Evidence Against Reinnervation of Cardiac Vagal Afferents After Human Orthotopic Cardiac Transplantation
Background Orthotopic cardiac transplantation results in total cardiac denervation. Recent studies in humans suggest that reinnervation of cardiac sympathetic nerves (cardiac efferents) may occur after cardiac transplantation. We hypothesized that reinnervation of cardiac afferents may occur as well. To test this hypothesis, we investigated reflex responses produced by stimulation of ventricular chemosensory endings subserved by vagal afferents (cardiac depressor reflex).
Methods and Results Two cardiac transplant groups were studied: an “early” group (n=18, <24 months after transplant) and a “late” group (n=18, >43 months after transplant); these groups were compared with a control group with intact innervation (n=18). The reflex response of the recipient sinus node (RSN) in the remnant right atrium, which remains innervated after transplantation, was observed during selective right coronary artery (RCA) and left coronary artery (LCA) injection of the radiographic contrast agent meglumine diatrizoate, which is known to stimulate ventricular chemosensory endings. A decrease in the rate of the RSN was expected if reinnervation of chemosensory endings had occurred and the afferent limb of the cardiac depressor reflex was intact. With injection, the RSN rate of both transplant groups did not decrease but increased (early: LCA, 7.2±1.4 beats per minute; RCA, 6.3±1.3 beats per minute; late: LCA, 5.9±1.0 beats per minute; RCA, 6.0±0.9 beats per minute) compared with the expected decrease in control patients (LCA, −20.8±2.5 beats per minute; RCA, −18.0±4.0 beats per minute; P<.001 versus transplants). Decreases in mean arterial pressure in the transplant groups (early: LCA, −11.3±1.4 mm Hg; RCA, −10.0±1.6 mm Hg; late: LCA, −13.0±1.6 mm Hg; RCA, −9.1±1.5 mm Hg) were less than those observed in the control group (LCA, −19.8±2.2 mm Hg; RCA, −18.7±4.0 mm Hg; P<.05 versus transplants).
Conclusions The results suggest that reinnervation of ventricular chemosensory endings subserved by vagal afferents in cardiac transplant patients does not occur up to 74 months after transplantation.
The heart is functionally innervated by sympathetic and parasympathetic divisions of the autonomic nervous system as well as by afferent connections arising from sensory endings in the atria and ventricles. Afferent fibers from mechanosensitive endings and chemosensitive endings respond to changes in chamber size (mechanical deformation)1 and a variety of chemical agents (capsaicin, prostaglandins, radiographic contrast agents),2 3 respectively. These sensory endings play an important role in regulating blood pressure, blood volume, and heart rate during adjustments to circulatory demands.
Orthotopic cardiac transplantation results in complete denervation of the donor atria and ventricles, resulting in attenuation of circulatory reflexes whose afferent or efferent limbs originate or terminate in the heart, respectively. Efferent reinnervation, both sympathetic and parasympathetic, has been demonstrated in the canine transplant model within 6 months after transplantation,4 but studies examining human sympathetic reinnervation have yielded conflicting results.5 6 7 8 9 Investigation of reinnervation of cardiac afferents has been limited. Studies in canines early after autotransplantation (<24 months) found no evidence for reinnervation, while late studies (8 to 12 years after) raised the possibility of reinnervation based on the partial return of cardiac depressor reflexes, which require functioning cardiac vagal afferents.10 Although the possibility of sympathetic afferent reinnervation has been raised by reports of typical angina and angina-like chest pain in cardiac transplant patients with documented graft atherosclerosis,11 12 to date no systematic studies have investigated whether reinnervation of cardiac vagal afferents occurs after human orthotopic cardiac transplantation.
