1. health and fitness
2. disease

Cardiovascular Research 69 (2006) 26 – 35
www.elsevier.com/locate/cardiores
Review
Cardiac and peripheral actions of growth hormone and its releasing
peptides: Relevance for the treatment of cardiomyopathies
Sylvie Marleau a, Mukandila Mulumba a, Daniel Lamontagne a, Huy Ong a,b,*
b
a
Faculty of Pharmacy, Universite´ de Montre´al, Que´bec, Canada, H3T 1J4
Department of Pharmacology, Faculty of Medicine, Universite´ de Montre´al, Que´bec, Canada, H3T 1J4
Received 20 April 2005; received in revised form 5 August 2005; accepted 26 August 2005
Available online 10 October 2005
Time for primary review 29 days
Abstract
Keywords: Cardiomyopathy; Heart failure; Growth factors
1. Introduction
Systolic heart failure (HF) evolves as a consequence of a
number of cardiac diseases including hypertension, valvulopathy, ischemic and nonischemic cardiomyopathies (CM)
[1]. Nonischemic CM are primary myocardial pathologies
associated with systolic and/or diastolic dysfunction classified clinically as dilated, hypertrophic, restrictive and
arrhytmogenic [2]. Dilated and hypertrophic forms are the
most prevalent and lead to significant morbidity and
mortality [2]. Dilated CM (DCM) remains the first cause
for cardiac transplantation in the USA [3]. DCM, previously
largely known as ‘‘idiopathic’’ (IDCM), has been associated
with a number of gene defects encoding for cytoskeletal
(dystrophin, desmin), cell membrane (y-sarcoglycan), sar* Corresponding author. Faculty of Pharmacy, Universite´ de Montre´al,
2940 Chemin de la Polytechnique, Montre´al, Que´bec, Canada, H3T 1J4.
Tel.: +1 514 343 6460; fax: +1 514 343 2102.
E-mail address: [email protected] (H. Ong).
comeric (titin, troponin T and actin) and inner nuclear
membrane (lamin A/C) proteins [4]. In addition to its
genetic and familial origin, CM may occur as a consequence
of secondary causes including ischemic, viral, immunologic,
inflammatory, metabolic, toxic or neoplastic nature [3].
Among CM of secondary origin, ischemic CM is the leading
cause of left ventricular systolic dysfunction and HF [5].
Ventricular remodelling following myocardial infarction
(MI) largely account for the decline in left ventricular
(LV) function [5,6]. There is a general consensus to treat
patients, regardless of the etiology of HF, with a conventional drug regimen including angiotensin-converting
enzyme inhibitors, h-adrenoreceptor antagonists, diuretics
and digoxin [6,7]. However, despite optimal drug dosage,
congestive HF (CHF) in cardiomyopathic patients remains a
therapeutic challenge with a 3 –5 years mean survival time,
notwithstanding the origin of the disease [8].
Novel strategies to improve cardiac function in HF have
recently included growth hormone (GH), the insulin growth
factor-1 (IGF-1) and more recently, GH secretagogues
0008-6363/$ - see front matter D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2005.08.022
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Ischemic and nonischemic cardiomyopathies are associated with significant morbidity and mortality in industrialized countries.
Cardiomyopathies of primary origin, and more specifically the dilated form of the disease, have been associated with a number of gene
defects in cytoskeletal, membrane, and sarcomeric proteins. Cardiomyopathies of secondary origin such as ischemic cardiomyopathy remain
the leading cause of left ventricular systolic dysfunction and heart failure. Among novel strategies to improve cardiac function in heart failure,
treatment with growth hormone, insulin growth factor-1 (IGF-1), and natural and synthetic growth hormone-releasing peptides such as
ghrelin and hexarelin have been explored. The present review focuses on the issues involved in the use of exogenous growth hormone and its
releasing peptides in experimental animal models of chronic heart failure and in clinical studies on cardiomyopathic patients as potential
releasing peptides for the treatment of chronic heart failure developing as a consequence of cardiomyopathy.
D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
S. Marleau et al. / Cardiovascular Research 69 (2006) 26 – 35
(GHS) such as ghrelin and hexarelin. The present review
will specifically summarize key experimental and clinical
studies on the use of GH and GHS for the treatment of CHF
as a consequence of CM.
