Role of Sympathetic Nervous System in
Cyclosporine-Induced Rise in Blood Pressure
Mario J. Carvalho, Anton H. van den Meiracker, Frans Boomsma, Joao Freitas, Arie J. Man in ‘t Veld,
Ovidio Costa, Antonio Falcão de Freitas
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Abstract—To clarify the role of the sympathetic nervous system in the development of cyclosporine A (CsA)-induced rise
in blood pressure (BP), the effects of CsA on 24-hour ambulatory BP (ABP) were studied in patients with familial
amyloid polyneuropathy (FAP) who underwent a liver transplantation. On the basis of autonomic function tests, patients
with absent or mild-to-moderate sympathetic damage (Group A, n511, age 29 to 43 years, disease duration 2 to 6 years)
and patients with severe sympathetic damage (Group B, n59, age 27 to 38 years, disease duration 3 to 9 years) were
identified. Both groups were followed for 1 year. The daily doses of CsA and the CsA whole blood trough levels
between the groups did not differ. Pretransplantation values of daytime and nighttime ABP were, respectively,
11768/7667 mm Hg and 108612/6869 mm Hg in group A and 10766/6664 mm Hg (P,0.05 group A versus group
B) and 10266/6264 mm Hg in group B. In response to CsA, BP increased in all patients, but more so in patients of
group B than in patients of group A. One year after transplantation, daytime and nighttime ABP had increased by
669/3611% and 12610/14614% in group A and by 1266/13610% (P,0.05) and 21611/27621% (P,0.01) in
group B. In both groups, the increase in nighttime ABP was greater than the increase in daytime ABP, which resulted
in an attenuation or, even, a reversal of the diurnal BP rhythm. Because the rise in BP was greater in patients with more
advanced sympathetic dysfunction, the sympathetic nervous system appears to counteract the CsA-induced rise in BP
rather than causing it. This implies involvement of factors other than sympathetic activation in the pathogenesis of
CsA-induced rise in BP in patients with familial amyloid polyneuropathy. (Hypertension. 1999;34:102-106.)
Key Words: amyloid neuropathies n cyclosporine n blood pressure monitoring, ambulatory n transplantation, liver
F
amilial amyloid polyneuropathy (FAP) type I is a hereditary
autosomal dominant disease of the peripheral nervous system. The biochemical basis of the disease is a point mutation of
the plasma protein transthyretin that causes replacement of
valine by methionine at position 30.1 This mutant protein is the
major component of the deposited amyloid. The first symptoms
of FAP type I usually occur in the third or fourth decade of life,
and the disease invariably progresses to death within 7 to 15
years.2 The clinical picture of FAP type I is dominated by a
sensorimotor polyneuropathy, starting in the distal parts of the
limbs, and a progressive failure of the parasympathetic and
sympathetic nervous system (SNS).2,3 Because more than 95%
of transthyretin is produced by the liver, orthotopic liver transplantation (OLTx) is currently the preferred treatment in FAP
patients to halt the progression of the disease by eliminating the
production of the mutant protein.4
The use of cyclosporine A (CsA) as the immunosuppressive
agent in organ transplantation is associated with a high incidence of
posttransplant hypertension. For example, 1 to 2 years after liver
transplantation, a 50% to 80% incidence of hypertension has been
reported. A large proportion of these patients require antihyperten-
sive medication.5–7 It has been well established that the CsAinduced rise in blood pressure (BP) is due to an increase in vascular
resistance in both systemic and renal circulation,7–9 but the precise
pathophysiological mechanisms mediating this increase are
unknown.7
Scherrer et al, 10 by measuring muscle sympathetic nerve activity
in heart transplant recipients and in patients with myasthenia gravis,
found that CsA treatment is accompanied by a sustained activation
of the SNS, which suggests that augmented sympathetic activation
is involved in CsA-induced hypertension. However, in a number of
other human studies using various techniques to assess the activity
of the SNS, no evidence for CsA-induced sympathetic activation
could be detected.11–14
A way to obtain more information about a possible pathogenetic role of the SNS in the development of CsA-induced rise in
BP is to study the effect of CsA in patients with various degrees
of sympathetic dysfunction. We hypothesized that if a normally
functioning SNS is critical to the development of the CsAinduced rise in BP, a relatively large increase in BP could be
expected to occur in those patients with a less severe impairment
of their SNS, and a small or absent increase in BP could be
Received October 2, 1998; first decision November 4, 1998; revision accepted March 15, 1999.
