Circulation: Heart Failure

EDITORIAL

Coupling Right Ventricular–Pulmonary

Arterial Research to the Pulmonary
Hypertension Patient Bedside

See Article by Tello et al Steven Hsu, MD

O
ver the last decade, there has been increasing appreciation for the im-
portance of right ventricular (RV) coupling to the pulmonary arterial (PA)
circulation. This relationship, so-called RV-PA coupling, is an application of
the left-sided ventriculo-arterial coupling first described in the 1980s.1 Whether it
refers to the left or right, coupling describes the energy transfer between ventricu-
lar contractility and arterial afterload. Ventricular contractility is well characterized
by end-systolic elastance (Ees), a load-independent measure of systolic function.
Arterial afterload, on the other hand, can be thought of in terms of net vascular
stiffness. Sunagawa et al1,2 created a term in 1983 called effective arterial elastance
(Ea), which encapsulates net stiffness by combining mean and pulsatile loading to
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yield a lumped parameter that reflects the load imposed upon the ventricle. An
important breakthrough came in 1992 when Kelly et al3 found in humans that
end-systolic pressure divided by stroke volume accurately represented Ea across a
wide afterload range. Because Ea is conveniently measured using the same units as
Ees, this allows the ratio of Ees to Ea to become a unit-less value that encapsulates
ventriculo-arterial coupling. The ideal Ees/Ea ratio is estimated to be 1.0 to 2.0.2
This ratio is seen in the healthy RV-PA unit and remains preserved even in the early
phases of pulmonary hypertension (PH) because compensatory RV hypertrophy
leads to an increase in RV Ees that matches increasing Ea. It is only with progressive
RV decompensation that RV Ees begins to fall, Ees/Ea declines, and the RV-PA unit
becomes uncoupled.4
RV-PA coupling is often talked about in academic circles and carefully measured
in animal and human experimental studies of PH. Coupling can describe RV com-
pensation not only in group I PH but also in PH secondary to a range of left-sided
cardiac conditions. Its importance has risen alongside increasing recognition of the
pivotal role that the RV plays in many cardiopulmonary conditions. But when was
the last time any of us talked to a patient or clinical colleague about coupling?
“Great news, your coupling ratio is 1.5!” Despite its common use in the literature
and its ability to describe the full range of RV-PA performance, there is a surprising
lack of correlation between coupling, as measured by Ees/Ea, and more clinically
The opinions expressed in this article are
utilized parameters of RV dysfunction, such as RV dilation or RV ejection fraction not necessarily those of the editors or
(RVEF). This leads to an unfortunate disconnect between the research and clinical of the American Heart Association.
applications of RV-PA coupling. Key Words: Editorials ◼ energy
In this issue of Circulation: Heart Failure, Tello et al5 lay out a much-needed blue- transfer ◼ pulmonary hypertension
◼ stroke volume ◼ vascular stiffness
print that relates RV-PA coupling to more clinically accessible measures of RV per-
formance in PH. In their study, they prospectively obtain pressure-volume loop mea- © 2019 American Heart Association, Inc.
surements alongside right heart catheterization and cardiac magnetic resonance https://www.ahajournals.org/journal/
imaging in 42 human patients with PH. In this cohort, the PH patients with more circheartfailure

Circ Heart Fail. 2019;12:e005715. DOI: 10.1161/CIRCHEARTFAILURE.118.005715 January 2019 1