2. Cardiovascular effects of GH replacement therapy in
patients with GH deficiency
3. GH and GHS in experimental heart failure
Experimental models have explored the effects of
exogenous GH and/or IGF-1, and more recently of GHS,
on cardiac function and survival in ischemic and nonischemic CM models. Whereas the effects of GH on
ischemic CM progression has mainly been investigated in
the context of post-ischemic cardiac failure in the rat, its
effects on nonischemic CM progression have essentially
relied on the use of models of genetically inherited CM in
hamsters and more recently, of genetically engineered CM
mice [20].
3.1. Effect of GH/IGF-1 on post-myocardial infarction heart
failure
As shown in Table 1, initial studies investigating the
effects of early GH treatment on ventricular remodelling
post-MI in rats reported a reduction of ventricular aneurysms 25 days post-infarction, following a 3-day treatment
with recombinant human GH (rhGH) (0.17 mg/kg daily)
beginning the day of left coronary artery ligation (LCAL)
[21]. The beneficial effects of GH were attributed to the
preservation of the collagen network. These results contrast
with those of Bollano et al. (2001) who did not find a
difference in aneurysms after a 9-day treatment with GH at a
10-fold higher dose [22]. Additional studies showed the
benefits of an early treatment with GH, inducing ventricular
hypertrophy and improving function following LCAL in
rats. A 3-week treatment with 3 mg/kg rhGH, starting the
day after LCAL, caused a beneficial hypertrophy of the noninfarcted myocardium, along with a reduction in LV dilation
and vascular resistance that led to an improved cardiac
performance [23]. A 4-week treatment with rhGH (0.67 mg/
kg), initiated immediately following LCAL, improved
considerably cardiac function, in association with reduced
pathological remodelling [24]. In a larger animal model,
recombinant bovine GH (rbGH) elicited a dose-dependent
cardiac hypertrophy following infarction, associated with an
increased cardiac level of IGF-1 [25]. In contrast, an early
treatment with rhGH (3 mg/kg per day for 3 weeks), starting
3 days post-surgery, attenuated LV remodelling without
induction of LV hypertrophy in rats with large MI, an effect
associated with an improved myocardial energy status, a
decreased myocardial and plasma catecholamines and brain
natriuretic peptide levels [26].
Beneficial effects of early combined treatment with IGF1 and GH post-infarction have also been reported, as shown
in Table 1. Early treatments with IGF-1 and/or GH, initiated
24 – 72 h after LCAL had no effect on the extent of MI
[23,27]. However, a beneficial effect on infarct size was
observed after initiating treatment with rhGH (1 mg/kg
twice daily) as early as 20 min post-surgery [28]. These
investigators observed that a 2-week treatment with GH
reduced infarct size by 18% and increased survival by 36%
up to 52 weeks post-MI. However, others failed to observe
beneficial effects of early recombinant rat GH (rrGH)
administration in rats with large MI [29] or in CHF in
volume-overloaded rats (rhGH, 2 mg/kg per day for 4
weeks), although renal function was improved, possibly as a
consequence of the enhanced renal nitric oxide (NO) system
activity [30]. Others reported that rhGH administration (0.8
mg/kg daily for 4 weeks) did not further stimulate the renin
system or sodium retention post-MI in rats [31].
The effect of late treatment (initiated 4 to 6 weeks after
LCAL) with GH and/or IGF-1 on heart function and
survival, has also been studied as shown in Table 1. A 2week treatment with rhGH (2 mg/kg daily), starting 4 weeks
after LCAL, was able to prevent the reduction in cardiac
index observed in untreated rats, despite similar extent of
MI between groups [32]. GH-treated rats had reduced
systemic vascular resistance (SVR) and increased dP / dt,
which might have contributed to the benefits of treatment.
Reduced SVR, possibly as a consequence of an increased
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One basis for investigating the effects of anabolic agents
in CHF relies on the observed benefits of GH replacement
therapy in improving cardiovascular performance in GHdeficient patients. Epidemiological studies of GH deficiency
(GHD) revealed this clinical condition to be associated with
an increased prevalence in cardiovascular mortality, mainly
as a consequence of HF [9].
GH replacement therapy in adults with either childhood
or adulthood GHD appears to be salutary and is accompanied with an increase in left ventricular mass (LVM)
[10,11], an improved LV function [12], a reduced diastolic
blood pressure [12] and a rise in exercise capacity [13,14].
