Acute arterio-venous fistula occlusion decreases sympathetic activity and improves baroreflex control in kidney transplanted patients

Sonia Velez-Roa1, Jolanta Neubauer1, Martin Wissing2, Alberto Porta3, Virend K. Somers4, Philippe Unger1 and Philippe van de Borne1

1Department of Cardiology, Erasme-ULB University Hospital, Brussels, 2Department of Nephrology, Erasme-ULB University Hospital, Brussels, Belgium, 3Department of Preclinical Science, University of Milan, Milan, Italy and 4Division of Cardiovascular Diseases and Division of Hypertension, Mayo Clinic, Rochester, USA

Correspondence and offprint requests to: Sonia Velez-Roa, MD, Department of Cardiology, Erasme Hospital, 808 Lennik Road, B-1070 Brussels, Belgium. Email: pvandebo{at}ulb.ac.be



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The acute bradycardia induced by the occlusion of an arteriovenous fistula (AVF), known as the Nicoladoni-Branham sign, is considerably larger than that which occurs during carotid sinus massage. This suggests increased arterial baroreflex sensitivity during acute AVF occlusion. Moreover, the influence of acute AVF occlusion on muscle sympathetic nerve traffic (MSNA, by microneurography) is unknown. We therefore assessed the effects of acute AVF occlusion on baroreflex sensitivity and on MSNA in patients with stable functional kidney grafts and patent AVF.

Methods. We measured blood pressure (BP), MSNA (n = 11), heart rate (HR), cardiac output (CO) and arterial baroreflex sensitivity (n = 18) at baseline and during acute, 30-s pneumatic AVF occlusions in 23 renal transplanted recipients.

Results. During the first 5 s of the AVF occlusion, mean BP increased from 98±4 to 112±4 mmHg (P<0.0001) while MSNA decreased to 28±5% of baseline values (P<0.0001) and HR decreased from 71±3 to 61±3 b.p.m. (P<0.0001). The largest increases in BP were accompanied by the most marked decreases in MSNA (r = –0.79, P = 0.003) and HR (r = –0.49; P = 0.01) during the first 5 s of the AVF occlusion. During AVF occlusion baseline CO of 6.9±0.3 decreased to 5.6±0.3 l/min (P<0.0001) while baroreflex sensitivity increased from 10±1 to 17±2 ms/mm Hg (P<0.001).

Conclusions. Arterial baroreceptor activation and increased arterial baroreflex sensitivity decrease heart rate during AVF occlusion. In addition, our study is the first to demonstrate that arterial baroreflex activation decreases sympathetic nerve traffic during the Nicoladoni-Branham sign.

Keywords: autonomic control; kidney transplant; Nicoladoni-Branham sign



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The haemodynamic changes induced by temporary arteriovenous fistula (AVF) occlusion are important predictors of the favourable cardiac effects of a surgical AVF closure [1,2], but are not well understood. The acute bradycardia induced by sudden occlusion of an AVF is known as the Nicoladoni-Branham sign [3] and may provide important clinical information on the haemodynamic significance of an AVF [4]. This increase in RR interval is mediated by the vagus nerve because it is suppressed by atropine [5]. However, the exact underlying mechanism responsible for this vagal activation is not well understood. Indeed, the increase in RR interval observed during acute AVF occlusion is considerably larger than that which occurs during carotid sinus massage [6]. We, therefore, hypothesized that arterial baroreflex sensitivity increases during AVF occlusion, and we assessed baroreflex sensitivity during acute AVF occlusions as well as during spontaneous fluctuations in arterial blood pressure (BP) at rest.

