Hc4099000d1p

Correspondence
Letters to the Editor must not exceed 400 words in length and may be subject to editing or abridgment. Letters must be limited to threeauthors and five references. They should not have tables or figures and should relate solely to an article published in Circulation withinthe preceding 12 weeks. Only some letters will be published. Authors of those selected for publication will receive prepublication proofs,and authors of the article cited in the letter will be invited to reply. Replies must be signed by all authors listed in the original publication. Mathematical Treatment of
4. Porter TR, Eckberg DL, Fritsch JM, Rea RF, Beightol LA, Schmedtje JF Autonomic Oscillations
Jr, Mohanty PK. Autonomic pathophysiology in heart failure patients:sympathetic-cholinergic interrelations. J Clin Invest. 1990;85:1362–1371.
5. Wallin BG, Sundlo¨f G, Eriksson B-M, Dominiak P, Grobecker H, Lindblad Montano et al1 measured RR interval and muscle sympathetic LE. Plasma noradrenaline correlates to sympathetic muscle nerve activity in nerve activity (MSNA) autoregressive spectral power before and normotensive man. Acta Physiol Scand. 1981;111:69 –73.
after small- and large-dose atropine and drew inferences regard- ing human central autonomic mechanisms. I have several ques- Recently, Montano et al1 claimed a central vagotonic effect of tions for the authors, as well as comments.
high-dose atropine was evidenced in peroneal nerve muscle Your finding that low-dose atropine does not alter low- sympathetic outflow (MSNA). However, the authors’ conclu- frequency RR-interval spectral power (Table 2) is at variance sions critically depend on “normalized units” to quantify low- with results published by Ikuta et al,2 which document significant frequency (LF) and high-frequency (HF) oscillations, a practice increases. Your observation also is at variance with one of your that can impart significance to the fluctuations beyond the principal conclusions (Abstract), that low-dose atropine de- regulatory mechanisms they subserve. This led to the conclusion creases low-frequency RR-interval spectral power. In the ab- that insight into parasympathetic nervous outflow can be gleaned sence of changes of measured low-frequency RR-interval spec- from activity in a sympathetic nerve. We take issue with the tral power, the reduction of normalized low-frequency RR- interpretation of these data and believe that despite cautionary interval spectral power that you report simply signifies that argument,2 this approach subsumes the physiological meaning of low-dose atropine increases respiratory sinus arrhythmia.3 cardiovascular oscillations to their spectral measures.
You report that low-dose atropine does not alter MSNA. This Heart period oscillations primarily derive from beat-by-beat confirms an observation we made earlier.4 You report also that autonomic control of systemic hemodynamics, ultimately buffering high-dose atropine reduces muscle sympathetic nerve burst or augmenting arterial pressure fluctuations.3 Vascular sympathetic frequency, expressed as bursts/100 heart beats and bursts/min.
rhythms have been identified also, although they may or may not be Our study4 also showed that large-dose atropine significantly related directly to pressure fluctuations.4,5 Spectral analysis conve- reduces sympathetic activity expressed as bursts/100 heart beats.
niently quantifies these rhythms but in itself does not reveal their However, contrary to your observations, we found that large- source. The findings of Montano et al rely solely on “normalizing” dose atropine does not significantly alter sympathetic activity power spectral data, a technique that uncouples the oscillations from expressed as bursts/min. This finding was supported by a related their physiological significance by measuring LF and HF relative to observation that large-dose atropine does not alter antecubital each other and making absolute amplitude irrelevant. In the present vein plasma norepinephrine concentrations (which correlate well study, average heart period variance after atropine was Ͻ1% of with MSNA).5 Can you explain the disparity between your control, representing almost complete elimination of beat-by-beat cardiac autonomic regulation. However, normalized units indicated You present only “normalized” MSNA; therefore, it is impos- that high-dose atropine reduced HF variability by only two thirds sible to determine whether measured MSNA frequency or and increased LF variability by one third, divorcing spectral mea- amplitude spectral power changed in high or low ranges or both.