Additional benefits of GH replacement therapy include
development of a favorable plasma lipid profile [15,16] and
a general sense of well-being in patients [17]. Short-term
treatment with GH also improves the altered ventricular
geometry [9]. The response to GH in GHD patients is timeand dose-dependent, and may take up to 6 months to be
fully appreciated [18]. In addition, peripheral vasodilatory
effects of GH replacement therapy through normalized/
enhanced production of NO, may contribute to the improved
cardiac performance observed in patients with GHD [19].
The apparent benefits of GH on the cardiovascular
function of patients with GHD gave rise to extensive
clinical and experimental studies of the effects of GH and
GHS on the cardiovascular function in different pathological
settings.
27
28
Table 1
Studies of GH and/or IGF-1 in experimental heart failure
Species
Model
Treatment
Dose, duration, initiation of treatment
Main outcomes
Early treatment with GH
Castagnigno, 1990 [21]
SD rats
LCAL*
rhGH
0.5 U (0.17 mg)**/kg/day 3 days, day of LCAL
Bollano, 2001 [22]
Cittadini, 1997 [23]
SD rats
SD rats
LCAL
LCAL
rhGH
rhGH
Grimm, 1998 [24]
Wistar rats
LCAL
rhGH
2
3
1
2
Reduction of ventricular aneurysms
25 days post-infarction
No change in aneurysms
Increased cardiomyocyte area
Matthews, 2004 [25]
Omerovic, 2000 [26]
Sheep
SD rats
LCAL
LCAL
rbGH
rhGH
0.3 – 1 mg/kg/day 30 days, after LCAL
3 mg/kg/day 3 weeks, 3 days post-infarct
Shen, Y.-T., 1996 [29]
SD rats (females)
rrGH
3.2 mg/kg/day 4 weeks, starting after surgery
Pagel, I., 2002 [30]
Wistar rats
Direct myocardial injury and
LCAL (infarct > 45% of the LV)
Infrarenal aortocaval shunt
Improved cardiac function and
decreased remodelling
Increased cardiomyocyte area
Improved myocardial energy
status and decreased remodelling
No beneficial effect
rhGH
2 mg/kg/day 4 weeks, starting
1 day after surgery
No improvement of cardiac
function but improved renal function
Early treatment with IGF-1 and/or GH
Duerr, R.L., 1995 [27]
SD rats (females)
Jin, H., 2002 [28]
SD rats
LCAL
LCAL
rhIGF-1
rhGH and
rhIGF-1
3 mg/kg/day 14 days, starting 2 days post-surgery
2 mg/kg/day each 14 days, starting
20 min post-surgery
Ventricular hypertrophy
Reduced infarct size and improved survival
Late treatment with GH and/or IGF-1
Yang, R., 1995 [32]
SD rats
Tivesten, A., 2001 [33]
SD rats
LCAL
LCAL
SD rats
SD rats (females)
LCAL
LCAL
Tajima, M., 1999 [36]
Shen, Y.T., 1998 [37]
SD rats, male
Mongrel dogs
LCAL
Rapid pacing
2 mg/kg/day 15 days, starting 4 weeks after surgery
1.1 mg/kg/day 4 weeks or, 3 mg/kg/day,
starting 4 weeks after surgery
1 mg/kg/day 1 week, starting 6 weeks after surgery
0.2 mg/kd/day and 3 mg/kg/day, starting 4 weeks
after LCAL
3.5 mg/kg/day 14 days, starting 6 weeks after surgery
0.06 mg/kg/day 4 weeks starting
on the 7th day of ventricular pacing
Improved cardiac function and reduced SVR
Improved systolic function and reduced SVR
Isgaard, J., 1997 [34]
Duerr, R.L., 1996 [35]
rhGH
rhGH
rhIGF-1
rhGH
rhGH
rhIGF-1
rhGH
rpGH
mg/kg/day 9 days, 3 days post-surgery
mg/kg/day (in 2 injections) 3 weeks,
day post-surgery
U (0.67 mg)/kg/day 4 weeks, after LCAL
Improved systolic function
Reduced SVR, increased CO
Improved contractile function
No beneficial effect
*Abbreviations: SD—Sprague Dawley; rbGH—recombinant bovine GH; rhGH—recombinant human GH; rrGH—recombinant rat GH; rhIGF—1-recombinant human IGF-1; rpGH—recombinant porcine GH;
CO—cardiac output, **1 mg rhGH IRP 88/624 = 3 U (Growth Hormone Research Society recommendation, 1997).
