Respiratory Sinus Arrhythmia
A Phenomenon Improving Pulmonary Gas Exchange and Circulatory Efficiency
Background The primary mechanisms of respiratory sinus arrhythmia (RSA) are understood to be the modulation of cardiac vagal efferent activity by the central respiratory drive and the lung inflation reflex, and the degree of RSA increases with cardiac vagal activity. However, it is unclear whether RSA serves an active physiological role or merely reflects a passive cardiovascular response to respiratory input. We hypothesized that RSA benefits pulmonary gas exchange by matching perfusion to ventilation within each respiratory cycle.
Methods and Results In seven anesthetized dogs, a model simulating RSA was made. After elimination of endogenous autonomic activities, respiration-linked heartbeat fluctuations were generated by electrical stimulation of the right cervical vagus during negative pressure ventilation produced by phrenic nerve stimulation (diaphragm pacing). The vagal stimulation was performed in three conditions: phasic stimulation during expiration (artificial RSA) and during inspiration (inverse RSA) and constant stimulation (control) causing the same number of heartbeats per minute as the phasic stimulations. Although tidal volume, cardiac output, and arterial blood pressure were unchanged, artificial RSA decreased the ratio of physiological dead space to tidal volume (Vd/Vt) and the fraction of intrapulmonary shunt (Qsp/Qt) by 10% and 51%, respectively, and increased O2 consumption by 4% compared with control. Conversely, reverse RSA increased Vd/Vt and Qsp/Qt by 14% and 64%, respectively, and decreased O2 consumption by 14%.
Conclusions These results support our hypothesis that RSA benefits the pulmonary gas exchange and may improve the energy efficiency of pulmonary circulation by “saving heartbeats.”
Heartbeat intervals in resting humans and animals show fluctuations linked with respiration, a phenomenon known as respiratory sinus arrhythmia (RSA). Since its first description by Ludwig1 in 1847, mechanisms mediating RSA have been the focus of many studies and are now understood to be modulation of the cardiac vagal efferent activity by the central respiratory drive and gating of excitatory input to the vagal motor neurons by the lung inflation reflex.2 3 4 Also, the degree of RSA is known to increase with cardiac vagal activation5 6 and the magnitude of RSA, particularly as assessed with the high-frequency component of heart rate variability (ie, at the respiratory frequency), is now generally used for estimating vagal cardiac modulation.7 8 9 Nevertheless, it remains unclear whether RSA bears an active physiological role or merely reflects a passive cardiovascular response to the respiratory input.10 11
To examine the hypothesis that RSA improves the pulmonary gas-exchange efficiency by matching perfusion to ventilation within each respiratory cycle, we developed a canine model simulating RSA. Resting awake dogs show marked RSA with heartbeats clustering during inspiration and scattering during expiration (Fig 1⇓).12 13 During inspiration, blood flow and volume into the thoracic vena cava are increased by a decreased intrathoracic pressure due to the descent of the diaphragm (respiratory pump).14 The increased heartbeats during inspiration, together with a concurrent increase in right ventricular stroke volume due to the increased venous return, results in an increased right ventricular output during inspiration.14 15 An increased pulmonary perfusion in time with an increasing lung volume would improve the ventilation-to-perfusion ratios16 and therefore may benefit gas exchange (Fig 2⇓). Conversely, an elimination of this relationship or further inversion of the relationship through clustering heartbeats during expiration would increase the fraction of alveolar gas volume unable to interface with sufficient blood flow during inspiration (wasted ventilation or physiological dead space17 ) and the fraction of capillary blood volume unable to interface with sufficient fresh gas during expiration (wasted blood flow or intrapulmonary shunt18 ).
