Download Cardiac natriuretic peptides during exercise and training after heart

Cardiovascular Research 51 (2001) 521–528
www.elsevier.com / locate / cardiores
Review
Cardiac natriuretic peptides during exercise and training after heart
transplantation
Bernard Geny*, Ruddy Richard, Bertrand Mettauer, Jean Lonsdorfer, François Piquard
´
´
,
Laboratoire des Regulations
Physiologiques et des Rythmes Biologiques chez l’ Homme, EA 3072, Institut de Physiologie, Faculte´ de Medecine
Strasbourg, France
Received 14 November 2000; accepted 5 February 2001
Keywords: Natriuretic peptide; Transplantation
1. Introduction
The cardiac natriuretic system, composed of atrial and
brain natriuretic peptides (ANP and BNP), plays a major
role in blood pressure and fluid homeostasis, protecting the
organism from volume and pressure overloads. Accordingly, the cardiac hormones have been shown to delay the
occurrence of overt heart failure through their diuretic,
natriuretric and vasodilatory properties [1–3]. Adrenomedullin, mainly produced by vascular smooth muscle
cells and by vascular endothelial cells, is also secreted by
the failing human heart. This potent vasorelaxing and
natriuretic peptide can thus be considered as a third cardiac
hormone, involved in circulation control [4,5].
Short term survival is no longer the pivotal issue for
most heart-transplant recipients (Htx) because of enhancement in organ preservation, surgical and medical therapies.
Consequently, improving quality of life after heart transplantation arises as an important goal, which might be
reached through exercise and training programs [6–8].
Since cardiac natriuretic peptides greatly participate in
cardiovascular adaptations, it appeared interesting to focus
this review on ANP, BNP and adrenomedullin (ADM)
responses to exercise and training after heart transplantation.
Relative rather than absolute work load will be used to
compare groups since it is generally considered to be a
better indicator of the magnitude of fluid-regulating hormone changes, both in normal subjects and in Htx [9].
*Corresponding author. Tel.: 133-390-243-439; fax: 133-390-243444.
E-mail address: [email protected] (B. Geny).
After discussing why circulating ANP, BNP and ADM are
elevated in Htx, we will investigate the stimuli of their
secretion during exercise and present the few data available concerning their response to exercise training after
heart transplantation.
2. Increased circulating cardiac natriuretic peptides
after heart transplantation
After successful cardiac transplantation, normalization
of filling pressures, as well as normalization of the renin–
angiotensin–aldosterone and the sympathetic systems,
generally occur, explaining why persistent elevation of
circulating ANP and BNP was unexpected [10–13]. In
fact, replacing the failing heart by a so-called ‘normal’
heart does not totally restore the cardiovascular system and
we yet know that the denervated transplanted heart is
characterized by diastolic dysfunction. Diastolic cardiac
dysfunction, together with vascular dysfunction (preexistant before transplantation and enhanced by the immunosuppressive therapy), associated with volume and / or pressure overload, appear thus to play a key role in the cardiac
natriuretic system stimulation observed in Htx. Endothelin
participates also likely in such increase after heart transplantation, either directly or through its hypertensive and
renal deleterious effects [10–16]. Circulating adrenomedullin has also been recently shown to be increased
after heart transplantation, likely in relation with endothelin, hypertension and increased left ventricular mass
index [17,18].
Time for primary review 30 days.
0008-6363 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 01 )00243-7
B. Geny et al. / Cardiovascular Research 51 (2001) 521 – 528
522
3. Cardiac natriuretic peptides responses to exercise
after heart transplantation
whose effects are modulated by humoral (catecholamines,
arginine vasopressin and endothelin) or nervous factors
(cardiac denervation), responsible for an eventual ANP
hypersecretion during exercise after heart transplantation
[9,24–34].
3.1. Stimuli for ANP secretion
In healthy humans, ANP has been shown to increase
during and immediately following exercise [19,20]. Rather
than an increase in atrial pressure, the predominant
stimulus for the cardiac hormone release is an increase in
atrial stretch secondary to increased venous return [21,22].
