Pulmonary Hypertension Due to Left Heart Disease

Marco Guazzi and Barry A. Borlaug

Circulation. 2012;126:975-990
doi: 10.1161/CIRCULATIONAHA.111.085761
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/126/8/975

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Circulation is online at:

http://circ.ahajournals.org//subscriptions/

Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012

 Contemporary Reviews in Cardiovascular Medicine

Pulmonary Hypertension Due to Left Heart Disease

Marco Guazzi, MD, PhD, FACC; Barry A. Borlaug, MD, FACC

P ulmonary hypertension (PH) due to left heart disease,

classified as group 2 according to the Dana Point 2008
classification, is believed to be the most common cause of PH
and is associated with high morbidity and mortality. Epide-
miological studies of group 2 PH are less exhaustive than for
rarer causes of PH such as isolated pulmonary vasculopathies,
but attention for this entity is growing rapidly. Group 2 PH
may be caused by passive downstream elevation in left heart
pressures or by a combination of the latter with pulmonary
arteriolar pathologies. Improved understanding of the pertur-
bations in pulmonary vascular structure and function that
cause PH due to left heart disease is essential to reduce heart
failure morbidity and mortality. In this review, epidemiology,
mechanisms, diagnostic approaches, hemodynamic models,
and clinical trials of heart failure complicated by group 2 PH
are reviewed, along with a discussion of novel treatment
strategies that are currently under investigation or hold
promise for the future.
Definitions
Interest in group 2 PH has historically been confined to mitral
valve disease and advanced stages of heart failure (HF),
wherein clinical manifestations of right ventricular (RV)
failure carry an extremely unfavorable prognosis.1–3 Clinical
recognition of group 2 PH has expanded, with recent studies
demonstrating that increases in rest and exercise pulmonary
arterial pressures may accompany normal aging4,5 and that
patients with HF and preserved ejection fraction (HFpEF)
frequently also display PH.6
Although left heart disease is believed to represent the
most common form of PH, epidemiological data are less
abundant in this group in comparison with others.7 The most
recent European Guidelines define group 1 PH as a chronic
elevation of a mean pulmonary arterial pressure ⱖ25 mm Hg
in association with normal pulmonary capillary wedge pres-
sure (PCWP; ⱕ15 mm Hg; Table).8 This type of PH has
historically been referred to as pulmonary arterial hyperten-
sion (PAH), because the pathological process resides at the
level of the vasculature. In this review, the term PH refers to
any elevation in mean pulmonary arterial pressure
ⱖ25 mm Hg, and PAH is referred to as group 1 PH. Previous
guidelines had stipulated that an increase in mean pulmonary
arterial pressure to ⱖ30 mm Hg with exercise was also
diagnostic of PAH, but a recent meta-analysis showed that
normal aging may be associated with significant elevation in
pulmonary arterial pressure (PAP) during exercise,9,10 even in
the apparent absence of disease. The updated guidelines have
removed this exercise criterion for PAH, although recent
studies in patients with unexplained dyspnea have shown that
PAP elevation during exercise may be an important clue to
the presence of underlying HF, suggesting an important role
for exercise hemodynamic assessment in the evaluation of
possible HFpEF.11,12
The key hemodynamic feature that differentiates group 2
PH from others is PCWP elevation (⬎15 mm Hg; Table).
Group 2 PH patients may present with elevation in PAP and
no or only minimal increase in the transpulmonary gradient
(TPG: mean PAP-PCWP ⱕ12–15 mm Hg). In these circum-
stances (often referred to as passive or postcapillary), PH is
merely a reflection of the increase in downstream left heart
pressures, and pulmonary vascular resistance (PVR) is nor-
mal. Group 2 PH patients may progress to a reactive PH
stage, with an increase in TPG and PVR. This form of group
2 PH is often termed precapillary or mixed. For reasons that
remain unclear, a number of patients do not progress to
develop marked reactive pulmonary vasoconstriction, despite
the presence of chronic advanced HF.1 Because TPG is flow
dependent (varying directly with cardiac output, CO), some
authorities prefer PVR (defined as TPG/CO) as a means of
distinguishing passive and reactive. The most recent Ameri-
can College of Cardiology Foundation/American Heart As-
sociation PH consensus document did not include a PVR ⬎3
Wood units (WU) in the definition of group 1 PH, although
this has been a matter of debate.13 An advantage of using
PVR over TPG is that it normalizes for blood flow. A
disadvantage is that any error incurred in the determination of
CO will affect the derived value of PVR. This can become
quite significant in low-output states as often observed in HF.
The widespread use of transthoracic echocardiography,
which allows estimation of the right ventricular systolic
pressure (RVSP) from the velocity of tricuspid regurgitation
by adding a given right atrial pressure, has led to increased
appreciation of the burden of PH in patients with cardiovas-
cular disease, and in the general population without apparent
cardiovascular disease, as well.14 Estimated RVSP is often
used interchangeably with pulmonary artery systolic pressure
(PASP), an assumption that relies on the absence of pulmo-
nary valve stenosis. PH is considered mild if the echo-

From the Heart Failure Unit, Cardiology, I.R.C.C.S., Policlinico San Donato, Department of Medical Sciences, University of Milano, San Donato
Milanese, Milano, Italy (M.G.); and the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (B.A.B.).
Correspondence to Marco Guazzi, MD, PhD, FACC, Heart Failure Unit, Cardiology, I.R.C.C.S., Policlinico San Donato, Department of Medical
Sciences, University of Milano, Piazza Malan 1 20097, San Donato Milanese, Milano, Italy. E-mail marco.guazzi@unimi.it
(Circulation. 2012;126:975-990.)
© 2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.085761

Downloaded from http://circ.ahajournals.org/

975 by guest on December 1, 2012
976 Circulation August 21, 2012

Table. Hemodynamic Classification of Pulmonary Hypertension patients in whom the pretest probability of HFpEF is inter-
Patient Mean PCWP TPG PVR (mm Hg/L
mediate after review of clinical and noninvasive data.12,20
Group PAP (mm Hg) (mm Hg) (mm Hg) per min)
Normal* 14⫾3 8⫾3 6⫾2 0.9⫾0.4
Epidemiology
Recent studies from Olmsted County5,6 have shed new light
Group 1 PH† ⱖ25 ⱕ15 ⬎12 to 15‡ ⬎2.5 to 3.0‡
on the burden of left-sided PH, both in the general community
Group 2 PH, ⱖ25 ⬎15 ⱕ12 to 15‡ ⬍2.5 to 3.0‡
and in HFpEF. Lam et al5 reported data from a prospective
passive†
study of randomly recruited adults, including 1413 subjects
Group 2 PH, ⱖ25 ⬎15 ⬎12 to 15‡ ⬎2.5 to 3.0‡
with estimated PASP at Doppler echocardiography. They
reactive†
showed that the median PASP by echocardiography was
PH indicates pulmonary hypertension; PAP, pulmonary artery pressure;
26 mm Hg, and 6.6% of the participants had a PASP
PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; and
PVR, pulmonary vascular resistance. ⱖ36 mm Hg. Aging, increased LV filling pressures (esti-
*Data taken from Kovacs et al.9,10 mated by E/e⬘ ratio), and systemic vascular stiffening
†Data taken from Galiè et al.8 (brachial pulse pressure) were each associated with in-
‡Partition values for TPG and PVR used for these definitions have varied creasing PASP. Importantly, PASP was the strongest
between studies and there is no strong evidence to support 1 partition value predictor of mortality in comparison with established
over the other at this time.
markers, and it similarly stratified outcomes in the general
population and in the subgroup of patients free of cardio-
estimated PASP is 35 to 45 mm Hg, moderate if it is 46 to pulmonary disease (Figure 1A and 1B).
60 mm Hg, and severe when ⬎60 mm Hg. However, it is In another prospective study from this group,6 the preva-
important to appreciate that correlations between echo and lence and significance of PH in HFpEF population was
invasive data are modest (r⬇0.7),15 and substantial disagree- examined. Patients with HFpEF (n⫽224, 96% with hyperten-
ment may be observed with gold standard invasive mea- sion) were compared with hypertensive subjects without HF
sures16 Previous studies have shown inaccurate PASP esti- (n⫽719). Median PASP was 28 mm Hg in asymptomatic
mation ranging from 48% to 54%, and PASP may be over- or hypertensive subjects and 48 mm Hg in patients with HFpEF
underestimated from the tricuspid regurgitant velocity.17,18 (P⬍0.0001). Elevated PASP (⬎35 mm Hg) was detected in
Catheterization is essential to make the diagnosis of PH 8% of hypertensive subjects and 83% of HFpEF patients. As
and is particularly critical when clinical decisions and thera- in the general population, PASP was highly predictive of
peutic interventions are going to be made based on PAP survival in HFpEF (Figure 1C). These observations empha-
measurements. The diagnosis of HFpEF is often made based size the relevance of elevated PASP as another echocardio-
on echocardiographic parameters alone,19 although catheter- graphic indicator of abnormal PCWP, and they suggest that
ization remains the gold standard to characterize diastolic its presence should trigger further consideration for the
properties at rest and with stress and is often required in diagnosis of HFpEF.6,11 The recently updated Dana Point

Figure 1. Pulmonary artery systolic pres-

sure (PASP) estimates are a risk factor for
death. Elevation in PASP as estimated
noninvasively by Doppler echocardiogra-
phy is associated with increased mortality
in the general population (A, modified
from Lam et al5) and patients without
apparent cardiopulmonary disease (B,
modified from Lam et al5), in addition to
heart failure with preserved (C, modified
from Lam et al6) or reduced ejection frac-
tion (D, modified from Abramson et al2).
PASP indicates pulmonary artery systolic
pressure; HFrEF, heart failure with
reduced ejection fraction; HFpEF, heart
failure with preserved ejection fraction;
and TR vel, tricuspid velocity.

Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012

 Guazzi and Borlaug
guidelines include LV diastolic dysfunction as a predominant
cause of group 2 PH.21
Epidemiological data regarding PH in HF with reduced
ejection fraction (HFrEF) are extensive but limited mostly to
populations with advanced (stage D) HF.22 Abramson et al2
found that echocardiography-estimated PH was associated
with markedly increased morbidity and mortality in HFrEF
(Figure 1D), whereas Ghio et al3 showed that the presence of
RV dysfunction has important implications for risk stratifi-
cation in group 2 PH above and beyond PAP. In a series of
320 HFrEF patients, Butler et al1 found that PVR was normal
(⬍1.5 WU) in 28%, mildly elevated (1.5–2.49 WU) in 36%,
moderately elevated (2.5–3.49 WU) in 17%, and severely
elevated (⬎3.5 WU) in 19%. More recent data suggest that
the prevalence of reactive PH is similar in all ejection fraction
groups. Indeed, in a recent study, 80% to 90% of patients with
HFrEF and HFpEF displayed PVR ⬎1.7 WU, and over half
had PVR ⬎3 WU or TPG ⬎15 mm Hg (Figure 2).23 Ghio et
al3 reported PH in ⬎60% of their patients with moderate or
severe HF. Among 388 HF patients investigated in an
echo-based study, the presence of PH (defined as PASP
ⱖ39 mm Hg) was associated with worse survival in both
HFrEF and HFpEF, with no between-group difference in the
magnitude of the effect.22
Pathobiology
Pulmonary Capillary Stress Failure and
Arterial Remodeling
In contrast to PAH, specific gene mutations conferring
increased susceptibility to reactive PH are not well under-
stood. However, candidate genetic determinants of suscepti-
bility would be expected to perturb pulmonary arteriolar
structure and function in HF, just they do in group 1 PH.
Primary or pathognomonic vascular changes in the arterial
wall may be absent in group 2 PH. Capillary and arterial
remodeling develop from backward transmission of increased
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
Pulmonary Hypertension and Heart Failure 977
Figure 2. Distribution of PVR and TPG in a
patients with group 2 PH due to HFrEF and
HFpEF. Data show a high prevalence of reactive
PH, where 80% to 90% of patients with HFrEF
and HFpEF displayed PVR ⬎1.7 WU (2 SDs
beyond normal), and over half displayed PVR ⬎3
WU or TPG ⬎15 mm Hg. Data adapted from
Schwartzenberg et al.23 PVR indicates pulmonary
vascular resistance; TPG, transpulmonary gradient;
IQR, interquartile range; HFrEF, heart failure with
reduced ejection fraction; and HFpEF, heart failure
with preserved ejection fraction.
left atrial pressure (LAP), challenging vascular structural
integrity and functional properties. Acuity and chronicity of
LAP elevation have important effects on the pathobiology of
group 2 PH.24 As the lung vasculature transits from acute to
sustained pressure-induced injury, abnormalities in the cap-
illary network precede those occurring at the arteriolar and
pulmonary artery levels. Acutely, lung capillaries are exposed
to stress failure, ie, loss of cellular integrity promoting edema
within the interstitial and alveolar compartments. This phe-
nomenon has classically been considered to be most relevant
to acute pulmonary edema, although it may function as a
trigger for maladaptive cellular processes that have more
sustained effects on the pulmonary vasculature.25 Experimen-
tal models of pressure and volume capillary overload have
defined the molecular bases of this process, while identifying
the critical capillary pressures required for edema forma-
tion26,27 and gas exchange impairment.28
In humans, stress failure of lung capillaries may be more
common than is typically considered, occurring in a number
of physiological conditions such as strenuous exercise and
high-altitude exposure.24 The normal pulmonary– capillary inter-
face exhibits remarkable plasticity, being able to restore its
integrity after normalization of LAP.29 With chronic and re-
peated barotrauma there is true capillary remodeling, with
demonstrable changes in the alveolar– capillary membrane inter-
face. In a canine model of pace-induced HF, alveolar– capillary
membrane thickness increased in comparison with controls,
principally because of a change in basement membrane compo-
sition and deposition of type IV collagen.30 These findings are
qualitatively similar to those observed in patients with mitral
stenosis and chronic pulmonary venous hypertension.31 Local
activation of growth stimuli, such as angiotensin II,
endothelin-1, and hypoxia, may contribute to this microvascular
remodeling.25 In a HF model induced by thoracic aortic banding,
alveolar– capillary remodeling was linked to loss of nitric oxide
(NO)-induced physiological oscillations in endothelial calcium
978 Circulation August 21, 2012