S. Marleau et al. / Cardiovascular Research 69 (2006) 26 – 35
First author, date
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Dogs
CHF 147 hamsters
UM-X7.1 hamsters
BIO TO-2 hamsters
Ryoke, 1999 [49]
Marleau, 2002 [50]
Iwase, 2004 [51]
Genetically transmitted
Genetically transmitted
Genetically transmitted
SD rats
De Gennaro Colonna,
1997 [43]
Shen, 2003 [44]
*Abbreviations: SD—Sprague Dawley. rhGH—recombinant human GH; rpGH—recombinant porcine GH; rbGH—recombinant bovine GH.
No beneficial effect;
improved cardiac function
Improved LV dysfunction at 4 months of age
Reduced cardiac performance and survival
GHRP-6 improved LV dysfunction independently
of GH-IGF-1
0.06 mg/kg/day,
0.2 mg/kg/day 3 weeks; 7 days after pacing
2 mg/kg BID 21 days; 4 or 10 months of age
1 mg/kg/day 80 or 210 days; 160 or 30 days of age
0.2 or 2 mg/kg/day 4 weeks,
100 Ag/kg/day; 8 weeks of age
rpGH
GHRP-6
rhGH
rbGH
rhGH
GHRP-6
Hexarelin, MK-0677
Ghrelin
Hexarelin
Wistar rats
Frascarelli, 2003 [42]
Isolated working rat heart
(ischemic injury)
Isolated working rat heart
(ischemic injury)
Pacing and LCAL
SD rats
Tivesten, 2000 [41]
LCAL
rhGH Hexarelin
1.25 mg/kg BID 5 or 50 Ag/kg BID 14 days;
4 weeks post-surgery
1 AM, 1 AM (20 min perfusion)
20 nM
80 Ag/kg BID from day 25 to 40
Improved LV dysfunction and attenuated
remodelling
Improved cardiac function and reduced total
peripheral resistance
Cardioprotective effect; no beneficial effect,
Cardioprotective effect
Cardioprotective effect
100 Ag/kg BID 3 weeks; 4 weeks after surgery
Wistar rats
Nagaya, 2001 [40]
LCAL*
Ghrelin
Main outcomes
Treatment
Model
Species
First author, date
An alternative approach for increasing systemic levels
GH, possibly in a more physiological manner, is the
administration of GHS [38], of which ghrelin is the
endogenous representative [39]. Ghrelin, a 28-amino acid
peptide n-octanoylated at serine 3, exerts its neuroendocrine
effects through stimulating 7 transmembrane G proteincoupled receptors (GHS-R1a) [39]. As shown in Table 2,
ghrelin, in a chronic HF model in rats, improved LV
function and attenuated the development of LV remodelling
and cardiac cachexia at a dose of 100 Ag/kg twice daily for 3
weeks [40]. These effects were attributed to both GH/IGF-1dependent and GH-independent vasodilatory effects of
ghrelin. Using a similar experimental model, Tivesten et
al. showed that hexarelin, at a dose of a 100 Ag/kg daily for
14 days, improved cardiac performance as shown by an
increased stroke volume and reduced total peripheral
resistance [41]. In additional studies, ghrelin or hexarelin,
in contrast to the non-peptidic MK-0677 GHS analogue,
decreased myocardial ischemic injury in isolated working
rat heart models [42,43]. In dogs rendered cardiomyopathic
following chronic pacing and subjected to acute ischemia by
Table 2
Studies of GH and/or GHS in experimental heart failure
3.2. Effects of GHS in cardiac cachexia and heart failure
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production of NO, contributed to the overall beneficial
cardiovascular effect of rhGH (1.1 mg/kg) or rhIGF-1 (3
mg/kg) treatment, initiated 4 weeks after LCAL in rats for a
period of 2 weeks [33]. Additional studies have confirmed
that late treatment with rhGH improved systolic function,
despite the absence of cardiac hypertrophy [34].
Combined administration of 3 mg/kg rhIGF-1 daily and
0.1 mg rhGH twice a day for four weeks, starting 4 weeks
after LCAL, increased cardiac output in treated rats,
probably due to the massive reduction in SVR [35].
