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(Circulation. 1997;95:316-319.)
© 1997 American Heart Association, Inc.

Articles

Sympathetic Alternans

Evidence for Arterial Baroreflex Control of Muscle Sympathetic Nerve Activity in Congestive Heart Failure

Shin-ichi Ando, MD, PhD; Hilmi R. Dajani, MASc; Beverley L. Senn, RN; Gary E. Newton, MD, FRCPC; John S. Floras, MD, DPhil, FRCPC

the Division of Cardiology and Center for Cardiovascular Research, University of Toronto, Ontario, Canada.

	Abstract

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Abstract Alternation in the amplitude of muscle sympathetic nerve activity (MSNA) was documented in three patients with severe heart failure. In the index patient with pulsus alternans, the amplitude of MSNA was inversely related to changes in the preceding diastolic pressure with a lag time of 1.2 to 1.3 seconds, indicating that oscillations in burst amplitude are determined primarily by changes in this component of blood pressure. Spectral analysis of the blood pressure and MSNA signals identified two spectral peaks, one at the cardiac frequency and a second peak, with greater spectral power, at the alternans frequency (ie, at half the heart rate). The latter peak for both blood pressure and MSNA disappeared when alternans was abolished by nitroglycerin. The presence of sympathetic alternans in synchrony with pulsus alternans and the rapid transduction of changes in the diastolic blood pressure afferent signal to the amplitude of sympathetic outflow indicate that the arterial baroreflex control of MSNA must be active and rapidly responsive in human heart failure.

Key Words: baroreceptors • heart failure • nervous system

	Introduction

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Pulsus alternans is a clinical feature of severe congestive heart failure.¹ The rapid and predictable nature of these oscillations in blood pressure with alternate beats renders this phenomenon particularly amenable to frequency analysis.

In most patients with severe heart failure, there is little beat-to-beat variation in either heart rate, diastolic blood pressure, or muscle sympathetic nerve burst amplitude. The latter is a quantitative representation of the strength of each burst of sympathetic outflow to muscle.² In the course of a microneurographic study in a patient with pulsus alternans, we noted an alternating amplitude of muscle sympathetic nerve bursts, occurring at the identical frequency and at a constant time lag with respect to the blood pressure signal. To the best of our knowledge, such "sympathetic alternans" has not been described previously.

The arterial baroreflex control of efferent sympathetic outflow is believed by some to be impaired in human heart failure.^{3 4} This conclusion is based on observations arising from the administration of vasoactive drugs that exert their effects over many seconds to minutes. The presence of "sympathetic alternans," in the context of rapid changes in blood pressure of relatively small magnitude, stimulates us to propose instead that the arterial baroreflex control of muscle sympathetic nerve traffic during high-frequency oscillations in blood pressure remains active and rapidly responsive in this condition.

	Methods and Results

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Our index patient, a 44-year-old man, developed edema, breathlessness at rest, and nocturnal dyspnea 4 years after aortic valve replacement for severe regurgitation and was referred for evaluation. His medications were digitalis, furosemide, lisinopril, and nitrates. He was in sinus rhythm. Echocardiography revealed global left ventricular hypokinesis; the ejection fraction was 10% by radionuclide evaluation. His cardiac index was 2.0 L·min^-1·m^-2, and his pulmonary capillary wedge pressure was 21 mm Hg. Simultaneous recordings of postganglionic multifiber muscle sympathetic nerve activity (MSNA) and the arterial pressure waveform (Finapres 2300, Ohmeda) identified a rhythmic alteration in burst amplitude in synchrony with the pulsus alternans (Fig 1A, top). These recordings were sampled at 200 Hz and digitized to obtain systolic and diastolic blood pressures and sympathetic burst amplitudes (LabVIEW, National Instruments). Fast Fourier transformation of the mean voltage neurogram and blood pressure waveform during 7- to 10-minute time intervals revealed two distinct spectral peaks, one at the cardiac frequency and a second peak, with greater spectral power, at the alternans frequency (ie, at half the heart rate) (Fig 1A, bottom). Time-velocity integrals, sampled at the suprasternal notch,⁵ revealed similar oscillations in stroke volume. Latency between the preceding diastolic blood pressure and the subsequent sympathetic burst was 1.3 seconds, consistent with previous observations in normal subjects.^{6 7} The amplitude of each sympathetic burst was inversely proportional to the preceding diastolic blood pressure (r=-.505) and even more tightly correlated with changes in diastolic blood pressure from the prior (n-2) to the preceding (n-1) beat (r=-.767) (Fig 2), indicating the reflexive nature of the neural response to this rapidly oscillating stimulus. (Because data points collected in a time series may lack independence, we subsequently analyzed eight sets of 10 points each, 90 points apart, and found that the mean correlation coefficient value [r=.83] was significantly different from zero [t=33.3, df=7, P<.001]). By contrast, changes in systolic blood pressure had little effect on the subsequent RR interval (ie, baroreflex sensitivity for heart rate; 0.81 ms/mm Hg).

