Advances in Heart Failure
Left Ventricular Dysfunction With Pulmonary Hypertension
Part 1: Epidemiology, Pathophysiology, and Definitions
Vasiliki V. Georgiopoulou, MD; Andreas P. Kalogeropoulos, MD, PhD; Barry A. Borlaug, MD;
Mihai Gheorghiade, MD; Javed Butler, MD, MPH
T he worsening heart failure (HF) epidemic and the asso-
ciated healthcare costs pose a major burden to public
health and the healthcare system.1 Despite significant thera-
peutic advances, outcomes for patients with HF remain sub-
optimal.2–4 Importantly, most clinical trials with novel agents
in HF during the past decade have yielded neutral or modest
results.5 The reasons for these unfavorable trends are com-
plex.6 One issue gaining wide acceptance is that the one-size-
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fits-all approach to HF therapies is unlikely to be beneficial,
especially when new therapies are given on top of comprehen-
sive neurohormonal blockade. Thus, it is crucial for the devel-
opment of novel therapies to better understand the various HF
phenotypes and their pathophysiology and subsequently target
relevant pathways in such subgroups of patients.
Pulmonary hypertension (PH) is a heterogeneous entity with
different causes leading to increased pressures in the pulmo-
nary circulation. PH is a major and frequent consequence of
left-sided HF, irrespective of left ventricular ejection fraction
(LVEF) or presence of valvular disease.7–9 The presence of PH
is associated with worse HF outcomes, regardless of LVEF
and stage of HF,7,8 and prognosis is further aggravated when
right ventricular (RV) dysfunction ensues, posing a number of
diagnostic and therapeutic dilemmas that influence decision
making.10,11 A combination of elevated LV filling pressures,
reactive pulmonary arterial vasoconstriction, and pulmonary
vascular remodeling results in PH secondary to left heart
disease.12 Abnormal hemodynamic parameters indicative of
PH in HF patients receiving optimal therapy may represent a
potential therapeutic target.
In this 2-part review, we summarize the current opinions
and evidence related to PH in HF. In the first part, we describe
the definitions and classification, cause, and epidemiology of
PH in HF. In the second part, we discuss its prognostic impact,
the contemporary evaluation approaches, the challenges and
results of the clinical trial targeting PH in HF, and potential
ways to overcome these challenges in future.
Classification of PH
The definition of PH has evolved during the past decades.
The widely accepted upper level of normal mean pulmonary
artery pressure (mPAP) is 20 mm Hg.13 The current working
Received August 31, 2012; accepted January 28, 2013.
From the Division of Cardiology, Emory University, Atlanta, GA (V.V.G., A.P.K., J.B.); Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B.);
and Center for Cardiovascular Innovation, Northwestern University, Feinberg School of Medicine, Chicago, IL (M.G.).
This is Part 1 of a 2-part article. Part 2 will appear in the May 2013 issue.
Correspondence to Javed Butler, MD, MPH, Emory Clinical Cardiovascular Research Institute, 1462 Clifton Rd NE, Suite 504, Atlanta, GA 30322.
E-mail javed.butler@emory.edu
(Circ Heart Fail. 2013;6:344-354.)
© 2013 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.112.000095
344
definition of PH is mPAP ≥25 mm Hg at rest obtained inva-
sively and covers all the 5 main PH groups defined by the
Dana Point convention (Table 1).14–16 Pulmonary capillary
wedge pressure (PCWP) is an important variable for charac-
terizing PH, and various hemodynamic types of PH can be
identified based on PCWP, pulmonary vascular resistance
(PVR), and cardiac output.
The distinction between precapillary (normal PCWP ≤15
mm Hg) and postcapillary (elevated PCWP >15 mm Hg) PH17
is extremely important from a therapeutic perspective. Indeed,
therapies effective in the precapillary PH may be detrimen-
tal in the postcapillary PH, or vice versa.18,19 Precapillary PH
includes Groups 1, 3, 4, and 5, whereas postcapillary PH refers
to Group 2 (Table 1) PH due to left-sided heart disease.16 The
latter is characterized by the combination of elevated mPAP
(≥25 mm Hg) and elevated PCWP (>15 mm Hg).
Types of PH in HF
Within Group 2 PH, there are subtypes characterized by the
presence or absence of pulmonary vascular disease, which
may coexist with elevated PCWP (Figure 1). The transpulmo-
nary pressure gradient (TPG), defined as mPAP minus PCWP,
and the PVR, calculated as TPG divided by the cardiac output,
can help differentiate among the subtypes of Group 2 PH.13–15
The normal TPG is 6±2 mm Hg,20 but for clinical purposes, a
gradient of <12 to 15 mm Hg is considered acceptable. Simi-
larly, PVR is normally 0.9±0.4 Wood Units (WU),20 but values
<2.5 to 3.0 WU are used in practice to differentiate the Group
2 PH subtypes.13–15
Passive PH
Group 2 PH is considered passive when the pressure
downstream of pulmonary arteries is the dominant cause of
elevated mPAP (Figure 1). By convention, this occurs when
the TPG and the PVR are normal. This type of PH is seen
most often in the early stages of HF and represents the form
with the highest prevalence. The absence of elevated TPG
(and PVR) implies that there are no significant abnormalities
in the pulmonary artery structure or function. In this case,
PH is caused by high left heart pressures and may remit
with HF-specific interventions such as diuresis and systemic
 Georgiopoulou et al   Group 2 PH, Part 1   345

Table 1.  Current Classification of Pulmonary Hypertension concert with only modestly elevated left-sided pressures. The
degree of PCWP elevation, or its chronicity, that qualifies as
Group 1: Pulmonary arterial hypertension (PAH)
out-of-proportion remains unresolved and is debated. Unlike
  1.1 Idiopathic PAH
passive PH, reactive Group 2 PH is considered a plausible
  1.2 Heritable target for therapy with a pulmonary arterial specific agent.
  1.2.1. BMPR2 Intervention that solely lowers the PCWP would not be
   1.2.2. ALK1, endoglin (with or without hereditary hemorrhagic expected to normalize the TPG and PVR in mixed PH in the
telangiectasia) short term. However, pulmonary vasodilator therapy may
  1.2.3 Unknown reverse the active component and lower TPG and PVR to
  1.3 Drugs and toxins induced clinically acceptable levels in a proportion of patients with
  1.4 Associated with the reversible form of reactive PH.12 It is presumed that at
   1.4.1 Connective tissue diseases
this stage there are functional, but not significant structural,
abnormalities of the pulmonary vascular bed. The reversibility
   1.4.2 HIV infection
of TPG and PVR in mixed PH is an important selection
   1.4.3 Portal hypertension criterion for heart transplantation candidacy and a prognostic
   1.4.4 Congenital heart diseases indicator of posttransplant outcomes.21
  1.4.5 Schistosomiasis If PVR cannot be reduced to <2.5 to 3 WU, PH is considered
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   1.4.6 Chronic hemolytic anemia
  1.5 Persistent pulmonary hypertension of the newborn
Group 1: Pulmonary veno-occlusive disease and pulmonary capillary
hemangiomatosis
Group 2: Pulmonary hypertension due to left heart disease
  2.1 Systolic dysfunction
  2.2 Diastolic dysfunction
  2.3 Valvular disease
Group 3: Pulmonary hypertension because of lung diseases and hypoxia
  3.1 Chronic obstructive pulmonary disease
  3.2 Interstitial lung disease
  3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
  3.4 Sleep-disordered breathing
  3.5 Alveolar hypoventilation disorders
  3.6 Chronic exposure to high altitude
  3.7 Developmental abnormalities
Group 4: Chronic thromboembolic pulmonary hypertension
Group 5: PH with unclear and multifactorial mechanisms
  5.1 Hematologic disorders: myeloproliferative disorders, splenectomy
 5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans cell
histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid
disorders
 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure
on dialysis
vasodilators. Passive PH would generally not be considered a
plausible target for therapy with a pulmonary arterial selective
agent.