However, no significant increase in cardiac index was
found with combined GH/IGF-1 treatment, except in rats
with larger infarct size. The beneficial effect of rhGH on
ventricular contractile function post-MI has been confirmed
in vitro, where cardiomyocytes isolated from rats treated
with 3.5 mg/kg daily for 2 weeks, 4 weeks after LCAL,
displayed improved contractile reserve and intracellular
calcium transients [36]. Besides these positive observations,
no beneficial effect of a late treatment with recombinant
porcine GH (rpGH, 0.06 mg/kg for 3 weeks) was observed
in a dog model of pacing-induced HF [37].
Although contradictory observations of early or late GH
treatment on cardiovascular performance in experimental
studies might be related to the heterogeneous origin of HF
[30], the different dosing regimens and duration of treatment
may also have a significant impact on these divergent
observations. A clear limitation of all these experimental
studies with GH and/or IGF-1 is their short duration. One of
the restrictions is due to the use of rhGH in rats and the
production of anti-GH antibodies. Therefore, the long-term
effects (either beneficial or deleterious) remain unknown in
these models.
29
Dose, duration; initiation of treatment
S. Marleau et al. / Cardiovascular Research 69 (2006) 26 – 35
30
S. Marleau et al. / Cardiovascular Research 69 (2006) 26 – 35
transient coronary occlusion, growth hormone-releasing
peptide (GHRP)-6, at a dose of 0.2 mg/kg for 3 weeks,
increased survival rate without any hemodynamic changes
in contrast to GH, suggesting that these effects are mediated
by GHS receptors rather than through the GH axis [44].
Overall, GHS exert beneficial effects on cardiovascular
function in experimental models of ischemia-reperfusion
injury and CHF which are, at least in part, mediated via GHindependent pathways.
3.3. Effect of GH and GHS in cardiomyopathic hamsters
4. GH and GHS in patients with heart failure secondary
to ischemic or nonischemic cardiomyopathy
Clinical studies in patients with GHD, suggested that
patients with either ischemic or nonischemic CM may
benefit from GH therapy, mainly from reduction of LV
maladaptive remodelling and cardiomyocyte loss [52].
However, clinical studies in patients with HF of different
etiologies led to conflicting conclusions. As for experimental studies, factors that have possibly contributed to the
divergent results include different dosing regimens, the
stage of the disease at treatment initiation, the concomitant
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Genetically inherited cardiomyopathies in Syrian hamsters (CMH) may be classified according to their prominent
feature, either ventricular dilatation in TO-2 [45] and
MS200 [46], both derived from BIO 53.58, or hypertrophy
in BIO 14.6 and derived strains including CHF-146, UMX7.1 and CHF-147, a UM-X7.1 CMH subline [47,48].
Ryoke et al. [49] have assessed the effect of a 4-week
treatment with doses of rhGH (2 mg/kg twice a day for 21
days) in CMH of the CHF 147 line, starting at 4 or 10
months of age. An increase in LV dP / dt max and a decrease
in SVR were observed in both groups. In addition,
meridional stress of the LV wall at end systole was
reduced in 4- but not 10-month old CMH. Meridional
stress of the LV wall at end diastole and LVEDP were
significantly increased in 10-month old CMH. These
observations suggest that GH may exert a beneficial effect,
however limited to conditions where diastolic function is
not impaired [49]. We have previously assessed the effect
of life span therapy with rbGH at a dose of 1 mg/kg per
day on the cardiovascular function of UM-X7.1 CMH
[50]. Long-term use of rbGH in CMH was not associated
with appearance of anti-GH antibodies up to 210 days of
treatment. Our results showed that a chronic treatment with
rbGH is associated with a reduced cardiac performance
and survival at the terminal stage of the disease [50]. The
effects of GHS were also investigated in TO-2 CMH, in
which a 4-week treatment with GHRP-6 (100 Ag/kg daily)
improved LV systolic performance and attenuated LV
dilation [51]. This beneficial effect was found to be
independent of GH/IGF-1 axis.
use of drugs [53], acquired GH resistance and disease origin
[54 – 56].
