Heart rate is determined by the frequency of heart contractions of the ventricles per minute to circulate blood around the body. Rates of cardiac contraction are expressed as normal (70 beats per min - healthy), fast (greater than 100 beats per min - tachycardia) or slow (less than 50 beats per min - bradycardia). Heart rate fluctuates as the body's demand for oxygen varies and is correspondent to that of the pulse rate.
Among healthy individuals the duration of heart cycle periods transforms over time, known as Heart Rate Variability (HRV) 1. It acts as a fundamental mechanism for the constituents of the autonomic nervous system, including the parasympathetic and sympathetic systems2.
1.1 Respiratory Sinus Arrhythmia
Respiratory Sinus Arrhythmia (RSA) refers to periodic fluctuations of heart rate in association with respiration, which is characterized by an increase in heart rate during inspiration and a decrease in heart rate during expiration3.
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Electrocardiogram (ECG) recordings present as appropriate indicators for RSA measurements and vagal nerve activity. In relation to the R-R intervals on an ECG, RSA demonstrates diminished intervals during inspiration, suggesting withdrawal of efferent vagal nerve activity, and extended intervals during expiration, suggesting maximum activation of efferent vagal nerve activity4.
1.2 RSA Physiology
Heart rate is usually established by the activity involving the pacemaker of the sinoatrial node (SA node) which is situated in the right atrium5. During expiration, innervation of the SA node by activation of vagal nerve activity causes a reduction in heart rate below that of the intrinsic rate. In comparison, the modulating effect of parasympathetic activity causes acceleration in heart rate during inspiration. This is accomplished through stretch receptor impulses which suppress the cardioinhibitory centre in the medulla. Consecutively there is removal of the vagal tone which is responsible for the slowness in breathing and therefore heart rate is increased above the intrinsic rate6, 7. This respiratory associated variation in heart rate assists in corresponding pulmonary blood flow to lung inflation and provides an adequate supply of oxygen in the lungs by sustaining a suitable diffusion gradient8-10. Previous studies have proposed that higher breathing frequency is characterised by parasympathetic activity, while low breathing frequency modulation is characteristic of sympathetic and parasympathetic activity collectively11.
The magnitude of fluctuations in heart rate for RSA is dependent on specific respiratory responses. Responses associated with low breathing patterns and high amplitudes lead to maximum variations in RSA, whilst responses associated with higher breathing patterns and lower amplitudes involve lesser changes in RSA12.
In the nucleus ambiguus (NA), premotor cardioinhibitory parasympathetic neurons (CPNs) are situated, whose activity is responsible for controlling the heart rate. NA is a region comparative to neurons considered to be vital in controlling respiratory rhythmic periods13-15. Due to the silent nature of the CPNs in the NA, their dependency rests among synaptic inputs to initiate their action16. A variety of neurotransmitters have been regarded for their contribution to synaptic delivery during RSA. The neurotransmitters which have been considered include acetylcholine, glycine and aminobutyric acid17. Gilbey et al (1984) recognises the inhibitory effect of acetylcholine on CPN activity during inspiration18 and the ability of endogenous acetylcholine to initiate presynaptic nicotinic acetylcholine receptor activity, which in turn augments the frequency of GABAergic and glycinergic synaptic inputs to CPNs19.
The information documented from a combination of studies demonstrate a link between the neurons that manage heart rate control and neurons that are imperative for respiration which unveil a physiological function of endogenous acetylcholine release and nicotinic receptor activity in the development of RSA17.
Berntson et al (1997) regarded the reduction in heart rate during expiration due to effects of the neurotransmitter acetylcholine binding to muscarinic receptors in the SA node20. Following release from vagus nerves in concordance with its immediate enzymatic breakdown, acetylcholine forms cholinesterase as a by-product, which donates to the withdrawal of vagal tone and swift heart rate response21. Subsequently this brief duration is what enables the heart rate and respiratory frequency to develop a synchronic pattern.
According to comprehensive and thorough literature it can be considered that there are numerous and complicated RSA mechanisms that are directly related to interactions among cardiovascular and respiratory systems22. As documented by Shykoff et al (1991), two fundamental mechanisms have shown recognition in mammals for RSA generation. These include a central respiratory drive responsible for modulation directly related to cardiac vagal preganglionic neurons and lung inflation accountable for the inhibitory effects associated with cardiac vagal efferent activity23. During expiration, cardiac vagal efferent fibres are preferentially fired24-26 and their excitation is considerably enhanced by arterial chemoreceptor and baroreceptor stimulation27, 28.
