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A third way of thinking
Comment on Point:Counterpoint: “Cardiovascular variability is/is not an index of autonomic control o
Heart Rate Variability Provides a Qualitative, not a Quantitative, Index of Cardiac Vagal Regulation
Cardiovascular variability signal processing: a bridge towards physiological modeling
Cardiovascular Variability is an index of autonomic control of the circulation
Counterpoint series which will present two sides of the following issue: “Cardiovascular variability
Is Heart Rate Variability an Index of Autonomic Function?
The relevance of cardiovascular variability indexes
Respiratory sinus arrhythmia is not an index of vagal control of heart rate
Untitled
Untitled
Why measure cardiovascular variability at all?
Physiological interpretation of cardiovascular variability by non-linear methods
Comment on Cardiovascular Variability as Index of Autonomic Control of Circulation
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Alberto Malliani, Head of Department of Medicine
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alberto.malliani{at}unimi.it Alberto Malliani
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The Point-Counterpoint article (1) stimulates a third way of thinking. Since our first study (2) we attempted to obtain non invasive markers of autonomic cardiovascular regulation. In relation to a simple physiological hypothesis, the sympathovagal balance, we stressed two components of heart rate variability spectrum (LF and HF), normalizing their values in order to evaluate them independently of variance. We also proposed the LF/HF ratio, and, as an index of vasomotor modulation, LF of blood pressure variability. Evaluation of direct recordings of peripheral nerves and central neurons (3) strenghtened the conceptual basis of the approach. Obviously the new tool, like all others, cannot apply to "all conditions", and sympathovagal balance is not a linear phenomenon. The sentence "if one simply knows the angle of tilt, there is no need to assess heart rate variability" (1) indicates that irony is not the only key for understanding. Similarly, there is no paradox in the fact that both vagal and sympathetic recordings may furnish a window on the same central rhythmicity (4). Finally all Authors (1) have disregarded the study that has proven beyond any doubt the information content embedded in our approach. With a forecasting linear method, using three variables (HR, LF and HF normalized) it was possible to discriminate and recognize the supine and the upright position, known to engender distinct levels of sympathovagal balance, in about 84 per cent of 350 healthy subjects (5). Is this finding of heuristic value or should we have simply watched the body position? References: 1.Parati G, di Rienzo M, Castiglioni P, and Mancia G; Taylor JA and Studinger P. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: XXX-XXX, 2006. 2.Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, Turiel M, Baselli G, Cerutti S, Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 1986; 58:178-193. 3.Malliani A. Principles of cardiovascular neural regulation in health and disease. Boston, Dordrecht, London: Kluwer Academic Publishers, 2000. 4.Montano N, Cogliati C, Porta A, Pagani M, Malliani A, Narkyewicz C, Abboud FM, Birkett C, Somers VK. Central vagotonic effects of atropine modulate spectral oscillations of sympathetic nerve activity. Circulation 1998;98:1394-1399. 5.Malliani A, Pagani M, Furlan R, Guzzetti S, Lucini D, Montano N, Cerutti S, Mela GS. Individual recognition by heart rate variability of two different autonomic profiles related to posture. Circulation 1997;96:4143-4145. |
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Claude JULIEN, Research Director CNRS - France
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julien{at}univ-lyon1.fr Claude JULIEN
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Claude JULIEN Laboratoire de Physiologie, Faculté de Pharmacie, Université Lyon 1, Lyon, France Equating the mean (autonomic tone) with variations around the mean (autonomic oscillations) may sometimes be justified (4). For example, respiratory sinus arrhythmia (RSA) is almost entirely generated by vagal modulation of the sinus node. In healthy subjects under strictly controlled conditions (supine position, paced breathing and beta- adrenoceptor blockade), the amplitude of RSA is very sensitive to changes in vagal tone (3), but this probably does not hold true in other physiological or pathological situations. Ten-s arterial pressure Mayer waves are produced by rhythmic fluctuations of sympathetic nerve activity (SNA) and are usually enhanced during states of sympathetic activation in healthy subjects. However, these quantitative associations are not observed within and across groups of individuals. Furthermore, patients with chronic heart failure (CHF), a condition associated with heightened sympathetic outflow, show depressed or even absent low-frequency variability of arterial pressure and SNA. These observations, therefore, preclude the indiscriminate use of Mayer waves’ amplitude as a quantitative index of SNA. This is probably because these oscillations depend on a myriad of factors besides the mean SNA level (1). Given the complexity of its underlying physiology, it is not surprising that an integrated index such as the gain of the transfer function from arterial pressure to heart rate computed in the low- frequency band (0.04 to 0.15 Hz) is only weakly related to pharmacological baroreflex sensitivity (2). However, this should not deter the clinician from measuring this index, simply because it carries significant prognostic information in CHF patients (5). REFERENCES 1. Julien C. The enigma of Mayer waves: Facts and models. Cardiovasc Res 70: 12-21, 2006. 