Figure 3. Endothelial and vascular smooth muscle cell pathways involved in the regulation of pulmonary arterial tone and pharmacolog-
ical approaches. Vasorelaxation is mediated by increases in cGMP, antagonism of the endothelin A and B receptors (ETra and ETrb), or
stimulation of adenylate cyclase by prostaglandins, primarily prostacyclin. Intracellular levels of cGMP can be targeted at different levels
by exogenous nitric oxide (inhaled NO), activators/ stimulators of soluble guanylate cyclase (sGC), or by inhibiting the catabolism of
cGMP by phosphodiesterase 5 inhibitors. PDE indicates phosphodiesterase; e-NOS, endothelial nitric oxide synthase.

handling, serving as a trigger for cytoskeleton disorganization.32
The alveolar– capillary interface remodeling induced results in
gas exchange abnormalities, including reductions in membrane
conductance, that have emerged as strong prognosticators in
group 2 PH.33
The pathobiology of changes in small and medium arteries
has been investigated in patients with advanced HFrEF
awaiting heart transplant.34 At this stage, arterial intima and
media undergo hypertrophy with peripheral migration of
smooth muscle into intra-acinar arterioles, effectively causing
muscularization of these vessels. A key step is the induction
of an endogenous vascular serine elastase, releasing growth
factors and glycoproteins (tenascin-C and fibronectin).
Pressure-induced endothelial disruption allows serum pro-
teins into the vessel wall that activate endogenous vascular
serine elastase and matrix metalloproteinases, disrupting the
elastic lamina, stimulating smooth muscle growth and colla-
gen and elastin synthesis.35 Fibroproliferative changes origi-
nate from growth of smooth muscle cells and myofibroblasts
derived from the media. As medial hypertrophy becomes
prominent, a process of pulmonary venous arterialization may
develop. Bronchial veins may become congested and dilated
because of increased flow through bronchopulmonary anas-
tomoses. True plexiform lesions, commonly seen in PAH, are
not observed in group 2 PH. There is a wide variability in the
pulmonary vascular structural changes with elevated venous
pressure. In patients with a variety of forms of PH (including
group 2 PH due to mitral valve disease), reduced expression
of bone-morphogenetic protein receptor has been observed,
coupled with increased expression of angiopoietin-1, suggest-
ing a common pathway in disease progression.36 However,
the mechanisms dictating these remodeling processes within
individual patients remain poorly understood. Regression of
pulmonary vascular remodeling after normalization of LAP
by cardiac transplantation, mitral valve surgery, or left ventric-
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
ular assist device (LVAD) may be substantial, although often
incomplete.37
Impaired Vascular Reactivity and
Endothelial Dysfunction
PVR may become elevated in left-sided PH as a result of
abnormalities in smooth muscle tone, caused by endothelial
dysfunction primarily as a consequence of the imbalances
between NO and endothelin-1 (ET1) signaling (Figure 3).38,39
A series of classical studies investigating the effects of NO
blockade in the pulmonary circulation have shown that endothe-
lium-derived NO mediates basal pulmonary vascular tone and
dilation to endothelium-dependent stimuli. In healthy humans,
systemic infusion of acetylcholine, an NO synthase agonist,
increases local pulmonary blood flow.39 Conversely, infusion of
NG-monomethyl-L-arginine, an inhibitor of NO synthase, de-
creases pulmonary flow velocity,39 promotes vasoconstriction
and elevation in PAP,40 aggravates hypoxia-induced pulmonary
vasoconstriction,41 and impairs gas diffusion by altering alveolar
membrane conductance properties.42 In HF patients with ele-
vated PVR, Cooper and colleagues43 noted that NG-monomethyl-
L-arginine infusion caused less vasoconstriction than in patients
with normal PVR, suggesting loss of NO-dependent regulation
of tone. Wensel and colleagues44 showed that the extent of
increase in pulmonary artery flow in response to acetylcholine
was correlated with resting PAP and PVR. Porter et al45 found
that intrapulmonary infusion of acetylcholine caused vasodila-
tion in subjects with HF and normal PAP, but failed to cause
dilation in those with PH, although measures were performed by
intravascular ultrasound in larger pulmonary artery (PA) branch
vessels that do not contribute to resistance vessel regulation.
Endothelial-derived NO also inhibits smooth muscle cell prolif-
eration and hypertrophy in tandem with prostacyclin, prevent-
ing platelet aggregation and adhesion.46
 Guazzi and Borlaug Pulmonary Hypertension and Heart Failure 979

Figure 4. Relationships between pulmonary arterial compliance and resistance. A, invasive data from 257 patients with HFpEF and
HFrEF undergoing sodium nitroprusside (SNP) infusion (data plotted from Tedford et al55), illustrating the inverse relationship between
pulmonary artery (PA) compliance and resistance. Because of the hyperbolic inverse relationship between resistance and compliance,
small increases in PVR that develop early in disease progression are associated with dramatic reductions in PA compliance (B, plot
modified from Saouti et al54). Reduced PA compliance or capacitance is a potent predictor of outcome in patients with group 1 PH (C,
modified from Mahapatra et al58). HFrEF indicates heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejec-
tion fraction; and PVR, pulmonary vascular resistance.

ET1, a 21-amino-acid vasoactive peptide with potent
vasoconstrictor and platelet-aggregating properties, is widely
distributed in the pulmonary endothelium.47 In mammals, 2
ET receptors have been described: ETA, through which
vasoconstriction and cellular growth are elicited, and ETB,
which can mediate either vasoconstriction by its effects on
smooth muscle or vasodilatation through an action on endo-
thelial cells.47 ETB receptors also play an important role in
ET1 clearance.48 The ratio of ETA to ETB receptors on human
resistance and conduit pulmonary arteries is ⬇9:1, and the net
effect of ET1 in pulmonary arteries is constriction.49 ET1 may
also contribute to pathological pulmonary vascular remodel-
ing by causing proliferation and hypertrophy of vascular
smooth muscle cells and increasing collagen synthesis. ET1
immunoreactivity is abundant in pulmonary vascular endo-
thelial cells from patients with left-sided PH,50 and aug-
mented plasma ET1 levels have been repeatedly reported in
both experimental51 and clinical HF.52 The extent of ET1
increase predicts mortality in HFrEF.53
Hemodynamic Derangements
Pulmonary Arterial Loading in PH
The pulmonary and systemic circulations have important
hemodynamic and anatomic differences. Vascular resistance
is 10-fold lower in the lung than in the systemic vasculature,
related to the fact that there are ⬇10-fold more vessels in the
pulmonary bed. This distributes arterial compliance evenly
across the lungs, in contrast to the systemic circuit where
⬇80% of compliance is located in the aorta. As a result, PA
systolic, mean, and diastolic pressures all show a fairly linear
relationship with one another, and the product of PVR and
compliance is a constant (at a given downstream LAP).54 A
plot of PVR versus compliance forms a hyperbola (Figure
4A) that is remarkably consistent across patients of variable
age, sex, or underlying disease process.55 In early stage PH,
relatively small increases in PVR are associated with more
dramatic reductions in compliance (Figure 4B).56,57 This may
explain why compliance is a more sensitive marker of
outcome than PVR in patients with group 1 PH (Figure 4C).58
Tedford et al55 have recently shown that acute or chronic
increases in LAP shift the resistance/compliance relationship
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
leftward, such that compliance is lower at any given PVR.
This effectively enhances the pulsatile (oscillatory) compo-
nent of afterload relative to resistive load on the right heart.
The implication is that RV hydraulic efficiency is compro-
mised in group 2 PH, because oscillatory work does not
contribute to net transport of blood.54
Although it is an oversimplification, RV afterload is
usually conceptualized in terms of mean PAP and PVR.
However, it is important to appreciate that arterial pressure is
produced by the integration of flow and vascular impedance,
summed with downstream pressure. In the systemic circula-
tion, downstream hydraulic pressure (in the right atrium)
contributes little (⬍5%) to systemic arterial pressure.59 In the
lung, downstream pressure (ie, LAP) is a much more impor-
tant contributor to mean PAP (⬇50%), and this proportion
can become even greater in HF. Indeed, in the early stages of
group 2 PH, PAP elevation may be associated with purely
passive increases in LAP, with normal TPG (Figure 5A) and
normal PVR. This stage appears to be completely reversible
if LAP elevation can be treated.
Subsequent stages of PH are defined as reactive when
structural and functional abnormalities intrinsic to the pulmo-
nary vasculature cause elevation in PVR and TPG (Figure
5B). This may be either reversible or fixed. In the former
case, vasodilating challenge may normalize the TPG, sug-
gesting a predominance of functional over structural abnor-
malities. Conversely, when PAP does not normalize after
alleviation of the high downstream pressure, the vasculature
behaves similar to what is seen in precapillary forms of PH,
such as PAH. According to the European Society of Cardi-
ology Guidelines,8 a condition that may be representative of
an early evolution to mixed PH is the so-called out-of-
proportion group 2 PH, a qualitative definition that is char-
acterized by an increase in PAP that appears excessive for the
mild degree of increase in PCWP (Figure 5C). This hemody-
namic status seems to reflect an early development of
precapillary vascular changes resembling the transition from
passive to reactive PH. Although this condition may play a
relevant pathophysiological role, additional information re-
garding its usefulness as a term and a precise hemodynamic
definition are needed.
980 Circulation August 21, 2012

Figure 5. Diagram showing the various hemody-

namic stages observed in group 2 PH. A, Passive.
The increase in pulmonary artery pressure (PAP) is
thought to be exclusively due to downstream left
atrial pressure (LAP) elevation and no component
of the PH seems to result from abnormalities
intrinsic to the arterial wall. B, Reactive. The
increase in PAP is due to intrinsic vascular
changes in addition to elevated LAP. The TPG is
increased and may or may not reverse under phar-
macological challenge. C, Out of proportion
increase in PH. This condition refers to some
cases of TPG increase occurring in the presence
of mild or no increase in PCWP. The pathobiologi-
cal arterial changes of this condition are not well
defined, even though some evolving reactive precap-
illary component is thought to take place earlier in
the expected course of the disease. PH indicates
pulmonary hypertension; TPG, transpulmonary gradi-
ent; PCWP, pulmonary capillary wedge pressure; RV,
right ventricle; and LA, left atrium.

