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Bradley A.

Maron
Ventricle Coming Into Focus
Targeting Neurohumoral Signaling to Treat Pulmonary Hypertension: The Right
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Copyright 2012 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation
doi: 10.1161/CIRCULATIONAHA.112.149534
2012;126:2806-2808; originally published online November 2, 2012; Circulation.
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Editorial
Targeting Neurohumoral Signaling to
Treat Pulmonary Hypertension
The Right Ventricle Coming Into Focus
Bradley A. Maron, MD
A
dverse remodeling of the right ventricle (RV) that
affects RV systolic or diastolic function directly or
indirectly by modulating changes to cavitary geometry is a
principal determinant of poor outcome across the global
spectrum of cardiopulmonary diseases.
1,2
Indeed, even sub-
clinical increases in RV mass are associated with substan-
tially elevated risk for future heart failure and decreased
lifespan.
3
Unique embryological and anatomic features of the
RV provide a pathophysiological basis by which to account
for this observation. For example, precursor cells of the RV
and left ventricle (LV) derive from the primary and anterior
heart fields,
4
respectively, indicating a different cellular
lineage for each ventricle despite their close proximity and
placement in series. In contrast to the LV, the RV is a
triangular structure that is thin walled and noncompacted,
and, thus, tolerates pressure-loading conditions poorly.
5
Moreover, poor coronary blood flow reserve with increased
RV strain due to elevations in wall tension is associated with
decreased RV microvascular perfusion.
6
Article see p 2859
Although these properties establish the RV-specific pres-
surevolume relationship profile, factors that precipitate im-
paired RV performance are less well characterized. Take, for
example, the wide swath of classical reports that describe LV
hemodynamic (patho)physiological responses to acute and
chronic myocardial ischemia, systemic hypertension, valvular
dysfunction, and pericardial disease.
7
By contrast, a paucity
of data exists to characterize the mechanistic and clinical
contributions of similar processes (including LV dysfunction)
to the natural history of adverse RV remodeling in non
congenital heart disease patients, despite the attendant clinical
relevance of RV failure. Furthermore, the basic mechanism(s)
that underpin RV dysfunction when contemporaneous with
pulmonary hypertension, the most common end-pathopheno-
type associated with changes to RV loading,
8
are largely
unknown. In fact, only recently has consideration been given
to RV function within the context of the larger lung-pulmo-
nary circulatory-RV apparatus.
5,9
This is a critical distinction,
however, because defining the right heart axis in this way
reidentifies the RV as a specific participant in the pathobiol-
ogy of pulmonary hypertension and potential therapeutic
target per se, thereby parting from traditional dogma in which
RV dysfunction is a consequence of pulmonary vascular
disease, an indicator of irreversible cardiac injury, and a
dismal prognostic marker.
Current work in the field has advanced our understanding
of RV myocyte pathobiology significantly in the context of
pulmonary vascular disease, particularly with respect to
maladaptive molecular mechanisms that modulate RV failure
through changes in cellular metabolism,
10
nitric oxide bio-
availability,
11,12
and ion channel dysfunction.
13
These basic
and translational scientific models, which emphasize novel
RV-specific targets to improve RV performance, have illu-
minated a number of cell-signaling pathways with future
therapeutic promise for patients afflicted with pulmonary
hypertensioninduced RV dysfunction.
Notwithstanding these cutting-edge discoveries, however,
a substantial knowledge gap persists with respect to the
fundamental mechanism by which classical cardiovascular
effectors associated with states of low cardiac output may
promote circulatory failure vis-a`-vis RV dysfunction, such as
upregulation of neurohumoral signaling that is linked to
unfavorable clinical outcome in patients with congestive
heart failure due to LV dysfunction.
14
For example, only
recently has overactivation of the renin-angiotensin axis been
described systematically in patients with pulmonary arterial
hypertension and RV remodeling.
15
Hyperaldosteronism,
long recognized as a mediator of poor outcome in congestive
heart failure due to LV dysfunction, now appears to be
present in the pulmonary arterial circulation of patients with
pulmonary arterial hypertension in the absence of abnormal
LV remodeling or impaired function, and correlates posi-
tively with adverse pulmonary vascular remodeling.
16
Others
have reported recently on changes to the RV pressure
volume relationship following the administration of catechol-
amines in acute RV failure.
17
However, overall, there remains
a limited understanding of the biological framework with
which these and other similar, systemically circulating vaso-
active effectors differentially influence RV function. This has
at least 2 important implications. First, neurohumoral hor-
mones may be underrecognized therapeutic targets to modu-
late RV function. Second, few mechanistic (or clinical) data
are available to inform clinicians on the consequences of
repurposing pharmacotherapies commonly used to manage
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Brigham and Womens Hospital and Harvard Medical
School, Department of Internal Medicine, Division of Cardiovascular
Medicine, Boston, MA; and Department of Cardiology, Veterans Affairs
Boston Healthcare System, West Roxbury, MA.
Correspondence to Bradley A. Maron, MD, Brigham and Womens
Hospital, Division of Cardiovascular Medicine, PBB-1, 75 Francis St,
Boston, MA 02115. E-mail bmaron@partners.org