To simulate these phenomena in anesthetized dogs, we generated the respiration-linked heart rate changes through electrical stimulation of the right vagal nerve19 during artificial negative pressure ventilation produced by electrical stimulation of the phrenic nerve (diaphragm pacing).20 21 22 Negative pressure ventilation was used to preserve the physiological respiratory pump effect on venous return and to avoid the reduction of pulmonary circulation and, therefore, deterioration of pulmonary gas exchange caused by positive pressure ventilation.23 The electrical vagal stimulations were performed under the following three conditions: (1) stimulation during expiration (artificial RSA), (2) stimulation during inspiration (inverse RSA), and (3) stimulation at a constant rate (control) that produced the same number of heartbeats per minute as artificial and inverse RSA. We compared the ratio of physiological dead space to tidal volume (Vd/Vt) and the fraction of intrapulmonary shunt (Qsp/Qt) among these three stimulation conditions.
Studies were performed on seven healthy adult mongrel dogs (weight, 15 to 20 kg) with approved protocols that conformed to the NIH “Guide for the Care and Use of Laboratory Animals” (DHEW Publication No. [NIH] 85-23, Revised 1985, Office of Science and Health Reports, DDR/NIH). Anesthesia was induced with thiopental sodium (3.5 mg/kg IV) and sustained with urethane-chloralose solution (25 g of urethane plus 2.5 g of chloralose in 100 mL saline; loading dose, 0.8 mL/kg; maintenance dosage, ≈0.3 mL·kg−1·h−1). Each dog was intubated with an endotracheal tube and ventilated mechanically with a respirator (model 613, Harvard Medical Apparatus) during surgical preparations.
The right femoral artery and the pulmonary artery were catheterized for arterial blood pressure monitoring and arterial and mixed venous blood sampling. The right jugular vein and the right and left vagus nerves were accessed through bilateral neck incisions.
For diaphragm pacing, a bipolar electrode catheter (USCI) was inserted into the jugular vein and placed on the wall of the superior vena cava ≈3 cm cephalic to the junction of the superior vena cava and the right atrium, through which the phrenic nerve was stimulated. An electrical stimulator (SEN 3201, Nihon Koden) was used to deliver a pulse train (2-ms width, 1.5 to 6.0 V, 50 Hz) for 2 seconds at every 4 seconds, resulting in 15-breath-per-minute artificial respiration with inspiratory and expiratory periods of 2 seconds each. We avoided positive pressure ventilation in this study because it has been reported to increase Vd/Vt in the dog due to the reduction in cardiac output.23 Also, the validity of transvenous phrenic nerve stimulation as a method for negative pressure ventilation in the dog has been proved in a previous study,21 in which we observed that the tidal volume and arterial O2 and CO2 tensions were maintained stably at the normal level over 60 minutes of phrenic nerve stimulation.
Sympathetic activity was eliminated through the injection of reserpine (0.3 mg/kg) 24 hours before the experiment. Endogenous vagal activity was blocked in the left vagus by sectioning the nerve and in the right vagus by infiltrating the nerve with 2% lidocaine at the level of the base of the skull. Because the right vagus nerve was used for electrical stimulation, the sectioning of the nerve was avoided to preserve blood supply to the nerve bundle. A pair of Ag/AgCl electrodes was placed across the right vagal nerve >10 cm caudal to the level of lidocaine blockade.
Simulation of RSA
A train of 2-ms-wide, 2- to 4-mA current pulses lasting 2 seconds was applied with an electrical stimulator (SEN 3201, Nihon Koden) in time with every expiration for artificial RSA and with every inspiration for inverse RSA (Fig 3⇓). The frequency of the pulse train was calibrated (typically 10 to 12 Hz) so that no, or only one, heartbeat occurred during the 2 seconds of stimulation and four or five beats occurred between stimulations. The features of artificial RSA were determined from the previous observations of the relationship between hemodynamic and respiratory parameters obtained in unanesthetized, awake, resting dogs (Fig 1⇑).24 During the control condition, a train of 2-ms-wide, 2- to 4-mA current pulses was applied continuously at the frequency (typically 5 to 6 Hz) that resulted in the same number of heartbeats per minute as during the artificial and inverse RSA conditions in each dog (60 to 75 bpm). Each condition of vagal stimulation was continued until steady state of both hemodynamic and respiratory parameters had been established for >2 minutes as mentioned below (the total length of each stimulation period was typically 5 to 6 minutes).