The purpose of this study was to determine if reinnervation of chemosensitive endings subserved by cardiac vagal afferents (endings connected to the central nervous system by fibers running alongside vagal fibers) occurs after human orthotopic cardiac transplantation. To do this, we investigated the cardiac depressor reflex (Bezold-Jarisch reflex), whose afferent limb originates with vagal afferent chemosensitive endings in the cardiopulmonary region.1 13 Stimulation of these endings in normally innervated ventricles induces reflex vagal activation and sympathetic withdrawal, resulting in heart rate slowing and a decrease in blood pressure. This depressor reflex is commonly observed during coronary angiography with the use of the radiographic contrast agent meglumine diatrizoate14 15 and during inferior myocardial infarction.16
Our objective was to determine if the afferent limb of the cardiac depressor reflex was intact after cardiac transplantation. To do this, we capitalized on the fact that the efferent limb of this reflex to the recipient sinus node (RSN) located in the atrial remnant remains intact in cardiac transplant patients. This is the result of the surgical procedure currently used for orthotopic cardiac transplantation,17 which leaves innervation (both afferent and efferent) to the recipient or remnant atria including the RSN intact. Thus, the RSN may respond to changes in sympathetic or vagal tone. Given this anatomy, we reasoned that by stimulating chemosensory endings in the donor ventricles with radiographic contrast and determining the response of the innervated RSN, we could evaluate whether innervation to chemosensory endings subserved by vagal afferents had returned. Thus, a reflex decrease in the rate of the RSN in response to contrast injection would suggest that connections to ventricular chemosensitive endings would be present. Because it is unclear whether and to what degree reinnervation had occurred to the donor sinus node (DSN) (sinus node controlling the transplanted heart rate), assessing its response to contrast injection could not yield information regarding the afferent limb of the depressor reflex and therefore whether reinnervation to chemosensory endings had occurred.
Thirty-six cardiac transplant patients and 18 control patients were studied during routine coronary arteriography for evaluation of possible coronary artery disease. The study protocol was approved by the Human Subjects Review Committee of the Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, and written informed consent was obtained from all patients participating. Eighteen cardiac transplant patients <24 months after transplantation (mean, 12.1±1.7 months; range, 1 to 24 months) comprised an “early group,” and an equal number of patients >43 months after transplantation (mean, 55.3±2.1 months; range, 43 to 74 months) comprised a “late group” (Table 1⇓). All three groups were without significant epicardial coronary artery disease, and left ventricular ejection fractions were normal. Cardiac allograft rejection was excluded in transplant patients by right ventricular endomyocardial biopsy obtained at the time of catheterization. Patients studied were not taking β-adrenergic–blocking agents and were without neurological or other diseases that would influence autonomic neural function. All cardiac transplant patients were receiving cyclosporine, and 35 were receiving azathioprine. Seventeen patients in the early group were receiving prednisone, while only 6 patients in the late group were receiving this medication. Thirty-two were receiving a calcium channel blocker, 7 enalapril or captopril, 2 hydrochlorothiazide, and 12 furosemide.
In the control group, the heart rate was measured by surface ECG. In the cardiac transplant groups, the RSN rate was determined by recording the recipient right atrial ECG, with a right atrial intracavitary electrode positioned posteriorly. The DSN rate (actual transplant heart rate) was determined from the surface ECG. The recipient right atrium is electrically isolated from the donor (transplanted) atrium and its sinus node, thereby allowing independent measurement of RSN and DSN rates. Eight cardiac transplant patients initially screened for study were observed to have atrial flutter or fibrillation in the remnant atrium and were excluded. Systemic arterial pressure was measured by a femoral artery catheter with the use of saline-filled pressure transducers (Abbott Critical Care Systems). All signals were displayed on a monitor/strip chart recorder (PPG Biomedical VR-12) and recorded at a paper speed of 50 mm/s.