Reactive or Mixed PH
When the TPG and PVR are elevated, Group 2 PH is referred to
as reactive (or active) or mixed, indicating that high mPAP is a
combination of elevated PCWP in conjunction with functional/
structural abnormalities of the pulmonary vasculature.14
Reactive PH is in turn further classified into reversible and
fixed or irreversible, depending on the response of TPG and
PVR to pharmacological interventions. Additionally, the term
out-of-proportion is used when mPAP is severely elevated in
fixed. At this stage, both functional and structural abnormali-
ties of the pulmonary vascular bed are presumed to exist, and
histological changes may be indistinguishable from precapil-
lary PH.15 Pathological findings in the pulmonary vasculature
have both similarities and differences among the various PH
groups. The histological findings in the pulmonary vascula-
ture of patients with severe Group 1 PH are a combination
of small pulmonary arterial medial and adventitial thicken-
ing, occlusive neointima proliferation, and complex plexi-
form lesions.22–24 Group 2 PH is characterized by enlarged and
thickened pulmonary veins, pulmonary capillary dilatation,
interstitial edema, alveolar hemorrhage, and lymphatic vessel
and lymph node enlargement. Distal pulmonary arteries may
be affected by medial hypertrophy and intimal fibrosis as a
result of remodeling mediated by smooth muscle cells, with
eccentric intima lesions and medial thickening.25 The extent
and pattern of arterial remodeling is similar to that seen in
Group 1 PH.26 In a study investigating the structural changes
in the pulmonary vasculature in patients who died after heart
transplant, the main pathological finding was medial hyper-
trophy of muscular pulmonary arteries.27 This increase in
medial thickness was greater than that observed in patients
with idiopathic PH despite a comparable elevation of pulmo-
nary pressures.28 In this specific population, intimal fibrosis of
pulmonary arteries was not observed; however, the majority of
cases had mild PH.27 Intimal fibrosis is common in the pulmo-
nary vasculature.29 All these structural changes affect response
to vasodilators (fixed PH). However, it is important to note
that although lack of reversibility with acute pharmacological
interventions may lead to labeling PH as fixed, emerging data
have reported delayed reversibility after heart transplantation
or LV assist device implantation.30,31 The potential for delayed
reversibility might be considered when candidacy for heart
transplantation is evaluated. Although acute reversibility is an
important selection criterion for heart transplantation, longer
term interventions to reduce PVR could be considered when
an acute vasodilator challenge is unsuccessful. Often PVR will
decline after 24 to 48 hours of treatment consisting of diuret-
ics, phosphodiesterase 3 inhibitors, and vasoactive agents,
although some patients may require therapy for weeks before
an acceptable reduction in PVR is obtained.21 These observa-
tions may have implications for long-term pharmacological
 346  Circ Heart Fail  March 2013
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therapies as well. Studies using the phosphodiesterase 5 inhib-
itors in patients with advanced, pretransplant HF, and severe
PH have shown beneficial effects on hemodynamics and clini-
cal status, whereas sildenafil seems to improve post-transplant
survival.32,33
PCWP Versus LV End-diastolic Pressure
To complicate things further, data suggest that PCWP does
not always correlate closely with LV end-diastolic pressure
(LVEDP). A retrospective study of patients undergoing left
and right heart catheterizations (RHCs) reported that ≥50%
of patients with PCWP <15 mm Hg had elevated LVEDP to
>15 mm Hg.34 This has led some to suggest that left heart
catheterization be broadly applied in the evaluation of PH.
However, measuring PCWP at mid-A wave after careful
verification by characteristic atrial waveforms and oximetry
confirmation (saturation >93%) of appropriate right heart
catheter placement shows better correlation with LVEDP.
Physiologically, it can be argued that an appropriately
measured PCWP is more important when evaluating the cause
of PH than LVEDP, because this is the immediate downstream
pressure that adds in series with the product of flow (cardiac
output) and resistance (PVR). If an adequate quality PCWP
tracing cannot be obtained, direct measurement of LVEDP is
indicated in the evaluation of PH.
Challenges in the Classification of PH Related to HF
Careful phenotyping of PH secondary to HF is important for
characterization of drug responses and selection of patients
for clinical trials, especially mechanistic studies. In the case of
mixed PH, especially in a setting of older patients with normal
EF, it might be challenging to distinguish between PH due to
Figure 1.  Types of pulmonary hypertension (PH) in
patients with heart failure (HF). HTx indicates heart
transplant; LVAD, left ventricular assist device;
mPAP, mean pulmonary artery pressure; PCWP,
pulmonary capillary wedge pressure; PDE, phos-
phodiesterase; PH, pulmonary hypertension; PVR,
pulmonary vascular resistance; and TPG, transpul-
monary pressure gradient.
HF (Group 2), PH of pulmonary disease origin (Group 3), and
pulmonary arterial hypertension (Group 1). Thus, in cases of
mixed PH, ruling out causes unrelated to LV dysfunction is
critical. Among studies investigating Group 2 PH, this has not
been done uniformly.35–38 Not surprisingly, the results of these
studies are conflicting, with reactive PH predicting mortality
only in one study.38
Pathophysiology of PH in HF
The pathophysiology of Group 2 PH is complex (Figure 2).
Patients with left heart disease may develop both passive and
reactive PH, with all cases having a passive component associ-
ated with increased left atrial pressure. In patients with HF with
reduced EF (HFrEF), both diastolic dysfunction and mitral
regurgitation may lead to an increase in left atrial pressure,39
whereas in patients with HFpEF, diastolic dysfunction is the
main cause of increased pressures because of the increased
passive stiffness. Thus, increased LV filling pressures, irre-
spective of LVEF,40 lead to pulmonary venous hypertension
and postcapillary PH. The hydrostatic pressure in turn cre-
ates a mechanical injury to the alveolar-capillary barrier that
fractures the delicate structure of the capillary wall, known
as alveolar-capillary stress failure (acute phase).41 When the
elevation in venous pressures is chronic, excessive, and per-
sistent, it triggers a multistep adaptive process that involves
the microcirculation and the alveolar wall and leads to exces-
sive production and accumulation of collagen IV in the extra-
cellular matrix.42,43 Collagen accumulation causes functional
and structural changes in the pulmonary vasculature, initially
in the capillaries and later on in the arterioles and arteries
(chronic phase).27 The role of endothelium is important in this
process. Endothelial dysfunction secondary to injury plays a
 Georgiopoulou et al   Group 2 PH, Part 1   347
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Figure 2.  Pathophysiology of Group 2 pulmonary hypertension. Left heart disease causes elevation of left atrial pressure, which in turn
leads to increased hydrostatic pressure in pulmonary capillaries. Diastolic dysfunction is the main contributor of increased atrial pressure
in heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and valvular heart disease.
Mitral regurgitation and left ventricular (LV) hypertrophy contribute further to increased atrial pressure in HFrEF and valvular heart dis-
ease, respectively. Elevated hydrostatic pressure causes injury to the alveolar-capillary barrier in the acute phase, whereas chronically
elevated pressure triggers various pathways involving the microcirculation and the alveolar wall. Mechanical injury because of hydrostatic
pressure (alveolar-capillary stress failure) leads to disruption of the alveolar-capillary membrane, resulting in transition from interstitial
leakage of protein (low permeability stage) to alveolar lumen leakage of protein and erythrocytes (high permeability stage). High perme-
ability pulmonary edema activates matrix metalloproteinases (MMPs), causing degradation of matrix proteoglycan and alteration in the
composition of membrane units, which in turn causes increased endothelial membrane fluidity. Initially, alveolar-capillary stress failure is
a reversible phenomenon. However, chronic pressure elevation leads to remodeling and thickening (excessive collagen deposition) of the
alveolar-capillary membrane, a process perpetuated by locally produced hormones (eg, angiotensin II [Ang II]) and inflammatory markers
(eg, tumor necrosis factor-α [TNF-α]). The increased capillary pressure also promotes hypertrophy and fibrotic changes in the pulmo-
nary arteries and veins with medial hypertrophy of smooth muscle cells (SMCs) and finally disruption of the elastic lamina. Imbalance in
endothelin-1 (ET-1) and nitric oxide (NO) release and genetic factors influence these pulmonary vascular structural changes. EC indicates
endothelial cell.
