Dissociation between microneurographic and heart rate variability estimates of sympathetic tone in normal subjects and patients with heart failure.

The concept that spectral analysis of heart rate variability (HRV) can estimate cardiac sympathetic nerve traffic in subjects with both normal and impaired left ventricular systolic function has not been validated against muscle sympathetic nerve activity (MSNA). We used coarse-graining spectral analysis to quantify the harmonic and non-harmonic, or fractal, components of HRV and to determine low-frequency (0.0-0.15 Hz; PL) and high-frequency (0.15-0.5Hz; PH) harmonic power. To test the hypothesis that MSNA and HRV representations of sympathetic nerve activity (PL and PL/PH) increase in parallel in heart failure, we recorded heart rate and MSNA during supine rest in 35 patients (age 52.4+/-2 years; mean+/-S. E.M.), with a mean left ventricular ejection fraction of 22+/-2%, and in 34 age-matched normal subjects. Power density was log10 transformed. Mean MSNA was 52.9+/-2.6 bursts/min in heart failure patients and 34.9+/-1.9 bursts/min in normal subjects (P<0.0001). In normal subjects, but not in heart failure patients, total power (PT) (r=-0.41; P=0.02) and fractal power (PF) (r=-0.36; P=0.04) were inversely related to age. In heart failure patients, total and fractal power were reduced (P<0.009 for both), and were inversely related to MSNA burst frequency (r=-0.55, P=0.001 and r=-0.60, P=0. 0003 respectively). In normal subjects, there was no relationship between MSNA and either PL or PH. In heart failure patients, as anticipated, PH was inversely related to MSNA (r=-0.41; P<0.02). However, PL was also inversely rather than directly related to MSNA (r=0.44 for 1/log10 PL; P<0.01). There was no relationship between other sympathetic (PL/PH) or parasympathetic (PH/PT) indices and MSNA in either heart failure patients or normal subjects. The lack of concordance between these direct and indirect estimates of sympathetic nervous system activity indicates that this component of HRV cannot be used for between-subject comparisons of central sympathetic nervous outflow. It is the absence of low-frequency power that relates most closely to sympathetic activation in heart failure.

Comparison of hemodynamic and sympathoneural responses to adenosine and lower body negative pressure in man.

Adenosine increases heart rate and sympathetic nerve activity reflexively in conscious humans through several mechanisms. The purpose of this study was to assess the relative contributions of arterial baroreceptor unloading, carotid chemoreceptor stimulation, and other adenosine-sensitive afferent nerves to these responses. In 12 healthy men, the effect on blood pressure, heart rate (HR), and muscle sympathetic nerve activity (MSNA; peroneal nerve) of lower body negative pressure (LBNP; -15 mmHg (1 mmHg = 133.3 Pa)) was compared with the effect of intravenous adenosine (35, 70, and l40 micrograms.kg-1.min-1). In eight subjects, the highest dose was reinfused during 100% oxygen to suppress arterial chemoreceptors. Blood pressure reductions during LBNP and adenosine (140 micrograms.kg-1.min-1) were similar. HR did not change significantly during LBNP (+2 +/- 2 beats/min; mean +/- SE) but increased at the highest adenosine dose (+25 +/- 3 beats/min; p < 0.05). MSNA increased significantly (p < 0.05) during both interventions (+255 +/- 82 and +247 +/- 58 units/100 beats for adenosine and LBNP, respectively), and there was no difference in the MSNA response to these two stimuli (p > 0.1). Oxygen inhibited adenosine-induced increases in HR and MSNA (from +305 +/- 99 to +198 +/- 75 units/100 beats and from +26 +/- 4 to +18 +/- 3 beats/min; p < 0.05 for both comparisons). The MSNA response to these combined stimuli was similar to that observed during LBNP. In contrast, the residual HR response (+18 +/- 3 beats/min) was significantly greter than the response to LBNP (+2 +/- 2 beats/min; p < 0.05). These data indicate that arterial baroreceptor unloading cannot account for the marked adenosine-induced increase in HR, but may be sufficient to explain its effect on MSNA. The effect of 100% oxygen confirms that stimulation of carotid chemoreceptors accounts for approximately one-third of the HR and MSNA response to adenosine. However, other mechanisms, such as stimulation of adenosine-sensitive afferent nerves in other vascular beds, are involved in the HR and possibly the MSNA response.

Sympathetic alternans. Evidence for arterial baroreflex control of muscle sympathetic nerve activity in congestive heart failure.

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.

Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin.

The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60, and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (P < .01), central venous pressure (P < .001), forearm blood flow (P < .05), and forearm vascular compliance (P < .05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (P < .01). Candoxatril lowered central venous pressure (P < .001) and increased systolic pressure (from 116 +/- 6 to 120 +/- 7 mm Hg; P < .05), endothelin (from 4.6 +/- 1.1 to 6.8 +/- 3.2 pmol/L; P < .02), and epinephrine (P < .05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.