2. Lipman RD, Salisbury JK, and Taylor JA. Spontaneous indices are inconsistent with arterial baroreflex gain. Hypertension 42: 481-487, 2003. 3. Médigue C, Girard A, Laude D, Monti A, Wargon M, and Elghozi JL. Relationship between pulse interval and respiratory sinus arrhythmia: a time- and frequency-domain analysis of the effects of atropine. Pflugers Arch 441: 650-655, 2001. 4. Parati G, di Rienzo M, Castiglioni P, and Mancia G; Taylor JA and Studinger P. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: XXX-XXX, 2006. 5. Pinna GD, Maestri R, Capomolla S, Febo O, Robbi E, Cobelli F, and La Rovere MT. Applicability and clinical relevance of the transfer function method in the assessment of baroreflex sensitivity in heart failure patients. J Am Coll Cardiol 46: 1314-1321, 2005. |
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George E. Billman, Professor of Physiology and Cell Biology The Ohio State University, Columbus, OH
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billman.1{at}osu.edu George E. Billman
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The present article (2) provides a succinct overview of the arguments for and against the concept that cardiovascular variability is an index of cardiac autonomic control. Neither low frequency (<0.15 Hz) nor high frequency (>0.15 Hz) can be used as exclusive markers of sympathetic and parasympathetic, respectively. It cannot be overemphasized that heart rate variability (HRV) represents the integrated end-organ response to the complex non-linear interaction between sympathetic, parasympathetic activity, and other factors. This is particularly true with regards to the relationship between low frequency power and cardiac sympathetic regulation. Low frequency power was reduced by selective cardiac parasympathectomy and was not totally eliminated when denervation was combined with beta-adrenoceptor blockade (3). Furthermore interventions that would be expected to increase cardiac sympathetic activity (acute exercise or myocardial ischemia) not only failed to increase low frequency power but actually elicited significant reductions in this variable (1). Sympathetic activity can also modulate the high frequency component of heart rate variability (4), albeit to a lesser extent than parasympathetic influence on low frequency power. Although the vast majority of clinical and experimental studies demonstrate a strong association between high frequency power and cardiac parasympathetic activity (2), this relationship is qualitative rather than quantitative in nature (i.e., low HRV = low parasympathetic, high HRV = high parasympathetic activity, as opposed to X units = Y nerve impulses/sec). Thus, even if data are interpreted with appropriate caution, HRV provides only a qualitative marker of cardiac parasympathetic regulation. References: 1. Houle MS and Billman GE. The low frequency component of the heart rate variability spectrum: A poor marker of sympathetic activity. Am J Physiol Heart Circ Physiol 276: H215-H233, 1999. 2. Parati G, di Rienzo M, Castiglioni P, and Mancia G; Taylor JA and Studinger. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: XXX-XXX, 2006. 3. Randall DC, Brown DR, Raisch RM, Yingling JD, and Randall WC. SA nodal parasympathectomy delineates autonomic control of heart rate power spectrum. Am J Physiol Heart Circ Physiol 260:H985-H988, 1991. 4. 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. |
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Sergio Cerutti, Professor Biomedical Engineering Deptm Bioengineering, Polytechnic University, Milano, Italy
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cerutti{at}biomed.polimi.it Sergio Cerutti
