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Clinical Features, Hemodynamics, and Outcomes of
Pulmonary Hypertension Due to Chronic Heart FailureWith Reduced
Ejection FractionPulmonary Hypertension and Heart Failure
Wayne L. Miller, MD, PHD,* Diane E. Grill, MSC,y Barry A.
Borlaug, MD*
Rochester, Minnesota
JACC: HEART FAILURE CME
This article has been selected as the months JACC: Heart
FailureCME activity.
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To obtain credit for JACC: Heart Failure CME, you must:
1. Be an ACC member or JACC: Heart Failure subscriber.
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CME Objective for This Article: After reading this article,
the
reader should be able to: 1) discuss the causes of pulmonary
hypertension in patients with systolic heart failure; 2) have
an
understanding of the differences between passive and mixed
pulmonary hypertension; and 3) discuss the impact of
pulmonary
hypertension subtypes on disease severity and risk of death.
CME Editor Disclosure: Deputy Managing Editor Mona Fiuzat,
PharmD, FACC, reports that she has equity interest or stock
options
in ARCA Biopharma, consults for CCA, and receives research
support from ResMed, GE Healthcare, Gilead, Critical
Diagnostics,
BG Medicine, Otsuka, Astellas, and Roche Diagnostics.
Author Disclosures: The authors report that they have no
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tionships relevant to the contents of this paper to
disclose.
Mediumof Participation: Print (article only); online (article
andquiz)
CME Term of Approval:
Issue date: August 2013
Expiration date: July 31, 2014
From the *Division of Cardiovascular Diseases, Mayo Clinic,
Rochester, Minnesota;
andthe yDepartment of Biomedical Statistics and Informatics,
MayoClinic, Rochester,Minnesota.This study was supported by the
Division of Cardiovascular Diseases, Mayo
Clinic and Foundation, Rochester,Minnesota. The authors
havereportedthat theyhave
no relationships relevant to the contents of this paper to
disclose.Manuscript received April 29, 2013; accepted May 3,
2013.
JACC: Heart Failure Vol. 1, No. 4, 2013 2013 by the American
College of Cardiology Foundation ISSN 2213-1779/$36.00Published by
Elsevier Inc. http://dx.doi.org/10.1016/j.jchf.2013.05.001
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Clinical Features, Hemodynamics, and Outcomes of Pulmonary
Hypertension
Due to Chronic Heart Failure With Reduced Ejection Fraction
Pulmonary Hypertension and Heart Failure
Objectives The purpose of this study was to assess the clinical,
functional, and hemodynamic characteristics of passive andmixed
pulmonary hypertension (PH), compare outcomes, and contrast
conventional and novel hemodynamic
partition values in patients with chronic heart failure of
reduced left ventricular ejection fraction (HFREF).
Background PH in HFREF may develop from left-sided venous
congestion (passive PH) or the combination of pulmonary
arterial
disease and venous congestion (mixed PH). Subgroup outcomes are
not well defined, and the partition values used
to define risk are based largely on consensus opinion rather
than outcome data.
Methods Ambulatory patients referred for hemodynamic
catheterization were analyzed retrospectively (N 463).
Results Comparingpatients with no PHto thosewithpassive PHand
mixedPH, a progressive gradientof more severelyderanged
hemodynamics, diastolic dysfunction, and mitral regurgitation
was observed. In multivariate analysis, the presence of
anyPH ormixedPH
wasassociatedwitholderage,diureticuse,atrialfibrillation, and
lowerpulmonary artery compliance
(PAC). Over a median follow-up of 2.1 years, patients with PH
displayed greater risk of death (hazard ratio [HR]: 2.24;
confidence limits[95% CL]: 1.39, 3.98; p4 Wood
units,systolic pulmonary artery pressure>35 mmHg, pulmonary
wedge pressure>25mmHg,andPAC18 years, LVEF40%,and measurable LV
diastolic and mitral valve function byechocardiography-Doppler
evaluation at the time of theindex catheterization. Exclusion
criteria were primary pa-renchymal lung disease; chronic
obstructive pulmonarydisease other than mild as defined by
pulmonary spirometrytesting (forced expiratory volume in 1 s [FEV1]
!80% ofexpected normal and the FEV1/forced vital capacity
[FVC]ratio
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included in the analysis. Thestudy was approved by theMayo
Foundation InstitutionalResearch Review Board andincluded only
those patients whoprovided informed consent as
required by Minnesota Statute144.335/CRF 21 (Part 50).Invasive
hemodynamic charac-terization. Right heart cathe-terization was
performed byflow-directed pulmonary artery
catheter using hemodynamic and fluoroscopic guidance.Hemodynamic
data were abstracted from the computerizedchart records and
included the following: pulmonary arterialsystolic, diastolic, and
mean pressures (sPAP, dPAP, mPAP,respectively); pulmonary capillary
wedge pressure (PCWP);right atrialpressure (RAP); transpulmonary
gradient (TPG
mPAP PCWP); cardiac output (CO), pulmonary vascularresistance
(PVR) in Wood units (WU) TPG/CO);systemic blood pressure
(systolic/diastolic), and heart rate.Cardiac output was measured by
the direct Fick method (i.e.,measured oxygen consumption) or by the
thermodilutionmethod if Fick method was not performed. Pulmonary
ar-tery compliance (PAC) was defined as stroke volume (SV)/[sPAP
dPAP].Noninvasive hemodynamic characteristics. Parameters ofLV
diastolic function including early transmitral flowvelocity (E),
late transmitral flow velocity (A), early diastolicmitral annular
velocity (e0), the ratio of peak E to peak e0 (E/e0)
and to peak A (E/), and the deceleration time (DT) of themitral
E-wave were abstracted from the Doppler echo-cardiography
evaluations obtained within 3 months of theindex catheterization.