Peripheral sympathetic activity is under both high- and low-pressure baroreflex control [7]. Acute AVF occlusion increases BP and decreases cardiac venous return [8,9]. The vasomotor centre will, therefore, receive opposite messages: the high-pressure baroreceptors, activated by the increase in BP, will produce bradycardia and exert an inhibitory influence on sympathetic nerve traffic, while the deactivation of low-pressure baroreceptors, by the decrease in cardiac venous return, will suppress their inhibitory influence on sympathetic nerve traffic and produce vasoconstriction [7,10]. The final integrated response elicited by both reflexes on peripheral sympathetic traffic is unknown. Microneurography allows direct measurement of the sympathetic nerve traffic directed to muscle circulation (MSNA) and is particularly valuable for dynamic measurements of peripheral sympathetic nerve activity [10]. We, therefore, assessed the effects of acute AVF occlusion on MSNA in patients with stable functional kidney grafts and patent AVF.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
Twenty-three renal transplant recipients aged 46±3 years (mean±SEM, 13 male, 10 female) with patent AVF (radiocephalic n = 14, brachiocephalic n = 8, femorosaphenous n = 1) participated in the study. All were in sinus rhythm. Mean time after transplantation was 55±9 months. Immunosuppression was achieved by combinations of cyclosporine (n = 15), tacrolimus (n = 6), azathioprine (n = 7), mycophenolate mofetil (n = 11), hydrocortisone (n = 11) and prednisolone (n = 6). Plasma levels of cyclosporine, mycophenolate and tacrolimus were within the therapeutic ranges in all the patients: 129±11 ng/ml (normal: 50–275 ng/ml); 4.3±1.3 µg/ml (normal: 2–5 µg/ml) and 9.3±0.6 ng/ml (normal: 6–15 ng/ml), respectively. All patients had stable renal function (mean serum creatinine of 1.6 mg/dl; range: 1.1–3.0 mg/dl). Sixteen patients received antihypertensive medications, namely angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (n = 8), diuretics (n = 6), beta-blockers (n = 10), calcium antagonists (n = 6) or central antihypertensive therapy (n = 1).

The Institutional Human Subjects Review Committee of the Erasme Hospital approved the study and informed consent was obtained from each patient.

Measurements
BP was measured with a Physiocontrol Colin BP-880 sphygmomanometer, and was also recorded continuously at the finger level using a volume oscillometric method (Finapres). The cuffed finger was kept at heart level during the entire recording procedure. BP recordings were performed on the arm without the AVF. Finger BP, RR interval (Siemens), respiration (Respitrace) and MSNA were recorded online on a Compaq 386/25 E computer and on a Power Macintosh with a MacLab 8/s data acquisition system (AD instruments) for subsequent analysis [1,11]. Cardiac echocardiographic studies were performed using an Agilent Technology Sonos 5500 ultrasound system with standard S3 imaging transducer. The measurements were performed according to the recommendations of the American Society of Echocardiography [12]. Left ventricular outflow tract diameter was measured using two-dimensional echocardiography. Doppler echocardiography allowed measurement of stroke volume and cardiac output (CO) at the level of the left ventricular outflow tract [12]. Fistula flow was not directly measured, but was estimated through the decrease in CO during occlusion. Indeed, previous observations have shown that this decrease correlates with fistula flow and this parameter has been used as a substitute for direct fistula flow measurement [8,13]. Total peripheral resistance (TPR) was calculated from CO (l/min) and mean arterial BP (MBP, mmHg) using the following formula: TPR = 80 * MBP/CO (dyne * s * cm–5).

Sympathetic nerve activity to the muscle circulation was recorded continuously by obtaining multiunit recordings of postganglionic sympathetic activity, measured from a nerve fascicle in the peroneal nerve posterior to the fibular head [12]. Electrical activity in the nerve fascicle was measured using tungsten recording microelectrodes (shaft diameter 200 µm, tapering to a non-insulated tip of 1–5 µm). A subcutaneous reference electrode was inserted 2–3 cm away from the recording electrode. The neural signals were amplified, filtered, rectified and integrated to obtain a mean voltage display of sympathetic nerve activity.

Protocol and interventions
All recordings were obtained at the same time of the day in carefully standardized conditions after a 15 min period of rest. Studies were conducted in the same room by the same investigator with subjects under quiet, resting, supine conditions. All measurements were obtained during relaxed free breathing. Patients did not talk during the recordings. Subjects were closely watched to prevent any drowsiness or sleeping during the recordings. Baseline recordings obtained for 20 min were followed by a sudden occlusion of the AVF using a sphygmomanometer cuff inflated 50 mmHg above systolic BP (SBP) for 30 s (Figure 1). This pressure was shown in preliminary experiments to offset any increase in BP induced by the occlusion of the AV shunt. We performed three AVF occlusions and the data presented are the average of the occlusions. A recovery period of 2 min was allowed between two occlusions.



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Fig. 1. Representative recording of BP, neurogram and MSNA and electrocardiogram tracings during AVF occlusion in a patient. Fistula occlusion (upward arrow) induces a sustained increase in BP. Subsequent baroreflex activation produces an increase in RR interval (from 767 to 877 ms), and MSNA inhibition that is most marked during the five first seconds of AVF occlusion, corresponding to the period of highest increase in BP. CO decreases from 10.0 to 7.9 l/min. The downward arrow indicates the end of the occlusion.