The chronicity of the transition from passive to reactive PH afterload for sustained periods of time. Although this pattern
is highly variable from patient to patient and does not appear of remodeling is often tolerated for many years, it may
to be consistently related to severity of LAP elevation. Lam et ultimately progress to chamber dilatation, functional tricuspid
al,5 found that, although pulmonary artery systolic pressure incompetence, and frank RV failure.64 RV hypertrophy may
increases as a function of estimated LAP (E/e⬘ ratio), it was decrease RV subendocardial perfusion, whereas dilatation
persistently higher in HFpEF patients than in controls, sug- results in increased wall stress, both enhancing myocardial
gesting elevation in PVR and a component of reactive PH. oxygen demand and provoking ischemia and symptoms of
effort angina. Further study is needed to better understand
Right Ventricular–Pulmonary Artery Coupling mechanistic differences between the RV and LV.
The RV is the ultimate victim of these vascular processes, and The RV and LV are connected in series, and reductions in
a common phenotype of end-stage HFrEF and HFpEF is that
RV output in advanced HF may lead to underfilling of the
of predominant RV failure, with systemic venous congestion,
LV. This was evidenced by a paradoxical decrease in PCWP
renal dysfunction, and ascites. Under normal conditions, the
during exercise noted in HFrEF patients with severe PH in an
RV operates against a low-impedance, high-capacitance, low-
early report by Butler and colleagues.1 In addition to series
pressure system, with a short isovolumic contraction period and
effects, the right and left heart share a common space in the
a prolonged systolic ejection time. Peculiar ontological and
morphological differences in the RV in comparison with LV
have been described, such as a differential distribution of RV
myofibers in series and differences in sarcomere shortening and
excitation– contraction coupling.60 Accordingly, although the
RV is well suited to accommodate an increase in volume load, it
is exquisitely afterload sensitive (similar to the LV in HFrEF).
The implication of this enhanced afterload sensitivity is that an
acute pressure overload causes much greater reduction in stroke
volume of the RV than of the LV (Figure 6).61,62 In a model of
pace-induced HF, early development of even mild PH led to a
profound RV-PA uncoupling, characterized by an inability of
the RV to adapt to the combined effects of increased pulmonary
arterial resistance and elastance.63 Exposure of a normal RV to
acute afterload mismatch can be catastrophic. This explains the
common observation of massive circulatory insufficiency and
death despite minimal PAP elevation in states such as acute
pulmonary embolism. The circulation fails in these instances
because the RV cannot generate sufficient pressure to overcome Figure 6. Enhanced afterload sensitivity of the right ventricle
the acute increase in arterial afterload. compared with the left. Right ventricular stroke volume is
impaired to a much greater extent in comparison with the left
Chronically, the RV may adapt to elevated afterload with ventricle with comparable acute increases in arterial pressure.
hypertrophy. This may allow ejection against tremendous Adapted from Abel and Waldhausen.61

Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012

 Guazzi and Borlaug
pericardial sac, so that changes in right heart pressure and
volume may affect the left heart in parallel.65 This cross talk
or coupling between the right and left sides, referred to as
diastolic ventricular interaction, is evidenced by an equaliza-
tion in right and left heart pressures during cardiac catheter-
ization (Figure 7A). Transmural LV filling pressure may be
estimated by the difference between intracavitary pressure
(ie, PCWP) and pericardial pressure. The latter can be
estimated by right atrial pressure (Figure 7B),66 and therefore
when right atrial pressure is elevated to a similar extent as
PCWP, right-sided chambers may effectively outcompete
those on the left for limited pericardial space, constraining
and compromising LV filling as the interventricular septum
bows from right to left (Figure 7C). Acute unloading of right
heart congestion with diuretics or venodilation in these
patients commonly improves LV filling by reducing right
heart/pericardial constraint and increasing transmural filling
pressure, even if PCWP remains unchanged or decreases
(Figure 7D).67
Chronic right HF in the setting of neurohumoral activation
and sodium retention leads to elevation of right atrial pres-
sure, and recent research suggests that this in itself carries
additional multiorgan toxicity. By increasing pressure in the
superior vena cava (where the thoracic ducts drain), lung
lymphatic drainage is compromised, leading to and sustaining
interstitial fluid accumulation in the lungs with reduced
compliance and impaired gas exchange, while promoting
effusion in the pleural spaces.68 Secondary elevation in
inferior vena cava pressure increases renal venous pressure,
challenging renal Na⫹ excretion by decreasing the driving
pressure through the kidney and contributing to the cardiore-
nal syndrome.69,70 Hepatic and splanchnic congestion may
cause cholestasis, impair gut absorption of nutrients and
medications, foster accumulation of ascites, and contribute
to translocation of gut microbes. It is noteworthy that the
latter observation led to the endotoxin hypothesis as an
explanation for the proinflammatory state frequently ob-
served in chronic HF.71 Thus, progressive RV failure in
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
Pulmonary Hypertension and Heart Failure 981
Figure 7. Ventricular interdependence in right
heart failure from group 2 PH. A, typical equaliza-
tion in RAP and PCWP from enhanced interde-
pendence in a patient with biventricular HF,
group 2 PH, and severe functional tricuspid insuf-
ficiency. Note the prominent V wave in the
PCWP that tracks closely with the RA V wave,
even in the absence of significant mitral insuffi-
ciency. This is caused by pressure changes in
the RA being transmitted to the LA across the
interatrial septum. B, External pericardial pres-
sure, which restrains left heart filling, can be esti-
mated by RAP (modified from Tyberg et al66).
Thus, when RA pressure is elevated near PCWP,
true LV preload volume may be reduced despite
marked elevation in left PCWP, because transmural
pressure is reduced (C). Unloading of right heart
congestion in this circumstance may enhance left-
sided preload, even if PCWP drops, because trans-
mural pressure increases (D) (see text for details).
RAP indicates right atrial pressure; PCWP, pulmo-
nary capillary wedge pressure; HF, heart failure; PH,
pulmonary hypertension; LV, left ventricle; RV, right
ventricle; FP, filling pressure; RA, right atrium; and
LA, left atrium.
response to PH triggers multiple positive feedback loops
that hasten evolution to stage D HF.68 –70 Future trials
testing therapies targeting RV dysfunction may offer hope
to improve outcomes in group 2 PH.72
Diagnosis and Clinical Assessment
Symptoms like orthopnea and paroxysmal nocturnal dyspnea
are more specific for left-sided PH, but the most common
symptom is exertional dyspnea. Chest radiography will often
reveal cardiomegaly, pulmonary vascular congestion, exces-
sive extravascular lung water, pleural effusion, or pulmonary
edema. It is noteworthy that overt right heart failure due to
reactive PH rarely coexists with pulmonary edema, presum-
ably because pulmonary vascular alterations that develop in
the former scenario protect the lungs against alveolar and
interstitial fluid transudation. Electrocardiographic clues fa-
voring group 2 PH include LV hypertrophy, left atrial
enlargement, or atrial fibrillation. High-resolution chest com-
puted tomography will often reveal a mosaic perfusion
pattern and ground-glass opacities consistent with chronic
interstitial lung edema. Pulmonary function tests may docu-
ment a restrictive pulmonary pattern, and gas diffusion is
generally reduced according to PVR and PAP increase.73
Plasma natriuretic peptide levels may be increased in any
type of PH, but tend to be the highest in group 2, particularly
when LVEF is depressed.74
When PH develops gradually, the RV can generate high
systolic pressures due to adaptive hypertrophy. As the RV
fails, PAP may become relatively low, despite marked ele-
vation of the PVR, leading to underappreciation of the extent
of pulmonary vascular disease present. Echocardiography is
an essential diagnostic test in the evaluation of PH. The
presence of systolic dysfunction (LVEF ⬍50%) or significant
left-sided valvular disease (especially mitral) makes left heart
disease the most likely cause of PH. In patients with HFrEF,
the extent of functional mitral regurgitation is a key determi-
nant of PH.75 The effective regurgitant mitral area is also a
strong predictor of increased pulmonary pressure and acute
982 Circulation August 21, 2012
pulmonary edema development in patients with functional
mitral regurgitation due to ischemic heart disease.76
HFpEF is an important cause of both acute77 and chronic
group 2 PH,78,79 although recent studies suggest that RV
failure may be less severe in HFpEF in comparison with
HFrEF.22 Patient demographics provide perhaps the greatest
predictive value for distinguishing HFpEF from PAH. Com-
ponents of the metabolic syndrome, including systemic hy-
pertension, obesity, and diabetes mellitus, are key risk factors
for HFpEF. Robbins and colleagues80 found that patients with
group 2 PH displayed 2 or more features of the metabolic
syndrome in 94% of cases, as opposed to 34% in patients with
group 1 PH. Increased age alone has been found to be the best
predictor of PH-HFpEF in comparison with group 1 PH,
followed by the presence of typical HFpEF comorbidities,
such as hypertension, diabetes mellitus, obesity, chronic
obstructive lung disease, atrial arrhythmias, and dyspnea on
exertion.4,5,78 – 80 Thenappan et al78 found that systolic blood
pressure was higher in HFpEF than PAH, whereas diastolic
pressure was similar, suggesting a higher pulse pressure (and
therefore higher systemic arterial stiffness) in HFpEF. A
more precise definition of how these factors truly contribute
to the risk of developing PH-HFpEF may come from specific
registries, although, registries devoted to Group 2 PH are
currently unavailable.81
Echocardiographic findings suggestive of HFpEF include
left atrial dilation and diastolic dysfunction, although mild
diastolic dysfunction is also common in group 1 PH. Tissue
Doppler early diastolic myocardial velocities (e⬘) correlate
with invasive measures of LV relaxation and are felt to be
independent of preload when relaxation is prolonged.82 The
ratio of early transmitral flow velocity (E) to tissue Doppler
early diastolic mitral annular velocity (E/e⬘ ratio) has been
widely embraced as a noninvasive measure of left heart filling
pressures,83,84 and one small study reported that E/e⬘ could
effectively distinguish groups 1 and 2 PH.85 However, a number
of studies have recently questioned the veracity of E/e⬘ as a
measure of left heart filling pressures in HF, and its use in the
evaluation of PH remains incompletely defined.20,86 – 89
Whereas echocardiography provides an extremely useful
tool to identify PH due to HFpEF, invasive testing is
frequently required, often with exercise provocation. This
allows direct measurement of left heart filling pressures and
transpulmonary gradient both at rest and with stress, when
patients typically report symptoms. Tolle and colleagues11
found that, among 406 consecutive patients referred for
invasive assessment because of dyspnea, 48% developed
exercise PH due to left heart disease, with diastolic dysfunc-
tion being the most common cause. Another series found that,
among patients with exertional dyspnea, normal natriuretic
peptide levels, and normal resting hemodynamics, over half
displayed hemodynamic findings diagnostic of HFpEF.12
Saline loading has been suggested as an alternative stressor in
laboratories without the capacity to perform exercise, but the
abnormal response remains unclear.90 An increase in PCWP
with pulmonary vasodilating therapy should raise the possi-
bility of HFpEF, because the reduction in PVR leads to
increased RV output that cannot be accommodated by the
noncompliant LV.11,91 It is possible that some patients hemo-
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
dynamically designated as having group 2 PH due to HFpEF
could, in fact, have group 1 PH with secondary elevation of
PCWP mediated by ventricular interdependence and right
heart congestion. Review of other clinical and echocardio-
graphic characteristics that travel with group 1 versus 2 PH
may be helpful in such circumstances to make this important
distinction.59,78
Because there may be disagreement between LV end-dia-
stolic pressure (LVEDP) and PCWP in some patients, it has
been suggested that left heart catheterization should be used
on a more regular basis in the evaluation of PH.92,93 Poor
agreement may be caused by nonsimultaneous acquisition,
inconsistent measurement during the respiratory cycle, or
overwedging, where PCWP is spuriously elevated. These
errors can be minimized by verifying PCWP position after
visualization of characteristic waveforms, demonstrating the
presence of well-saturated pulmonary venous blood (⬎94%),
and taking measures at quiet end expiration. Even with this
approach, the mean area under the curve in the PCWP tracing
may exceed LVEDP, especially when prominent A and V
waves are present. However, PCWP measured at mid-A wave
agrees well with LVEDP, and it can be argued that the
downstream load imposed by the left heart on the RV is better
represented by the pulmonary venous pressure than LVEDP.
When accurate PCWP cannot be determined, LVEDP should
be directly measured.
Assessment of the reversibility of PH and PVR elevation in
HF is critical in the evaluation for cardiac transplantation. A
vasodilator94 or inotropic challenge95 may demonstrate revers-
ibility while predicting subsequent outcomes after transplanta-
tion. Dynamic mitral regurgitation with exertion greatly in-
creases PAP in HFrEF, but its role in HFpEF remains unclear.96
Clinical Correlates
Exertional dyspnea is the most frequent concern in group 2
PH, and its pathophysiology is complex, resulting from
multiple interrelated pathways. These may be better under-
stood and interpreted by the use of cardiopulmonary exercise
testing.97 Exercise capacity is potently influenced by pulmo-
nary vascular function. Absence of dynamic pulmonary
vasodilation imposes an increased load to the RV in HF, as
evidenced by the positive correlation between RV ejection
fraction and peak VO2 in advanced HFrEF.98 Patients with HF
display a number of ventilatory abnormalities that are likely
related to the pulmonary vasculature. An impaired ventilation
efficiency (VE/VCO2 slope ⬎34) may be observed in early
HF as a consequence of a dysregulation of peripheral control
of ventilation (ie, increased chemo/metaboreflex gain). How-
ever, patients with steeper VE/VCO2 slope (⬎40) reflects
greater pulmonary vasoconstriction,99 elevated PAP, and
more severe RV dysfunction, reaching in most advanced
cases a slope similar to what is observed in group 1 PH
(⬇60).100 –102 This has important prognostic implications
considering the established predictivity of VE/VCO2 slope for
adverse clinical events in HF.103,104 Moreover, the occurrence
of an oscillatory breathing pattern during exercise has been
related to pulmonary vasoconstriction, depressed RV func-
tion, and low exercise CO.105,106
 Guazzi and Borlaug
Periodic breathing at rest is common in group 2 PH and is
intimately related to the degree of sympathetic activation in
these patients.107 In HF patients with elevated PCWP, the
incidence of central sleep apnea is enhanced, and a highly
significant relationship exists between PCWP and central
apnea severity.108 The mechanisms remain unclear. Francis et
al109 showed that low arterial pCO2 may stabilize ventilation
as a result of lower plant gain, although more recent work
from this group has shown that hypocapnia may serve as a
trigger of oscillatory ventilation that can be treated by CO2
administration.110
Intriguingly, PAP and PCWP are both positively correlated
with cardiac norepinephrine spillover in HFrEF patients,111
and acute reduction in left heart filling pressures with
nitroprusside is associated with diminution of cardiac sym-
pathetic nerve outflow and reduction in periodic breathing in
this group.112 These data emphasize the important cross talk
between hemodynamic derangements, autonomic activation,
and dysregulation of respiration at rest and with exertion in
group 2 PH. This further implies that achievement of better
hemodynamic profiles in these patients may have multiple
pleiotropic salubrious effects.
Morbidity and Mortality
The presence and extent of PH is a well-established prognos-
tic factor in HF,1–3,113,114 and this finding has recently been
extended to the general population5 (Figure 1). Increased
mortality and hospitalization rates have been reported in HF
patients with echocardiographically estimated PH,115 and
PAP is an independent predictor of the need for cardiac
transplant.116 At least two thirds of patients with severe
systolic LV dysfunction have PH with associated RV failure,
and mortality in this group is 2-fold higher in comparison