Cardiac catheterization was performed in all patients in the fasting state after premedication with diphenhydramine 50 mg IV. Each patient was instrumented, and selective left coronary artery (LCA) and right coronary artery (RCA) coronary arteriography was then performed by standard Judkins technique. A premeasured volume of meglumine diatrizoate (Renografin-76, Squibb Diagnostics) was used for each injection (5 to 10 mL, depending on arterial distribution). Measurements were recorded continuously, beginning with a 10-beat baseline period before each injection, during injection, and then after injection for approximately 25 seconds. Patients were instructed to breathe normally during each injection period. One early transplant patient and four control patients were observed to have left dominant coronary circulations with small right coronary arteries. Therefore, only left coronary injections were used for analysis in these patients.
For a given injection, baseline mean arterial pressure (MAP) (calculated by adding one third of the pulse pressure to the diastolic pressure) and heart rate in control patients or RSN (AA interval) and DSN rate (RR interval) in cardiac transplant patients were measured as the average during the 10-beat preinjection period. These baseline values were compared with the maximum change occurring in these parameters during contrast injection. The time for the maximum changes to occur from the start of injection was also measured.
Changes in parameters from baseline to injection within groups were tested for statistical significance by paired t test. One-way ANOVA was used to assess the changes from baseline among groups. Estimate of the relation between the change in recipient sinus rate during contrast injection and time after cardiac transplantation was determined by calculation of Pearson correlation coefficients.
Baseline values for the control group and the two groups of cardiac transplant patients are displayed in Table 1⇑. MAP was elevated in the transplant groups compared with the control group, probably secondary to immunosuppressive therapy with cyclosporine. RSN rates in the transplant groups were similar to control heart rates, whereas DSN rates were elevated compared with control, reflecting a diminution of vagal tone in the transplant groups.
An illustration of a typical recording from a transplant patient during data collection is shown in Fig 1⇓. Fig 1A⇓ shows a baseline recording just before contrast injection, and Fig 1B⇓ shows a recording during contrast injection. Note that compared with baseline, the recording during injection shows a drop in systemic arterial pressure, an increase in the DSN RR interval, and a decrease in the RSN AA interval.
Responses of Recipient Sinus Node to Contrast Injection
Fig 2⇓ and Table 2⇓ display the maximum change in MAP in response to coronary contrast injection. Significant decreases in MAP occurred in all groups. This decrease was similar in both early and late transplant groups but was less than that observed in the control group. The time to the maximum decrease in MAP was slightly longer in the control group compared with the transplant groups (Table 2⇓).
Fig 3A⇓ and Table 2⇑ display the maximum change in RSN rate for both transplant groups compared with the maximum change in control heart rate during coronary contrast injection. As expected, there was a sizeable and significant decrease in heart rate in the control group, reflecting engagement of the Bezold-Jarisch reflex from stimulation of ventricular chemosensory endings. The RSN rate in both transplant groups, however, did not slow but was observed to increase in response to contrast injection. This was true for the response in all transplant patients except for one in the late group (Fig 4B⇓). For this patient, a decrease in RSN rate was seen for injection of the RCA only, and this was minimal at −2 beats per minute (bpm) compared with the 5-bpm increase observed with left coronary injection for this patient. As with the MAP responses, RSN responses were similar in both cardiac transplant groups. The time to the maximum increase in RSN rate was similar in both transplant groups but was slightly longer (approximately 2 seconds) compared with the time observed to the maximum decrease in heart rate for the control group. The time to the maximum increase in RSN rate was in all cases 1 to 2 seconds longer than the time to the maximum decrease in MAP for both transplant groups.
Responses of Donor Sinus Node to Contrast Injection
Fig 3B⇑ and Table 2⇑ display the maximum change in DSN rate in the transplant group compared with the change in control heart rate in response to coronary contrast injection. Similar slowing occurred in both transplant groups, and this was significantly less than in the control group. The time to the maximum slowing of the DSN was similar in both transplant groups. Compared with slowing of the control sinus node, this time was slightly longer for left coronary injections but similar for right coronary injections.