The presence and extent of mitral valveinsufficiency were
quantified from the effective mitral regur-gitant orifice area
(EROA) as previously described (1618).EROA was considered to be
zero in patients with no or tracemitral regurgitation by color flow
imaging. Glomerularfiltration rate (eGFR [ml/min/1.73 m2]) was
estimated usingthe modification of diet in renal disease equation
(19).Hemodynamic definitions. The passive PH cohort wasdefined as
mPAP !25 mm Hg, PCWP !15 mm Hg, and
PVR
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variable, the regression equation was mPAP 0.615,sPAP 3 (r 0.93,
p < 0.001). Lesser, but still significantcorrelations, were also
demonstrated for mPAP with PVR(r 0.669, p < 0.001), and TPG (r
0.696, p < 0.001).There was a much weaker correlation between
sPAP and
systemic arterial pressure (Fig. 1B).As expected, PA pressures,
PVR, and TPG were higher,
while PAC was lower in patients with PH than in thosewithout PH
(Table 2). Other hemodynamic markers ofincreasing HF severity,
including HR, RAP, and PCWP,were higher, while CO and SV were lower
in patients withPH than in patients without PH.
Compared to patients with passive PH, those with mixedPH had
higher PA pressures, PVR, and TPG, with lowerPAC, CO, and SV (Table
2). However, PCWP and RAPwere similar in both subgroups, indicating
that the presenceof pulmonary vascular disease was the principle
determinant
of mixed PH rather than a difference in downstream
leftheartfilling pressures.
Noninvasive hemodynamic characteristics. Compared toHF patients
without PH, patients with PH had similar LVsize and mass, slightly
lower LVEF, more profound diastolicdysfunction (higher E/A and E/e0
ratio, shorter DT, largerleft atrial volume), more severe mitral
valve regurgitation,
and more right ventricular dysfunction (Table 2). Comparedto
patients with passive PH, patients with mixed PH hadmore severe LV
diastolic dysfunction and more severe mitralvalve regurgitation
(higher EROA) and tended to displaymore severe RV
dysfunction.Correlates of pulmonary hypertension in HFREF.
Clini-cal and hemodynamic variables associated with PH (passiveor
mixed) by unadjusted univariate and multivariateanalyses are shown
in Table 3. In univariate analysis, dia-betes, atrial fibrillation,
diuretic use, hemoglobin, renalfunction, LVEF, and PAC were
predictors of the presenceof PH. Age was a borderline univariate
predictor but was
included in the multivariate analysis because of its
commonassociation with PH. After multivariate adjustment, age,
Table 1 Demographic and Clinical Characteristics PH defined by
PVR
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diuretic use, atrial fibrillation, and PAC remained indepen-dent
predictors of PH. After multivariate adjustment, age,atrial
fibrillation, and PAC remained predictors of mixedPH as compared to
passive PH.Relationship of PH subtypes to mortality. There were171
deaths (37%) over a median follow-up of 2.1 (95%confidence interval
[CI]: 0.1 to 3.8) years. Using PVR todefine the PH subgroups, we
found a gradient of increasing
risk of death from patients with no PH to those with passivePH
and to those with mixed PH (Fig. 2A). However, whenpassive and
mixed PH were defined according to TPG(passive, TPG 2.3)revealed
PAC values less than the median identified the
subgroup of PH patients with highest risk (HR: 2.28, 95%CL:
1.64, 3.15, p < 0.001) (Fig. 4). PVR !3.5 WUidentified greater
risk of death (HR: 1.97, 95% CI: 1.42 to2.74, p < 0.0001) (Fig.