 348  Circ Heart Fail  March 2013
predominant role in the impaired pulmonary vascular smooth
muscle relaxation, which in turn has an integral role in mediat-
ing the functional alterations of the pulmonary vasculature.44
The endothelium-mediated local control of vascular tone is
primarily based on a balanced release of nitric oxide45 and
endothelin-146; PVR is critically sensitive to imbalance of
these 2 opposing systems.45,46 Over time, histological changes
in the pulmonary vasculature occur, similar to those observed
in patients with primary PH.27 Reactive increase in pulmonary
arterial tone and eventually intrinsic arterial remodeling lead
to a superimposed, precapillary component of PH.12 Genetic
modifiers may also play a role in development of Group 2 PH,
given that the degree of change in vessel structure and PVR in
response to pulmonary venous pressure varies widely among
patients with HF. This suggests that, in addition to hemody-
namic triggers, individual genetic characteristics may affect
development of PH.47
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Right Ventricle in PH
PH affects RV function also. Chronic exposure of RV to ele-
vated afterload, and often to elevated preload as a result of
RV dilation and functional tricuspid regurgitation, leads to RV
systolic dysfunction. The prognosis of patients with PH is fur-
ther aggravated by RV dysfunction.10,11 The development of
RV dysfunction portends worsening of HF symptoms. Com-
promised RV output facilitates edema formation by raising
right atrial pressure. In addition, a vicious circle of increased
pulmonary vasculature resistance occurs, because of the inter-
stitial fluid accumulation, which in turn can further increase
resistance. RV dysfunction causes atrial distention, leading
to release of atrial natriuretic peptides, and increases renal
venous pressure with a consequent reduction in the filtration
pressure through the kidney. The latter impairs renal sodium
excretion and can trigger positive feedback loops that lead to
refractory HF.48
Echocardiographic Definition of PH
The gold standard for the evaluation of pulmonary hemody-
namics is RHC.49 However, RHC is an invasive procedure
with associated risks, complications, cost, and need for an
experienced operator and team to both perform the procedure
and obtain reliable results. Therefore, RHC is not suitable as
a screening tool for all patients with suspected PH, especially
on a broad basis, for example, those individuals with Stage
C HF. Accurate noninvasive alternatives to assess pulmonary
hemodynamics are, therefore, desirable. Echocardiography
is a suitable screening tool, and also provides valuable infor-
mation on cardiac structure and performance, important for
identification of the cause of PH. RV systolic pressure (RVSP)
by Doppler echocardiography can provide an estimate of the
systolic PAP (sPAP) with acceptable accuracy in patients with
HF,50,51 especially in those with advanced disease.52,53 Vari-
able criteria have been used for echocardiographic defini-
tion of PH.54 However, an RVSP ≤36 mm Hg makes PH very
unlikely,54,55 whereas values ≥45 mm Hg have been consis-
tently associated with worse prognosis in various HF popu-
lations.40,56–58 Using the tricuspid regurgitant velocity, a <2.5
m/s may be classified as normal, 2.5 to 2.8 m/s as borderline,
and >2.8 m/s as indicative of PH.59 Concomitant evaluation
of other echocardiographic parameters is also recommended,
which we will discuss in the second part of this review.
PH in Valvular Heart Disease
The structural alterations present in valvular heart disease
result in hemodynamic abnormalities that in turn lead to
PH, the prevalence of which increases in parallel with the
severity of the defect and the associated symptoms. Mitral
valve disease results in elevated left atrial pressure, which
in turn leads to PH accompanied by structural alterations of
the pulmonary vasculature, especially when mitral stenosis is
present. Increased levels of endothelin-1 have been observed
in patients with severe mitral stenosis.60 Mitral valve disease
has been the prototype of cardiac disease associated with
PH,61,62 and the presence of PH in mitral valve disease plays
a key role in the management of the primary disease.63,64
Mitral stenosis, when moderate to severe, is associated with
PH in the majority of patients, although the degree of PH is
variable. In candidates for mitral valvuloplasty, the prevalence
of PH has been reported to be as high as 75%.65 In patients
with chronic isolated mitral regurgitation and preserved LV
function, the prevalence of PH defined as sPAP ≥30 mm Hg
by RHC was 76%,66 whereas sPAP ≥50 mm Hg was present
in 17% of patients.66 In patients with asymptomatic mitral
regurgitation, exercise-induced PH defined as sPAP >60
mm Hg during exercise was very common, with a reported
prevalence of 46%, whereas resting PH defined as sPAP >50
mm Hg in the same population was only 15%.67 These findings
were confirmed by an independent study showing that almost
50% of patients with asymptomatic mitral regurgitation have
exercise-induced PH.68
Aortic stenosis results in PH by inducing LV hypertrophy
and reduced LV diastolic function, which in turn leads to ele-
vated pulmonary pressures. Over time, structural changes in
the pulmonary vasculature occur. In patients with severe aor-
tic stenosis, the prevalence for PH has been reported to reach
50%, defined as sPAP >30 mm Hg,69 whereas 29% of patients
with severe aortic stenosis had PH when PH was defined as
sPAP >50 mm Hg.70 Mild-to-moderate and severe PH was
present in 50% and 15% of patients, respectively, in another
study.71 Albeit less frequently, aortic regurgitation can also
lead to PH secondary to chronic elevation of LVEDP, which
in turn leads to an increase in left atrial and pulmonary artery
pressures. The prevalence of PH in severe aortic regurgitation
has been reported to be 10% to 20%.72
Epidemiology of PH in HF
Determinants of PH
The severity of PH in left heart disease is thought to be a func-
tion of the cumulative exposure to pulmonary venous hyper-
tension over time, regardless of LV systolic function or HF
stage.73,74 Consequently, LV filling pressures and degree of
mitral regurgitation play a major role in the development and
progression of PH.40 Chronic elevation of LV filling pressures
is reflected in left atrial enlargement, which strongly corre-
lates with sPAP in patients with HF and reduced or preserved
LVEF.75,76 The severity of PH parallels that of mitral regurgi-
tation in patients with advanced HF.77 Genetic predisposition

may also play a role in the development of PH in patients with
HF and LV systolic dysfunction.47 Data on factors predispos-
ing to reactive PH are conflicting. Berger et al78 identified no
clinical, echocardiographic, or laboratory parameters predic-
tive of reactive PH (compared with passive PH), whereas
recently a study in Japanese patients reported that women are
more prone to reactive PH.79
Increased PAP directly affects RV systolic function,80 and
the severity of RV systolic dysfunction strongly parallels pro-
gression of LV failure in patients with severe systolic HF.81
Diastolic dysfunction and severe tricuspid regurgitation fur-
ther aggravate RV dysfunction.81 Finally, reduced RV systolic
function is more frequently encountered among patients with
nonischemic cause of LV systolic dysfunction, independent of
PH and LV status.82
The Role of Diastolic Dysfunction
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The importance of diastolic dysfunction in the development of
PH in patients with HFrEF is increasingly being recognized.73
In patients with HFrEF, the severity of concomitant diastolic
dysfunction rather than LVEF or cardiac output correlates best
with the severity of PH in one study.39 Recently, a study inves-
tigating the role of LV diastolic properties in patients with
HFrEF elucidated the significant contribution of LV diastolic
dysfunction to PH.83 The probability of PH was a function of
diastolic dysfunction indices (higher E/e′ and shorter decel-
eration time) and mitral regurgitation; of note, LVEF was not
a predictor of PH in this study.83 An E/e′ ≥15 and deceleration
time ≤150 ms, reflecting at least moderate LV diastolic dys-
function, were highly predictive of RVSP ≥45 mm Hg.83
Diastolic dysfunction associated with valvular disease,
reduced LVEF, or in isolation, is the common mediator of
chronic pulmonary venous hypertension and secondary PH.
Older persons would be more vulnerable to development of
PH, considering that age-related vascular stiffening, including
the pulmonary vasculature, has been consistently reported.84–86
Moreover, age-related increases in arterial stiffening are worse
in women than in men,84,86–88 indicating that older female
patients who develop HF with diastolic dysfunction may also
be more prone to PH. The prevalence of LV diastolic dysfunc-
tion in the general population varies from 11.1% to 34.7%
depending on of the population studied, the criteria applied,
and the imaging modality used.89–93 Similar to LV diastolic
dysfunction prevalence,86,92 the normal PAP also increases
with age,94 pointing to a common vascular aging process.
PH in HFrEF
The reported prevalence of PH in patients with HFrEF varies
depending on the patient population studied, the chronicity of
the disease, and the definition used7,9,10,40,56,57,83,95–97 (Table 2).
