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We compared haemodynamic and peripheral vasomotor responses to lower body negative pressure (LBNP) in cardiac transplant recipients who had undergone bicaval anastomoses, involving right atrial deafferentation (−RA), and the conventional procedure in which some atrial baroreceptor afferents remain intact (+RA). We measured mean forearm blood flow (FBF) responses using Doppler/ultrasound during three randomised trials involving 0 (baseline), −20 and −40 mmHg LBNP in 15 transplant recipients (9 −RA, 6 +RA) and in eight healthy matched controls. A significant effect of LBNP on FBF existed between control and transplant groups (P < 0.05; two-way ANOVA). Mild LBNP (−20 mmHg), significantly decreased FBF by 29.7 ± 10.0% relative to baseline in +RA subjects (P < 0.05), whereas the 17.7 ± 10.3% decrease in −RA subjects was not significant. In response to −40 mmHg LBNP, FBF significantly decreased in control (42.4 ± 4.6%, P < 0.05) and +RA subjects (33.3 ± 11.4%, P < 0.05) with no significant change in the −RA group. The response of systolic blood pressure (SBP) to −40 mmHg significantly differed between groups (P < 0.05): −RA subjects decreased significantly (P < 0.05) whilst the decrease in SBP in +RA subjects did not achieve significance and control subjects exhibited an increase. The heart rate increase from baseline to −40 mmHg was significantly attenuated in −RA relative to controls and the +RA group (P < 0.05). The present study demonstrates that atrial deafferentation impairs reflex vasomotor control of the circulation in response to low- and high-level LBNP, indicating that atrial deafferentation may contribute to abnormal arterial pressure regulation.
Cardiac transplantation has been an established treatment for end-stage cardiac failure for several decades. Because cardiac failure impairs reflex cardiovascular function (Goldsmith et al. 1983; Mohanty et al. 1986), much interest has focused on the effects of cardiac transplantation on reflex sympathetic responses to physiological stimuli such as orthostatic stress. In healthy humans, lower body negative pressure (LBNP)-induced decreases in venous return result in increased vascular resistance without altering arterial pressure. The findings of Mohanty et al. (1987) indicate that cardiac deafferentation attenuates the normal vasoconstrictor response to LBNP, implicate unloading of cardiopulmonary baroreceptors, possibly located in the atria, ventricles, coronary arteries and pulmonary veins, in the reflex vasoconstriction in response to LBNP. In contrast, Jacobson et al. (1993) suggested that sinoaortic baroreflexes are more important than their ventricular counterparts in regulating sympathetic outflow and resultant peripheral vasoconstrictor tone during LBNP. This study did not consider the role of atrial receptors in mediating the responses to LBNP as the subjects involved had undergone transplantation with the conventional technique developed by Lower and Shumway (1960) in which afferents arising from the recipient atrial remnant and venoatrial junctions remain intact. Indeed, animal studies suggest that atrial baroreceptors, which densely innervate the venoatrial junction of both left and right atria, are important in reflex responses to physiological stimuli (Hainsworth, 1991), raising the possibility that cardiopulmonary receptors may, in fact, play an important role in reflex responses to orthostasis and decreased venous return.
Although the standard technique for transplantation may preserve peripheral sympathetic vasomotor responses to LBNP (Jacobsen et al. 1993), it has also been reported to alter atrial dimensions and function (Angermann et al. 1990) and cause early postoperative arrhythmias (Milano et al. 2000) and mitral regurgitation (Stevenson et al. 1987). To prevent these common postoperative complications, the bicaval anastomoses technique, involving right atrial and ventricular denervation, was popularized (Webb et al. 1959; Sievers et al. 1991). However, the reflex vascular effects of the bicaval anastomoses and the Lower and Shumway techniques have not been compared.
In the present study, we compared two groups of cardiac transplant recipients with distinct baroreflex anatomy to determine the contribution of right atrial baroreceptor afferents to reflex vasomotor and haemodynamic responses to decreased venous return. We report haemodynamic and peripheral vascular responses to LBNP in both standard and bicaval cardiac transplant recipients.
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The results of the present study indicate that transplant patients who have undergone bicaval anastamoses, with consequent atrial deafferentation, exhibit impaired peripheral vasomotor responses to mild orthostatic stress induced by −20 mmHg LBNP when compared to transplant patients with preserved right atrial afferents (standard transplantation). No changes in arterial pressure were evident in any group at this mild level of LBNP, indicating that sinoaortic baroreceptor unloading is unlikely to have occurred. These data indicate that right atrial cardiopulmonary afferents may contribute to reflex vasoconstrictor responses during moderate decreases in central venous pressure. At higher levels of LBNP (−40 mmHg), neither transplanted group exhibited further significant vasoconstrictor responses relative to the mild LBNP condition, whereas FBF and FVC decreased significantly between −20 and −40 mmHg in control subjects. The absence of a vasoconstrictor response was associated with decreased systolic blood pressure in both transplant groups, particularly in those without atrial innervation, whereas systolic pressure was maintained in healthy control subjects, probably due to the peripheral vasoconstriction.
