Chronic Fatigue Syndrome (CFS) has an increasing literature describing neuro-cardiovascular abnormalities with associated episodic hypotension associated with CFS relapse. Streeten and Bell have added the observation of a reduced red blood cell (RBC) mass, a finding confirmed by the Miami research group. This observation is consistent with that of Natelson's group of a reduced stroke volume in CFS. The role of both orthostatic intolerance and reduced RBC mass and the relationship of these observations to each other in the pathophysiology of CFS is poorly understood. Moreover, the relationship of orthostatic intolerance to impaired venous contractility, abnormalities of the renin-angiotensinaldosterone system, adrenocortical function as well as autonomic function has not been elucidated. The observation of a reduced RBC mass in CFS is particularly puzzling because erythropoietin (EPO) levels are normal to low. A major drive of erythropoiesis is EPO, which is released in response to hypoxemia by the kidney, and would normally be quite elevated in the setting of low RBC mass. We postulate that the low to normal EPO levels in the face of low RBC mass can result from more than one mechanism: l) By shunting adequate blood supply to the kidney, the need for elevated EPO is not sensed; 2) A sensory defect at the level of the tubules exists which blunts the appropriate response; and/or 3) EPO production is directly suppressed by soluble mediators. In this protocol, we will test the interaction of these mechanisms. We predict a mixed mechanism including a sensory defect and EPO suppression. We will perform studies of renal blood flow, renal vascular resistance, and renal function as well as studies to compare renal hemodynamics to peripheral hemodynamics to test both adequacy of blood flow and renal vs. peripheral sympathetic tone. Additional studies will evaluate the influence of the renin-angiotensin-aldosterone system and adrenalcortical function on renal hemodynamics. The hemodynamic profiles between the supine and upright position will also be compared. Finally, cardiovascular fitness pre- and post- plasma or RBC volume expansion will be studied to further delineate the role of hypovolemia and/or RBC mass reduction on these parameters. Direct suppression of EPO via the inflammatory cytokines TNF-alpha, IL- lbeta, TGF-beta or IL-6 is another reasonable explanation of normal to low EPO levels in the face of a reduced RBC mass. These cytokines have been demonstrated in vitro and in vivo to inhibit EPO production and have been shown to be elevated in significant numbers of CFS subjects. Studies to examine the role of inflammatory cytokines in EPO inhibition will include plasma measures of cytokine peptide as well as mRNA measures of the message encoding these cytokines from the mononuclear cells. Jn vitro studies of CFS sera vs. control sera on EPO production in Hep3B cell lines will be performed to determine if the level of elevated of cytokines seen in CFS is sufficient to reduce hypoxia induced EPO production.
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