(Hypertension. 2000;35:1258.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Study of Arterial and Autonomic Effects of Cyclosporine in Humans
From Centro di Ricerca sulla Terapia Neurovegetativa, Medicina Interna I, Ospedale "L. Sacco," Centro Ricerche Cardiovascolari, CNR, Università di Milano, Milano, Italy (D.L., M.P.); and the Department of Cardiology, Ochsner Medical Institutions, New Orleans, La (R.V.M., H.O.V., M.R.M., F.M.).
Correspondence to Massimo Pagani, MD, FACC, Medicina Interna I, Università di Milano, Via G.B. Grassi, 74, 20157 Milano, Italy. E-mail massimop{at}fisiopat.sacco.unimi.it
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Abstract |
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Abstract—Altered sympathetic activity and peripheral vascular function are suspected as a mechanism of the development of arterial hypertension in organ transplantation recipients treated with cyclosporine. We assessed whether cyclosporine might alter peripheral vascular properties or autonomic modulation of the sinus node and the vasculature during rest and standing. We examined 17 orthotopic heart transplantation recipients, 8 solid organ transplantation recipients, 17 patients with essential hypertension, and 42 normotensive control subjects. All except the normotensive control subjects were treated with a long-acting dihydropyridine calcium entry blocker; transplantation recipients also received cyclosporine-based immunosuppression. Radial artery compliance was reduced in patients with essential hypertension and in patients with heart and solid organ transplantation as compared with normotensive control subjects, with this reduction being more marked in heart transplantation recipients. At rest, R-R variance was lowest in heart transplantation recipients, denoting denervation. The spectral profile of both R-R and systolic blood pressure variability as well as the index of baroreflex gain was normal at rest in patients with solid organ transplantation. On standing, both transplantation groups demonstrated reduced responsiveness in markers of autonomic modulation. The decrease in arterial compliance in cyclosporine-induced hypertension seems to imply a degree of ventricular vascular uncoupling more apparent in heart transplantation recipients. These changes are associated with alterations in autonomic modulation that are evidenced by an orthostatic stimulus.
Key Words: autonomic nervous system • arterial mechanics • baroreflex • heart transplantation • compliance, arterial
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Introduction |
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The mechanisms by which cyclosporine can induce hypertension are still under active scrutiny.1 2 The most commonly investigated mechanisms include alterations in the sympathetic nervous system activity3 and peripheral vascular function.4
Studies that have addressed sympathetic nervous system activation have provided disparate results. Experimental studies in animals have demonstrated that the acute administration of cyclosporine increased renal and lumbar sympathetic nerve activity5 and that the increase in blood pressure is related to the activation of excitatory neural reflexes arising from subdiaphragmatic regions.6 Moreover, in a clinical study of heart transplantation recipients with cyclosporine-induced hypertension, Scherrer et al3 proved an increase in sympathetic activity measuring peroneal nerve discharges.
Other studies have shown that cyclosporine does not affect sympathetic nervous system activity. Stein et al7 and Kaye et al8 demonstrated normal norepinephrine spillover and normal muscle sympathetic discharges in patients receiving cyclosporine compared with control subjects. In addition, plasma and urinary catecholamines have been reported to be within normal ranges in heart transplantation recipients treated with cyclosporine.9 We have previously shown by using spectral analysis of heart rate and systolic arterial pressure variability the maintenance of baroreflex circulatory control in patients with organ transplantation treated with cyclosporine.10 The latter suggested that cyclosporine does not markedly alter the autonomic control of the sinus node nor of the peripheral vasculature at rest. In addition, these findings also reinforced the concept that cyclosporine might induce hypertension through an impairment in peripheral vasodilation or changes in vascular mechanics largely independent of the sympathetic nervous system. This hypothesis of vascular alterations in the pathogenesis of cyclosporine-induced hypertension is gaining increasing credibility, as indicated by several recent studies underlying a pivotal role of this mechanism in the development of this disease.11 12 13 14
The purpose of this study was first to assess the effects of cyclosporine-induced hypertension on arterial vascular mechanics and second to assess the autonomic modulation of the sinus node and the vasculature on standing in cohorts of patients with solid organ transplantation, heart transplantation, and essential hypertension.
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Methods |
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Study Population
Four groups of patients were included in the study (Table 1). Group 1 consisted of 42 normal control subjects, group 2 included 17 patients with essential hypertension, group 3 included 17 hypertensive patients with orthotopic heart transplantation (time elapsed since transplantation 10±3 months), and group 4 consisted of 9 hypertensive patients with other solid organ (kidney or liver) transplantation (time elapsed since transplantation 22±18 months). Clinical evaluation and definition of hypertension (diastolic blood pressure >90 mm Hg measured by cuff method) followed established guidelines.
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All patients who underwent transplantation received the same triple immunosuppressive therapy, including cyclosporine (4 mg/kg per day) to achieve a blood level of 183±20 ng/mL in patients with heart transplantation and of 178±16 in patients with solid organ transplantation, respectively, prednisone (0.1 mg/kg per day), and azathioprine (2 mg/kg per day); all were free of acute allograft rejection at the time of the study. In addition, patients with essential hypertension or cyclosporine-induced hypertension were receiving the same dose of a long-acting dihydropyridine calcium channel blocker at the time of the study.