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Finding bold correlations is a difficult art which requires experience and competence: to correlate the number of personal computers sold per year with the number of publications on Heart Rate Variability (HRV) may bring to the conclusion that babies are brought by storks either in Strasbourg or in South Africa simply correlating the peak of births with the incidence of arrival of storks. Both parts agree on the fact that obtaining parameters which could “measure” at some extent autonomic control is a challenging (and probably not yet solved) task. Our group was involved in the two milestone papers (1) (2) also reported by (3). Previously (4), we set up original methods of signal processing with a parametric approach able to detect efficiently the possible presence of rhythmic components embedded in wide band noise, according to a simple model of sympatho-vagal balance. Nobody may state that cardiovascular variability parameters (CVV) are quantitative measures of autonomic outflow, but certainly they helped many researchers of the more than 8500 papers actually cited on Medline to provide some physiological interpretation and possible clinical application. CVV does not reflect “simple” mechanisms: the community of Biomedical Engineers and Computer Scientists have greatly contributed to the studying of the “complexity” of the various signals related to it. A recent issue of IEEE Trans BME was dedicated to “Recent Advances in HRV Signal Processing and Interpretation” (5) and original and different approaches have been suggested, thus indicating multiple new roads open to build bridges between CVV signal processing and physiological modelling. 1. Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, Turiel M, Baselli G, Cerutti S, Malliani A, Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog, Circ Res, vol.58 : 178-193, 1986. 2. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, Circulation, vol.93 (5) : 1043-65, 1996. 3. Parati G, di Rienzo M, Castiglioni P, and Mancia G; Taylor JA and Studinger P. Point : Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: XXX-XXX, 2006. 4. Bartoli F, Baselli G, Cerutti S, AR identification and spectral estimate applied to the R-R interval measurements, Int J Biomed Comput., vol. 16 (3-4) : 201-15, 1985. 5. Cerutti S, Goldberger AL, Yamamoto Y eds, Recent advances in Heart Rate Variability signal processing and interpretation, Special Issue on IEEE Trans BME, vol 53: 1-139, 2006. |
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Massimo F Piepoli, MD Heart Failure Unit, Gugliemo da Saliceto Polichirurgico, Piacenza I-29100, Italy
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m.piepoli{at}imperial.ac.uk Massimo F Piepoli
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Heart rate variability (HRV) provides valuable prognostic information. Attenuation of HRV and baroreflex sensitivity (BRS) predicts poor outcome after myocardial infarction and in patients with chronic heart failure. (2,3) Limitation points have restricted the diffusion of these methods. HRV assessment is available from 24 hour Holter monitoring, but accurate analysis is time-consuming, dependence on multiple uncontrolled physiological stimuli mars interpretation (4). Conventional measures of BRS require the beat-to-beat measurement of blood pressure either invasively or non-invasively with expensive equipment. Taylor and Studinger who clearly express the scepticism of the clinical community towards these indices (5) indicates an our study as a further demonstration of the HRV shortcomings (1). We assessed BRS by asking subjects to breathe gently at 0.1 Hz. Breathing at 0.1 Hz provides a standard blood pressure (BP) stimulus and concentrates spectral power of heart rate at one frequency, enabling simple evaluation of BRS even when BP measurement is not available. This entrains oscillations in blood pressure, which act via the baroreflex to cause oscillations in heart rate. BRS measurement by this technique was found to be highly reproducible (by comparison with conventional techniques) and to agree well with conventional measures. (1). This method was validated in heart failure and diabetes mellitus patients. The widespread use of simple, cheap and easy methods of identifying patients at high risk of adverse cardiovascular events should be promoted since it would therefore allow the correct allocation of limited resources and of potentially dangerous interventions. References 1. Davies LC, Francis DP, Jurak P, Kara T, Piepoli M, Coats AJS. Reproducibility of methods for assessing baroreflex sensitivity in normal controls and in patients with chronic heart failure. Clinical Science 1999;97:515-522. 2. Farrell T, Odemuyiwa O, Bashir Y, Cripps T, Malik M, Ward D, Camm J. Prognostic value of baroreflex sensitivity testing after acute myocardial infarction. British Heart Journal 1992;67:129-137.. 3. La Rovere M, Bigger T, Marcus F, Mortara A, Schwartz P. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998;351:478-484 4. Scalvini S, Volterrani M, Zanelli, Pagani M, Mazzuero G, Coats AJS, Giordano A. Is heart rate variability a reliable method to assess autonomic modulation in left ventricular dysfunction and heart failure? Assessment of autonomic modulation with heart rate variability. International Journal of Cardiology 1998;67:9-17. 5. Taylor AJ and Studinger P. Counterpoint: cardiovascular variability is not an index of autonomic control of the circulation. J Appl Physiol 2006, this issue. |
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Luciano Bernardi, Associate Professor of Internal Medicine Univ. of Pavia and IRCCS S.Matteo, Pavia Italy, and Cardiovascular Medicine, Univ. of Oxford, UK, Peter Sleight
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lbern1ps{at}unipv.it Luciano Bernardi, et al.
