Acta Physiol 2014, 211, 297–313
REVIEW
Assessment of human baroreflex function using carotid ultrasonography: what have we learnt? C. E. Taylor,1 C. K. Willie,2 P. N. Ainslie2 and Y.-C. Tzeng3 1 School of Science and Health, University of Western Sydney, Sydney, NSW, Australia 2 School of Health and Exercise Sciences, Centre for Heart Lung and Vascular Health, University of British Columbia Okanagan, Kelowna, BC, Canada 3 Cardiovascular Systems Laboratory, Centre for Translational Physiology, University of Otago, Wellington, New Zealand
Received 2 April 2014, accepted 9 April 2014 Correspondence: C. Taylor, School of Science and Health, University of Western Sydney, Campbelltown Campus, Locked Bag 1797, Penrith NSW 2751, Australia. E-mail: [email protected]
Abstract The arterial baroreflex is critical to both short- and long-term regulation of blood pressure. However, human baroreflex research has been largely limited to the association between blood pressure and cardiac period (or heart rate) or indices of vascular sympathetic function. Over the past decade, emerging techniques based on carotid ultrasound imaging have allowed new means of understanding and measuring the baroreflex. In this review, we describe the assessment of the mechanical and neural components of the baroreflex through the use of carotid ultrasound imaging. The mechanical component refers to the change in carotid artery diameter in response to changes in arterial pressure, and the neural component refers to the change in R-R interval (cardiac baroreflex) or muscle sympathetic nerve activity (sympathetic baroreflex) in response to this barosensory vessel stretch. The key analytical concepts and techniques are discussed, with a focus on the assessment of baroreflex sensitivity via the modified Oxford method. We illustrate how the application of carotid ultrasound imaging has contributed to a greater understanding of baroreflex physiology in humans, covering topics such as ageing and diurnal variation, and physiological challenges including exercise, postural changes and mental stress. Keywords blood pressure, cardiac, carotid artery, mechanical, neural, sympathetic.
The arterial baroreflex – what is it and why is it important? Oxygen delivery to vital organs such as the brain, heart and kidneys is essential for human survival. For most mammalian species, the perfusion of organs with blood is maintained by the intravascular hydrostatic gradient between the arterial and venous circulation. Thus, the regulation of arterial blood pressure via baroreflex-mediated changes in cardiac output and total peripheral resistance is a key mechanism for maintaining adequate organ perfusion and oxygenation.
Low baroreflex sensitivity (BRS) is associated with an increased risk of mortality following myocardial infarction (La Rovere et al. 2001) and in patients with chronic heart failure (La Rovere et al. 2009). Furthermore, evidence suggests that depressed baroreflex function elevates the risk of both ischaemic and haemorrhagic strokes (Sykora et al. 2009). It is therefore imperative that the mechanisms and modulating factors involved in normal baroreflex function in humans are identified and understood. Baroreceptors, located in the carotid sinuses and aortic arch, detect vessel stretch caused by increasing
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arterial pressure. The detection of vascular distention and not blood pressure per se is an important point, and although the term ‘baroreceptors’ is most commonly used, these receptors may be more accurately described as mechanoreceptors (Shepherd 1982). Baroreceptor afferents project to the nucleus tractus solitarius which, in turn, projects to other structures important to the central integration of the baroreflex response, such as the rostral ventrolateral medulla, responsible for muscle vasoconstrictor drive (Dampney et al. 2003), and the nucleus ambiguous, responsible for vagal activity (Benarroch 2008). These neural pathways serve to alter total peripheral resistance and cardiac output, respectively, to form an integrated baroreflex response that can promptly ameliorate transient perturbations to blood pressure. Human baroreflex research has been largely limited to the association between blood pressure and cardiac period (or heart rate) or indices of vascular sympathetic function (e.g. muscle sympathetic nerve activity, MSNA). However, emerging techniques based on carotid ultrasound imaging, first documented by Hunt et al. (2001a), have enabled researchers to examine the individual components of the baroreflex in humans without the limitations of invasive animal experiments. The primary objective of this review is to highlight the pivotal role that carotid ultrasound imaging plays in generating deeper insights into human baroreflex function and to encourage its wider application. Thus, this review extends on previous reports focused on technical considerations relevant to carotid ultrasound imaging (Kornet et al. 2002, Reneman et al. 2005, Tzeng 2012), by reviewing recent literature where its practical application has generated new mechanistic insights. Comprehensive reviews of general baroreflex physiology can be found elsewhere (Fadel et al. 2003).
arm of the autonomic nervous system. For this reason, the term sympathetic baroreflex is most commonly used in the literature to describe baroreflex modulation of blood pressure via the vasculature. Sympathetic stimulation increases vascular resistance, thus increasing arterial pressure, and so sympathetic BRS is expressed as the decrease in MSNA per unit increase in arterial pressure. It should be noted, however, that the use of the term ‘sympathetic baroreflex’ has the potential to be misleading, given that sympathetic activity also influences the heart. However, for consistency with the current literature, we will continue to use the term sympathetic baroreflex in this review. Cardiac BRS is determined by plotting the relationship between changes in systolic blood pressure and R-R interval (or heart rate). Although the changes in R-R interval more accurately reflect changes in parasympathetic vagal tone (Parker et al. 1984), the nonlinear reciprocal relationship between R-R interval and heart rate means that differences in baseline heart rate between experimental conditions can lead to misleading values for BRS (O’Leary 1996). Therefore, results are often expressed as both R-R interval and heart rate to confirm their findings. Sympathetic BRS is typically quantified as the relation between changes in diastolic blood pressure and sympathetic neural recordings made at superficial sites, such as a muscle fascicle of the peroneal nerve posterior to the fibular head (MSNA). The values for the slopes that are generated when plotting these variables against each other provide the BRS, also referred to as baroreflex gain. Steeper slopes signify greater, and therefore more effective, responses to changes in blood pressure. There are currently no official figures to define normal BRS, and there can be large variability amongst healthy individuals. However, La Rovere and colleagues (1988) identified a threshold for cardiac BRS of 3 ms mmHg 1, below which myocardial infarction patients are at a significantly greater risk of subsequent mortality over a 2-year follow-up. Cardiac BRS has also been reported to be lower in patients with hypertension (Bristow et al. 1969), coronary artery disease (Airaksinen et al. 1993) and chronic heart failure (Mortara et al. 1997), when compared to healthy controls, suggesting that low cardiac BRS is a marker for cardiovascular disease (La Rovere et al. 1988). In contrast to cardiac BRS, results for the sympathetic arm have not been unanimous, with studies indicating reduced (Korner 1988, Matsukawa et al. 1991) and similar (Grassi et al. 1998) baroreflex responses in hypertensives compared with normotensives. Reduced sympathetic BRS has been reported in patients with obstructive sleep apnoea (Narkiewicz et al. 1998) and vasovagal syncope (Bechir et al. 2003). Although the two arms of the baroreflex receive the same afferent
Ultrasound assessment of the baroreflex
Cardiac and sympathetic baroreflex sensitivity The autonomic nervous system has two effector arms: the parasympathetic and the sympathetic arm. Major target organs are the heart and the vasculature. If we discuss the cardiac baroreflex, this relates to the sympathetic as well as to the parasympathetic influences on the heart. Sympathetic stimulation increases heart rate, conductivity, contractility and lusitropy. Parasympathetic stimulation counteracts sympathetic stimulation (Levy 1971, Schwartz & Ferrari 2011). Cardiac BRS is a measure of the heart rate response for a given change in arterial pressure, typically expressed as the R-R interval increase per unit increase in systolic pressure. Throughout the body, the vasculature is mainly influenced by the sympathetic 298
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12302
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input via the nucleus tractus solitarius, research suggests that cardiac and sympathetic BRS are not correlated (Dutoit et al. 2010).
