Original article 1327 Low-frequency fluctuations in heart rate, cardiac output and mean arterial pressure in humans: what are the physiological relationships? Maja Elstada, Lars Walløea, Ki H. Chonb and Karin Toskaa Objective Cardiovascular variability is a complex Conclusion TPR oscillations produce fluctuations in MAP physiological phenomenon associated with the outcome of at 0.1 Hz. HRV produces CO variations, but CO variations do cardiovascular diseases. Blood pressure oscillations may not efficiently buffer MAP variations during supine rest and cause cardiovascular complications, which, however, are mild ortostasis. Both feedback and feedforward also claimed to have antihypertensive effects. The mechanisms are responsible for the interaction between HR physiological understanding is limited. This study evaluates and MAP. J Hypertens 29:1327–1336 Q 2011 Wolters whether oscillations in heart rate (HR) and cardiac output Kluwer Health | Lippincott Williams & Wilkins. (CO) buffer fluctuations at approximately 0.1 Hz in arterial blood pressure (Mayer waves). Journal of Hypertension 2011, 29:1327–1336 Method We recorded mean arterial pressure Keywords: blood pressure variability, cardiac output, heart rate variability, (MAP), left cardiac stroke volume (SV), and HR in phase angles, spectral analysis, stroke volume 10 healthy humans during autonomic blockade in supine Abbreviations: CO, cardiac output; HR, heart rate; HRV, heart rate and tilted (30 degrees) position. Variability in the variability; HUT, head up tilt (30 degrees); HUTcontrol, head up tilt control; cardiovascular variables at 0.04–0.15 Hz and phase angles HUTVblocked, head up tilt vagal blockade; MAP, mean arterial blood (time lags) between the variables were calculated by pressure; RR, RR interval; SUPcontrol , supine control; SUPTblocked, supine total autonomic blockade; SV, stroke volume; TPR, total peripheral resistance spectral analysis. aDepartment of Physiology, Institute of Basic Medical Sciences, University of Results Fluctuations in cardiovascular variables at 0.1 Hz Oslo, Blindern, Oslo, Norway and bDepartment of Biomedical Engineering, decreased after removal of HR variability (HRV) by Worcester Polytechnic Institute, Worcester, Massachusetts, USA propranolol and atropine in the supine position. Tilting from Correspondence to Maja Elstad, Department of Physiology, Institute of Basic supine did not change fluctuations in MAP or total Medical Sciences, University of Oslo, P.O. Box. 1103 Blindern, NO-0317 Oslo, Norway peripheral resistance (TPR), whereas variations in CO Tel: +47 22851219; fax: +47 22851249; e-mail: [email protected] decreased. Variations in CO remained decreased in tilt after atropine compared to supine control, whereas variations in Received 12 February 2010 Revised 27 March 2011 Accepted 8 April 2011 MAP and in TPR were unchanged. HRV were in phase with oscillations in CO. Variations in CO were in inverse phase See editorial comment on page 1285 with variations in TPR. Introduction variations in cardiac output (CO). HRV is neurally All cardiovascular variables show oscillations, as observed regulated, whereas CO variations are also affected by in humans with a range of physiological and pathological mechanical factors such as the afterload and ventilation conditions for over a hundred years [1,2]. The power effects on stroke volume (SV) [9–11]. In addition, spectrum of the heart rate variability (HRV) signal is fluctuations in total peripheral resistance (TPR) affect usually divided into three separate frequency domains for arterial blood pressure oscillations, for instance through healthy adult humans: below 0.04 Hz, approximately sympathetic vasomotor activity [12]. 0.1 Hz and respiratory frequency (0.25 Hz) [3]. There are close relationships between all the cardiovas- Cardiovascular oscillations are complex physiological cular variables, but few investigators have included beat- phenomena [4] that are predictors of the outcome of by-beat measurements of SV and TPR. The latter is cardiovascular diseases independent of other predictors always a derived variable, as there is no method available such as arterial blood pressure [5,6]. to provide direct measurements of TPR. In addition to In this study, we focus on oscillations at 0.1 Hz (low- analyzing oscillations in each of the cardiovascular vari- frequency power), corresponding to 10 s. Such fluctu- ables separately, it is valuable to observe how fluctuations ations in arterial blood pressure are called Mayer waves in these variables are related. In cross-spectral analysis, [2] and have been shown to have antihypertensive effects information on relationships is obtained by calculating in dogs [7]. These waves may be of peripheral (baroreflex phase angles (or time lags) and coherence. Phase resonance) or central origin, or a combination of the two angles between two variables can be used to estimate [8]. Regardless of its origin, HRV can only influence the relationship between them, but do not necessarily oscillations in mean arterial pressure (MAP) through provide any causal information. 