Although the precise cause or causes of Gulf War Illness (GWI) remain unknown, evidence indicates that veterans of the 1990-91Gulf War were exposed to a variety of toxins, such as chemical nerve agents and pesticides of the organophosphate (OP) family. These drugs have been implicated in GWI’s initiation and progression. One OP of interest is sarin, a highly toxic nerve agent whose low-dose, sub-symptomatic exposure has been connected with GWI etiology.
Dr. Mariana Morris and colleagues used a Fiscal Year 2006 GWI Research Program Investigator-Initiated Research Award to develop a mouse model of GWI which examines low-dose exposure to sarin. In the model, a non-symptomatic dose of sarin produced long-lasting changes in central neural function and decrements in cardiac function seen as reductions in heart rate variance.
The global objective of the study was to elucidate the pathophysiological mechanisms of GWI in an animal model, study the autonomic and cardiac biomarkers, and evaluate the effectiveness of some commercially available drugs targeting adrenergic (such as beta blockers in cardiac dysfunction) and cholinergic nervous systems. Dr. Morris also examined complementary cardiac changes focused on the structural and functional effects on the mouse heart using echocardiography, electrocardiography, and histology.
Some of Dr. Morris’ findings on the effects of low-dose sarin exposure in the model include:
- Sarin produced delayed and long-term effects on cardiac function such as reduced ejection fraction.
- Sarin caused left ventricular dilation two months after an asymptomatic dose. This is a marker for dilated cardiomyopathy.
- Levels of atrial and brain natriuretic peptides in the heart were increased, indicating cardiac remodeling possibly due to volume overload.
- Low-dose sarin produced regionally specific changes in brain dopamine.
- A stress test with dobutamine, a selective B adrenergic agonist, showed reduced cardiac function, reduced contractile function, and ischemia, as determined by echocardiographic and electrocardiographic analyses.
These findings have important implications for military or civilian populations since low-dose, non-symptomatic exposure to sarin may result in long-lasting cardiac dysfunction.
After completing cardiovascular studies of pharmacological agents, Dr. Morris is continuing studies to further select appropriate agents capable of ameliorating autonomic symptoms and performing behavioral, anatomical, and endocrine tests. Effective agents will move forward to clinical studies leading to potential treatments for GWI. Since the agents used are already approved drugs for other diseases such as Alzheimer’s or hypertension, the timeframe necessary for clinical implementation could be shortened.
2010 Gulf War Illness Research Highlights