The presence and severity of PH within an individual patient
may vary not only longitudinally over time, but also in the
short term depending on their compensation status.98 In a
recent study from the United Kingdom, among 413 patients
with newly diagnosed HF and measured RVSP, 25% had a
tricuspid gradient >35 mm Hg, corresponding to an RVSP
>45 mm Hg.40 However, these patients represented only 30%
of the entire cohort, because RVSP was not obtained in the
remaining participants.40 In the same study, a tricuspid gradient
Georgiopoulou et al   Group 2 PH, Part 1   349
>35 mm Hg was present in 29% of those with HFrEF.40 In a
study using peak velocity of tricuspid regurgitation to assess
sPAP in patients with severely reduced LVEF, the prevalence
of tricuspid regurgitation jet velocity >2.5 m/s was 25.9%.95
In a large retrospective cohort from Scotland, among patients
with reduced LVEF, loop diuretics prescription, and measured
RVSP, 47.5% had RVSP >45 mm Hg.97 Prevalence increases
with progression of HF.10 In 377 consecutive New York Heart
Association (NYHA) Class II to III outpatients with LVEF
<35%, PH by RHC was present in 62.3% of patients10;
however, the definition of PH used in this study was mPAP
>20 mm Hg, underscoring the impact of population selection
and definition on prevalence of PH. Overall, the prevalence of
PH in HFrEF seems to range from 25% to >50%.
PH in Advanced HF
In advanced HF, the measure used to define PH (PAP versus
PVR) affects prevalence estimates. In 320 patients with severe
LV systolic dysfunction (LVEF 23±9%),96 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% of the patients; 35% to 40% of
patients in NYHA class III and IV had moderately or severely
elevated PVR (≥2.5 WU). Similarly, PH defined as PVR ≥2.5
WU was present in 41.3% of a pretransplant HF population
a median of 2.7 months before transplantation.99 In the
Evaluation Study of Congestive Heart Failure and Pulmonary
Artery Catheterization Effectiveness (ESCAPE) trial, PH was
present in 47% of hospitalized HF patients with LVEF ≤30%,37
using a definition of mPAP ≥25 mm Hg at rest, PCWP >15
mm Hg, and PVR ≥3 WU. These data are in line with an
earlier observational study on transplant recipients where PVR
>2.5 was present in 50.4% of the transplant recipients.100 Thus,
in advanced HF populations, the prevalence of PH requiring
evaluation for reactive PH (PVR ≥2.5) is ≈40% to 50%.
PH in HFpEF
Similarly, the prevalence of PH in HFpEF depends on the pop-
ulation studied and the definition used for PH, and also, on the
criteria used for HFpEF diagnosis. In the UK study, a tricus-
pid gradient >35 mm Hg was present in 18% of 143 patients
with HFpEF and measured RVSP.40 In contrast, among 244
patients with HFpEF from Olmsted County, Minnesota, 83%
had PH by echocardiography using a definition of RVSP >35
mm Hg.73 However, the cutoff used to define PH in this study
was low, especially considering that normal RVSP increases
with age94 and a mixed population of outpatients and inpa-
tients with HF was studied. The median RVSP in that study
was 48 mm Hg,73 implying that PH prevalence with a defini-
tion of >45 mm Hg would have been closer to 50%. In all, the
prevalence of PH in HFpEF varies widely, from 18% to >50%,
and data from prospective epidemiological studies are limited.
Exercise-induced PH
Although most data on PH pathophysiology are based on rest-
ing hemodynamics, patients develop symptoms indicative of
PH more often during exercise.35 PAP response to exercise
has been used as a diagnostic criterion for PH, and exercise
 350  Circ Heart Fail  March 2013

Table 2.  Prevalence of Pulmonary Hypertension in Patients With Heart Failure

Study N Population Method Definition Prevalence
Heart failure with reduced ejection fraction
  Abramson 199295 108 Dilated cardiomyopathy; mean LVEF 17.2% Echo TR jet velocity >2.5 m/s 25.9%
  Butler 199996 320 Ambulatory patients for Tx evaluation; LVEF 23±9% RHC PVR >1.5 WU 72%
PVR >2.5 WU 36%
  Ghio 2001 10
377 Ambulatory patients for Tx evaluation; LVEF 21.8±6.7% RHC mPAP >20 mm Hg 62.3%
  Cappola 20027 1134 New-onset cardiomyopathy; LVEF: N/A RHC No a priori definitionm 46%
PAP ≥25 mm Hg
  Grigioni 20069 196 NYHA class III-IV; LVEF 27±9% RHC mPAP >25 mm Hg 40.3%
  Shalaby 200856 270 CRT recipients; LVEF 22.6±9.7% Echo RVSP ≥45 mm Hg 34.8%
  Adhyapak 201057 147 Ambulatory patients Echo RVSP >45 mm Hg 53.7%
  Damy 2010 40
270 HF with LVEF ≤45% and measured RVSP Echo TR gradient >25 mm Hg 50%
TR gradient >35 mm Hg 30%
  Miller 201183 1541 HF with LVEF ≤40%; LVEF 30.5±8.3% Echo RVSP ≥45 mm Hg 34.6%
Downloaded from http://circheartfailure.ahajournals.org/ by guest on January 11, 2018

  Szwejkowski 201297 1612 LVSD (qualitative), loop diuretics, and measured RVSP Echo No a priori definition 47.5%
RVSP ≥45 mm Hg
Heart failure with preserved ejection fraction
  Lam 200973 244 Community inpatients and outpatients; LVEF ≥50% Echo RVSP >35 mm Hg 83%
  Leung 201074 455 Cardiac catheterization registry; LVEDP >15 mm Hg; RHC mPAP >25 mm Hg 52.5%
LVEF ≥50%
  Damy 201040 143 HF patients with LVEF >45%, NT-proBNP ≥50 pmol/L, Echo TR gradient >25 mm Hg 46%
and measured TR TR gradient >35 mm Hg 18%
Heart failure with reduced or preserved ejection fraction
  Tatebe 201179 676 HF patients NYHA II-IV referred for RHC RHC mPAP ≥25 mm Hg, PCWP >15 mm Hg 23.4%
PVR ≤2.5 WU (passive) 14.8%
PVR >2.5 WU (reactive) 8.6%
  Bursi 201258 1049 Community inpatients and outpatients with HF Echo RVSP >35 mm Hg 79%
Acute heart failure
  Kjaergaard 20078 388 Admitted for acute HF; LVEF 33 (23–50)% Echo No a priori definition
RVSP ≥39 mm Hg 50%
RVSP ≥50 mm Hg 25%
  Khush 200937 171 Acute HF, clinical trial; SBP ≤125 mm Hg; LVEF ≤30% RHC Mixed PH: mPAP ≥25 mm Hg; 47%
PCWP >15 mm Hg; PVR ≥3 WU
  Aronson 201138 242 Acute HF, clinical trial; LVEF 25±13% RHC mPAP >25 mm Hg 76.0%
PVR ≤3 WU (passive) 51.2%
PVR >3 WU (reactive) 24.8%
No a priori definition: investigators presented distribution of measurements without a prespecified cutoff point.
CRT indicates cardiac resynchronization therapy; HF, heart failure; LVEF, left ventricular ejection fraction; LVEDP, left ventricular end-systolic pressure; LVSD, left ventricular
systolic dysfunction; mPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PCWP, pulmonary capillary
wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RHC, right heart catheterization; RVSP, right ventricular systolic pressure; SBP, systolic blood
pressure; TR, tricuspid regurgitation; Tx, transplantation; and WU, Wood units.

remains a significant physiological stressor for patients with
PH.15 However, its role in the evaluation of PH has been ques-
tioned, mainly because of the age-dependent increase of mPAP
during exercise,101 limited normative data in various postures
during exercise, and different types and protocols of exercise
tests.54 Exercise-induced PH is common in HF35,36,96,102 and is a
prognostic factor, especially when accompanied by increased
LV filling pressures during exercise.103 The response of PAP
to increases in cardiac output during exercise provides valu-
able insights into the pathophysiology of exercise intoler-
ance and cardiovascular reserve.104 In a study on patients with
exertional dyspnea and preserved (≥50%) LVEF referred for
invasive exercise testing, more than half were diagnosed with
HFpEF; 88% developed mPAP >30 mm Hg during exercise.35
However, this was a highly selected cohort with normal resting
hemodynamics and cardiac load biomarkers despite exertional
symptoms, and the European Society of Cardiology criteria105
would have identified one third of cases as HFpEF patients
before testing.35 Also, the definition of HFpEF was itself based
on hemodynamics.35 Another study reported that almost half
the patients referred for invasive exercise evaluation had exer-
cise-induced PH because of pulmonary venous hypertension.36
The authors suggested that exercise-induced PH may be part
of the continuum from normal to severe pulmonary vascular
disease.36 In this study, however, most patients were referred
because of exercise intolerance, making it unclear whether

invasive exercise testing can identify truly asymptomatic PH.