Responses Relative to Time After Transplantation
Fig 4⇑ displays the change in RSN rate during injection as a function of the time after transplantation for a given patient in the early and late groups, respectively. Although the correlation was better for the late group (r=−.43) compared with the early group (r=−.21), neither correlation was significant (P>.05).
Sensory endings are prevalent throughout the cardiopulmonary region; they are subserved by fibers associated with parasympathetic (vagal afferent fibers) and sympathetic (sympathetic afferent fibers) nerves and may be myelinated or nonmyelinated. Our experiments were specifically directed to address whether ventricular chemosensory endings subserved by nonmyelinated nerve fibers associated with the vagus nerve had functionally reinnervated. The results from our study suggest that reinnervation of these fibers is unlikely up to 74 months after cardiac transplantation.
Previous investigations1 2 using direct neural recordings of action potentials from these fibers have confirmed the existence of two types of vagal sensory endings, chemosensitive and mechanosensitive, which respond to chemical stimulation and mechanical deformation, respectively. Reflex responses mediated by these endings have been studied extensively and support the view that these endings contribute importantly to cardiopulmonary reflex control of the circulation.1 16 18 Thus, it is clinically relevant to determine if reinnervation of ventricular sensory endings occurs after cardiac transplantation.
Cardiopulmonary chemosensitive endings may be activated by exposure to irritant chemicals such as capsaicin and phenyl diguanide as well as by iodinated contrast agents used in coronary arteriography.2 Chemosensitive endings are also stimulated by prostaglandins3 and bradykinin,19 which are naturally occurring endogenous substances. When left ventricular endings of this type are stimulated, powerful cardioinhibitory and vasodepressor responses occur involving both augmentation of parasympathetic and withdrawal of sympathetic outflow from central vasomotor centers. For these reflexes (termed cardiac depressor or Bezold-Jarisch reflexes13 ) to be observed, both the afferent limb (vagal afferents from sensory endings) and the efferent limb (sympathetic and vagal efferents to the heart and blood vessels) of the reflex arc must be intact.
The technique of orthotopic cardiac transplantation removes the recipient ventricles and portions of the atria, leaving only remnants of the atria. The great vein-atrial junctions and notably the RSN remain in situ,17 and it has been shown that efferent innervation to the RSN remains intact.20 Thus, the donor ventricles and DSN are denervated, whereas the atrial remnants including the RSN remain innervated. Immediately after cardiac transplantation, the afferent limb of the cardiac depressor reflex is interrupted, but the efferent limb to the RSN remains intact. To detect whether ventricular chemosensory endings subserved by vagal afferent fibers reinnervate, we investigated the response of the cardiac depressor reflex. We hypothesized that if reinnervation had occurred, then stimulation of ventricular chemosensory endings by coronary injection of radiographic contrast would result in slowing of the RSN and a fall in systemic arterial blood pressure.
In this study, coronary injection with meglumine diatrizoate evoked the expected decrease in heart rate and blood pressure in the control group (Figs 2⇑ and 3⇑ and Table 2⇑). In contrast, the RSN rate in the transplant patients failed to decrease but instead increased during coronary injection. Arterial blood pressure decreased, but this fall was about half that observed in the control group. There were similar changes in both blood pressure and RSN rate for both the early and late cardiac transplant groups. Examination of the data for individual patients demonstrates that with the exception of one patient as described in “Results,” in no patients did the RSN rate decrease with coronary injection (Fig 4⇑).
We considered the possibility that as time after transplantation lengthened, the increase in RSN rate observed with contrast injection might diminish. This could be interpreted as an increased influence of cardiac depressor reflexes on the RSN and would suggest a degree of reinnervation of ventricular chemosensory endings subserved by vagal afferents. Our results for the late group of transplant patients (Fig 4B⇑) suggest a possible trend in this direction, but the correlation was weak (r=−.43) and not significant. For the early group, the correlation was weaker (r=−.21) (Fig 4A⇑). Overall, these data strongly suggest that reinnervation of ventricular chemosensory endings subserved by vagal afferents is unlikely even in the long term (up to 74 months) after cardiac transplantation.