The first report on ANP response during exercise after
heart transplantation supported an ANP hypersecretion in
Htx, as compared to controls [23]. Controversial data have
nevertheless been reported thereafter (Tables 1 and 2),
challenging the proposed factor (altered atrial anatomy),
3.1.1. Altered atrial anatomy
The first factor proposed to explain ANP hypersecretion
during exercise in Htx was increased atrial volume and
mass resulting from the surgical procedure [23]. Indeed,
according to Laplace’s law, higher atrial volume induces
higher diastolic and systolic wall stress, which is known to
be an important determinant of ANP secretion [1]. Moreover, an increased atrial mass may augment the heart’s
ability to release ANP. Nevertheless, maximal atrial ejec-
Table 1
Selected data from studies investigating the ANP response to maximal exercise in controls and heart transplant recipients d
References
Keogh et al. [23]
Subjects
Age
(years)
Delay
(months)
Position
Type
12
Htx
4463
10
Upright
Max
7
7
Starling et al. [25]
Braith et al. [29]
` et al. [31]
Bussiere
13
Ctrl
Htx
Ctrl
Htx
5364
4664
4462
Ctrl
2562
11
Htx
50614
11
Ctrl
50614
12
6
6
Htx
Htx
Htx
Ctrl
Upright
3–13
3363
13
12
Perrault et al. [30]
Period
State
7
Singer et al. [24]
Exercise
n
4464
5163
3865
Upright
Upright
762
18612
1264
3267
1764
3865
Upright
Power
(W)
Max
Max
Max
103612
176614
Max
Upright
Max
Upright
Max
10966
Upright
Max
198614
Upright
Supine
Upright
Upright
Max
Max
Max
Max
12569
160610
Plasma ANP
Values
(pmol/l)
Rest
Peak
Rest
Peak
6669
207650
2663
56614
Rest
Peak
Rest
Peak
10.261.0
Rest
Peak
Rest
Peak
37.066.0
121.268.6
6.860.5
29.964.6
Rest
Peak
Rest
Peak
1462 b
4566 b
661 b
1662 b
Rest
Peak
Rest
Peak
59.266.8
90.064.0
55.968.1
136.2616.1
Rest
Peak
Rest
Peak
66.0617.9
170.0640.0
23.065.5
44.968.1
4466
2865
Supine
Max
100633
Rest
Peak
89.1619.6
142.4623.1
Gullestad et al. [9]
9
Htx
4564
52612
Upright
Max
200611
Rest
Peak
4667 b
84612 b
Rest
Peak
Rest
Peak
15.263.7
29.564.2
4.460.8
12.863
8
a
Ctrl
4563
4362
3863
Upright
Upright
Max
Max
123612
199614
9263
13164
7663
13967
MAP
D
(%)
10962
133
123
9564
1151
9062
12763
D
(%)
1109
7465
1228
Values
(mmHg)
142
10165
1204
Htx
Htx
1115
2.660.5
9
8
1214
Values
(bpm)
1151
Jahnke et al. [32]
Geny et al. [34]
Heart rate
D
(%)
141
130
11563
11964
14
1339
102 a
125 a
93 a
123 a
1163
9463
147615
6862
16865
152
14464
126 a
1143
14365
129 a
1221
1157
196
157
1149
8562
13666
73614
18265
1149
9564 b
17464 b
183
160
109 a
121 a
88 a
112 a
123
132
111
127
160
183
1138
1 203
10064
16065
8164
18069.7
160
1125
11365
13267
9965
12366
116
122
MAP was calculated from mean systolic and diastolic blood pressures.
Values were estimated from graphs.
d
Values are mean6S.E.M. Delay is time elapsed since transplantation. D, relative increase between peak and rest values. MAP, mean arterial blood
pressure; Htx, heart transplant patients; Ctrl, health control subjects; Max, exercise was performed until exhaustion.
b
B. Geny et al. / Cardiovascular Research 51 (2001) 521 – 528
523
Table 2
Selected data from studies investigating the ANP response to submaximal exercise in controls and heart transplant recipients d
References
Subjects
n
Mettauer et al. [26]
Angermann et al. [28]
Braith et al. [29]
9
14
11
11
Braith et al. [29]
11
11
Pepke-Zaba et al. [27]
Sehested et al. [33]
Geny et al. [81]
Hachida et al. [67]
10
Exercise
State
Age
(years)
Delay
(months)
Position
Type
Power
(W)
Htx
5062
1363
Supine
Submax
90
Htx
Htx
Ctrl
Htx
Ctrl
Htx
10
Htx
10
Ctrl
7
10
6
Period
Htx
Htx
Ctrl
4469
50614
1269
18612
50614
50614
Supine
Upright
Upright
18612
50614
Upright
Upright
Submax
Submax
Submax
Submax
Submax
45
80
75
Upright
Submax
75
4264
1161
Submax
42.264.0
79.3612.2
195
9064
11264
Rest
Peak
Rest
Peak
b
1262
21636 b
661 b
1061 b
11767
50
50
Rest
Peak
Rest
Peak
175
167
b
34.164.3
65.067.9
75
Upright
Rest
Peak
Rest
Peak
Submax
17–52
9963
14464
58611 b
86614 b
1263 b
2163 b
Upright
Submax
1110
Rest
Peak
Rest
Peak
20
(6–54)
Upright
74.0610.0
155.4620.6
25.664.7
53.569.5
34
(18–49)
32
(25–40)
12–61
Rest
Peak
Rest
Peak
Upright
17–52
Values
(bpm)
84
(75–100)
34
(24–48)
Submax
D
(%)
1462
29636 b
661 b
1061 b
140
Heart rate
Values
(pmol/l)
Rest
Peak
Rest
Peak
43
(23–56)
Upright
Submax
50
Plasma ANP
1107
167
1109
9463
137 c
6862
149 c
10667
15766 b
175
8664 b
12766 b
7264 b
12169 b
192
10064
13264
147
b
24
182 b
6b
29 b
9463
121 c
6862
114 c
1658
1383
90610
122610 b
7969
114630 b
MAP
D
(%)
Values
(mmHg)
D
(%)
145
10363
12764
123
124
121 a
126 a
14
129
168
146
1119
148
10764
13267 b
168
96 a,b
108 a,b
87 a,b
103 a,b
132
11065
11568
148
123
118
113
15
135
144
a
MAP was calculated from mean systolic and diastolic blood pressures.