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Sir, Taylor & Studinger use “heart” rate variability (HRV) arguments to attack circulatory variability indices of “circulatory” control (1), ignoring the role of activity or breathing (2,3,4,5) and much favourable evidence (2,3,4,5). Citations are misquoted; our physiological study of slow breathing is described as a study of religion! Their main argument against blood pressure (BP) low frequency components (LF) as an index of sympathetic activity is the lack of “perfect” correlation between sympathetic nerve activity (MSNA) and LF-BP, while admitting the existence of significant correlations. They regard MSNA as their gold standard; but the circulatory response depends on the hypertrophy/responsiveness of the target (5) – negating their interpretation of their ref 29. Taking this into account, their ref. 29- figure 3 correlates BP-LF with MSNA within each group, even if at rest and supine. Parati’s group rely mainly on consistent human studies of blockade, disease, or prognosis. Neither group reports the tight coherence between single sympathetic bursts and BP-LF (3, figure 1) - clear evidence that BP-LF is indeed related to sympathetic activity. In cardiac transplantation studies, before/during re-innervation, spectral analysis and specific interventions demonstrate neural and non-neural components of circulatory variability, and LF dependence on sympathetic activity (4). While we agree with Parati (though encouraging also a more physiologic approach), Taylor & Studinger require perfect correlation with sympathetic nerve recordings; not finding perfection, they then reject existing reasonable correlations (eg their refs 21,25,29), considering them as “contamination by lack of validation”. Perfect correlations do not exist in biology. References 1) Parati G, di Rienzo M, Castiglioni P, and Mancia G; Taylor JA and Studinger P. Point:counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: xxx-xxx, 2006. 2) Bernardi L, Valle F, Coco M, Calciati A, and Sleight P. Physical activity influences heart rate variability and very-low-frequency components in Holter electrocardiograms. Cardiovasc Res 32: 234-237,1996. 3) Bernardi L, Hayoz D, Wenzel R, Passino C, Calciati A, Weber R, and Noll G. Synchronous and baroceptor-sensitive oscillations in skin microcirculation: evidence for central autonomic control. Am J Physiol 273: H1867-878, 1997. 4) Bernardi L, Bianchini B, Spadacini G, Leuzzi S, Valle F, Marchesi E, Passino C, Calciati A, Vigano M, Rinaldi M, Martinelli L, Finardi G, and Sleight P. Demonstrable cardiac reinnervation after human heart transplantation by carotid baroreflex modulation of RR interval. Circulation 92: 2895-2903, 1995. 5) Piepoli M, Adamopoulos S, Bernardi L, Sleight P, and Coats AJ. Sympathetic stimulations by exercise-stress testing and by dobutamine infusion induce similar changes in heart rate variability in patients with chronic heart failure. Clin Sci (Lond) 89: 155-164, 1995. |
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Michael A. Cohen, Associate Professor Department of Cognitive and Neural System, Boston University, Can O. Tan
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mike{at}cns.bu.edu Michael A. Cohen, et al.
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Is Heart Rate Variability an Index of Autonomic Function?Both the Point and Counterpoint [1] agree that heart rate variability (HRV) is related to the activity of the autonomic nervous system (ANS), and that spectral variation of the heart rate in the lower (LF) and higher (HF) frequencies typically have a stronger relationship to sympathetic activity and vagal outflow, respectively. What is at issue is whether HRV is an index, or "a benchmark of activity or performance" of ANS. Only an explicit definition will make this assessment concrete. The counterpoint shows the difficulty of such a definition. This comes as no surprise. HRV, produced as a by-product of homeostatic function of ANS [1] is in turn one of many inputs to the ANS via "sensors" [2] such as baro- and chemo-receptors. However, so far, only a few, if any, of the quantitative relationships between the specific mechanisms of control and the sensor inputs have been investigated and explained [3]. HRV reflects both the operation of multiple controllers such as the sympathovagal input to the sinoatrial nodes, or prior calibration of one of the sensor inputs [4]. Thus without explicit knowledge of these relationships the point cannot be established. Nonetheless, rough mutable correlations between the properties of controlled cardiac output and the ANS input are to be expected. The authors of the point also propose that HRV should be used in clinical practise. We all welcome better diagnosis, and treatment of heart disease. To date, HRV has not been shown to be better than standard clinical tools for individual treatment. Since these measures are relatively cheap and noninvasive, we look forward to this demonstration. [1] Parati, G., di Rienzo, M., Castiglioni, P., Mancia, G., Taylor, J. A., and
Studinger, P. 2006. Point:counterpoint: Cardiovascular variability is/is not an index
of autonomic control of circulation. J. Appl. Physiol., this issue. |
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Dominique LAUDE, Engineer INSERM U652, Paris
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dlaude{at}bhdc.jussieu.fr Dominique LAUDE
