J Appl Physiol 101: 690-691, 2006;
doi:10.1152/japplphysiol.00584.2006
8750-7587/06 $8.00
LETTER TO THE EDITOR
Cardiovascular variability is/is not an index of autonomic control of circulation
To the Editor: As repeatedly underlined in this debate, neural cardiovascular (CV) regulation is characterized by a complex interaction between central and reflex mechanisms, with the contribution of other important factors such as respiratory frequency and depth. It would therefore be unrealistic to believe that the simple assessment of CV variability (CVV) parameters might provide a specific and univocal quantification of mean autonomic tone on circulation, which cannot be provided even by classical laboratory methods in humans. We did never support this theory. Moreover, evidence is available that CVV is an expression of neural cardiovascular modulation dynamics more than of mean autonomic tone. Because of all these considerations, a tight correlation between indexes of CVV and other measures of autonomic CV control was not even to be expected. This, however, is not an argument against the ability of CVV to quantitatively reflect the features of neural CV regulation, which can be assessed by proper handling of the complex interaction between the different mechanisms involved. On top of this, as properly emphasized by L. Bernardi, perfect correlations can never be seen in biology (4). It would therefore be a serious error not to acknowledge the important information carried by CVV analysis, now available also through simple and noninvasive approaches (5). Continuous progress in technology and in linear and nonlinear mathematical models of CVV is likely to allow further insight into the dynamic features of CV regulation. Therefore, our word is far from being the "last" one, in this rapidly evolving field. However, it would dare to be a word of confidence toward the value of CVV analysis, based on the evidence gathered by thousands of papers published at a regular pace over a few decades, on the ability of this approach to explore not only the physiology of CV regulation, but also the pathophysiological and clinical relevance of its changes in several diseases. Indeed, CVV parameters, in particular those estimating baroreflex sensitivity, have been shown to be of prognostic relevance in patients with cardiomyopathy (3), after stroke (7), or with diabetes mellitus (2). We wish to conclude this debate with a methodological recommendation. Techniques of CVV analysis are cheap and noninvasive and appear simple and easy to use. However, because they measure parameters that may be strongly influenced by multiple, often nonlinear, factors, they should be applied with wisdom and caution. We agree with J. M. Evans (4) that "CVV results must be carefully examined by authors, editors, and reviewers of manuscripts for appropriate analyses and interpretation." The example reported in the comment by Elstad (4) is illuminating in this regard. The apparent contradiction of a HF power increasing in parallel with the decrease of vagal tone during exercise when HF is measured in beats per minute squared rather than in milliseconds squared is known (1). It does not mean that HF power is not an index of vagal activity, however. This phenomenon depends on the hyperbolic relation between heart rate and R-R interval (1) and on the linear relation between R-R interval and vagal outflow (6). A measure of HF power in milliseconds squared would have followed the changes of vagal tone. Finally, we wish to thank all those who contributed to our debate, by filling the gaps we left, because of space constraints, and by better clarifying the messages carried by their own papers.
REFERENCES
- Castiglioni P, Parati G, Omboni S, and Di Rienzo M. Influences of the selection between Heart-Period and Heart-Rate on the spectral evaluation of heart-rhythm variability during exercise. Proc Computers in cardiology 561–564, Bethesda, MD, 1994.
- Frattola A, Parati G, Gamba P, Paleari F, Mauri G, Di Rienzo M, Castiglioni P, and Mancia G. Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia 40: 1470–1475. 1997.[CrossRef][Web of Science][Medline]
- La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, Bigger JT Jr, Camm AJ, Schwartz PJ; ATRAMI Investigators. Autonomic Tone and Reflexes After Myocardial Infarcton. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias. Implications for clinical trials. Circulation 103: 2072–2077, 2001.[Abstract/Free Full Text]
- Malliani A, Julien C, Billman GE, Cerutti S, Piepoli MF, Bernardi L, Sleight P, Cohen MA, Tan CO, Laude D, Elstad M, Toska K, Evans JM, and Eckberg DL. Comments on Point:Counterpoint series "Cardiovascular variability is/is not an index of autonomic control of circulation." J Appl Physiol 101: 684–688, 2006.[Free Full Text]
- Parati G. Arterial baroreflex control of heart rate: determining factors and methods to assess its spontaneous modulation. J Physiol 565: 706–707, 2006.[CrossRef]
- Parker P, Celler BG, Potter EK, and McCloskey DI. Vagal stimulation and cardiac slowing. J Auton Nerv Syst 11: 226–231, 1984.[CrossRef][Web of Science][Medline]
- Robinson TG, Dawson SL, Eames PJ, Panerai RB, and Potter JF. Cardiac baroreceptor sensitivity predicts long-term outcome after acute ischemic stroke. Stroke 34: 705–712, 2003.[Abstract/Free Full Text]
Gianfranco Parati
Giuseppe Mancia
Department of Clinical Medicine
Prevention and Applied Biotechnology
University of Milano-Bicocca, Milan, and
II Cardiology Unit
San Luca Hospital, IRCCS
Istituto Auxologico Italiano
Milan, Italy
Marco Di Rienzo
Paolo Castiglioni
Centro di Bioingegneria
Fondazione Don Gnocchi
Milan, Italy
To the Editor: Cardiovascular variabilities indeed represent an area of extensive research, and our aim was to illuminate the limitations in the methods applied. Although there seems to be general agreement about certain limitations, their weight is assessed differently.