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Mechanical stimulation of pulmonary stretch receptors initiates acceleration in heart rate. A reduction in intrathoracic pressure leads to a greater flow of blood to the heart's right side and therefore an increased venous return. This in turn increases pressure in the superior and inferior vena cava which causes extension of the right atrium and stimulation of atrial stretch receptors which characterises the Bainbridge reflex4, 29 (figure 1).
Figure 1: The physiological processes involved in the variation of heart rate, relating to that of RSA29
Due to a slight delayed interval, the heart's left side experiences an increase in venous return which leads to an increased cardiac output via the left ventricle, resulting in an elevated blood pressure4, 29. Specialised neurons, baroreceptors, which are situated in blood vessels, are responsible for sensing elevations in blood pressure. The stimulation to response of baroreceptors provides a mechanism which acts as a negative feedback loop known as a baroreceptor reflex29. This short-term mechanism is fundamental in the regulation and stabilization of blood pressure and provides enhancement for RSA development5. The baroreceptor reflex mechanism promotes an effect on heart rate which is opposite to that of the Bainbridge reflex. In relation to figure 1, an elevation in blood pressure causes the carotid and aortic stretch sensitive baroreceptors to become distended leading to stretching and thus firing of action potentials. The larger the magnitude of stretching the greater the frequency of baroreceptor firing, enabling variations to therefore be detected. Stimulation of baroreceptors results in the activation of the parasympathetic activity and inhibition of the sympathetic activity. This leads to a reduction in both the heart contractility and heart rate, reflex bradycardia, which therefore results in a decreased cardiac output and blood pressure, enabling the blood pressure to regulate to a normal level. According to extensive and documented literature regarding RSA it can be concluded that parasympathetic activity provides a greater influential effect on heart rate than in comparison to sympathetic activity. Furthermore, the medulla oblongata which is occupied by the respiratory centre provides a significant role that contains autonomic functions dependent on a variety of factors which are also responsible for RSA. Factors involved in the manipulation of RSA can in effect create variations in the physiological procedure illustrated in figure 1.
1.3 RSA Function
During inspiration, heart rate is accelerated in order to enhance both alveolar ventilation and perfusion. Hyano et al (2004) hypothesised the ability of RSA to enhance the effectiveness of pulmonary gas exchange by ventilation/perfusion matching throughout each respiratory cycle4.Studies conducted on seven anaesthetized dogs revealed an implication involving the physiology of RSA, which revealed that continuous hypercapnia contributed to a more prominent RSA30.Shykoff et al (1991) proposed that regulation of RSA was managed centrally with a magnitude relative to respiratory drive. In relation to humans, exposure to continuous hypercapnia requires diffusion of CO2 from the lungs, providing respiratory stimulation which is essential for survival. Accordingly, an increased intensity of pulmonary gas exchange is required, resulting in an exaggerated RSA23.
Research documented by Giardino et al (2003) demonstrated that the period amid respiration and heart rate was related to the exchange efficiency of CO231, which verified the outcomes conducted by Hyano et al (2004) that RSA enhances pulmonary gas exchange efficiency and conserves energy by confining needless heartbeats during the expiratory phase30.
1.4 Factors affecting RSA
1.4.1 Age and RSA
Through extensive and varied research, RSA has shown to decline with increasing age and prevalence of cardiac diseases32-34. Stratton et al (1992) documented a decrease in sympathetic control of the heart with advancing age35. Additionally, Brodde et al (1998) recognized a moderation in control of parasympathetic activity and outcomes from previous literature suggests an eventual reduced dependency of parasympathetic control on the resting heart rate36. Further research by Stratton et al (2003) supported this finding as blockade of parasympathetic activity amongst older subjects (ages 65-80, mean 70 years) in comparison to younger subjects (ages 18-32, mean 26 years) documented a less of an increase in heart rate37.
Evaluating the effects involving withdrawal of vagal activation and cardiovascular diseases is imperative as they are recognised as variables which can modify the degree of RSA magnitude. Due to this conclusion, it was suitable for this study to exclude the elderly population.
1.4.2 Breathing Frequency and RSA
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Research conducted by Hirsh and Bishop et al (1981) recognised that the magnitude of RSA was inversely proportional to the respiratory rate but in direct proportion to tidal volume38. Grossman et al (2007) documented that reduction in respiratory rate and enhancement in the intensity of breathing frequency had been recognised to emphasize RSA22. Consequently, variables such as these are capable of determining the magnitude of RSA. Extensive discussions have been documented regarding the action of vagal influences upon the heart and its association with RSA versus that of voluntary modifications of respiratory parameters and its potential to influence RSA22. Grossman and Kollai et al (1993) documented a study which recognised that variations in the respiratory rate and tidal volume had pronounced effects on the magnitude of RSA that were irrespective of the level of cardiac vagal tone. An understanding of such outcomes can be classified as a phasic response of RSA11.
