JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO.

2, 2017

2017 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN ISSN 0735-1097

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THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

REVIEW TOPIC OF THE WEEK

The Relationship Between the

Right Ventricle and its Load in
Pulmonary Hypertension
Anton Vonk Noordegraaf, MD, PHD,a Berend E. Westerhof, PHD,a,b Nico Westerhof, PHDa

ABSTRACT

In pulmonary hypertension, the right ventricle adapts to the increasing vascular load by enhancing contractility
(coupling) to maintain ow. Ventriculoarterial coupling implies that stroke volume changes little while preserving
ventricular efciency. Ultimately, a phase develops where ventricular dilation occurs in an attempt to limit the
reduction in stroke volume, with uncoupling and increased wall stress as a consequence. With pressurevolume
analysis, we separately describe the changing properties of the pulmonary vascular system and the right ventricle, as
well as their coupling, as important concepts for understanding the changes that occur in pulmonary hypertension.
On the basis of the unique properties of the pulmonary circulation, we show how all relevant physiological parameters
can be derived using an integrative approach. Because coupling is maintained by hypertrophy until the end stage
of the disease, when progressive dilation begins, right ventricular volume is the essential parameter to measure
in follow-up of patients with pulmonary hypertension. (J Am Coll Cardiol 2017;69:23643) 2017 The Authors.
Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

T he pulmonary circulation and right ventricle

(RV) have been undiscovered land for a long
time. It is only recently that we learned to un-
derstand the unique structure and function of the pul-
monary circulation, and their consequences with
regard to RV load and function in pulmonary
hypertension (PH). There are striking differences be-
tween the pulmonary circulation and the systemic cir-
culation, both anatomically and functionally. The
systemic arterial system consists of a large main artery
with side branches, whereas the pulmonary arterial
bed is more like a system of short vessels repeatedly
branching into, on average, 3 daughter vessels (1,2).
Not only does the anatomy differ, but functional differ-
ences also exist. One example is the response to
hypoxia, with vasoconstriction in the pulmonary
vasculature, but dilation in the systemic vasculature.
A hemodynamic comparison between aortic and pul-
monary artery pressures (PAP) with increasing
vascular resistance, as in hypertension, is schemati-
cally shown in Figure 1 (3). The increased vascular
load on the RV in PH and its consequences for RV func-
tion are not well understood. The difference in RV fail-
ure in PH in comparison to left ventricular (LV) failure
is that the RV fails after a course of immense adapta-
tion, with RV contractility able to increase 4- to
5-fold. Therefore, RV failure can only be understood
in relation to its load, called coupling. Combining he-
modynamic assessments with novel imaging tech-
niques allows these changes to be measured over time.

Listen to this manuscripts

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Pulmonary Diseases, VU University Medical Center, Amsterdam, the Netherlands; and the bLaboratory
for Clinical Cardiovascular Physiology, Center for Heart Failure Research, Academic Medical Center, Amsterdam, the Netherlands.
Dr. Vonk Noordegraaf was supported by the Netherlands CardioVascular Research Initiative, the Dutch Heart Foundation, Dutch
Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, the Royal
Netherlands Academy of Sciences, and NWO-VICI (2002406). Dr. B.E. Westerhof was supported by NWO-VICI (2002406). Dr. Nico
Westerhof has reported that he has no relationships relevant to the contents of this paper to disclose.