During the experiments, air flow from the endotracheal tube was measured with a heated pneumotachograph (Minisensor, Minato Medical Science), and airway CO2 and O2 tensions were assessed with a gas analyzer (MG-360, Minato Medical Science). These signals were integrated with a respiration monitor (RM-300, Minato Medical Science) to obtain breath-by-breath measurement of tidal volume, inspired and expired gas composition, and O2 consumption and then transferred to a personal computer for off-line analysis.
The three conditions of vagal stimulation (artificial RSA, inverse RSA, and control) were performed twice each in random order under artificial ventilation produced by diaphragm pacing. At the end of each period of vagal stimulation, when the heart rate, blood pressure, and end-tidal O2 and CO2 tensions in the expired gas had plateaued for >2 minutes, arterial and mixed venous blood were sampled over a couple of respiratory cycles, and the hemoglobin concentration, O2 and CO2 tensions, and O2 saturation were assessed with a blood gas analyzer (ABL300, Radiometer). The cardiac output was estimated on the basis of the O2 consumption and the difference in O2 concentration between arterial and mixed venous blood according to the Fick method, and the oxygen delivery was calculated as the product of cardiac output and arterial O2 concentration. Each period of vagal stimulation was followed by a period of mechanical ventilation without vagal stimulation, which was continued until the end-tidal O2 and CO2 tensions in the expired gas reestablished the baseline levels in each dog (typically 108 to 115 and 28 to 35 mm Hg, respectively).
Assessment of Gas-Exchange Efficiency
The Vd/Vt was calculated according to the modification by Enghoff25 of the Bohr equation:V\mbox|<|\textsc|<|d|>||>|/V\mbox|<|\textsc|<|t|>||>||<|=|>|(Pa\mbox|<|\textsc|<|co|>||>|_|<|2|>||<|-|>|Pe\mbox|<|\textsc|<|co|>||>|_|<|2|>|)/Pa\mbox|<|\textsc|<|co|>||>|_|<|2|>|where Paco2 and Peco2 are the CO2 tensions in the arterial blood and mixed expired gas, respectively.
Qsp/Qt was calculated according to the standard shunt equation26 :Q_|<|sp|>|/Q_|<|t|>||<|=|>|(Cc|<|^\prime|>|\mbox|<|\textsc|<|o|>||>|_|<|2|>||<|-|>|Ca\mbox|<|\textsc|<|o|>||>|_|<|2|>|)/(Cc|<|^\prime|>|\mbox|<|\textsc|<|o|>||>|_|<|2|>||<|-|>|Cv\mbox|<|\textsc|<|o|>||>|_|<|2|>|)where Cc′o2, Cao2, and Cvo2 are the O2 concentrations of end-capillary blood, arterial blood, and mixed venous blood, respectively. The O2 concentration of end-capillary blood was calculated from the alveolar O2 tension and oxygen dissociation curve in the dog.27 The alveolar O2 tension was calculated from the alveolar equation26 :P\mbox|<|\textsc|<|ao|>||>|_|<|2|>||<|=|>|P\mbox|<|\textsc|<|io|>||>|_|<|2|>||<|-|>|Pa\mbox|<|\textsc|<|co|>||>|_|<|2|>|/R|<|+|>|Pa\mbox|<|\textsc|<|co|>||>|_|<|2|>||<|\cdot|>| F\mbox|<|\textsc|<|io|>||>|_|<|2|>| |<|\cdot|>| (1|<|-|>|R)/RandR|<|=|>|Pe\mbox|<|\textsc|<|co|>||>|_|<|2|>|(1|<|-|>|F\mbox|<|\textsc|<|io|>||>|_|<|2|>|)/(P\mbox|<|\textsc|<|io|>||>|_|<|2|>||<|-|>|P\mbox|<|\textsc|<|eo|>||>|_|<|2|>||<|-|>|Pe\mbox|<|\textsc|<|co|>||>|_|<|2|>||<|\cdot|>|F\mbox|<|\textsc|<|io|>||>|_|<|2|>|)where Pao2, Pio2, and Peo2 are the O2 tensions in the alveolar, inspired, and mixed expired gas, respectively; Paco2 and Peco2 are the CO2 tensions in the arterial blood and mixed expired gas, respectively; Fio2 is the fractional concentration of O2 in the dry inspired gas; and R is the respiratory exchange ratio.