with isolated LV dysfunction.3 Data from the International
Society of Heart Transplantation registry suggest that RV
failure accounts for 50% of all cardiac complications and
19% of early deaths.117 RV dysfunction may also be an
underrecognized complication in HFpEF.78,118
Identification of PH reversibility is critical to demonstrate
low risk for adverse postoperative outcomes in this group.95
Abnormal increase in PAP with exercise is associated with
increased mortality in HFrEF, and a recent study of patients
hospitalized for acutely decompensated HF refined the prog-
nostic impact of PH further by showing that the presence of
both high PCWP and elevated PVR (mixed PH) is associated
with greater risk of death in comparison with PH because of
elevated PCWP alone or absence of PH.119 Although data are
far less abundant in HFpEF, some studies have established
that the presence and extent of PH are strongly predictive of
outcome in this group as well.6,21
Treatment
The potent prognostic impact of PH in HF suggests an
important role for the pulmonary vasculature as a novel
therapeutic target.7 Surgical and percutaneous treatments for
HF due to mitral valve disease are well known to produce
substantial improvements in PH,120 –123 although recent data
suggest that the negative impact of PH may persist, empha-
sizing the importance of early intervention before the devel-
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
Pulmonary Hypertension and Heart Failure 983
opment of pulmonary vascular disease.124 Application of
established HF therapies such as vasodilators and diuretics
may improve PH through reduction in filling pressures, PVR,
and functional mitral insufficiency,125 but the effects of
neurohormonal antagonists on PH have not been systemati-
cally evaluated, and traditional vasoactive drugs such as
angiotensin-system antagonists and ␤-blockers are less effec-
tive on the pulmonary circuit.
No approved therapeutic strategies or algorithms are avail-
able that apply to the treatment of group 2 PH, and trials of
agents targeted to the pulmonary vasculature tested thus far
have consistently failed to demonstrate benefit in HFrEF.
There is a propensity to consider group 2 PH of clinical
relevance only after pulmonary vascular disease and RV
failure are advanced and potentially irreversible, and it may
be that therapies delivered earlier in disease course will be
more effective. Most therapies that have been tested in group
2 to date have targeted endothelial control of vascular tone
and permeability (Figure 3). The following discussion fo-
cuses on agents targeting the pulmonary vasculature, and it is
less likely that these therapies would be effective to improve
outcome in purely passive group 2 PH. Many of these
therapies also target abnormalities outside the pulmonary
vasculature, which may independently affect their efficacy
(or lack thereof).
Pharmacological Agents
Prostaglandins
Prostaglandins are powerful vasodilators that lead to consis-
tent hemodynamic improvements in group 1 PH. Small,
short-term, nonrandomized studies suggested promising ef-
fects on hemodynamics in patients with severe left-sided
PH.126 –130 In postcardiac surgery patients, inhaled prostacy-
clin decreased PVR by 29% and improved RV perfor-
mance.131 During mitral valve surgery, inhaled iloprost was
superior to intravenous nitroglycerin in preventing RV failure
during weaning from cardiopulmonary bypass.132,133 Intrave-
nous prostacyclin reduces PCWP and PVR and increases CO,
but it is also associated with marked reductions in systemic
arterial resistance that may promote secondary neurohor-
monal activation.134 Despite these favorable hemodynamic
effects in early studies, the Flolan International Randomized
Survival Trial (FIRST, n⫽418 patients, New York Heart
Association class III–IV)135 demonstrated that intravenous
epoprostenol therapy was associated with a trend toward
increased mortality, leading to premature termination of the
trial. It should be noted that the FIRST trial enrolled a fairly
heterogenous patient population (eg, including patients with
coronary disease who might be expected to tolerate prosta-
glandin therapy poorly), and this broad enrollment might
have compromised the ability to detect a benefit to prosta-
glandin therapy in HF.
Endothelin Receptor Antagonists
ET1 is one of the most potent endogenous vasoconstrictors in
humans and plays a crucial role in the regulation of pulmo-
nary vascular tone in HF.136 Trials testing ET1 receptor
antagonist therapies in group 2 PH have consistently pro-
duced disappointing results,137,138 although it is notable that
984 Circulation August 21, 2012
the presence of PH was not an entry criterion in these studies.
In a small human HF trial, acute and short-term intravenous
nonselective ET1 blockade with bosentan reduced PAP, right
atrial pressure, PCWP, and PVR while increasing CO and
stroke volume.139 However, a series of large-scale trials
performed in patients with chronic HF have not produced
corresponding favorable results on harder end points. In the
Endothelin Antagonist Bosentan for Lowering Cardiac
Events in Heart Failure (ENABLE) study,140 bosentan in-
creased the risk of worsening HF. Packer et al141 reported an
increased risk of HF hospitalization during the first month of
treatment. In the Heart Failure ET(A) Receptor Blockade
Trial (HEAT),142 short-term administration of darusentan
improved cardiac index, but did not change PCWP, PVR, or
right atrial pressure. A trend toward increased death and early
exacerbation of HF was observed. In the only long-term trial
addressing group 2 PH as a predefined end point, patients on
bosentan experienced more serious adverse events than con-
trols.143 The EndothelinA Receptor Antagonist Trial in Heart
Failure (EARTH)144 and the Value of Endothelin Receptor
Inhibition With Tezosentan in Acute Heart Failure Studies
(VERITAS)145 also failed to demonstrate improvements in
death or HF hospitalizations. Although the endothelin recep-
tor antagonist trials were negative, it is possible that lower
doses may have been effective without toxicity. Additionally,
diuretic usage may have been suboptimal, because the in-
creased morbidity was largely attributable to increased hos-
pitalizations from fluid retention.
Nitric Oxide
Inhaled NO diffuses rapidly across the alveolar– capillary
membrane into the smooth muscle of pulmonary vessels, and
concentrations from 5 to 80 parts per million have been tested
for the treatment of advanced group 2 PH, especially after
LVAD placement and cardiac transplant. In post-LVAD
patients, inhaled NO reduces PAPs and increases LVAD
flow.146 In posttransplant PH management, inhaled NO, in
comparison with intravenous prostacyclin, prostaglandin E1,
and sodium nitroprusside, induced a selective decrease in
PVR, with no changes in systemic resistance.147 A potential
drawback of inhaled NO is the short half-life that requires
continuous administration, because acute interruption may
lead to rebound effects including hypotension and shock.
There is a theoretical risk of methemoglobinemia that is
seldom observed in adult populations. Another concern re-
garding inhaled NO therapy in group 2 PH stems from the
effects of unbalanced pulmonary vasodilation, which may
lead to dramatic increases in PCWP from preload excess in
the setting of a poorly compliant LV.148,149 This has been
reported to precipitate acute pulmonary edema,150 although
other reports have documented dramatic PCWP elevation in
the absence of symptoms.91 Further study is required to define
the role of inhaled NO to treat group 2 PH, especially when
awaiting transplantation, and to define hemodynamic pertur-
bations during acute inhaled NO on LV dynamics and lung
vessel compliance. Acute infusion of L-arginine, the substrate
for NO production by NO synthase, has been shown to
produce reduction in PAP and PVR in patients with PAH, but
HF patients with PH were not examined in this study.151
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
Phosphodiesterase 5 Inhibition
Phosphodiesterase 5 inhibitors (PDE5Is) hold great promise
for treating PH in left heart disease by increasing cGMP levels,
with consequent vasodilating and antiproliferative effects.152 In
contrast to other pulmonary vasodilators, there is a growing
evidence base suggesting the effectiveness of PDE5I in group 2
PH. These compounds are especially attractive for HF patients
prone to systemic hypotension.127 Acute153–157 and chronic158 –161
administration of oral sildenafil reduces PA pressure and PVR
without substantial changes in systemic arterial pressure and
resistance. No cases of pulmonary edema have been reported,
and long-term administration has been well tolerated thus far in
small clinical trials. In a recent study by Lewis et al102 the
increase in TPG during submaximal exercise was attenuated by
sildenafil, suggesting a favorable reduction in precapillary vas-
cular tone. Sildenafil may improve alveolar– capillary membrane
conductance and gas exchange, suggesting an important role for
cGMP downstream pathway in the protection of endothelial
permeability, attenuation of alveolar hypoxia, and facilitation of
alveolar gas conductance.154
Both acute and chronic trials to date in group 2 PH in patients
with reduced ejection fraction have shown that PDE5Is improve
exercise capacity, ventilation efficiency, breathing patterns, and
quality of life.155–160 These effects may be due to the beneficial
effects on pulmonary vascular tone and RV function, reduction
in PCWP, or direct modulation on the peripheral skeletal muscle
ergoreceptor overstimulation, possibly mediated by improve-
ments in small-vessel endothelium-dependent vasodilation. In a
recent study by Melenovski et al,157 the transpulmonary
release of cGMP was assessed in group 2 HF patients before
and after a single dose of sildenafil (40 mg). Subjects with
elevated PVR displayed impaired cGMP release in compar-
ison with normal PVR, and acute PDE5Is restored the cGMP
gradient in this group, independent of effects on PCWP.
Benefits from PDE5Is have recently been extended to HF
patients with recalcitrant PH despite hemodynamic unloading
with LVADs.161 Two studies have addressed whether exer-
cise oscillatory breathing could be a peculiar target of chronic
PDE5Is in systolic HF, both showing the drug effectiveness
in reversing the abnormal ventilatory oscillatory pattern to a
physiological behavior.105,162
Recently, the effects at long-term (1 year) PDE5I with
sildenafil were investigated in a randomized controlled trial
of patients with PH and HFpEF. Sildenafil was well tolerated
and reduced pulmonary vasoconstriction and right atrial
hypertension. In addition, chronic treatment was associated
with a reduction RV dilatation, enhanced RV contractile
function, and improvements in measures of alveolar– capil-
lary gas exchange.163 Less dramatic but significant benefits
were observed in the left heart, with 15% reduction in PCWP
and improvements in tissue Doppler measures of LV func-
tion. The mechanism by which other pulmonary vasodilators
increase PCWP whereas PDE5Is do not is unclear, but may
relate to the direct beneficial effects on LV diastolic stiffness
with PDE5Is, mediated by cGMP-dependent phosphorylation
of titin, or reduction in systemic arterial pressure and LV
afterload.164 –166 The ongoing PhosphodiesteRasE-5 Inhibi-
tion to Improve Quality of Life And EXercise Capacity in
Diastolic Heart Failure (RELAX) trial is testing the effects of
 Guazzi and Borlaug
chronic PDE5Is on exercise capacity and ventricular structure
and function in HFpEF.
PDE5I have not been tested in other forms of HF, such as
valvular heart diseases or acutely decompensated HF. The use
of PDE5Is as RV unloading agents with direct biological
effects on RV myocytes represents a promising field of investi-
gation,167 especially in view of the recent demonstration of
upregulated levels of PDE5 in myocytes isolated from RV of PH
patients with HF.168 Larger prospective multicenter controlled
trials are urgently needed to better define the safety, tolerability,
and effectiveness of PDE5I in group 2 PH, because short-term
hemodynamic and functional benefits may not extend with
chronic use.169 Other strategies to enhance cGMP levels are
currently under investigation, including direct guanylate cyclase
activators and stimulators.170
Nonpharmacological Therapies
Improvements in PA pressure, PVR, and RV remodeling have
been reported with cardiac resynchronization therapy, although
further study is required regarding the mechanisms, because
these benefits may simply be mediated by salubrious effects of
resynchronization on LV function and PCWP.171–174 Ameliora-
tion or reversibility of what was previously considered to be
fixed PH with LVAD therapy has also been described.175
Most findings in LVAD recipients with fixed PH suggest that
reversibility can be observed within 6 months from implan-
tation,176 making many previously ineligible patients with
advanced PH listed for cardiac transplantation.177–179 Data
comparing survival in PH patients who received LVAD
versus those who do not are not available.
Conclusions
Group 2 PH is a common consequence of chronic left atrial
hypertension in HF caused by myocardial and valvular
disease. These processes activate a cascade of deleterious
anatomic and functional alterations of pulmonary arterial,
capillary, and venous circulation, ultimately promoting RV
dysfunction and failure. These changes are clearly associ-
ated with increased morbidity and mortality in both HFpEF
and HFrEF, mediated by effects on multiple organ systems.
Therapeutic interventions targeting or preventing pulmonary
vascular abnormalities and development or progression of
RV failure in group 2 PH are important priorities for the
future. PDE5Is hold great promise in this regard. Further
research is urgently needed to define the processes that
promote pulmonary vascular remodeling in HF, in addition to
multicenter randomized, controlled trials of agents targeted to
these derangements to treat and prevent group 2 PH and its
effects on the right heart.
Sources of Funding
