Download Heart Failure as a Multiple Hormonal Deficiency Syndrome

Heart Failure as a Multiple Hormonal Deficiency Syndrome
Luigi Saccà, MD
T
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he classic neurohormonal model of heart failure (HF) is
rooted in the overexpression of neurohormonal molecules. To complement this paradigm, increasing evidence
indicates that a variety of hormones and metabolic signals
may be downregulated in HF patients. The list of downregulated molecules includes growth hormone (GH), its tissue
effector insulin-like growth factor-1 (IGF-1), thyroid hormone, and anabolic steroids.1– 4 In addition, HF is complicated by insulin resistance (IR), which ultimately means
downregulation of insulin signaling.5,6 This review examines
the evidence in support of the concept that HF is a multiple
hormonal and metabolic deficiency syndrome (MHD). Particular attention is focused on the relevance of MHD in terms
of cardiac performance and physical capacity and its impact
on HF progression. Translation of new concepts into potential
therapeutic options is also discussed.
the initial stages of HF, a fetal pattern of metabolic genes
re-emerges and causes a major shift in substrate preference,
with glucose becoming the primary substrate that is oxidized.17,18 This shift provides 40% to 50% more ATP per
oxygen molecule consumed.19 When IR superimposes on HF,
the increased FFA flux maximizes myocardial FFA oxidation, whereas glucose uptake is downregulated.20 The consequent reduction in energy production and metabolic flexibility accounts for the so-called “IR cardiomyopathy.”21 The
role of impaired glucose uptake is supported by the finding
that cardiac-specific overexpression of GLUT1 prevents cardiac dysfunction.22
IR is a new potential target in the treatment of HF.23
However, few measures are able to improve myocardial
metabolism. Some of them (diet, physical exercise, and
carvedilol among ␤-blockers) are components of standard HF
treatment. Hyperinsulinemia is a powerful tool to overcome
IR. However, there are well-grounded reservations regarding
insulin use in type 2 diabetics with HF. In a study of 554
patients with advanced HF, insulin-treated diabetes was an
independent predictor of mortality (hazard ratio, 4.3).24
Metabolic modulators (trimetazidine, perhexiline, ranolazine) block mitochondrial FFA entry or FFA ␤-oxidation.
However, there are no clinical data about the myocardial and
long-term effects of these drugs. Moreover, if myocardial
insulin sensitivity is not restored, inhibiting FFA oxidation
may further compromise cardiac dysfunction.25
The insulin-sensitizers thiazolidinediones (TZDs) improve
myocardial glucose uptake and contractile dysfunction.26 –28
Unfortunately, meta-analyses of clinical trials revealed a high
incidence of HF symptoms in the TZD arms.29,30 This
finding led health authorities (the European Medicines
Agency and the Food and Drug Administration) to issue
contraindications or warnings against the use of TZDs in
HF. However, there are no reports of increased mortality
from HF during TZD treatment. Moreover, TZD-related
HF does not appear to be due to the worsening of cardiac
performance but to peripheral mechanisms (fluid retention
and increased vascular permeability).