3), while partition values w4.0 WU, sPAP >w35 mm Hg, PCWP
>w25 mmHg, and PAC
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population meeting study criteria displayed PH and thatamong
these patients over half showed evidence of pul-monary vascular
disease (mixed PH) superimposed onelevations in left heart filling
pressures. Patients with anyPH and particularly those with mixed PH
displayedprogressively more severe hemodynamic derangements
withgreater burden of diastolic dysfunction, mitral
regurgitation,
and right ventricular dysfunction despite grossly
similarclinical profiles. Sensitivity analyses were performed
toevaluate partition values of hemodynamic parameters
thatidentified greater risk of death, and we further show thatPAC
refines risk assessment in group 2 PH and may bea novel therapeutic
target in addition to PVR and mPAP.These data reinforce the
important role of PH in the
Table 3 Variables Associated With the Presence of PH
Variable
Univariate Odds Ratio
(95% CL) p Value C Stat
Multivariate* Odds Ratio
(95% CL) p Value
Age 1.12 (0.971.28) 0.098 0.540 1.40 (1.081.82) 0.011
Diabetes 1.67 (1.082.60) 0.020 0.568 2.02 (1.044.07) 0.037
Atrial fibri llation 2.22 ( 1.473.39) 0.001 0.598 2.85
(1.485.62) 0.002
Diuretic use 2.55 (1.284.99) 0.008 0.539 1.49 (0.484.46)
0.486
Hemoglobin 2.03 (1.163.57) 0.012 0.584 1.59 (0.683.73) 0.283
eGFR 1.10 (1.021.21) 0.035 0.595 1.01 (0.871.18) 0.885
LVEF 1.24 (1.091.41) 0.001 0.598 1.13 (0.921.39) 0.258
PAC 8.58 (5.6413.70)
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pathophysiology and progression of HF with reduced LVEFand
support the need for trials of agents targeting passiveand mixed PH
in HF.
Numerous studies have shown that PH carries a greaterrisk of
death in HF than LV dysfunction alone, but therehave been few
studies in HFREF patients that have evalu-ated the prognostic
implications of the different subtypes ofPH (11,15). These studies
were performed in hospitalizedpatients with acute decompensated HF
(ADHF), withheterogeneous clinical and PH origin status, relatively
short-term follow-up (6 months), and conflicting results. Usingdata
from the ESCAPE (Evaluation Study of CongestiveHeart Failure and
Pulmonary Artery CatheterizationEffectiveness) trial, Khush et al.
(11) found no differencesin clinical outcomes between patients with
passive andthose with mixed PH and also no differences in
mortalitycompared with patients without PH. In contrast, using
datafrom the VMAC (Vasodilation in the Management ofAcute
Congestive Heart Failure) trial, Aronson et al. (12)demonstrated a
significant increased risk of death
advancing from no PH to passive and mixed PH, similar toour
currentfindings. A key difference between these studieswas in the
timing of the assessment of PH subgroups: priorto treatment of ADHF
(11) and after treatment (15). Bycomparison, our data reflect the
largest and most compre-hensively phenotyped cohort of outpatients
with chronicHFREF where causes of PH other than LV
systolicdysfunction were excluded, and baseline right heart
hemo-dynamic catheterization data were collected under
stabletherapeutic conditions and with long follow-up.
The partition values currently used to
identifyabnormalhemodynamics have been based largely on
consensusopinion, and few studies have provided objective
sensitivityanalyses to identify which cutoff values best stratify
risk. Theadoption of empirically derived partition values may
betteralign the magnitude of abnormalities with objective risk.Our
sensitivity analyses suggest that cutoff points of PVRof!3.5 WU and
PAC of2.0 ml/mm Hg (unadjusted) aremost strongly associated with
risk separation, although riskof death was suggested to be
increased above unity, even at
Figure 2 Survival of HFREF Patients With PH
(A) Kaplan-Meier estimates of survival in patients with heart
failure of reduced left ventricular ejection fraction (HFREF)
relative to passive pulmonary hypertension (PH) and
mixed PH as defined by pulmonary vascular resistance (PVR) <
or!3.0 Wood units (WU) and no PH. (B) Kaplan-Meier estimates of
survival in patients with HFREF relative to
passive PH and mixed PH as defined by transpulmonary gradient
(TPG) < and !12 mm Hg and no PH.