From the Centro de Estudos de Função Autonomica, Hospital S. Joao, Oporto Medical School, Oporto (M.J.C., J.F., O.C., A.F.), Portugal, and the
Department of Internal Medicine I, University Hospital Dijkzigt, Erasmus University, Rotterdam (A.H.M., F.B., A.J.M.), The Netherlands.
Correspondence to Dr A.H. van den Meiracker, Department of Internal Medicine I, University Hospital Dijkzigt, Room L253, Dr Molewaterplein 40,
3015 GD Rotterdam, The Netherlands. E-mail [email protected]
© 1999 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
102
Carvalho et al
Autonomic Nervous System and Cyclosporine
TABLE 1.
Results of Autonomic Function Tests in 2 Groups of Patients With FAP Before OLTx
Parameter
Group A (n511) Group B (n59)
Change in systolic BP during tilt, mm Hg
Valsalva maneuver: overshoot phase IV: present, delayed, absent, n
Plasma norepinephrine concentration, pg/mL
20.265.0
219622
2/2/7
0/0/9
137668
21
Dose of Norepinephrine to Increase Mean BP by 30 mm Hg, ng z kg
z min
21
103
49628
178668
51623
HR response to atropine, (range), bpm
5 (0–17)
0 (0–0)
HR variability deep breathing test, (range), bpm
5 (0–12)
0 (0–0)
Group A is comprised of patients with a composite score of sympathetic damage 0 – 4. Group B, composite score
of sympathetic damage 5– 8.
expected in those patients with more severe impairment of their
SNS. To test this hypothesis, the response of 24-hour ambulatory
BP (ABP) to CsA was studied in FAP patients with more or less
severe impairment of their SNS, who had undergone OLTx.
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Methods
Patients
FAP patients who underwent OLTx in either the in São João Hospital
or Santo António Hospital, in Oporto, were studied. The diagnosis of
FAP was based on the clinical picture, a positive familial history of
FAP, the presence of the abnormal transthyretin in plasma, and a
subcutis biopsy positive for amyloid.
All patients who participated in this study had sensorimotor
polyneuropathy, but they were in good general clinical condition and
were able to stand up and walk without support. None of the patients
used BP lowering agents or other agents that could interfere with the
function of the SNS. Because severe cardiac conduction disturbances
occur frequently in FAP, all patients had received a permanent
pacemaker before transplantation. In addition, the patients underwent
a training session to get accustomed to the various autonomic
function tests. Patients were informed about the purpose and procedures of the study, and all gave written informed consent. The study
was approved by the ethics review committees of Oporto Medical
School and University Hospital Dijkzigt. In this report, the results of
investigations on the first 20 consecutive patients who survived the
OLTx for at least 1 year are presented.
Evaluation of Cardiovascular Autonomic Function
All autonomic function tests were performed during the morning in
a temperature-controlled room, before OLTx and for one year after
OLTx. We evaluated cardiovascular autonomic function 30 minutes
after insertion of a catheter (Venflon, BOC, Ohmeda AB) in one of
the forearm veins. During the studies, finger BP (Finapres BP
monitor, Ohmeda 2300) and ECG were monitored continuously, and
data were stored in a computer for off-line analysis.3
Cardiac Parasympathetic Function
Parasympathetic cardiac innervation was assessed by a deepbreathing test and an intravenous atropine infusion (0.04 mg z kg21 z
min21 for 10 minutes). For the deep breathing test, patients were
instructed to breathe deeply at 6 breaths per minute for 1 minute
while maintaining a supine position. The maximum and minimum
heart rate (HR) of each breathing cycle was measured, and the mean
of the difference between maximum and minimum HRs for the 6
cycles was used as an index of cardiac parasympathetic function. A
value of 15 bpm or higher is considered to be normal.15 For the
atropine infusion, an increase in HR of 40 bpm or higher is
considered to be normal.16
Cardiovascular Sympathetic Function
Cardiovascular sympathetic function was assessed by a head-up tilt
test, a Valsalva maneuver, a norepinephrine infusion, and the
determination of plasma-norepinephrine concentration. A 10-minute,
60° head-up tilt test was performed after patients had rested in a
supine position on a tilt-table for 30 minutes. The erect BP (minus
the first 2 minutes) and supine BP were averaged and their difference
was calculated. Just before the tilt test, blood was sampled for
determination of plasma-norepinephrine concentration. For the Valsalva maneuver, patients had to maintain an expiratory pressure of
40 mm Hg for 15 seconds by blowing through a mouthpiece and
tubing attached to a mercury manometer. Norepinephrine was
infused to assess the sensitivity of vascular a-adrenoceptors. The
starting dose was 2.5 ng z kg21 z min21. The dose was doubled every
6 minutes until mean BP increased by 30 mm Hg.3 In 6 apparently
healthy normotensive control subjects (4 men, 2 women) the mean
dose of norepinephrine needed to increase mean BP by 30 mm Hg
was 249 ng z kg21 z min21 (range, 200 –300 ng z kg21 z min21).
