Published online before print March 29, 2004, doi: 10.1161/01.HYP.0000126689.12940.cd
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2004;43:e32.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
Assessing the Sensitivity of Spontaneous Baroreflex Control of the Heart: Deeper Insight Into Complex Physiology
University of Milano-Bicocca and Ospedale San Luca, IRCCS, Istituto Auxologico Italiano, Milano, Italy
Centro di Bioingegneria FDG, IRCCS, Fondazione Don Gnocchi, Milano, Italy
Physiologie-Centre Hospitalier Universitaire, Besançon, France
Génomique Fonctionnelle dans l’Athérothrombose Faculté de Médecine Laennec, Lyon, France
Physiologie (CNRS UMR 5123), Campus de la Doua, Lyon-Villeurbanne, France
Pharmacologie Clinique / Néphrologie 2, Hôpital Necker, Paris, France
Laboratoire de Physiologie, UMR CNRS 6188, Faculté de Médecine, Angers, France
Pharmacologie Clinique / Néphrologie 2, Hôpital Necker, Paris, France
Department of Pharmacology & Toxicology, Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands
CNRS FRE 2678, Faculté de Pharmacie, Lyon, France
Department of Physiology, Academic Medical Center, University of Amsterdam, The Netherlands
Dipartimento di Medicina Interna, Centro di Riabilitazione Cardiologia San Raffaele, Università di Roma "Tor Vergata", Italy
INSERM E0107, Paris, France
Laboratory of Cardiovascular System Control, Institute of Experimental Cardiology National Cardiology Research Center, Moscow, Russia
University of Milano–Ospedale L Sacco, Milan, Italy
Johannes-Müller Institut für Physiologie, Berlin, Germany
Physiologie (CNRS UMR 5123), Lyon-Villeurbanne, France
Jacques Regnard Physiologie–Explorations fonctionnelles, Centre Hospitalier Universitaire, Besançon, France
University of Technology, Dresden, Germany
South Carolina Children’s Heart Center, Medical University of South Carolina, Charleston
University of Milano-Bicocca and Ospedale San Luca,, IRCCS, Istituto Auxologico Italiano, Milano, Italy
FMS, Finapres Medical Systems BV, Arnhem, The Netherlands
University of Milano-Bicocca and Ospedale San Luca,, IRCCS, Istituto Auxologico Italiano, Milano, Italy
on behalf of the European Society of Hypertension Working Group on Blood Pressure and Heart Rate Variability;
To the Editor:
While several papers support the physiological and clinical relevance of indices quantifying the sensitivity of spontaneous baroreflex control of heart rate (BRS),1 Lipman et al2 claim that they are unable to properly explore baroreflex function because spontaneous BRS was found to be quantitatively different from BRS values provided by the vasoactive drug injection technique and is unrelated to common carotid artery distensibility. We believe that this conclusion is not supported by Lipman’s data, for the following reasons.
- The time honored (and still valuable) method for assessing BRS through vasoactive drugs injection3,4 cannot be a "gold standard"5 due to pharmacological alteration of baroreceptor activity through both changes in blood pressure (BP) and unquantifiable mechanical distortion of the vessel;6 direct drug effect on the sinus node;7 simultaneous stimulation of cardiopulmonary stretch receptors; and limited reproducibility of the few spot BRS estimates obtainable.1,8
- Pharmacological and spontaneous BRS values are significantly correlated in most instances,9 as demonstrated by Parlow et al in a study10 not cited by Lipman et al. Moreover, spontaneous and drug-related BRS values display directionally similar changes under different conditions, thus reflecting virtually superimposable baroreflex physiology.
- Both the drug injection and the spontaneous sequence technique focus on the slope of the RR interval response to progressive Systolic (S) BP changes. Whether the origin of SBP ramps is spontaneous or by pharmacological means must be immaterial to the baroreceptors, with the partial physiological exception of spontaneous BP changes due to central influences simultaneously responsible also for arterial baroreflex resetting.