 
Analysis
Technically excellent studies examining the effects of acute AVF occlusion on MSNA were obtained in 11 patients. MSNA was expressed as frequency (burst/min) and as integrated activity (burst frequency * mean amplitude, in arbitrary units, a.u.) [14]. Moreover, changes in integrated MSNA activity were expressed as per cent changes of baseline values [14,15].

Stroke volume, CO and TPR were determined 1 min before the pneumatic occlusion. These measures were then repeated 20 s after the onset of the AVF occlusion, in order to largely exceed the time needed for transmission of changes in right ventricular venous return into modifications in left-ventricular output [16].

Analogue-to-digital conversion was performed at 300 samples/s for the electrocardiogram, BP and respiratory signals in 23 patients. Five out of these 23 recordings could not be analysed due to technical limitations. Arterial baroreflex sensitivity was determined by the sequence method [1,11,13]. Briefly, the time series of BP and RR interval were scanned to identify sequences in which BP and RR interval concurrently increased or decreased over three or more beats [1,11,13]. We used the standard thresholds of 1 mmHg for the variation in BP and 5 ms for the variation in RR interval, and a correlation coefficient for the linear regression between BP and RR interval values >0.85 [1,11,13] for the determination of baroreflex sensitivity. Arterial baroreflex sensitivity was determined during AVF occlusion and compared with baseline values.

Statistical analysis
Results are expressed as mean±SEM. Statistical analysis was performed using Student's paired and unpaired t-test (two-tailed). Changes in BP, MSNA and heart rate (HR) during successive 5 s periods of AVF occlusion were analysed using a multiple ANOVA for repeated measures. A linear regression analysis determined if changes in BP affected HR and MSNA during the acute AVF occlusion. Significance was assumed at P<0.05.



   Results
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 Abstract
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 Subjects and methods
 Results
 Discussion
 References
 
The increase in MBP elicited by the interruption of blood flow through the AVF remained significant during the 30 s period of the occlusion (from 98±4 to 111±4 mmHg, Figures 1 and 2, ANOVA P<0.0001). This increase in MBP was followed by a 30-s reduction in MSNA (from 40±5 to 31±6 burst/min, while MSNA amplitude decreased to 65±8% of the baseline value, both ANOVA P<0.01) and HR (from 71±3 to 63±3 b.p.m., ANOVA P<0.0001). The relative changes in integrated MSNA were more pronounced than those in HR during the five first seconds of the occlusion (HR decreased from 71±3 to 61±3 b.p.m., while sympathetic activity decreased from 40±5 to 15±4 burst/min, and MSNA amplitude decreased to 28±5% of baseline values, all P < 0.001). Antihypertensive therapy and immunosuppression did not affect the BP and HR responses to the fistula occlusion (ANOVA P >= 0.30).



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Fig. 2. Reductions in heart rate (HR, ANOVA P<0.001) and MSNA (ANOVA P = 0.0002) and increase in mean BP (MBP, ANOVA P<0.0001) in response to the AVF occlusion.

 
The largest relative increases in MBP upon AVF occlusion were accompanied by the most marked relative decreases in both integrated MSNA (r = –0.75 for burst/min and r = –0.79 for MSNA amplitude, both P < 0.01) and HR (r = –0.49; P = 0.01) during the five first seconds of the fistula occlusion (Figure 3).



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Fig. 3. The largest increases in MBP ({triangleup} = absolute changes from baseline values) are accompanied by the most marked decreases in both HR [{triangleup} = absolute changes from baseline values, left panel, r = –0.49, P = 0.01 (n = 23)] and integrated MSNA [{triangleup} = percentage changes from baseline values, right panel, r = –0.79, P = 0.003 (n = 11)] during the five first seconds of the AVF occlusion.

 
CO decreased from 6.9±0.3 to 5.6±0.3 l/min upon AVF occlusion, while TPR increased from 1183±72 to 1690±113 dyne * s* cm–5 (both P<0.0001).

Arterial baroreflex sensitivity increased from 10±1 ms/mmHg at baseline to 17±2 ms/mmHg during the AVF occlusion (Figure 4, P<0.001). Baroreflex sensitivity at baseline and the changes in response to AVF occlusion did not differ between patients treated by cyclosporine and tacrolimus (ANOVA P >= 0.15).



