# Cardiac Autonomic Dysfunction in Gulf War Syndrome



## M&M (Jan 20, 2002)

Posted to the Co-Cure mailing list:


> quote:Cardiac autonomic dysfunction in gulf war syndrome: Veteransï¿½ heartsdonï¿½t rest at nightJournal: The American Journal of Medicine, Volume 117, Issue 7 , 1October 2004, Pages 531-532Author: Philippe van de Borne, MD, PhDAffiliation: Department of Cardiology and Hypertension Clinic, ErasmeHospital, Brussels, BelgiumAvailable online 29 September 2004.Almost 700,000 members of the U.S. armed forces served during the1990ï¿½1991 Persian Gulf War. Since returning home, 1 of 7 Gulf Warveterans have presented a wide range of symptoms that involve manydifferent organs and systems (1). Physicians who care for these patientsare often convinced that the infectious, gastrointestinal, respiratory,and neurological complaints (2) are real and not driven by the desire forcompensation (3).These complaints have promoted intense research on the epidemiology andphysiopathology of what is now called the Gulf War syndrome. Animalmodels of Gulf War exposure have been created (4 and 5), and more than450 publications have improved our knowledge of the disease, butimportant questions remain. The numerous publications have not alwayshelped the patients and seem to have promoted the belief that there is nomedical or scientific consensus about the mechanisms and physiopathologyof the disease (6). In court, a damage claim was accepted on the basis ofï¿½symptoms and signs of ill defined conditions,ï¿½ as the Gulf War syndromewas neither recognized as a discrete medical disease nor as a syndrome(6).Epidemiologic studies have revealed that Gulf War veterans reportunexplained symptoms more frequently but have not consistentlyexperienced increased disease-related mortality (7). The symptoms,including loss of memory, cognitive impairment, confusion, emotionalchanges, headache, sexual dysfunction, and insomnia, suggest that theseveterans may experience a currently undefined but troublesome disease ofthe central nervous system.Gulf War veterans have been exposed to numerous and often poorlyidentified potentially harmful factors. Although increased risk ofpostwar morbidity from exposure to smoke from oil-well fires seemsunlikely (8), some exposure to neurotoxic chemical warfare agents wasacknowledged by the U.S. Department of Defence (3). The potentiallong-term deleterious effects of low-level intoxication by these highlyharmful agents should not be underestimated (5). Serum paraoxonaseactivity is responsible for the metabolism of organophosphates in serumand is a major determinant of organophosphate toxicity in humans (9).Paroxaonase activity is decreased in patients with Gulf War syndrome, afinding not explained by a range of potential confounders (9).Because of these findings, together with other observations suggestingneuronal damage in Gulf War syndrome patients, Robert Haley andcolleagues conducted an elegant study testing the hypothesis that GulfWar veterans may show subtle cardiovascular autonomic dysfunction (10).The authors performed a thorough evaluation of autonomic regulation usingHolter monitoring, spectral analysis of heart rate variability, QTinterval analysis, ambulatory blood pressure recordings, Valsalvamaneuvers, direct recordings of sympathetic nerve activity at rest andduring reductions in central venous pressure, sudomotor functionanalysis, and polysomnographic recordings. The authors observed thatreductions in heart rate at night were less pronounced in the veteranswho were ill than in the control subjects. Nighttime heart rate was onaverage 8 beats per minute higher in the patients than in the controlsduring the Holter monitoring. These results are very convincing becausethe authors were able to reproduce their observation during automatedblood pressure recordings and polysomnographic recordings. Interestingly,the high frequency heart rate variability, a marker of cardiacparasympathetic modulation (11), increased less during the night,suggesting that heart rate decreased less in the ill Gulf War veteransbecause of an inadequate nocturnal rise in parasympathetic activity.Breathing frequency markedly affects the high frequency heart ratevariability (12); however, respiratory rate did not differ duringpolysomnography between the patients and the controls, suggesting thatdifferences in breathing rate cannot explain these results. Remarkably,the authors could also demonstrate that sleep pathologies did notconfound their findings because the number of apneas per hour and oxygensaturation were not different.The lower panel of Figure 2 (10) is very interesting as it discloseschanges in heart rate over time corrected for differences in sleep onset.Indeed, all were awakened at 6:00 AM and total sleep time was 35 minutesless in the veterans who were ill, which indicates that the patientsstarted to sleep somewhat later than the controls. Figure 2 reveals thatheart rate is identical in patients and control veterans before they fallasleep but starts to diverge approximately 2 hours and 30 minutes aftersleep