The results of this study confirm the results of a previous study from our institution that was designed to determine if the bradycardia and hypotension produced during engagement of the cardiac depressor reflex in humans was mediated through stimulation of ventricular chemosensitive endings.14 Although this hypothesis had been tested in animals, it had not been possible to test directly in humans, since this would require selective interruption of ventricular afferents. Cardiac transplantation provided a situation in which ventricular afferents were interrupted. This previous study tested only transplant patients <2 years after transplant (mean, 17±3 months) because ventricular deafferentation was a requirement. The present study, designed to examine whether reinnervation of ventricular chemosensory endings occurred after cardiac transplantation, extends the observations of the previous study by not only examining responses in an early group of transplant patients but also a late group of patients >43 months after cardiac transplantation. As noted above, the responses in both groups were similar, confirming the results of the previous study and providing evidence against reinnervation up to 74 months after cardiac transplantation.
It was of interest that the RSN rate in the cardiac transplant groups increased in response to contrast injection. Given the decline in blood pressure observed, it is postulated that this increase in rate was mediated mainly through arterial baroreceptor influences in the absence of cardioinhibitory influences from ventricular chemosensory endings. This is suggested by the time to the maximum change in blood pressure and heart rate data shown in Table 2⇑. The maximum increase in the RSN rate occurred after the maximum decrease in blood pressure, suggesting a cause-and-effect relation. In contrast, in the control group, the maximum decrease in heart rate was achieved before the maximum decrease in blood pressure, in keeping with the concept that this heart rate decrease was mediated directly through the cardiac depressor reflex.
Slowing of the DSN in both cardiac transplant groups was observed in response to coronary contrast injection but was significantly attenuated compared with control (Fig 3B⇑). In the absence of the afferent limb of the depressor reflex, due to denervation it is likely that this slowing was mediated through a direct depressant effect of contrast on the DSN. Eckberg et al21 observed a similar attenuation in cardiac slowing during contrast injection after efferent limb blockade with atropine as well as after direct injection of contrast into the artery supplying the sinus node.22 It was suggested that these direct effects appear to be mediated by the increased osmolarity of the contrast agent.22
MAP responses in both early and late cardiac transplant groups in response to contrast injection were attenuated compared with controls and also provide evidence against reinnervation of ventricular chemosensory endings. The postulated mechanism for the blood pressure decrease observed with intact cardiac innervation is through reflex sympathetic withdrawal and vasodilation of peripheral vessels as part of the cardiac depressor reflex.23 24 Studies suggesting this mechanism were done in isolated, perfused skeletal muscle beds in experimental animals. While this may be contributory, it is likely that the decrease in cardiac output that accompanies the bradycardic response contributes to the decrease in blood pressure as well. We speculate that the small decrease observed in the donor heart rate with contrast injection coupled with the negative inotropic effects of contrast on myocardium with limited sympathetic support accounted for the decrease in blood pressure observed in the cardiac transplant patients. It is unlikely that reinnervation of chemosensory endings accounted for the decrease in blood pressure in the absence of a bradycardic response in the RSN.