Previous studies employing cardiac transplantation as a model to examine autonomic control of the circulation have produced disparate findings regarding the importance of cardiopulmonary and sinoaortic afferents in reflex responses to orthostatic stress. Early studies indicated that ventricular deafferentation was associated with attenuated increases in forearm vascular resistance in response to LBNP and decreased central venous pressure (Mohanty et al. 1987; Morgan et al. 1987). Other studies observed that maintenance of arterial pressure (Johnson et al. 1974) or carotid baroreflex stimulation with neck suction (Abboud et al. 1979) during high levels of LBNP did not abolish the typical vasoconstrictor responses observed. These studies, along with the observation that increases in forearm vascular resistance may be closely related to decreases in central venous pressure during ramp LBNP (Johnson et al. 1974) and the results of the present study, strongly imply a role for cardiopulmonary baroreceptors in reflex vasoconstrictor responses to orthostatic stress.
However more recently, Jacobsen and colleagues (1993) measured peroneal sympathetic nerve activity (SNA) and forearm blood flow responses during graded LBNP with and without intravenous phenylephrine infusion to prevent sinoaortic baroreceptor unloading in transplant recipients and control subjects. They observed similar SNA and vascular resistance responses to −15 and −40 mmHg LBNP in transplant and control subjects, suggesting that the neural stimulus for vasoconstriction is not attenuated after transplantation. They also abolished the increased SNA observed in transplant patients during mild (−15 mmHg) LBNP when phenylephrine was infused to prevent sinoaortic receptor unloading. This finding implies that the fall in arterial pressure mediating sinoaortic baroreceptor unloading in these transplant recipients was able to compensate for the loss of ventricular and/or coronary artery baroreceptors. Finally, Jacobsen et al. (1993) did not observe a close relationship between changes in SNA and changes in graded LBNP, indicating that LBNP may not be as closely associated with changes in central venous pressure as previously suggested (Johnson et al. 1974). Collectively, these data were interpreted as indicating that sinoaortic baroreceptors play the major role in reflex control of skeletal muscle blood flow during orthostatic stress in transplant recipients. Consistent with the data of Jacobsen et al. (1993), other studies have reported that combined heart and lung transplantation, with removal of the majority of cardiopulmonary afferents, does not impair forearm vasoconstriction during LBNP (Joyner et al. 1990) or tilt (Banner et al. 1990). In contrast, our results, indicating that at mild levels of LBNP the decrease in FBF observed was lower in the −RA group relative to +RA subjects, strongly suggest that atrial receptors participate in the organization of vasoconstrictor responses to decreases in arterial pressure. This may have implications for the interpretation of previous transplant studies that have enrolled only patients who have undergone the standard technique (Jacobsen et al. 1993) described by Lower & Shumway (1960).
In the present study, heart rate responses to LBNP were relatively intact in subjects with preserved native right atrium, whereas subjects with atrial denervation exhibited impaired heart rate responsiveness. Several factors may have influenced this finding. The first, and most likely, is that intact atrial reflex innervation may play a role in the exaggerated heart rate response to LBNP in the +RA group. However, a second contributor to the increased heart rate responsiveness in the +RA group may be elevated catecholaminergic control (Gilbert et al. 1989). In the present study, whilst noradrenaline increased step-wise with the level of LBNP in each group, LBNP had no effect on adrenaline levels, and during all LBNP conditions adrenaline levels were significantly higher in the +RA group relative to controls, as previously demonstrated by Gilbert et al. (1989), and to the −RA group. The reason for increased plasma adrenaline levels in the +RA group is unclear, but may not be physiologically significant given that the magnitude of difference is modest compared to, for example, the effect of exercise on circulating concentrations (Pott et al. 1996; Kjær et al. 2004). Although this finding relating to sympathoadrenal control may reflect longer time from transplant and possibly reinnervation of the sinus node (Gilbert et al. 1989; van de Borne et al. 2001), it is unlikely because adrenaline levels did not significantly correlate with time from transplant (r= 0.701, P= NS). In any event, the fact that the +RA group had a greater vasoconstrictor response to LBNP than the −RA group in the presence of a greater baseline concentration of adrenaline, a β2-agonist which would oppose the sympathetic vasoconstriction of the LBNP, provides further evidence of the involvement of the cardiopulmonary baroreflex.
