Determinants of heart rate and heart rate variability

The assessment of heart rate and blood pressure variability is increasingly used to evaluate the dynamic features of cardiovascular control mechanisms. Both experimental and clinical studies have shown that this approach may offer a unique insight into autonomic cardiovascular modulation in health and disease [1–6], and may allow monitoring of the effects of therapeutic interventions on neural cardiovascular regulation [7–11], both in a laboratory environment and under daily life conditions [12–15]. The widespread diffusion of this approach has been greatly facilitated by technological progress in the methods for non-invasive beat-by-beat recording of cardiovascular signals [16–23]. It has also been facilitated by the development of powerful data analysis procedures. Among the latter, spectral analysis techniques may offer a detailed quantification of the various frequency components, characterizing blood pressure and heart rate variability, that have been reported to reflect the patterns of autonomic cardiovascular regulation. In particular, two methods for spectral analysis of heart rate and blood pressure variability are frequently employed in pathophysiological and clinical studies: (i) the selective quantification of fast and regular oscillations with periods ranging from 2 to 20–30 s, that generate well-defined peaks in either the blood pressure or heart rate spectrum [4,6,24], and (ii) the comprehensive assessment not only of fast, but also of slower and sometimes less regular blood pressure and heart rate fluctuations, spanning over a wider range of frequencies, through use of broad-band spectral analysis techniques [25–30]. An additional and more complex approach is based on the simultaneous quantification of fluctuations in several biological signals and on the evaluation of their mutual interactions, sometimes with the help of mathematical models [31–33]. A typical example of these advanced methods is represented by the techniques, developed both in the frequency and in the time domain, for the assessment of the interactions between blood pressure and heart rate fluctuations. These techniques allow the quantification of ‘spontaneous’ sensitivity of baroreflex control of heart rate, with no need for external interventions such as injection of vasoactive drugs or application of a neck chamber device, and are now increasingly being used both in pathophysiological studies and in the diagnostic and prognostic approach to a number of diseases [34–43]. In order to guarantee a safe, physiologically and clinically reliable, application of the methods for heart rate and blood pressure variability analysis, a few theoretical assumptions need to be verified. It is particularly important to obtain: (i) the demonstration of a close association between the parameters derived from the analysis of cardiovascular variability and specific cardiovascular control mechanisms and (ii) the identification of the most important factors that systematically affect blood pressure and heart rate variability, in order to clarify its main determinants, and therefore to standardize the procedures for its quantification. In particular, this may allow correction for possible confounders when comparing the features of cardiovascular variability typical of different subjects or characterizing different clinical conditions. Evidence on the former issue has been gathered mostly in the experimental animal by studies that have investigated the association between experimentally induced alterations in specific neural control mechanisms, and the resulting changes in blood pressure and heart rate fluctuations. This is exemplified by studies based on arterial baroreceptor deafferentation through sinoaortic denervation, or chemical and/or surgical sympathectomy [44–51]. Evidence on the latter issue has been obtained also in humans through a number of studies carried out under standardized laboratory conditions and aimed at identifying the possible determinants of the different components that contribute to heart rate and blood pressure variability (Table 1).Table 1: Factors determining the degree of heart rate variabilityIn this issue of the Journal, Stolarz et al. [52] provide additional information in this field. In particular, the authors evaluated the effects on heart rate and heart rate variability exerted by factors such as gender, age, posture, breathing frequency, body mass index, systolic blood pressure, family history of hypertension and life style factors (such as smoking, alcohol and coffee consumption, physical activity). This was peformed by recruiting a large number of subjects, sampled from different European countries and from the Asian portion of the Russian Federation. The large sample size separately collected from different countries is a distinctive feature of this paper compared to previous studies. In most instances, previous observations were carried out either in selected, and often small, groups of patients mainly recruited in a restricted geographical area or, in case of a wider recruitment, by pooling in a single dataset the observations obtained in all included patients, regardless their origin. Such a methodological approach is probably among the reasons for which these studies have been largely unable to identify all the determinants involved in the genesis