The role of peripheral resistance

1
The role of peripheral resistance

• T Lüscher, Zürich, Switzerland

2
Chain of events leading to endstage heart disease
Myocardial
infarction
Coronary
Arrhythmia
Sudden death
thrombosis
loss of muscle
Silent
Myocardial
Remodelling
Angina
ischaemia
Hibernation
Ventricular
CAD
dilatation
Stroke
Congestive
Atherosclerosis
heart failure
LVH
Endstage
Risk factors
heart
(CHOL, BP
a
, DM, smoking)
disease
platelets, fibrinogen
3
Haemodynamic features of congestive heart failure
4
Haemodynamic effectsRole of neurohormones in
progressive heart failure
Vasoconstriction ? Peripheral resistance
Neurohormonal stimulation
LV dysfunction
LV remodelling
?
Impaired myocardial function
Cohn (1995)
5
Microneurography
Multi-unit, postganglionic sympathetic
activity
of muscle vasoconstrictor fibres
R
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R
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6
Muscle sympathetic nerve activity in congestive
heart failure
Normal subject
Heart failure patient
Leimbach (1996)
7
(No Transcript)
8
Local vascular regulatory mechanisms
Adrenergic nerve ending
Action
potential
Prostanoids
Histamine
Dopamine
Epinephrine
ADP/ATP




5-HT
Angiotensin II
Ach
a
2
NE
(ATP)
(NPY)
a
a
2
1
P
Smooth muscle cell
Relaxation
Contraction
9
Neurohumoral adaptations in congestive heart
failure
Median plasma norepinephrine (pg/ml)
Median plasma renin activity (ng/ml/h)
600
2.0
p0.02
p0.0001
p0.0003
400
1.0
p0.03
200
n54
n151
n81
n56
n151
n80
0
0
Control Prevention Treatment (242450)
(312566) (368644)
Control Prevention Treatment (0.30.9)
(0.31.6) (0.53.8)
Median plasma AVP (pg/ml)
Median plasma ANF (pg/ml)
4
200
p0.0001
p0.0001
3
p0.005
p0.0001
100
2
1
n54
n147
n80
n54
n147
n80
0
0
Control Prevention Treatment (3165)
(69139) (91203)
Control Prevention Treatment (1.42.3)
(1.73.0) (2.34.4)
10
Pharmacotherapy of congestive heart failure
Positive inotropic
Vasodilators
Neurohumoral
Diuretics
agents
blockers
Nitrovasodilators
ACE inhibitors
Loop diuretics


Na
/K
-ATPase inhibitors
Thiazides
Hydralazine
AII antagonists
-adrenergic agonists
b
Aldosterone
blockers
b
antagonists
(Phosphodiesterase inhibitors)
(Flosequina
n)
(ET antagonists)
11
Haemodynamic and metabolic effects of
vasoconstriction

• Haemodynamic
• increase in cardiac afterload
• decrease in renal perfusion
• Metabolic
• increase in insulin resistance
• dyslipidaemia

12
Haemodynamic effects of unopposed b blockade
Unopposed b blockade
Heart
Vasculature
? Heart rate ? Blood pressure
? Systemic vascular resistance ? Peripheral blood
flow ? Substrate utilisation
? Myocardial oxygen demand
13
Pharmacological differences within the b blocker
classAgents currently evaluated for heart failure
b1 b2 a1
Ancillary blockade blockade blockade
ISA effects
Carvedilol -
Metoprolol - - - - Bisoprolol
- - - - Bucindolol - -
anti-oxidant, anti-endothelin, anti-proliferative
14
Chronic haemodynamic effects of carvedilol in
elderly hypertensives
Mean calf blood flow (n11) (ml/100 ml tissue/min)
4.0 3.0 2.0 1.0 0.0
Right side Left side
plt0.001
plt0.01
2.6
2.5
1.8
1.7
Baseline 8 weeks
Baseline 8 weeks
Mean age 68.6 years
Nagakawa (1990)
15
Effect of acute propranolol and carvedilol
treatment on peripheral blood flow
Lower limb blood flow (ml blood/100 ml tissue/min)
Lower limb blood flow (ml blood/100 ml tissue/min)
4.0 3.0 2.0 1.0 0.0
4.0 3.0 2.0 1.0 0.0
1min 2min 10 min
Post exercise
1min 2min 10 min
Post exercise
Before propranolol
Before carvedilol
After propranolol
After carvedilol
Wendt (1992)
16
Effect of 4 weeks carvedilol treatment in POAD
patients (n11)
Mean walking distance (m)
Doppler index
1.0
160
140
0.9


120
0.8
100


0.7

80

0.6
0.5
0.4
0.3
Day 2
Day 16
Day 30
Baseline
plt0.05 vs baseline (rest) plt0.05 vs baseline
(post-exercise)
Doppler index (rest) Doppler index
(post-exercise) Mean walking distance
Bauriedel et al (2000)
17
Reduction of hypertrophy by vasodilation
a-antagonist versus hydralazine in patients
receiving ? blockers diuretics
Left ventricular mass (g/m2)
10
0
Hydralazine (20015)
-10
Prazosin (18118)
-20
plt0.05
-30
-40
3
6
9
12
End of titration
Months of maintenance
Leenen et al (1987)
18
Absolute changes in LV ejection fraction and
volumes After long-term treatment with
metoprolol or carvedilol
LV ejection fraction
ml/m2
LV EDV
LV ESV
0
16
p0.038
-5
14