In the present study, the three conditions of vagal stimulation were performed twice in each dog. The reproducibility of the observations, including the respiratory parameters, arterial and mixed venous gas tensions, hemoglobin concentration, expired gas compositions, and hemodynamic parameters, were assessed through the use of paired t tests of the differences between two measurements and correlation coefficients between them within each stimulation condition.
Differences in mean values among the three stimulation conditions were assessed with a one-way ANOVA with repeated measures; the Bonferroni method was used to adjust for multiple comparisons. All tests are two tailed; a value of P<.05 was considered statistically significant. Data are presented as mean±SD in the text and tables and as mean±SEM in graphs.
There were no significant differences in the breathing frequency, tidal volume, end-tidal or mixed expired gas O2 or CO2 tension, arterial or mixed venous blood O2 or CO2 tension, O2 saturation or hemoglobin concentration, minute heart rate, or blood pressure between the two observations of the same stimulation condition in each dog. They also showed a good correlation (r>.90) except for the tidal volume during control (r=.83). Because this indicates a good reproducibility of the observations, two observations of the same condition were averaged in each dog. Further analyses were performed on the averaged values.
Effects of Vagal Stimulation
There was no difference in the breathing frequency, tidal volume, cardiac output, minute heart rate, or arterial blood pressure among control, artificial RSA, and inverse RSA conditions (Table⇓). Blood hemoglobin concentration, arterial O2 saturation, and CO2 tension also did not differ significantly among the three conditions.
On the other hand, repeated measures ANOVA revealed a significant effect of the vagal stimulation condition (control, artificial RSA, and reverse RSA) on the O2 consumption (P=.04) and oxygen delivery (P=.004), with a significant reduction of these values during reverse RSA compared with control and artificial RSA (P<.05 for all multiple comparisons). Also, arterial O2 tension showed a tendency toward an increase during artificial RSA compared with control (P=.07).
More importantly, however, a highly significant effect was observed on the Vd/Vt (P=.0002) and Qsp/Qt (P=.0001), with both values being lowest during artificial RSA and highest during reverse RSA (P<.05 for all multiple comparisons, Fig 4⇓). During artificial RSA, Vd/Vt decreased by 10% compared with the value during control, and Qsp/Qt decreased by 51%. Conversely, during inverse RSA, Vd/Vt increased by 14% and Qsp/Qt increased by 64% compared with the value during control.
We developed a model of RSA in anesthetized dogs, in which vagally mediated changes in heart rate were generated by electrical stimulation of the vagus nerve in time with changes in lung volume caused by negative pressure ventilation produced by diaphragm pacing. Using this model, we demonstrated that fluctuations in the occurrence of heartbeats in phase with the changes in lung volume (artificial RSA) result in a significant improvement in pulmonary gas-exchange efficiency (Vd/Vt and Qsp/Qt) and, consequently, an enhancement of oxygen transport (oxygen consumption and delivery) compared with the constant distribution of heartbeats at the equivalent number of heartbeats per minute. Conversely, an inversion of the phase relationship between heart rate and lung volume changes (inverse RSA) resulted in a significant deterioration in these indexes. These observations support the hypothesis that RSA benefits pulmonary gas exchange.