Assessment of the mechanical and neural components of the baroreflex The initial stage of the integrated baroreflex response is the transduction of blood pressure into barosensory vessel stretch, referred to as the mechanical component. The transduction of barosensory vessel stretch into changes in heart rate (via changes in efferent parasympathetic and/or sympathetic neural outflow) is referred to as the neural component. This component therefore incorporates afferent activity, central integration and efferent activity. Carotid ultrasound imaging allows the relative contribution of these components to the integrated baroreflex response to be quantified (Hunt et al. 2001a). For the purpose of this review, the carotid ultrasound scanning protocol will be briefly outlined. However, more detailed descriptions can be found elsewhere (Black et al. 2008, Tzeng 2012).
Figure 1 Schematic diagram showing the common carotid artery, the carotid bulb and the bifurcation into the internal and external carotid arteries.
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· Ultrasound assessment of the baroreflex
Carotid ultrasound imaging The transducer is placed parallel to the vessel to capture a longitudinal section of the common carotid artery, approx. 1–2 cm from the bifurcation (Fig. 1). Human and animal data suggest that changes in carotid artery diameter are proportional to carotid sinus nerve activity (Landgren 1952, Angell-James & Lumley 1975). This suggests that these measures of barosensory vessel deformation reflect the stimulus at the bulb as well as the degree of baroreceptor afferent activity in response to this stimulus (Hunt et al. 2001a). Upon locating the common carotid immediately proximal to the bulb, the vessel wall boundaries are identified in the longitudinal B-mode image. Clear imaging of the near and far walls is important to allow carotid diameter to be determined, and therefore, the probe should be adjusted to obtain the best view of the arterial walls. Continuous video recordings are made of the optimized B-mode images and saved for offline analysis using custom-written or commercially available edge-tracking software (Fig. 2). Provided that adequate ultrasound images of the carotid artery can be obtained, the mechanical and neural components of the baroreflex can theoretically be determined using any method of baroreflex assessment. To date, this approach has been applied to the modified Oxford method, Valsalva manoeuvre and transfer function analysis. The advantages and disadvantages of the various techniques used to determine BRS have been examined and discussed previously (Blaber et al. 1995, Pitzalis et al. 1998, Colombo et al. 1999, Lipman et al. 2003, Diaz & Taylor 2006, Kamiya et al. 2011, Tzeng 2012). The modified Oxford method, often regarded as the gold standard technique for assessing baroreflex function, has been
Figure 2 Sample screen shot showing the edge tracking of the carotid diameter. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12302
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used successfully in conjunction with carotid imaging to investigate a number of research questions. Therefore, in this review, the methods of determining the mechanical and neural components of the baroreflex will be presented in relation to the modified Oxford method.
et al. 1999, Kienbaum & Peters 2004). In addition, studies in animals and isolated carotid sinuses indicate that alpha-adrenergic agonists, such as phenylephrine, activate smooth muscle fibres within the wall of the carotid sinus (Peveler et al. 1983, Bell et al. 1986). These results led to the suggestion that smooth muscle contraction, and hence carotid vasoconstriction, influences baroreceptor afferents. Based on the reasoning that a change in carotid artery diameter is the net effect of smooth muscle constriction and passive stretch, Bonyhay et al. (1997) examined the contribution of these two opposing effects on human carotid arteries during elevations and reductions in arterial pressure induced by vasoactive drugs. Unlike previous animal studies, the authors reported increases in carotid artery diameter in response to drug-induced elevations in arterial pressure. Likewise, falls in pressure led to reductions in carotid diameter. These relationships between arterial pressure and carotid diameter reflected the relationships between arterial pressure and R-R interval, including the difference in slopes for rising and falling pressures (hysteresis). The results indicate that baroreceptor activity in humans is influenced more by passive stretch than by smooth muscle contraction. The findings are consistent with those of many subsequent studies of the mechanical and neural components of the cardiac baroreflex as changes in systolic blood pressure are positively correlated with carotid artery diameter (Hunt et al. 2001a,b, Studinger et al. 2007, Deley et al. 2009a,b, Tzeng et al. 2009, 2010, Taylor et al. 2011, 2013, Willie et al. 2011). The differences in structure of the carotid artery between animals and humans may explain why the data from animal studies do not apply to humans in this case. In contrast to many species of animal, the viscoelastic nature of the carotid artery in humans (Arndt, 1991) allows passive stretch to dominate over smooth muscle tension during pharmacological manipulation of blood pressure (Bonyhay et al. 1997). A major advantage of the modified Oxford method is that it allows blood pressure to be perturbed across a wide range in a short period of time in order to engage the baroreflex. It is important that the drugs are administered using bolus injections rather than steady state infusions of vasodilators, as have been used in some previous studies (Hossman et al. 1980). When attempting to assess baroreflex control using infusions, an ‘infinite’ gain can be observed between the pressure ‘input’ and the cardiac and/or sympathetic ‘output’. That is, the system has effectively counter-regulated against the potential pressure perturbation such that the haemodynamic milieu is an unchanged systemic pressure with elevated heart rate and/or vascular sympathetic activity. Therefore, the rapid changes in arterial pressure that occur during
Ultrasound assessment of the baroreflex
The modified Oxford method The ‘Oxford method’ was an early and popular measure of baroreflex function. Although the assessment was originally carried out using injections of angiotensin (Smyth et al. 1969), the method has since been modified, notably with the addition of vasodilator drugs to determine the baroreflex responses to falling arterial pressure (Pickering et al. 1972). The administration of vasodilator and vasoconstriction drugs in sequence was introduced later (Ebert & Cowley 1992) and has been termed the modified Oxford method. When Hunt et al. (2001a) introduced the method of isolating the mechanical and neural components of the baroreflex, they used the modified Oxford technique to describe the cardiac baroreflex. Since then, this technique has been applied in many studies of cardiac baroreflex function (Hunt et al. 2001a,b, Studinger et al. 2007, Deley et al. 2009a,b, Tzeng et al. 2009, 2010, Taylor et al. 2011, 2013, Willie et al. 2011), and more recently to the sympathetic baroreflex (Studinger et al. 2009). The modified Oxford method consists of bolus injections of sodium nitroprusside (SNP) and phenylephrine hydrochloride (PE) administered intravenously to cause a fall and subsequent rise in arterial pressure. The injection of SNP should only be administered once blood pressure is stable, followed approx. 60 s later by the injection of PE. Doses given are typically 100 and 150 lg for SNP and PE respectively (Hunt et al. 2001a,b, Studinger et al. 2007, Deley et al. 2009a,b). However, this should be adjusted according to the age and size of the individual and responses to previous doses (if any), to ensure blood pressure perturbations of >15 mmHg (Taylor et al. 2011, Willie et al. 2011). In some cohorts of young volunteers, higher doses of up to 300 lg (SNP) and 400 lg (PE) have been required to achieve sufficient perturbations in systolic blood pressure (Tzeng et al. 2009). A potential disadvantage of the Oxford method is the use of vasoactive agents. The depressor effects of the modified Oxford method tend to be produced by bolus injection of sodium nitroprusside, which causes vasodilation via nitric oxide. It has been suggested that nitric oxide has central neural effects that could cause BRS to be underestimated, such as inhibition of the nuclei responsible for sympathetic outflow (Hogan 300