Values were estimated from graphs.
c
Heart rate was recalculated from author’s data.
d
Values are mean6S.E.M. Delay is time elapsed since transplantation. D, relative increase between peak and rest values; MAP, mean arterial blood
pressure; Htx, heart transplant patients; Ctrl, health control subjects; Submax, submaximal exercise.
b
tion force is similar in Htx and controls [35] and ANP
hypersecretion was also observed in Htx with total excision of recipient atria [32,36].
3.1.2. Humoral modulation
Stretch-induced ANP secretion has been shown to be
enhanced by humoral factors such as epinephrine, norepinephrine, arginine vasopressin (AVP) and endothelin (ET)
[37–40]. Exercise-induced epinephrine increase is reduced
in Htx mainly because of their lower peak exercise
capacity [30,34]. Higher or similar norepinehrine levels,
together with AVP hypersecretion were observed during
exercise in Htx [29,30]. Together with the fact that basal
plasma endothelin is generally increased [41,42], it suggests that these hormones might participate in an exaggerated ANP secretion in Htx, directly or through volumeand / or pressure overload [1]. To date, however, evidence
of a stimulating effect of norepinephrine, AVP or ET on
ANP release remain to be demonstrated during exercise
after heart transplantation.
3.1.3. Therapy
As previously reported, antihypertensive treatment could
decrease ANP secretion during exercise if associated with
a decrease in atrial wall stress [28]. On the other hand,
b-blockers resulting in attenuated heart rate increase
induce ANP hypersecretion during exercise [43,44]. Cyclosporine might also enhance ANP secretion during exercise
in Htx through both an increase in cardiac afterload and
mass resulting in diastolic dysfunction and through its
potential stimulatory effects on the sympathetic system and
endothelin [45]. Similarly, the corticotherapy could result
in saline retention, leading to volume overload. It is also
known to directly stimulate the transcription of the gene
encoding for ANP [46]. Thus, therapy will either enhance
or reduce exercise-induced ANP secretion in Htx.
3.1.4. Cardiac denervation and atrial stretch
Cardiac innervation is not necessary for ANP secretion,
but the cardiac hormone release may be under neural
control. Although controversial, an inhibitory role of
cardiac innervation on ANP release has been proposed, and
524
B. Geny et al. / Cardiovascular Research 51 (2001) 521 – 528
heart transplantation, by means of cardiac denervation,
could correspond to a breakdown of this inhibition [47,48].
Cardiac denervation may also indirectly stimulate ANP
release during exercise through both the need for elevated
catecholamine concentrations for chronotropic incompetence limitation and elevated AVP resulting from loss of
afferent information from cardiac mechanoreceptors
[29,49].
However, atrial stretch being the most likely explanation
for exercise-induced increase in ANP, cardiac denervation
might act predominantly on ANP release by modulating
atrial stretch. This effect may further be amplified in Htx,
because of lessened pericardial restriction and impairment
in ventricular compliance [28,50–52]. ANP hypersecretion
in Htx may thus reflect greater atrial stretching [30,53]. In
this view, the cardiac denervation-induced chronotropic
limitation [6,54–57] may result in heart rate and venous
return mismatch, favoring distention of the cardiac chambers through a compensatory increase in stroke volume.
Such a mechanism occurs early during exercise and has
been nicely demonstrated after heart transplantation [58].
Accordingly, an inverse relationship between ANP and
heart rate increase has been recently reported during early
exercise in Htx [34] (Fig. 1). Interestingly however, and
consistently with the analysis of all data reported in the
literature (Fig. 2), peak exercise ANP level was similar in
Htx and controls, probably because of the lower power
output reached after heart transplantation [34]. Further
supporting this assumption, an attenuated increase in ANP
was observed in Htx showing a nearly normal heart rate
response to exercise, corresponding likely to partial cardiac
reinnervation or exercise training [9,59].
3.2. Stimuli for BNP secretion in Htx
In healthy humans, all but one report showed a lack of
significant BNP change in response to exercise [34,60–63].
This is consistent with the idea that BNP is released
mainly from the ventricles in a constitutive manner and
that short term exercise cannot stimulate synthesis and / or
secretion of the cardiac hormone. However, BNP has also
been shown to be acutely released during exercise in
patients presenting with congestive heart failure, ischemia
and / or hypertension [64–66], challenging such hypothesis.
To the best of our knowledge, there are only two reports
on the BNP response to exercise after heart transplantation
[34,67]. Although similar and non-significant increases
were observed during a graded 50-W, 10-min submaximal
exercise [67], enhanced BNP increase has been observed in
Htx as compared to normal subjects, in response to a
graded 10-min maximal bicycle exercise performed until
exhaustion [34]. Atrial stretch, ventricular hypertrophy and
cardiac diastolic dysfunction have been proposed as potential stimuli for the BNP release during exercise.