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Fig. 4. AVF occlusion increases arterial baroreflex sensitivity, P<0.001. Illustration of individual responses and mean±SEM changes for the entire group (n = 18).

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our study reveals that the rise in BP during AVF closure activates the arterial baroreflex and thereby decreases both sympathetic nerve traffic and heart rate. Moreover, we demonstrate that AVF occlusion increases arterial baroreceptor sensitivity. This is the first study, to the best of our knowledge, on sympathetic nerve traffic and arterial baroreceptor sensitivity control in patients with AVF.

The autonomic changes in response to AVF occlusion were believed previously to be mediated only by changes in cardiac vagal activity [5] because no attempts to measure sympathetic nerve traffic had been made. In addition, there are no studies on the interrelationship between changes in BP upon temporary AVF closure and the HR and sympathetic responses. Our study reveals that AVF occlusion induces a marked peripheral sympathetic inhibition that parallels the bradycardic response to the BP rise induced by the AVF occlusion. Moreover, arterial baroreflex activation elicited by the rise in BP during AVF occlusion appears to be an important determinant of both HR and sympathetic responses, particularly during the initial phases of the AVF occlusion where the largest rises in BP are accompanied by the most pronounced MSNA inhibition and bradycardia.

Renal transplantation improves [17] but does not normalize [18] arterial baroreflex sensitivity. Baseline arterial baroreflex sensitivity was only 10±1 ms/mmHg in our patients, and was markedly improved by the acute AVF occlusion.

The mechanisms responsible for the rise in arterial baroreflex gain in our study are, however, unclear: AVF occlusion markedly decreased CO, while TPR increased, as reported previously [8,9]. In the clinical setting, hypotension and hypovolaemia often occur together so that the arterial and cardiopulmonary baroreceptors are deactivated simultaneously. In contrast, the occlusion of an AVF affects the low- and high-pressure baroreceptors in opposite directions as it unloads the cardiopulmonary baroreceptors by a sudden reduction in cardiac venous return of almost 1.5 l/min, but activates the arterial baroreceptors by a rapid increase in arterial BP. Thus, our observation of increased arterial baroreceptor sensitivity could be due to a removal of the inhibitory influence of the cardiopulmonary baroreceptors on the arterial baroreceptors during the AVF occlusion [19]. However, the sequence method used to assess baroreflex control in our study is strongly affected by cardiac vagal drive because the sequences almost disappear following atropine injection [6]. The sequence technique shares an important variance with cardiac vagal tone and our findings may simply reflect a large increase in cardiac vagal control during the AVF occlusion [6].

Hausberg et al. demonstrated that sympathetic nerve activity remains elevated after kindney transplantation [20] to levels similar to those we observed in our study. It is of interest that these patients can still manifest substantial sympathetic nerve inhibition during AVF occlusion. This finding suggests that the arterial baroreceptors are stronger modulators of peripheral sympathetic drive than the cardiopulmonary baroreceptors during AVF closure, because the reduction in cardiac venous return did not override the sympathetic inhibition produced by the rise in systemic BP. However, the limited rise in MSNA observed at the end of the AVF occlusion could be related to the deactivation of the low-pressure cardiopulmonary baroreceptors, partially counteracting arterial baroreflex activation [10].

AVF used for haemodialysis often remain patent after kidney transplantation [1,2]. Whether these patent fistulas contribute to the heightened sympathetic drive [20] and the impaired baroreflex sensitivity [1617] of kidney transplanted patients is not known and will need further studies.

In conclusion, our study in patients with kidney transplants is the first to reveal that an acute AVF occlusion decreases sympathetic nerve traffic. Moreover, we also report that acute occlusion of the AVF increases arterial baroreceptor gain. Further studies are needed to determine if surgical AVF closure may induce sustained reductions in sympathetic activity and chronic improvements in arterial baroreceptor gain after kidney transplantation.



   Acknowledgments
 
We are indebted to Dr Karen Pickett for editorial assistance and to Françoise Pignez for the drawing of the Figures. This study was supported by the Erasme Foundation, Belgium (S.V.-R.), the National Fund for Research, the Marc Hurard Foundation and the Foundation for Cardiac Surgery, Belgium (P.v.d.B.). J.N. was supported by Pfizer and AstraZeneca Inc. V.K.S. is an Established Investigator of the American Heart Association and is also supported by NIH HL61560, HL65176 and RR00585.

Conflict of interest statement. There is full disclosure of any potential conflict of interest.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 6. 6.03
Accepted in revised form: 17.12.03





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