By activating AMPK, metformin stimulates GLUT4 translocation and glucose uptake in cardiac muscle and in insulinresistant cardiomyocytes.31,32 Until recently, metformin was
contraindicated in diabetics with HF because of the remote
IR and HF
A bidirectional link exists between IR and HF. IR predicts HF
independently of other risk factors.7 Conversely, patients with
HF are predisposed to IR or type 2 diabetes.5,8 In the
OPTIMIZE-HF study, 42% of patients hospitalized for HF
also had diabetes.9 IR is present in about one third of
nondiabetic. HF patients and associates with more severe
HF symptoms, worse functional capacity, and poor survival.5,6 IR per se, independent of hyperglycemia and hyperinsulinemia, may exert deleterious cardiovascular
effects.10
IR specifically involves the myocardial tissue. In a dog
model of HF, myocardial glucose uptake was 32% lower
(P⬍0.01) than pre-HF values, and this decrease was associated with reduced translocation of GLUT4 and downregulation of phosphorylated Akt.11 A positron emission tomography study showed impaired myocardial uptake of glucose and
increased uptake of free fatty acid (FFA) in HF patients.12
Several mechanisms may explain why HF is complicated
by IR. A key factor is adrenergic overactivity. The insulinantagonistic effect of catecholamines is well established.13,14
Angiotensin II, which is overproduced in HF, may inhibit
norepinephrine reuptake in the myocardium. A more recent
positron emission tomography study showed that the reduced
norepinephrine reuptake correlates with regional IR.15
The failing heart is characterized by a marked fall in
phosphocreatine and in the phosphocreatine/ATP ratio.16 In
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy.
Correspondence to: Luigi Saccà, MD, Department of Internal Medicine, Via Pansini 5, 80131 Naples, Italy. E-mail [email protected]
(Circ Heart Fail. 2009;2:151-156.)
© 2009 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
151
DOI: 10.1161/CIRCHEARTFAILURE.108.821892
152
Circ Heart Fail
March 2009
Table 1. Clinical Studies Reporting Serum IGF-1 Levels
(ng/mL) in Patients With Moderate to Severe HF and Controls
HF
Broglio et al
38
Anker et al39
Al-Obaidi et al40
Anwar et al41
135⫾47 (n⫽39)
Controls
194⫾64 (n⫽42)
124⫾9 (n⫽21)
151⫾9 (n⫽26)
121⫾18 (n⫽12)
108⫾15 (n⫽21)
83⫾5 (n⫽60)
95⫾5 (n⫽103)
Saeki et al
101⫾34 (n⫽18)
173⫾27 (n⫽15)
Kontoleon et al2
124⫾49 (n⫽23)
236⫾66 (n⫽23)
42
Jankowska et al3
Weighted mean
208 (n⫽183)
168
299 (n⫽366)
236
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possibility of lactic acidosis. The FDA’s stance has recently
changed from contraindication to a black-box warning.
Glucagon-like peptide-1 is a novel antidiabetic agent that
stimulates GLUT1 translocation and myocardial glucose
uptake.33 A 5-week infusion of glucagon-like peptide-1 in HF
patients with New York Heart Association class III/IV
improved LV ejection fraction (EF) (from 21⫾3% to
27⫾3%; P⬍0.01) and maximal oxygen consumption.34
Given its efficacy and good tolerability, glucagon-like
peptide-1 and its analogs are promising candidates for the
treatment of IR cardiomyopathy.
The Low IGF-1 Syndrome in HF
GH and IGF-1 are essential for preserving both cardiac
morphology and performance in adult life.35,36 Patients with
GH deficiency have impaired cardiac performance, increased
peripheral vascular resistance (PVR), and reduced exercise
capacity.37 Table 1 reports the basal, unstimulated serum
concentration of IGF-1 in patients with HF.2,3,38 – 42 In most
studies, IGF-1 was reduced in HF patients and more in
patients with either advanced HF43 or cardiac cachexia.39 The
prevalence of IGF-1 deficiency, defined as an IGF-1 level
below the tenth percentile of healthy peers, was as high as
64%.3
The finding of low IGF-1 in HF patients is relevant for
many reasons. First, individuals with low IGF-1 levels
undergo cardiovascular alterations that are reminiscent of
those observed in HF patients and are corrected by replacement therapy.37,44 These observations demonstrate the continuing ability of IGF-1 to modulate the plasticity of cardiac
tissue in adult life. Second, large population-based studies
(Framingham, DAN-MONICA, and Rancho Bernardo) show
that a low level of IGF-1 is predictive of HF, ischemic heart
disease, and cardiovascular mortality.45– 47 Third, low IGF-1
levels in HF patients are associated with greater cytokine and
neurohormonal activation, reduced skeletal muscle performance, endothelial dysfunction, and poor outcome.43,48,49
These data support the concept that low IGF-1 in HF is not a
simple biomarker, but it is also mechanistically linked to HF
and its severity.
