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Introduction
It has been long recognized that cardiac norepinephrine (NE) is depleted in patients with congestive heart
failure[1,2]. Early studies have shown that NE depletion is associated with increased release of cardiac NE secondary to heightened
sympathetic nervous activity and decreased synthesis of NE in patients with congestive heart
failure[2_5]. It was thought initially
that the heightened sympathetic activity was an important adaptive mechanism to support the failing myocardium, and that
the subsequent depletion of cardiac NE stores contributed to the progressive deterioration of cardiac function and the
decreased myocardial contractility seen in chronic heart failure. However, it was later discovered that the intrinsic
contractility of the heart muscle remains normal after depletion of myocardial NE by reserpine treatment or cardiac
denervation[6]. Thus, normal cardiac stores of NE are not essential for maintaining the intrinsic myocardial contractility, and NE depletion
does not account for the myocardial depression in heart failure. However, as an overwhelming majority of NE is stored in the
intraneuronal storage vesicles, tissue content of NE does
not accurately reflect myocardial interstitial NE
concentration which is elevated in heart failure. Recent studies from
our laboratory and others have provided new insights into
cardiac sympathetic nerve terminal function in heart failure,
and it has been suggested that abnormal NE uptake in the
sympathetic nerve ending plays an important
pathophysiological role in dilated cardiomyopathy. The findings
further indicate that the change in NE uptake in chronic heart
failure is maladaptive, and might be a novel therapeutic
target in the treatment of congestive heart failure.
Reduction of NE uptake transporter in heart failure
Myocardial uptake of NE is known to be reduced in the
failing heart. In experimental heart failure produced by aortic
constriction, Spann et al[7] showed that the intravenous
infusion of NE resulted in a much smaller increase in cardiac
NE in guinea pigs with heart failure than normal animals, but
the increase of NE in the kidneys did not differ between the
2 groups of animals. They attributed the organ-specific
difference of tissue NE uptake to a diminished number of
sympathetic nerves and/or binding sites in the failing heart. We
now know that the primary defect is caused by a reduction
of neuronal NE transporter (NET) density at the sympathetic
nerve endings[8]. Since the NE uptake mechanism is
responsible for a rapid removal of interstitial NE after the
sympathetic release of NE, this defect of NE uptake has been used
to explain, at least in part, the selective increase of the
cardiac washout of NE. The amount of NE in the myocardial
interstitial space is also expected to increase and causes
greater actions on the postsynaptic adrenergic receptors.
NET, a 617 amino acid protein, comprises of 12
transmembrane domains at the sympathetic nerve
endings[9]. It is a member of the
Na+ and Cl_-dependent family of
neurotransmitter transporters. It takes up NE from the interstitial space
back to the adrenergic nerve terminals with the
stoichiometric exchange of Na+ and
Cl_ against their electrochemical
gradients[10].
Our laboratory has studied the pre- and postsynaptic
function of the cardiac sympathetic nerves for many years.
Our interest began with a novel observation in experimental,
right ventricle heart failure dogs produced by tricuspid
avulsion, and progressive pulmonary artery constriction
where myocardial β-receptor density was reduced only in
the failing right ventricle[11]. The chamber-specific
reduction of myocardial β-receptor density was later confirmed in
the failing human right ventricles associated with primary
pulmonary hypertension[12]. We speculated that the decrease
of myocardial β-receptors occurred because of a
chamber-specific reduction of cardiac sympathetic NE uptake activity,
leading to an increase of interstitial NE of the failing right
ventricular myocardium. Indeed, we have shown that
myocardial neuronal NE uptake activity as measured by the
tissue accumulation of [3H]NE ex vivo
is reduced only in the failing right ventricular myocardium, and this change
correlated with the reduction of myocardial β-receptors (Figure
1)[13]. We later studied the cardiac sympathetic nerve terminal
dysfunction in heart failure by measuring the NE binding site
density and numbers of sympathetic neuronal marker NE
and tyrosine hydroxylase, using sucrose-potassium
phosphate-glycoxylic acid-induced NE histofluorescence and
tyrosine hydroxylase immunocytochemistry,
respectively[13,14]. The sympathetic neuronal markers were reduced in the
failing ventricle (Figure 2). In contrast, the contralateral
non-failing left ventricle is relatively spared without reductions
of myocardial β-receptors, NE uptake activity, NE uptake
binding sites, or the numbers of neuronal profiles of NE and
tyrosine hydroxylase. The NE uptake binding site density
also did not change in the kidneys of the heart failure animals.
These findings suggest that the changes in cardiac
sympathetic nerve endings are produced by a local mechanism,
and is organ- and chamber-specific, occurring only in the
failing ventricle.