sures from the oscillations’ minimal physiological significance. It is I am aware of substantial uncertainty regarding what high- and unclear how normalized units affected measures of MSNA variabil- low-frequency MSNA oscillations signify individually. My ity, since absolute values were not provided.
sense is that when you divide one by the other (and thereby The use of normalized units seems to presume that cardiovas- “normalize” them), you enter largely uncharted territory. The cular oscillations are rather than derive from autonomic out- notion that a change of this quotient documents central parasym- flows; that is, that HF is parasympathetic outflow and LF is pathetic modulation of sympathetic oscillations is provocative.
sympathetic outflow. Furthermore, the authors apply this as- However, high-dose atropine is a complex intervention that sumption to direct MSNA recordings, arriving at the curious profoundly alters autonomic function; there may be several conclusion that parasympathetic effects may be “revealed only alternative explanations for your results.
by examination of the HF oscillation of MSNA.”1 Outflow from Dwain L. Eckberg, MD
sympathetic nerves measured by peroneal microneurography is Hunter Holmes McGuire Department of Veterans Affairs simply sympathetic outflow, regardless of the frequency at which it oscillates. However, “normalizing” HF and LF oscillations to one another and equating HF oscillations with parasympathetic at Virginia Commonwealth University outflow lead to a conclusion that ignores this simple fact.
J. Andrew Taylor, PhD
1. Montano N, Cogliati C, Porta A, Pagani M, Malliani A, Narkiewicz K, Abboud FM, Birkett C, Somers VK. Central vagotonic effects of atropine modulate spectral oscillations of sympathetic nerve activity. Circulation.
Director, Laboratory for Cardiovascular Research HRCA Research and Training Institute 2. Ikuta Y, Shimoda O, Kano T. Quantitative assessment of the autonomic nervous system activities during atropine-induced bradycardia by heartrate spectral analysis. J Auton Nerv Syst. 1995;52:71–76.
Christopher W. Myers, PhD
3. Raczkowska M, Eckberg DL, Ebert TJ. Muscarinic cholinergic receptors Shuman Cardiovascular Research Fellow modulate vagal cardiac responses in man. J Auton Nerv Syst. 1983;7: HRCA Research and Training Institute 1
2
Correspondence
1. Montano N, Cogliati C, Porta A, Pagani M, Malliani A, Narkiewicz K, Blood pressure in his study was measured noninvasively by use Abboud FM, Birkett C, Somers VK. Central vagotonic effects of atropine of an intermittent blood pressure monitor. By contrast, we report modulate spectral oscillations of sympathetic nerve activity. Circulation.
actual measures of continuous recordings of intra-arterial blood pressure and MSNA. We are very comfortable with our data 2. Eckberg DL. Sympathovagal balance: a critical appraisal. Circulation.
showing that tachycardia after high-dose atropine is associated with an increase in intra-arterial systolic pressure and that this 3. Taylor JA, Eckberg DL. Fundamental relations between short-term RR interval and arterial pressure oscillations in humans. Circulation. 1996; increase in systolic pressure is associated with an unequivocal reduction in MSNA, whether expressed as bursts per minute, 4. Taylor JA, Williams TD, Seals DR, Davy KP. Low-frequency arterial bursts per 100 heart beats, arbitrary units, or normalized units. In pressure fluctuations do not reflect sympathetic outflow: gender and age view of the unreported data and qualitative descriptions of differences. Am J Physiol. 1998;274:H1194 –H1201.
changes in blood pressure and MSNA referred to by Dr Eckberg, 5. Pagani M, Montano N, Porta A, Malliani A, Abboud FM, Birkett C, we are not comfortable speculating on theoretical reasons for Somers VK. Relationship between spectral components of cardiovascular inconsistencies in the findings in his study compared with more variabilities and direct measures of muscle sympathetic nerve activity in explicit data from our and other investigators’ studies.2 humans. Circulation. 1997;95:1441–1448.