Reduced IGF-1 levels in HF patients may be due to
deficient GH secretion or to reduced responsiveness of
IGF-1-generating tissues to GH. GH secretion was assessed
by the GHRH plus arginine test in 34-well-nourished patients
with HF (EF, 23%) and compared with a group of 39 healthy
controls.1 The GH response was markedly impaired in the HF
patients (18⫾3 ng/mL versus 34⫾5; P⬍0.01). Also spontaneous GH secretion is defective in HF patients. The mean
nocturnal GH and the peak GH were markedly reduced in HF
patients with severely compromised LV function (EF,
⬍20%).50
With regard to GH resistance, the response of IGF-1 to GH
was assessed in 39 patients with HF in good nutritional state
and in 42 age-matched controls. After 4 days of 5 or 10
mU/kg per day GH administration, IGF-I levels in HF
patients rose to levels similar to those of the controls,
indicating that GH sensitivity was preserved in HF patients.38
Subsequent studies addressed the issue of GH resistance in
HF patients in relation to the presence of cardiac cachexia.39
The IGF-1/GH ratio was 12-fold higher in noncachectic
patients than in cachectic patients with HF. The difference is
impressive and, although the IGF-1/GH ratio is a crude index
of GH sensitivity, the data strongly suggest that cardiac
cachexia causes GH resistance. However, cachexia is not the
only cause of GH resistance because the response of IGF-1 to
GH administration is extremely variable and may be independent of nutritional problems. This point is well discussed
in a recent meta-analysis in which the effects of GH were
analyzed in relation to the IGF-1 response.51
As yet, no study has evaluated whether administration of
customized amounts of GH or IGF-1 will benefit HF patients
who have documented GH deficiency and low IGF-1 levels.
The Low-T3 Syndrome in HF
T3 is generated from T4 by the activity of 5⬘monodeiodinase. T3 increases cardiac output by affecting all
the determinants of cardiac performance (ie, preload, afterload, contractility, and heart rate).52 An important, nongenomic effect of T3 is exerted in the resistance vessels,
where T3 induces relaxation of the vascular smooth muscle
cells.53 This effect of T3 is mediated by the endothelial
PI3-K/Akt/endothelial nitric oxide synthase signaling complex.54,55 The augmented nitric oxide availability activates
guanosine 3⬘,5⬘-cyclic monophosphate in the vascular smooth
muscle cells with a consequent fall in calcium flux, relaxation, and decrease in PVR.
Patients with HF may have decreased T3 levels, in the
presence of normal or near-normal T4 and TSH levels.56 –58
This hormonal combination defines the low-T3 syndrome, in
all likelihood caused by alterations of the conversion mechanisms. In experimental HF, the cardiac activity of type III
deiodinase, which converts T4 into rT3 and T3 into T2, was
increased 5-fold.59
In a series of 199 patients with HF, 31% of patients with
severe HF had low-T3 syndrome, defined as total T3⬍80
ng/dL.56 A similar prevalence (34%) was reported in another
study of 132 HF patients.57 In a sample of 573 cardiac
patients (mostly affected by ischemic heart disease), a low-T3
syndrome, defined by a free T3 ⬍2 pg/mL, was found in 30%
of the patients.58 After a 12-month follow-up, cardiac and
all-cause-mortality was higher in the low-T3 group, and free
T3 was the strongest and an independent predictor of death in
a multivariate analysis. The value of low T3 as a predictor of
poor prognosis was confirmed in a more recent study in 311
Saccà
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patients with HF.4 The T3 level also correlates with maximal
O2 consumption and LVEF.4,60
Experimental models of low-T3 syndrome have provided
insights into how low T3 affects cardiac biology. After a
4-week caloric restriction, serum T3 decreased remarkably,