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The Point-Counterpoint article (1) poses the problem of the relevance of indices derived from blood pressure (BP) and heart rate (HR) variability. The most convincing index of autonomic function is by far respiratory sinus arrhythmia (RSA), studied by Pyetan et al. (2), Médigue et al. (3) and others. The study by Médigue (3) showed that an infusion of atropine induced changes in amplitude of RSA. This RSA follows perfectly atropine infusion and corresponding changes in vagal tone. At low doses of atropine, the amplitude of RSA was increased, and then decreased at higher doses. This study shown that RSA was sensitive to slight changes in vagal activity resulting from the vagomimetic and the vagolytic effect of atropine. Also, indexes derivated from rapid reflex HR changes, produced good markers of the vagal activity. Furthermore the estimation of baroreflex sensitivity (BRS), by combining the BP and HR fluctuations offers some benefit in the early detection of autonomic neuropathy in animals (4) and humans (5). The study by Ziegler et al. (5) compared different indexes derived from BP and HR variability. This shows that some of them followed the degree of neuropathy in diabetic subjects. But only a few of them, such as the slope of the sequence method, were able to show significant modifications at an early stage of neuropathy, when conventional autonomic function tests were unable to detect any alterations. This estimate of BRS provides a powerful tool for the assesment of autonomic neuropathy, with direct implications in clinical practice. References: 1. Parati G, di Rienzo M, Castiglioni P, and Mancia G; Taylor JA and Studinger P. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: XXX-XXX, 2006 2. Pyetan E, Zoran O, Toledo E and Akselrod S. A theoretical model for the dependency of heart rate on gradual vagal blockade by atropine. Comput Cardiol 28: 653-656, 2001 3. Médigue C, Girard A, Laude D, Monti A, Wargon M, and Elghozi JL. Relationship between pulse interval and respiratory sinus arrhythmia: a time- and frequency-domain analysis of the effects of atropine. Pflugers Arch 441: 650-655, 2001. 4. Mésangeau D, Laude D, and Elghozi JL. Early detection of cardiovascular autonomic neuropathy in diabetic pigs using blood pressure and heart rate variability. Cardiovasc Res 45: 889-899, 2000 5. Ziegler D, Laude D, Akila F, and Elghozi JL. Time- and frequency- domain estimation of early diabetic cardiovascular autonomic neuropathy. Clin Auton Res 11: 369-376, 2001 |
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Maja Elstad, Ph.D. Student, M.D. Department of Physiology, University of Oslo, Norway, Karin Toska.
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majaelstad{at}yahoo.no Maja Elstad, et al.
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In their point-counterpoint discussion on whether cardiovascular variability is/is not an index of autonomic control of circulation both groups present valuable points. However, we would like to press the point that in order to be an index of autonomic control, cardiovascular variability must be a quantitative measure of the autonomic control. In the following, we present one example of the inadequacy of respiratory sinus arrhythmia (RSA) on being an index of vagal tone in healthy humans. In a healthy supine 19 yr old female we recorded heart rate and respiration. A beautiful, prominent RSA (amplitude ~15 beats/min (bpm)) appeared and HR was about 60 bpm when she performed a moderate dynamic leg exercise. In supine rest her HR averaged 39 bpm, indicating a pronounced vagal tone. However, RSA was of lesser amplitude (~6 bpm) and the integration of the HR power spectrum in the interval 0.15-0.40 Hz was 0.9 bpm² in rest compared to 7.8 bpm² in exercise. This is one example where RSA is not a quantitative index of vagal tone. If RSA is not an index of vagal tone in healthy young resting humans, we definitely need more knowledge before using RSA as a clinical tool to assess vagal autonomic control. The phenomenon presented here may be caused by saturation of M2- receptors for ACh in SA node cells.(2) In addition, to make sure all aspects are considered during discussion of RSA and its origin and function, it is important to include the respiratory variation in stroke volume.(3), (1) Reference List 1. Elstad M, Toska K, Chon KH, Raeder EA and Cohen RJ. Respiratory sinus arrhythmia: opposite effects on systolic and mean arterial pressure in supine humans. J Physiol 536: 251-259, 2001. 2. Pyetan E and Akselrod S. Do the high-frequency indexes of HRV provide a faithful assessment of cardiac vagal tone? A critical theoretical evaluation. Ieee Transactions on Biomedical Engineering 50: 777-783, 2003. 3. Toska K and Eriksen M. Respiration-synchronous fluctuations in stroke volume, heart rate and arterial pressure in humans. J Physiol (Lond) 472: 501-512, 1993. |
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Joyce M Evans, Biomedical scientist Biomedical Engineering, University of Kentucky
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jevans1{at}uky.edu Joyce M Evans