Over the last forty years it has become apparent that the magnitude of RSA is intensified during slow, deep breathing while a reduction in RSA magnitude is developed during faster, shallower breathing39. This is confirmed from findings by Asmundson et al (1994) whom undertook breathing pace trials .The investigation concluded that subjects whom breathed at a baseline rate of approximately 14-16 breaths per minute, developed an increase in RSA after restraining to 12 breaths per minute, which in effect was almost doubled after further slowing down to 6 breaths per minute. In contrast, when breathing became more rapid to 20 breaths per minute, there was a considerable decline in RSA40.
1.4.3 Exercise and RSA
Schafer et al (2008) concluded similar to the situation regarding that of advancing age, that during an increase in strain or performance of physical exercise, the components regarding RSA are strongly weakened resulting in a suppression of RSA41. This is supported by findings from Grossman et al (2004) whom observed that an acceleration in physical activity resulted in a diminished RSA42. Several studies have recognised that heart rate is primarily under the influence of parasympathetic activity during a variation in physical activity ranging from mild to moderate.
Investigations conducted by Hatfield et al (1998) studied the association between RSA and both that of respiratory frequency and tidal volume during the exercise period. The report concluded that between subject correlations involving RSA amplitude and both respiration frequency and tidal volume were principally irrelevant, therefore implying that RSA is independently related to individual variances in ventilatory activity, thus allowing comparisons among groups during exercise43.
1.4.4 Gender and RSA
Stein et al (1997) recognised considerable lowering in the frequency domain indexes of HRV among younger females than in comparison with younger males (ages 26-42 years). Comparisons of HRV involving gender within age groups demonstrated no considerable variations between older men and women (ages 64-72 years)44.The notion behind this observation is that younger women acquire a reduced activation of parasympathetic control and therefore potentially a reduced RSA.
1.4.5 Hypertension and RSA
As a collection of studies have identified a link involving hypertension and RSA, hypertension is acknowledged as a physiological factor of importance that needs to be considered in the exclusion of subjects. A study conducted by Fouad et al (1984) based on a combination of hypertensive and normotensive data, confirmed the known theory that hypertension is associated with both a reduced RSA and cardiac vagal tone45.Such findings are also supported by Masi et al (2007) whom investigated the relationship between RSA and hypertension and recognised that a reduction in cardiac vagal tone could donate to hypertension46. Due to the cardiac vagal tone's modulating effect on RSA, hypertensive participants would not necessarily present an accurate interpretation of RSA.
1.4.6 Obesity and RSA
Research conducted on adults and adolescents collectively, distinguished a link between the autonomic system and obesity46. Zahorskamarkiewicz et al (1993) recognised in obese subjects, an enhancement in sympathetic activity involving an elevated blood pressure response to hand grip exercise47. Additionally, research involving obese individuals displayed a reduced parasympathetic activity48. A study by Arrone et al (1995) confirmed this finding as investigations amongst non-obese adults whom gained 10% body weight experienced a reduction in parasympathetic activity. Observations were assessed by measuring the differences in mean R-R intervals prior to and following atropine administration. An enhanced sympathetic activity was also observed amongst these individuals. In comparison, investigations amongst non-obese adults whom decreased their body weight by 10% revealed an enhanced parasympathetic activity along with a reduced sympathetic activity49. The findings and observations concluded in this research proposed that through the activation of parasympathetic and sympathetic effects on HRV, the autonomic nervous system could control energy storage and metabolism49. The effects of obesity can also be transcribed on lung volumes and mechanistic processes involving respiration. Studies by Baydur et al (2004) and Ladosky et al (2001) that investigated the effects associated in the presence of obesity, recognised considerable restrictions in lung volume especially involving forced vital capacity (FVC) and forced expiratory volume (FEV)50, 51. These effects then evoked faster and shallower breathing which subsequently results in a diminished RSA39.
1.4.7 Posture and RSA
Adjustments in posture provide significant physiological variations which result in blood pressure elevation52. Several cardiovascular modifications including elevated heart rate and reduced cardiac output are enforced following changes in posture from supine to sitting to standing, as observed in research documented by Houtveen et al (2005)53. Alteration in posture from supine to upright position primarily results in correlation of blood and therefore a decrease in systemic venous return. This decrease in blood flow back to the heart causes left ventricular preload reduction and thus a decreased stroke volume by the Frank-Starling mechanism. In turn, systolic blood pressure is reduced leading to restrictions in baroreceptor stimulation52.