View larger version (23K): [in this window] [in a new window]   Figure 1. A, The ECG, muscle sympathetic nerve activity (MSNA), systemic blood pressure (BP), and power spectra of sympathetic nerve activity (FFT-SNA) and blood pressure (FFT-BP) during pulsus alternans. B, Recordings during intravenous nitroglycerin with disappearance of pulsus alternans. During pulsus alternans, there were relatively small changes in BP yet large oscillations in the amplitude of nerve bursts. Each sympathetic burst followed the preceding diastolic BP by 1.2 to 1.3 seconds, with a fall in amplitude as diastolic BP rose and vice versa. Power spectra were derived by use of fast Fourier transformation (FFT) from all cardiac cycles during a 7-minute period. During alternans (A), there were two peaks in both the BP and the MSNA signal, one at the prevailing heart rate and a second at half this rate, ie, corresponding to the alternans frequency (0.9 Hz). MSNA power at the alternans frequency was greater than at the cardiac frequency, indicating that sympathetic alternans was present at this frequency throughout most of this 7-minute recording period. The lower frequency peak disappeared when pulsus alternans was abolished (B); the residual BP and MSNA peaks are at this patient's heart rate. C, Similar recordings of ECG, MSNA, and BP and the power spectra for MSNA and BP in a patient with heart failure but without pulsus alternans (for purposes of comparison with A and B). A single peak of high spectral power falls on the heart rate frequency (arrow) in both the MSNA and BP spectra.

View larger version (19K): [in this window] [in a new window]   Figure 2. Inverse relation between muscle sympathetic nerve activity (MSNA) burst amplitude (V) and the change in diastolic blood pressure (DBP) from the preceding cardiac cycle (n-2) to the DBP for the cardiac cycle immediately before this burst (n-1) over a 7-minute sampling period (n=712; r=-.767). Note the two clusters reflecting the presence of alternans. When DBP rises from one cardiac cycle to the next, MSNA burst amplitude is extremely low or suppressed; conversely, the highest sympathetic burst amplitudes are seen in response to a fall in DBP.

Nitroglycerin (8 µg/min IV) lowered central venous pressure, systemic arterial pressure, and heart rate and abolished the pulsus and sympathetic alternans, resulting in a single residual spectral peak for both variables at the cardiac frequency (Fig 1B). Mean sympathetic burst amplitude (and therefore integrated MSNA) increased as an appropriate reflex response to the fall in diastolic blood pressure across all cardiac cycles.⁸ The spectral pattern in Fig 1B resembles that of patients with sympathetic activation in the setting of left ventricular dysfunction, but without pulsus alternans (Fig 1C).

During a similar study of a 47-year-old man with idiopathic dilated cardiomyopathy (ejection fraction of 4%), a single premature ventricular beat elicited a brief train of pulsus and sympathetic alternans (Fig 3). The baroreflex sensitivity for heart rate during alternans was 2.91 ms/mm Hg. These two values represent a marked suppression of baroreflex sensitivity for heart rate, whether compared with those obtained in our laboratory using this noninvasive method in healthy volunteers (32.7±4.8ms/mm Hg)⁹ or with values predicted for these 2 patients (10.2 and 8.2 ms/mm Hg, respectively) from a systematic evaluation of intra-arterial blood pressure and pulse-interval responses to pressor infusion of phenylephrine in 61 patients manifesting broad ranges for age and blood pressure.¹⁰

View larger version (18K): [in this window] [in a new window]   Figure 3. Sympathetic alternans elicited by pulsus alternans (seven beats) evoked by a ventricular premature contraction (arrow). MSNA indicates muscle sympathetic nerve activity; BP, blood pressure.