Despite the well-elucidated mechanisms underlying RSA, ie, the central respiratory drive and inspiratory gating of excitatory input to the vagal motor neurons,2 3 4 the physiological role of these distinctive mechanisms remains unclear. In a recent study, Triedman and Saul28 investigated the effects of total cardiac autonomic blockade on the relationship between variations of instantaneous lung volume and arterial blood pressure in humans. They found that although during autonomic blockade both systolic and diastolic blood pressures decreased in synchrony with inspiration by mechanical effect, in the autonomically intact state the decrease in diastolic blood pressure lagged behind by a phase angle of 90° in the presence of RSA. Because the lag in the decrease in diastolic blood pressure could offset the decrease in systolic blood pressure, mean blood pressure may be maintained. They therefore suggested that a possible physiological role of RSA may be stabilization of mean arterial blood pressure against the mechanical effect of the intrathoracic pressure on arterial blood pressure. This is unlikely, however, because it is apparent in Figs 1 and 3⇑⇑ that the presence of RSA does increase but does not decrease the fluctuation of arterial blood pressure compared with the state of its absence (control condition in Fig 3⇑).
Some mechanisms other than temporal variations of heartbeats need to be considered for the improved gas-exchange efficiency during artificial RSA. An increase in cardiac output is associated with a reduction of Vd/Vt as well as increased oxygen transport.16 23 RSA could increase cardiac output by increasing heart rate in time with increased right ventricular filling caused by the respiratory pump effect on the venous return.14 In the present study, however, the increase in cardiac output with RSA was not significant. The effect of RSA on cardiac output may be reduced by the feature of diaphragmatic pacing used in our study; it caused a rapid inhalation at the beginning of inspiration phase (see tidal volume in Fig 3⇑), which could attenuate the respiratory pump effect. Our observations are not attributable to the effect of RSA on cardiac output. Furthermore, a reduction in Qsp/Qt is not explained by an increase in cardiac output.
Pulmonary oxygen transport is dependent on blood hemoglobin concentration,16 which could be changed through splenic contraction or relaxation that may occur during the vagal stimulation. In the present study, however, the intensity of vagal stimulation was identical among the three stimulation conditions in terms of the minute heart rate that they produced, and no significant difference was observed in the blood hemoglobin concentration among the three conditions.
Although our hypothesis that RSA benefits pulmonary gas exchange may be unique, it is supported by many facts that are relatively well established. First, although ≈10% of the total blood volume is located in the lung, the pulmonary capillary blood volume participating in gas exchange is only 10% of that amount,29 which is comparable to the stroke volume of the heart. This observation suggests that most of the capillary blood volume interfacing with the alveolar gas is replaced with each heartbeat. Thus, it seems reasonable to speculate that the regulation of the timing of heartbeats in synchrony with breathing movements results in improved pulmonary gas exchange efficiency.
Second, it is also well known that RSA is affected by respiratory parameters. The degree of RSA is enhanced by a decrease in breathing frequency and an increase in tidal volume.30 31 A decreased breathing frequency is usually accompanied by a prolonged interval (exhalation and brief apneic periods) between inspirations; during the apneic periods, the lung volume remains at a low level and no replenishment of the alveolar gas occurs. Increased tidal volume, on the other hand, causes greater differences in the lung volume between inspiratory and expiratory periods. In both situations, increased temporal difference in the alveolar gas-exchange capacity is assumed. Thus, a greater degree of RSA may be necessary for maintaining the pulmonary gas-exchange efficiency.
Finally, the phase relationship between respiration and RSA changes with breathing frequency.32 33 As breathing frequency increases from 5 to 30 cpm, the phase of maximum heart rate shifts progressively from early inspiration to midexpiration,32 although the maximum heart rate occurs approximately in phase with the maximum lung volume for a breathing frequency of 10 to 20 cpm, as simulated in the present study as artificial RSA. Considering the time required for alveolar gas exchange, from a physiological perspective it also seems reasonable to shift the relative phase of the maximum heart rate to later in the respiratory cycle as the absolute time for the influx of fresh air into the alveoli becomes short.