Table 4 Unadjusted and Adjusted Cox Proportional Hazards Model
of All-Cause Mortality
Variable
Unadjusted Hazard Ratio
(95% CL) p Value
Adjusted Hazard Ratio
(95% CL) p Value
Mixed PH defined as PVR !3.0 WU 3.06 (1.984.89)
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PVR values less than 2.5 WU (Fig. 5). If these risk markersare
validated in other HFREF populations, they may servevaluable roles
in both risk stratification and potentially asmodifiable endpoints
in treatment trials.
We found that PH and particularly mixed PH were quitecommon in
this referral population. While the cause of
mixed PH cannot be determined from this analysis
(i.e.,structural vs. functional changes), the current and
previous-ly published data (23,24) suggest that it may relate to
in-creasing severity and chronicity of the underlying HFREF,as
there was progressively more severe diastolic
dysfunction, mitral regurgitation, and right
ventriculardysfunction identified progressing from no PH to
passiveand mixed PH. It is also notable that these groups
werenearly indistinguishable on clinical grounds, with
similarchamber remodeling, right- and left-sided filling
pressures,and LVEF. The concept that mixed PH is associated
with
greater anatomic pulmonary artery remodeling is supportedby the
above-cited small study in transplant patients (23),where relative
medial thickness was greater in the group withmixed PH than in
those with passive PH. Future studiescorrelating clinicopathologic
findings with pulmonaryhemodynamics might offer further insight
into the mecha-nism of disease.
Prior studies in healthy controls and in patients withgroup 1 PH
have shown that PA systolic, mean, anddiastolic pressures are very
highly correlated, and weshow that this relationship also extends
to group 2 PH.Interestingly, the linear least squares regression
equation
relating mPAP to sPAP in the current sample was re-markably
similar to that reported by Chemla et al. (25). Apractical
implication of these findings is that an assessmentof sPAP is as
valid as mPAP for identifying PH, withsPAP values of !35 mm Hg
corresponding to mPAPof!25 mm Hg, based upon current and prior
data. OftensPAP is reported in the context of systemic blood
pressure,implying that there is some mechanistic
relationshipbetween the 2 parameters. However, the poor
correlationobserved between sPAP and systolic systemic BP in
thecurrent study (Fig. 1B) suggests that this is not a
validconclusion.
Previous studies have variably used PVR and TPG inthe
nomenclature of PH. An advantage of PVR is that inaddition to
assessing the hydraulic pressure drop across thepulmonary vascular
bed, it accounts forflow (CO), whichvaries directly with TPG. The
currentfindings support theuse of PVR rather than TPG to identify
mixed PH.Indeed, outcomes were similar between mixed and passivePH
when the subgroups were defined using TPG values
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shown that the RV response to PH is as important or
moreimportant than the extent of pulmonary vascular
diseasepresent(13). While we provide qualitative assessment of
RVfunction from echocardiographic evaluations, more quantita-
tive assessment might further refine risk stratification
inaddition to the hemodynamic parameters. Cardiopulmonaryexercise
testing is a validated prognostic tool in HFREF, andthis study does
not provide data regarding exercise capacity.Further studies are
warranted to explore potential relationshipsbetween pulmonary
hemodynamics and exercise physiology.The cubic spline analyses
(Fig. 5) were unadjusted, andcomparisons were made only with the
reference levels.
Conclusions
Group 2 PH is commonly identified in patients with chronic
stable HFREF and carries a significantly increased
mortalityrisk. The development of mixed PH with structural
and/or
functional pulmonary vascular disease is related to othermarkers
of increased HF severity and chronicity, and carriesincrementally
greater risk of death. While several parameterscan be used to
distinguish the subgroups of PH, PVR and
PAC appear most robust in separating patients at higher riskand
may serve as novel targets for therapy.
Reprint requests and correspondence: Dr. Wayne L.
Miller,Cardiovascular Division, Mayo Clinic, 200 First Street SW,
GondaBuilding 5S 130, Rochester, Minnesota 55905. E-mail:
miller.
[email protected].
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Key Words: heart failure - mixed pulmonary hypertension -
outcomes -passive pulmonary hypertension - risk prediction.
JACC: Heart Failure Vol. 1, No. 4, 2013 Miller et al.
August 2013:2909 Pulmonary Hypertension Due to Chronic HF
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