Article

Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation*

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ABSTRACT

Background. Power spectral analysis of heart rate variability (HRV) has been used to indicate cardiac autonomic function. High-frequency power relates to respiratory sinus arrhythmia and therefore to parasympathetic cardiovagal tone; however, the relationship of low-frequency (LF) power to cardiac sympathetic innervation and function has been controversial. Alternatively, LF power might reflect baro reflexive modulation of autonomic outflows. Objective. We studied normal volunteers and chronic autonomic failure syndrome patients with and without loss of cardiac noradrenergic nerves to examine the relationships of LF power with cardiac sympathetic innervation and baroreflex function. Methods. We compared LF power of HRV in patients with cardiac sympathetic denervation, as indicated by low myocardial concentrations of 6-[18F]fluorodopamine-derived radioactivity or low rates of norepinephrine entry into coronary sinus plasma (cardiac norepinephrine spillover) to values in patients with intact innervation, at baseline, during infusion of yohimbine, which increases exocytotic norepinephrine release from sympathetic nerves, or during infusion of tyramine, which increases non-exocytotic release. Baroreflex-cardiovagal slope (BRS) was calculated from the cardiac interbeat interval and systolic pressure during the Valsalva maneuver. Results. LF power was unrelated to myocardial 6-[18F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover. In contrast, the log of LF power correlated positively with the log of BRS (r = 0.72, P < 0.0001). Patients with a low BRS (≤3 msec/mm Hg) had low LF power, regardless of cardiac innervation. Tyramine and yohimbine increased LF power in subjects with normal BRS but not in those with low BRS. BRS at baseline predicted LF responses to tyramine and yohimbine. Conclusion. LF power reflects baroreflex function, not cardiac sympathetic innervation.


 

References

Spectral analysis of heart rate variability (HRV) has been used widely as a noninvasive technique for examining sympathetic and parasympathetic nervous outflows to the heart. Low-frequency (LF) and high-frequency (HF) power have been used most commonly. Human and animal experiments have repeatedly confirmed the dependence of HF power on respiration-related alterations in parasympathetic cardiovagal outflow–respiratory sinus arrhythmia; however, whether LF power provides an indirect measure of cardiac sympathetic activity has been contentious. Pagani et al1 reported that LF power (normalized to total spectral power) increased during states associated with sympathetic noradrenergic activation and that bilateral stellectomy in dogs reduced LF power. Alvarenga et al,2 however, reported that LF power was unrelated to all measures of norepinephrine kinetics in the heart; and in congestive heart failure, which is associated with a high rate of entry of norepinephrine into coronary sinus plasma (cardiac norepinephrine spillover),3 LF power is decreased, not increased as might be expected if LF power reflected sympathetic activity.4–7

Sleight et al8 proposed an alternative explanation for the origin of LF power. In a small group of human subjects, power spectral analysis of HRV showed that the amplitude of LF power was related to baroreflex gain and not to the level of sympathetic activity. Carotid sinus stimulation increased LF power only in individuals with normal baroreflex sensitivity and did not do so in those with depressed baroreflex gain. Therefore, results of power spectral analysis of LF power might reflect baroreflex-cardiovagal function.9

Studies of patients with dysautonomias provide an unusual opportunity to examine neurocirculatory correlates of LF power. Some chronic autonomic failure syndromes feature cardiac sympathetic denervation, whereas others do not. Parkinson disease with neurogenic orthostatic hypotension and pure autonomic failure feature cardiac sympathetic denervation, whereas multiple system atrophy does not.10 All 3 diseases involve baroreflex-cardiovagal and baro-reflex-sympathoneural failure.11 Chronic orthostatic intolerance syndromes (postural tachycardia syndrome, neurocardiogenic syncope) do not entail either cardiac sympathetic denervation or baroreflex failure.12

For this article, we carried out power spectral analyses of HRV on digitized electrocardiographic recordings from dysautonomia patients and normal volunteers during supine rest, measurement of cardiac norepinephrine spillover, and intravenous infusion of yohimbine and tyramine, 2 drugs that are known to release norepinephrine from cardiac sympathetic nerves.13,14 Cardiac sympathetic innervation was assessed by 6-[18F]fluorodopamine positron emission tomographic scanning.15

We hypothesized that if LF power indicated cardiac sympathetic innervation and function, then patients with neuroimaging or neurochemical evidence of cardiac sympathetic denervation would have low LF power and attenuated increments in LF power in response to yohimbine and tyramine. Alternatively, if LF power was reflective of baroreflex function, alterations of LF power would be independent of cardiac sympathetic innervation status and correlate with changes in baroreflex gain.