“You present only ‘normalized’ MSNA”: The following are the Response
absolute values, in arbitrary units squared (au2): MSNA LF: We thank Dr Eckberg for his comments on our work.
baseline 277Ϯ179, low-dose atropine 107Ϯ80 (PϽ0.05 versus Normalization of burst amplitudes and normalization of spec- baseline), and high-dose atropine 117Ϯ103. MSNA HF: baseline tral power: Low-dose atropine did not cause a significant change 189Ϯ124, low-dose atropine 108Ϯ66, and high-dose atropine in MSNA (Ϫ15Ϯ14%). High-dose atropine decreased MSNA by 161Ϯ153. Thus, the decrease in normalized LF of MSNA after 62Ϯ7% (PϽ0.03). Dr Eckberg correctly refers to potential low-dose atropine is accompanied by a decrease in absolute LF effects of “uncontrollable differences” in burst amplitude be- of MSNA, demonstrating that the effect of low-dose atropine on tween subjects. These bursts are arbitrary measures and are best the variability profile of MSNA is not simply a function of understood when they are normalized, an approach clearly favored by Dr Eckberg. Later in his comments, however, he “When you divide one by the other . . . , you enter largely suggests that our normalization of LF and HF powers of MSNA uncharted territory”: We are in uncharted territory whether we may not be appropriate. Since absolute LF and HF spectral refer to ratios or absolute values, since we do not know the measures are derived from absolute and arbitrary measures of precise mechanism of the oscillations. By looking at simulta- MSNA, we believe that normalization helps mitigate the problem neous oscillatory characteristics of 2 different autonomic out- of variability between individuals and is consistent with the flows, RR and MSNA, we may arrive at more reasonable principles inherent in normalization of burst amplitudes.
interpretations. The only certainty is that methodological and Comparisons of our data with those of Ikuta et al1: They found conceptual paradigms will change as new experimental knowl- a slight increase in LF RR spectral power after low-dose atropine, whereas we found no change. This difference in our We also appreciate Drs Taylor and Myers’ interest in our studies needs to be kept in perspective. First, all subjects in our study were male. Ikuta et al studied only females. Second, we “Heart period oscillations primarily derive from beat-by-beat used a bolus dose of atropine; Ikuta et al used steady-state autonomic control of systemic hemodynamics”: This thesis is infusions increasing every 4 to 5 minutes to a total duration of 24 flawed for several reasons. First, LF oscillations have been minutes. Third, we used an autoregressive algorithm, whereas demonstrated in the discharge of single brain stem neurons Ikuta et al used a fast Fourier transform with an LF band between recorded in sinoaortic denervated cats; furthermore, this LF oscillation was present even in the absence of similar blood “Your observation is at variance with one of your principal pressure fluctuations.3 Second, in patients with heart failure conclusions”: There is no conflict between the results and the studied before and after implantation of a left ventricular assist conclusions in our Abstract. The Abstract refers exclusively to device, there is a striking, newly evident LF oscillation in RR normalized data. It would then seem logical that the conclusion interval of the native heart after device implantation.4 This LF would also refer to normalized data.
oscillation is manifest in the absence of any similar oscillation in Reduced normalized LF RR power simply signifies increased blood pressure (which is dependent on the artificial heart output sinus arrhythmia: This suggestion highlights the importance of and independent of RR characteristics of the native heart). Third, simultaneous measurements of both RR and MSNA spectral in our study of atropine, low-dose atropine induced significant powers. Sinus arrhythmia (breathing-related changes in RR changes in the spectral patterns of both RR and MSNA in the interval) occurs in the HF range. During low-dose atropine, the absence of any changes in absolute or spectral components of decrease in normalized LF RR in our study was accompanied by intra-arterial blood pressure. Fourth, Dr Taylor himself con- a decreased normalized LF of MSNA, and as described later, a cludes in one of his recent studies5 that “respiratory sinus decreased absolute LF power of MSNA. Thus, the similar effects arrhythmia does not represent simple baroreflex buffering of of low-dose atropine not only on heart rate but also on MSNA demonstrate very clearly that effects of low-dose atropine on RR “HF is parasympathetic outflow and LF is sympathetic out- interval and on other measures of cardiovascular variability flow”: Drs Taylor and Myers have misinterpreted and misrepre- involve mechanisms other than sinus arrhythmia alone.