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12302
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application of the modified Oxford method are considered a major advantage of this technique. The baroreflex is a closed-loop system, and it has been argued that the loop must be opened to allow accurate quantification of the relationships between input and output variables (Lipman et al. 2003, Diaz & Taylor 2006). Whilst the loop cannot be fully opened in the majority of human experimental settings, the active perturbation of blood pressure that the modified Oxford method provides does allow the loop to be partially opened.
approach, breakpoints at the upper and lower end of the raw data can be identified statistically using piecewise linear regression (Studinger et al. 2007, Taylor et al. 2011; see Fig. 4). The linear segment is considered acceptable if the correlation coefficient reaches an arbitrary threshold, typically set at 0.5. Data binning is usually applied using bins of 2 or 3 mmHg, to minimize fluctuations in heart rate caused by respiration (Tzeng et al. 2009). To determine the mechanical component, systolic carotid lumen diameter measurements are plotted against systolic blood pressure. To determine the neural component, R-R intervals or heart rate is plotted against systolic carotid lumen diameter. As with the integrated BRS, the mechanical and neural components can be calculated separately for the fall and rise in blood pressure, with the exclusion of the threshold and saturation regions.
Assessment of cardiac BRS
Assessment of sympathetic BRS The general approach for assessing the sympathetic baroreflex is similar in concept to that of cardiac BRS. However, instead of systolic carotid diameters and pressures, integrated and mechanical BRS for the sympathetic baroreflex are derived using diastolic diameters and pressures. Diastolic pressure correlates more strongly with MSNA (Sundl€ of & Wallin 1978), which in humans is typically measured via microneurographical recordings from the peroneal nerve (Vallbo et al.
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Cardiac BRS is assessed by examining the relation between R-R interval and systolic blood pressure. Figure 3 illustrates the R-R interval, carotid artery diameter and blood pressure responses of one individual during a modified Oxford test. The fall in systolic blood pressure tends to occur around 30 s after the SNP injection. It is at the onset of the systolic blood pressure decrease through to the nadir that cardiac BRS for falling pressures is assessed. To assess the baroreflex response to a rise in pressure, the data are selected from the nadir in systolic pressure to the peak that occurs following the PE injection. Threshold and saturation regions, where there are no changes in R-R interval at the lowest and highest pressures, respectively, can be removed by visual inspection (Lipman et al. 2003, Tzeng et al. 2009). For a more objective
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Figure 3 Representative recording of systolic blood pressure, carotid diameter and heart rate during a modified Oxford baroreflex test in one subject. A bolus injection of sodium nitroprusside is administered to initiate a fall in arterial pressure, followed approx. 60 s later by phenylephrine hydrochloride to initiate a pressure rise.
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Figure 4 Piecewise regression model for elimination of threshold and saturation regions of the integrated baroreflex response to rising pressures. Open circles (○) represent the threshold and saturation regions, while closed circles (●) represent the linear portion of the baroreflex gain (Taylor et al. 2011).
1979). Integrated sympathetic BRS can be quantified by plotting MSNA against diastolic blood pressure, and the slope of the relationship provides an index of sensitivity. As with the cardiac baroreflex, the data are typically grouped into 1, 2 or 3 mmHg pressure bins to reduce the statistical impact of inherent beatto-beat variability in nerve activity (Hart et al. 2010). One method of assessing sympathetic BRS is to determine total MSNA for each pressure bin by calculating the total area (or amplitude) of all MSNA bursts relative to the number of cardiac cycles. Cardiac cycles associated with no MSNA burst are usually assigned a value of zero, although in some analyses, these cardiac cycles are removed altogether (Kienbaum et al. 2001, Keller et al. 2006). It is common for the linear regression analysis to be weighted according to the number of cardiac cycles per bin (Kienbaum et al. 2001, Ogoh et al. 2007). This removes the bias caused by the low number of cardiac cycles within some bins, usually at the highest and lowest pressures. The fact that not every cardiac cycle is associated with an MSNA burst can cause problems when assessing sympathetic BRS, particularly during high pressures when there is significant sympathoinhibition, or if a subject’s resting MSNA is low. Therefore, methods based on MSNA burst incidence have been used, providing an alternative approach in which the percentage of cardiac cycles associated with a burst (expressed as bursts per 100 heartbeats) is plotted against diastolic pressure (Sundl€ of & Wallin 1978). Again, pressure bins and weighted linear regression 302
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are typically applied. This technique, often referred to as the threshold technique, has been applied to resting data and found to be highly successful and reproducible when compared with BRS based upon burst strength (Kienbaum et al. 2001). Its effectiveness when applied to the Oxford method, whilst yet to be explored, is likely to be less given that the number of data points will be significantly reduced. Although the methods outlined above for sympathetic BRS have been applied during spontaneous fluctuations in arterial pressure (Hart et al. 2010, Greaney et al. 2013, Yang & Carter 2013) and more rapid changes in pressure during the Valsalva manoeuvre (Yang & Carter 2013), the modified Oxford is the only method that has been used to determine the mechanical and neural components of the sympathetic baroreflex (Studinger et al. 2009). Pharmacological methods of baroreflex assessment tend to involve wide ranges of blood pressures, which typically lead to a large number of cardiac cycles that are not associated with a sympathetic burst. Therefore, Studinger et al. (2009) adopted another variation on the weighting approach in which the cardiac cycles without a burst were weighted according to the diastolic pressure. Cardiac cycles with zeros below the lowest pressure associated with a burst of MSNA were assigned a weight of 0 (‘false’ zero), whereas zeros above the highest pressure associated with a burst of MSNA were assigned a weight of 1 (‘true’ zero). Between these lowest and highest pressures, each cardiac cycle without a burst was assigned a weight that progressively increased in proportion to the range of pressures. In addition, any data points that were 2 mmHg above the highest diastolic pressure associated with a burst were excluded. For the neural component, in which MSNA is plotted against carotid diameter during diastole, any diameters that were 0.05 mm above the largest diameter associated with a burst were also excluded. The relationship between carotid diameter and diastolic pressure was found to be linear, and so no data were eliminated for the mechanical component. However, piecewise linear regression was still applied to ensure that the saturation and threshold regions could be identified and removed.