Scoring the Degree of Sympathetic Damage
To score the degree of sympathetic damage in individual patients, a
composite grading system was developed, taking into account the
response of systolic BP to the head-up tilt test (fall in systolic BP,5,
5 to 15, or .15 mm Hg; score 0, 1, or 2), the BP response during
phase IV of the Valsalva maneuver (overshoot present, delayed, or
absent; score 0, 1, or 2), the dose of norepinephrine needed to
increase mean BP by 30 mm Hg (.160, 80 to 160, or ,80 ng z kg21 z
min21; score 0, 1, or 2) and the baseline plasma norepinephrine
concentration (.100, 50 to 100, or ,50 pg/mL; score 0, 1, or 2).
This composite grading system denotes absence of sympathetic
damage when the sum of scores is 0 and maximal sympathetic
damage when the sum of scores is 8. The combination of the results
of the 4 tests provides a reproducible estimate of sympathetic
damage per patient. In 18 FAP patients with different degrees of
sympathetic dysfunction, the mean difference in score at an interval
of 3 months was 0.160.7. Based on the grading system, 2 groups of
patients, referred to as group A (score 0 to 4, absent or mild-tomoderate sympathetic damage) and group B (score 5 to 8, severe
sympathetic damage), were distinguished (Table 1).
24-Hour ABP Monitoring
24-Hour ABP monitoring (SpaceLabs 90207, ABP monitor) was
performed before OLTx and at intervals of 3, 6, and 12 months after
OLTx. ABP was measured at 20-minute intervals during the day (8 AM
to 11 PM) and at 30-minute intervals during the night (midnight to 7 AM).
Data Analysis
The BP and HR values stored in the computer were analyzed
beat-by-beat with AT- and MCA-Codas programs (Dataq Instruments). Plasma norepinephrine concentration was determined by
fluorimetric detection after HPLC separation.17 In 20 healthy volunteers, matched with respect to age with the FAP patients, the mean
value was 184 (range, 158 –210) pg/mL.
Data are presented as mean6SD. For comparison Student paired
and unpaired t tests were used. A value of P,0.05 was considered to
indicate statistical significance.
Results
Relevant characteristics of the 2 groups of patients are given
in Table 2. The 2 groups did not differ with respect to
number, age, body weight, supine BP, or serum creatinine
104
Hypertension
July 1999
TABLE 2. Characteristics of 2 Groups of Patients With FAP
Before OLTx
Variable
TABLE 4. Daily Oral Doses of Cyclosporine, Prednisone, and
Azathioprine in the 2 Patient Groups, 3, 6, and 12 Months
After OLTx
Group A (n511)
Group B (n59)
P
35 (29–43)
32 (27–38)
0.14
Agent
CsA mg/kg
Age, (range), y
Body weight, kg
Group A (n511)
Group B (n59)
P
52610
5667
0.34
Disease duration, (range), y
3.6 (2–6)
5.9 (3–9)
0.007
3 months
6.061.2
6.062.7
0.40
Systolic BP, mm Hg
118615
115615
0.61
6 months
5.461.4
5.462.2
0.44
0.55
12 months
4.961.7
4.461.8
0.86
3 months
0.4460.27
0.3560.06
0.33
6 months
0.2860.07
0.2960.09
0.65
12 months
0.2360.11
0.1760.09
0.17
3 months
0.9560.26
0.9660.14
0.92
6 months
0.9960.28
0.9660.14
0.86
12 months
1.0860.17
0.8660.25
0.25
Diastolic BP, mm Hg
71614
68610
HR, bpm
81611
7166
0.001
Serum creatinine, mmol/L
85611
82610
0.47
Group A is comprised of patients with a score of sympathetic damage 0 – 4.
Group B, score of sympathetic damage 5– 8. Values are mean6SD, unless
indicated otherwise.
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concentration. Duration of disease was longer in group B than
in group A. All patients in group B had complete cardiac
parasympathetic failure as reflected by absent HR responses
to the deep breathing test and atropine. In 5 patients in group
A, residual cardiac parasympathetic function was present
(Table 1). The degree of sympathetic damage and duration of
disease were correlated (r50.46, P,0.05). The degree of
sympathetic damage in each individual patient remained
stable during the year of follow-up (mean difference6SD of
sympathetic score – 0.260.7)
Daytime and 24-hour values of the pretransplantation systolic
and diastolic ABP were significantly higher in group A than in
group B, but nighttime systolic and diastolic ABP between the 2
groups did not differ (Table 3). As a consequence, the day-night
differences of systolic and diastolic BP were larger in patients in
group A than in group B, reflecting the more severe sympathetic
dysfunction in this latter group. Day, night, and 24-hour values
of HR tended to be lower in group B than in group A (Table 3).
