Chronic fatigue syndrome (CFS) is associated with orthostatic intolerance which often takes the form of postural orthostatic tachycardia syndrome (POTS) in adolescents. Preliminary data suggest the novel concept that defective vasoconstriction produces POTS in CFS with cardiac autonomic changes as a secondary response. CFS patients will be compared to healthy controls and to controls with simple faints to test 3 hypotheses: 1) Blood is redistributed peripherally and redistribution is enhanced during orthostasis producing increased microvascular filtration and dependent edema. Central hypovolemia causes decreased cardiac output, reflex tachycardia and reduced cerebral blood flow. This is enhanced during orthostasis producing increased microvascular filtration, dependent edema, and peripheral pooling. These changes alter the interstitium, and cause reflex tachycardia, reduced cerebral blood flow and often hypotension. Blood volume and cardiac output using the indocyanine green dye dilution technique will be measured supine, during conventional 700 head-up tilt, and during low angle head-up tilt. Cerebral blood flow velocity (CBFv) will be estimated by transcranial Doppler ultrasonography. Thoracic, splanchnic, and pelvic vascular volumes will be measured by impedance plethysmography, and limb blood flow, arterial flow, venous volume-pressure relation, and venous pressure will be measured by venous occlusion strain gauge plethysmography. These will show increased blood flow to lower extremities when upright. Central hypovolemia will occur and will reduce CBF and produce symptoms of CFS. Cardiac autonomic status including baroreflex will be assessed by heart rate and blood pressure variability and transfer function. Baroreflex and heart rate variability will be decreased and blood pressure variability will be increased related to circulatory deficit 2) The defect in vasoconstriction is heterogeneous comprising abnormal arterial baroreflex mediated sympathetic vasoconstriction in one subgroup of CFS patients and abnormal local vasoconstriction in a second subgroup with defective veno-arteriolar reflex (arterial baroreflex insensitive dysfunction). Low angle tilt will be used to activate baroreflex mediated and local reflexes. Local reflexes including myogenic, metabolic and veno-arteriolar will be sorted out through use of supine testing designed to specifically stimulate a specific reflex (limb hang, large pressure step and reactive hyperemia) and measuring peripheral resistance. 3) Cardiac autonomic findings are secondary to circulatory changes. Thus, tachycardia relates to vagal withdrawal because of circulatory insufficiency. CFS patients will be treated with midodrine or placebo in a cross-over study. Using supine and low angle tilt experiments, circulatory measurements and psychological instruments will be combined to demonstrate that circulatory abnormalities, autonomic abnormalities and symptoms correct in a subgroup of CFS patients with low resting peripheral resistance.
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