Fig. 1. Relative hormones and heart rate (HR) changes between rest and
70% of peak values obtained during a maximal exercise test in control
subjects (white bars) and heart transplant recipients (black bars). Data
were obtained from Refs. [30] and [34] for atrial natriuretic peptide
(ANP), from Ref. [34] for brain natriuretic peptide (BNP) and unpublished data for adrenomedullin (ADM). Means6S.E.M. *, Difference
between Ctrl and Htx groups, P,0.05.
3.2.1. Atrial stretch leading to ANP and BNP
cosecretion
Both ANP and BNP have been colocated in atrial
granules and might be cosecreted as shown during supraventricular tachyarrhythmias [68,69]. Since atrial stretch
is the main stimulus for ANP release during exercise, it
might be hypothesized that atrial stretch may participate in
BNP release during exercise through ANP and BNP
cosecretion. Accordingly, a positive correlation was observed during exercise between ANP and BNP after heart
transplantation [34]. Such correlation was nevertheless
weak and the specific enhancement of BNP release in Htx
suggests that BNP might originate from other tissues such
as the ventricles rather then from atrial granules [70].
3.2.2. Ventricular hypertrophy
Interestingly, exercise-induced increase in BNP is greater in hypertensive patients with left ventricular hypertrophy as compared to patients without cardiac hyper-
B. Geny et al. / Cardiovascular Research 51 (2001) 521 – 528
525
and BNP may be partly explained by diastolic dysfunction.
Thus, plasma BNP level is increased in proportion with the
degree of cardiac diastolic dysfunction [71]. Although
cardiac diastolic dysfunction was not investigated, it might
have participated in Htx’s enhanced BNP response to
exercise since both altered late-diastolic passive LV properties and blunted acceleration of LV relaxation during
exercise contribute to the exaggerated exercise-induced
elevation of LV end-diastolic pressure (LVEDP) after heart
transplantation [34,50,54]. Accordingly, enhanced BNP is
correlated to LVEDP at rest and throughout exercise in
cardiovascular patients [61,64]. Such approach might be
particularly interesting in Htx in view of the direct positive
lusitropic effect of BNP [72,73], since it has been recently
demonstrated that BNP infusion causes beneficial hemodynamic and neurohormonal effects during exercise in
patients with isolated diastolic heart failure [72].
3.3. Stimuli for adrenomedullin release during exercise
after cardiac transplantation
In healthy humans, in contrast to submaximal exercise,
maximal exercise increased significantly circulating ADM
[61,63,74]. Similarly, maximal exercise-induced increase
in ADM was significant after heart transplantation but it
tended to be lower in Htx as compared to normal controls
[75]. Heart rate and exercise intensity or duration have
been discussed in the literature as potential stimuli for
ADM release during exercise.
Fig. 2. Maximal ANP, BNP and ADM changes, from rest to peak
exercise, in controls subjects (Ctrl) and heart transplant recipients (Htx).
For ANP changes, data were obtained from Refs. [23–25,29,30,34]. For
BNP changes, data were obtained from Ref. [34]. For ADM changes, data
were obtained from Ref. [75]; means6S.E.M.
trophy [63,66]. This supports a role for increased cardiac
mass in BNP release. Accordingly, BNP increment from
rest to peak exercise was positively correlated with left
ventricular mass index after heart transplantation [34].
Although not demonstrating a causal relationship, it further
supports that BNP release is related to cardiac mass and
that the enhanced BNP secretion observed in Htx might be
due to their cardiac hypertrophy, directly and / or through
cardiac diastolic dysfunction.
3.2.3. Cardiac diastolic dysfunction
Indeed, the relationship between left ventricular mass
3.3.1. Heart rate
Exercise physiology after heart transplantation allows an
unique opportunity to study the effect of heart rate on
ADM release during exercise. Indeed, the comparison of
ADM and heart rate changes in controls and Htx (heart
rate increase being both delayed and blunted in Htx),
suggested clearly that heart rate does not play a key role in
ADM release during exercise [75].
3.3.2. Exercise intensity and duration
From previous studies performed in both normal and
cardiovascular subjects, it appeared that exercise duration
is not critical for ADM secretion during exercise. Thus,
submaximal exercises, consisting of two fixed work loads
(40 and 80 W) for 4 min each, failed to increase ADM in
controls and in patients presenting with hypertension or
myocardial infarction [61,63]. Similarly, our preliminary
data suggest that a 45-min endurance exercise test, mainly
performed below 50% of peak VO 2 , does not significantly
modify plasma ADM in either controls or Htx (unpublished). On the other hand, short duration (10 min) graded
maximal exercise, performed until exhaustion, increased
circulating ADM both in controls and in Htx [75].
Thus, exercise intensity, rather than duration, predomi-
526
B. Geny et al. / Cardiovascular Research 51 (2001) 521 – 528
nantly stimulates ADM secretion, the main factor modulating such ADM response still needs to be determined.
4. Cardiac natriuretic peptides and training after
heart transplantation
Endurance and resistance exercise training are well
tolerated in Htx and are now considered an essential
adjunct therapy after heart transplantation [6–8,59,76,77].
Indeed, long term endurance training allows Htx to achieve
peak heart rate and VO 2 values that approach age-matched
norms [59]. Similarly, resistance exercise training counteracts corticosteroid-induced osteoporosis and skeletal
muscle myopathy [77].
