Effects of Hemoconcentration and Sympathetic Activation on Serum Lipid Responses to Brief Mental Stress ELIZABETH A. BACHEN,PHD, MATTHEW F. MULDOON, MD, MPH, KAREN A. MATTHEWS,PHD, AND STEPHEN B. MANUCK,PHD Objective: Previous studies suggest that hemoconcentration may be one mechanism by which acute psychological stress causes elevations of serum total cholesterol and its subfractions. Alternatively, such elevations may result from sympathetically mediated changes in lipid metabolism. This study evaluated these two hypotheses by manipulation of sympathetically mediated responses to stress using a nonselective adrenoceptor antagonist, labetalol. Method: In a 2  2 factorial design, 52 healthy male participants were randomly assigned to a stress or no-stress condition and, within each condition, were administered either labetalol or saline. Participants assigned to stress completed three cognitive and evaluative tasks lasting a total of 18 minutes. Indices of hemoconcentration (hematocrit and hemoglobin), heart rate, blood pressure, and serum lipids (total, high-density lipoprotein (HDL), low-density lipoprotein (LDL), free fatty acids, and triglycerides) were assessed at preinfusion and infusion baselines and after mental stress (or rest). Results: Labetalol reduced sympathetic activation, as shown by a substantial reduction in heart rate elevation during stress, but did not alter changes in blood pressure or in hemoconcentration, as indicated by equivalent increases in hematocrit and hemoglobin in the two stressed groups. Labetalol blocked stress-induced increases in free fatty acid concentrations and lowered triglyceride levels but did not influence rises in total, HDL, or LDL cholesterol among stressed subjects. However, arithmetic correction for hemoconcentration eliminated the increases in total, HDL, and LDL cholesterol. Conclusions: These findings suggest that elevations in total cholesterol and its HDL and LDL subfractions during acute stress are caused by accompanying hemoconcentration, whereas concomitant rises in free fatty acids and triglycerides result from the direct metabolic effects of sympathetic activation. Key words: cholesterol, lipids, stress, hemoconcentration, sympathetic nervous system. HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein; DBP = diastolic blood pressure; SBP = systolic blood pressure; HR = heart rate. INTRODUCTION Substantial evidence indicates that risk for develop- ing coronary heart disease rises with elevated levels of total cholesterol, triglycerides, and LDL cholesterol and with lower levels of HDL cholesterol (1, 2). Addi- tionally, there has been much interest in possible in- fluences of behavioral factors on serum lipids and lipoproteins. Research of the past four decades has shown that many stressful life events, such as impor- tant academic examinations or threats of unemploy- ment, are associated with elevations in total choles- terol and related lipid fractions (3, 4). Studies have also found that acute stressors, such as those presented in laboratory settings, are also capable of eliciting rises in total cholesterol and its fractions. Despite these observations, the mechanism(s) underlying relation- ships between stress exposure and elevated concentra- tions of blood lipids remain poorly understood (4). With respect to potential mechanisms, one possibil- ity is that activation of the sympathetic nervous system during psychological stress increases the production of serum lipids and lipoproteins by altering lipid met- abolic processes (5). It is well known, for example, that catecholamines induce lipolysis and release free fatty acids into the circulation; free fatty acids, in turn, serve as substrate for the resynthesis of triglycerides and, subsequently, VLDL production by the liver (6 – 8). An alternative pathway for stress-related changes in serum lipids involves altered hemoconcentration, whereby acute loss of plasma volume within the intra- vascular space concentrates nondiffusable blood con- stituents. By this hypothesis, rises in serum lipid and lipoprotein levels reflect a filtration of fluid out of the intravascular space (ie, a passive increase in choles- terol) rather than an increase in the synthesis of these compounds per se. Several studies have suggested that hemoconcentration accounts for rises in total and HDL cholesterol during brief exposure to experimental stressors, such as challenging mental arithmetic and word tasks (9 –12). However, Stoney and colleagues found that adjusting for hemoconcentration did not eliminate increases in lipid concentrations evoked by an especially provocative public-speaking task (13– From the Department of Psychology (E.A.B.), Mills College, Oak- land, CA; Departments of Medicine (M.F.M.), Psychiatry (K.A.M., S.B.M.), and Behavioral Physiology Laboratory (S.B.M.), University of Pittsburgh, Pittsburgh, PA. Address reprint requests to: Elizabeth A. Bachen, Department of Psychology, Mills College, 5000 MacArthur Boulevard, Oakland, CA 94613. Email: bachen@mills.edu Received for publication March 23, 2001; revision received Au- gust 20, 2001. DOI: 10.1097/01.PSY.0000021943.35402.8A 587 Psychosomatic Medicine 64:587–594 (2002) 0033-3174/02/6404-0587 Copyright © 2002 by the American Psychosomatic Society