In nonischemic HF such as IDCM, global, rather than
localized ventricular dysfunction as seen in ischemic CM is
observed [57]. Studies conducted in patients with CM are
summarized in Table 3. The first non-randomized study of
rhGH administration (0.05 mg/kg per week for 3 months) in
a few patients with IDCM, was reported by Fazio et al. in
1996 [58]. GH therapy was associated with an increase in
LVM and cardiac output and with a reduced neurohormonal
activation, which led to an increased tolerance and a reduced
energetic cost at effort in patients [59]. In contrast, Osterziel
et al. (1998), in a larger randomized, placebo-controlled
study, showed that GH, at a dose of 0.67 mg/day for 3
months, was not beneficial to the cardiac function of
patients with IDCM, despite increased LVM and IGF-1
levels [60]. Perrot et al. (2001) observed that elevated IGF-1
circulating levels above 80 ng/ml in response to GH
administration led to an increase in LV ejection fraction
(LVEF) in patients [8]. Jose et al. (1999) observed an
increase in LVM associated with functional improvement
following a 6-month treatment with 0.67 mg of rhGH on
alternate days [61]. Similar observations were reported
recently by Adamopolous et al. (2003), who showed that
GH, at a dose of 1.33 mg on alternate days for 3 months,
induced an increase in myocardial wall thickness and
contractile reserve associated with a decrease in end systolic
volume and wall stress in patients with IDCM [52]. These
investigators proposed that the potent anti-inflammatory and
anti-apoptotic effects of GH may contribute to attenuate
maladaptive remodelling in end-stage HF [52].
The potentially beneficial effect of GH therapy in
patients with ischemic HF was initially reported in isolated
case reports [62]. Non-randomized studies in a low number
of patients showed clinical improvement associated with
reduced systolic wall stress and increased exercise performance at dosing regimens ranging from 0.002 to 0.67 mg/kg
daily for periods of 3 to 6 months [63 –65]. In contrast, a
randomized study in 22 patients with ischemic HF, treated
with a maintenance dose of 0.77 mg rhGH per day for 6
months, did not show beneficial effects on either systolic or
diastolic function [53,66].
Studies conducted in patients with HF of mixed
etiologies, showed that GH treatment at a dose of 0.03
mg/kg per week for 1 week, followed by 0.08 mg/kg per
week during 3 months, increased IGF-1 levels but did not
improve cardiac function [67]. In agreement, Acevedo et al.
(2003) did not observe benefits in their patients after 8
weeks of treatment with rhGH at a dose of 0.012 mg/kg/day
for 8 weeks [68]. However, Napoli et al. (2002) observed
improvement of the endothelial function in 16 patients
treated with 1.33 mg GH every second day after a period of
3 months [69].
In healthy volunteers and in patients with GHD, an acute
administration of hexarelin (2 Ag/kg) elicited a short-term
increase in contractility and LVEF in a GH-independent
Table 3
GH and GHS in patients with cardiomyopathies of different origin
Etiology
Type of study number of patients
Treatment
Dose, duration
Main outcomes
Treatment with GH
Fazio, 1996 [58]
DCM*
Non randomized or controlled, 7 patients
rhGH
Osterziel, 1998 [60]
DCM
Randomized, placebo-controlled, 50 patients
rhGH
Reduced LV chamber size; improved
hemodynamics and clinical status
Increased LVM but no clinical benefit
Perrot, 2001 [8]
DCM
Randomized, placebo-controlled, 50 patients
rhGH
Jose, 1999 [61]
DCM
rhGH
Adamopoulos,
2003 [52]
O_Driscoll, 1997 [62]
DCM
Non randomized or placebo-controlled,
6 patients
Randomized cross-over study 12 patients
0.15 (0.05 mg)** to 0.2 U
(0.07 mg)/kg/week 3 months
0.5 U (0.17 mg)/day up to 2 U
(0.67 mg)/day 12 weeks
0.5 U (0.17 mg)/day up to 2 U
(0.67 mg)/day 12 weeks
2 U (0.67 mg) on alternate days 6 months
rhGH
4 U (1.33 mg) on alternate days 12 weeks
Ischemic, severe HF
Case reports, 2 patients
rhGH
Genth-Zotz, 1999 [63]
Non randomized or placebo-controlled,
7 patients
Placebo controlled, 20 patients