All patients provided informed consent to a protocol approved by the Ochsner Medical Institutions Review Board.
Recording Procedure
Recordings were performed in a quiet room, with a
comfortable temperature (22° to 24°C), always in the same time
window (between 7 AM and 1 PM). On the
morning of the study, every subject had a light breakfast, with no
caffeinated beverages (coffee or tea) that might produce long-lasting
autonomic effects.
Each participant was connected to a 2-channel telemetry system (Marazza) that provided continuous ECG and respiratory signals (obtained with a piezoelectric transducer). Arterial pressure was continuously estimated with a noninvasive device (Finapres, Ohmeda). After a 10-minute period allowed for stabilization, a control recording of 10 minutes was obtained in the supine position, to be followed by a further period of 7 minutes of recording during active standing, leading to a shift of the sympathovagal balance toward sympathetic predominance.15
Spectral Analysis of Heart Rate and Blood Pressure
Variability
With the use of a PC with a D/A board from the ECG
signal,16 17 a continuous R-R interval series (ie,
tachogram) was obtained, as previously reported with the use of an
autoregressive algorithm; the power and frequency of every spectral
component were computed both in absolute (ie, s2)
and normalized units (ie, nu) (see References 16 and
17 for details). Spectral analysis was also
performed on the systolic arterial pressure and the
respiratory signals with the use of a similar
procedure.17
Baroreflex Gain
From the simultaneous analysis of
arterial pressure and R-R interval variability, a frequency
domain index 
can be derived,18 19 which is a measure
of the overall gain of the arterial pressure heart period
relation and provides results similar to those obtained with the
phenylephrine slope approach, as already
described.18
Arterial Compliance
The arterial pressure wave contour was obtained
noninvasively from the right brachial artery with a hand-held
7-mm-diameter pencil-type probe incorporating a
micromanometer (Millar Instruments Inc). The
brachial artery waveform was digitized at a rate of 250 Hz and stored
on a PC computer for off-line analysis. Two to 5 digitized
signals were signal-averaged and analyzed, excluding premature
and postpremature beats from analysis. Arterial
compliance was determined by means of the area
method,20 21 which is based on the 2-element Windkessel
model of the arterial circulation according to Yin’s
approach,20 in which
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Statistics
Data that were not normally distributed are presented as
median±semi-interquartile. Two-way ANOVA for repeated measures, with
the Geisser-Greenhouse conservative test and Bonferroni correction, was
used to compare the 4 groups. A level of P<0.05 was
considered significant.
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Results |
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Blood Pressure
Systolic and diastolic blood pressures were significantly elevated at rest in patients with cyclosporine-induced hypertension or essential hypertension compared with normal control subjects (Table 2 and Figure 1). On standing, only patients with essential hypertension demonstrated a higher level of systolic and diastolic blood pressures compared with normal subjects (Table 2).
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Indexes of Autonomic Nervous System Activity
As a result of the effects of cardiac denervation, patients
with orthotopic heart transplantation had a significantly lower R-R
interval, both at rest and standing, compared with the other 3
groups.
The LFRR components (in nu) at rest are shown in all groups in Figure 1 and Table 2. Heart transplantation recipients displayed very small values of R-R low-frequency components but with a high degree of variability (Figure 2). The latter was related to the presence of an LFRR component in 9 heart transplantation recipients (18.8 nu, time elapsed after heart transplantation 10 months, range 4 to 46 months) compared with 8 in whom LFRR component was not observed (time elapsed after heart transplantation 6 months, range 1 to 14 months). During standing (Table 2), patients with essential hypertension and normal subjects demonstrated an increase in LFRR compared with solid organ or heart transplantation recipients. This spectral component in heart transplantation recipients displayed very small values on standing.
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On standing, the HFRR component was significantly reduced in normal subjects and only slightly diminished in patients with essential hypertension; this index was unchanged in the transplantation groups. Heart transplantation recipients had an HFRR component in 16 of 17 subjects.
The LFSAP component was present in all subjects in all groups. Patients with essential hypertension (Figure 1 and Table 2) had the greatest LFSAP both at rest and during standing up. In all groups, the power of LFSAP increased from supine to upright positions; the greatest value being observed in hypertensive patients and the smallest in patients with solid organ transplantation (P<0.05).
Baroreflex Gain
The gain of the heart period–arterial baroreflex, as
measured by the index , was lowest in orthotopic heart
transplantation recipients. In addition, whereas the index was
similar in patients with solid organ transplantation and normal control
subjects, patients with essential hypertension had a lower index
compared with that in normal subjects (Table 2 and Figure 1). On standing, a significant reduction of the index was
observed in normal control subjects, and a slight decrease was observed
in patients with essential hypertension. Conversely, patients with
solid organ transplantation had a very small reduction of the index
(Table 2).