whereas T4 remained unchanged, as predicted by the low-T3
model.61 These changes were associated with LV dysfunction, downregulation of SERCA2, and myosin heavy chain
shift toward the slower ␤ isoform. T3 supplementation
normalized cardiac dysfunction. In models of acute myocardial infarction, T3 replacement restored LV function, normalized some of the dysregulated genes (phospholamban,
Kv1.5), and inhibited cardiomyocyte apoptosis by inducing
Akt phosphorylation.62,63
With regard to clinical studies, 23 patients with advanced
HF (EF, 22%) received T3 infusions for 6 to 12 hour. The
main finding was the expected decrease in PVR, which was
followed by a rise in cardiac output.64 More recently, a
controlled study was performed to assess the effects of a
3-day infusion of T3 in a group of patients with HF and
low-T3 syndrome (basal free T3: 1.74 pg/mL).65 The T3
infusion normalized the low-T3 levels, and resulted in a
significant improvement in stroke volume. Interestingly, T3
infusion decreased circulating levels of such key neurohormones and biomarkers, as norepinephrine, aldosterone, and
pro-B–type natriuretic peptide.
Although encouraging, the studies of T3 administration to
HF patients are very few and short term. The deterrent to
robust studies is the concern that T3 may be harmful due
to (1) the increased heart rate, (2) the arrhythmogenic effect,
and (3) the increased energy demand. These concerns are
based on the knowledge that T3 acts on the cardiomyocytes
of the sinoatrial node and activates the ␤1-adrenergic receptors.52 In reality, neither an increase of heart rate nor evidence
of ischemia or clinical arrhythmia was observed in any study
in which HF patients received T3 or T4, even when serum T3
was raised above the normal range.64 – 66 In contrast, a
reduction in heart rate and noradrenergic activity were observed, possibly because of improved hemodynamics.65
Acute T3 administration increases stroke volume but not
cardiac work, which suggests that T3 acts mainly on PVR and
afterload and that T3 does not raise cardiac work or energy
demand.65,67 Accordingly, PVR and afterload are increased in
hypothyroid patients, whereas LV mechanical efficiency,
estimated by positron emission tomography methodology, is
impaired.68 In the isolated perfused heart, T3 enhanced
cardiac performance without raising oxygen demand. Therefore, the ratio of cardiac work to myocardial oxygen consumption, a reliable measure of myocardial efficiency, was
improved.69 The ability of T3 to reduce the oxygen cost of
contractility is a crucial aspect of the T3-HF interaction,
given that myocardial energetics play a pivotal role in the
progression of HF.16 This peculiar effect of T3 provides yet
another convincing argument in support of T3 as treatment
for patients with HF and low-T3 syndrome. An alternative
approach would be thyroid hormone analogs.70,71 One of
them, 3,5-diiodothyropropionic acid (DITPA) shares many of
T3’s cardiac effects, including the gene profile (eg, both
reactivate SERCA2), without affecting heart rate. In a pilot
Hormones and Heart Failure
153
study of 19 patients with moderately severe HF, administration of DITPA for 4 weeks improved cardiac performance
and reduced PVR.70 A more ambitious, phase II trial has been
recently completed, but the results were disappointing as
DITPA worsened HF symptoms.72 The reason for this negative outcome may be related to the high dose of DITPA. In
reality, it is difficult to ascertain the doses most likely to be
effective yet safe in human trials.
An intrinsic limitation of thyroid hormone analogs is the
pharmacological nature of the approach as opposed to the
physiological hormonal replacement afforded by T3. This
becomes crucial if the goal is to treat selected patients with
the low-T3 syndrome.