sented our Results and Discussion in their last paragraph. We “Can you explain the disparity between your results and refer them to our extensive experimental evidence showing, for ours?”: Our data are consistent with human studies by others2 example, that despite high sympathetic drive, patients with heart demonstrating that atropine increases blood pressure and de- failure have decreased or absent LF powers of RR and MSNA creases norepinephrine, which is also at odds with Dr Eckberg’s variability.6 We also refer them to our unequivocal statements findings. In Dr Eckberg’s study, only descriptive information of that “our data do not imply that the frequency composition of an the qualitative absence of changes in blood pressure, MSNA (in oscillatory signal can be equated with the strength of that signal”7 bursts per minute), and norepinephrine was provided. No actual and “[our] findings should not be misinterpreted as implying that measurements of these variables were reported. It is surprising power spectral variability can be equated to direct measurements that blood pressure did not increase after high-dose atropine.
of sympathetic or other autonomic function.”8 Correspondence
3
“Outflow from sympathetic nerves . . . is simply sympathetic 9. Haunstetter A, Haass M, Yi X, Kru¨ger C, Ku¨bler W. Muscarinic inhi- outflow, regardless of the frequency at which it oscillates”: It is bition of cardiac norepinephrine and neuropeptide Y release during is- not clear why Drs Taylor and Myers presume that central effects chemia and reperfusion. Am J Physiol. 1994;267:R1552–R1558.
of low-dose atropine would affect heart rate exclusively and that 10. Rorie DK, Rusch NJ, Shepherd JT, Vanhoutte PM, Tyce GM. Prejunc- sympathetic and parasympathetic outflows are mutually exclu- tional inhibition of norepinephrine release caused by acetylcholine in thehuman saphenous vein. Circ Res. 1981;49:337–341.
sive and devoid of interaction. Cholinergic muscarinic receptorblockade modulates adrenergic neurotransmission and norepi- C-Reactive Protein, Serum Amyloid A Protein,
nephrine release. Parasympathetic mechanisms therefore exertinhibitory effects on both cardiac9 and vascular10 sympathetic and Coronary Events
“The authors . . . [arrive] at the curious conclusion that Ridker et al1 examined C-reactive protein (CRP) and serum parasympathetic effects ‘may be revealed only by examination of amyloid A protein (SAA) in patients from CARE, a secondary- the HF oscillation of MSNA.’” Any central parasympathetic prevention study of pravastatin after myocardial infarction. They muscarinic influence of high-dose atropine on RR variability observed that the median plasma concentrations of CRP (0.31 would be masked by the peripheral (sinoatrial nodal) muscarinic versus 0.28 mg/dL; Pϭ0.05) and SAA (0.34 versus 0.28 mg/dL; blockade by atropine and the ensuing tachycardia. Changes in the Pϭ0.006) were significantly higher among those in whom MSNA oscillatory profile are consistent with central vagotonic coronary events occurred than in age- and sex matched controls.
effects of atropine, are evident whether one considers normalized They concluded that the plasma concentrations of CRP and SAA or absolute measures, and occur even in the absence of any predict the risk of recurrent coronary events among patients with change in overall MSNA. These effects cannot be ignored. We welcome a better strategy for assessing in humans the influence However, the matching of the subjects and controls was not of central muscarinic modulation of cardiovascular oscillations.
