Resting heart rate (HR) and its variability (HRV) reflect cardiac sympathovagal balance that can stimulated by head-up tilting. HRV is significantly influenced by the level of HR, but how much HRV offers additional information about cardiac autonomic tone than HR alone remains unresolved. We examined the relation of resting HR with short term HRV during passive head-up tilt.Methods Hemodynamics of 569 subjects without medications with direct cardiovascular effects and known cardiovascular

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... es were recorded using whole-body impedance cardiography, continuous radial pulse wave analysis and electrocardiography based HRV analysis in supine and upright positions. For statistical analyses the study population was divided into tertiles of resting heart rate according to sexes.Results Higher low frequency to high frequency ratio (LF/HF) of HRV (reflecting sympathovagal balance) was associated with higher HR in supine (p<0.001) and upright positions (p=0.008). The outcome was similar when the HRV analysis was based on HR instead of RRintervals (p<0.001 supine, p=0.012 upright). The lowest HR tertile presented with higher supine to upright increase in LF/HF than the highest HR tertile (1.1 vs. 0.85, respectively, p=0.037).Conclusion Higher resting HR is related to higher LF/HF in supine and upright positions, reflecting higher cardiac sympathovagal balance. Lower resting HR is associated with lower resting LF/HF, but with a more pronounced increase in both HR and LF/HF during head-up tilt, suggesting greater change cardiac sympathovagal balance in response to upright posture. Background Heart rate variability (HRV) is associated with heart rate (HR), and this association is determined by cardiac autonomic nervous tone. Hence, higher sympathetic activity is related to higher HR and lower HRV [1] [2] [3] . Sympathetic tone can be easily stimulated by the change of body position from supine to upright [2, 4]. HRV has been widely studied and lower HRV is a risk factor for adverse cardiovascular outcomes [5] and a predictor of mortality of cardiac but also of other causes [6, 7]. Reduced HRV is also observed in psychic conditions such as mental stress and depression [8, 9]. Higher resting HR has been related with cardiovascular events and less favourable prognosis in healthy men and women [10, 11]. A 4 recent meta-analysis concluded that resting HR is a predictor of cardiovascular and all-cause mortality in the general population independent of the classic cardiovascular risk factors [12]. The mechanisms of these relations are not well understood but an imbalance between vagal and sympathetic tone is a conceivable factor. Both HR and HRV represent the prevailing cardiac sympathovagal tone, and the association of reduced HRV with poor prognosis may be attributed to the concomitant level of HR [13] [14] [15] . The relation of HRV to HR is not only physiological but also mathematical, and the relation is not linear [3, 16] . HRV is usually calculated from consecutive RR-intervals reciprocal to HR measures. Therefore, when lower and higher initial HR levels are compared, a similar change in HR results in a greater change in RR-interval during lower HR. HRV is usually evaluated by the use of time or frequency domains, both of which provide information about vagal and sympathetic tone [3]. From the frequency domain parameters the high frequency (HF) component represents vagal activation and the low frequency (LF) component predominantly represents the sympathetic component of HRV [2]. From the time domain parameters the square root of mean squared differences of normal to normal RR-intervals (RMSSD) mostly represents vagal tone while the standard deviation of normal to normal RR-intervals (SDNN) is an estimate of total HRV [3]. There are mathematical methods that can be applied to strengthen or weaken the dependence of HRV on HR [17]. Because HRV includes information of HR and its variation, it has not been ascertained which one of these factors (i.e. HR or HRV) relates HRV to poor prognosis [13, 18]. Furthermore, both HR and HRV are related with sex, and typically HR is lower but sympathovagal balance (LF/HF ratio) is higher among men [4, 19, 20]. In addition, the relation of higher resting HR with less favourable prognosis seems more pronounced among men than women in population based studies [10, 11, 19]. In this study we examined whether resting HR level predicts sympathovagal balance measured by HRV in time domain and frequency domain parameters during supine and upright position. The study population was without cardiovascular diseases and medications with direct cardiovascular influences. Because of the nonlinear relationship between RR-interval and HR, we tested the association of resting HR with HRV that was analysed from both HR and RR-intervals. Methods Subjects This research is a part of DYNAMIC-study which is an on-going study focusing on non-invasive recording of hemodynamics from subjects with and without cardiovascular diseases (Clinicaltrialsregister.eu 2006-002065-39; Clinicaltrials.gov NCT01742702). The study has been approved by the ethics committee of the Tampere University Hospital and all study subjects gave informed consent. Volunteers for the research were recruited by announcements delivered in public organizations including Tampere University Hospital, Tampere University, Varala sports institute and occupational health care organizations. All study subjects were interviewed and examined by a physician who documented medical history and lifestyle habits. Smoking habits were determined as never smokers, previous smokers and current smokers and smoking in pack years was registered. Alcohol consumption was documented as weekly amounts of standard drinks (i.e. ~12 g alcohol). Physical activity was determined as number of exercise sessions (lasting at least 30 minutes) per week with at least moderate level of work load (for example brisk walking or jogging). From the present study subjects with a history or cardiovascular disease, diabetes mellitus, kidney disease, heart rhythm other than sinus, alcohol or substance abuse, concurrent malignancy, or medications with direct effects on the cardiovascular system were excluded. Also subjects with incomplete hemodynamic recordings (i.e. missing HR or HRV values) were excluded. Altogether 569 subjects (mean age 44.9, 95% confidence intervals of the mean (CI) (43.9, 45.9) years; 287 men) were included. The following stable medical conditions with adequate medications were included: asthma (medicated with inhaled corticosteroids, n=12), allergy (n=7), depression (n=29), dyslipidemia (n=13), dyspepsia (n=10), epilepsy (n=3), hypothyroidism (n=16), and rheumatoid arthritis or lupus (n=3). In total 74 females (26%) were on low dose hormone therapy, i.e. intrauterine device (44 subjects) or peroral combination therapy (30 subjects). Laboratory tests during hemodynamic measurements was not included in the analyses. Conclusions In the present investigation the relation of resting HR and its short term variability during supine and upright position was studied in 569 subjects. Resting HR was significantly associated with HRV regardless of the HRV determination method. Higher resting HR was related with higher LF/HF in both supine and upright position, but in addition lower resting HR anticipated a more pronounced increase in sympathovagal balance during head-up tilt. These findings suggest that even though HRV is a mathematical derivative of HR (or RR-interval) and they are both markers of autonomic nervous activity, HRV is not only a substitute for HR. Nevertheless, on the grounds of resting HR level it is possible to estimate autonomic nervous system activity and function. Abbreviations avRRI 4 , average RR-interval to the fourth power; CI, confidence interval; eGFR, estimated glomerular filtration rate; HF, high frequency component; HDL, high-density lipoprotein; HR, heart rate; HRV, heart rate variability; LDL, low-density lipoprotein; LF, low frequency component; LF/HF, low to high frequency ratio; PWV, pulse wave velocity; RMSSD, square root of mean squared differences of normal to normal RR-intervals; SDNN, standard deviation of normal to normal RR-intervals; SVRI, systemic vascular resistance index Declarations Ethics approval and consent to participate Fagard RH, Kawecka-Jaszcz K, Nikitin Y: Host and environmental determinants of heart rate and heart rate variability in four European populations. J Hypertens 2003, 21(3):525-535. 5. 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Abbreviations: SDNN, standard deviation of all normal RR intervals; RMSSD, the root mean square of differences between adjacent normal RR intervals. Figures