Although neuroendocrine activation is well known to be
associated with poor long-term prognosis in heart failure,
there are relatively few data concerning cardiac natriuretic
peptides and training in cardiovascular diseased patients
[78–80]. Interestingly however, it has been recently
shown, in the first randomized controlled study, that a
16-week endurance training significantly reduces rest
vasoconstrictive (angiotensin, aldosterone, vasopressin)
and ANP plasma levels in heart failure patients [80].
Controversially, after heart transplantation, no significant changes were observed in circulating ANP and
vasopressin before and after a 6 week modified interval
training program [81]. Nevertheless, the fact that plasma
renin activity and aldosterone tended to decrease after
similar training when considering both exercise and recuperation values, suggests that longer-term exercise training might also be beneficial by reducing neurohormonal
activation after heart transplantation [82]. Indeed, although
resulting in a significant increase in maximal tolerated
power, it might be hypothesized that the 6-week training
program performed by the patients was too short to greatly
reduce their neurohormonal activation [82].
In summary, despite an early ANP hypersecretion,
maximal exercise-induced increase in the cardiac hormone
appears similar in Htx and controls. The lower peak power
reached after heart transplantation might therefore counterbalance the early greater atrial stretching secondary to
heart rate and venous return mismatch, resulting in a
smaller ANP increase during late exercise. A key factor
modulating the ADM release during exercise is unknown,
but BNP appears to be hypersecreted during exercise in
Htx, likely because of ventricular hypertrophy associated
with diastolic dysfunction.
The physiological role of the cardiac natriuretic peptides
during exercise remains to be investigated. However, in
view of the beneficial effect of BNP infusion during
exercise in patients with diastolic heart failure [72], one
may suggest that BNP might favor ventricular relaxation in
cardiac hypertrophic Htx. Furthermore, BNP acting in
synergy with ANP and probably with ADM, could exert
modulatory influences on the vasoconstrictive and fluid
retention systems thus allowing a better oxygen supply to
the working muscles. Similarly, although the percentage
fall in renal blood flow at peak exercise appeared greater in
Htx than in controls [83], our preliminary data showed
similar natriuresis after maximal exercise in normal subjects and after heart transplantation. This is further supported by previous data showing that exogenous and
endogenous ANP significantly participate in sodium and
water renal excretion after heart transplantation [84–87].
Finally, long-term exercise training are warranted after
heart transplantation, but not only because of their well
known beneficial effects on physical status and lowering
effect on the therapy-induced complication rate. Indeed,
such a training program may reduce the neurohormonal
activation, thus improving the long-term survival of hearttransplant recipients. Further studies will be useful to
investigate this important issue.
References
[1] Brenner BM, Ballermann BJ, Gunning ME et al. Diverse biological
actions of atrial natriuretic peptide. Physiol Rev 1990;70:665–687.
[2] Lang CC, Choy AMJ, Struthers AD. Atrial and brain natriuretic
peptides: a dual natriuretic peptide system potentially involved in
circulatory homeostasis. Clin Sci 1992;83:519–527.
[3] Grantham JA, Burnett Jr. JC. Natriuretic peptides in cardiovascular
disease. In: Samson WK, Levin E, editors, Contemporary endocrinology: natruretic peptides in health and diseases, Totowa, NJ:
Human Press, 1997, pp. 309–326.
[4] Richards AM, Nicholls MG, Lewis L et al. Adrenomedullin. Clin
Sci 1996;91:3–16.
[5] Jougasaki M, Wei CM, McKinley LJ et al. Elevation of circulating
and ventricular adrenomedullin in human congestive heart failure.
Circulation 1995;92:286–289.
[6] Banner NR. Exercise physiology and rehabilitation after heart
transplantation. J Heart Lung Transplant 1992;11:S237–S240.
[7] Badenhop DT. The therapeutic role of exercise in patients with
orthotopic heart transplant. Med Sci Sports Exer 1995;27:975–985.
[8] Braith RW. Exercise training in patients with cardiac heart failure
and heart transplant recipients. Med Sci Sports Exer 1998;30:S367–
S378.
[9] Gullestad L, Myers J, Noddeland H et al. Influence of the exercise
protocol on haemodynamic, gas exchange, and neurohumoral responses to exercise in heart transplant recipients. J Heart Lung
Transplant 1996;15:304–313.
[10] Singer DR, Buckley MG, Mac Gregor GA et al. Raised concentrations of plasma atrial natriuretic peptide in cardiac transplant
recipients. Br Med J 1986;293:1391–1392.
[11] Buckley MG, Sethi D, Markandu ND et al. Plasma concentrations
and comparisons of brain natriuretic peptide and atrial natriuretic
peptide in normal subjects, cardiac transplant recipients and patients
with dialysis-independent or dialysis-dependent chronic renal failure. Clin Sci 1992;83:437–444.
[12] Masters RG, Davies RA, Keon WJ et al. Neuroendocrine response to
cardiac transplantation. Can J Cardiol 1993;9:609–617.