complete. The group in whom events occurred contained asignificantly higher proportion of diabetic patients (22.3% versus Nicola Montano, MD, PhD
Chiara Cogliati, MD
9.7%; Pϭ0.001), who are known to be at high risk of coronary Alberto Porta, MD
Massimo Pagani, MD
We investigated 23 diabetic patients (mean age 62.0 years, SD Alberto Malliani, MD
10.3, range 42 to 76; 18 men, 5 women) and 33 nondiabetic controls (61.3 years, SD 9.2, range 39 to 86; 31 men, 2 women), all with similar symptoms of stable angina and angiographically confirmed coronary disease. There were no significant differ- ences between the groups in the mean number of affected coronary vessels (2.47 in diabetic and 2.21 in controls) or in history of hypertension, smoking, total cholesterol, cholesterolsubfractions, or use of statins and aspirin. However, we found Krzysztof Narkiewicz, MD, PhD
that the diabetic patients had significantly higher plasma concen- Francois M. Abboud, MD
trations of both CRP (mean, SD of log values 2.78, Ϫ0.60, Virend K. Somers, MD, PhD
ϩ0.77 versus 1.52, Ϫ1.00, ϩ2.92 mg/L, Pϭ0.05) and SAA (mean, SD of log values 2.33, Ϫ1.52, ϩ4.38 versus 1.15, Ϫ0.86, ϩ3.38 mg/L, Pϭ0.042). The values of these analytes were highly skewed, as usual, but were normalized by log transfor- mation and were then subjected to a 1-way ANOVA.
In view of these findings, it is possible that higher levels of CRP and SAA observed by Ridker et al may have been due to an 1. Ikuta Y, Shimoda O, Kano T. Quantitative assessment of the autonomic nervous system activities during atropine-induced bradycardia by heart excess of diabetic patients in the event group. Larger studies will rate spectral analysis. J Auton Nerv Syst. 1995;52:71–76.
establish the role of CRP and SAA as predictors of future events 2. Goldstein DS, Keiser HR. Pressor and depressor responses after cho- in diabetic patients. The inflammatory response may be an linergic blockade in humans. Am Heart J. 1984;107:974 –979.
important factor in the predisposition to atherothrombotic events 3. Montano N, Gnecchi Ruscone T, Porta A, Lombardi F, Malliani A, in diabetes. The stimuli responsible for the acute-phase response Barman SM. Presence of vasomotor and respiratory rhythms in the in higher-risk atherosclerosis patients may arise from more discharge of single medullary neurons involved in the regulation of severe, extensive, or unstable arterial lesions and/or from inflam- cardiovascular system. J Auton Nerv Syst. 1996;57:116 –122.
mation or low-grade infection elsewhere.
4. Cooley R, Montano N, Cogliati C, van de Borne P, Oren R, Richenbacher W, Somers VK. Evidence for a central origin of the low frequency Robin P. Choudhury, MA, MRCP
oscillation in RR interval variability. Circulation. 1998;98:556 –561.
Francisco Leyva, MD, MRCP
5. Taylor JA, Eckberg DL. Fundamental relations between short-term RR interval and arterial pressure oscillations in humans. Circulation. 1996; 6. van de Borne P, Montano N, Pagani M, Oren R, Somers VK. Absence of low frequency variability of sympathetic nerve activity in severe heartfailure. Circulation. 1997;95:1449 –1454.
1. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, 7. Pagani M, Montano N, Porta A, Milliani A, Abboud FM, Birkett C, Flaker GC, Braunwald E, for the Cholesterol and Recurrent Events Somers VK. Relationship between spectral components of cardiovascular (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary variabilities and direct measures of muscle sympathetic nerve activity in events after myocardial infarction in patients with average cholesterol humans. Circulation. 1997;95:1441–1448.
levels. Circulation. 1998;98:839 – 844.
8. van de Borne P, Montano N, Pagani M, Zimmerman B, Somers VK.
2. Haffner SM, Lehto S, Ro¨nnemaa T, Pyo¨ra¨la¨ K, Laakso M. Mortality from Relationship between repeated measures of hemodynamics, muscle sym- coronary heart disease in subjects with type 2 diabetes and in nondiabetic pathetic nerve activity, and their spectral oscillations. Circulation. 1997; subjects with and without prior myocardial infarction. N Engl J Med.
4
Correspondence
C-Reactive Protein After First-Ever
2. Tracy RP. Inflammation in cardiovascular disease: cart, horse, or both? Ischemic Stroke
Circulation. 1998;97:2000 –2002.