On the contrary, in patients with HFrEF undergoing invasive
cardiopulmonary exercise testing, the decrease in exercise
capacity paralleled PH severity.96 However, 7% of patients did
not have exertional symptoms despite severe PH.96
Obtaining reliable invasive measurements during exercise is
challenging because of wide swings in intrathoracic pressure
secondary to increased respiratory rate and tidal volume,106
technical difficulties, and patients’ inability to maintain peak
exercise during hemodynamic acquisition. Therefore, assess-
ment at submaximal exercise might be preferable. Changes in
PCWP during graded supine exercise are not linear, because
most (>80%) of the increase occurs during the initial exercise
stages.35 In patients with recent HF, when PVR is typically
normal or near normal, PAP essentially tracks PCWP during
exercise.35 Thus, assessment at maximal exercise may not be
necessary for insights into the mechanism of exercise-induced
Downloaded from http://circheartfailure.ahajournals.org/ by guest on January 11, 2018
PH in HF.
Although there are data supporting the value of exercise-
induced PH in early diagnosis of PH and prognosis, sev-
eral aspects are still unclear.107 Prior studies have evaluated
patients with exertional symptoms, and some patients with
severe PH may have relatively preserved exercise capacity.96
Therefore, the value of exercise-induced PH for the diagnostic
assessment of dyspnea as an early indicator of PH in asymp-
tomatic patients and as a potential target for treatment in these
populations needs further clarification.
Provocative maneuvers, including exercise or saline load,
may unmask excessive PAP elevations under mild stress in
patients with diastolic dysfunction at risk of HFpEF or with
already manifest exercise intolerance and HFpEF.35 In these
patients, the absence of elevated PAP at rest, similar to the
absence of other signs of congestion or elevated natriuretic
peptide levels, may be less informative than exercise param-
eters. Thus, PAP elevations with mild exercise in patients with
normal pressures at rest could represent a target for future pul-
monary vasoactive therapies, assuming that agents lowering
PAP during exercise would improve functional capacity and
symptoms. However, this hypothesis requires further study.
PH in Acute HF
The role of PH in acute HF is less well studied. Hemodynamic
worsening is characteristic of acute HF; however, few studies
have described the changes over time and the short- and long-
term implications of hemodynamics in acute HF. In ambulatory
patients, dynamic changes in PAP predict acute HF events,108
and elevations in 24-hour filling pressures precede episodes
of decompensation in both HFrEF and HFpEF patients.109
Aronson et al38 reported that before treatment, among 242
patients, only 2 (0.83%) had normal PAP (defined as RHC
mPAP ≤25 mm Hg); 59.1% had passive PH (mPAP >25
mm Hg, PCWP >15 mm Hg, and PVR ≤3 WU); and 40.1%
had reactive PH (mPAP >25 mm Hg, PCWP >15 mm Hg, and
PVR >3 WU). After diuretic and vasoactive therapy for ≤48
hours, passive and reactive PH was present in approximately
25% and 50% of patients, respectively. Patients with persistent
reactive PH were classified as fixed PH. A rapidly reversible
passive PH component, likely because of pure volume overload,
was present in all 3 groups. However, 13% of patients with
Georgiopoulou et al   Group 2 PH, Part 1   351
passive PH during decompensation were classified into the
reactive (fixed) PH category at final measurement. Also, 45%
of patients with an initial reactive profile had lower PCWP,
mPAP, and PVR after treatment, indicating a passive profile.
Thus, fixed PH cannot be easily ascertained during acute HF.
Further research is needed to identify the neurohormonal
and other factors that temporarily alter pulmonary vascular
function in acute HF. One factor to consider related to the wide
variation of the reactive component of PH is the variability of
RHC measurements. In a study with serial hemodynamics in
patients with pulmonary arterial hypertension, there was wide
spontaneous intraindividual variability in PAP, by >20 mm Hg
in some patients, with a mean coefficient of variation of 8% in
the group.110 Considering that the progress of HF deteriorates
significantly after a hospitalization for decompensated
HF, it would be reasonable to consider and investigate all
the abnormalities that are present during decompensation,
including hemodynamic abnormalities. This could help us
identify potential clues for the accelerated deterioration with
the ultimate goal to intervene and delay the progress of HF.
Conclusions
Secondary PH is highly prevalent among patients with HF
regardless of LVEF. Although varying definitions lead to vary-
ing estimates of PH prevalence in HF, especially in echocar-
diographic studies at the population level, the proportion of
HF patients with PH increases with HF severity and ranges
from 25% to >50% in referred populations. A persistently ele-
vated TPG and PVR after treatment optimization and reduc-
tion of PCWP in patients with HF may indicate structural
changes in the pulmonary vascular bed, and these patients
may benefit from pulmonary vasoactive agents. The role of
exercise-induced PH and the response of PAP during acute HF
treatment need further elucidation.
Disclosures
Dr. Gheorghiade has been a consultant for Abbott Laborato-
ries, Astellas, AstraZeneca, Bayer HealthCare AG, CorThera,
Cytokinetics, DebioPharm S.A., Errekappa Terapeutici,
GlaxoSmithKline, Ikaria, Johnson & Johnson, Medtronic,
Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin
Technologies, Pericor Therapeutics, Protein Design Labora-
tories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals,
Takeda Pharmaceutical, and Trevena Therapeutics. Dr. But-
ler has been a consultant for Ono Pharma, Trevena, Bayer,
and Amgen. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.
References
1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden
WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C,
Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT,
Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar
DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, So-
liman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND,
Woo D, Turner MB; American Heart Association Statistics Committee and
Stroke Statistics Subcommittee. Heart disease and stroke statistics–2012
update: a report from the American Heart Association. Circulation.
2012;125:e2–e220.
2. Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J,
Yawn BP, Jacobsen SJ. Trends in heart failure incidence and survival in a
community-based population. JAMA. 2004;292:344–350.
 352  Circ Heart Fail  March 2013
3. Chen J, Normand SL, Wang Y, Krumholz HM. National and regional
trends in heart failure hospitalization and mortality rates for Medicare
beneficiaries, 1998-2008. JAMA. 2011;306:1669–1678.
4. Shafazand M, Schaufelberger M, Lappas G, Swedberg K, Rosengren A.
Survival trends in men and women with heart failure of ischaemic and
non-ischaemic origin: data for the period 1987-2003 from the Swedish
Hospital Discharge Registry. Eur Heart J. 2009;30:671–678.
5. Krum H, Teerlink JR. Medical therapy for chronic heart failure. Lancet.
2011;378:713–721.
6. Felker GM, Pang PS, Adams KF, Cleland JG, Cotter G, Dickstein K, Filip-
patos GS, Fonarow GC, Greenberg BH, Hernandez AF, Khan S, Komajda
M, Konstam MA, Liu PP, Maggioni AP, Massie BM, McMurray JJ, Mehra
M, Metra M, O’Connell J, O’Connor CM, Pina IL, Ponikowski P, Sab-
bah HN, Teerlink JR, Udelson JE, Yancy CW, Zannad F, Gheorghiade M;
International AHFS Working Group. Clinical trials of pharmacological
therapies in acute heart failure syndromes: lessons learned and directions
forward. Circ Heart Fail. 2010;3:314–325.
7. 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.
8. Kjaergaard J, Akkan D, Iversen KK, Kjoller E, Køber L, Torp-Pedersen C,
Downloaded from http://circheartfailure.ahajournals.org/ by guest on January 11, 2018
Hassager C. Prognostic importance of pulmonary hypertension in patients
with heart failure. Am J Cardiol. 2007;99:1146–1150.
9. Grigioni F, Potena L, Galiè N, Fallani F, Bigliardi M, Coccolo F, Magnani
G, Manes A, Barbieri A, Fucili A, Magelli C, Branzi A. Prognostic impli-
cations of serial assessments of pulmonary hypertension in severe chronic
heart failure. J Heart Lung Transplant. 2006;25:1241–1246.
10. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbus-
tini E, Recusani F, Tavazzi L. Independent and additive prognostic value
of right ventricular systolic function and pulmonary artery pressure in pa-
tients with chronic heart failure. J Am Coll Cardiol. 2001;37:183–188.
11. Meyer P, Filippatos GS, Ahmed MI, Iskandrian AE, Bittner V, Perry GJ,
White M, Aban IB, Mujib M, Dell’Italia LJ, Ahmed A. Effects of right
ventricular ejection fraction on outcomes in chronic systolic heart failure.
Circulation. 2010;121:252–258.
12. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hyperten-
sion in chronic heart failure: the role of the endothelium in pathophysiol-
ogy and management. Circulation. 2000;102:1718–1723.
13. Hoeper MM. Definition, classification, and epidemiology of pulmonary
arterial hypertension. Semin Respir Crit Care Med. 2009;30:369–375.
14. 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 di-
agnosis and treatment of pulmonary hypertension: the Task Force for the
Diagnosis and Treatment of Pulmonary Hypertension of the European So-
ciety 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.
15. Galie 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. Guidelines for the diagnosis and treatment of pulmonary hypertension.
Eur Respir J. 2009;34:1219–1263.
16. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M,
Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ,
Langleben D, Nakanishi N, Souza R. Updated clinical classification of
pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 suppl):S43–S54.
17. Oudiz RJ. Pulmonary hypertension associated with left-sided heart dis-
ease. Clin Chest.Med. 2007;28:233–41, x.
18. 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 symp-
tomatic heart failure patients with severe systolic dysfunction, associated
with secondary pulmonary hypertension–a multi-center randomized study.
Cardiology. 2008;109:273–280.
19. Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF, Mc-
Nulty SE, Darius H, Schulman K, Zannad F, Handberg-Thurmond E,
Harrell FE Jr, Wheeler W, Soler-Soler J, Swedberg K. A randomized con-
trolled trial of epoprostenol therapy for severe congestive heart failure:
the Flolan International Randomized Survival Trial (FIRST). Am Heart J.
1997;134:44–54.
20. 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.
21. Mehra MR, Kobashigawa J, Starling R, Russell S, Uber PA, Parameshwar
J, Mohacsi P, Augustine S, Aaronson K, Barr M. Listing criteria for heart
transplantation: International Society for Heart and Lung Transplantation
guidelines for the care of cardiac transplant candidates–2006. J Heart
Lung Transplant. 2006;25:1024–1042.
22. Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir
Crit Care Med. 2009;30:376–385.
23. Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, Reid
LM, Tuder RM. Pathologic assessment of vasculopathies in pulmonary
hypertension. J Am Coll Cardiol. 2004;43(12 suppl S):25S–32S.
24. Meyrick B. The pathology of pulmonary artery hypertension. Clin
Chest.Med. 2001;22:393–404, vii.
25. Heath D, Edwards JE. Histological changes in the lung in diseases associ-
ated with pulmonary venous hypertension. Br J Dis Chest. 1959;53:8–18.
26. Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B.
Pulmonary artery adventitial changes and venous involvement in primary
pulmonary hypertension. Am J Pathol. 1995;146:389–397.
27. 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.
28. Gómez-Sánchez MA, Mestre de Juan MJ, Gómez-Pajuelo C, López JI,
Díaz de Atauri MJ, Martínez-Tello FJ. Pulmonary hypertension due to
toxic oil syndrome. A clinicopathologic study. Chest. 1989;95:325–331.
29. Wagenvoort CA, Mooi WJ. Congestive vasculopathy. In: Wagenvoort CA,
Mooi WJ, eds. Biopsy Pathology of the Pulmonary Vasculature. London,
UK: Chapman & Hall Medical; 1989:171–198.
30. Goland S, Czer LS, Kass RM, De Robertis MA, Mirocha J, Coleman B,
Capelli C, Raissi S, Cheng W, Fontana G, Trento A. Pre-existing pul-
monary hypertension in patients with end-stage heart failure: impact on
clinical outcome and hemodynamic follow-up after orthotopic heart trans-
plantation. J Heart Lung Transplant. 2007;26:312–318.
31. Mikus E, Stepanenko A, Krabatsch T, Dandel M, Lehmkuhl HB, Lo-
forte A, Hetzer R, Potapov EV. Left ventricular assist device or heart
transplantation: impact of transpulmonary gradient and pulmonary
vascular resistance on decision making. Eur J Cardiothorac Surg.
2011;39:310–316.
32. Pons J, Leblanc MH, Bernier M, Cantin B, Bourgault C, Bergeron S, Proulx
G, Morin J, Nalli C, O’Connor K, Chateauvert N, Sénéchal M. Effects of
chronic sildenafil use on pulmonary hemodynamics and clinical outcomes
in heart transplantation. J Heart Lung Transplant. 2012;31:1281–1287.
33. Reichenbach A, Al-Hiti H, Malek I, Pirk J, Goncalvesova E, Kautzner J,
Melenovsky V. The effects of phosphodiesterase 5 inhibition on hemody-
namics, functional status and survival in advanced heart failure and pul-
monary hypertension: a case-control study. Int J Cardiol. Epub ahead of
print October 8, 2012.
34. Halpern SD, Taichman DB. Misclassification of pulmonary hypertension
due to reliance on pulmonary capillary wedge pressure rather than left
ventricular end-diastolic pressure. Chest. 2009;136:37–43.
35. 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.
36. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom
DM. Exercise-induced pulmonary arterial hypertension. Circulation.
2008;118:2183–2189.
37. Khush KK, Tasissa G, Butler J, McGlothlin D, De Marco T; ESCAPE
Investigators. Effect of pulmonary hypertension on clinical outcomes in
advanced heart failure: analysis of the Evaluation Study of Congestive
Heart Failure and Pulmonary Artery Catheterization Effectiveness (ES-
CAPE) database. Am Heart J. 2009;157:1026–1034.
38. Aronson D, Eitan A, Dragu R, Burger AJ. Relationship between reactive
pulmonary hypertension and mortality in patients with acute decompen-
sated heart failure. Circ Heart Fail. 2011;4:644–650.
39. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determi-
nants of pulmonary hypertension in left ventricular dysfunction. J Am Coll
Cardiol. 1997;29:153–159.
40. Damy T, Goode KM, Kallvikbacka-Bennett A, Lewinter C, Hobkirk J,
Nikitin NP, Dubois-Randé JL, Hittinger L, Clark AL, Cleland JG. Deter-
minants and prognostic value of pulmonary arterial pressure in patients
with chronic heart failure. Eur Heart J. 2010;31:2280–2290.
41. Guazzi M. Alveolar gas diffusion abnormalities in heart failure. J Card
Fail. 2008;14:695–702.
42. Negrini D, Passi A, de Luca G, Miserocchi G. Pulmonary interstitial pres-
sure and proteoglycans during development of pulmonary edema. Am J
Physiol. 1996;270(6 pt 2):H2000–H2007.

43. Palestini P, Calvi C, Conforti E, Botto L, Fenoglio C, Miserocchi G. Com-
position, biophysical properties, and morphometry of plasma membranes
in pulmonary interstitial edema. Am J Physiol Lung Cell Mol Physiol.
2002;282:L1382–L1390.
44. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmo-
nary hypertension. Circulation. 2004;109:159–165.
45. Cooper CJ, Jevnikar FW, Walsh T, Dickinson J, Mouhaffel A, Selwyn
AP. The influence of basal nitric oxide activity on pulmonary vascu-
lar resistance in patients with congestive heart failure. Am J Cardiol.
1998;82:609–614.
46. Ooi H, Colucci WS, Givertz MM. Endothelin mediates increased pulmo-
nary vascular tone in patients with heart failure: demonstration by direct in-
trapulmonary infusion of sitaxsentan. Circulation. 2002;106:1618–1621.
47. Olson TP, Snyder EM, Frantz RP, Turner ST, Johnson BD. Repeat length
polymorphism of the serotonin transporter gene influences pulmonary ar-
tery pressure in heart failure. Am Heart J. 2007;153:426–432.
48. Schrier RW, Bansal S. Pulmonary hypertension, right ventricular failure,
and kidney: different from left ventricular failure? Clin J Am Soc Nephrol.
2008;3:1232–1237.