This work was supported by the Monzino Foundation, Milano, Italy
(to Dr Guazzi) and the Marie Ingalls Career Development Award in
Cardiovascular Research (to Dr Borlaug).
Disclosures
None.
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
Pulmonary Hypertension and Heart Failure 985
References
1. Butler J, Chomsky DB, Wilson JR. Pulmonary hypertension and
exercise intolerance in patients with heart failure. J Am Coll
Cardiol. 1999;34:1802–1806.
2. Abramson SV, Burke JF, Kelly JJ Jr, Kitchen JG 3rd, Dougherty MJ,
Yih DF, McGeehin FC 3rd, Shuck JW, Phiambolis TP. Pulmonary
hypertension predicts mortality and morbidity in patients with dilated
cardiomyopathy. Ann Intern Med. 1992;116:888 – 895.
3. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R,
Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic
value of right ventricular systolic function and pulmonary artery
pressure in patients with chronic heart failure. J Am Coll Cardiol.
2001;37:183–188.
4. Shapiro BP, McGoon MD, Redfield MM. Unexplained pulmonary
hypertension in elderly patients. Chest. 2007;131:94 –100.
5. Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ, Redfield
MM. Age-associated increases in pulmonary artery systolic pressure in
the general population. Circulation. 2009;119:2663–2670.
6. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield
MM. Pulmonary hypertension in heart failure with preserved ejection
fraction: a community-based study. J Am Coll Cardiol. 2009;53:
1119 –1126.
7. Guazzi M, Arena R. Pulmonary hypertension with left-sided heart
disease. Nat Rev Cardiol. 2010;7:648 – 659.
8. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera
JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA,
Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M,
Simonneau G; ESC Committee for Practice Guidelines (CPG).
Guidelines for the diagnosis and treatment of pulmonary hypertension:
the Task Force for the Diagnosis and Treatment of Pulmonary Hyper-
tension of the European Society of Cardiology (ESC) and the European
Respiratory Society (ERS), endorsed by the International Society of
Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:
2493–2537.
9. Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial
pressure during rest and exercise in healthy subjects: a systematic
review. Eur Respir J. 2009;34:888 – 894.
10. Kovacs G, Olschewski A, Berghold A, Olschewski H. Pulmonary
vascular resistances during exercise in normal subjects: a systematic
review. Eur Respir J. 2012;39:319 –328.
11. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom
DM. Exercise-induced pulmonary arterial hypertension. Circulation.
2008;118:2183–2189.
12. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise
hemodynamics enhance diagnosis of early heart failure with preserved
ejection fraction. Circ Heart Fail. 2010;3:588 –595.
13. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW,
Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin
LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER,
Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs
AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D,
Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy
CM, Weitz HH, Wesley DJ; ACCF/AHA. ACCF/AHA 2009 expert
consensus document on pulmonary hypertension: a report of the
American College of Cardiology Foundation Task Force on Expert
Consensus Documents and the American Heart Association: developed
in collaboration with the American College of Chest Physicians,
American Thoracic Society, Inc., and the Pulmonary Hypertension
Association. Circulation. 2009;119:2250 –2294.
14. Ristow B, Schiller NB. Obtaining accurate hemodynamics from echo-
cardiography: achieving independence from right heart catheterization.
Curr Opin Cardiol. 2010;25:437– 444.
15. Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocar-
diography for pulmonary hypertension: a systematic review and meta-
analysis. Heart. 2011;97:612– 622.
16. Fisher MR, Forfia PR, Chamera E, Housten-Harris T, Champion HC,
Girgis RE, Corretti MC, Hassoun PM. Accuracy of Doppler echocardi-
ography in the hemodynamic assessment of pulmonary hypertension.
Am J Respir Crit Care Med. 2009;179:615– 621.
17. Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler
echocardiographic estimates of pulmonary artery pressures in patients
with pulmonary hypertension: implications for clinical practice. Chest.
2011;139:988 –993.
986 Circulation August 21, 2012
18. Testani JM, St John Sutton MG, Wiegers SE, Khera AV, Shannon RP,
Kirkpatrick JN. Accuracy of noninvasively determined pulmonary artery
systolic pressure. Am J Cardiol. 2010;105:1192–1197.
19. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA,
Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira
AF, Borbély A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B,
Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart
failure: a consensus statement on the diagnosis of heart failure with
normal left ventricular ejection fraction by the Heart Failure and Echo-
cardiography Associations of the European Society of Cardiology. Eur
Heart J. 2007;28:2539 –2550.
20. Penicka M, Bartunek J, Trakalova H, Hrabakova H, Maruskova M,
Karasek J, Kocka V. Heart failure with preserved ejection fraction in
outpatients with unexplained dyspnea: a pressure-volume loop analysis.
J Am Coll Cardiol. 2010;55:1701–1710.
21. Hoeper MM, Barberà JA, Channick RN, Hassoun PM, Lang IM, Manes
A, Martinez FJ, Naeije R, Olschewski H, Pepke-Zaba J, Redfield MM,
Robbins IM, Souza R, Torbicki A, McGoon M. Diagnosis, assessment,
and treatment of non-pulmonary arterial hypertension pulmonary hyper-
tension. J Am Coll Cardiol. 2009;54:S85–S96.
22. Kjaergaard J, Akkan D, Iversen KK, Kjoller E, Køber L, Torp-Pedersen
C, Hassager C. Prognostic importance of pulmonary hypertension in
patients with heart failure. Am J Cardiol. 2007;99:1146 –1150.
23. Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA,
Borlaug BA. Effects of vasodilation in heart failure with preserved or
reduced ejection fraction: implications of distinct pathophysiologies on
response to therapy. J Am Coll Cardiol. 2012;59:442– 451.
24. West JB, Mathieu-Costello O. Vulnerability of pulmonary capillaries in
heart disease. Circulation. 1995;92:622– 631.
25. Guazzi M. Alveolar gas diffusion abnormalities in heart failure. J Card
Fail. 2008;14:695–702.
26. Tsukimoto K, Mathieu-Costello O, Prediletto R, Elliott AR, West JB.
Ultrastructural appearances of pulmonary capillaries at high transmural
pressures. J Appl Physiol. 1991;71:573–582.
27. Saldías FJ, Azzam ZS, Ridge KM, Yeldandi A, Rutschman DH,
Schraufnagel D, Sznajder JI. Alveolar fluid reabsorption is impaired by
increased left atrial pressure in rats. Am J Physiol. 2001;281:
L591–L597.
28. Conforti E, Fenoglio C, Bernocchi G, Bruschi O, Miserocchi GA.
Morpho-functional analysis of lung tissue in mild interstitial edema.
Am J Physiol. 2002;282:L766 –L774.
29. Elliott AR, Fu Z, Tsukimoto K, Prediletto R, Mathieu-Costello O,
West JB. Short-term reversibility of ultrastructural changes in pul-
monary capillaries caused by stress failure. J Appl Physiol. 1992;73:
1150 –1158.
30. Townsley MI, Fu Z, Mathieu-Costello O, West JB. Pulmonary micro-
vascular permeability. Responses to high vascular pressure after
induction of pacing-induced heart failure in dogs. Circ Res. 1995;77:
317–325.
31. Lee JS. Electron microscopic studies on the alveolar-capillary barrier
in patients with chronic pulmonary edema. Jpn Circ J. 1979;43:
945–954.
32. Kerem A Yin J, Kaestle SM, Hoffmann J, Schoene AM, Singh B, Kuppe
H, Borst MM, Kuebler WM. Lung endothelial dysfunction in congestive
heart failure: role of impaired Ca2⫹ signaling and cytoskeletal reorga-
nization. Circ Res. 2010;16:1103–1116.
33. Guazzi M, Pontone G, Brambilla R, Agostoni P, Rèina G. Alveolar-
capillary membrane gas conductance: a novel prognostic indicator in
chronic heart failure. Eur Heart J. 2002;23:467– 476.
34. Delgado JF, Conde E, Sánchez V, López-Ríos F, Gómez-Sánchez MA,
Escribano P, Sotelo T, Gómez de la Cámara A, Cortina J, de la Calzada
CS. Pulmonary vascular remodeling in pulmonary hypertension due to
chronic heart failure. Eur J Heart Fail. 2005;7:1011–1016.
35. Rabinovitch M. EVE and beyond, retro and prospective insights. Am J
Physiol. 1999;277:L5–L12.
36. Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL, Yuan JX,
Deutsch R, Jamieson SW, Thistlethwaite PA. Signaling molecules in
nonfamilial pulmonary hypertension. N Engl J Med. 2003;348:
500 –509.
37. Stobierska B, Awad H, Michler RE. The evolving management of acute
right-sided heart failure in cardiac transplant recipients. J Am Coll
Cardiol. 2001;38:923–931.
38. Ooi H, Colucci WS, Givertz MM. Endothelin mediates increased pul-
monary vascular tone in patients with heart failure: demonstration by
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
direct intrapulmonary infusion of sitaxsentan. Circulation. 2002;106:
1618 –1621.
39. Cooper CJ, Landzberg MJ, Anderson TJ, Charbonneau F, Creager MA,
Ganz P, Selwyn AP. Role of nitric oxide in the local regulation of
pulmonary vascular resistance in humans. Circulation. 1996;93:
266 –271.
40. Stamler JS, Loh E, Roddy MA, Currie KE, Creager MA. Nitric oxide
regulates basal systemic and pulmonary vascular resistance in healthy
humans. Circulation. 1994;89:2035–2040.
41. Blitzer ML, Loh E, Roddy MA, Stamler JS, Creager MA. Endotheli-
um-derived nitric oxide regulates systemic and pulmonary vascular
resistance during acute hypoxia in humans. J Am Coll Cardiol. 1996;
28:591–596.
42. Guazzi M, Arena R, Vicenzi M, Guazzi MD. Regulation of alveolar gas
conductance by NO in man, as based on studies with NO donors and
inhibitors of NO production. Acta Physiol. 2009;196:267–277.
43. Cooper CJ, Jevnikar FW, Walsh T, Dickinson J, Mouhaffel A, Selwyn
AP. The influence of basal nitric oxide activity on pulmonary vascular
resistance in patients with congestive heart failure. Am J Cardiol. 1998;
82:609 – 614.
44. Wensel R, Opitz CF, Kleber FX. Acetylcholine but not sodium nitro-
prusside exerts vasodilation in pulmonary hypertension secondary to
chronic congestive heart failure. J Heart Lung Transplant. 1999;18:
877– 883.
45. Porter TR, Taylor DO, Cycan A, Fields J, Bagley CW, Pandian NG,
Mohanty PK. Endothelium-dependent pulmonary artery responses in
chronic heart failure: influence of pulmonary hypertension. J Am Coll
Cardiol. 1993;22:1418 –1424.
46. Radomski MW, Palmer RM, Moncada S. An L-arginine/nitric oxide
pathway present in human platelets regulates aggregation. Proc Natl
Acad Sci U S A. 1990;87:5193–5197.
47. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui
Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide
produced by vascular endothelial cells. Nature. 1988;332:411– 415.
48. Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating
endothelin-1 in dogs in vivo: exclusive role of ETB receptors. J Appl
Physiol. 1996;81:1510 –1515.
49. Fukuroda T, Kobayashi M, Ozaki S, Yano M, Miyauchi T, Onizuka M,
Sugishita Y, Goto K, Nishikibe M. Endothelin receptor subtypes in
human versus rabbit pulmonary arteries. J Appl Physiol. 1994;76:
1976 –1982.
50. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H,
Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of
endothelin-1 in the lungs of patients with pulmonary hypertension.
N Engl J Med. 1993;328:1732–1739.
51. Ray L, Mathieu M, Jespers P, Hadad I, Mahmoudabady M, Pensis A,
Motte S, Peters IR, Naeije R, McEntee K. Early increase in pulmonary
vascular reactivity with overexpression of endothelin-1 and vascular
endothelial growth factor in canine experimental heart failure. Exp
Physiol. 2008;93:434 – 442.
52. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin
correlates with the extent of pulmonary hypertension in patients with
chronic congestive heart failure. Circulation. 1992;85:504 –509.
53. Hülsmann M, Stanek B, Frey B, Sturm B, Putz D, Kos T, Berger R,
Woloszczuk W, Putz D, Kos T, Berger R, Woloszczuk W, Maurer G,
Pacher R. Value of cardiopulmonary exercise testing and big endothelin
plasma levels to predict short-term prognosis of patients with chronic
heart failure. J Am Coll Cardiol. 1998;32:1695–1700.
54. Saouti N, Westerhof N, Postmus PE, Vonk-Noordegraaf A. The arterial
load in pulmonary hypertension. Eur Respir Rev. 2010;19:197–203.
55. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann
DR, Mudd JO, Cingolani OH, Borlaug BA, Redfield MM, Lederer DJ,
Kass DA. Pulmonary capillary wedge pressure augments right ventric-
ular pulsatile loading. Circulation. 2012;125:289 –297.
56. Lankhaar JW, Westerhof N, Faes TJ, Marques KM, Marcus JT, Postmus
PE, Vonk-Noordegraaf A. Quantification of right ventricular afterload in
patients with and without pulmonary hypertension. Am J Physiol Heart
Circ Physiol. 2006;291:H1731–H1737.
57. Lankhaar JW, Westerhof N, Faes TJ, Gan CT, Marques KM,
Boonstra A, van den Berg FG, Postmus PE, Vonk-Noordegraaf A.
Pulmonary vascular resistance and compliance stay inversely related
during treatment of pulmonary hypertension. Eur Heart J. 2008;29:
1688 –1695.
58. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Rela-
tionship of pulmonary arterial capacitance and mortality in idiopathic
 Guazzi and Borlaug
pulmonary arterial hypertension. J Am Coll Cardiol. 2006;47:
799 – 803.
59. Borlaug BA. Discerning pulmonary venous from pulmonary arterial
hypertension without the help of a catheter. Circ Heart Fail. 2011;4:
235–237.
60. Kondo RP, Dederko DA, Teutsch C, Chrast J, Catalucci D, Chien KR,
Giles WR. Comparison of contraction and calcium handling between
right and left ventricular myocytes from adult mouse heart: a role for
repolarization waveform. J Physiol. 2006;571:131–146.
61. Abel FL, Waldhausen JA. Effects of alterations in pulmonary vascular
resistance on right ventricular function. J Thorac Cardiovasc Surg.
1967;54:886 – 894.
62. Konstam MA, Cohen SR, Salem DN, Conlon TP, Isner JM, Das D, Zile
MR, Levine HJ, Kahn PC. Comparison of left and right ventricular
end-systolic pressure-volume relations in congestive heart failure. J Am
Coll Cardiol. 1985;5:1326 –1334.
63. Pagnamenta A, Dewachter C, McEntee K, Fesler P, Brimioulle S, Naeije
R. Early right ventriculo-arterial uncoupling in borderline pulmonary