[13] Ationu A, Burch M, Singer D et al. Cardiac transplantation affects
ventricular expression of brain natriuretic peptide. Cardiovasc Res
1993;27:188–191.
[14] Geny B, Piquard F, Follenius M et al. Endothelin participates in
increased circulating atrial natriuretic peptide early after human
heart transplantation. J Heart Lung Transplant 1998;17:167–175.
B. Geny et al. / Cardiovascular Research 51 (2001) 521 – 528
[15] El Gamel A, Yonan NA, Keevil B et al. Significance of raised
natriuretic peptides after bicaval and standard cardiac transplantation. Ann Thorac Surg 1997;63:1095–1100.
[16] Drake-Holland AJ, Noble MIM. Neural-natriuretic hormone interactions. Eur Heart J 2000;21:424–426.
[17] Geny B, Brandenberger G, Lonsdorfer J et al. Circulating adrenomedullin is increased after heart transplantation. Cardiovasc Res
1999;41:731–736.
[18] Geny B, Hardy H, Lampert E et al. Short-term effect of cyclosporine
on circulating adrenomedullin after heart transplantation. J Thorac
Cardiovasc Surg 1999;117:391–392.
[19] Freund BJ, Wade CE, Claybaugh JR. Effects of exercise on atrial
natriuretic factor. Release mechanism and implications for fluid
homeostasis. Sports Med 1988;6:364–376.
[20] Mannix ET, Palange P, Aronoff GR et al. Atrial natriuretic peptide
and the renin–aldosterone axis during exercise in man. Med Sci
Sports Exer 1990;22:785–789.
[21] Edwards BS, Zimmerman RS, Schwab TR et al. Atrial stretch, not
pressure, is the principal determinant controlling the acute release of
atrial natriuretic factor. Circ Res 1988;62:191–195.
[22] Miller TD, Rogers PJ, Bauer BA et al. What stimulates atrial
natriuretic factor release during exercise? J Lab Clin Med
1990;116:487–491.
[23] Keogh A, Nicholls G, Spratt P et al. Enhanced atrial natriuretic
factor release during exercise in cardiac transplant recipients.
Transpl Proc 1989;21:2576–2578.
[24] Singer DR, Banner NR, Cox A et al. Response to dynamic exercise
in cardiac transplant recipients: implications for the sodium regulatory hormone atrial natriuretic peptide. Clin Sci 1990;78:159–163.
[25] Starling RC, O’Dorisio TM, Malarkey WB et al. Preserved atrial
natriuretic peptide secretory function after cardiac transplantation.
Am J Cardiol 1991;68:237–241.
[26] Mettauer B, Lampert E, Lonsdorfer J et al. Cardio–respiratory and
neuro-hormonal responses to incremental maximal exercise of
patients with denervated transplanted hearts. Transpl Proc
1991;23:1178–1181.
[27] Pepke-Zaba J, Higenbottam TW, Morice A et al. Exercise increases
the release of atrial natriuretic peptide in heart transplant recipients.
Eur Clin Pharmacol 1992;42:21–24.
[28] Angermann CE, Spes CH, Dominiak P et al. Effects of graded
exercise on blood pressure, heart rate and plasma hormones in
cardiac transplant recipients before and during antihypertensive
therapy. Clin Invest 1992;70:14–21.
[29] Braith RW, Wood CE, Limacher MC et al. Abnormal neuroendocrine
responses during exercise in heart transplant recipients. Circulation
1992;86:1453–1463.
[30] Perrault H, Melin B, Jimenez C et al. Fluid-regulating and sympathoadrenal hormonal responses to peak exercise following cardiac
transplantation. J Appl Physiol 1994;76:230–235.
`
[31] Bussieres-Chafe
L, Pflugfelder PW, Henderson AR et al. Effect of
cardiac filling pressures on the release of atrial natriuretic peptide
during exercise in heart transplant recipients. Can J Cardiol
1994;10:245–250.
[32] Jahnke AW, Leyh R, Bernhard A et al. Atrial natriuretic peptide
release at rest and with exercise after cardiac transplantation with
bicaval anastomoses. J Thorac Cardiovasc Surg 1995;110:1600–
1605.
[33] Sehested J, Reinicke G, Ishino K et al. Blunted humoral responses to
mental stress and physical exercise in cardiac transplant recipients.
Eur Heart J 1995;16:852–858.
[34] Geny B, Charloux A, Lampert E et al. Enhanced brain natriuretic
peptide response to peak exercise in heart transplant recipients. J
Appl Physiol 1998;85:2270–2276.
[35] Geny B, Piquard F, Follenius M et al. Atrial natriuretic factor
secretion: a role for atrial systolic ejection force? Eur J Appl Physiol
1996;72:440–444.
[36] Farge D, Couetil JP, Guillemain R et al. Atrial natriuretic factor after
orthotopic heart transplantation. New Engl J Med 1991;4:777.
527
[37] de Bold A, Bruneau BG, Kuroski-de Bold M. Mechanical and
neuroendocrine regulation of the endocrine heart. Cardiovasc Res
1996;31:7–18.