We also observed sympathetic alternans accompanying atrial bigeminy in a 61-year-old man with ischemic cardiomyopathy (ejection fraction of 10%) who died suddenly 6 months later. Diastolic pressure in that patient was relatively constant, whereas the RR interval and hence the diastolic time interval oscillated at 50% of the cardiac frequency. There was a significant positive relation between each RR interval and the subsequent burst amplitude (r=.79, P<.0001). All observations arose during the course of approved protocols and after informed written consent was obtained.

	Discussion

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The arterial baroreflex exerts a stabilizing effect on the heart and peripheral vasculature by its tonic modulation of parasympathetic and sympathetic nerve discharge. Whereas parasympathetic withdrawal is a characteristic feature of heart failure^{11 12 13} and one that likely contributes to the blunted heart rate response to blood pressure changes in our index patient, observations on the arterial baroreflex control of peripheral vascular resistance, mediated via efferent sympathetic nerve traffic, are less consistent.^{3 4 14} Our unique demonstration of sympathetic alternans in the context of pulsus alternans indicates that the arterial baroreflex control of MSNA must be active and rapidly responsive in heart failure.

It has been assumed that the high MSNA documented in patients with heart failure¹⁵ results from less inhibitory input from arterial and cardiopulmonary mechanoreceptor afferents.^{12 16 17 18 19} Grassi et al⁴ reported attenuated MSNA and heart rate responses to both increases and decreases in blood pressure elicited by phenylephrine and sodium nitroprusside, respectively. The degree of the impairment observed was related to the severity of heart failure. However, because the response to vasoactive agents in that study was assessed in terms of burst frequency, its attenuation can also be explained by the blunted heart rate response to these interventions.^{11 12 13 20}

Alternatively, sympathetic activation may represent an appropriate baroreceptor reflex response to the lower arterial and pulse pressures of heart failure. Consistent with this, Creager and Creager²⁰ demonstrated that the reflex blood pressure increase in response to carotid sinus baroreceptor unloading by positive neck pressure was attenuated in the setting of heart failure, whereas the fall in blood pressure in response to carotid sinus baroreceptor loading by negative neck pressure was intact. Those authors concluded that the blood pressure set point must lie closer to the threshold for baroreceptor activation than in normal subjects. Thus, additional decreases in blood pressure would not increase MSNA, which may be nearly maximal at rest,^{3 4 15} but MSNA should drop appropriately in response to baroreceptor stimulation. Indeed, Ferguson et al³ reported less reflex sympathetic activation in heart failure patients in response to hypotension induced by sodium nitroprusside but similar sympathoinhibition in normal and heart failure subjects when phenylephrine was infused to raise blood pressure. More recently, Dibner-Dunlap et al¹⁴ demonstrated that the major defect in heart failure lies in the cardiopulmonary rather than in the arterial baroreceptor reflex control of sympathetic nerve activity.

Although clinical attention has been directed primarily at the changes in systolic blood pressure in pulsus alternans, it is worth emphasizing that diastolic blood pressure also alternates, because it is the descent of systemic blood pressure that removes the tonic inhibitory restraint that baroreceptor input exerts on central sympathetic outflow. Thus, the principal stimulus to a muscle sympathetic burst is the cessation of arterial baroreceptor afferent discharge during diastole. This explains why there is a strong inverse correlation between the changes in diastolic blood pressure and the magnitude of muscle sympathetic nerve activity in individual subjects.^{8 21} The relation between longer diastolic times and higher sympathetic burst amplitudes in our third patient can be accounted for by a similar mechanism.

In young subjects with normal ventricular function, 20% to 50% of cardiac cycles are accompanied by a muscle sympathetic burst.²² The patients described herein are characteristic of patients with severe heart failure in that baroreflex sensitivity for heart rate was markedly reduced and a sympathetic nerve burst accompanied virtually every cardiac cycle.