hypertension on experimental heart failure. J Appl Physiol. 2010;109:
1080 –1085.
64. Champion HC, Michelakis ED, Hassoun PM. Comprehensive invasive
and noninvasive approach to the right ventricle-pulmonary circulation
unit: state of the art and clinical and research implications. Circulation.
2009;120:992–1007.
65. Guazzi M, Pepi M, Maltagliati A, Celeste F, Muratori M, Tamborini G.
How the two sides of the heart adapt to graded impedance to venous
return with head-up tilting. J Am Coll Cardiol. 1995;26:1732–1740.
66. Tyberg JV, Taichman GC, Smith ER, Douglas NW, Smiseth OA, Keon
WJ. The relationship between pericardial pressure and right atrial pres-
sure: an intraoperative study. Circulation. 1986;73:428 – 432.
67. Atherton JJ, Moore TD, Lele SS, Thomson HL, Galbraith AJ, Belenkie
I, Tyberg JV, Frenneaux MP. Diastolic ventricular interaction in chronic
heart failure. Lancet. 1997;349:1720 –1724.
68. Guazzi MD, Agostoni P, Perego B, Lauri G, Salvioni A, Giraldi F,
Matturri M, Guazzi M, Marenzi G. Apparent paradox of neurohumoral
axis inhibition after body fluid volume depletion in patients with chronic
congestive heart failure and water retention. Br Heart J. 1994;72:
534 –539.
69. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC,
Young JB, Tang WH. Importance of venous congestion for worsening of
renal function in advanced decompensated heart failure. J Am Coll
Cardiol. 2009;53:589 –596.
70. Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circu-
lation. 2010;121:2592–2600.
71. Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR,
Rauchhaus M, Poole-Wilson PA, Coats AJ, Anker SD. Endotoxin and
immune activation in chronic heart failure: a prospective cohort study.
Lancet. 1999;353:1838 –1842.
72. McDonald MA, Ross HJ. Trying to succeed when the right ventricle
fails. Curr Opin Cardiol. 2009;24:239 –245.
73. Guazzi M, Marenzi G, Alimento M, Contini M, Agostoni P.
Improvement of alveolar-capillary membrane diffusing capacity with
enalapril in chronic heart failure and counteracting effect of aspirin.
Circulation. 1997;95:1930 –1936.
74. Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, Goto
Y, Nonogi H. B-type natriuretic peptide strongly reflects diastolic
wall stress in patients with chronic heart failure: comparison between
systolic and diastolic heart failure. J Am Coll Cardiol. 2006;47:
742–748.
75. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Deter-
minants of pulmonary hypertension in left ventricular dysfunction. J Am
Coll Cardiol. 1997;29:153–159.
76. Pierard LA, Lancellotti P. The role of ischemic mitral regurgitation in
the pathogenesis of acute pulmonary edema. N Engl J Med. 2004;351:
1627–1634.
77. Gandhi SK, Powers JC, Nomeir AM, Fowle K, Kitzman DW, Rankin
KM, Little WC. The pathogenesis of acute pulmonary edema associated
with hypertension. N Engl J Med. 2001;344:17–22.
78. Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati A,
Shroff P, Rich S. Clinical characteristics of pulmonary hypertension in
patients with heart failure and preserved ejection fraction. Circ Heart
Fail. 2011:4;257–265.
79. Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence and risk
factors of pulmonary hypertension in patients with elevated pulmonary
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
Pulmonary Hypertension and Heart Failure 987
venous pressure and preserved ejection fraction. Am J Cardiol. 2010;
106:284 –286.
80. Robbins IM, Newman JH, Johnson RF, Hemnes AR, Fremont RD, Piana
RN, Zhao DX, Byrne DW. Association of the metabolic syndrome with
pulmonary venous hypertension. Chest. 2009;136:31–36.
81. Frost AE, Badesch DB, Barst RJ, Benza RL, Elliott CG, Farber HW,
Krichman A, Liou TG, Raskob GE, Wason P, Feldkircher K, Turner M,
McGoon MD. The changing picture of patients with pulmonary arterial
hypertension in the United States: how REVEAL differs from historic
and non-US Contemporary Registries. Chest. 2011;139:128 –137.
82. Lester SJ, Tajik AJ, Nishimura RA, Oh JK, Khandheria BK, Seward JB.
Unlocking the mysteries of diastolic function: deciphering the Rosetta
Stone 10 years later. J Am Coll Cardiol. 2008;51:679 – 689.
83. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quiñones MA.
Doppler tissue imaging: a noninvasive technique for evaluation of left
ventricular relaxation and estimation of filling pressures. J Am Coll
Cardiol. 1997;30:1527–1533.
84. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield
MM, Tajik AJ. Clinical utility of Doppler echocardiography and tissue
Doppler imaging in the estimation of left ventricular filling pressures: a
comparative simultaneous Doppler-catheterization study. Circulation.
2000;102:1788 –1794.
85. Willens HJ, Chirinos JA, Gomez-Marin O, Fertel DP, Ghany RA,
Alfonso CE, Hare JM. Noninvasive differentiation of pulmonary arterial
and venous hypertension using conventional and Doppler tissue imaging
echocardiography. J Am Soc Echocardiogr. 2008;21:715–719.
86. Mullens W, Borowski AG, Curtin RJ, Thomas JD, Tang WH. Tissue
Doppler imaging in the estimation of intracardiac filling pressure in
decompensated patients with advanced systolic heart failure.
Circulation. 2009;119:62–70.
87. Maeder MT, Thompson BR, Brunner-La Rocca HP, Kaye DM. Hemo-
dynamic basis of exercise limitation in patients with heart failure and
normal ejection fraction. J Am Coll Cardiol. 2010;56:855– 863.
88. Bhella PS, Pacini EL, Prasad A, Hastings JL, Adams-Huet B, Thomas
JD, Grayburn PA, Levine BD. Echocardiographic indices do not reliably
track changes in left-sided filling pressure in healthy subjects or patients
with heart failure with preserved ejection fraction. Circ Cardiovasc
Imaging. 2011;4:482– 489.
89. From AM, Lam CS, Pitta SR, Kumar PV, Balbissi KA, Booker JD,
Singh IM, Sorajja P, Reeder GS, Borlaug BA. Bedside assessment of
cardiac hemodynamics: the impact of noninvasive testing and examiner
experience. Am J Med. 2011;124:1051–1057.
90. Pacold I, Hwang MH, Palac RT, Scanlon PJ, Loeb HS. The effects of
rapid volume expansion on the right and left cardiac filling pressures
after coronary artery bypass surgery. Chest. 1988;93:1144 –1147.
91. Boilson BA, Schirger JA, Borlaug, BA. Caveat medicus! Pulmonary
hypertension in the elderly: a word of caution. Eur J Heart Fail.
2010;12:89 –93.
92. Halpern SD, Taichman DB. Misclassification of pulmonary hyper-
tension due to reliance on pulmonary capillary wedge pressure rather
than left ventricular end-diastolic pressure. Chest. 2009;136:37– 43.
93. Soto FJ, Siegel R, Marks D, et al. Performance of pulmonary capillary
wedge pressure (PCWP) vs left ventricular end diastolic pressure
(LVEDP) in the diagnosis/classification of patients with suspect pulmo-
nary arterial hypertension [abstract]. Chest. 2005;128:137S.
94. Costard-Jäckle A, Fowler MB. Influence of preoperative pulmonary
artery pressure on mortality after heart transplantation: testing of
potential reversibility of pulmonary hypertension with nitroprusside
is useful in defining a high risk group. J Am Coll Cardiol. 1992;19:
48 –54.
95. Givertz MM, Hare JM, Loh E, Gauthier DF, Colucci WS. Effect of bolus
milrinone on hemodynamic variables and pulmonary vascular resistance
in patients with severe left ventricular dysfunction: a rapid test for
reversibility of pulmonary hypertension. J Am Coll Cardiol. 1996;28:
1775–1780.
96. Guazzi M. Pulmonary hypertension in heart failure with preserved
ejection fraction any pathophysiological role of mitral regurgitation.
J Am Coll Cardiol. 2009;54:1191–1192.
97. Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman
D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R,
Mancini D, Milani RV; American Heart Association Exercise, Cardiac
Rehabilitation, and Prevention Committee of the Council on Clinical
Cardiology; Council on Epidemiology and Prevention; Council on Pe-
ripheral Vascular Disease; Interdisciplinary Council on Quality of Care
and Outcomes Research. Clinician’s Guide to cardiopulmonary exercise
988 Circulation August 21, 2012
testing in adults: a scientific statement from the American Heart Asso-
ciation. Circulation. 2010;122:191–225.
98. Di Salvo TG, Mathier M, Semigran MJ, Dec GW. Preserved right
ventricular ejection fraction predicts exercise capacity and survival in
advanced heart failure. J Am Coll Cardiol. 1995;25:1143–1153.
99. Reindl I, Wernecke KD, Opitz C, Wensel R, König D, Dengler T,
Schimke I, Kleber FX. Impaired ventilatory efficiency in chronic heart
failure: possible role of pulmonary vasoconstriction. Am Heart J. 1998;
136:778 –785.
100. Methvin AB, Owens AT, Emmi AG, Allen M, Wiegers SE, Dries DL,
Margulies KB, Forfia PR. Ventilatory inefficiency reflects right ventric-
ular dysfunction in systolic heart failure. Chest. 2011;139:617– 625.
101. Lewis GD, Shah RV, Pappagianopolas PP, Systrom DM, Semigran MJ.
Determinants of ventilatory efficiency in heart failure. The role of right
ventricular performance and pulmonary vascular tone. Circ Heart Fail.
2008;1:227–233.
102. Lewis GD, Murphy RM, Shah RV, Pappagianopoulos PP, Malhotra R,
Bloch KD, Systrom DM, Semigran MJ. Pulmonary vascular response
patterns during exercise in left ventricular systolic dysfunction predict
exercise capacity and outcomes. Circ Heart Fail. 2011;4:276 –285.
103. Arena R, Myers J, Abella J, Peberdy MA, Bensimhon D, Chase P,
Guazzi M. Development of a ventilatory classification system in patients
with heart failure. Circulation. 2007;115:2410 –2417.
104. Guazzi M, Myers J, Arena R. Cardiopulmonary exercise testing in the
clinical and prognostic assessment of diastolic heart failure. J Am Coll
Cardiol. 2005;46:1883–1890.
105. Murphy RM, Shah RV, Malhotra R, Pappagianopoulos PP, Hough SS,
Systrom DM, Semigran MJ, Lewis GD. Exercise oscillatory ventilation
in systolic heart failure: an indicator of impaired hemodynamic response
to exercise. Circulation. 2011;124:1442–1451.
106. Olson TP, Frantz RP, Snyder EM, O’Malley KA, Beck KC, Johnson
BD. Effects of acute changes in pulmonary wedge pressure on periodic
breathing at rest in heart failure patients. Am Heart J. 2007;153:
104.e1–104.e7.
107. Mansfield D, Kaye DM, Brunner La Rocca H, Solin P, Esler MD,
Naughton MT. Raised sympathetic nerve activity in heart failure and
central sleep apnea is due to heart failure severity. Circulation. 2003;
107:1396 –1400.
108. Solin P, Bergin P, Richardson M, Kaye DM, Walters EH, Naughton MT.
Influence of pulmonary capillary wedge pressure on central apnea in
heart failure. Circulation. 1999;99:1574 –1579.
109. Francis DP, Willson K, Davies LC, Coats AJ, Piepoli M. Quantitative
general theory for periodic breathing in chronic heart failure and its
clinical implications. Circulation. 2000;102:2214 –2221.
110. Giannoni A, Baruah R, Willson K, Mebrate Y, Mayet J, Emdin M,
Hughes AD, Manisty CH, Francis DP. Real-time dynamic carbon
dioxide administration: a novel treatment strategy for stabilization of
periodic breathing with potential application to central sleep apnea. J Am
Coll Cardiol. 2010;56:1832–1837.
111. Kaye DM, Lambert GW, Lefkovits J, Morris M, Jennings G, Esler MD.
Neurochemical evidence of cardiac sympathetic activation and increased
central nervous system norepinephrine turnover in severe congestive
heart failure. J Am Coll Cardiol. 1994;23:570 –578.
112. Kaye DM, Jennings GL, Dart AM, Esler MD. Differential effect of acute
baroreceptor unloading on cardiac and systemic sympathetic tone in
congestive heart failure. J Am Coll Cardiol. 1998;31:583–587.
113. Saxon LA, Stevenson WG, Middlekauff HR, Fonarow G, Woo M,
Moser D, Stevenson LW. Predicting death from progressive heart failure
secondary to ischemic or idiopathic dilated cardiomyopathy. Am J
Cardiol. 1993;72:62– 65.
114. Cappola TP, Felker GM, Kao WH, Hare JM, Baughman KL, Kasper
EK. Pulmonary hypertension and risk of death in cardiomyopathy:
patients with myocarditis are at higher risk. Circulation. 2002;105:
1663–1668.
115. Damy T, Goode KM, Kallvikbacka-Bennett A, Lewinter C, Hobkirk J,
Nikitin NP, Dubois-Randé JL, Hittinger L, Clark AL, Cleland JG.
Determinants and prognostic value of pulmonary arterial pressure in
patients with chronic heart failure. Eur Heart J. 2010;31:2280 –2289.
116. Rickenbacher PR, Trindade PT, Haywood GA, Vagelos RH, Schroeder
JS, Willson K, Prikazsky L, Fowler MB. Transplant candidates with
severe left ventricular dysfunction managed with medical treatment:
characteristics and survival. J Am Coll Cardiol. 1996;27:1192–1197.
117. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The
Registry of the International Society for Heart and Lung Transplan-
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
tation: seventeenth official report-2000. J Heart Lung Transplant. 2000;
19:909 –931.
118. Zakir RM, Al-Dehneh A, Maher J, Saric M, Berkowitz RL. Right
ventricular failure in patients with preserved ejection fraction and dia-
stolic dysfunction: an underrecognized clinical entity. Congest Heart
Fail. 2007;13:164 –169.
119. Aronson D, Eitan A, Dragu R, Burger AJ. Relationship between reactive
pulmonary hypertension and mortality in patients with acute decom-
pensated heart failure. Circ Heart Fail. 2011;4:644 – 650.
120. Braunwald E, Braunwald N, Ross J, Morrow AG. Effects of mitral valve
replacement on pulmonary vascular dynamics of patients with pulmo-
nary hypertension. N Engl J Med. 1965;273:509 –514.
121. Zener JC, Hancock EW, Shumway NE, Harrison DC. Regression of
extreme pulmonary hypertension after mitral valve surgery. Am J
Cardiol. 1972;30:820 – 826.
122. Levine M, Weinstein J, Diver D, Berman AD, Wyman RM, Cun-
ningham MJ, Safian RD, Grossman W, McKay RG. Progressive
improvement in pulmonary vascular resistance following percutaneous
mitral valvuloplasty. Circulation. 1989;79:1061–1067.
123. Fawzy ME, Hassan W, Stefadouros M, Moursi M, El Shaer F,
Chaudhary MA. Prevalence and fate of severe pulmonary hypertension
in 559 consecutive patients with severe rheumatic mitral stenosis
undergoing mitral balloon valvotomy. J Heart Valve Dis. 2004;13:
942–947.
124. Barbieri A, Bursi F, Grigioni F, Tribouilloy C, Avierinos JF, Michelena
HI, Rusinaru D, Szymansky C, Russo A, Suri R, Bacchi Reggiani ML,
Branzi A, Modena MG, Enriquez-Sarano M; Mitral Regurgitation Inter-