- Spontaneous BRS assessment by the sequence and spectral method was validated not only by the drug injection approach, but also by surrogate data analysis11 and for baroreceptor denervation in animals, which led to disappearance of baroreflex sequences12 and to a marked reduction in the
coefficient values.13
- The relation between carotid distensibility and BRS should be assessed in absence of diseases altering the baroreflex arch, while in some patients recruited in Lipman’s study normal carotid distensibility coexisted with disease-induced alterations of BRS. Moreover, there is evidence, in absence of drug injection, of spontaneous low frequency oscillations in carotid diameter that are related with low-frequency heart rate oscillations, further supporting the relevance of spontaneous methods to baroreflex physiology.14
- No BRS estimation technique, including drug injections, can produce stable numbers due to the physiological variability in BRS.15–19 Thus BRS estimates provided by only a few drug injections may be less reliable than spontaneous estimates assessed by averaging data over a sufficiently long time period.
- Lipman et al’s paper also faces other methodological problems: patients selection criteria;20–22 excessive focus on subjects with low baroreflex gain in whom a decrease in the between-method correlation is mathematically expected given the larger bias of low BRS estimates; sequential performance of drug injections with insufficient time to resume baseline conditions;3,4 use of different algorithms to derive pharmacological and spontaneous BRS values;15,22–25 and improper use of the Bland-Altman approach to assess between-method discrepancies.26,27
The conclusions of Lipman et al should thus be carefully reconsidered and the finding of quantitative discrepancies between pharmacological and spontaneous BRS values should not be interpreted as a difference between "real" and "biased" BRS estimates but rather as the expected difference in result of methods that explore baroreflex function from different but complementary perspectives.
References
1. Parati G, Di Rienzo M, Mancia G. How to measure baroreflex sensitivity: from the cardiovascular laboratory to daily life. J. Hypertens. 2000; 18: 7–19.[Medline] [Order article via Infotrieve]
2. Lipman RD, Salisbury JK, Taylor JA. Spontaneous indices are inconsistent with arterial baroreflex gain. Hypertension. 2003; 42: 481–487.
3. Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterial pressure during sleep in man: a quantitative method of assessing baroreflex sensitivity. Circ Res. 1969; 24: 109–121.
4. Mancia G, Mark AL. Arterial baroreflexes in humans. In: Shepherd JT, Abboud FM eds. Handbook of Physiology, sect. 2, cardiovascular system IV, vol. 3, part 2. Bethesda, Md. American Physiologic Society; 1983: 755–793.
5. Rudas L, Crossman AA, Morillo CA, Halliwill JR, Tahvanainen KUO, Kuusela TA, and Eckberg DL. Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine. Am J Physiol Heart Circ Physiol. 1999; 276: H1691–H1698.
6. Peveler RC. Bergel DH. Robinson JL Sleight P. The effect of phenylephrine upon arterial pressure, carotid sinus radius and baroreflex sensitivity in the conscious greyhound. Clinical Science. 1983; 64: 455–461.[Medline] [Order article via Infotrieve]
7. Musialek P, Lei M, Brown HF, Paterson DJ, Casadei B. Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, If. Circ Res. 1997; 81: 60–68.
8. Parati G, Pomidossi G, Ramirez AJ, Cesana B, Mancia G. Variability of the haemodynamic responses to laboratory tests employed in assessment of neural cardiovascular regulation in man. Clin. Sci. 1985; 69: 533–540.[Medline] [Order article via Infotrieve]
9. Pitzalis MV, Mastropasqua F, Passantino A, Massari F, Ligurgo L, Forleo C, Balducci C, Lombardi F, Rizzon P. Comparison between noninvasive indices of baroreceptor sensitivity and the phenylephrine method in post-myocardial infarction patients. Circulation. 1998; 97: 1362–1367.
10. Parlow J, Viale JP, Annat G, Hughson R, Quintin L. Spontaneous cardiac baroreflex in humans: comparison with drugs-induced responses. Hypertension. 1995; 25: 1058–1068.