3. Salonen JK, Nysso¨nen K, Korpela H, Tuomilehto J, Seppa¨nen R, Salonen R. High stored iron levels are associated with excess risk of myocardial We would like to compliment Paul Ridker and colleagues on infarction in eastern Finnish men. Circulation. 1992;86:803– 811.
the interesting study published in Circulation1 regarding the role 4. Da`valos A, Fernandez-Real JM, Ricart W, Soler S, Molins A, Planas E, of inflammation in secondary prevention after myocardial infarc- Genı´s D. Iron-related damage in acute ischemic stroke. Stroke. 1994;25: tion and add further observations. In their study, Ridker and colleagues1 found an intriguing association between evidence ofinflammation after myocardial infarction and an increased risk of Response
Inflammatory parameters may be elevated among individuals recurrent coronary events. Though the mechanism responsible with diabetes mellitus, and Drs Choudhury and Leyva hypothe- for this increased risk was unclear, the authors’ recommendation size on this basis that the elevations of C-reactive protein (CRP) to stratify postinfarction patients into relatively high- and low- and serum amyloid A (SAA) we observed among post–myocar- risk groups according to inflammation levels sounds appropriate dial infarction (MI) patients in the CARE trial might be con- considering that the relevance of inflammation in cardiovascular founded by this factor. However, as described in our original disease is not completely established,2 and it encourages us to article,1 adjustment for diabetes had minimal impact on risk study the role of C-reactive protein (CRP) levels in short-term estimates. Specifically, in logistic regression analyses, the crude prognosis after first-ever ischemic stroke.
relative risk (RR) of recurrent coronary events for those with We studied 30 ischemic stroke patients (10 men and 20 SAA levels above the 90th percentile was 1.61 (Pϭ0.03), women) between 49 and 90 years of age (meanϮSD 72Ϯ10 whereas the RR after adjustment for diabetes was 1.54 (Pϭ0.04).
years) within 4 weeks of their qualifying event who were Similarly, the crude RR associated with baseline CRP levels prospectively included in the Villa Pini Stroke Data Bank, Chieti, above the 90th percentile was 1.62 (Pϭ0.03), whereas the RR Italy. To avoid confounding factors, no patients with evidence of after adjustment for diabetes was 1.58 (Pϭ0.04). Thus, at least acute infection were included in the series. CRP samples were among the 782 participants evaluated, we found no important collected a median of 14 days from stroke event. The meanϮSD differences between diabetic and nondiabetic subjects with re- Canadian Neurological Stroke Scale score was 9.0Ϯ2.7.
gard to either SAA (0.29 versus 0.30 mg/dL) or CRP (0.36 versus Increased CRP levels were detected in all examined patients.
0.38 mg/dL). Our data do not, however, address whether or not There was a notable difference in the mean level of CRP between diabetes has an important effect on inflammatory parameters patients and our healthy control subjects (3.8 mg/dL [95% CI 1.4 among those without a prior history of MI.