How has the application of carotid ultrasound imaging provided new insights into baroreflex physiology? It is vital that the human body is capable of coping with a range of physiological challenges to maintain homeostasis and meet the demands of the environment or the task at hand. The responses of the cardiovascular system, and of the baroreflex in particular, differ according to the nature of the stressor or
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12302
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stimulus. It is also known that baroreflex function can be affected in the long-term by ageing, pathologies and exercise training. A range of topics will be discussed to illustrate how the application of carotid ultrasound imaging has contributed to a greater understanding of baroreflex physiology in humans.
to different degrees within subjects. This information would not be available if sympathetic baroreflex responses to rising and falling pressures were combined.
The physiology of baroreflex hysteresis Research indicates that cardiac baroreflex responses to rising pressures are greater than to falling pressures. This phenomenon, termed hysteresis, has been observed with both the modified Oxford method (Rudas et al. 1999) and neck suction/pressure techniques (Eckberg 1976). It was thought that this might be explained by the viscoelastic properties of barosensory vessels such that, for a given blood pressure, vessel diameters are greater during falling rather than rising blood pressures. However, this would not explain the hysteresis observed using the neck suction/pressure techniques, which directly stimulate the carotid baroreceptors, It has recently been shown that hysteresis in the cardiac baroreflex is also due to differences in the neural component, which can offset changes in the mechanical component (Studinger et al. 2007). These results highlight the importance of determining the mechanical and neural components that make up the integrated baroreflex response to gain a more in-depth understanding of the mechanisms underlying baroreflex function. Although previous studies have shown no hysteresis in sympathetic baroreflex gain (Rudas et al. 1999), recent data demonstrate that hysteresis is in fact present in the sympathetic arm, particularly in young subjects (Studinger et al. 2009, Hart et al. 2011). Unlike the cardiac arm, the integrated baroreflex responses are typically greater in response to falling pressure compared with rising. Studinger et al. (2009) investigated hysteresis in the mechanical and neural components of the sympathetic baroreflex. In their cohort of young and older individuals, the authors found that hysteresis was present in the mechanical component for over 90% of trials. As has previously been reported in the cardiac arm, there was a positive relationship between pressure and carotid artery diameter, with greater gains for rising pressures. Hysteresis was found to be present in the neural component in approx. 50% of trials, and in contrast to the mechanical gain, greater gains were observed for falling pressures. Despite these opposing effects, the hysteresis in the integrated gain remained significant, demonstrating greater gains for falling pressures as has recently been observed by Hart et al. (2011). Studinger et al. (2009) also highlighted the potential for factors, such as age, to alter sympathetic activation and inhibition
Baroreflex changes with ageing in men and women Several studies, involving a variety of techniques, indicate that cardiac BRS is reduced with age (Bristow et al. 1969, Laitinen et al., 1998, Monahan et al. 2001a,b, Hunt et al. 2001b, Kornet et al. 2002). Ultrasound technology has been used to examine compliance of the carotid artery to determine the contribution of the mechanical component to the decline in BRS with age. Monahan et al. (2001a) found significant correlations between cardiac BRS and measures of arterial compliance in sedentary men over a wide age range (19–76 years). Although it is possible that lifestyle factors may influence these results, it is generally accepted that the reduction in vascular compliance that occurs with age reduces the ability of the barosensory vessels to stretch in response to a given change in pressure. This provides the baroreceptors with a smaller stimulus, ultimately leading to smaller changes in R-R interval. This cross-sectional study suggests that the decline in BRS is due, at least in part, to arterial stiffening that occurs with ageing. The use of ultrasound to determine changes in R-R interval in relation to changes in carotid artery diameter has also allowed researchers to determine the effects of ageing on baroreflex function whilst removing the influence of arterial stiffness on measures of BRS. Kornet et al. (2002) applied this concept using measures of end-diastolic carotid artery diameter across a series of cardiac cycles during spontaneous fluctuations in BP. They found that when the neural component was isolated from the integrated baroreflex response, BRS was still significantly lower in older (51–71 years) compared with younger individuals (20–30 years). This suggests that vagal control is also impaired with ageing and is consistent with the findings of Hunt et al. (2001b) who examined the effects of ageing on both the mechanical and neural components of the cardiac baroreflex during pharmacologically driven changes in BP. The authors found that BRS was significantly lower in older than in younger untrained men due to reductions in both the components. However, when physically active older men were compared with the younger untrained group, BRS was found to be similar due mostly to maintenance of the neural component. Hunt et al. (2001b) reported modestly greater mechanical transduction in older physically active males compared with their untrained counterparts, suggesting that regular
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exercise may also attenuate the arterial stiffness that develops with ageing. After 13 weeks of aerobic exercise training, Monahan et al. (2001a) reported improvements in the mechanical component in older males, which led to significant improvements in integrated cardiac BRS. These findings have yet to be confirmed in older females. However, research indicates that the menopause is an independent risk factor that augments the age-related increase in arterial stiffness (Zaydun et al., 2006). This is likely to add to the decline in baroreflex function with age via reductions in the mechanical component. Indeed, Laitinen et al. (1998) reported lower cardiac BRS in women compared with men, with 24% of women >40 years old and 18% of men >60 years old expressing markedly low BRS (
REVIEW
Assessment of human baroreflex function using carotid ultrasonography: what have we learnt? C. E. Taylor,1 C. K. Willie,2 P. N. Ainslie2 and Y.-C. Tzeng3 1 School of Science and Health, University of Western Sydney, Sydney, NSW, Australia 2 School of Health and Exercise Sciences, Centre for Heart Lung and Vascular Health, University of British Columbia Okanagan, Kelowna, BC, Canada 3 Cardiovascular Systems Laboratory, Centre for Translational Physiology, University of Otago, Wellington, New Zealand
Received 2 April 2014, accepted 9 April 2014 Correspondence: C. Taylor, School of Science and Health, University of Western Sydney, Campbelltown Campus, Locked Bag 1797, Penrith NSW 2751, Australia. E-mail: [email protected]