While the main focus of the present study was to detect the effects of right atrial denervation on vasomotor responses to LBNP, the results provide some additional insights into the contributions of other cardiac reflexes. Despite denervated right atrium and ventricles, some residual vasoconstriction was evident in the −RA group in response to decreased venous return (−20 mmHg). This suggests that some baroreceptor function persists in these subjects and it is possible that afferents arising from the remnant recipient left atrium, vena cavae or pulmonary vasculature may play a role. It would be interesting to further investigate this possibility by comparing patients in this study to a group who have undergone heart–lung transplantation resulting in left atrium and pulmonary receptor denervation. In one preliminary study of three subjects, reported in abstract form, some residual vasoconstrictor function persisted following the heart–lung procedure (Joyner et al. 1990), suggesting that vena caval afferents may play a role in response to decreased venous return.
In clinical terms, the current study has important implications. Our data indicate that patients who have undergone bicaval transplantation do not possess intact vasoconstrictor responses when venous return is reduced. Indeed, the bicaval subjects were the only group to exhibit a significant fall in blood pressure during LBNP, possibly indicating that preservation of the right atrium may therefore produce some cardiovascular benefits post transplantation. However, these favourable effects must be balanced against the purported benefits of the bicaval approach in terms of decreasing the risk of rhythm abnormalities (Kaye et al. 1992; Deleuze et al. 1995; Leyh et al. 1995; Aziz et al. 1999) and tricuspid regurgitation (Angermann et al. 1990; Laske et al. 1995).
There are several limitations in the present study. Time from transplantation differed significantly between the groups, reflecting the contemporary popularity of the bicaval technique. Because post-transplantation time is associated with increases in sympathetic activity (van de Borne et al. 2001), this raises the possibility that more physiological disturbance may have evolved over time in the +RA group, though this seems unlikely as these subjects exhibited relatively preserved vasomotor responsiveness to LBNP compared to the more recently transplanted −RA group. It is also possible that more reinnervation may have occurred over time in the +RA group and that this, rather than presence of intact afferents from the remnant atria, may have been responsible for the relatively preserved cardiopulmonary baroreflex function in these subjects. However, the removal of the +RA subject with the longest post-transplantation time (132 months), which normalizes the difference in post-transplantation time between +RA versus−RA groups, did not change our findings in terms of heart rate, mean arterial, systolic and diastolic blood pressures or absolute mean blood flow and conductance. In addition, reinnervation is unlikely because (i) considerable evidence suggests that post-transplant reinnervation does not occur (Stinson et al. 1972; Mohanty et al. 1987; Yusuf et al. 1987; Arrowood et al. 1995), (ii) no differences were evident between the transplant groups in terms of resting heart rate or FBF and (iii) cardiac reinnervation, if it is apparent, probably relates to intrinsic rather than extrinsic cardiac nerves (Yusuf et al. 1987). A second limitation is that our group of transplant recipients were administered a range of drug regimens and doses, and we did not stop these during the study for ethical reasons. Our data therefore reflect the reflex responses of a group of transplant recipients on typically administered contemporary therapies, and we cannot exclude the possibility that impaired vasomotor responses to high-level LBNP may result, in part, from drug effects. However, it seems unlikely that differences between the transplant patients can be explained by drug effects, as both groups were managed on similar medications. Furthermore, when statistical comparison between the groups was performed excluding the three patients in the −RA group to whom prazosin was administered, no difference was evident in either the pattern or significance of difference in vasomotor responses between the groups (P= 0.048 for n= 6 versusP= 0.047 for n= 9 in −RA, two-way ANOVA versus+RA). Finally, it remains a possibility that transplant patients possess impaired responses to all physiological stimuli and that our data are simply a manifestation of this generalized reflex impairment. However, we think this unlikely because increases in FBF during chemoreflex activation with hypoxia, which we assessed separately in each group using a methodological approach we have detailed previously (Weisbrod et al. 2001, 2004), were similar between groups (normoxia to hypoxia: controls, 81.2 ± 16.3 to 101.4 ± 37.5 ml min−1; +RA, 92.3 ± 18.1 to 111.8 ± 22.8 ml min−1; −RA, 92.6 ± 18.2 to 101.9 ± 19.4 ml min−1). These data strongly suggest that both transplant groups have intact chemoreflex responses and imply that the differences in vasomotor responses to LBNP we observed are a specific consequence of differences in atrial contribution to cardiopulmonary baroreflex control.
In summary, the present study has demonstrated for the first time that patients with atrial deafferentation exhibit abnormal reflex haemodynamic and vasomotor responses to LBNP, suggesting that right atrial baroreceptor afferents contribute significantly to cardiovascular control during orthostatic stress.