(Circulation. 2012;126:2806-2808.)
2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.112.149534
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LV heart failure, such as - or -adrenergic receptor (ant)ag-
onists, to patients with pulmonary hypertension and RV
dysfunction, despite the frequency with which this occurs in
clinical practice.
18
Thus, investigating the functional conse-
quences of neurohumoral hormones on RV and LV perfor-
mance in the context of RV failure is a timely and attractive
avenue of investigation.
In the current issue of Circulation, Piao and colleagues
19
investigate the contribution of /-adrenergic and dopami-
nergic (D) receptor signal transduction to changes in RV
functional (ie, inotropic) reserve under conditions of acute
and chronically increased RV afterload. To accomplish this,
the investigators thoughtfully selected 3 different rodent
models of pulmonary hypertension (pulmonary artery band-
ing [mechanical ligation of the pulmonary artery, acute RV
dysfunction], monocrotaline-induced pulmonary hyperten-
sion [inflammatory pulmonary vascular injury, chronic RV
dysfunction], and chronic hypoxia/Sugen-5416 [angioprolif-
erative pulmonary vascular injury, chronic RV dysfunction])
to test their hypothesis that, akin to LV heart failure,
dysregulation of -adrenergic receptor signaling impairs
inotropic reserve in the hypertrophied RV. An additional
objective of this work was to further characterize the patho-
biological mechanisms that modulate RV dysfunction-
dependent changes to LV performance
17
to identify optimal
vasopressor pharmacotherapy for improving cardiopulmo-
nary circulation in RV failure in vivo.
The central findings of the work are 3-fold. First, RV
myocyte
1
-,
1
-, and D
1
-receptor expression levels and
receptor-dependent signal transduction are downregulated in
the hypertrophied RV in patients with pulmonary arterial
hypertension, and, in the tested animals models, this limits
RV contractile reserve, particularly in chronic RV failure.
Second, G-proteincoupled receptor kinase 2, which is an
established intermediary involved in the reversible inhibition
of
1
- and D
1
-receptor expression/activation in LV myo-
cytes,
19
is identified as a legitimate potential therapeutic
target by which to restore RV contractile reserve, cardiac
output, and functional capacity in RV failure. Third, the
investigators demonstrate the superiority of dobutamine over
dopamine for enhancing RV systolic function in the tested
models, an observation that is internally consistent with their
findings of dysfunctional D
1
receptors in RV myocytes,
which interact with dopamine and not dobutamine. To make
this determination, a clever experimental design was used in
which the effects of inotropes was assessed in separate RV
and LV Langendorff models, thereby allowing for the assess-
ment of contractile reserve in each ventricular chamber
independent of pre- and afterload.
Collectively, these observations provide a comprehensive
evaluation of catecholamine-dependent changes to RV func-
tion in pulmonary hypertension and identify provocative
differences in the molecular profile of RV myocytes based on
acute versus chronic temporal patterns of RV injury. Al-
though the mechanism(s) by which to account for these
differences were not addressed fully in this work, obvious
future endeavors are likely to include characterizing these
differences further, and to account for the observation that
inhibition of G-proteincoupled receptor kinase 2 improved
RV contractile reserve without attendant changes to
1
-
receptor expression levels, as well. This finding raises the
possibility that inhibition of G-proteincoupled receptor ki-
nase 2 may modulate beneficial effects on RV performance,
at least in part, indirectly via off-target suppression of
G-proteincoupled receptor kinase 2dependent catechol-
amine hyperactivity in adrenal tissue.
20,21
Moreover, the
observation that, in 1 model of chronic (but not acute) RV
heart failure, downregulation of
1
-adrenergic signaling was
noted in both RV and LV myocardium is intriguing and may
ultimately prove to be an important clue in identifying
(mal)adaptive cross-talk between RV and LV cardiomyocyte
cell-signaling pathways involved in regulating inotropic
reserve.
Taken together, Piao and colleagues have synthesized a
series of observations that leverages classical catecholamine
physiology to redefine RV myocyte biology in the context of
pulmonary hypertension. The broader implications of this
work are that RV
1
-,
1
-, and D
1
-receptor signaling is
actively involved in the pathobiology of pulmonary hyper-
tension. Pursuing answers to questions derived from the
authors observations is evident; defining neurohumoral ef-
fects on RV function is likely to provide a novel window into
understanding LV function and add clarity to the unresolved
controversy over appropriate strategies by which to target

1
-,
1
-, and D
1
-receptorsignaling pathways in patients with
heart failure from RV and/or LV dysfunction. In this way, the
current work is well within the ideals outlined at the recently
concluded international Right Heart Failure Summit (Boston,
MA),
22
which provided strong evidence for placing the RV
into better focus within the framework of cardiovascular
disease, far beyond its traditionally held position as simply an
orphan structure adversely affected as a bystander in cardio-
vascular pathophysiology.
Sources of Funding
This work was supported in part by the American Heart Association
(11POST6720000) and The Lerner Foundation at Brigham and
Womens Hospital.
Disclosures
None.
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KEY WORDS: Editorials

hypertension, pulmonary

receptors, adrenergic,
beta

right ventricular dysfunction
2808 Circulation December 11, 2012
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