Influence of atrial natriuretic factor on spontaneous baroreflex sensitivity for heart rate in humans.

Our objective in these experiments was to evaluate the effects of atrial natriuretic factor on the gain of the spontaneous baroreceptor-heart rate reflex in humans. On two separate study days, we gave either atrial natriuretic factor during supine rest (16 nmol over 3 minutes, then 16 pmol/kg per minute) or saline (as vehicle) to nine healthy men (age, 23 +/- 1 years; mean +/- SEM) according to a random, double-blind design. Beat-by-beat RR interval and systolic pressure were recorded noninvasively. Sequences during which systolic pressure and the RR interval of the following beat changed in parallel (either increasing [Up] or decreasing [Down]) over at least three consecutive beats were identified and classified as baroreceptor-heart rate reflex sequences. Regression lines relating RR interval to the preceding systolic pressure were derived for each individual sequence. The mean value of the slopes of these regression lines was calculated to obtain the mean spontaneous baroreflex sensitivity for heart rate for each subject. Saline infusion did not change RR interval, systolic pressure, or number of baroreflex sequences nor the slope of the mean spontaneous baroreflex sensitivity for heart rate or slopes of Up or Down sequences. Atrial natriuretic factor, at a dose that lowers central venous pressure, did not affect systolic pressure, respiratory rate, or the number of baroreflex sequences but reduced RR interval from 952 +/- 35 to 930 +/- 40 ms (P < .04) and the mean slope of spontaneous baroreflex sensitivity for heart rate from 32.7 +/- 4.8 to 23.1 +/- 2.8 ms.mm Hg-1 (P < .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of atrial natriuretic factor on heart rate variability in normal men.

To study the effects of atrial natriuretic factor (ANF) on sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) control of heart rate, we gave ANF (50 micrograms over 3 min, then 50 ng.kg-1.min-1) and saline (vehicle) to six normal men [age 22 +/- 2 (SE) yr] during supine rest on two separate study days according to a random double-blind design. R-R interval data were sampled at 1,000 Hz over 7-min time segments, then analyzed by coarse graining spectral analysis of heart rate variability (HRV) to yield indicators of PNS and SNS activity. From the harmonic component of HRV, the integrated power in the low-frequency region (0.0-0.15 Hz, PL) and in the high-frequency region (0.15-0.50 Hz, PH) were calculated. Total spectral power (PT) was obtained and used to normalize the PNS indicator as PH/PT. The quantity PL/PH was taken as an indicator of SNS activity. By the 20th min of its infusion, ANF lowered PT, PH, and the SNS indicator (4.20 +/- 1.9 to 2.37 +/- 0.65; P < 0.05) but did not significantly change the PNS indicator (PH/PT). In contrast, 20-min saline infusion had no effect on these variables. These observations are consistent with our previous documentation of a relative sympathoinhibitory action of ANF on muscle sympathetic nerve activity and support the concept that ANF acts on the autonomic nervous system to decrease sympathetic outflow.

Absence of post exercise hypotension and sympathoinhibition in normal subjects: additional evidence for increased sympathetic outflow in borderline hypertension.

OBJECTIVE: In young men (mean age 25 years) with borderline hypertension the authors have documented a reduction in systolic blood pressure and muscle sympathetic nerve activity 60 mins after 45 mins of submaximal treadmill exercise. The aim of this study was to determine if post exercise hypotension occurs in normotensive young men, and if so, if it is accompanied by a decrease in sympathetic nerve activity. DESIGN: Replicating a previous protocol, the authors recorded blood pressure, heart rate, plasma noradrenaline and muscle sympathetic nerve activity (microneurography; peroneal nerve) before and 60 mins after submaximal treadmill exercise. SUBJECTS: Ten healthy male volunteers (mean age 28 +/- 5 years). INTERVENTION: Forty-five minutes of treadmill exercise at 70% of resting heart rate reserve. MAIN RESULTS: In contrast to borderline hypertensive subjects, prior exercise had no effect on either systolic or diastolic blood pressure or muscle sympathetic nerve activity in healthy volunteers. Plasma noradrenaline concentrations were similar before and after exercise. Resting heart rate (56 +/- 3 versus 70 +/- 3 beats/min; P less than 0.002), and sympathetic burst frequency (10 +/- 4 versus 20 +/- 2 bursts/min; P = 0.026) were lower in normal than in borderline hypertensive men. CONCLUSIONS: At rest, discharge to muscle sympathetic nerves is increased in young borderline hypertensive men; and blood pressure and sympathetic nerve activity are decreased after exercise in borderline hypertensive but not normotensive men. These observations suggest that the depressor response to prolonged rhythmic exercise in young men with borderline hypertension may be due in part to transient suppression of augmented central sympathetic outflow.