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Thank you for the opportunity to respond to the Point-Counterpoint cardiovascular variability (CVV) topic (4). For those of us who study healthy human volunteers, CVV indexes are our only non-invasive window into autonomic control and therefore this topic is of vital interest. We have used spectral power (in conjunction with plasma catecholamines) to gain insight into autonomic control associated with gender (2), simulations of spaceflight (5), cardiorespiratory interactions (3) and artificial gravity training (1). Currently we find that resting measures of spectral power predict the subsequent orthostatic tolerance limit of healthy women and discriminate levels of damage to cardiovascular regulation in spinal cord injured patients. The principals in this argument actually agree on the potential of CVV to discriminate autonomic activity. They disagree as to where problems exist: Taylor and Studinger argue that quantification of autonomic activity has not been achieved, warn that achievement may not expose “complex and largely undiscovered, physiology“ and suggest that efforts be focused on establishing more direct links to underlying physiology. Parati et al propose that the field has already established a basis for autonomic interpretation of results, and that future modeling will expose underlying physiology. We argue that, even though currently limited in interpretation, indexes of autonomic change are legitimate research tools. The current argument highlights the fact that CVV results must be carefully examined by authors, editors and reviewers of manuscripts for appropriate analyses and interpretation of autonomic control. However, it is our firm opinion that ever-increasing refinement of CVV indexes will lead to increasingly quantitative measures of autonomic activity. 1. Evans JM, Stenger MB, Moore FB, Hinghofer-Szalkay H, Rossler A, Patwardhan AR, Brown DR, Ziegler MG, and Knapp CF. Centrifuge training increases presyncopal orthostatic tolerance in ambulatory men. Aviat Space Environ Med 75: 850-858, 2004. 2. Evans JM, Ziegler MG, Patwardhan AR, Ott JB, Kim CS, Leonelli FM, and Knapp CF. Gender differences in autonomic cardiovascular regulation: spectral, hormonal, and hemodynamic indexes. J Appl Physiol 91: 2611-2618, 2001. 3. Krishnamurthy S, Wang X, Bhakta D, Bruce E, Evans J, Justice T, and Patwardhan A. Dynamic cardiorespiratory interaction during head-up tilt- mediated presyncope. Am J Physiol Heart Circ Physiol 287: H2510-2517, 2004. 4. Parati G. Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: xxx-xxx, 2006. 5. Wang M, Hassebrook L, Evans J, Varghese T, and Knapp C. An optimized index of human cardiovascular adaptation to simulated weightlessness. IEEE Trans Biomed Eng 43: 502-511, 1996. |
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Dwain Eckberg Departments of Medicine and Physiology, Hunter Holmes McGuire Department of Veterans Affairs Medical
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deckberg{at}ekholmen.com Dwain Eckberg
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I agree with Taylor and Studinger (4) that there is more to be learned from cardiovascular periodicities than what they may or not say regarding baseline levels of autonomic nerve traffic. Respiratory activity gates the responsiveness of sympathetic as well as vagal motoneurons to stimulatory inputs; therefore, both neural outflows fluctuate at respiratory frequencies (2). Respiratory fluctuations depend critically on the rate at which this gate is opened and closed (the breathing rate). Each breath releases boluses of acetylcholine and norepinephrine; at rapid breathing rates, each neurotransmitter bolus arrives on the heels of the preceding bolus, whose effects have not dissipated. Slow breathing fully expresses, and rapid breathing minimizes transmitter peaks and valleys, and corresponding neuroeffector responses. Proper understanding of high frequency rhythms requires knowledge of respiratory activity. Cardiovascular fluctuations also depend importantly on the intrinsic antagonism that exists between sympathetic stimulation and vagal inhibition. When breathing rate and depth are controlled, sympathetic activity reduces vagal heart period fluctuations at all, including low frequencies (5). Not surprisingly, there is no published evidence that low frequency heart period oscillations – measured, or modified mathematically – correlate significantly with muscle sympathetic nerve activity or cardiac norepinephrine spillover (1). Largely unexplored fluctuations of vagal baroreflex gain may explain disparities between pharmacological and spontaneous baroreflex measures. Prognostically-important very low frequency heart period rhythms are associated strongly with very low frequency, major fluctuations of baroreflex gain (3). I suggest that new insights into cardiovascular rhythms might be obtained by study of mechanisms modulating baroreflex gain, particularly at very low frequencies, and the physiological implications of intrinsic sympathetic – vagal antagonism. REFERENCES 1. Eckberg DL. Sympathovagal balance. A critical appraisal. Circulation 96: 3224-3232, 1997. 2. Eckberg DL. The human respiratory gate. J Physiol Lond 548: 339-352, 2003. 3. Eckberg DL and Kuusela TA. Human vagal baroreflex sensitivity fluctuates widely and rhythmically at very low frequencies. J Physiol Lond 567: 1011-1019, 2005. 4. Parati G, di Rienzo M, Castiglioni P, Mancia G, Taylor JA and Studinger P. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: xxx-xxx, 2006. 5. 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: H2808- H2814, 2001. |