national DAtabase (MIDA) Investigators. Prognostic and therapeutic
implications of pulmonary hypertension complicating degenerative
mitral regurgitation due to flail leaflet: a multicenter long-term interna-
tional study. Eur Heart J. 2011;32:751–759.
125. Rosario LB, Stevenson LW, Solomon SD, Lee RT, Reimold SC. The
mechanism of decrease in dynamic mitral regurgitation during heart
failure treatment: importance of reduction in the regurgitant orifice size.
J Am Coll Cardiol. 1998;32:1819 –1824.
126. Haddad F, Ashley E, Michelakis ED. New insights for the diagnosis and
management of right ventricular failure, from molecular imaging to
targeted right ventricular therapy. Curr Opin Cardiol. 2010;25:131–140.
127. Kieler-Jensen N, Milocco I, Ricksten SE. Pulmonary vasodilation after
heart transplantation. A comparison among prostacyclin, sodium nitro-
prusside, and nitroglycerin on right ventricular function and pulmonary
selectivity. J Heart Lung Transplant. 1993;12:179 –184.
128. Braun S, Schrötter H, Schmeisser A, Strasser RH. Evaluation of pul-
monary vascular response to inhaled iloprost in heart transplant can-
didates with pulmonary venous hypertension. Int J Cardiol. 2007;115:
67–72.
129. von Scheidt W, Costard-Jaeckle A, Stempfle HU, Deng MC, Schwaab
B, Haaff B, Naegele H, Mohacsi P, Trautnitz M; PROPHET Study
Group. Prostaglandin E1 testing in heart failure-associated pulmonary
hypertension enables transplantation: the PROPHET study. J Heart
Lung Transplant. 2006;25:1070 –1076.
130. Sueta CA, Gheorghiade M, Adams KF Jr, Bourge RC, Murali S, Uretsky
BF, Pritzker MR, McGoon MD, Butman SM, Grossman SH, et al.
Safety and efficacy of epoprostenol in patients with severe congestive
heart failure. Epoprostenol Multicenter Research Group. Am J Cardiol.
1995;75:34A– 43A.
131. Haraldsson A, Kieler-Jensen N, Ricksten SE. Inhaled prostacyclin for
treatment of pulmonary hypertension after cardiac surgery or heart
transplantation: a pharmacodynamic study. J Cardiothorac Vasc Anesth.
1996;10:864 – 8.
132. Rex S, Schaelte G, Metzelder S, Flier S, de Waal EE, Autschbach R,
Rossaint R, Buhre W. Inhaled iloprost to control pulmonary artery
hypertension in patients undergoing mitral valve surgery: a prospective,
randomized-controlled trial. Acta Anaesthesiol Scand. 2008;52:65–72.
133. Martischnig AM, Tichy A, Nikfardian M, Heinz G, Lang IM, Bon-
derman D. Inhaled iloprost for patients with precapillary pulmonary
hypertension and right-side heart failure. J Cardiac Fail. 2011;17:
813– 818.
134. Yui Y, Nakajima H, Kawai C, Murakami T. Prostacyclin therapy in
patients with congestive heart failure. Am J Cardiol. 1982;50:
320 –324.
135. Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF,
McNulty SE, Darius H, Schulman K, Zannad F, Handberg-Thurmond E,
Harrell FE Jr, Wheeler W, Soler-Soler J, Swedberg K. A randomized
controlled trial of epoprostenol therapy for severe congestive heart
 Guazzi and Borlaug
failure: the Flolan International Randomized Survival Trial (FIRST). Am
Heart J. 1997;134:44 –54.
136. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hyper-
tension in chronic heart failure: the role of the endothelium in patho-
physiology and management. Circulation. 2000;102:1718 –1723.
137. Mulder P, Richard V, Derumeaux G, Hogie M, Henry JP, Lallemand F,
Compagnon P, Macé B, Comoy E, Letac B, Thuillez C. Role of endog-
enous endothelin in chronic heart failure: effect of long-term treatment
with an endothelin antagonist on survival, hemodynamics, and cardiac
remodeling. Circulation. 1997:96;1976 –1982.
138. Wada A, Tsutamoto T, Fukai D, Ohnishi M, Maeda K, Hisanaga T,
Maeda Y, Matsuda Y, Kinoshita M. Comparison of the effects of
selective endothelin ETA and ETB receptor antagonists in congestive
heart failure. J Am Coll Cardiol. 1997:30;1385–1392.
139. Sütsch G, Kiowski W, Yan XW, Hunziker P, Christen S, Strobel W,
Kim JH, Rickenbacher P, Bertel O. Short-term oral endothelin-receptor
antagonist therapy in conventionally treated patients with symptomatic
severe chronic heart failure. Circulation. 1998:98;2262–2268.
140. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin
Antagonist Bosentan for Lowering Cardiac Events in Heart Failure)
study spell the end for non-selective endothelin antagonism in heart
failure? Int J Cardiol. 2002;85:195–197.
141. Packer M, McMurray J, Massie BM, Caspi A, Charlon V, Cohen-Solal
A, Kiowski W, Kostuk W, Krum H, Levine B, Rizzon P, Soler J,
Swedberg K, Anderson S, Demets DL. Clinical effects of endothelin
receptor antagonism with bosentan in patients with severe chronic heart
failure: results of a pilot study. J Card Fail. 2005;11:12–20.
142. Lüscher TF, Enseleit F, Pacher R, Mitrovic V, Schulze MR, Wil-
lenbrock R, Dietz R, Rousson V, Hürlimann D, Philipp S, Notter T,
Noll G, Ruschitzka F. Heart Failure ET(A) Receptor Blockade Trial.
Hemodynamic and neurohumoral effects of selective endothelin A
(ET(A)) receptor blockade in chronic heart failure: the Heart Failure
ET(A) Receptor Blockade Trial (HEAT). Circulation. 2002;106:
2666 –2672.
143. Kaluski E, Cotter G, Leitman M, Milo-Cotter O, Krakover R, Kobrin I,
Moriconi T, Rainisio M, Caspi A, Reizin L, Zimlichman R, Vered Z.
Clinical and hemodynamic effects of bosentan dose optimization in
symptomatic heart failure patients with severe systolic dysfunction,
associated with secondary pulmonary hypertension–a multi-center ran-
domized study. Cardiology. 2008;109:273–280.
144. Anand I, McMurray J, Cohn JN, Konstam MA, Notter T, Quitzau K,
Ruschitzka F, Lüscher TF; EARTH investigators. Long-term effects of
darusentan on left-ventricular remodelling and clinical outcomes in the
EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH):
randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:
347–354.
145. McMurray JJ, Teerlink JR, Cotter G, Bourge RC, Cleland JG, Jondeau
G, Krum H, Metra M, O’Connor CM, Parker JD, Torre-Amione G, van
Veldhuisen DJ, Lewsey J, Frey A, Rainisio M, Kobrin I; VERITAS
Investigators. Effects of tezosentan on symptoms and clinical outcomes
in patients with acute heart failure: the VERITAS randomized controlled
trials. JAMA. 2007;298:2009 –2019.
146. Argenziano M, Choudhri AF, Moazami N, Rose EA, Smith CR, Levin
HR, Smerling AJ, Oz MC. Randomized, double-blind trial of inhaled
nitric oxide in LVAD recipients with pulmonary hypertension. Ann
Thorac Surg. 1998;65:340 –345.
147. Kieler-Jensen N, Lundin S, Ricksten SE. Vasodilator therapy after heart
transplantation: effects of inhaled nitric oxide and intravenous prosta-
cyclin, prostaglandin E1, and sodium nitroprusside. J Heart Lung
Transplant. 1995;14:436 – 443.
148. Hare JM, Shernan SK, Body SC, Graydon E, Colucci WS, Couper GS.
Influence of inhaled nitric oxide on systemic flow and ventricular filling
pressure in patients receiving mechanical circulatory assistance.
Circulation. 1997;95:2250 –2253.
149. Kieler-Jensen N, Ricksten SE, Stenqvist O, Bergh CH, Lindelöv B,
Wennmalm A, Waagstein F, Lundin S. Inhaled nitric oxide in the
evaluation of heart transplant candidates with elevated pulmonary
vascular resistance. J Heart Lung Transplant. 1994;13:366 –375.
150. Bocchi EA, Bacal F, Auler Júnior JO, Carmone MJ, Bellotti G, Pileggi
F. Inhaled nitric oxide leading to pulmonary edema in stable severe heart
failure. Am J Cardiol. 1994;74:70 –72.
151. Mehta S, Stewart DJ, Langleben D, Levy RD. Short-term pulmonary
vasodilation with L-arginine in pulmonary hypertension. Circulation.
1995;92:1539 –1545.
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
Pulmonary Hypertension and Heart Failure 989
152. Guazzi M. Clinical use of phophodiesterase-5 inhibitors in chronic heart
failure. Circ Heart Fail. 2008;1:272–280.
153. Alaeddini J, Uber PA, Park MH, Scott RL, Ventura HO, Mehra MR.
Efficacy and safety of sildenafil in the evaluation of pulmonary hyper-
tension in severe heart failure. Am J Cardiol. 2004;94:1475–1477.
154. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The
effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary
hemodynamics and diffusion capacity, exercise ventilatory efficiency,
and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol.
2004;44:2339 –2348.
155. Lepore JJ, Maroo A, Bigatello LM, Dec GW, Zapol WM, Bloch KD,
Semigran MJ. Hemodynamic effects of sildenafil in patients with con-
gestive heart failure and pulmonary hypertension: combined adminis-
tration with inhaled nitric oxide. Chest. 2005;127:1647–1653.
156. Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME,
Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise
hemodynamics and oxygen uptake in patients with systolic heart failure.
Circulation. 2007;115:59 – 66.
157. Melenovsky V, Al-Hiti H, Kazdova L, Jabor A, Syrovatka P, Malek I,
Kettner J, Kautzner J. Transpulmonary B-type natriuretic peptide uptake
and cyclic guanosine monophosphate release in heart failure and pul-
monary hypertension: the effects of sildenafil. J Am Coll Cardiol.
2009:54;595– 600.
158. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use
of sildenafil in the therapeutic management of heart failure. J Am Coll
Cardiol. 2007;50:2136 –2144.
159. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP,
Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran
MJ. Sildenafil improves exercise capacity and quality of life in patients
with systolic heart failure and secondary pulmonary hypertension.
Circulation. 2007;116:1555–1562.
160. Behling A, Rohde LE, Colombo FC, Goldraich LA, Stein R, Clausell N.
Effects of 5⬘-phosphodiesterase four-week long inhibition with
sildenafil in patients with chronic heart failure: a double-blind, placebo-
controlled clinical trial. J Card Fail. 2008;14:189 –197.
161. Telford RJ, Hemnes AR, Russel SD, Wittstein IS, Mahmud M, Zaiman
AL, Mattai SC, Thiemann DR; Hassoun PM, Girgis RE, Orens JB, Shah
AS, Yuh D, Conte JVm Champion HC. PDE5 inhibitor treatment of
persistent pulmonary hypertension after mechanical circulatory support.
Circ Heart Fail. 2008;1:213–219.
162. Guazzi M, Vicenzi M, Arena R. Phosphodiesterase 5 inhibition with
sildenafil reverses exercise oscillatory breathing in chronic heart failure:
a long-term cardiopulmonary exercise testing placebo-controlled study.
Eur J Heart Fail. 2012;14:82–90.
163. Guazzi M. Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in
heart failure with preserved ejection fraction: a target of
phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:
164 –174.
164. Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T, Ogut O,
Brozovich FV, Burnett JC Jr, Linke WA, Redfield MM. Sildenafil and
B-type natriuretic peptide acutely phosphorylate titin and improve dia-
stolic distensibility in vivo. Circulation. 2011;124:2882–2891.
165. Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase
type 5 inhibition in hypertension. Hypertension. 2006;48:622– 627.
166. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with
sildenafil improves left ventricular diastolic function, cardiac geometry,
and clinical status in patients with stable systolic heart failure: results of
a 1-year, prospective, randomized, placebo-controlled study. Circ Heart
Fail. 2011;4:8 –17.
167. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A,
St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR,
Michelakis ED. Phosphodiesterase type 5 is highly expressed in the
hypertrophied human right ventricle, and acute inhibition of phospho-
diesterase type 5 improves contractility. Circulation. 2007;116:
238 –248.
168. Shan X, Quaile MP, Monk JK, French B, Cappola TP, Margulies KB.
Differential expression of PDE5 in failing and nonfailing human myo-
cardium. Circ Heart Fail. 2012;5:79 – 86.
169. Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophys-
iology and therapeutics. Pharmacol Ther. 2009;122:216 –238.
170. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an
emerging therapeutic target in cardiopulmonary disease. Circulation.
2011;123:2263–2273.
990 Circulation August 21, 2012
171. Healey JS, Davies RA, Tang AS. Improvement of apparently fixed
pulmonary hypertension with cardiac resynchronization therapy. J Heart
Lung Transplant. 2004;23:650 – 652.
172. Bleeker GB, Schalij MJ, Nihoyannopoulos P, Steendijk P, Molhoek SG,
van Erven L, Bootsma M, Holman ER, van der Wall EE, Bax JJ. Left
ventricular dyssynchrony predicts right ventricular remodeling after
cardiac resynchronization therapy. J Am Coll Cardiol. 2005;46:
2264 –2269.
173. Shalaby A, Voigt A, El-Saed A, Saba S. Usefulness of pulmonary artery
pressure by echocardiography to predict outcome in patients receiving
cardiac resynchronization therapy heart failure. Am J Cardiol. 2008;101:
238 –241.
174. Haddad H, Elabbassi W, Moustafa S, Davies R, Mesana T, Hendry P,
Masters R, Mussivand T. Left ventricular assist device as bridge to heart
transplantation in congestive heart failure with pulmonary hypertension.
ASAIO J. 2005;51:456 – 460.
175. Mikus E, Stepanenko A, Krabatsch T, Loforte A, Dandel M, Lehmkuhl
HB, Hetzer R, Potapov EV. Reversibility of fixed pulmonary hyper-
tension in left ventricular assist device support recipients. Eur J Car-
diothorac Surg. 2011;40:971–977.
Downloaded from http://circ.ahajournals.org/ by guest on December 1, 2012
176. Zimpfer D, Zrunek P, Roethy W, Czerny M, Schima H, Huber L, Grimm
M, Rajek A, Wolner E, Wieselthaler G. Left ventricular assist devices
decrease fixed pulmonary hypertension in cardiac transplant candidates.
J Thorac Cardiovasc Surg. 2007;133:689 – 695.
177. Etz CD, Welp HA, Tjan TD, Hoffmeier A, Weigang E, Scheld HH,
Schmid C. Medically refractory pulmonary hypertension: treatment with
nonpulsatile left ventricular assist devices. Ann Thorac Surg. 2007;83:
1697–1705.
178. Torre-Amione G, Southard RE, Loebe MM, Youker KA, Bruckner B,
Estep JD, Tierney M, Noon GP. Reversal of secondary pulmonary
hypertension by axial and pulsatile mechanical circulatory support.
J Heart Lung Transplant. 2010;29:195–200.
179. Liden H, Haraldsson A, Ricksten SE, Kjellman U, Wiklund L. Does
pretransplant left ventricular assist device therapy improve results after
heart transplantation in patients with elevated pulmonary vascular
resistance? Eur J Cardiothorac Surg. 2009;35:1029 –1034.
KEY WORDS: pulmonary hypertension 䡲 heart failure 䡲 pulmonary
vasodilators