METHODS

The study protocols were approved by the Intramural Research Board of the National Institute of Neurological Disorders and Stroke. All subjects were studied at the National Institutes of Health Clinical Center after giving informed, written consent.

Subjects

The study population consisted of a total of 98 subjects who participated in research protocols studying chronic orthostatic intolerance and chronic autonomic failure (Table 1). The subjects underwent autonomic function testing and had reviewable, digitized electrocardiographic data enabling retrospective power spectral analysis of HRV. ECG and blood pressure data were sampled at 1 kHz.

The study subjects were separated into 4 groups, depending on their state of cardiac sympathetic innervation and baroreflex-cardiovagal slope (BRS; see below). There were 40 subjects with intact sympathetic innervation and normal BRS (Innervated-Normal BRS), 24 with intact sympathetic innervation and low BRS (Innervated-Low BRS), 4 with sympathetic denervation and normal BRS (Denervated-Normal BRS), and 30 with sympathetic denervation and low BRS (Denervated-Low BRS).

Autonomic function testing

Each subject was studied while supine with head on pillow after an overnight fast. Each patient had monitoring of the electrocardiogram and beat-tobeat blood pressure using either noninvasive devices (Finometer, Finapres Medical Systems, Amsterdam, the Netherlands; Portapres, Finapres Medical Systems; or Colin tonometer, Colin Medical Instruments, San Antonio, TX) or a brachial intra-arterial catheter. We previously studied formally and reported excellent agreement between intra-arterial and these noninvasively obtained measures of beat-to-beat blood pressure.16 Continuous vital signs data were digitized and recorded using a PowerLab (AD Instruments Pty Ltd, Castle Hill, Australia) data acquisition system and stored for later analysis on an Apple PowerBook G4 computer (Apple, Cupertino, CA).

After about a 10-min baseline period, each subject performed a Valsalva maneuver (30 mm Hg for 12 sec) at least 3 times.

Baroreflex function

As an index of baroreflex function, we used the slope of the relationship between cardiac interbeat interval and systolic blood pressure during phase II of the Valsalva maneuver.17 BRS, in units of msec/mm Hg, was calculated from the linear regression equation for the relationship between interbeat interval (with 1-beat delay) and systolic pressure. A BRS value of ≤3 msec/mm Hg was considered low.11

Pharmacologic testing

Pharmacologic testing was performed on completion of the autonomic evaluation, using either tyramine or yohimbine. If a subject received both drugs, each drug administration was on a separate day. The durations of drug infusion were sufficient for heart rate and blood pressure to reach plateau values.

In a total of 22 subjects (Table 1), yohimbine was infused intravenously at 62.5 μg/kg over 3 min and then at 0.5 μg/kg/min for 12 min. In a total of 50 subjects, tyramine was infused at a rate of 1 mg/min for 10 min. In patients with severe supine hypertension (systolic pressure more than 200 mm Hg) and orthostatic hypotension, the test drugs were infused during head-up tilting (15° to 30°), to decrease baseline pressure, or else the drugs were not given.

HRV analysis

LF power (0.04 to 0.15 Hz), HF power (0.16 to 0.4 Hz), and total power (TP, 0.0 to 0.4 Hz) were calculated using Chart 5.4.2 and the HRV module version 1.03 (PowerLab, AD Instruments Pty Ltd, Castle Hill, Australia). Stable heart rate epochs 3 to 5 min in duration were chosen for analysis. One epoch was sampled immediately before initiation of drug testing; the second followed attainment of steady-state hemodynamic effects. Interbeat interval data were reviewed carefully to eliminate artifacts from noise and T waves, using segments with little to no premature beats. LF power and HF power were calculated as absolute power (msec2), with or without normalization for total power (0.04 to 0.4 Hz). Reported LF or HF power was integrated within their defined frequency bands.

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