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John M. Karemaker, Assoc. prof. of Physiology Acad.Med.Center, Univ. of Amsterdam
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j.m.karemaker{at}amc.uva.nl John M. Karemaker
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The point-counterpoint on CVV discussion caught my attention as it raises a number of questions on which I also have philosophized in the past (1-3). However interesting the arguments that are put forward, the only difference between the two p-cp camps seems to be the conclusion: may we or may we not use CVV-derived parameters in daily clinical practice? Strangely enough, no one ever questions the outcome of classical autonomic function tests, like the phenylephrine test (4) to ‘measure’ baroreflex sensitivity. Anyone who ever did the test, knows that a difference of factor of 2 in outcome between successive runs is not uncommon. Underpinning the fact that autonomic outflow from the CNS may be highly variable from moment to moment. Only in neuropathy or after brain injury do we find stable (mostly low) outflow. Continuous variability in nervous activity is a fact of life, and quantification by direct (MSNA) or indirect measurement (CVV) only may give rough estimates of a patients’ condition. Much less exact than the concentration of ions in the blood, but a telltale when longer periods of illness in one and the same patient are to be followed. There lies, in my opinion, the true power of clinical application of CVV, not in the one-point measurement, unless the condition is extremely clear-cut. References 1.Karemaker, JM. Heart rate variability: why do spectral analysis? Heart 77: 99-101, 1997 (editorial). 2.Karemaker JM. The riddles of heart rate variability. Clin Auton Res 11: 65-66, 2001 (editorial). 3.Karemaker JM. Why do we measure baroreflex sensitivity the way we do? Clin Auton Res 12: 427-428, 2002 (editorial). 4.Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterial pressure during sleep in man. A quantitative method of assessing baroreflex sensitivity. Circ Res 24: 109-121, 1969. |
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Dirk Cysarz Medical Theory and Conplementary Medicine, University of Witten/Herdecke, Germany
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d.cysarz{at}rhythmen.de Dirk Cysarz
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To the Editor: In principle, the analysis of heart rate variability (HRV) via spectral analysis offers the ability to quantify the amount of the modulation of both branches of the autonomic nervous system (4). Obviously, the physiological interpretation of the results of HRV analysis is more precise if the confounding factors are minimized. Hence, the experimental conditions need different methodological (e.g. steady state conditions imposed by the spectral analysis) as well as physiological constraints (e.g. control of respiration). Such restrictions are often difficult to realize. Furthermore, the extrapolation of results obtained under restricted conditions to everyday conditions (like e.g. obtained from ambulatory Holter recordings) is limited. To overcome these shortcomings different methodological improvements have been proposed, e.g. refinements of the spectral analysis (3). Interestingly, the physiological interpretation of cardiovascular variability is essentially based on linear methods, especially spectral analysis. The oscillatory model seems to be adequate to quantify the modulations of the two branches of the autonomic nervous system. However, the various limitations of this model show its shortcomings and, hence, call for complementary approaches. The physiological interpretation of most non-linear methods (e.g. approximate entropy) is still limited because the mathematical formalism underlying such methods cannot be transformed easily into physiological models of the autonomic nervous system. Nevertheless, there are other methods which probably could be interpreted in terms of physiology more easily. One example is the analysis of symbolic dynamics symbolizing acceleration and deceleration of instantaneous heart rate. Such dynamics may be relatively easy to interpret and also supply additional information (1, 2). The refinement of the physiological interpretation of cardiovascular variability is not only a matter of constraints imposed by accepted methods but also depends on the potential physiological interpretation based on linear and non-linear methods. References: 1. Bettermann H, Amponsah D, Cysarz D and Van Leeuwen P. Musical rhythms in heart period dynamics - a cross-cultural and interdisciplinary approach to cardiac rhythms. Am J Physiol 277: H1762-H1770, 1999. 2. Cysarz D, Lange S, Matthiessen PF and Van Leeuwen P. Regular heartbeat dynamics are associated with cardiac health. Am J Physiol Regul Integr Comp Physiol doi:10.1152/ajpregu.00161.2006, 2006. 3. Mateo J and Laguna P. Improved heart rate variability signal analysis from the beat occurrence times according to the IPFM model. IEEE Trans Biomed Eng 47: 985-996, 2000. 4. Parati G, Mancia G, Rienzo MD, Castiglioni P, Taylor JA and Studinger P. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: 676-682, 2006. |
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Catherine F Notarius, PhD University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada, John S. Floras MD, D.Phil.