[38] Donckier J, Hanet C, Galanti L et al. Low-dose endothelin-1
potentiates volume-induced secretion of atrial natriuretic factor. Am
J Physiol 1992;263:H939–H944.
[39] Ruskoaho H, Vakkuri O, Arjamaa O et al. Pressor hormones regulate
atrial-stretch induced release of atrial natriuretic peptide in the
pithed rat. Circ Res 1989;64:482–492.
[40] Fyhrquist F, Sirvio¨ ML, Helin K et al. Endothelin antiserum
decreases volume-stimulated and basal plasma concentration of
atrial natriuretc peptide. Circulation 1993;88:1172–1176.
[41] Lerman A, Kubo SH, Tschumperlin LK et al. Plasma endothelin
concentrations in humans with end-stage heart failure and after
transplantation. J Am Coll Cardiol 1992;20:849.
[42] Geny B, Piquard F, Lonsdorfer J et al. Endothelin and heart
transplantation. Cardiovasc Res 1998;39:556–562.
[43] Kushwaha SS, Banner NR, Patel N et al. Effect of bblockade on the
neurohumoral and cardiopulmonary response to dynamic exercise in
cardiac transplant recipients. Br Heart J 1994;71:431–436.
[44] Thamsborg G, Sykulski R, Larsen J et al. Effect of b-adrenorceptor
blockade on plasma levels of atrial natriuretic peptide during
exercise in normal man. Clin Physiol 1987;7:313–318.
[45] Scherrer U, Vissing SF, Morgan BJ et al. Cyclosporine-induced
sympathetic activation and hypertension after heart transplantation.
New Engl J Med 1990;323:693–699.
[46] Dananberg J, Grkin RJ. Corticoid regulation of atrial natriuretic
factor secretion and gene expression. Am J Physiol
1992;263:H1377–H1381.
[47] McDowell G, Cave M, Bainbridge A et al. Is the secretion of atrial
natriuretic peptide in man under neural control? Eur Heart J
2000;21:498–503.
[48] Geny B, Piquard F, Follenius M et al. Role of cardiac innervation in
atrial natriuretic peptide secretion in transplanted heart recipients.
Am J Physiol 1993;265:F112–F118.
[49] Quigg RJ, Rocco MB, Gauthier DF et al. Mechanism of the
attenuated peak heart rate response to exercise after orthotopic
cardiac transplantation. J Am Coll Cardiol 1989;14:338–344.
[50] Paulus WJ, Bronzwaer JGF, Felice H et al. Deficient acceleration of
left ventricular relaxation during exercise after heart transplantation.
Circulation 1992;86:1175–1185.
[51] Hall C, Sanderud J, Risoe C. Is there pericardial restriction to the
cardiac secretion of atrial natriuretic factor? Eur Surg Res
1993;25:155–161.
[52] Stone JA, Wilkes PR, Keane PM et al. Pericardial pressure attenuates release of atriopeptin in volume-expanded dogs. Am J
Physiol 1989;256:H648–H654.
[53] Perrault H, Cantin M, Thibault G et al. Plasma atrial natriuretic
peptide during brief upright and supine exercise in humans. J Appl
Physiol 1989;66:2159–2167.
[54] Kao AC, van Trigt P, Shaeffer-McCall GS et al. Central and
peripheral limitations to upright exercise in untrained cardiac
transplant recipients. Circulation 1994;89:2605–2615.
[55] Pope SE, Stinson EB, Daughters GT et al. Exercise response of the
denervated heart in long-term cardiac transplant recipients. Am J
Cardiol 1980;46:213–218.
[56] Rudas L, Pflugfelder PW, McKenzie FN et al. Normalisation of
upright exercises hemodynamics and improved exercise capacity 1
year after orthotopic cardiac transplantation. Am J Cardiol
1992;69:1336–1339.
[57] Young JB, Wintersz WL, Bourge R et al. Function of the heart
transplant recipient. J Am Coll Cardiol 1993;22:31–41.
[58] Braith RW, Plunkett MB, Mills RM. Cardiac output responses
during exercise in volume-expanded heart transplant recipients. Am
J Cardiol 1998;81:1152–1156.
[59] Richard R, Verdier JC, Duvallet A et al. Chronotropic competence in
trained heart transplant recipients. J Am Coll Cardiol 1999;33:192–
197.
528
B. Geny et al. / Cardiovascular Research 51 (2001) 521 – 528
[60] Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial
and brain natriuretic peptides during acute myocardial ischaemia
induced by dynamic exercise in patients with angina pectoris. Clin
Sci 1995;88:551–556.
[61] Morimoto A, Nishikimi T, Takaki H et al. Effect of exercise on
plasma adrenomedullin and natriuretic peptides levels in myocardial
infarction. Clin Exp Pharmacol Physiol 1997;24:315–320.
[62] Nicholson S, Richards M, Espiner E et al. Atrial and brain
natriuretic peptide response to exercise in patients with ischaemic
heart disease. Clin Exp Pharmacol Physiol 1993;20:535–540.
[63] Nishikimi T, Morimoto A, Ishikawa K et al. Different secretion
patterns of adrenomedullin, brain natriuretic peptide, and atrial
natriuretic peptide during exercise in hypertensive and normotensive
subjects. Clin Exp Hypertens 1997;19:503–518.