We have extended our observations in right ventricle
heart failure animals to dogs with biventricular heart failure
produced by rapid ventricular
pacing[14]. In these animals, we also produced direct proof that myocardial interstitial NE
increased in the failing heart, and that the interstitial NE
correlated inversely with number of myocardial β-receptors
(Figure 3)[15], indicating that the changes in the myocardial
β-adrenoceptor density is agonist induced, secondary to the
reduction of NE neuronal uptake.
The functional importance of the NE uptake site was
further studied in rabbits at various time intervals after the start
of rapid ventricular pacing[16]. We found that rapid
ventricular pacing caused early sympathetic nervous system
activation, followed in sequence by the reduced myocardial
NE uptake, loss of neuronal NE, and downregulation of
myocardial β-adrenoceptors. However, there was no significant
reduction of the protein gene product 9.5, a panneuronal
marker, suggesting that the anatomic integrity of the cardiac
sympathetic nerves probably is intact, and the changes of
sympathetic neurotransmitters within the nerve endings are
caused by functional abnormalities that are potentially
reversible with either effective therapy or the removal of a
primary insult that causes heart failure. The interdependence
of increased sympathetic stimulation, decreased cardiac NE
uptake, and myocardial β-adrenoceptor downregulation is
further discussed in a study by Leineweber et
al[17] who found that neurohumoral activation is essential for the
reduction of myocardial β-receptors in the hypertrophied right
ventricle produced by monocrotaline. This study, which is
similar to our earlier studies of right ventricle heart failure, is
characterized by a chamber-specific reduction of myocardial
NE uptake sites[18].
Significance of NE re-uptake for cardiac function in heart failure
The physiological significance of the NE re-uptake
mechanism in the regulation of myocardial β-receptor density and
postsynaptic β-adrenergic inotropic responsiveness was
further studied in heart failure animals treated with
desipramine[19] and
selegiline[20]. Desipramine is a NET inhibitor.
In the present study, it increased myocardial interstitial NE
in heart failure, and caused further reductions of myocardial
β-adrenoceptor density and β-adrenergic subsensitivity.
In contrast, selegiline, which is a central
α2-agonist with a neuroprotective effect, attenuated the increase in plasma NE
and the decrease of myocardial β-receptor density and
improved cardiac mechanical function in pacing-induced
cardiomyopathy. These findings support the concept that
interstitial NE is a modifiable variable, important in the
mediation of agonist-induced postsynaptic events seen in heart
failure.
To study the mechanism responsible for the NE uptake
inhibition in heart failure, experiments have been conducted
in our laboratory to show that the reductions of cardiac
sympathetic transmitters and NET can be induced by
exogenous NE[21,22] and inhibited by
desipramine[19,23] and
antioxidants[22,24] in intact animals. Studies also have been
conducted in cultured rat neuroblastoma cells (PC12) cells,
indicating that NE reduces NE uptake activity and the NET
protein in a dose-dependent fashion[25]. The changes of NE on
the NET protein are reproduced by well-known endoplasmic
reticulum stressors such as tunicamycin and thapsigargin
(Figure 4). These effects of NE are most likely caused by
endoplasmic reticulum stress, the resultant reduced
glyco-sylation and the trafficking of NET to the cell
membrane[26]. Our
studies[26] have also shown that the reduction of the
NET protein by NE in PC12 cells was not associated with
changes in NET mRNA, suggesting that the NET protein
downregulation is a post-transcriptional event. These
findings are consistent with an earlier study of experimental heart
failure in which the reduction of the cardiac NET protein in
aortic-banded rats was associated with no change of NET
mRNA in the left stellate ganglion[27]. NET gene expression
also was unchanged in the stellate ganglia of rats with
cardiac hypertrophy induced by pressure overload, despite a
marked reduction of NE uptake site density in the
hypertrophied left ventricle[28]. There is also evidence that the
effects of NE on NET are associated with an increase in
reactive oxygen species, and can be attenuated by the
free-radical scavenger mannitol, or antioxidant enzymes
superoxide dismutase and catalase. The findings suggest that the
cardiac sympathetic nerve terminal dysfunction is probably
caused by increased interstitial NE in heart failure, and the
neuronal damage effect of NE involves the uptake of NE or
its oxidative metabolites into the sympathetic nerve endings.
More recently, endothelin-1 also has been shown to inhibit
cardiac NE uptake and promote NE release from the failing
heart via ETA receptors[29]. Endothelin blockade also
improves survival in experimental heart
failure[30,31], but no long-term beneficial effects of either
ETA-specific[32] or non-specific endothelin receptor
inhibitors[33] have been demonstrated in human heart failure.
