1. Herpes Viruses, Cytokines & Hemostasis in Vital Exhaustion A psychobiological pathway to coronary artery disease?

2. 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

3. Grants The studies are supported by grants from:  The Dutch Heart Foundation.  Profileringsfonds azM.

4. 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.

5. Herpes Viruses & Atherosclerosis (II) The group of herpes viruses include:  Herpes simplex virus (HSV).  Varicella Zoster virus (VZV).  Epstein Barr virus (EBV).  Cytomegalovirus (CMV).

6. 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.

7. 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.

8. Objectives To examine :  The association of VE with PB.  The interaction of VE and PB with measures of hemostasis and inflammation.

9. Methods (I) Participants Mean age  29 exhausted males 51.1 SD = 4.5  30 control males52.2 SD = 5.1

10. Methods (II) The following measures were assessed: Infection I gG 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).

11. 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 PBseropositivity to 1-3 of these viruses.  High PBseropositivity to all 4 viruses.

12. Results (I) Exhausted individuals did not differ from controls in:  Physical exercise, body mass index.  Heart rate, blood pressure.  Glucose, lipids & routine blood chemistry.

13. Results (II) Exhausted individuals displayed significantly higher levels of:  Fibrinogen.  Plasminogen activator inhibitor activity.  IL-1ra, IL-6 and IL-10.

14. Results (III) 16.7%72.4%4 0.00183.3%27.6% 2 or 3 P Controls (N=30) Exhausted (N=29) PB Pathogen burden was higher in vital exhaustion

15. Results (IV) 3 groups were identified to investigate the interaction of VE and PB on hemostasis and inflammation:  Low VE / low PBN = 25  IntermediateN = 13  High VE / high PBN = 21

16. Results (V)

17. 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.

18. 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.

19. Vital Exhaustion & Inflammation  Cytokine levels are increased in:  Exhausted healthy individuals.  Exhausted PCI patients.  Exhausted individuals may suffer from a low level inflammatory state.

20. Atherosclerosis & Inflammation  Considerable evidence has emerged that atherosclerosis is a chronic inflammatory process.

21. Background  The next study is part of the EXIT project.  EXIT tested the hypothesis that lowering VE decreases the risk of new cardiac events.

22. Objectives 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. Exhausted individuals may suffer from a low level inflammatory state.

23. Methods (I) In one participating center (Maastricht) blood samples were collected at:  1 month after the intervention.  6 months.  18 months of follow-up.

24. Methods (II) Participants Maastricht250 Medication- 22 Total228 Intervention group111 Control group117

25. 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.

26. Methods (IV) Serological measures of infection (IgG):  CMV  CP  HSV (1 & 2)  VZV  EBV Physical evidence of pathogen presence (PCR):  CMV  CP

27. Results (I) Biography No differences were found for smoking

28. Results (II) Biographyp=0.036

29. Preliminary Results (I) CP IgA CP IgG

30. Preliminary Results (II) TNF-alpha soluble p55 soluble p75

31. Preliminary Results (III) Log IL-1 receptor antagonist over time Time in months 02468101214161820 Log IL-1 receptor antagonist -0,80 -0,78 -0,76 -0,74 -0,72 -0,70 -0,68 Intervention Control IL-1 receptor antagonist

32. Preliminary Results (IV) C-reactive protein: Fast events (within 180 days) Slow events (after 180 days) 106103No 0.15811YesPHighLow Cardiac events 9294No 0.03149YesPHighLow

33. Preliminary Results (IV) C-reactive protein: Slow events