Abstract The arterial baroreflex is critical to both short- and long-term regulation of blood pressure. However, human baroreflex research has been largely limited to the association between blood pressure and cardiac period (or heart rate) or indices of vascular sympathetic function. Over the past decade, emerging techniques based on carotid ultrasound imaging have allowed new means of understanding and measuring the baroreflex. In this review, we describe the assessment of the mechanical and neural components of the baroreflex through the use of carotid ultrasound imaging. The mechanical component refers to the change in carotid artery diameter in response to changes in arterial pressure, and the neural component refers to the change in R-R interval (cardiac baroreflex) or muscle sympathetic nerve activity (sympathetic baroreflex) in response to this barosensory vessel stretch. The key analytical concepts and techniques are discussed, with a focus on the assessment of baroreflex sensitivity via the modified Oxford method. We illustrate how the application of carotid ultrasound imaging has contributed to a greater understanding of baroreflex physiology in humans, covering topics such as ageing and diurnal variation, and physiological challenges including exercise, postural changes and mental stress. Keywords blood pressure, cardiac, carotid artery, mechanical, neural, sympathetic.
The arterial baroreflex – what is it and why is it important? Oxygen delivery to vital organs such as the brain, heart and kidneys is essential for human survival. For most mammalian species, the perfusion of organs with blood is maintained by the intravascular hydrostatic gradient between the arterial and venous circulation. Thus, the regulation of arterial blood pressure via baroreflex-mediated changes in cardiac output and total peripheral resistance is a key mechanism for maintaining adequate organ perfusion and oxygenation.
Low baroreflex sensitivity (BRS) is associated with an increased risk of mortality following myocardial infarction (La Rovere et al. 2001) and in patients with chronic heart failure (La Rovere et al. 2009). Furthermore, evidence suggests that depressed baroreflex function elevates the risk of both ischaemic and haemorrhagic strokes (Sykora et al. 2009). It is therefore imperative that the mechanisms and modulating factors involved in normal baroreflex function in humans are identified and understood. Baroreceptors, located in the carotid sinuses and aortic arch, detect vessel stretch caused by increasing
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12302
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arterial pressure. The detection of vascular distention and not blood pressure per se is an important point, and although the term ‘baroreceptors’ is most commonly used, these receptors may be more accurately described as mechanoreceptors (Shepherd 1982). Baroreceptor afferents project to the nucleus tractus solitarius which, in turn, projects to other structures important to the central integration of the baroreflex response, such as the rostral ventrolateral medulla, responsible for muscle vasoconstrictor drive (Dampney et al. 2003), and the nucleus ambiguous, responsible for vagal activity (Benarroch 2008). These neural pathways serve to alter total peripheral resistance and cardiac output, respectively, to form an integrated baroreflex response that can promptly ameliorate transient perturbations to blood pressure. Human baroreflex research has been largely limited to the association between blood pressure and cardiac period (or heart rate) or indices of vascular sympathetic function (e.g. muscle sympathetic nerve activity, MSNA). However, emerging techniques based on carotid ultrasound imaging, first documented by Hunt et al. (2001a), have enabled researchers to examine the individual components of the baroreflex in humans without the limitations of invasive animal experiments. The primary objective of this review is to highlight the pivotal role that carotid ultrasound imaging plays in generating deeper insights into human baroreflex function and to encourage its wider application. Thus, this review extends on previous reports focused on technical considerations relevant to carotid ultrasound imaging (Kornet et al. 2002, Reneman et al. 2005, Tzeng 2012), by reviewing recent literature where its practical application has generated new mechanistic insights. Comprehensive reviews of general baroreflex physiology can be found elsewhere (Fadel et al. 2003).
arm of the autonomic nervous system. For this reason, the term sympathetic baroreflex is most commonly used in the literature to describe baroreflex modulation of blood pressure via the vasculature. Sympathetic stimulation increases vascular resistance, thus increasing arterial pressure, and so sympathetic BRS is expressed as the decrease in MSNA per unit increase in arterial pressure. It should be noted, however, that the use of the term ‘sympathetic baroreflex’ has the potential to be misleading, given that sympathetic activity also influences the heart. However, for consistency with the current literature, we will continue to use the term sympathetic baroreflex in this review. Cardiac BRS is determined by plotting the relationship between changes in systolic blood pressure and R-R interval (or heart rate). Although the changes in R-R interval more accurately reflect changes in parasympathetic vagal tone (Parker et al. 1984), the nonlinear reciprocal relationship between R-R interval and heart rate means that differences in baseline heart rate between experimental conditions can lead to misleading values for BRS (O’Leary 1996). Therefore, results are often expressed as both R-R interval and heart rate to confirm their findings. Sympathetic BRS is typically quantified as the relation between changes in diastolic blood pressure and sympathetic neural recordings made at superficial sites, such as a muscle fascicle of the peroneal nerve posterior to the fibular head (MSNA). The values for the slopes that are generated when plotting these variables against each other provide the BRS, also referred to as baroreflex gain. Steeper slopes signify greater, and therefore more effective, responses to changes in blood pressure. There are currently no official figures to define normal BRS, and there can be large variability amongst healthy individuals. However, La Rovere and colleagues (1988) identified a threshold for cardiac BRS of 3 ms mmHg 1, below which myocardial infarction patients are at a significantly greater risk of subsequent mortality over a 2-year follow-up. Cardiac BRS has also been reported to be lower in patients with hypertension (Bristow et al. 1969), coronary artery disease (Airaksinen et al. 1993) and chronic heart failure (Mortara et al. 1997), when compared to healthy controls, suggesting that low cardiac BRS is a marker for cardiovascular disease (La Rovere et al. 1988). In contrast to cardiac BRS, results for the sympathetic arm have not been unanimous, with studies indicating reduced (Korner 1988, Matsukawa et al. 1991) and similar (Grassi et al. 1998) baroreflex responses in hypertensives compared with normotensives. Reduced sympathetic BRS has been reported in patients with obstructive sleep apnoea (Narkiewicz et al. 1998) and vasovagal syncope (Bechir et al. 2003). Although the two arms of the baroreflex receive the same afferent
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Cardiac and sympathetic baroreflex sensitivity The autonomic nervous system has two effector arms: the parasympathetic and the sympathetic arm. Major target organs are the heart and the vasculature. If we discuss the cardiac baroreflex, this relates to the sympathetic as well as to the parasympathetic influences on the heart. Sympathetic stimulation increases heart rate, conductivity, contractility and lusitropy. Parasympathetic stimulation counteracts sympathetic stimulation (Levy 1971, Schwartz & Ferrari 2011). Cardiac BRS is a measure of the heart rate response for a given change in arterial pressure, typically expressed as the R-R interval increase per unit increase in systolic pressure. Throughout the body, the vasculature is mainly influenced by the sympathetic 298
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input via the nucleus tractus solitarius, research suggests that cardiac and sympathetic BRS are not correlated (Dutoit et al. 2010).