49. Patel MR, Bailey SR, Bonow RO, Chambers CE, Chan PS, Dehmer GJ,
Kirtane AJ, Wann LS, Ward RP. ACCF/SCAI/AATS/AHA/ASE/ASNC/
Downloaded from http://circheartfailure.ahajournals.org/ by guest on January 11, 2018
HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for
diagnostic catheterization: a report of the American College of Cardiology
Foundation Appropriate Use Criteria Task Force, Society for Cardiovas-
cular Angiography and Interventions, American Association for Thoracic
Surgery, American Heart Association, American Society of Echocardiog-
raphy, American Society of Nuclear Cardiology, Heart Failure Society of
America, Heart Rhythm Society, Society of Critical Care Medicine, Soci-
ety of Cardiovascular Computed Tomography, Society for Cardiovascular
Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Car-
diol. 2012;59:1995–2027.
50. Lanzarini L, Fontana A, Lucca E, Campana C, Klersy C. Noninvasive esti-
mation of both systolic and diastolic pulmonary artery pressure from Dop-
pler analysis of tricuspid regurgitant velocity spectrum in patients with
chronic heart failure. Am Heart J. 2002;144:1087–1094.
51. Nagueh SF, Bhatt R, Vivo RP, Krim SR, Sarvari SI, Russell K, Edvardsen
T, Smiseth OA, Estep JD. Echocardiographic evaluation of hemodynam-
ics in patients with decompensated systolic heart failure. Circ Cardiovasc
Imaging. 2011;4:220–227.
52. Kuppahally SS, Michaels AD, Tandar A, Gilbert EM, Litwin SE, Bader
FM. Can echocardiographic evaluation of cardiopulmonary hemodynam-
ics decrease right heart catheterizations in end-stage heart failure patients
awaiting transplantation? Am J Cardiol. 2010;106:1657–1662.
53. Temporelli PL, Scapellato F, Eleuteri E, Imparato A, Giannuzzi P. Dop-
pler echocardiography in advanced systolic heart failure: a noninvasive
alternative to Swan-Ganz catheter. Circ Heart Fail. 2010;3:387–394.
54. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes
A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis
and assessment of pulmonary arterial hypertension. J Am Coll Cardiol.
2009;54(1 suppl):S55–S66.
55. Chemla D, Castelain V, Provencher S, Humbert M, Simonneau G, Hervé
P. Evaluation of various empirical formulas for estimating mean pulmo-
nary artery pressure by using systolic pulmonary artery pressure in adults.
Chest. 2009;135:760–768.
56. Shalaby A, Voigt A, El-Saed A, Saba S. Usefulness of pulmonary ar-
tery pressure by echocardiography to predict outcome in patients re-
ceiving cardiac resynchronization therapy heart failure. Am J Cardiol.
2008;101:238–241.
57. Adhyapak SM. Effect of right ventricular function and pulmonary pres-
sures on heart failure prognosis. Prev Cardiol. 2010;13:72–77.
58. Bursi F, McNallan SM, Redfield MM, Nkomo VT, Lam CS, Weston SA,
Jiang R, Roger VL. Pulmonary pressures and death in heart failure: a com-
munity study. J Am Coll Cardiol. 2012;59:222–231.
59. Nef HM, Möllmann H, Hamm C, Grimminger F, Ghofrani HA. Pulmo-
nary hypertension: updated classification and management of pulmonary
hypertension. Heart. 2010;96:552–559.
60. Snopek G, Pogorzelska H, Rywik TM, Browarek A, Janas J, Korewicki
J. Usefulness of endothelin-1 concentration in capillary blood in patients
with mitral stenosis as a predictor of regression of pulmonary hyper-
tension after mitral valve replacement or valvuloplasty. Am J Cardiol.
2002;90:188–189.
61. Braunwald E, Braunwald NS, Ross J Jr, Morrow AG. Effects of mitral-
valve replacement on the pulmonary vascular dynamics of patients with
pulmonary hypertension. N Engl J Med. 1965;273:509–514.
Georgiopoulou et al   Group 2 PH, Part 1   353
62. Zener JC, Hancock EW, Shumway NE, Harrison DC. Regression of ex-
treme pulmonary hypertension after mitral valve surgery. Am J Cardiol.
1972;30:820–826.
63. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed
MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA,
Otto CM, Shah PM, Shanewise JS. 2008 Focused update incorporated into
the ACC/AHA 2006 guidelines for the management of patients with valvu-
lar heart disease: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee
to Revise the 1998 Guidelines for the Management of Patients With Val-
vular Heart Disease): endorsed by the Society of Cardiovascular Anesthe-
siologists, Society for Cardiovascular Angiography and Interventions, and
Society of Thoracic Surgeons. Circulation. 2008;118:e523–e661.
64. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G,
Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A,
Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler
G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker
S, Zamorano JL, Zembala M. Guidelines on the management of valvular
heart disease (version 2012). Eur Heart J. 2012;33:2451–2496.
65. Hart SA, Krasuski RA, Wang A, Kisslo K, Harrison JK, Bashore TM.
Pulmonary hypertension and elevated transpulmonary gradient in patients
with mitral stenosis. J Heart Valve Dis. 2010;19:708–715.
66. Alexopoulos D, Lazzam C, Borrico S, Fiedler L, Ambrose JA. Isolated
chronic mitral regurgitation with preserved systolic left ventricular function
and severe pulmonary hypertension. J Am Coll Cardiol. 1989;14:319–322.
67. Magne J, Lancellotti P, Piérard LA. Exercise pulmonary hypertension in as-
ymptomatic degenerative mitral regurgitation. Circulation. 2010;122:33–41.
68. Magne J, Lancellotti P, O’Connor K, Van de Heyning CM, Szyman-
ski C, Piérard LA. Prediction of exercise pulmonary hypertension in as-
ymptomatic degenerative mitral regurgitation. J Am Soc Echocardiogr.
2011;24:1004–1012.
69. Johnson LW, Hapanowicz MB, Buonanno C, Bowser MA, Marvasti
MA, Parker FB Jr. Pulmonary hypertension in isolated aortic stenosis.
Hemodynamic correlations and follow-up. J Thorac Cardiovasc Surg.
1988;95:603–607.
70. Silver K, Aurigemma G, Krendel S, Barry N, Ockene I, Alpert J. Pulmo-
nary artery hypertension in severe aortic stenosis: incidence and mecha-
nism. Am Heart J. 1993;125:146–150.
71. Faggiano P, Antonini-Canterin F, Ribichini F, D’Aloia A, Ferrero V, Cer-
vesato E, Pavan D, Burelli C, Nicolosi G. Pulmonary artery hypertension
in adult patients with symptomatic valvular aortic stenosis. Am J Cardiol.
2000;85:204–208.
72. Khandhar S, Varadarajan P, Turk R, Sampat U, Patel R, Kamath A, Pai RG.
Survival benefit of aortic valve replacement in patients with severe aortic re-
gurgitation and pulmonary hypertension. Ann Thorac Surg. 2009;88:752–756.
73. 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.
74. Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence and
risk factors of pulmonary hypertension in patients with elevated pul-
monary venous pressure and preserved ejection fraction. Am J Cardiol.
2010;106:284–286.
75. Tumminello G, Lancellotti P, Lempereur M, D’Orio V, Pierard LA. De-
terminants of pulmonary artery hypertension at rest and during exercise in
patients with heart failure. Eur Heart J. 2007;28:569–574.
76. Maréchaux S, Neicu DV, Braun S, Richardson M, Delsart P, Bouabdal-
laoui N, Banfi C, Gautier C, Graux P, Asseman P, Pibarot P, Le Jemtel TH,
Ennezat PV; Lille HFpEF Study Group. Functional mitral regurgitation:
a link to pulmonary hypertension in heart failure with preserved ejection
fraction. J Card Fail. 2011;17:806–812.
77. Patel JB, Borgeson DD, Barnes ME, Rihal CS, Daly RC, Redfield MM.
Mitral regurgitation in patients with advanced systolic heart failure. J Card
Fail. 2004;10:285–291.
78. Berger G, Hardak E, Obaid W, Shaham B, Carasso S, Kerner A, Yigla M,
Azzam ZS. Characterization of pulmonary venous hypertension patients
with reactive pulmonary hypertension as compared to proportional pulmo-
nary hypertension. Respiration. 2012;83:494–498.