onset. Intriguingly, sleep architecture, assessed by the relativeduration of sleep stages and awakenings, was very similar in both groups,except for the duration of paradoxical sleep, which was slightly greaterin the veterans who were ill (P = 0.06). Paradoxical sleep increasesheart rate and occurs predominantly at the end of the sleep period (11),when differences in heart rate between both groups became greater aswell. Thus, subtle differences in sleep architecture between patients andcontrols may have contributed to the findings of the authors.Whatever the exact mechanism, the study by Haley et al providesconvincing evidence of an inadequate nocturnal fall in heart rate inveterans with Gulf War syndrome. The study has, however, somelimitations. The number of subjects studied is relatively small, but itmust be noted that the investigators performed a very sophisticatedevaluation of autonomic function and that such elaborate measure cannotbe performed in large numbers of patients. A weakness of the protocol wasthat the 24-hour Holter recording could not be scheduled uniformly.Approximately half of the subjects wore the Holter monitors during thefirst, second, or third day of hospitalization, and half wore them afterthey returned home. The Holter recordings were not performed during thesleep studies. Again, this limitation does not invalidate the observationof impaired nocturnal decrease in heart rate, as this finding was alsoconsistently observed in pulse rate dip during the sleep recordings, butit does preclude an analysis of cardiac autonomic control abnormalitiesduring specific sleep stages (11). Also, 76% of the patients disclosedmajor depression or post-traumatic stress disorder, which was observedonly in 12% of the control veterans. Did depression in these patientscontribute to the authors' findings? Changes in high frequencyvariability remained significant in Haley's study (10) after controllingfor a diagnosis of depressive disorder. In addition, diagnosis ofdepression was not related to high frequency variability in their study.The authors also reference studies that suggest that depression does notaffect the high frequency variability of heart rate. This issue is,however, somewhat controversial as others have documented the oppositefinding, namely that depression impairs cardiac vagal modulation (13, 14and 15). Thus, some confounding effects of depressive disorders inveterans with Gulf War syndrome cannot be excluded.Highly stressful and traumatic life events encountered during militaryconflicts are clearly associated with adverse health effects (16). Theodds ratio of post-traumatic stress disorder is 3.1 and the odds ratio ofchronic fatigue syndrome is 4.8 in Gulf War veterans compared withnonï¿½Gulf War veterans (17). Disentangling the specific physiopathology ofcomplaints of Gulf War syndrome from other concomitant diseases is adifficult task.In conclusion, the study by Haley and coworkers clearly indicatesconsistent abnormal nighttime cardiac regulation in veterans who are ill.This important finding should promote large, prospective, and carefullycontrolled studies on cardiac autonomic control during sleep stages inpatients with Gulf War syndrome.References1 S.T. Donta, D.J. Clauw and C.C.J Engel et al., Cognitive behavioraltherapy and aerobic exercise for Gulf War veterans' illnesses arandomized controlled trial, JAMA 289 (2003), pp. 1396ï¿½1404.2 H.A. Young, S.J. Simmens and H.K Kang et al., Factor analysis offatiguing syndrome in Gulf War era veterans implications for etiology andpathogenesis, J Occup Environ Med 45 (2003), pp. 1268ï¿½1273.3 P.J. Landrigan, Illness in Gulf War veterans Causes and consequences,JAMA 277 (1997), pp. 259ï¿½261.4 R.F. Henderson, E.B. Barr and W.B Blackwell et al., Response of F344rats to inhalation of subclinical levels of sarin exploring potentialcauses of Gulf War illness, Toxicol Ind Health 17 (2001), pp. 294ï¿½297.5 A. Abdel-Rahman, S. Abou-Donia and E El-Masry et al., Stress andcombined exposure to low doses of pyridostigmine bromide, DEET, andpermethrin produce neurochemical and neuropathological alterations incerebral cortex, hippocampus, and cerebellum, J Toxicol Environ Health A67 (2004), pp. 163ï¿½192.6 C. Dyer, Court stands by decision on Gulf war syndrome, BMJ 326 (2003),p. 1350.7 G.C. Gray, B.D. Coate and C.M Anderson et al., The postwarhospitalization experience of U.S veterans of the Persian Gulf War, NEngl J Med 335 (1996), pp. 1505ï¿½1513.8 T.C. Smith, J.M. Heller and T.I Hooper et al., Are Gulf War veteransexperiencing illness due to exposure to smoke from Kuwaiti oil wellfires? Examination of Department of Defense hospitalization data, Am JEpidemiol 155 (2002), pp. 908ï¿½917.9 M. Hotopf, M.I. Mackness and V Nikolaou et al., Paraoxonase in PersianGulf War veterans, J Occup Environ Med 45 (2003), pp. 668ï¿½675.10 R.W. Haley, W. Vongpatanasin and G.I Wolfe et al., Blunted circadianvariation in autonomic regulation of sinus node function in veterans withGulf War syndrome, Am J Med 117 (2004
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