Assessment of the mechanical and neural components of the baroreflex The initial stage of the integrated baroreflex response is the transduction of blood pressure into barosensory vessel stretch, referred to as the mechanical component. The transduction of barosensory vessel stretch into changes in heart rate (via changes in efferent parasympathetic and/or sympathetic neural outflow) is referred to as the neural component. This component therefore incorporates afferent activity, central integration and efferent activity. Carotid ultrasound imaging allows the relative contribution of these components to the integrated baroreflex response to be quantified (Hunt et al. 2001a). For the purpose of this review, the carotid ultrasound scanning protocol will be briefly outlined. However, more detailed descriptions can be found elsewhere (Black et al. 2008, Tzeng 2012).
Figure 1 Schematic diagram showing the common carotid artery, the carotid bulb and the bifurcation into the internal and external carotid arteries.
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Carotid ultrasound imaging The transducer is placed parallel to the vessel to capture a longitudinal section of the common carotid artery, approx. 1–2 cm from the bifurcation (Fig. 1). Human and animal data suggest that changes in carotid artery diameter are proportional to carotid sinus nerve activity (Landgren 1952, Angell-James & Lumley 1975). This suggests that these measures of barosensory vessel deformation reflect the stimulus at the bulb as well as the degree of baroreceptor afferent activity in response to this stimulus (Hunt et al. 2001a). Upon locating the common carotid immediately proximal to the bulb, the vessel wall boundaries are identified in the longitudinal B-mode image. Clear imaging of the near and far walls is important to allow carotid diameter to be determined, and therefore, the probe should be adjusted to obtain the best view of the arterial walls. Continuous video recordings are made of the optimized B-mode images and saved for offline analysis using custom-written or commercially available edge-tracking software (Fig. 2). Provided that adequate ultrasound images of the carotid artery can be obtained, the mechanical and neural components of the baroreflex can theoretically be determined using any method of baroreflex assessment. To date, this approach has been applied to the modified Oxford method, Valsalva manoeuvre and transfer function analysis. The advantages and disadvantages of the various techniques used to determine BRS have been examined and discussed previously (Blaber et al. 1995, Pitzalis et al. 1998, Colombo et al. 1999, Lipman et al. 2003, Diaz & Taylor 2006, Kamiya et al. 2011, Tzeng 2012). The modified Oxford method, often regarded as the gold standard technique for assessing baroreflex function, has been
Figure 2 Sample screen shot showing the edge tracking of the carotid diameter. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12302
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used successfully in conjunction with carotid imaging to investigate a number of research questions. Therefore, in this review, the methods of determining the mechanical and neural components of the baroreflex will be presented in relation to the modified Oxford method.
et al. 1999, Kienbaum & Peters 2004). In addition, studies in animals and isolated carotid sinuses indicate that alpha-adrenergic agonists, such as phenylephrine, activate smooth muscle fibres within the wall of the carotid sinus (Peveler et al. 1983, Bell et al. 1986). These results led to the suggestion that smooth muscle contraction, and hence carotid vasoconstriction, influences baroreceptor afferents. Based on the reasoning that a change in carotid artery diameter is the net effect of smooth muscle constriction and passive stretch, Bonyhay et al. (1997) examined the contribution of these two opposing effects on human carotid arteries during elevations and reductions in arterial pressure induced by vasoactive drugs. Unlike previous animal studies, the authors reported increases in carotid artery diameter in response to drug-induced elevations in arterial pressure. Likewise, falls in pressure led to reductions in carotid diameter. These relationships between arterial pressure and carotid diameter reflected the relationships between arterial pressure and R-R interval, including the difference in slopes for rising and falling pressures (hysteresis). The results indicate that baroreceptor activity in humans is influenced more by passive stretch than by smooth muscle contraction. The findings are consistent with those of many subsequent studies of the mechanical and neural components of the cardiac baroreflex as changes in systolic blood pressure are positively correlated with carotid artery diameter (Hunt et al. 2001a,b, Studinger et al. 2007, Deley et al. 2009a,b, Tzeng et al. 2009, 2010, Taylor et al. 2011, 2013, Willie et al. 2011). The differences in structure of the carotid artery between animals and humans may explain why the data from animal studies do not apply to humans in this case. In contrast to many species of animal, the viscoelastic nature of the carotid artery in humans (Arndt, 1991) allows passive stretch to dominate over smooth muscle tension during pharmacological manipulation of blood pressure (Bonyhay et al. 1997). A major advantage of the modified Oxford method is that it allows blood pressure to be perturbed across a wide range in a short period of time in order to engage the baroreflex. It is important that the drugs are administered using bolus injections rather than steady state infusions of vasodilators, as have been used in some previous studies (Hossman et al. 1980). When attempting to assess baroreflex control using infusions, an ‘infinite’ gain can be observed between the pressure ‘input’ and the cardiac and/or sympathetic ‘output’. That is, the system has effectively counter-regulated against the potential pressure perturbation such that the haemodynamic milieu is an unchanged systemic pressure with elevated heart rate and/or vascular sympathetic activity. Therefore, the rapid changes in arterial pressure that occur during
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The modified Oxford method The ‘Oxford method’ was an early and popular measure of baroreflex function. Although the assessment was originally carried out using injections of angiotensin (Smyth et al. 1969), the method has since been modified, notably with the addition of vasodilator drugs to determine the baroreflex responses to falling arterial pressure (Pickering et al. 1972). The administration of vasodilator and vasoconstriction drugs in sequence was introduced later (Ebert & Cowley 1992) and has been termed the modified Oxford method. When Hunt et al. (2001a) introduced the method of isolating the mechanical and neural components of the baroreflex, they used the modified Oxford technique to describe the cardiac baroreflex. Since then, this technique has been applied in many studies of cardiac baroreflex function (Hunt et al. 2001a,b, Studinger et al. 2007, Deley et al. 2009a,b, Tzeng et al. 2009, 2010, Taylor et al. 2011, 2013, Willie et al. 2011), and more recently to the sympathetic baroreflex (Studinger et al. 2009). The modified Oxford method consists of bolus injections of sodium nitroprusside (SNP) and phenylephrine hydrochloride (PE) administered intravenously to cause a fall and subsequent rise in arterial pressure. The injection of SNP should only be administered once blood pressure is stable, followed approx. 60 s later by the injection of PE. Doses given are typically 100 and 150 lg for SNP and PE respectively (Hunt et al. 2001a,b, Studinger et al. 2007, Deley et al. 2009a,b). However, this should be adjusted according to the age and size of the individual and responses to previous doses (if any), to ensure blood pressure perturbations of >15 mmHg (Taylor et al. 2011, Willie et al. 2011). In some cohorts of young volunteers, higher doses of up to 300 lg (SNP) and 400 lg (PE) have been required to achieve sufficient perturbations in systolic blood pressure (Tzeng et al. 2009). A potential disadvantage of the Oxford method is the use of vasoactive agents. The depressor effects of the modified Oxford method tend to be produced by bolus injection of sodium nitroprusside, which causes vasodilation via nitric oxide. It has been suggested that nitric oxide has central neural effects that could cause BRS to be underestimated, such as inhibition of the nuclei responsible for sympathetic outflow (Hogan 300