What accounts for the high level of sympathetic outflow in heart failure? Our observations argue that it is not impaired arterial baroreflex control of MSNA. Five characteristics of blood pressure–MSNA relations in human heart failure provide strong evidence that the arterial baroreflex control of MSNA remains exquisitely sensitive in this condition: (1) the pulse synchronicity of sympathetic discharge, which is lost in sinoaortic baroreceptor–denervated humans²³ ; (2) the synchronous relation between sympathetic alternans and pulsus alternans, at a phase delay consistent with the known latency of this reflex arc; (3) the simultaneous abolition and induction of sympathetic and pulsus alternans by nitroglycerin and a ventricular premature beat, respectively; (4) the well-documented augmentation of sympathetic burst amplitude, subsequent to a ventricular premature beat, in heart failure; and (5) the strong inverse relation between the prevailing diastolic blood pressure or changes in diastolic blood pressure (stimulus) and the amplitude of the sympathetic nerve burst (response) in our index patient. The slope of the relationship in Fig 2 is similar to the relationship between transient variations in diastolic blood pressure and sympathetic burst amplitude previously described for both normotensive and hypertensive subjects.^{2 21} An alternative explanation, namely, that these oscillations in stroke volume and blood pressure represent a closely coupled (cardiac or peripheral vascular) effector response to the alternating pulses of sympathetic discharge (and subsequent neurotransmitter release), is inconsistent with the known time course of such transduction. Entrainment of brain-stem neurons by these cardiac oscillations can also be discounted because sympathetic alternans was observed only in the presence of pulsus alternans and ceased when alternans was abolished (Fig 1).

The principal limitation to our study is that observations arise from only three patients with severe heart failure. A second limitation is that we did not measure left atrial pressure; however, there is considerable and consistent experimental and human evidence that cardiopulmonary baroreflex control of MSNA is impaired in this condition.^{14 17 19}

The analysis of spontaneous changes in blood pressure and MSNA provides novel insights into arterial baroreceptor reflex function that are not available from studies using vasoactive drug administration. The latter method relies on burst frequency (which is a function of cardiac frequency) for interpretation and will therefore be affected by any primary disturbance of the baroreceptor–heart rate reflex. Atrial pressures are also affected by phenylephrine and nitroprusside.⁴ Alternans caused fluctuations in blood pressure within a narrower range (-6 to 6 mm Hg) than is induced by these drugs; this range lies more within the linear portion of the blood pressure–MSNA relation in heart failure.^{3 4 14 20} Studies in anesthetized rabbits²⁴ and conscious humans²⁵ indicate that baroreceptor nerve discharge is more sensitive to high- than to low-frequency changes in blood pressure. When static and sinusoidal neck pressure are applied to stimulate carotid baroreceptors, the greatest effect on MSNA is observed at the highest stimulus frequency.²⁵ In contrast, there is little or no effect on muscle sympathetic outflow when negative pressure is applied as a ramp for a 12-second period, ie, analogous to the slower time course over which these vasoactive drugs alter blood pressure. Consequently, responses to pulsus alternans may provide a better representation of the frequency at which arterial baroreceptor afferents optimally transduce changes in pulsatile pressure.

We have demonstrated for the first time the presence of sympathetic alternans in heart failure with pulsus alternans. The rapid transduction of relatively small changes in the diastolic blood pressure afferent signal to the amplitude of sympathetic outflow indicates that the arterial baroreflex control of MSNA is active, rapidly responsive, and indeed exquisitely sensitive in human heart failure.

	Acknowledgments

 
This study was supported by an operating grant from the Heart and Stroke Foundation of Ontario (T-2326). Dr Ando was supported by a Canadian Hypertension Society/Merck Frosst Fellowship and by the George R. Gardiner Foundation of Toronto. Dr Floras is the recipient of a Career Scientist Award of the Heart and Stroke Foundation of Ontario.

	Footnotes

 
Reprint requests to Dr John S. Floras, Division of Cardiology, Mount Sinai Hospital, 600 University Ave #1614, Toronto, Ontario M5G 1X5, Canada.

Received July 29, 1996; revision received October 23, 1996; accepted November 16, 1996.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ando, S.-i. Articles by Floras, J. S. Search for Related Content PubMed PubMed Citation Articles by Ando, S.-i. Articles by Floras, J. S.