 Hsu; Coupling Pulmonary Hypertension Research to the Bedside
severe disease demonstrated predictable increase in RV
mass and end-diastolic volume , decrease in RVEF, as well
as worsening PA stiffness, capacitance, and distensibility.
Ees/Ea showed progressive decline alongside worsening
RV end-diastolic volume, mass, and RVEF. By mapping
out Ees/Ea across tertiles of each parameter, the authors
show that Ees/Ea maintains a ratio of 0.89:1.09 in PH
patients with compensated RVs (best tertile), drifts to
0.58:0.70 in early RV decompensation (middle tertile),
and falls to 0.56:0.61 in the most decompensated ter-
tile. Little is known about the clinical relevance of Ees/
Ea, and so by using receiver operator curve analysis, the
authors show that an Ees/Ea of <0.805 best predicted
a cardiac magnetic resonance RVEF of <35%, the latter
being an established indicator of RV decompensation in
PH. Last, they show that RV stroke volume divided by
end-systolic volume, a measure readily attainable from
cardiac magnetic resonance, is at least as good at pre-
dicting RVEF <35% as Ees/Ea, if not better.
Using pressure-volume loops, the authors also cal-
culate single-beat end-diastolic elastance (Eed), a co-
efficient of diastolic stiffness attainable from RV pres-
sure-volume data. Eed indexes RV diastolic dysfunction,
increases with diastolic stiffness, and has been shown
to be predictive of outcomes in PH.6,7 The authors show
that Eed increases alongside worsening RV mass, vol-
ume, and ejection fraction, as well as worsening T1
mapping of RV fibrosis. Interestingly, Eed trends up-
ward just as RV mass and end-diastolic volume increase
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and Ees/Ea declines, illustrating just how tightly inter-
woven coupling, mass, dilation, and diastolic dysfunc-
tion are in PH.5
RV Ees/Ea has been widely used in research; its clin-
ical validity has generally been assumed. The current
study thus does an important job of validating Ees/
Ea, and even Eed, against multiple established clini-
cal benchmarks of RV decompensation. Second, the
authors verify that Ees/Ea maintains coupling at ≈1.0 in
early PH and show us that Ees/Ea has to fall below 0.8
before we see RV dilation and overt worsening of RV
systolic function. These values help us to understand
the range of Ees/Ea in the context of known clinical
markers of RV decompensation. Tello et al5 thus pro-
vide a much-needed link between the growing body of
RV-PA coupling research to the bedside assessment of
RV function in PH. One fly in the ointment, however,
is the single-beat method by which Ees/Ea was deter-
mined. Ees is traditionally measured by altering RV pre-
load, obtaining a family of pressure-volume loops, and
measuring the slope of multiple end-systolic pressure
points. This is known as the multi-beat method. The
single-beat method determines Ees without need for
filling changes to the RV. It was originally proposed by
Sunagawa et al8 and Senzaki et al9 in the left ventricle
and shown to be practical for the RV by Brimioulle et
al.10 The single-beat method extrapolates a theoretical
Circ Heart Fail. 2019;12:e005715. DOI: 10.1161/CIRCHEARTFAILURE.118.005715
pressure of isovolumic contraction (Pisovol) and combines
that with the end-systolic pressure point to calculate
Ees. It should be noted that although RV Pisovol has been
validated in animal models, it has not been validated in
humans with severe PH,4 and a recent study failed to
show correlation between single-beat and multi-beat
measures of Ees in a human cohort with and without
PH.11 That said, both methodologies, on the whole,
capture the same overall relationship of RV contractil-
ity to PA afterload, and Ea is measured the same either
way. Also, the current study may help to bolster the
validity of single-beat Ees/Ea by relating it to well-estab-
lished metrics of RV decompensation.
Now that we have a blueprint with which to under-
stand the clinical implications of Ees/Ea, where do we
go from here? More work needs to be done to link Ees/
Ea to the bedside. Despite its common use in research,
Ees/Ea has never been shown to predict outcomes in
PH patients. Does Ees/Ea even predict clinical events? It
would be a much more relevant parameter if so. Also,
the current study shows that readily available clinical
metrics of RV performance serve as an adequate surro-
gate for reduced Ees/Ea. But is there perhaps a role for
Ees/Ea in identifying early uncoupling in PH patients?
Ees does remain a very sensitive measure of RV systolic
function and captures declining RV contractility well
before right heart catheterization or cardiac magnetic
resonance can detect.12,13 RV dilation, stroke volume/
end-systolic volume, and reduced RVEF all capture the
uncoupled RV, and so perhaps Ees/Ea can be better put
to use in capturing earlier RV disease. Now that we are
guided by Tello et al5 with a more robust clinical frame-
work for RV-PA coupling, future studies in the field will
hopefully provide more context and utility to the bed-
side application of Ees/Ea.
ARTICLE INFORMATION
Guest Editor for this article was Ryan J. Tedford, MD.
Correspondence
Steven Hsu, MD, Division of Cardiology, Department of Medicine, Johns Hop-
kins University School of Medicine, 600 N Wolfe St, Carnegie 591A, Baltimore,
MD 21205. Email steven.hsu@jhmi.edu
Affiliation
Division of Cardiology, Department of Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD.
Disclosures
None.
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