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application of the modified Oxford method are considered a major advantage of this technique. The baroreflex is a closed-loop system, and it has been argued that the loop must be opened to allow accurate quantification of the relationships between input and output variables (Lipman et al. 2003, Diaz & Taylor 2006). Whilst the loop cannot be fully opened in the majority of human experimental settings, the active perturbation of blood pressure that the modified Oxford method provides does allow the loop to be partially opened.
approach, breakpoints at the upper and lower end of the raw data can be identified statistically using piecewise linear regression (Studinger et al. 2007, Taylor et al. 2011; see Fig. 4). The linear segment is considered acceptable if the correlation coefficient reaches an arbitrary threshold, typically set at 0.5. Data binning is usually applied using bins of 2 or 3 mmHg, to minimize fluctuations in heart rate caused by respiration (Tzeng et al. 2009). To determine the mechanical component, systolic carotid lumen diameter measurements are plotted against systolic blood pressure. To determine the neural component, R-R intervals or heart rate is plotted against systolic carotid lumen diameter. As with the integrated BRS, the mechanical and neural components can be calculated separately for the fall and rise in blood pressure, with the exclusion of the threshold and saturation regions.
Assessment of cardiac BRS
Assessment of sympathetic BRS The general approach for assessing the sympathetic baroreflex is similar in concept to that of cardiac BRS. However, instead of systolic carotid diameters and pressures, integrated and mechanical BRS for the sympathetic baroreflex are derived using diastolic diameters and pressures. Diastolic pressure correlates more strongly with MSNA (Sundl€ of & Wallin 1978), which in humans is typically measured via microneurographical recordings from the peroneal nerve (Vallbo et al.
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Cardiac BRS is assessed by examining the relation between R-R interval and systolic blood pressure. Figure 3 illustrates the R-R interval, carotid artery diameter and blood pressure responses of one individual during a modified Oxford test. The fall in systolic blood pressure tends to occur around 30 s after the SNP injection. It is at the onset of the systolic blood pressure decrease through to the nadir that cardiac BRS for falling pressures is assessed. To assess the baroreflex response to a rise in pressure, the data are selected from the nadir in systolic pressure to the peak that occurs following the PE injection. Threshold and saturation regions, where there are no changes in R-R interval at the lowest and highest pressures, respectively, can be removed by visual inspection (Lipman et al. 2003, Tzeng et al. 2009). For a more objective
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Figure 3 Representative recording of systolic blood pressure, carotid diameter and heart rate during a modified Oxford baroreflex test in one subject. A bolus injection of sodium nitroprusside is administered to initiate a fall in arterial pressure, followed approx. 60 s later by phenylephrine hydrochloride to initiate a pressure rise.
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Figure 4 Piecewise regression model for elimination of threshold and saturation regions of the integrated baroreflex response to rising pressures. Open circles (○) represent the threshold and saturation regions, while closed circles (●) represent the linear portion of the baroreflex gain (Taylor et al. 2011).
1979). Integrated sympathetic BRS can be quantified by plotting MSNA against diastolic blood pressure, and the slope of the relationship provides an index of sensitivity. As with the cardiac baroreflex, the data are typically grouped into 1, 2 or 3 mmHg pressure bins to reduce the statistical impact of inherent beatto-beat variability in nerve activity (Hart et al. 2010). One method of assessing sympathetic BRS is to determine total MSNA for each pressure bin by calculating the total area (or amplitude) of all MSNA bursts relative to the number of cardiac cycles. Cardiac cycles associated with no MSNA burst are usually assigned a value of zero, although in some analyses, these cardiac cycles are removed altogether (Kienbaum et al. 2001, Keller et al. 2006). It is common for the linear regression analysis to be weighted according to the number of cardiac cycles per bin (Kienbaum et al. 2001, Ogoh et al. 2007). This removes the bias caused by the low number of cardiac cycles within some bins, usually at the highest and lowest pressures. The fact that not every cardiac cycle is associated with an MSNA burst can cause problems when assessing sympathetic BRS, particularly during high pressures when there is significant sympathoinhibition, or if a subject’s resting MSNA is low. Therefore, methods based on MSNA burst incidence have been used, providing an alternative approach in which the percentage of cardiac cycles associated with a burst (expressed as bursts per 100 heartbeats) is plotted against diastolic pressure (Sundl€ of & Wallin 1978). Again, pressure bins and weighted linear regression 302
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are typically applied. This technique, often referred to as the threshold technique, has been applied to resting data and found to be highly successful and reproducible when compared with BRS based upon burst strength (Kienbaum et al. 2001). Its effectiveness when applied to the Oxford method, whilst yet to be explored, is likely to be less given that the number of data points will be significantly reduced. Although the methods outlined above for sympathetic BRS have been applied during spontaneous fluctuations in arterial pressure (Hart et al. 2010, Greaney et al. 2013, Yang & Carter 2013) and more rapid changes in pressure during the Valsalva manoeuvre (Yang & Carter 2013), the modified Oxford is the only method that has been used to determine the mechanical and neural components of the sympathetic baroreflex (Studinger et al. 2009). Pharmacological methods of baroreflex assessment tend to involve wide ranges of blood pressures, which typically lead to a large number of cardiac cycles that are not associated with a sympathetic burst. Therefore, Studinger et al. (2009) adopted another variation on the weighting approach in which the cardiac cycles without a burst were weighted according to the diastolic pressure. Cardiac cycles with zeros below the lowest pressure associated with a burst of MSNA were assigned a weight of 0 (‘false’ zero), whereas zeros above the highest pressure associated with a burst of MSNA were assigned a weight of 1 (‘true’ zero). Between these lowest and highest pressures, each cardiac cycle without a burst was assigned a weight that progressively increased in proportion to the range of pressures. In addition, any data points that were 2 mmHg above the highest diastolic pressure associated with a burst were excluded. For the neural component, in which MSNA is plotted against carotid diameter during diastole, any diameters that were 0.05 mm above the largest diameter associated with a burst were also excluded. The relationship between carotid diameter and diastolic pressure was found to be linear, and so no data were eliminated for the mechanical component. However, piecewise linear regression was still applied to ensure that the saturation and threshold regions could be identified and removed.