79. Tatebe S, Fukumoto Y, Sugimura K, Miyamichi-Yamamoto S, Aoki T,
Miura Y, Nochioka K, Satoh K, Shimokawa H. Clinical significance of
reactive post-capillary pulmonary hypertension in patients with left heart
disease. Circ J. 2012;76:1235–1244.
80. Gavazzi A, Ghio S, Scelsi L, Campana C, Klersy C, Serio A, Raineri C,
Tavazzi L. Response of the right ventricle to acute pulmonary vasodilation
predicts the outcome in patients with advanced heart failure and pulmo-
nary hypertension. Am Heart J. 2003;145:310–316.
 354  Circ Heart Fail  March 2013
81. Desai RV, Meyer P, Ahmed MI, Mujib M, Adamopoulos C, White M,
Aban IB, Iskandrian AE, Ahmed A. Relationship between left and right
ventricular ejection fractions in chronic advanced systolic heart failure:
insights from the BEST trial. Eur J Heart Fail. 2011;13:392–397.
82. Berkowitz R, Alhaj E, Manchikalapudi RB, Satya K, Dadfarmay S, Zakir
R. Determinants of right ventricular failure in patients admitted with acute
left heart failure. Congest Heart Fail. 2010;16:243–248.
83. Miller WL, Mahoney DW, Michelena HI, Pislaru SV, Topilsky Y, En-
riquez-Sarano M. Contribution of ventricular diastolic dysfunction to
pulmonary hypertension complicating chronic systolic heart failure. J Am
Coll Cardiol Cardiovasc Imaging. 2011;4:946–954.
84. Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Va-
san RS, Levy D. Changes in arterial stiffness and wave reflection with
advancing age in healthy men and women: the Framingham Heart Study.
Hypertension. 2004;43:1239–1245.
85. Vaitkevicius PV, Fleg JL, Engel JH, O’Connor FC, Wright JG, Lakatta
LE, Yin FC, Lakatta EG. Effects of age and aerobic capacity on arterial
stiffness in healthy adults. Circulation. 1993;88(4 pt 1):1456–1462.
86. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age-
and gender-related ventricular-vascular stiffening: a community-based
study. Circulation. 2005;112:2254–2262.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on January 11, 2018
87. Smulyan H, Asmar RG, Rudnicki A, London GM, Safar ME. Comparative
effects of aging in men and women on the properties of the arterial tree. J
Am Coll Cardiol. 2001;37:1374–1380.
88. Hayward CS, Kelly RP. Gender-related differences in the central arterial
pressure waveform. J Am Coll Cardiol. 1997;30:1863–1871.
89. Fischer M, Baessler A, Hense HW, Hengstenberg C, Muscholl M, Holmer S,
Döring A, Broeckel U, Riegger G, Schunkert H. Prevalence of left ventricular
diastolic dysfunction in the community. Results from a Doppler echocardio-
graphic-based survey of a population sample. Eur Heart J. 2003;24:320–328.
90. Bella JN, Palmieri V, Roman MJ, Liu JE, Welty TK, Lee ET, Fabsitz RR,
Howard BV, Devereux RB. Mitral ratio of peak early to late diastolic fill-
ing velocity as a predictor of mortality in middle-aged and elderly adults:
the Strong Heart Study. Circulation. 2002;105:1928–1933.
91. Abhayaratna WP, Marwick TH, Smith WT, Becker NG. Characteristics
of left ventricular diastolic dysfunction in the community: an echocardio-
graphic survey. Heart. 2006;92:1259–1264.
92. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Ro-
deheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the
community: appreciating the scope of the heart failure epidemic. JAMA.
2003;289:194–202.
93. Kuznetsova T, Herbots L, López B, Jin Y, Richart T, Thijs L, González
A, Herregods MC, Fagard RH, Díez J, Staessen JA. Prevalence of left
ventricular diastolic dysfunction in a general population. Circ Heart Fail.
2009;2:105–112.
94. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates
and reference intervals for pulmonary artery systolic pressure among echo-
cardiographically normal subjects. Circulation. 2001;104:2797–2802.
95. Abramson SV, Burke JF, Kelly JJ Jr, Kitchen JG III, Dougherty MJ, Yih
DF, McGeehin FC III, Shuck JW, Phiambolis TP. Pulmonary hypertension
predicts mortality and morbidity in patients with dilated cardiomyopathy.
Ann Intern Med. 1992;116:888–895.
96. Butler J, Chomsky DB, Wilson JR. Pulmonary hypertension and exer-
cise intolerance in patients with heart failure. J Am Coll Cardiol. 1999;34:
1802–1806.
97. Szwejkowski BR, Elder DH, Shearer F, Jack D, Choy AM, Pringle SD,
Struthers AD, George J, Lang CC. Pulmonary hypertension predicts all-
cause mortality in patients with heart failure: a retrospective cohort study.
Eur J Heart Fail. 2012;14:162–167.
  98. Stevenson LW. Are hemodynamic goals viable in tailoring heart failure
therapy? Hemodynamic goals are relevant. Circulation. 2006;113:1020–
1027; discussion 1033.
  99. Chang PP, Longenecker JC, Wang NY, Baughman KL, Conte JV, Hare
JM, Kasper EK. Mild vs severe pulmonary hypertension before heart
transplantation: different effects on posttransplantation pulmonary hy-
pertension and mortality. J Heart Lung Transplant. 2005;24:998–1007.
100. Costard-Jäckle A, Fowler MB. Influence of preoperative pulmonary ar-
tery 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.
101. 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.
102. Ha JW, Choi D, Park S, Shim CY, Kim JM, Moon SH, Lee HJ, Choi
EY, Chung N. Determinants of exercise-induced pulmonary hyperten-
sion in patients with normal left ventricular ejection fraction. Heart.
2009;95:490–494.
103. Shim CY, Kim SA, Choi D, Yang WI, Kim JM, Moon SH, Lee HJ, Park
S, Choi EY, Chung N, Ha JW. Clinical outcomes of exercise-induced
pulmonary hypertension in subjects with preserved left ventricular ejec-
tion fraction: implication of an increase in left ventricular filling pressure
during exercise. Heart. 2011;97:1417–1424.
104. Borlaug BA, Jaber WA, Ommen SR, Lam CS, Redfield MM, Nishimura
RA. Diastolic relaxation and compliance reserve during dynamic exercise
in heart failure with preserved ejection fraction. Heart. 2011;97:964–969.
105. 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.
106. Innes JA, De Cort SC, Kox W, Guz A. Within-breath modulation of left
ventricular function during normal breathing and positive-pressure venti-
lation in man. J Physiol (Lond). 1993;460:487–502.
107. Redfield MM, Borlaug BA, Lewis GD, Mohammed SF, Semigran MJ,
Lewinter MM, Deswal A, Hernandez AF, Lee KL, Braunwald E; Heart
Failure Clinical Research Network. PhosphdiesteRasE-5 Inhibition to
Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure
(RELAX) trial: rationale and design. Circ Heart Fail. 2012;5:653–659.
108. Stevenson LW, Zile M, Bennett TD, Kueffer FJ, Jessup ML, Adam-
son P, Abraham WT, Manda V, Bourge RC. Chronic ambulatory in-
tracardiac pressures and future heart failure events. Circ Heart Fail.
2010;3:580–587.
109. Zile MR, Bennett TD, St John Sutton M, Cho YK, Adamson PB, Aaron
MF, Aranda JM Jr, Abraham WT, Smart FW, Stevenson LW, Kueffer FJ,
Bourge RC. Transition from chronic compensated to acute decompen-
sated heart failure: pathophysiological insights obtained from continuous
monitoring of intracardiac pressures. Circulation. 2008;118:1433–1441.
110. Rich S, D’Alonzo GE, Dantzker DR, Levy PS. Magnitude and impli-
cations of spontaneous hemodynamic variability in primary pulmonary
hypertension. Am J Cardiol. 1985;55:159–163.
Key Words: definition ◼ epidemiology ◼ heart failure ◼ pathophysiology
◼ pulmonary hypertension
 Left Ventricular Dysfunction With Pulmonary Hypertension: Part 1: Epidemiology,
Pathophysiology, and Definitions
Vasiliki V. Georgiopoulou, Andreas P. Kalogeropoulos, Barry A. Borlaug, Mihai Gheorghiade
and Javed Butler
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Circ Heart Fail. 2013;6:344-354

doi: 10.1161/CIRCHEARTFAILURE.112.000095
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