of specific patterns of heart rate and blood pressure variability, leaving unsolved the problem of whether and to what extent heart rate and heart rate variability are also influenced by genetic and life style factors, and whether differences in these factors may explain differences characterizing different populations. A major merit of the study by Stolarz et al. [52], in which data on heart rate and heart rate variability were collected from more than 800 out of 1208 screened subjects, is related not only to its considerable size, but also to the inclusion of different ethnic groups. Indeed, the study takes advantage of subjects recruited in the frame of the European Project on Genes in Hypertension (EPOGH), which allowed the authors to investigate the features of both heart rate mean levels and heart rate variability in a considerable number of subjects sampled from the populations of Bucharest (Romania), Cracow (Poland), Mirano (Italy) and Novosibirsk (Russian Federation). The results of this study confirm, in a large database, previous observations that gender, age and body position are consistent and independent correlates of heart rate and heart rate variability. Considering, in particular, heart rate variability, both in the supine and in the standing position, a strong association with respiratory frequency was also found. Furthermore, this study also provides the demonstration that the above associations can be found in all investigated populations, by separately considering subjects from different countries. This means that the association between heart rate variability and the above determinants is robust enough as to remain evident in spite of differences in genetic, behavioural and environmental factors, regardless of the geographical origin of the subjects under evaluation. On the same database, the previous reports on the differences and similarities in heart rate and heart rate variability between male and female subjects, as well as between parents and their offspring, have been confirmed. The practical implication of these observations, in agreement with the outcome of a number of previous experimental studies, is that gender and age differences, as well as differences in blood pressure levels and, in particular, in respiratory activity patterns, need to be carefully considered in all studies aimed at deriving reliable and clinically useful information from the analysis of heart rate and blood pressure variability. The focus on the importance in this context of respiratory patterns is in accordance with the results of studies which have emphasized the role not only of respiratory frequency, but also of respiratory amplitude as major determinants of heart rate and blood pressure variability [6,31–33]. A puzzling additional result of this study refers to the relation between lifestyle factors and heart rate or heart rate variability. The authors conclude that life style factors and local habits, as quantified by the measures of physical activity, body mass, smoking habit, alcohol and caffeine assumption adopted in their study, showed only weak effects on heart rate and heart rate variability, and these influences differed between centres. This is at variance with the results of experimental studies which conversely showed that at least some of these factors, when individually assessed, do have an important effect on heart rate and blood pressure variability [6,8, 12,15,38,53,54]. Such discrepancy could depend on the fact that in the real life conditions considered in the present study, two or more among these behavioural factors might have been simultaneously present in the same subject. This could have prevented the proper identification of their individual contribution to heart rate variability. Additionally, the above discrepancy could also depend on how these factors were quantified in the present study. As acknowledged by the authors, the assessment of lifestyle factors such as smoking, and consumption of alcohol and caffeine, was heavily dependent on the information provided by study participants, and was scored in a categorical fashion (yes/no) which obviously leaves unaddressed a quantitative estimate of their impact (e.g. number of cigarettes, number of drinks, etc.). A final general consideration on this study deserves to be made. Although investigation of genetic aspects was not included among the aims of their study, given the nature of the Europen Union Project from which this study is derived, it would have been both appropriate and desirable to provide at least some indication of the degree of ‘genetic homogeneity’ of the populations considered for the study, and to explore or at least speculate on the possibility that genetic differences might play a role in determining different heart rate or heart rate variability patterns, as suggested by recent studies [55–56]. However, the above problems do not detract from the overall relevance of the study findings, which confirm on a population basis that, irrespective of ethnic differences and lifestyle factors, factors such as age, gender, body posture and respiratory patterns should always be taken into account when quantifying heart rate and heart rate variability. This is particularly relevant for studies aimed at assessing the prognostic relevance of cardiovascular variability parameters in different clinical conditions [57,58].