Artery Compliance
All 3 groups of patients with hypertension, either
cyclosporine-induced heart transplantation recipients
and solid organ transplant recipients or patients with essential
hypertension, had a significantly lower value of arterial
compliance as compared with normal subjects (0.44±0.62, 2.15±1.66,
and 2.34±1.95, respectively, vs 3.97±1.4 au) (See Figure 1).
Among patients, heart transplantation recipients displayed the lowest
value of arterial compliance (0.44±0.62 au).
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Discussion |
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The present study shows that cyclosporine-induced hypertension in organ transplantation is associated with a decrease in radial artery compliance, particularly evident in orthotopic heart transplantation recipients. In addition, autonomic responsiveness to standing appeared to be reduced in transplantation recipients.
Arterial Compliance
Compared with control subjects, radial artery compliance was
reduced in hypertensive subjects and in organ transplantation
recipients. This reduction in hypertensive subjects has been
demonstrated, and it is likely to be a reflection of the well-known
widespread alterations in arterial
mechanics.22 The impaired compliance observed in
transplantation recipients might reflect the
cyclosporine-induced hypertension, through an
impairment in peripheral vasodilation or alterations in
vascular mechanics.7 12 Although the direct vascular
action by which cyclosporine causes hypertension is
controversial, several studies, in addition to the present results,
support this mechanism because it has been shown that
cyclosporine might affect functional properties of the
vasculature by an increase in endothelin
production11 and reduction in nitric oxide
synthesis. Thus, the significant decrease in regional
arterial compliance observed in patients with solid organ
or heart transplantation supports the notion that
cyclosporine alters vascular mechanics. The more marked
decrease in arterial compliance observed in heart
transplantation recipients suggests that some factors other than the
development of hypertension and the vascular effect of
cyclosporine might be involved. An increased average
sympathetic outflow to blood vessels, as occurs in heart
transplantation recipients,23 might lead to an increase in
arterial smooth muscle tone and hence to a further increase
in arterial stiffness.
Autonomic Modulation of Sinoatrial Node and of the
Vasculature
An interpretation of the autonomic effects of
cyclosporine must consider the complex, dual nature of
cardiac innervation. Patients with solid organ transplantation had
similar indexes either of the autonomic modulation of the sinoatrial
(SA) node and vasculature at rest when they were compared with control
subjects. These findings support the concept that these patients
maintain resting oscillatory properties of autonomic circulatory
control. In contrast, on standing, minimal changes were observed in
oscillatory markers of the autonomic modulation of the SA node and of
the vasculature, indicating a reduced responsiveness to excitatory
stimuli. Heart transplantation recipients demonstrate markedly reduced
heart rate variability secondary to the condition of cardiac
denervation. Interestingly, the LFRR components
showed a great deal of variability because heart transplantation
recipients with longer postoperative periods demonstrated the presence
of LFRR, a finding that supports previous studies
suggesting reinnervation with time.24 Also of note is the
small value of LFRR in treated hypertensive
subjects as compared with control subjects and with prior studies on
untreated hypertensives,25 possibly reflecting some
beneficial autonomic effects of long-acting
dihydropyridine treatment.26
As previously reported by our laboratory10 and others,27 heart transplantation recipients maintained a normal blood pressure variability at rest, suggesting a preservation of oscillatory properties of efferent sympathetic vasomotor control23 even in the near absence of LFRR. These patients also had a clear increase in the LFSAP components on standing. Thus, despite a possible increase in average resting sympathetic vasomotor drive,23 heart transplantation recipients appear to display a normal response to orthostatism in LFSAP, an oscillatory marker of the sympathetic control of vasomotion.
Limitations of the Study
The method used to measure compliance,20 21 although
sensitive and based on high-fidelity sensors measuring both local
pressure and blood flow velocity, was limited to a single
peripheral distal arterial bed and therefore
cannot be considered an estimation of global vascular compliance.
Spectral analysis of R-R interval and systolic arterial pressure variability provide indexes of the oscillatory properties of autonomic control of the SA node and of the vasculature and is not a measure of autonomic traffic. However, despite a debate about some aspects of interpretations,28 29 this approach has reached a large consensus30 and has been recently validated against direct measures of efferent sympathetic nerve activity in humans31 in a wide range of levels of sympathovagal balance with the use of vasoactive substances and muscarinic receptor blockade.32
Conclusions
Cyclosporine-induced hypertension is associated
with abnormal vascular mechanics, as evidenced by a decrease in
arterial compliance. Heart transplantation recipients have
a greater decrease in arterial compliance compared with
patients with solid organ transplantation, possibly implying as well a
greater degree in ventricular vascular uncoupling. In
addition, the abnormality in peripheral vascular mechanics
is associated in transplantation recipients with changes in autonomic
modulation that are more apparent during an orthostatic
stimulus.
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Acknowledgments |
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Partial financial support by MURST 40%, ASI and IRCEA and the typing assistance of Giovanna Macciò are gratefully acknowledged. During her stay at Ochsner Medical Institutions, Dr Lucini was a recipient of an International Research Fellowship from the Italian Society of Hypertension.
Received October 22, 1999; first decision December 3, 1999; accepted January 7, 2000.
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