Depending on the posture position employed, differing frequencies occur for RSA and fluctuations in heart rate. Research conducted by Kobayashi et al (1996) documented the effect on RSA amplitude by alterations among horizontal and vertical positioning states. The results revealed a considerable reduction of RSA amplitude in the vertical position in contrast with the horizontal position54. Several studies including that of Pagani et al (1986)55 concluded that lower frequency situations of RSA are mediated by both parasympathetic and sympathetic nervous systems while higher frequency situations involving RSA are mediated individually by the parasympathetic nervous system7.
The muscarinic receptor antagonist, atropine, is a naturally occurring alkaloid which is extracted from deadly nightshade (Atropa belladonna)56. As shown in figure 2, Binding between muscarinic receptor antagonists and muscarinic receptors leads to an inhibition in receptor activation due to prevention in the binding of acetylcholine. By blocking the effects of acetylcholine, muscarinic receptor antagonists efficiently inhibit the effects associated with vagal nerve activity on the heart and therefore potentiate an increased heart rate and conduction velocity.
Figure 2: The antagonistic effects of atropine on muscarinic receptors and the Gi-protein pathway in the heart65
Atropine inhibits acetylcholine effects at muscarinic receptors without affecting nicotinic receptors. As the release of acetylcholine is initiated with nicotinic receptors at both parasympathetic and sympathetic preganglionic fibres, inhibition at synapses involving nicotinic receptors would eliminate both of these autonomic systems. As muscarinic receptors entail sites of parasympathetic postganglionic action, selective disruption of acetylcholine binding only at muscarinic junctions, enables atropine to effectively inhibit parasympathetic activity without inducing a sympathetic effect whatsoever5.
Administration of atropine involves parental formulations by subcutaneous, intramuscular or intravenous injection. Atropine can also be administered orally as a liquid, which is the route of administration focussed in this study.
1.5.2 Effect of Atropine on Heart Rate and RSA
Several studies56-59 have recognised that variations in cardiac vagal tone via pharmacological intervention can be monitored by RSA amplitude. Hence, increasing dosage of atropine or several other vagally blocking drugs which donate a diminished cardiac vagal tone are supplemented by a dose related decrease in the magnitude of RSA.
Inhibition of muscarinic receptors by atropine induces tachycardia. This is due to blockage of only parasympathetic activity without any effect on the sympathetic system60. As there is no systematic activity induced on respiratory parameters, modifications involving RSA and cardiac vagal tone during the administration of atropine, are not corresponded by variations in respiration or tidal volume11, 61. The administration of atropine at low doses leads to an enhanced vagal activity which causes a paradoxical bradycardia60, 62. The opposite effect is induced for higher doses of atropine in which the cardiac vagal tone is eliminated, irrespective of increased cardiac vagal activity63.
A study by Medigue et al (2001) investigated the notion that the non-invasive index associated with cardiac vagal tone is employed for the estimation of RSA57. Examination of this theory was implemented by inhibiting vagal tone using atropine. To conduct an instant time frequency domain assessment of the continuous variations occurring in vagal activity, the smoothed pseudo-Wigner-Ville transformation (SPWVT) was implemented. Comparisons were made between the estimations of RSA acquired during the infusion of atropine against estimations involving instant cardiac vagal tone. The results documented a significant elevation in heart rate subsequent to blockage of beta-adrenoceptors by atropine. The SPWVT showed an expansion in the range of RSA amplitude following the gradual infusion of atropine. Furthermore, variations involving pulse intervals and RSA were equivalent, which primarily involved an increase associated with early vagomimetic effects of atropine and then preceded by a decrease throughout the vagolytic phase57.
Another study by Paso et al (1996) explored if the baroreflex sensitivity could be implemented as another measure to examine parasympathetic effects on the heart. Intravenous atropine was used to initiate parasympathetic blockade. Results concluded, following the administration of atropine, there was a significant reduction in RSA amplitude and baroreceptor sensitivity to values near that of zero which established their vagal origin.
Prior evidence suggests there is a link between the inducing effects of atropine associated with both an increase in heart rate and a decrease in RSA, so the aims of the study were to determine whether the time course of effect of oral atropine on heart rate and RSA were correlated.
1.6.1 Primary Hypothesis
There is a significant negative correlation between both the changes in heart rate and RSA at different time courses during oral atropine administration.
1.6.2 Secondary Hypothesis
There is a more prominent change in RSA and heart rate amongst males than in comparison to females following oral atropine administration.