Our discussants (4) acknowledge that cardiovascular variabilities cannot apply to all conditions (Malliani), do not correlate linearly with autonomic outflows (Malliani), do not reflect simple mechanisms (Cerutti), are rather qualitative than quantitative measures of autonomic outflow (Cerutti, Billman), and depend on myriad of factors besides mean level of autonomic outflow such as respiration (Eckberg) or the responsiveness/hypertrophy of the target organ (Bernardi).
We agree that the level of autonomic outflow can relate to variance around the mean level, but this is true only under specific conditions. Indeed, the linear correlation between vagal tone and respiratory sinus arrhythmia exists only at very low to moderately high vagal outflow and only after eliminating sympathetic effects (3; Laude in Ref. 4). However, robust parasympathetic activation or high vagal tone is associated with decreased heart rate variability, indicating nonlinear relationship (2; Elstad in Ref. 4). Moreover, sympathetic contributions to respiratory sinus arrhythmia may also affect its relationship to vagal tone (5).
Indexes of "sympathovagal balance" also seem to reflect autonomic activity only under specific conditions, namely, when observing postural effects. However, the finding that heart rate and normalized heart rate variability indexes discriminate between two body positions (Malliani in Ref. 4) does not imply that normalized heart rate variability indexes are adequate markers of autonomic outflows. In most cases, observing changes in heart rate alone would probably discriminate the two body positions. Additionally, the finding that normalized low-frequency oscillations increased and normalized high-frequency oscillations decreased with standing in many subjects indicates that these variables solely contain some broad information about autonomic outflows but do not necessarily quantify them.
Despite the limitations mentioned above, cardiovascular variabilities are thought to be valid indexes of autonomic outflows by many, because they 1) are simple and cheap methods (Piepoli) that represent the only noninvasive window into autonomic control (Evans), 2) provide some physiological interpretation (Cerutti), based on significant although not perfect correlations (Bernardi), and 3) have possible clinical application (Cerutti) and provide valuable prognostic information (Piepoli, Laude, Evans, Julien) (all Ref. 4).
Noninvasiveness, price, and availability are advantageous yet have no bearing on validity.
Physiological interpretation is surely needed, but it should not be based on overextrapolation. For example, we agree that the same central rhythmicity may appear in both vagal and sympathetic recordings; still, this should not be overextrapolated to mean that high-frequency oscillations are vagal and low-frequency oscillations are sympathetic in origin in any given variable.
We do not expect perfect correlations, but we do expect that changes in indexes reflect and quantify the underlying changes in various autonomic conditions. Neither absolute nor normalized values of cardiovascular variabilities fulfill this criterion (1).
Finally, calculation of the predictive power of any index deals solely with numbers and ignores the physiological meaningfulness. Clinical treatment, however, should be directed to improve (patho)physiological conditions and not to numbers with a questionable link to autonomic physiology.
REFERENCES
- Goldberger JJ. Sympathovagal balance: how should we measure it? Am J Physiol Heart Circ Physiol 276: H1273–H1280, 1999.[Abstract/Free Full Text]
- Goldberger JJ, Challapalli S, Tung R, Parker MA, and Kadish AH. Relationship of heart rate variability to parasympathetic effect. Circulation 103: 1977–1983, 2001.[Abstract/Free Full Text]
- Hayano J, Sakakibara Y, Yamada A, Yamada M, Mukai S, Fujinami T, Yokoyama K, Watanabe Y, and Takata K. Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects. Am J Cardiol 67: 199–204, 1991.[CrossRef][Web of Science][Medline]
- Malliani A, Julien C, Billman GE, Cerutti S, Piepoli MF, Bernardi L, Sleight P, Cohen MA, Tan CO, Laude D, Elstad M, Toska K, Evans JM, and Eckberg DL. Comments on Point:Counterpoint series "Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: 684–688, 2006.[Free Full Text]
- Taylor JA, Myers CW, Halliwill JR, Seidel H, and Eckberg DL. Sympathetic restraint of respiratory sinus arrhythmia: implications for vagal-cardiac tone assessment in humans. Am J Physiol Heart Circ Physiol 280: H2804–H2814, 2001.[Abstract/Free Full Text]
J. Andrew Taylor
Péter Studinger
Department of Physical Medicine and Rehabilitation
Harvard Medical School and Cardiovascular Research Laboratory
Spaulding Rehabilitation Hospital
Boston, MA
jandrew_taylor{at}hms.harvard.edu
Copyright © 2006 by the American Physiological Society.