From the aspect of circulatory energy expenditure, RSA also may benefit the energy efficiency of the pulmonary circulation. RSA may be considered to serve a useful physiological function in that it suppresses the unnecessary heartbeats that may result in wasted pulmonary blood flow. Heart rate deceleration through cardiac vagal activation is accompanied by an augmentation of RSA,6 33 and both the degree of RSA and cardiac vagal activity increases at rest34 35 and during sleep.36 37 RSA may save cardiac energy by effectively reducing the number of heartbeats while keeping the efficiency of pulmonary gas exchange in resting animals and humans.
Our observations that RSA reduces the fraction of physiological dead space and intrapulmonary shunt and enhances the oxygen transport strongly suggest that RSA bears an active physiological role. We propose the new concept that RSA benefits pulmonary gas exchange and may improve the energy efficiency of pulmonary circulation during rest.
This study was supported in part by a Research Grant (1995) for Aging and Health from the Japanese Ministry of Health and Welfare and by Grant-in-Aid No. 06304056 for scientific research from the Japanese Ministry of Education, Science and Culture. We gratefully acknowledge Dr Richard L. Horner for his scientific comments on the manuscript.
- Received January 3, 1996.
- Revision received February 14, 1996.
- Accepted February 16, 1996.
- Copyright © 1996 by American Heart Association
Ludwig C. Beitra¨ge zur Kenntniss des Einflusses der Respirationsbewegungen auf den Blutlauf im Aortensysteme. Arch Anat Physiol Leipzig. 1847;13:242-302.
De Burgh Daly M. Interactions between respiration and circulation. In: Cherniack NS, Widdicombe JG, eds. Handbook of Physiology, Section 3: The Respiratory System, Vol II: Control of Breathing, Part 2. Bethesda, Md: American Physiological Society; 1986:529-594.
Shykoff BE, Naqvi SSJ, Menon AS, Slutsky AS. Respiratory sinus arrhythmia in dogs: effects of phasic afferents and chemostimulation. J Clin Invest. 1991;87:1621-1627.
Horner RL, Brooks D, Kozar LF, Gan K, Phillipson EA. Respiratory-related heart rate variability persists during central apnea in dogs: mechanisms and implications. J Appl Physiol. 1995;78:2003-2013.
Fouad FM, Tarazi RC, Ferrario CM, Fighaly S, Alicandri C. Assessment of parasympathetic control of heart rate by a noninvasive method. Am J Physiol.. 1984;246:H838-H842.
Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation. 1991;84:482-492.
Saul JP, Berger RD, Chen MH, Cohen RJ. Transfer function analysis of autonomic regulation, II: respiratory sinus arrhythmia. Am J Physiol. 1989;256:H153-H161.
Saul JP, Berger RD, Albrecht P, Stein SP, Chen MH, Cohen RJ. Transfer function analysis of the circulation: unique insights into cardiovascular regulation. Am J Physiol. 1991;261:H1231-H1245.
Hamlin RL, Smith CR, Smetzer DL. Sinus arrhythmia in the dog. Am J Physiol. 1966;210:321-328.
Scher AM, Young AC. Reflex control of heart rate in the unanesthetized dog. Am J Physiol. 1970;218:780-789.
Rothe CF. Venous system: physiology of the capacitance vessels. In: Shepherd JT, Abboud FM, eds. Handbook of Physiology, Section 2: The Cardiovascular System, Vol III: Peripheral Circulation and Organ Blood Flow, Part 2. Bethesda, Md: American Physiological Society; 1983:397-452.
Smith JJ, Kampine JP. Pressure and flow in the arterial and venous systems. In: Smith JJ, Kampine JP, eds. Circulatory Physiology: The Essentials. Baltimore, Md: Williams & Wilkins; 1990:89-109.
Rahn H, Farhi LE. Ventilation, perfusion, and gas exchange: the VA/Q concept. In: Fenn WO, Rahn H, eds. Handbook of Physiology, Section 3: Respiration, Vol I. Washington, DC: American Physiological Society; 1964:735-765.
