Larry A. Beightol

Vagal and Sympathetic Mechanisms in Patients With Orthostatic Vasovagal Syncope

BACKGROUND Autonomic and particularly sympathetic mechanisms play a central role in the pathophysiology of vasovagal syncope. We report direct measurements of muscle sympathetic nerve activity in patients with orthostatic vasovagal syncope. METHODS AND RESULTS We studied 53 otherwise healthy patients with orthostatic syncope. We measured RR intervals and finger arterial pressures and in 15 patients, peroneal nerve muscle sympathetic activity before and during passive 60 degree head-up tilt, with low-dose intravenous isoproterenol if presyncope did not develop by 15 minutes. We measured baroreflex gain before tilt with regression of RR intervals or sympathetic bursts on systolic or diastolic pressures after sequential injections of nitroprusside and phenylephrine. Orthostatic vasovagal reactions occurred in 21 patients, including 7 microneurography patients. Presyncopal and nonsyncopal patients had similar baseline RR intervals, arterial pressure, and muscle sympathetic nerve activity. Vagal baroreflex responses were significantly impaired at arterial pressures below (but not above) baseline levels in presyncopal patients. Initial responses to tilt were comparable; however, during the final 200 seconds of tilt, presyncopal patients had lower RR intervals and diastolic pressures than nonsyncopal patients and gradual reduction of arterial pressure and sympathetic activity. Frank presyncope began abruptly with precipitous reduction of arterial pressure, disappearance of muscle sympathetic nerve activity, and RR interval lengthening. CONCLUSIONS Patients with orthostatic vasovagal reactions have impaired vagal baroreflex responses to arterial pressure changes below resting levels but normal initial responses to upright tilt. Subtle vasovagal physiology begins before overt presyncope. The final trigger of human orthostatic vasovagal reactions appears to be the abrupt disappearance of muscle sympathetic nerve activity.

Autonomic pathophysiology in heart failure patients. Sympathetic-cholinergic interrelations.

We conducted this study in an effort to characterize and understand vagal abnormalities in heart failure patients whose sympathetic activity is known. We measured sympathetic (peroneal nerve muscle sympathetic recordings and antecubital vein plasma norepinephrine levels) and vagal (R-R intervals and their standard deviations) activities in eight heart failure patients and eight age-matched healthy volunteers, before and after parasympathomimetic and parasympatholytic intravenous doses of atropine sulfate. At rest, sympathetic and parasympathetic outflows were related reciprocally: heart failure patients had high sympathetic and low parasympathetic outflows, and healthy subjects had low sympathetic and high parasympathetic outflows. Low dose atropine, which is known to increase the activity of central vagal-cardiac motoneurons, significantly increased R-R intervals in healthy subjects, but did not alter R-R intervals in heart failure patients. Thus, our data document reciprocal supranormal sympathetic and subnormal parasympathetic outflows in heart failure patients and suggest that these abnormalities result in part from abnormalities within the central nervous system.

Human autonomic rhythms : vagal cardiac mechanisms in tetraplegic subjects

1. We studied eight young men (age range: 20‐37 years) with chronic, clinically complete high cervical spinal cord injuries and ten age‐matched healthy men to determine how interruption of connections between the central nervous system and spinal sympathetic motoneurones affects autonomic cardiovascular control. 2. Baseline diastolic pressures and R‐R intervals (heart periods) were similar in the two groups. Slopes of R‐R interval responses to brief neck pressure changes were significantly lower in tetraplegic than in healthy subjects, but slopes of R‐R interval responses to steady‐state arterial pressure reductions and increases were comparable. Plasma noradrenaline levels did not change significantly during steady‐state arterial pressure reductions in tetraplegic patients, but rose sharply in healthy subjects. The range of arterial pressure and R‐R interval responses to vasoactive drugs (nitroprusside and phenylephrine) was significantly greater in tetraplegic than healthy subjects. 3. Resting R‐R interval spectral power at respiratory and low frequencies was similar in the two groups. During infusions of vasoactive drugs, low‐frequency R‐R interval spectral power was directly proportional to arterial pressure in tetraplegic patients, but was unrelated to arterial pressure in healthy subjects. Vagolytic doses of atropine nearly abolished both low‐ and respiratory‐frequency R‐R interval spectral power in both groups. 4. Our conclusions are as follows. First, since tetraplegic patients have significant levels of low‐frequency arterial pressure and R‐R interval spectral power, human Mayer arterial pressure waves may result from mechanisms that do not involve stimulation of spinal sympathetic motoneurones by brainstem neurones. Second, since in tetraplegic patients, low‐frequency R‐R interval spectral power is proportional to arterial pressure, it is likely to be mediated by a baroreflex mechanism. Third, since low‐frequency R‐R interval rhythms were nearly abolished by atropine in both tetraplegic and healthy subjects, these rhythms reflect in an important way rhythmic firing of vagal cardiac motoneurones.

