medulla

Catecholamine Production

Vascular Muscle

Vasodilation BP

SA node

HR

NeuromuscularSynapse

NE Release

SympatheticGanglia

SynapticTransmission

Adapted from Kailasam et al., Hypertension, 1995; 26: 143-149

The use of BB in clinical practiceThe use of BB in clinical practice

1. Anti Hypertensive Properties1. Anti Hypertensive Properties

· Established· since 2006 : CONTROVERSIAL

British Hypertension Society Guidelines–2004; based on renin levels

British Hypertension Society Guidelines–2004; based on renin levels

Younger (< 55 years)and non-black

Older (≥ 55 years)and black

Step 1

Step 2

Step 3

Step 4(Resistant hypertension)

A = ACE inhibitor or angiotensin receptor blocker, B = Beta-blocker, C = Calcium channel blocker, D = Duiretic (thiazide or thiazide – like)

A or B C or D

A or B plus C or D

A or B + C + D

Add either blocker or spironolactone or other

diuretic

Young HypertensiveYoung Hypertensive

· Diastolic HT ~ BMI>· Central obesity· Stimulate sympathomimetic activity

Mech of action BB in young hypertensive

Mech of action BB in young hypertensive

· Depends on renin level

· High renin or normal renin : effective

· Low renin: not effective

• Fall of systemic vascular resistance (b2) through NO release

• Fall in Plasma Nor-adr• Renin little effect

ISA (-) ISA (+)

-Antagonist may be either 1-cardioselective or non-cardioselective (1- 2 antagonism).

-Antagonist may be either 1-cardioselective or non-cardioselective (1- 2 antagonism).

Bradycardia

Negative inotropy

Lessbronchopasm

Bradycardia

Negative inotropy

Lessbronchopasm

GOOD ANTIHYPERTENSIVE EFFECTGOOD ANTIHYPERTENSIVE EFFECT

1-SELECTIVE1-SELECTIVE

Metabolic

Fewer peripheral effects

Circulatory

Metabolic

Fewer peripheral effects

Circulatory

NONSELECTIVE

(1-2)NONSELECTIVE

(1-2)

Similar cardiac and antihypertensive effects

More marked pulmonary and peripheral effects

Similar cardiac and antihypertensive effects

More marked pulmonary and peripheral effects

Sinus rate Renin inhibitonSinus rate Renin inhibiton

2. Anti Heart Failure Properties2. Anti Heart Failure Properties

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

· Bisoprolol, Carvedilol, Metoprolol: Mort <35%

Xamoterol

Bucindolol

Nevibolol

Mortality >25%

Mortality n.n. <10% ISA +

Mortality n.s.<12% (elderly)

Mechanism of anti heart failureMechanism of anti heart failure

• Bradycardia-prolonged diastolic coronary filling time

• Anti-ischaemia-decreased oxyg. requirement

• Anti-arrhythmic( sudden death)

• Inhibition of catecholamine-induced necrosis and apoptosis (beta-1)

• Up-regulation of B-1 receptors

• Inhibition of renin-angiotensin-aldosterone system

• Increase in atrial natriuretic factor

CIBIS IIIDose titration

1.25 2.5 3.75

2010

5

Random-isation

Monotherapy Combination therapy

6 to 18 months6 months

57.5

105

10

107.5

53.752.51.25

20

bisoprolol (mg/d)

enalapril (mg/d)

enalapril (mg/d)

24 months6 monthsweek

12108 36343230286420weekweek weekweek weekweek weekweek weekweek week

bisoprolol (mg/d)

3. BB and metabolic changes3. 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

DM2/obese

Insulin resistance

Insulin/leptin

Noradrenaline Release

Ventriculararrhythmias

B1 stimulation-induced cardiac and coronary artery damage

(atheroma)

BP + non-dipping at night

PRA Angiotensin II

Intra-glomerular pressure +

nephropathy

:1-blockade

4. UNSTABLE ANGINA AT REST4. UNSTABLE ANGINA AT REST

Increased O2 demand Increased

O2 demand Hypertension tachycardia O2 wastage

Hypertension tachycardia O2 wastage

Subendocardial ischemia

Subendocardial ischemia

LV end-diastolic pressure

LV end-diastolic pressure

Increased sympathetic

drive

Increased sympathetic

drive

LV failure pain

LV failure pain

Regional ischemiaRegional ischemia

Increasing ischemic damage

Increasing ischemic damage

PLATELET AGGREGATION

PLATELET AGGREGATION

HEPARIN or LMWH Aspirin

HEPARIN or LMWH Aspirin

NITRATES (intravenous) -BLOCKADE-BLOCKADE

• Gp IIb/IIIa blockers

• If troponin• High risk group

• Gp IIb/IIIa blockers

• If troponin• High risk group

Diltiazem in selectec cases

Diltiazem in selectec cases

Secondary prevention of myocardial infarction with different types of b - blockers

b1 - selectivewithout ISA

b1 - selectivewith ISA

non-selectivewithout ISA

non-selectivewith ISA

b - blockerswithout ISA

Red

uctio

n of

mor

tality

b - blockerswith ISA

-30

-20

-10

-

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

100

75

50

25

0

ICI 118,551

B1/B2

Selectivity

Ratios

PropranololMetoprolol

AtenololBetaxolol

Bisoprolol

1/25

20/1

35/135/1

75/1

1/50

1/300

1/300

12/

Wellstein et al Europ Heart J 1987

Beta1 and Beta2 Selectivity Ratios

Efektif, Aman, Terjangkau

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

Concor 2,5 & Concor 5

(Bisoprolol 2,5 & 5 mg)

Efektif, Aman, Terjangkau

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

Concor 2,5 & Concor 5

(Bisoprolol 2,5 & 5 mg)