11. Blaber AB, Yamamoto Y, Hughson RL. Methodology of spontaneous baroreflex relationship assessed by surrogate date analysis. Am J Physiol Heart Circ Physiol. 1995; 268: H1682–H1687.
12. Bertinieri G, Di Rienzo G, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G. Evaluation of baroreceptor reflex by blood pressure monitoring in unanesthetized cats. Am J Physiol Heart Circ Physiol. 1988; 254: H377–H383.
13. Mancia G, Parati G, Castiglioni P, di Rienzo M. Effect of sinoaortic denervation on frequency-domain estimates of baroreflex sensitivity in conscious cats. Am J Physiol Heart Circ Physiol. 1999; 276: H1987–H1993.
14. Kornet L, Hoeks AP, Janssen BJ, Willigers JM, Reneman RS et al. Carotid diameter variations as a non-invasive tool to examine cardiac baroreceptor sensitivity. J. Hypertens. 2002; 20: 1165–1173.[CrossRef][Medline] [Order article via Infotrieve]
15. Parati G, Saul JP, Di Rienzo M, Mancia G. Spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation: a critical appraisal. Hypertension. 1995; 25: 1267–1286.
16. Furlan R, Guzzetti S, Crivellaro W, Dassi S, Tinelli M, Baselli G, Cerutti S, Lombardi F, Pagani M, Malliani A. Continuous 24-hour assessment of neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects. Circulation. 1990; 81: 537–547.
17. Parati G, Di Rienzo M, Bertinieri G, Pomidossi G, Casadei R, Groppelli A, Pedotti A, Zanchetti A, Mancia G. Evaluation of the baroreceptor-heart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans. Hypertension. 1988; 12: 214–222.
18. Pagani M, Somers V, Furlan R, Dell’Orto S, Conway J, Baselli G, Cerutti S, Sleight P, and Malliani A. Changes in autonomic regulation induced by physical training in mild hypertension. Hypertension. 1988; 12: 600–610.
19. Laude D, Elghozi JL, Girard A, Bellard E, Bouhaddi M, Castiglioni P, Cerutti C, Cividjian A, Di Rienzo M, Fortrat JO, Janssen B, Karemaker JM, Leftheriotis G, Parati G, Persson PB, Porta A, Quintin L, Regnard J, Rudiger H, Stauss HM. Comparison of various techniques used to estimate spontaneous baroreflex sensitivity (the EuroBaVar study). Am J Physiol Regul Integr Comp Physiol. 2004; 286: R226–R231.
20. Frattola A, Parati G, Gamba P, Paleari F, Mauri G, Di Rienzo M, Castiglioni P, Mancia G. Time and frequency domain estimates of spontaneous baroreflex sensitivity provide early detection of autonomic dysfunction in diabetes mellitus. Diabetologia. 1997; 40: 1470–1475.[CrossRef][Medline] [Order article via Infotrieve]
21. Parati G, Frattola A, Di Rienzo M, Castiglioni P, Pedotti A, Mancia G. Effects of aging on 24 hour dynamic baroreceptor control of heart rate in ambulant subjects. Am J Physiol Heart Circ Physiol. 1995; 268: H1606–H1612.
22. Gribbin B, Pickering TG, Sleight P, Peto R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res. 1971; 29: 424–431.
23. Robbe HWJ, Mulder LJM, Ruddel H, Langewitz WA, Veldman JBP, Mulder G. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension. 1987; 10: 538–543.
24. Borst C, Karemaker JM. Time delays in the human baroreceptor reflex. J Auton. Nervous System. 1983; 9: 399–409.[CrossRef][Medline] [Order article via Infotrieve]
25. Barbieri R, Parati G, Saul JP. Closed-loop versus open-loop assessment of heart rate baroreflex. IEEE Engineering in Medicine and Biology Magazine. 2001; 20: 33–42.[Medline] [Order article via Infotrieve]
26. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986; i: 307–310.