-10
12
-15
10

-20
8


-25
6
-30
4

-35
2

-40
plt0.01 (versus baseline) plt0.001 (versus
baseline)
0
Metoprolol
Carvedilol
Metra (2000)
19
Haemodynamic benefits of combined a/b blockade
Combined a/b blockade
Heart
Vasculature
? Heart rate ? Blood pressure
? Systemic vascular resistance ? Peripheral blood
flow ? Substrate utilisation
? Myocardial oxygen demand
20
Central and peripheral effects of adrenergic
system activation
Adrenergic activation
Vasculature
Heart
? Renal blood flow
Adverse metabolic effects
? Afterload
Tachycardia
Remodelling
Increased myocardial oxygen consumption
Hypertrophy Apoptosis
? Fluid retention
Worse risk profile
Worsening of heart failure
21
Prognostic significance of renal function in
heart failure patientsSOLVD prevention trial
Cr Cl Cr Cl p RR p lt60
ml/min ?60 ml/min
Total mortality 22.1 13.6 lt0.001 1.41 ?0.001
Pump failure death 7.5 3.7 lt0.001
1.68 ?0.01
Creatinine clearance - moderate renal failure
defined as lt60 ml/min
Dries et al (2000)
22
Carvedilol improves renal blood flow in heart
failure patients
Renal blood flow (ml/min)

900
Baseline
800
6 months
700
600
500
400
300
200
100
0
Placebo
Metoprolol
Carvedilol
(n4)
(n4)
(n6)
p0.02 vs placebo and metoprolol (6
months) p0.03 vs baseline
Abraham et al (1998)
23
Change in urinary albumin level with carvedilol
or atenolol
Patients ()
30
Carvedilol (n65)
Atenolol (n69)
25
20
15
10
5
0
Reduction
Increase
Duration 2 monthsThe overall between-drug
comparison was statistically significant in
favour of carvedilol (p0.017)
Marchi and Ciriello (1998)
24
Central and peripheral effects of adrenergic
system activation
Adrenergic activation
Vasculature
Heart
? Renal blood flow
Adverse metabolic effects
? Afterload
Tachycardia
Remodelling
Increased myocardial oxygen consumption
Hypertrophy Apoptosis
? Fluid retention
Worse risk profile
Worsening of heart failure
25
Mechanisms by which b blocking agents alter
lipid profile
Untreated Treatment with
Metabolic hypertension b blockade consequenc
es Muscle LPL activity ? ? ? ? Clearance of
triglycerides LCAT activity ? ? ? HDL Body
weight Often? ? weight gain ? Insulin sensitivity
Insulin secretion ? 1st phase ? 2nd phase,
prolonged hyperinsulinemia Insulin
clearance ? ? ? Hyperinsulinemia ?
Insulin resistance Peripheral blood flow ? ? ?
? Substrate delivery ? Glucose uptake TPR
? (?) ? Peripheral blood flow
Jacob et al (1998)
26
Effects of subchronic b blockade treatment (gt2
months) on insulin sensitivity
Celiprolol
Carvedilol
Dilevalol
Pindolol
Atenolol
Metoprolol
Propranolol
-30
-20
-40
-10
0
10
20
30
40
Change above baseline
Jacob et al (1998)
27
Relative changes in insulin sensitivity Effect
of 24-week selective b1 and combined a / b
blockade
Relative change ()
Carvedilol Metoprolol
25
20
15
plt0.05 vs baseline
10
5
0
-5
-10
-15

-20


-25
GIR MCR ISI
GIR glucose infusion rate MCR metabolic
clearance rateISI insulin sensitivity index
Jacob (1996)
28
Glucose metabolism and insulin sensitivity in
diabetics with hypertension
Glucose level
Insulin sensitivity index
Insulin level during clamp procedure
Absolute change (mmol/l)
Absolute change (pmol/l)
120
1.0
0.03
0.8
0.02
80
0.6
0.4
0.01
40
0.2
0.03
0
0
-0.2
-0.01
-40
-0.4
-0.6
-0.02
-80
-0.8
-1.0
-0.03
-120
Carvedilol (n23)
Treatment duration 24 weeks
Atenolol (n22)
Giugliano et al (1997)
29
Lipid levels during selective b1 or a / b
blockade in diabetics with hypertension
Carvedilol (n23)
Atenolol (n22)
Absolute change (mmol/l)
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
-0.8
TG
HDL
TG
HDL
Giugliano et al (1997)
30
Changes in lipid profiles after 6 months
treatment with carvedilol and captopril
Change after 6 months ()
Carvedilol 2550 mg o.d. (n110) Captopril 255
0 mg o.d. (n110)
15 10 5 0 -5 -10 -15 -20
plt0.0001
Total cholesterol
Triglyceride
HDL cholesterol
LDL cholesterol
Hauf-Zachariou (1993)
31
Chain of events leading to endstage heart disease
Myocardial
infarction
Coronary
Arrhythmia
Sudden death
thrombosis
loss of muscle
Silent
Myocardial
Remodelling
Angina
ischaemia
Hibernation
Ventricular
CAD
dilatation
Stroke
Congestive
Atherosclerosis
heart failure
LVH
Endstage
Risk factors
heart
(CHOL, BP
a
, DM, smoking)
disease
platelets, fibrinogen