Myocardial metaiodobenzylguanidine scinti-graphy and its clinical utility in heart failure
Recently, radio-iodinated
metaiodobenzylguanidine (MIBG), a structural analogue of NE, has been used to study
the integrity and function of the cardiac sympathetic
nervous system[34]. MIBG shares the same reuptake
mechanism and storage site with NE. Thus, its uptake into the
myocardium reflects both the distribution of cardiac
sympathetic innervation and the extent of neuronal NE uptake
activity. The failing heart is characterized by reduced
distribution and washout of MIBG[35]. Abnormal MIBG uptake,
calculated by the ratio of heart and mediastinum uptake,
correlates with reduced myocardial contractile reserve in
patients with dilated
cardiomyopathy[36]. Similarly, c-11-HED,
a PET-based NE analog, is significantly correlated to the
NET density, and has been used to demonstrate regional
variations of NE content in
cardiomyopathy[37]. Thus, the MIBG and HED-PET patterns can be used as a non-invasive
means to investigate the changes of cardiac sympathetic
innervation in the hearts of cardiomyopathic patients.
Studies have now shown that cardiac sympathetic nerve
innerva-tion, as demonstrated by MIBG scintigraphy, is an
independent predictor for adverse clinical outcomes, including
mortality in patients with heart
failure[38,39]. Improvements in MIBG patterns also have been shown to occur in
patients who respond favorably to
carvedilol[40],
metoprolol[41],
spironolactone[42,43],
enalapril[44], and cardiac
resynchronization therapy[45]. In contrast, bucindolol therapy, which showed
only marginal survival benefits[46], did not improve the
sympathetic nerve function as measured by
MIBG[47]. However, because prior studies involved only small numbers of
patients, the application of MIBG scintigraphy in heart
failure remains investigational. In a recent editorial, Motherwell
et al[48] discussed the proper use of MIBG scintigraphy and
the limitations of current imaging protocols, as well as need
of a better understanding of the kinetics of MIBG and
standardization of imaging techniques and analyses in cardiac
imaging. They concluded that a large multicenter trial with a
standardized imaging protocol is required to establish the
clinical utility of the MIBG in congestive heart failure in
patients.
Therapeutic implications
Long-term β-blocker therapy is now widely accepted as
a pillar in the treatment of systolic heart failure. Effective
utilization of β-receptor blockers can not only improve left
ventricular systolic function, but also increase survival in
patients with chronic heart failure secondary to left
ventricular systolic dysfunction[49_52]. Given the overwhelming
success of the β-adrenoceptor blocker therapy, attempts have
been made to determine if similar or greater beneficial effects
can be derived from potent sympatholytic agents such as
moxonidine, which has been shown to decrease peripheral
sympathetic outflow and circulating plasma NE by
stimulating the brain stem imidazoline-1
receptor[53]. Unfortunately, despite early enthusiasm with the centrally-acting
sympatholytic agents[54,55], moxonidine therapy was considered
detrimental because it tended to increase mortality and
morbidity in chronic systolic heart failure in a large clinical
trial[56]. Thus, the sympathetic nervous system activation
can be both adaptive and maladaptive, depending on the
degree of basal sympathetic activation and the extent of
sympa-tholysis or β-receptor blockade. Furthermore,
generalized sympathetic nervous system inhibition probably has
limited therapeutic utility, and localized adrenergic
inhibition at the cardiac receptor level is the preferred mode of
therapy for heart failure.
Alternatively, the results of several recent studies
suggest that without directly affecting the central sympathetic
drive, cardiac function in heart failure may be modified by
agents or interventions that upregulate the neuronal NET in
the myocardium. Kreusser et al[57]
reported that an injection of nerve growth factor into the stellate ganglia of rats with
heart failure produced by transverse aortic constriction,
improved NE uptake, repleted cardiac NE stores, and
increased left ventricular fractional shortening. The number
of cardiac sympathetic nerves, however, was unaffected. In
a separate study[58], adenoviral gene transfer was used to
overexpress NET in the myocardium of rabbits with
pacing-induced cardiomyopathy. This resulted in increased NE
uptake capacity and the reversal of β-receptor
downregula-tion in the cardiac tissue. Local overexpression of cardiac
NET also improved the systolic function and contractile
reserve of the cardiomyopathic hearts. These findings not
only confirm the importance of NET in the initiation or
progression of cardiomyopathy, but also suggest that cardiac
NET may be a novel therapeutic target in the treatment of
congestive heart failure. Future research should be directed
at the development of pharmacological agents or
interventions that reduce the cardiac noradrenergic drive while
preserving the integrity and NE reuptake function of the
sympathetic nerve terminals.
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