There have been limited investigations examining reinnervation of cardiac vagal afferents after cardiac transplantation. After cardiac autotransplantation in dogs <24 months after transplantation, plasma renin responses to hemorrhage were attenuated compared with control animals, suggesting the absence of ventricular vagal afferent reinnervation to mechanosensitive endings.25 In another set of experiments to elicit the cardiac depressor reflex, injection of cryptenamine into the left ventricle resulted in characteristic bradycardia and hypotension in only one of four dogs tested, remotely raising the possibility of vagal afferent reinnervation to chemosensitive endings.25 In a later series of experiments, Mohanty et al10 were able to examine these reflexes in three dogs 8 to 12 years after cardiac autotransplantation. With injection of cryptenamine into the left ventricle, MAP and renal nerve activity responses were markedly impaired in short-term autotransplanted dogs (6 to 8 weeks after) but were improved in the long-term group. Responses in the long-term group, however, remained attenuated compared with sham-operated dogs with intact innervation.10 To the best of our knowledge, there have been no published studies in humans that have addressed whether reinnervation of cardiac vagal afferents occurs after cardiac transplantation. Preliminary results from our institution investigating the function of mechanosensory endings subserved by vagal afferents after cardiac transplantation suggest improved responses late after transplantation but only in certain patients.26
Limitations of the Study
Meglumine diatrizoate has been shown to stimulate ventricular chemosensory endings,2 and in turn that stimulation of these endings activates cardiac depressor reflexes.1 13 We questioned whether the amount of contrast used provided an adequate stimulus to these endings and also whether the sensitivity of the method used (measuring responses of cardiac depressor reflexes) was adequate for detecting reconnection of these endings with the central nervous system. These questions have not been previously investigated in humans; however, all of the control patients studied had substantial bradycardic responses and decreases in blood pressure with contrast injection. Since similar amounts of contrast were used in the cardiac transplant patients, we reasoned that chemosensory endings were stimulated adequately and that there would be few false-negatives with this method.
It is known that cyclosporine treatment is accompanied by sustained sympathetic activation, which may be accentuated by cardiac denervation.27 An additional concern was that cyclosporine might attenuate cardiac depressor reflex function, resulting in the negative responses we observed. This has not been investigated directly in humans; however, three lines of available evidence suggest that this is unlikely, considering that the afferent and efferent limbs of this reflex depend on sensory endings subserved by vagal afferent fibers and parasympathetic activation, respectively. First, baseline parasympathetic activity has been investigated after cardiac transplantation and was found to approach that in healthy, normally innervated subjects, particularly if hypertension is controlled.28 Second, vagally mediated decreases in the RSN rate in cardiac transplant patients after baroreflex activation with intravenous phenylephrine injection were found to be no different than responses in normal subjects.20 28 Third, we have previously shown that after renal transplantation, patients have normal cardiopulmonary baroreflex responses. These depend primarily on ventricular mechanosensitive endings, which are subserved by vagal afferents.29 Since the patients referred to in the studies above were all given cyclosporine, these data suggest that both the afferent and efferent limbs of the cardiac depressor reflex are capable of functioning normally in the presence of this drug. Therefore, it seems unlikely that cardiac depressor reflex function would be attenuated by cyclosporine.
Last, 18 cardiac transplant patients in the late group were studied. Although none exhibited responses suggesting any degree of return of cardiac depressor reflex function, these data suggest but do not prove that reinnervation of ventricular chemosensitive endings subserved by vagal afferents cannot occur after cardiac transplantation. Reinnervation of vagal afferents may occur in patients >74 months after transplantation compared with the patients studied here; however, confirmation of this supposition would require additional study. The data presented in this study suggest that ventricular chemosensory endings subserved by vagal afferents do not reinnervate to any significant degree up to 74 months after transplantation.
This study was supported in part by the American Heart Association (Virginia Affiliate), Research Award VA-91-G-38, and Medical College of Virginia Clinical Research Center, National Institutes of Health Grant M01-RR-00065. The authors thank Karla Conway and Michelle Martin for typing the manuscript; the staff of the cardiac catheterization laboratories at the Medical College of Virginia and McGuire Veterans Affairs Medical Center for their assistance with testing; and Gilda C. Sneed, RN, Mary W. Baldecchi, RN, BSN, and Jo Ann Mitterer, Cardiopulmonary Transplantation, for assistance with recruiting.
- Received August 23, 1994.
- Revision received January 23, 1995.
- Accepted January 23, 1995.
- Copyright © 1995 by American Heart Association
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