Controlled breathing protocols probe human autonomic cardiovascular rhythms

The purpose of this study was to determine how breathing protocols requiring varying degrees of control affect cardiovascular dynamics. We measured inspiratory volume, end-tidal CO2, R-R interval, and arterial pressure spectral power in 10 volunteers who followed the following 5 breathing protocols: 1) uncontrolled breathing for 5 min; 2) stepwise frequency breathing (at 0.3, 0.25, 0.2, 0.15, 0.1, and 0.05 Hz for 2 min each); 3) stepwise frequency breathing as above, but with prescribed tidal volumes; 4) random-frequency breathing (∼0.5-0.05 Hz) for 6 min; and 5) fixed-frequency breathing (0.25 Hz) for 5 min. During stepwise breathing, R-R interval and arterial pressure spectral power increased as breathing frequency decreased. Control of inspired volume reduced R-R interval spectral power during 0.1 Hz breathing ( P < 0.05). Stepwise and random-breathing protocols yielded comparable coherence and transfer functions between respiration and R-R intervals and systolic pressure and R-R intervals. Random- and fixed-frequency breathing reduced end-tidal CO2modestly ( P < 0.05). Our data suggest that stringent tidal volume control attenuates low-frequency R-R interval oscillations and that fixed- and random-rate breathing may decrease CO2 chemoreceptor stimulation. We conclude that autonomic rhythms measured during different breathing protocols have much in common but that a stepwise protocol without stringent control of inspired volume may allow for the most efficient assessment of short-term respiratory-mediated autonomic oscillations.

Sympathetic neural responses to induced ventricular tachycardia

Although sympathetic mechanisms play a major role in buffering abrupt arterial pressure reductions, including those that occur during tachyarrhythmias, human sympathetic nervous system responses to ventricular tachycardia have not been measured. Muscle sympathetic nerve activity was recorded directly from the peroneal nerve in 16 patients during diagnostic induction of 19 episodes of sustained monomorphic ventricular tachycardia (average rate 189 beats/min, range 130 to 250). Average systolic and diastolic pressures decreased from 149/78 to 61/49 mm Hg by 10 s and increased toward baseline levels to 88/64 mm Hg by 1 min of ventricular tachycardia. Average sympathetic nerve activity increased by 92% at 10 s in direct proportion to arterial pressure reductions and in inverse proportion to ventricular rate and remained 83% above baseline levels at 1 min. The late recovery of arterial pressure during ventricular tachycardia was related significantly to the magnitude of early sympathetic responses. Sympathetic activity tended to lose its discrete bursting pattern during ventricular tachycardia, and power spectral analysis showed that the large sympathetic peaks at the heart rate frequency present during sinus rhythm are absent during ventricular tachycardia. This study is the first to delineate human sympathetic nervous system responses to ventricular tachycardia. The results suggest that in the patients studied, large early sympathetic surges differed from those that occur during sinus rhythm and contributed to hemodynamic stability during ventricular tachycardia.

Contributions of tidal lung inflation to human R–R interval and arterial pressure fluctuations

We studied the effects of mechanical lung inflation on respiratory frequency R-R interval and arterial pressure fluctuations in nine healthy young adults undergoing elective orthopedic surgery. We conducted this research to define the contribution of pulmonary and thoracic stretch receptor input to respiratory sinus arrhythmia. We compared fast Fourier transform spectral power during three modes of ventilation: (1) spontaneous, frequency-controlled (0.25 Hz) breathing, (2) intermittent positive pressure ventilation (0.25 Hz, with a tidal volume of 8 ml/kg) and (3) high frequency jet ventilation (5.0 Hz, 2.5 kg/cm2), after sedation and vecuronium paralysis. Mean R-R intervals, arterial pressures and arterial blood gas levels were comparable during all three breathing conditions. Respiratory frequency systolic pressure spectral power was comparable during spontaneous breathing and conventional mechanical ventilation, but was significantly reduced during high frequency jet ventilation (P < 0.05). Respiratory frequency R-R interval spectral power (used as an index of respiratory sinus arrhythmia) declined dramatically with sedation and muscle paralysis (P < 0.05), but was greater during conventional mechanical, than high frequency jet ventilation (P < 0.05). These results suggest that although phasic inputs from pulmonary and thoracic stretch receptors make a statistically significant contribution to respiratory sinus arrhythmia, that contribution is small.

Interactions between CO2 chemoreflexes and arterial baroreflexes

We studied interactions between CO2 chemoreflexes and arterial baroreflexes in 10 supine healthy young men and women. We measured vagal carotid baroreceptor-cardiac reflexes and steady-state fast Fourier transform R-R interval and photoplethysmographic arterial pressure power spectra at three arterial pressure levels (nitroprusside, saline, and phenylephrine infusions) and three end-tidal CO2 levels (3, 4, and 5%, fixed-frequency, large-tidal-volume breathing, CO2 plus O2). Our study supports three principal conclusions. First, although low levels of CO2 chemoreceptor stimulation reduce R-R intervals and R-R interval variability, statistical modeling suggests that this effect is indirect rather than direct and is mediated by reductions of arterial pressure. Second, reductions of R-R intervals during hypocapnia reflect simple shifting of vagally mediated carotid baroreflex responses on the R-R interval axis rather than changes of baroreflex gain, range, or operational point. Third, the influence of CO2 chemoreceptor stimulation on arterial pressure (and, derivatively, on R-R intervals and R-R interval variability) depends critically on baseline arterial pressure levels: chemoreceptor effects are smaller when pressure is low and larger when arterial pressure is high.