Severinghaus JW, Stupfel M. Alveolar dead space as an index of distribution of blood flow in pulmonary capillaries. J Appl Physiol. 1957;10:335-348.
Hass F, Bergofsky EH. Effect of pulmonary vasoconstriction on balance between alveolar ventilation and perfusion. J Appl Physiol. 1968;24:491-497.
A˚blad B, Axenborg J, Bjo¨rkman JA, Olsson G, Sutherland I. Can vagal and sympathetic effects on heart rate be assessed by spectral analysis of respiratory sinus arrhythmia (RSA)? J Am Coll Cardiol. 1993;21:156A. Abstract.
Wanner A, Sackner MA. Transvenous phrenic nerve stimulation in anaesthetized dogs. J Appl Physiol. 1973;34:489-494.
Yasuma F, Nomura H, Ogawa S, Miyaguchi K, Narita G, Hama Y, Hayashi H. Hemodynamic study of negative pressure ventilation using diaphragm pacing. Ko to Jun. 1989;37:977-981.
Suwa K, Hedley-Whyte J, Bendixen HH. Circulation and physiologic dead space changes on controlling the ventilation of dogs. J Appl Physiol. 1966;21:1855-1859.
Yasuma F, Hayano J, Yokota M, Hayashi H, Shimokata K, Okada T. Respiratory sinus arrhythmia during progressive hypoxia and hypercapnea in conscious dogs. Ko to Jun. 1995;42:679-684.
Enghoff H. Holumen inefficax: Benerkunge zur Frage des Schadlichen Raumes. Ups Lak Forhandl. 1938;44:191-218.
Riley RC, Cournand A. ‘Ideal’ alveolar air and the analysis of ventilation-perfusion relationship in the lung. J Appl Physiol. 1949;1:825-847.
Rossing R, Cain SM. A nomogram relating Po2, pH, temperature, and hemoglobin saturation in the dog. J Appl Physiol. 1966;21:195-201.
Triedman JK, Saul JP. Blood pressure modulation by central venous pressure and respiration: buffering effects of the heart rate reflexes. Circulation. 1994;89:169-179.
Forster RE. Diffusion of gases. In: Fenn WO, Rahn H, eds. Handbook of Physiology, Section 3: Respiration, Vol I. Washington, DC: American Physiological Society; 1964:839-872.
Hirsch JA, Bishop B. Respiratory sinus arrhythmia in humans: how breathing pattern modulates heart rate. Am J Physiol. 1981;241:H620-H629.
Hayano J, Mukai S, Sakakibara M, Okada A, Takata K, Fujinami T. Effects of respiratory interval on vagal modulation of heart rate. Am J Physiol. 1994;267:H33-H40.
Angelone A, Coulter NA. Respiratory sinus arrhythmia: a frequency dependent phenomenon. J Appl Physiol. 1964;19:479-482.
Eckberg DL. Human sinus arrhythmia as an index of vagal cardiac outflow. J Appl Physiol. 1983;54:961-966.
Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, Turiel M, Baselli G, Cerutti S, Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympathovagal interaction in man and conscious dog. Circ Res. 1986;59:178-193.
Pomeranz B, Macaulay RJB, Caudill MA, Kutz I, Adam D, Gordon D, Kilborn KM, Barger AC, Shannon DC, Cohen RJ, Benson H. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol. 1985;248:H151-H153.
Huikuri HV, Niemela¨ MJ, Ojala S, Rantala A, Ika¨heimo MJ, Airaksinen KEJ. Circadian rhythms of frequency domain measures of heart rate variability in healthy subjects and patients with coronary artery disease: effects of arousal and upright posture. Circulation. 1994;90:121-126.
Vanoli E, Adamson PB, Ba-Lin, Pinna GD, Lazzara R, Orr WC. Heart rate variability during specific sleep stages: a comparison of healthy subjects with patients after myocardial infarction. Circulation. 1995;91:1918-1922.