[64] Matsumoto A, Hirata Y, Momomura S et al. Effects of exercise on
plasma level of brain natriuretic peptide in congestive heart failure
with and without left ventricular dysfunction. Am Heart J
1995;129:139–145.
[65] Tanaka M, Ishizaka Y, Ishiyama Y et al. Exercise-induced secretion
of brain natriuretic peptide in essential hypertension and normal
subjects. Hypert Res 1995;18:159–166.
[66] Kohno M, Yasurani K, Yokogawa K et al. Plasma brain natriuretic
peptide during ergometric exercise in hypertensive patients with left
ventricular hypertrophy. Metabolism 1996;45:1326–1329.
[67] Hachida M, Saitou S, Nonoyama M et al. Mechanisms of exercise
response in the denervated heart after transplantation. Transpl Proc
1999;31:1966–1969.
[68] Hasegawa K, Fujiwara H, Itoh H et al. Light and electron microscopic localization of brain natriuretic peptide in relation to atrial
natriuretic peptide in porcine atrium: immunohistocytochemical
study using specific monoclonal antibodies. Circulation
1991;84:1203–1209.
[69] Kohno M, Horio T, Toda I et al. Cosecretion of atrial and brain
natriuretic peptides during supraventricular tachyarrhythmias. Am
Heart J 1992;123:1382–1384.
[70] Thibault T, Charbonneau C, Bilodeau J et al. Rat brain natriuretic
peptide is localized in atrial granules and released into the circulation. Am J Physiol 1992;263:R301–R309.
[71] Cheung B. Plasma concentration of brain natriuretic peptide is
related to diastolic function in hypertension. Clin Exp Pharmacol
Physiol 1997;24:966–968.
[72] Clarkson PBM, Wheeldon ML, MacFadyen RJ et al. Effect of brain
natriuretic peptide on hemodynamics and neurohormones in isolated
diastolic failure. Circulation 1996;93:2037–2042.
[73] Florkowski CM, Richards AM, Espiner EA et al. Renal, endocrine
and hemodynamic interactions of atrial and brain natriuretic peptides
in normal men. Am J Physiol 1994;266:R1244–R1250.
[74] Tanaka M, Kitamura K, Ishizaka Y et al. Plasma adrenomedullin in
various diseases and exercise-induced change in adrenomedullin in
healthy subjects. Intern Med 1995;34:728–733.
[75] Piquard F, Charloux A, Mettauer B et al. Exercise-induced increase
in circulating adrenomedullin is related to mean blood pressure in
heart transplant recipients. J Clin Endoc Metab 2000;85:2828–2831.
[76] Braith RW, Edwards DG. Exercise following heart transplantation.
Sports Med 2000;30:171–192.
[77] Braith RW, Welsch MA, Mills RM et al. Resistance exercise
prevents glucocorticoid-induced myopathy in heart transplant recipients. Med Sci Sports Exer 1998;30:483–489.
[78] Shoemaker JK, Green HJ, Ball-Burnett M et al. Relationships
between fluid and hormones and plasma volume during exercise
with training and detraining. Med Sci Sports Exer 1998;30:497–505.
[79] Kiilavuori K, Naveri H, Leinonen H et al. The effect of physical
training on hormonal status and exertional hormonal response in
patients with chronic congestive heart. Eur Heart J 1999;20:456–
464.
[80] Braith RW, Welsch MA, Feigenbaum MS et al. Neuroendocrine
activation in heart failure is modified by endurance exercise training.
J Am Coll Cardiol 1999;34:1170–1175.
[81] Geny B, Saini J, Mettauer B et al. Effect of short-term endurance
training on exercise capacity, haemodynamics and atrial natriuretic
peptide secretion in heart transplant recipients. Eur J Appl Physiol
1996;73:259–266.
[82] Saini J, Geny B, Brandenberger G et al. Training effects on the
hydromineral endocrine responses of cardiac transplant patients. Eur
J Appl Physiol 1995;70:226–233.
[83] Haywood GA, Counihan PJ, Sneddon JF et al. Increased renal and
forearm vasoconstriction in response to exercise after heart transplantation. Br Heart J 1993;70:247–251.
[84] Lang CC, Choy AM, Pringle TH et al. Renal, hemodynamic and
neurohormonal effects of atrial natriuretic factor in cardiac allograft
recipients treated with cyclosporin A. Am J Cardiol 1993;72:1083–
1084.
[85] Valsson F, Ricksten SE, Hedner T et al. Effect of atrial natriuretic
peptide on renal function after cardiac surgery and in cyclosporine
treated heart-transplant recipients. J Cardiothorac Vasc Anesth
1994;8:425–430.
[86] Geny B, Charloux A, Schaefer A et al. Normal short-term renal
response to acute volume expansion in heart-transplant recipients: a
role for atrial natriuretic peptide? J Heart Lung Transplant
1998;17:1081–1088.
[87] Geny B, Hardy H, Lonsdorfer J et al. Enhanced natriuretic response
to neutral endopeptidase inhibition in heart-transplant recipients.
Hypertension 1999;33:969–974.