(Circulation. 1995;92:402-408.)
© 1995 American Heart Association, Inc.
Articles |
Evidence Against Reinnervation of Cardiac Vagal Afferents After Human Orthotopic Cardiac Transplantation
From Medical College of Virginia, Virginia Commonwealth University and Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Va.
Correspondence to James A. Arrowood, MD, Medical College of Virginia, PO Box 980051, Richmond, VA 23298.
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Abstract |
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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.
Key Words: afferent • transplantation • reflex • vagus nerve • ventricles
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Subjects
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
ß-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.
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Measurements
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.
Protocol
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.
Data Analysis
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.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Baseline Parameters
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.
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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).
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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.
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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).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Acknowledgments |
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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.
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