After OLTx, all patients used CsA and prednisone as immunosuppressive therapy. Azathioprine was also used by 10 patients,
5 in each group. The daily doses of the immunosuppressive
agents at 3, 6, and 12 months after OLTx did not differ between
Prednisone mg/kg
Azathioprine mg/kg
Definitions as in Table 2.
groups, and in both groups they were reduced to a similar extent
during follow-up (Table 4). CsA whole blood trough levels in
groups A and B were similar; values in the 2 groups were,
respectively, 3316120 and 2996158 mg/L at 3 months,
245671 and 2566119 mg/L at 6 months, and 177644 and
173680 mg/L at 12 months after transplantation.
ABP at intervals of 3, 6, and 12 months after OLTx
significantly increased (Figures 1 and 2), but in only 1 patient
did daytime diastolic BP become .90 mm Hg, and none of
the patients required antihypertensive medication. The increase in BP, especially nighttime BP, was '2 times larger in
group B than in group A (Figure 2).
Serious events after OLTx did not occur in any of the
patients. Serum creatinine increased by 28613 mmol/L
(P,0.001) in group A and by 41617 mmol/L (P,0.001) in
group B, 1 year after transplantation. Body weight at that time
increased by 4.064.7 (P,0.001) kg in group A and by
1.762.1 kg (P50.046) in group B.
TABLE 3. Pretransplantation Values of 24-Hour, Daytime, and Nighttime Ambulatory Systolic and Diastolic
BP and HR and Their Day-Night Difference in the 2 Patient Groups
Group A (n511)
Group B (n59)
Group A vs B P
Parameter
Pre OLTx
Post OLTx
Pre OLTx
Post OLTx
Pre OLTx
24-h SBP, mm Hg
11469
12367**
10665
12169***
0.016
0.58
24-h DBP, mm Hg
7367
7767
6664
7767**
0.008
0.89
0.92
24-h HR, bpm
87612
Post OLTx
83612
8266
8267
0.36
Day SBP, mm Hg
11768
12469*
10766
11967***
0.003
0.25
Day DBP, mm Hg
7767
7868
6865
7664**
0.002
0.57
Day HR, bpm
91613
8767
8567
8568
0.36
0.93
Night SBP, mm Hg
107613
120610**
10266
123610***
0.28
0.41
Night DBP, mm Hg
67611
7569*
6267
7869**
0.24
0.38
Night HR, bpm
80613
74612*
7567
7668
0.33
0.63
D-N SBP, mm Hg
9.7610.4
4.4610.4
4.368.6
24.2610.3*
0.24
0.08
5.367.9
22.068.3*
0.20
0.14
10.564.2
9.366.7
0.97
0.40
D-N DBP, mm Hg
D-N HR, bpm
9.967.6
11.169.0
3.667.9*
13.167.7
Values are mean6SD. SBP indicates systolic BP, DBP, diastolic BP; D-N, day-night difference. *P,0.05, **P,0.01, ***P,0.001
after vs before OLTx.
Carvalho et al
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Figure 1. Profiles of hourly averages of 24-hour ABP recordings in
the 2 groups of patients. Open symbols indicate pretransplantation
recordings; closed symbols, recordings 1 year after transplantation.
Group A is comprised of patients with absent or mild-to-moderate
sympathetic damage; group B, patients with severe sympathetic
damage.
Discussion
The present study shows that CsA in patients with autonomic
dysfunction due to FAP is associated with a rise in BP. The rise
in BP was more pronounced in the subgroup of patients with
more severe sympathetic damage. Our findings, therefore, do not
favor the hypothesis that activation of the SNS is critical to the
development of CsA-induced rise in BP in patients with FAP but
do suggest that the CsA-induced rise in BP is counteracted by
the autonomic nervous system. In agreement with previous
studies,8,18 –21 CsA, by increasing nighttime BP more than
daytime BP, caused an attenuation of the day-night difference in
BP. This effect was more pronounced in the group of patients
with more severe sympathetic damage.