Testosterone and HF
In men with HF, serum levels of free testosterone and
dehydroepiandrosterone were decreased2,3 in proportion to
HF severity.73 The average prevalence of testosterone deficiency, spanning all age classes, was as high as 43%.3 More
importantly, low testosterone and dehydroepiandrosterone are
independent predictors of death in men with HF.3 A reduced
testosterone level may be one of the factors that contribute to
the anabolic or catabolic imbalance that is characteristically
present in many patients with advanced HF.
Testosterone receptors are present in endothelial cells, vascular smooth muscle cells, and cardiomyocytes. After binding to its
receptors, testosterone may exert both genomic and nongenomic
effects.74 Testosterone acts on the vascular arterial wall, where
it induces vasodilation. This effect is nongenomic because
the response is rapid and primarily involves the vascular
smooth muscle cells, in which testosterone lowers the
intracellular Ca2⫹ flux, secondary to interaction with
voltage-operated calcium and potassium channels.74
Testosterone induces protein synthesis and hypertrophy in
the cardiomyocytes of several species, including humans,
through a receptor-specific interaction.75 In a postmyocardial
infarction model of HF, testosterone induced physiological
cardiac growth with no increment in hypertrophy markers or
collagen accumulation.76 In a model of ischemia-reperfusion
injury, testosterone exerted protective effects on cardiomyocytes by activating ATP-sensitive K channels and upregulating cardiac ␣(1)-adrenoceptor.77
Testosterone is important to myocardial contractility. Gonadectomy in male rats reduced the expression of genes
encoding the L-type Ca2⫹ channel, the Na⫹/Ca2⫹ exchanger,
␤(1)-adrenoceptors, and myosin heavy chain subunits.78,79 In
parallel, cardiomyocyte contractile capacity deteriorated. The
role of testosterone was explored in a recent clinical study in
25 patients with Klinefelter syndrome and 25 matched controls. There was evidence of systolic dysfunction in the
patients, as documented by reduced peak systolic velocities
(4.4⫾1.3 versus 5.3⫾1.0 cm/s, P⬍0.01) and strain rate
(⫺1.3⫾⫺0.3 versus ⫺1.6⫾0.3 s⫺1, P⬍0.01).80
The notion that testosterone deficiency affects cardiac
function encouraged studies of testosterone replacement in
patients with HF. In a controlled study, a single dose of
testosterone (60 mg orally) was given to 12 patients with New
York Heart Association class II–III HF.81 Testosterone decreased PVR and afterload, and cardiac output was conse-
154
Circ Heart Fail
March 2009
Table 2. Clinical Features of the Hormonal or Metabolic Deficiencies Associated With Chronic HF and Effects of
Replacement Therapy
Prevalence
Clinical Relevance
Replacement Studies
33%
(not including diabetes)
Altered myocardial energetics
and function
Insulin sensitizers (metformin and TZDs) are not indicated in HF. In
short-term studies (5 weeks), the insulinomimetic GLP-1 improved
cardiac function and exercise capacity
Poor survival
No adverse effects with GLP-1
64%
Impaired cardiac and skeletal
muscle performance
Pharmacologic but not replacement studies are available
Low T3 syndrome
18%–34%
Cardiac dysfunction, reduced
exercise capacity
Poor survival
No adverse effects
Testosterone deficiency
24%–43%
Cardiac dysfunction
Improved exercise capacity and NYHA class after
12 months of testosterone patch applications
Poor survival
Skin reactions in 55% of patients
Insulin resistance
Low IGF-1 syndrome
Poor survival
Improved cardiac function in acute studies with T3
(6 hours–3 days)
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GLP indicates glucagon-like peptide; NYHA, New York Heart Association.
quently higher than in the placebo study. These results
prompted a more robust clinical study in which 76 men with
moderately severe HF were randomized to receive testosterone or placebo for 12 months.82 Testosterone, administered
by means of an adhesive skin patch (5 mg/day), raised the
serum testosterone level by 40%. Testosterone did not affect
LV morphology or function but improved exercise capacity,
as shown by the significant increase in shuttle walk distance
(P⫽0.006). The clinical severity of HF improved by at least
1 New York Heart Association class in 35% of patients
treated with testosterone and in 8% of patients given placebo
(P⫽0.01). Testosterone also enhanced dominant handgrip
strength (P⫽0.04). The data suggest that the functional
improvement was due to an effect of testosterone on skeletal
muscle. Even so, the data are of interest given the relevant
role that peripheral abnormalities play in HF progression.