0263-6352 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/HJH.0b013e328347a17a Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 1328 Journal of Hypertension 2011, Vol 29 No 7 In our experimental set-up, we included measurement of rapidly, so we analyzed recordings made within 5–10 min SV using the ultrasound Doppler technique in order to of atropine administration in both supine and tilted obtain both CO and TPR, and we recorded and calculated positions in order to capture full atropine effect. Full all cardiovascular variables beat-by-beat. Mechanical effect of atropine was defined as being reached when effects on CO can be modified by neural regulation of two successive atropine doses gave no further increase heart rate (HR). If HRV at 0.1 Hz effectively buffers in HR. This experimental set-up gave four autonomic oscillations in MAP at 0.1 Hz, the low-frequency power in situations: almost pure parasympathetic in supine MAP will increase after HRV removal. On the contrary, if position (SUPcontrol), total cardiac autonomic blockade HRV produces MAP fluctuations, removal of HRV will with atropine and propranolol in supine position reduce low-frequency power in MAP. An inverse-phase (SUPTblocked), mainly parasympathetic in HUT relationship between two cardiovascular variables (HR- (HUTcontrol) and pure sympathetic (vagal blockade) SV or CO-TPR) suggests that they counteract each in HUT (HUTVblocked). other, thus reducing the oscillations in their product (CO or MAP in this case). To test the hypothesis that Cardiovascular recordings were obtained before, during HR fluctuations buffer MAP oscillations at 0.1 Hz, we and after medication on two different experimental days. investigated how low-frequency power in MAP changes The complete experimental set-up is described in Fig. 1. when HRV is removed by pharmacological cardiac auto- Each position lasted for 15 min after a period of nomic blockade. A better understanding of the relation- stabilization lasting for a minimum of 5 min. The record- ships between HR, CO and MAP and their oscillations ing started with 5 min of spontaneous breathing followed may provide insight into why these variables are by 10 min of random breathing. In this analysis, we have independent clinical predictors and how this can be used used recordings made during spontaneous breathing from in clinical practice. both test days. In randomized order, four participants were tested in the supine position on the first day and six Methods in the tilted position. All 10 participants completed both Participants test days. Ten healthy volunteers – five women – were studied The participants received a mean of 0.04 mg/kg atropine [age 25.2 Æ 3.7 years (mean Æ SD); height 170.3 Æ 8.6 cm; and 1 mg þ 0.2 mg/kg propranolol (on average 14.6 mg per weight 68.2 Æ 8.4 kg]. All participants were non-smokers participant according to weight) [9,13]. The ambient and none was taking any medication. Written informed temperature was kept at 20–248C. consent was obtained from all participants, and the experimental protocol was approved by the Massachu- setts Institute of Technology Committee on the Use of Recordings Humans as Experimental Subjects. All experiments were Lung volume was measured by two-belt chest-abdomen performed at the Clinical Research Center, Massachu- inductance plethysmography (Respitrace System, setts Institute of Technology, and conformed to the Ambulatory Monitory Systems, Ardsley, New York, Declaration of Helsinki. USA), which was calibrated by 800 ml inflation at the initiation of each experimental run. Beat-by-beat SV was Experimental set-up recorded using an ultrasound Doppler method (CFM This investigation was part of a more extensive study, and 750; Vingmed AS, Horten, Norway) [14]. HR was methods and data material are the same as published obtained from the duration of each R-R interval of the previously [10] and are summarized in the current pub- ECG signal, sampled at 300 Hz, and beat-by-beat CO lication. Parts of the protocol are therefore not relevant was calculated from the corresponding HR and SV to the present analysis. The intention of the part of the values (CO ¼ HR Â SV). Finger arterial pressure was study presented here was to test the participants under recorded continuously (2300 Finapres BP monitor; different cardiac autonomic neural conditions. At supine Ohmeda, Madison, Wisconsin, USA).