to 6.1] versus 0.3 mg/dL [95% CI 0 to 0.5]). Higher CRP levels The role of CRP and other inflammatory markers as risk also correlated with a significant neurological deficit (Pϭ0.01) factors for ischemic stroke is less well established. However, in and a relevant disability (Pϭ0.05), assessed with the Canadian the prospective Physicians’ Health Study of apparently healthy Neurological Scale (Pearson correlation coefficient, rϭϪ0.6) men, those with elevated baseline levels of CRP had a 2-fold and the Barthel Index (rϭϪ0.4), respectively. Patients with the increase in the risk of developing thromboembolic stroke over an highest CRP levels (Ͼ5.0 mg/dL) at study entry died (nϭ2), had 8-year follow-up period (RRϭ1.9, 95% CI 1.1 to 3.3).2 Similar severe complications after stroke (nϭ1; pulmonary embolism), risk estimates have been reported for apparently healthy women.3 or had no evidence of recovery (nϭ3) during the 2-month Thus, the data provided from Drs Di Napoli, Di Gianfilippo, and Bocola regarding CRP levels among patients with acute stroke In conclusion, CRP was increased in patients with cerebral syndromes add to our understanding of the role of inflammation ischemia and appears to provide additional information regarding prognosis after ischemic stroke, as it appears to do after myo-cardial infarction. We believe that the role of CRP after ischemic Paul M. Ridker, MD
stroke is far more complicated than perhaps we realize. CRP may Marc A. Pfeffer, MD
be primarily an indicator of other vascular risk factors that are Frank M. Sacks, MD
themselves related to prognosis. In our patients, CRP levels were Eugene Braunwald, MD
correlated with serum ferritin levels (rϭ0.7; Pϭ0.002), suggest- ing that the effect of CRP may rely on a positive association with serum ferritin. Iron overload may elevate the risk of atheroscle- rotic disease and has been identified as a risk factor and an Nader Rifai, PhD
Children’s Hospital Medical Center The overall benefit of a preliminary study of CRP levels in all patients with cerebral ischemia is still undetermined, but thismarker appears to provide additional information and should be Lemuel A. Moye, MD
included in future investigations of prognostic factors in stroke.
University of Texas School of Public Health Mario Di Napoli, MD
Giacinto Di Gianfilippo, MD
Steven Goldman, MD
Veterans Administration Medical Center Vittorio Bocola, MD
Department of Neurology and Neurorehabilitation Greg C. Flaker, MD
1. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, 1. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E, for the Cholesterol and Recurrent Events Flaker GC, Braunwald E, for the Cholesterol and Recurrent Events (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol events after myocardial infarction in patients with average cholesterol levels. Circulation. 1998;98:839 – 844.
levels. Circulation. 1998;98:839 – 844.
Correspondence
5
2. Ridker PM, Cushman M, Stampfer MJ, Tracey RP, Hennekens CH.
Response
Inflammation, aspirin, and the risk of cardiovascular disease in apparently Swenne and colleagues raise the question of the lack of healthy men. N Engl J Med. 1997;336:973–979.
concomitant fluctuations in heart rate (HR) and in the oscillatory 3. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective components of its variability (HRV) in subjects before tilt- study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998;98:731–733.
In broad terms, HR depends on pacemaker intrinsic discharge, sympathetic and vagal neural activity, and circulatory neurohor- Cardiac Neural Changes Before
mones. Conversely, HRV reflects autonomic modulation of Vasovagal Syncope
sinoatrial node activity. Thus, HR and HRV cannot be equated.
At least 3 variables (RR, low-frequency RR [LFRR], and Furlan and colleagues1 present 2 scenarios leading to ortho- high-frequency RR [HFRR]) are necessary to define the individual statically induced syncope in healthy young subjects: “progres- autonomic profile corresponding to a given posture,2 which sive sympathetic activation” and “progressive sympathetic inhi- suggests that LFRR and HFRR contain information that is not bition.” Their physiological characterization of the scenarios is simply inherent in the HR value. In addition, we found that a based in large part on the observed changes in heart rate group of patients with syncope was characterized during tilt by a blunted increase of peroneal sympathetic nerve discharge HRV interpretation is complex. Muscle sympathetic nerve (MSNA) and plasma norepinephrine levels but an exaggerated recordings show that sympathetic firing fluctuates on a beat-to- enhancement of epinephrine compared with controls.3 Accord- beat basis (see, for example, Reference 2).However, due to the ingly, HR increased to a similar level in both groups.3 Thus, under certain circumstances (eg, in the presence of an time constants involved, the sinoatrial pacemaker can only increased concentration of circulating catecholamines before synco- follow the low-frequency fluctuations in sympathetic firing pe), HR may not parallel the changes of the spectral components of (10-second rhythm and slower), whereas faster-changing sympa- HRV. This seems to also apply to the other statement by Swenne thetic activity is integrated and becomes apparent only in the and colleagues that vagal withdrawal is necessary to explain average heart rate (HR). There is more uncertainty as to the tachycardia while sympathetic tone is lessening.
