Transcript Herpes Viruses, Cytokines & Hemostasis in Vital Exhaustion

Herpes Viruses, Cytokines
& Hemostasis
in Vital Exhaustion
A psychobiological pathway
to coronary artery disease?
Participants
R. Van Diest
M. Kwaijtaal
A. Appels
M. Maes
A. Van der Ven
C. Bruggeman
M. De Baets
F. Bär
K. Hamulyak
G. Van der Pol
Grants
The studies are supported by grants from:
 The Dutch Heart Foundation.
 Profileringsfonds azM.
Herpes Viruses &
Atherosclerosis (I)
Herpes virus infections have been implicated
in atherosclerosis by:




Infecting the arterial wall.
Altering vascular cell lipid metabolism.
Induction of cytokines and growth factors.
Procoagulant effects on the vascular
endothelium.
Herpes Viruses &
Atherosclerosis (II)
The group of herpes viruses include:




Herpes simplex virus (HSV).
Varicella Zoster virus (VZV).
Epstein Barr virus (EBV).
Cytomegalovirus (CMV).
Herpes Viruses &
Atherosclerosis (III)
Association of herpes viruses with CAD.
 Individual herpes viruses do not
consistently raise the risk of CAD.
Association of pathogen burden with CAD.
Pathogen burden (PB) is the aggregate number of
herpes viruses to which individuals have been
exposed during their life.
 An increased PB raises the risk of CAD.
Vital Exhaustion
 VE focuses on the fatigue, irritability, and
general malaise that precedes CAD in over
50% of all cases.
 VE predicts future CAD or new cardiac events
in both healthy and cardiac populations.
Objectives
To examine:
 The association of VE with PB.
 The interaction of VE and PB with measures of
hemostasis and inflammation.
Methods (I)
Participants
 29 exhausted males
 30 control males
Mean age
51.1 SD = 4.5
52.2 SD = 5.1
Methods (II)
The following measures were assessed:
Infection IgG antibodies HSV (1 & 2), VZV,
EBV, CMV.
Inflammation
lL-1ra, IL-6, IL-8, IL-10.
Coagulation
fibrinogen.
Fibrinolysis
plasminogen activator
inhibitor activity (PAI-1).
Methods (III)
Definition of PB:
 The aggregate number of seropositive tests to
IgG-antibodies for HSV, VZV, EBV, and CMV.
Definition of low and high PB:
 Low PB seropositivity to 1-3 of these viruses.
 High PB seropositivity to all 4 viruses.
Results (I)
Exhausted individuals did not differ from controls
in:
 Physical exercise, body mass index.
 Heart rate, blood pressure.
 Glucose, lipids & routine blood chemistry.
Results (II)
Exhausted individuals displayed significantly
higher levels of:
 Fibrinogen.
 Plasminogen activator inhibitor activity.
 IL-1ra, IL-6 and IL-10.
Results (III)
PB Exhausted (N=29) Controls (N=30) P
2 or 3
27.6%
83.3%
0.001
4
72.4%
16.7%
Pathogen burden was higher in vital exhaustion
Results (IV)
3 groups were identified to investigate the
interaction of VE and PB on hemostasis and
inflammation:
 Low VE / low PB
 Intermediate
 High VE / high PB
N = 25
N = 13
N = 21
Results (V)
PAI-1:act (U/m l )
FNG (g/l )
3,5
12
3
7,5
p = 0.02
p = 0.01
2,5
3
0
1
2
Grou p
3
4
0
1
2
Grou p
3
4
Conclusions (I)
 VE is associated with a high PB.
 The interaction of VE with PB revealed
significant linear increases in measures of
hemostasis and inflammation.
Conclusions (II)
Stress-related alterations in hemostasis and
inflammation are not necessarily linked to one
particular herpes virus infection, but rather to:

An increase in aggregated
seropositivity to herpes virus
infections in general.
Vital Exhaustion &
Inflammation
 Cytokine levels are increased in:
 Exhausted healthy individuals.
 Exhausted PCI patients.
 Exhausted individuals may suffer
from a low level inflammatory state.
Atherosclerosis &
Inflammation
 Considerable evidence has emerged that
atherosclerosis is a chronic inflammatory
process.
Background
 The next study is part of the EXIT project.
 EXIT tested the hypothesis that lowering VE
decreases the risk of new cardiac events.
Objectives
Exhausted individuals may suffer from a
low level inflammatory state.
To test the hypothesis that:
 Lowering of VE in PCI patients reduces the
risk of new cardiac events by reducing this low
level inflammatory state.
Methods (I)
In one participating center (Maastricht) blood
samples were collected at:
 1 month after the intervention.
 6 months.
 18 months of follow-up.
Methods (II)
Participants
Maastricht
Medication
Total
Intervention group
Control group
-
250
22
228
111
117
Methods (III)
 Pro-inflammatory markers:
 IL-6, soluble IL-6 receptor.
 IL-8, TNF-.
 C-reactive protein, neopterin.
 Anti-inflammatory markers:
 IL-10.
 soluble TNF- p55 and p75 receptors.
 IL-1 receptor antagonist.
Methods (IV)
Serological measures of infection (IgG):
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CMV
CP
HSV (1 & 2)
VZV
EBV
Physical evidence of pathogen presence (PCR):
 CMV
 CP
Results (I)
Biography
Intervention
Control
Age
54.9 (0.6)
52.8 (0.7)
BMI
26.9 (0.4)
27.2 (0.4)
BP sys
132.5 (1.9) 132.6 (2.0)
BP dias
82.4 (1.0)
83.4 (1.1)
No differences were found for smoking
p
NS
NS
NS
NS
Results (II)
Biography
Male
Female
Intervention N=111 80.2% 19.8%
Controls N=117
74.4% 25.6%
p=0.036
Preliminary Results (I)
CP IgA
CP IgG
100
80
60
40
20
0
2
4
6
8
10
12
14
16
18
0
20
Intervention
Control
0
2
4
6
8
10
12
14
16
18
20
Preliminary Results (II)
Log soluble TNF-p55 receptor over time
soluble p55
0.13
Log Soluble TNF-alpha p55 receptor
Log TNF-over time
TNF-alpha
0,73
0.11
0.10
0.09
0.08
0.07
0.06
0.05
0,71
0
2
4
6
8
10
12
14
16
18
20
18
20
Time in months
Intervention
Log soluble
Control
TNF-p75 receptor over time
soluble p75
0,70
0,42
0,40
0,69
0,68
0
2
4
6
8
10
12
Time in months
Intervention
Control
14
16
18
20
Log TNF-alpha p75 receptor
Log TNF-alpha
0,72
0.12
0,38
0,36
0,34
0,32
0,30
0,28
0
2
4
6
8
10
12
Time in months
Intervention
14
16
Preliminary Results (III)
Log IL-1 receptor antagonist over time
IL-1 receptor antagonist
Log IL-1 receptor antagonist
-0,68
-0,70
-0,72
-0,74
-0,76
-0,78
-0,80
0
2
4
6
8
10
12
Time in months
Intervention
Control
14
16
18
20
Preliminary Results (IV)
C-reactive protein:
Fast events (within 180 days)
Cardiac events
Low
High
P
Yes
11
8
0.15
No
103
106
Slow events (after 180 days)
Cardiac events
Low
High
P
Yes
9
14
0.03
No
94
92
Preliminary Results (IV)
C-reactive protein:
Slow events
Survival Function
1.02
1.00
.98
.96
.94
.92
Cum Survival
.90
CRP group
.88
.86
High
.84
Low
-200
0
200
400
600
days between endpoint - intake
800
1000
1200