27. Bland JM, Altman DG. Comparing methods of measurement: why plotting difference against standard method is misleading. Lancet. 1995; 346: 1085–1087.[CrossRef][Medline] [Order article via Infotrieve]
Response
Laboratories for Cardiovascular Research, HRCA Research and Training Institute, Boston, Mass
Division on Aging, Harvard Medical School, Boston, Mass
The logical principle that underlies all scientific modeling and theory building cautions against favoring the complex explanation over the simple one (ie, Occam’s razor, ca. 1285 to 1349). There are an infinite number of possible explanations for any scientific finding. For example, although 2 data points fall on a straight line, a variety of the most complicated curves could be construed to pass through those same 2 points and fit the data just as well. However, logic dictates choosing the linear relation as the best explanation. The simplest interpretation of our findings is that spontaneous indices do not relate adequately to baroreflex gain or to carotid distensibility.
The European Society of Hypertension Working Group on Blood Pressure and Heart Rate Variability cite a host of publications that could be construed to support their perspective that spontaneous indices can be used to reflect baroreflex gain. As a result, they are critical of our work, contending that it suffers serious methodological shortcomings and that the simple explanation of our findings is not supported by the data. Indeed, there is literature that could be interpreted to support the use of various indirect approaches to the baroreflex; we hope our work might be viewed as a comprehensive assessment of some of these approaches, adding to the literature a fair critique of the utility of spontaneous indices. We used a large, heterogenous sample to provide the strongest test of correlations; we also examined a subset of subjects with low baroreflex gain for whom sensitive measures may be most important; we made serial measurements for each subject to provide the most representative gain value; we allowed sufficient time for return to baseline between measures based on the known half-lives of nitroprusside and phenylephrine; we used techniques for the spontaneous indices previously published in papers with high citation rates; we were exacting in our determination of the linear baroreflex gain from drug-induced blood pressure changes; and, we sought the most complete statistics to test the relationships among spontaneous indices, baroreflex gain, and carotid distensibility. Our approach was rigorous, yet simple and straightforward, allowing clear interpretation of our findings. Although there was a relation between the spontaneous indices and baroreflex gain, in all cases this existed with gross bias and an error that exceeded the mean baroreflex gain of the population studied. In addition, no spontaneous index related to carotid distensibility while pharmacologically derived baroreflex gain did. These results do not indict the prognostic utility of cardiovascular oscillations, but they are a simple caution against exploiting these oscillations for indices of baroreflex gain.
This article has been cited by other articles:
 |
|
 |
|
  A. C. da Costa-Goncalves, J. Tank, R. Plehm, A. Diedrich, M. Todiras, M. Gollasch, A. Heuser, M. Wellner, M. Bader, J. Jordan, et al. Role of the Multidomain Protein Spinophilin in Blood Pressure and Cardiac Function Regulation Hypertension, October 1, 2008; 52(4): 702 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Laude, V. Baudrie, and J.-L. Elghozi Applicability of recent methods used to estimate spontaneous baroreflex sensitivity to resting mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R142 - R150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. E. Westerhof, J. Gisolf, J. M. Karemaker, K. H. Wesseling, N. H. Secher, and J. J. van Lieshout Time course analysis of baroreflex sensitivity during postural stress Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2864 - H2874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gulli, V. E. Claydon, V. L. Cooper, and R. Hainsworth R-R interval-blood pressure interaction in subjects with different tolerances to orthostatic stress Exp Physiol, May 1, 2005; 90(3): 367 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Gross, J. Tank, M. Obst, R. Plehm, K. J. Blumer, A. Diedrich, J. Jordan, and F. C. Luft Autonomic nervous system and blood pressure regulation in RGS2-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1134 - R1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Carrington, R. Barbieri, I. M. Colrain, K. E. Crowley, Y. Kim, and J. Trinder Changes in cardiovascular function during the sleep onset period in young adults J Appl Physiol, February 1, 2005; 98(2): 468 - 476. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||