A collateral observation, pertinent to HF, is that testosterone replacement therapy may exert beneficial metabolic
effects. Thirteen patients with moderate to severe HF received either replacement testosterone treatment or placebo
for 4 weeks.83 IR was estimated by the homeostatic model
index (HOMA-IR). Testosterone treatment improved IR
(⫺1.9⫾0.8 HOMA units; P⫽0.03), and the response was
inversely correlated with the increase in bioavailable testosterone. The improvement in IR was associated with an
increase in total body mass (⫹1.5 kg; P⫽0.008) and a
decrease in body fat mass (⫺0.8%; P⫽0.02).
Summary
The MHD model extends the classic neurohormonal theory
and its application by focusing on restoring HF-related
metabolic or hormonal deficiencies. Each component of
MHD is associated with impaired functional capacity and
poor clinical outcome. However, the replacement approaches
so far attempted have provided additional benefits on top of
standard therapy (Table 2). There are no data regarding the
crucial question of whether life expectancy is also improved.
Each component of MHD may interact negatively with the
deficiency of other hormones. This is not a minor issue
because the number of deficiencies has a profound impact on
the progression of HF and outcome. In HF patients with
concurrent deficiency of testosterone, dehydroepiandrosterone, and IGF-1, the 3-year survival rate was as low as 27%
versus 75% when only 1 anabolic hormone was defective.3
Another important issue is the definition of hormonal or
metabolic deficiency. Whereas IR is diagnosed by the
HOMA-IR and the insulin clamp tests, and GH deficiency is
easily identified by the GHRH plus arginine test, a standardized
procedure for GH resistance has not yet been officially recommended. The low-T3 syndrome is currently diagnosed by an
arbitrarily low-T3 value in the presence of near-normal T4 and
TSH. With regard to testosterone and dehydroepiandrosterone,
the Endocrine Society has recently issued guidelines for the
diagnosis of androgen deficiency in adult men.84
A final, but fundamental, question relates to the meaning of
the MHD syndrome. MHD may be one outcome of HF as a
complex multiorgan disease. In this scenario, the pituitary
gland might be a particular target of HF, with consequent
dysfunction of cell lines that control the production of some
of the hormones involved in the MHD syndrome. In this case,
MHD must be searched for and rectified by adequate hormonal supplementation. If MHD is an ensemble of biomarkers that are not mechanistically linked to HF, MHD may be
useful only for staging and monitoring purposes. Finally, if
MHD represents the body’s attempt to limit energy dissipation, we must acknowledge such an adaptive response and
leave the status quo.
The evidence presented in this review strongly suggests
that MHD is not a simple disease marker or a compensatory
response. Even assuming that it originates as an adaptive
reaction, ultimately, each hormonal deficiency is associated with reduced functional capacity and, more importantly, is a powerful and independent predictor of poor
clinical outcome.3,6,43,48,58,60 This finding in itself justifies
the implementation of robust clinical trials to determine
whether either single or multiple hormone replacement is a
workable strategy to adopt in HF patients in addition to
current pharmacotherapy.
Disclosures
None.
Saccà
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KEY WORDS: endothelium
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glucose
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heart failure
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norepinephrine
Heart Failure as a Multiple Hormonal Deficiency Syndrome
Luigi Saccà
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Circ Heart Fail. 2009;2:151-156
doi: 10.1161/CIRCHEARTFAILURE.108.821892
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