interpretation of low-frequency (LF) HRV, and the Task Force The time-variant spectral approach enabled us to assess the time on Heart Rate Variability disagrees as to whether it is sympa- course of the changes in the oscillatory components of HRV (ie, the thetic or sympathetic-plus-vagal modulations that are represented cardiac neural modulation) preceding the onset of syncope that would be otherwise undetectable by simple perusal of HR values. In If the sympathovagal balance changes, HR changes too.4 The the example shown in Figure 1,1 the trends of HFRR and LFRR LF dips and HF peaks that occur several times before the fainting suggest a progressive rise in cardiac vagal modulation and decrease episode in the sudden syncope case depicted in Figure 1 of the in sympathetic modulation in the case of “syncope with latency” article by Furlan et al1 are not reflected in HR itself. In their before the onset of bradycardia. Clinical observation of these study, Furlan and colleagues present control subjects and fainting subjects also detected signs and symptoms of vagal progressive subjects categorized according to the 2 above-mentioned scenar- activation, such as increasing nausea, dizziness, and yawning that ios. HR increases in all groups, no matter the HRV responses (see Tables 2 and 3). The strongest increase is seen in the sudden Only after a “critical level” is reached, overwhelming the fainters, the smallest in the control subjects. Therefore, progres- residual neurohormonal adrenergic activation, might vagal exci- sive sympathetic inhibition is unlikely in any of the studied tation and sympathetic inhibition silence the intrinsic sinoatrial groups. An increase in HR while the sympathetic tone is lessening can only be conceived in the setting of simultaneously Raffaello Furlan, MD
withdrawing vagal activity, for which the presented data bear no Simona Piazza, MD
evidence. The assessment of vagal tone, sympathetic tone, or the Simonetta Dell’Orto, MD
sympathovagal balance from HRV remains speculative, espe- Franca Barbic, MD
Anna Bianchi, MS
Luca Mainardi, MS
Cees A. Swenne, PhD
Sergio Cerutti, MS
Joost Frederiks, MD
Massimo Pagani, MD
Albert V.G. Bruschke, MD
Alberto Malliani, MD
Centro Ricerche Cardiovascolari, CNR 1. Furlan R, Piazza S, Dell’Orto S, Barbic F, Bianchi A, Mainardi L, Cerutti S, Pagani M, Malliani A. Cardiac autonomic patterns preceding occa- sional vasovagal reactions in healthy humans. Circulation. 1998;98:1756 –1761.
1. Furlan R, Piazza S, Dell’Orto S, Barbic F, Bianchi A, Mainardi L, Cerutti 2. Furlan R, Jacob G, Snell M, Robertson D, Porta A, Harris P, Mosqueda- S, Pagani M, Malliani A. Cardiac autonomic patterns preceding occa- Garcia R. Chronic orthostatic intolerance: a disorder with discordant sional vasovagal reactions in healthy humans. Circulation. 1998;98: cardiac and vascular sympathetic control. Circulation. 1998;98: 2. Malliani A, Pagani M, Furlan R, Guzzetti S, Lucini D, Montano N, 3. Camm AJ, et al. Heart rate variability: standards of measurement, phys- Cerutti S, Mela S. Individual recognition by heart rate variability of two iological interpretation, and clinical use. Circulation. 1996;93: different autonomic profiles related to posture. Circulation. 1997;96: 4. Swenne CA, Bootsma M. Sympathovagal balance and graded orthostatic 3. Mosqueda-Garcia R, Furlan R, Fernandez-Violante R, Desai T, Snell M, tilt. Circulation. 1995;91:2292. Letter.
Jarai Z, Ananthram V, Robertson RM, Robertson D. Sympathetic and 5. Eckberg DE. Sympathovagal balance: a critical appraisal. Circulation.
baroreceptor reflex function in neurally mediated syncope evoked by tilt.
J Clin Invest. 1997;99:2736 –2744.

Source: http://c.a.swenne.net/publications-pdf/Swenne-1999.pdf