How has the application of carotid ultrasound imaging provided new insights into baroreflex physiology? It is vital that the human body is capable of coping with a range of physiological challenges to maintain homeostasis and meet the demands of the environment or the task at hand. The responses of the cardiovascular system, and of the baroreflex in particular, differ according to the nature of the stressor or
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stimulus. It is also known that baroreflex function can be affected in the long-term by ageing, pathologies and exercise training. A range of topics will be discussed to illustrate how the application of carotid ultrasound imaging has contributed to a greater understanding of baroreflex physiology in humans.
to different degrees within subjects. This information would not be available if sympathetic baroreflex responses to rising and falling pressures were combined.
The physiology of baroreflex hysteresis Research indicates that cardiac baroreflex responses to rising pressures are greater than to falling pressures. This phenomenon, termed hysteresis, has been observed with both the modified Oxford method (Rudas et al. 1999) and neck suction/pressure techniques (Eckberg 1976). It was thought that this might be explained by the viscoelastic properties of barosensory vessels such that, for a given blood pressure, vessel diameters are greater during falling rather than rising blood pressures. However, this would not explain the hysteresis observed using the neck suction/pressure techniques, which directly stimulate the carotid baroreceptors, It has recently been shown that hysteresis in the cardiac baroreflex is also due to differences in the neural component, which can offset changes in the mechanical component (Studinger et al. 2007). These results highlight the importance of determining the mechanical and neural components that make up the integrated baroreflex response to gain a more in-depth understanding of the mechanisms underlying baroreflex function. Although previous studies have shown no hysteresis in sympathetic baroreflex gain (Rudas et al. 1999), recent data demonstrate that hysteresis is in fact present in the sympathetic arm, particularly in young subjects (Studinger et al. 2009, Hart et al. 2011). Unlike the cardiac arm, the integrated baroreflex responses are typically greater in response to falling pressure compared with rising. Studinger et al. (2009) investigated hysteresis in the mechanical and neural components of the sympathetic baroreflex. In their cohort of young and older individuals, the authors found that hysteresis was present in the mechanical component for over 90% of trials. As has previously been reported in the cardiac arm, there was a positive relationship between pressure and carotid artery diameter, with greater gains for rising pressures. Hysteresis was found to be present in the neural component in approx. 50% of trials, and in contrast to the mechanical gain, greater gains were observed for falling pressures. Despite these opposing effects, the hysteresis in the integrated gain remained significant, demonstrating greater gains for falling pressures as has recently been observed by Hart et al. (2011). Studinger et al. (2009) also highlighted the potential for factors, such as age, to alter sympathetic activation and inhibition
Baroreflex changes with ageing in men and women Several studies, involving a variety of techniques, indicate that cardiac BRS is reduced with age (Bristow et al. 1969, Laitinen et al., 1998, Monahan et al. 2001a,b, Hunt et al. 2001b, Kornet et al. 2002). Ultrasound technology has been used to examine compliance of the carotid artery to determine the contribution of the mechanical component to the decline in BRS with age. Monahan et al. (2001a) found significant correlations between cardiac BRS and measures of arterial compliance in sedentary men over a wide age range (19–76 years). Although it is possible that lifestyle factors may influence these results, it is generally accepted that the reduction in vascular compliance that occurs with age reduces the ability of the barosensory vessels to stretch in response to a given change in pressure. This provides the baroreceptors with a smaller stimulus, ultimately leading to smaller changes in R-R interval. This cross-sectional study suggests that the decline in BRS is due, at least in part, to arterial stiffening that occurs with ageing. The use of ultrasound to determine changes in R-R interval in relation to changes in carotid artery diameter has also allowed researchers to determine the effects of ageing on baroreflex function whilst removing the influence of arterial stiffness on measures of BRS. Kornet et al. (2002) applied this concept using measures of end-diastolic carotid artery diameter across a series of cardiac cycles during spontaneous fluctuations in BP. They found that when the neural component was isolated from the integrated baroreflex response, BRS was still significantly lower in older (51–71 years) compared with younger individuals (20–30 years). This suggests that vagal control is also impaired with ageing and is consistent with the findings of Hunt et al. (2001b) who examined the effects of ageing on both the mechanical and neural components of the cardiac baroreflex during pharmacologically driven changes in BP. The authors found that BRS was significantly lower in older than in younger untrained men due to reductions in both the components. However, when physically active older men were compared with the younger untrained group, BRS was found to be similar due mostly to maintenance of the neural component. Hunt et al. (2001b) reported modestly greater mechanical transduction in older physically active males compared with their untrained counterparts, suggesting that regular
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exercise may also attenuate the arterial stiffness that develops with ageing. After 13 weeks of aerobic exercise training, Monahan et al. (2001a) reported improvements in the mechanical component in older males, which led to significant improvements in integrated cardiac BRS. These findings have yet to be confirmed in older females. However, research indicates that the menopause is an independent risk factor that augments the age-related increase in arterial stiffness (Zaydun et al., 2006). This is likely to add to the decline in baroreflex function with age via reductions in the mechanical component. Indeed, Laitinen et al. (1998) reported lower cardiac BRS in women compared with men, with 24% of women >40 years old and 18% of men >60 years old expressing markedly low BRS (