Autonomic Nervous System and Cyclosporine
105
A characteristic feature of FAP patients is that their BP
becomes lower with more advanced disease. In part, this is
related to the occurrence of orthostatic hypotension as a result
of the progressive insufficiency of their SNS. This explains
why daytime ABP, but not nighttime ABP, was considerably
lower in the patient group with more severe sympathetic
damage. This difference in daytime ABP between the 2
groups disappeared completely after initiation of CsA immunosuppressive therapy because of the greater rise in BP in the
patients with more pronounced sympathetic damage.
The greater rise in BP in the patient group with more severe
impairment of their SNS could not be explained by differences
in immunosuppressive therapy or CsA-induced impairment of
renal function. In addition, evaluation of autonomic function 1
year after transplantation revealed a stable degree of sympathetic
damage in each individual patient. Therefore, the more severe
degree of sympathetic damage in the patients of group B most
likely accounted for the observed greater rise in BP in that group.
As has been emphasized recently, the baroreflex is crucial to
counteract the rise in BP induced by pressure agents.21 If the
buffering capacity of the baroreflex is impaired, as was certainly
the case in the patients in group B, the sensitivity to agents that
increase BP, irrespective of the underlying mechanism, will be
augmented. This is in accordance with previous observations,
which show that similar doses of CsA were associated with a
greater rise in BP in heart transplant recipients than in patients
with myasthenia gravis.10,22 Removal of the inhibitory afferent
restraint on sympathetic outflow due to interruption of the
ventricular-baroreceptor reflex has been mentioned to explain
this greater BP rise in cardiac transplant recipients.22
Previous studies have shown that the CsA-induced rise in BP is
associated with an attenuation of the nocturnal fall in BP.18–20 The
simultaneous use of glucocorticoids may contribute to this blunted
diurnal BP rhythm.23 As a consequence of their autonomic dysfunction, the diurnal BP rhythm was already attenuated before the start
of immunosuppressive therapy in a substantial number of our
patients. During immunosuppressive therapy, a further blunting of
Figure 2. Percentage of change in daytime and
nighttime averages of ambulatory systolic and diastolic blood pressure, 3, 6, and 12 months after
transplantation. Open symbols indicate patient
group with absent or mild-to-moderate sympathetic
damage; closed symbols, patient group with severe
sympathetic damage. * P,0.05; ** P,0.01 for differences between groups.
106
Hypertension
July 1999
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the diurnal BP rhythm was observed. This effect was more
pronounced in the group with more severe impairment of their SNS
(Figure 1B). Volume expansion related to CsA-induced renal
vasoconstriction and to the use of glucocorticoids is a likely
explanation of this blunting of the diurnal BP rhythm.20,23–25
Volume expansion will lead to a greater venous return during
nighttime recumbency, when extracellular fluid shifts from the
periphery to central parts of the body. This greater venous return,
through an increase in cardiac output, forces BP to rise. We suggest
that in the absence of sympathetic dysfunction, this rise in BP is
counterbalanced by the baroreflex, although not completely, as the
day-night difference in BP is attenuated during CsA therapy. If the
function of the baroreflex is impaired or fails, the rise in BP during
the night will be greater than during the day.
Although administration of CsA was associated with a rise in
BP, hypertension, as defined as a daytime ambulatory diastolic
BP of $90 mm Hg, was observed in only 1 patient and none of
the patients required antihypertensive medication during the 1
year of follow-up. This extremely low incidence of de novo
hypertension contrasts with the prevalence of CsA-induced
hypertension after liver transplantation observed in other studies.5–7 The question of why hypertension did not develop in our
patients is not easy to answer. The daily doses of CsA and
prednisone used by our patients were similar to those reported
for other transplant patient groups, as were the CsA whole blood
trough levels. It is possible that the deposition of amyloid within
the vascular wall and the kidney prevented the development of
hypertension in our patients. Although after liver transplantation
the production of the transthyretin mutant will stop, it is not to be
expected that the already formed amyloid will disappear quickly.26,27 Indeed, autonomic function tests 1 year after transplantation showed no evidence of either improvement or progression
of autonomic dysfunction in our population.
As activation of the SNS appears not to be critical to the
development of CsA-induced rise in BP in our patients, other factors
should be investigated. There is evidence that the use of CsA is
associated with an inhibition of vasodilator pathways and an
activation of vasoconstrictor pathways leading to an increase in
vascular resistance.7,13,22,28 CsA-induced renal vasoconstriction, especially with the concomitant use of glucocorticoids, promotes fluid
retention, which likely contributes to the development of the rise in
BP.24,25 In the present study, some deterioration in renal function
and an increase in body weight were found. These findings favor
renal vasoconstriction and fluid retention as pathogenetic mechanisms in the observed rise in BP.
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Hypertension. 1999;34:102-106
doi: 10.1161/01.HYP.34.1.102
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