Send letter to journal:
c.notarius{at}utoronto.ca Catherine F Notarius, et al.
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Changes in heart rate variability (HRV) or blood pressure variability (BPV) may well track qualitatively changes in vagal or sympathetic nerve traffic induced by some interventions in experimental models or human volunteers (6). However, contextual and interpretive limitations to their broader application to between-person comparisons or cardiovascular disease states have not been emphasized sufficiently in prior correspondence. HRV is a marker of sino-atrial node responsiveness to oscillations in sympathetic and vagal nerve traffic, not necessarily of nerve firing rates (5). Thus, conditions of high but relatively invariate sympathetic nerve firing and heart rates, such as exercise (2) or advanced heart failure (4) are characterized by loss, rather than gain of low frequency (LF) HRV spectral power. Even within healthy subjects, a very modest (1.6 mm Hg) reduction in central venous pressure without effect on stroke volume or blood pressure elicits marked discordance between muscle sympathetic nerve firing rates (increased) and both LF power and the LF/HF ratio (unchanged) (3). Even though BPV in the LF range tracks sympathetic nerve discharge within healthy subjects (6), it is not increased, but similar in subjects with and without heart failure (1). There is evidence, from large population studies, that low HRV increases the risk of premature cardiovascular death, but as yet none that such data quantifies reliably risk in a specific individual, or that selectively increasing HRV pharmacologically or non-pharmacologically without affecting other known modifiable risk markers improves outcome. Thus, HRV and BPV analyses are best reserved for focused within- subject mechanistic investigations. Catherine F. Notarius PhD, John S. Floras MD, D.Phil. Clinical Cardiovascular Physiology Research Laboratory, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada References 1. Butler, G. C., S. Ando, and J. S. Floras. Fractal component of variability of heart rate and systolic blood pressure in congestive heart failure. Clin.Sci. 92: 543-550, 1997. 2. Casadei, B., S. Cochrane, J. Johnston, J. Conway, and P. Sleight. Pitfalls in the interpretation of spectral analysis of the heart rate variability during exercise in humans. Acta.Physiol.Scand. 153: 125-131, 1995. 3. Floras, J. S., G. C. Butler, S. Ando, S. C. Brooks , M. J. Pollard, and P. Picton. Differential sympathetic nerve and heart rate spectral effects of nonhypotensive lower body negative pressure. Am.J.Physiol.(Regulatory Integrative Comp.Physiol.) 281: R468-R475, 2001. 4. Notarius, C. F., G. C. Butler, S. Ando, M. J. Pollard, B. Senn, and J. S. Floras. Dissociation between microneurographic and heart rate variability estimates of sympathetic tone in normal subjects and patients with heart failure. Clin.Sci. 96: 557-565, 1999. 5. Notarius, C. F. and J. S. Floras. Limitations of the use of spectral analysis of heart rate variability for the estimation of cardiac sympathetic activity in heart failure. Europace 3: 29-38, 2001. 6. Parati, G., G. Mancia, M. Di Rienzo, J. Castiglioni, A. Taylor, and P. Studinger. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J.Appl.Physiol. 101: 676- 682, 2006. |
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