rhGH
rhGH
0.006 (2 Ag) – 0.002 (0.7 Ag)/kg 6 months
Van Thiel, 2004 [53]
Ischemic, mild to
moderate HF
Ischemic, NYHA
class II or III HF
Ischemic, LVEF < 40%
14 U (4.7 mg)/day 7 days or 10 U
(3.3 mg) 6 weeks
2 U (0.67 mg)/day 3 months
study
rhGH
Smit, 2001 [66]
Ischemic, LVEF < 40%
study
rhGH
Isgaard, 1998 [67]
Mixed, NYHA
class II or III HF
Mixed, NYHA
class III HF
Randomized, placebo-controlled
11 patients per group
Randomized, placebo-controlled
11 patients per group
Randomized, placebo-controlled
11 patients per group
Randomized, placebo-controlled
9 (placebo) and
10 (GH) patients per group
Randomized, placebo-controlled
8 patients per group
study
rhGH
study
rhGH
0.5 U (0.17 mg) up to 2 U
(0.67 mg)/day 26 weeks
0.5 U (0.17 mg) up to 2 U
(0.67 mg)/day 26 weeks
0.1 U (0.033 mg) up to 0.25 U (0.83 mg)/kg
(4 U (1.33 mg)/day maximum) 3 months
0.035 U (0,012 mg)/kg/day 8 weeks
No beneficial effect
study
rhGH
4 U (1.33 mg) every other day 3 months
Normalized endothelial dysfunction
Hexarelin
2 Ag/kg (bolus)
Short-lasting, positive inotropic effect
Hexarelin
2 Ag/kg (bolus)
Ghrelin
0, 1, 5 and 10 Ag/kg (bolus)
Ghrelin
0.1 Ag/kg/min 60 min
Increased LVEF in ischemic DCM
not in IDCM
Enhanced cardiac performance;
dose-dependent GH release
Decreased mean arterial blood pressure and
increased cardiac and stroke volume index
Spallarossa, 1999 [64]
Acevedo, 2003 [68]
Napoli, 2002 [69]
Treatment with GHS
Bisi, 1999 [71]
Imazio, 2002 [72]
Enomoto, 2003 [73]
Nagaya, 2001 [74]
Mixed, NYHA
class II or III HF
GHD patients and
control subjects
Mixed, NYHA class
II HF
Control subjects
Mixed, NYHA class
II or III HF
Placebo-controlled study 7 GHD patients
9 control subjects
Non randomized or placebo-controlled
study 13 patients
Randomized order of administration
6 control subjects
Randomized, placebo-controlled study
6 patients per group
Increased LVEF
(if IGF-1 elevation > 80 pg/ml)
Increased wall thickness and improved
clinical status
Decreased pro-inflammatory cytokines and
improved LV contractile performance
Improved exercise tolerance
Improved clinical status and reduced
LV remodelling
Increase in exercise tolerance; deleterious
if severe HF
No beneficial effect
No beneficial effect
No beneficial effect
S. Marleau et al. / Cardiovascular Research 69 (2006) 26 – 35
First author, date
*Abbreviations: NYHA—New York Heart Association; rhGH—recombinant human GH; **1 mg rhGH IRP 88/624 = 3 U.
31
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32
S. Marleau et al. / Cardiovascular Research 69 (2006) 26 – 35
manner [70,71]. Similar results were observed in patients
with ischemic CM, not with IDCM [72]. Studies with
ghrelin showed an improved cardiac performance following
acute administration, although this effect was associated
with a dose-dependent increase in GH [73]. When administered in healthy volunteers and in patients with HF of
different origins, a short-term infusion of ghrelin (0.1 Ag/kg/
min 60 min) decreased mean arterial pressure and
increased cardiac and stroke volume index, which may be
related to a reduced SVR through GHSR-1a in the
vasculature [73,74].
5. Effect of GH/IGF-1 and GHS in regulating
cardiomyocyte apoptosis
6. Concluding remarks
Although promising effects of GH/IGF-1 were observed
in experimental HF models, the only significantly positive
clinical outcome was the improvement of cardiovascular
function in patients with GHD. The lack of significant
benefits of GH/IGF-1 therapy in human patients with HF
secondary to CM of different origins might be related to the
clinical stage at the onset of therapy, the dosing regimen and
duration of treatment. Further studies are required for the
optimization of GH/IGF-1 therapy in patients with CM. The
GH-independent effect of GHS for the treatment of CM
might be related to their role in the prevention of apoptosis
associated with the development of HF.
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Cardiomyocyte loss through apoptosis has been shown
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