Human vagal baroreflex mechanisms in space

Although astronauts’ cardiovascular function is normal while they are in space, many have altered haemodynamic responses to standing after they return to Earth, including inordinate tachycardia, orthostatic hypotension, and uncommonly, syncope. Simulated microgravity impairs vagal baroreceptor–cardiac reflex function and causes orthostatic hypotension. Actual microgravity, however, has been shown to either increase, or not change vagal baroreflex gain. In this study, we tested the null hypothesis that spaceflight does not impair human baroreflex mechanisms. We studied 11 American and two German astronauts before, during (flight days 2–8), and after two, 9‐ and 10‐day space shuttle missions, with graded neck pressure and suction, to elicit sigmoid, vagally mediated carotid baroreflex R–R interval responses. Baseline systolic pressures tended to be higher in space than on Earth (P= 0.015, repeated measures analysis of variance), and baseline R–R intervals tended to be lower (P= 0.049). Baroreceptor–cardiac reflex relations were displaced downward on the R–R interval axis in space. The average range of R–R interval responses to neck pressure changes declined from preflight levels by 37% on flight day 8 (P= 0.051), maximum R–R intervals declined by 14% (P= 0.003), and vagal baroreflex gain by 9% (P= 0.009). These measures returned to preflight levels by 7–10 days after astronauts returned to Earth. This study documents significant increases of arterial pressure and impairment of vagal baroreflex function in space. These results and results published earlier indicate that microgravity exposure augments sympathetic, and diminishes vagal cardiovascular influences.

Automated solid-phase extraction and high-performance liquid chromatographic determination of ranitidine from urine, plasma and peritoneal dialysate

Ranitidine is an H2-receptor antagonist primarily used to treat peptic ulcer. The present automated solid-phase extraction technique involves sorbent conditioning of a cyano (CN) cartridge with 0.5 ml of methanol and 1.0 ml of extraction buffer (0.005 M phosphate, pH 9). Plasma samples were applied by passing 1.0 ml of plasma through the cartridge and subsequently washing with 2 ml of the extraction buffer. Appropriate larger volumes of dialysate were used to concentrate ranitidine onto the cartridge so that the amount eluted was increased to within detectable limits. Urine samples were deluted with distilled water to decrease the ranitidine concentration to within the range of the standard curve. The high-performance liquid chromatographic method (mobile phase 88-89% of 0.02 M phosphate buffer pH 3 and 11-12% of methanol; Spherisorb phenyl cartridge column, 10 cm X 0.46 cm I.D., 5 micron particle diameter, flow-rate 1.1 ml/min; detection at 228 nm) is sensitive to 2 ng/ml in 1 ml of sample. The internal standard of choice was determined to be n-propionylprocainamide as compared to cimetidine and lidocaine. The method was cost-efficient, rapid and simple due to the automated sample processing. The coefficient of variation on replicate assays was less than 10% over all concentrations studied. Recoveries were between 97 and 110%, and the method was linear over the range 1.90-687.20 with a mean correlation coefficient of 0.999.

Baroreflex physiology studied in healthy subjects with very infrequent muscle sympathetic bursts

Because it is likely that, in healthy human subjects, baroreflex mechanisms operate continuously, independent of experimental interventions, we asked the question, In what ways might study of unprovoked, very infrequent muscle sympathetic bursts inform baroreflex physiology? We closely examined arterial pressure and R-R interval responses of 11 supine healthy young subjects to arterial pressure ramps triggered by large isolated muscle sympathetic bursts. We triggered data collection sweeps on the beginnings of sympathetic bursts and plotted changes of arterial pressure (finger volume clamp or intra-arterial) and R-R intervals occurring before as well as after the sympathetic triggers. We estimated baroreflex gain from regression of R-R intervals on systolic pressures after sympathetic bursts and from the transfer function between cross-spectra of systolic pressure and R-R intervals at low frequencies. Isolated muscle sympathetic bursts were preceded by arterial pressure reductions. Baroreflex gain, calculated with linear regression of R-R intervals on systolic pressures after bursts, was virtually identical to baroreflex gain, calculated with the cross-spectral modulus [mean and (range): 24 (7-43) vs. 24 (8-45) ms/mmHg], and highly significant, according to linear regression (r(2) = 0.91, P = 0.001). Our results indicate that 1) since infrequent human muscle sympathetic bursts are almost deterministically preceded by arterial pressure reductions, their occurrence likely reflects simple baroreflex physiology, and 2) the noninvasive low-frequency modulus reliably reproduces gains derived from R-R interval responses to arterial pressure ramps triggered by infrequent muscle sympathetic bursts.