Manuscript received July 14, 2016; revised manuscript received October 3, 2016, accepted October 5, 2016.
JACC VOL. 69, NO. 2, 2017
JANUARY 17, 2017:23643
The aim of this review is to summarize recent
hemodynamic insights in the pulmonary circulation
in PH, indicate the consequence of these ndings for
daily practice in the clinic, and identify the limita-
tions and gaps in our current knowledge. All rele-
vant physiological parameters will be discussed
using an integrative approach. We will start with a
description of the pulmonary vascular load and its
changes in PH, and subsequently outline
response of the RV (Central Illustration).
THE PULMONARY VASCULAR SYSTEM
THE ORIGIN OF PH. The pivotal hemodynamic change
in PH is the increase in resistance as the consequence
of pulmonary vascular remodeling. Resistance may
increase by a factor of 4 or more, rather than the 50%
increase in systemic hypertension (Figure 1). Because
pulmonary vascular resistance (PVR) is calculated as:
PVR (mPAP  PAWP)/CO (with mPAP mean pul-
monary artery pressure, PAWP pulmonary arterial
wedge pressure, and CO cardiac output), it includes
the resistance in capillaries and veins. The contribu-
tion of the veins to the different types of PH is un-
known. Animal experiments have shown that venous
resistance may contribute up to 40% of PVR (4). In
addition, quantitative information on the number of
vessels affected and their (average) decrease in
diameter is still limited. Arterial and venous data in
health and PH reported by Chazova et al. (5) suggest
that changes in the veins may indeed contribute to
PVR. Reid (6) has suggested that rarefaction may also
play a role. Further research in this area is required to
understand the structural basis of increased resis-
tance in the pulmonary vascular bed.
THE PRESSURES ARE PROPORTIONAL IN PH. As a
consequence of the increased resistance, PAP will
increase. One of the most striking features of the
pulmonary circulation in PH is that pulmonary artery
systolic and diastolic pressures are proportional to
mPAP (7,8). Even in left heart failure, with consider-
ably increased PAWP, this proportionality is main-
tained (9).
Echocardiography or invasively measured
systolic pressure (Ps ) in patients with patent pulmo-
nary valves allows for a reliable calculation of mean
and diastolic pressures: systolic PAP Ps ; diastolic
PAP 0.36 Ps ; mPAP 0.6 P s; and pulse pressure
(PP) 0.6 Ps (9).
RESISTANCE AND COMPLIANCE ARE INVERSELY
RELATED. The proportionality of the pressures fol-
lows from the unique properties of the pulmonary
vascular system. Kind et al. (10) showed that it results
Vonk Noordegraaf et al. 237
The Right Ventricle in Pulmonary Hypertension
from an inverse relationship between the 2 ABBREVIATIONS
major components of the vascular load: PVR AND ACRONYMS
and total arterial compliance (TAC). Although
CMR = cardiac magnetic
this inverse relationship was already indi- resonance
cated in 1971 (11), it was Lankhaar et al. (12,13)
CO = cardiac output
who demonstrated that this inverse relation-
CTEPH = chronic
ship holds in patients with pulmonary arterial thromboembolic pulmonary
hypertension (PAH) and chronic thrombo- hypertension
the embolic pulmonary hypertension (CTEPH), as Ea = arterial elastance
schematically represented in Figure 2. For the Eed = end-diastolic elastance
inverse relation, it holds that PVR $ TAC is Ees = end-systolic elastance
constant and is called the arterial time con- LV = left ventricle/ventricular
stant (abbreviated as RC). In a study of Saouti
mPAP = mean pulmonary
et al. (14) in CTEPH patients, it was shown artery pressure
that the inverse relationship is valid for the PAH = pulmonary arterial
left and right pulmonary artery, even though hypertension
the clots were asymmetrically distributed PAP = pulmonary artery
over both lungs. This suggests that the pressure
impact of proximal or distal obstruction has a PAWP = pulmonary arterial
wedge pressure
similar effect on the relationship. Whether
PH = pulmonary hypertension
the inverse relation also holds for central
obstructions in the main pulmonary artery Pisovol = single-beat
method-predicted isovolumic
is debated (15,16). In a large patient cohort, systolic pressure
the relationship was conrmed (17,18), but it
PP = pulse pressure
was also established that the relationship
P-V = pressurevolume
shifts to the left in patients with PH due to
PVR = pulmonary vascular
left-sided heart failure, as illustrated in resistance
Figure 2.
RC = arterial time constant
It is an open question whether the PVR $ TAC
decreased RC-time with increased PAWP re- RV = right ventricle/ventricular
ects a larger stiffness (smaller compliance) RVEF = right ventricular
of the pulmonary vascular system at a similar ejection fraction
pressure in pre-capillary PH patients than in RVESV = right ventricular
patients with left heart failure PH or a smaller end-systolic volume
resistance at similar compliance (Figure 2). It SV = stroke volume
may also be the consequence of an over- TAC = total arterial compliance
simplication of the calculation of TAC as
stroke volume (SV) divided by PP (19). The calculation
of PVR contains PAWP, but TAC is calculated from
SV/PP and does not contain PAWP; therefore, their
product depends on PAWP. Measurement of the
decay of PAP in diastole, thereby directly determining
RC, could give the answer.
RV
CLINICAL RELEVANCE. The clinical relevance of the
proportionality of pressures is that all pressures can
be derived from a single measurement.
The constant RC-time is an arterial property and is
called the arterial time constant because its units
are time. In the systemic circulation, where the
aorta mainly determines compliance, this constant
RC-time is not seen. This constant inverse relation-
ship between PVR and TAC has 3 important
implications:
238 Vonk Noordegraaf et al. JACC VOL. 69, NO. 2, 2017

The Right Ventricle in Pulmonary Hypertension JANUARY 17, 2017:23643

obtained by constructing pressurevolume (P-V)

F I G U R E 1 Comparison of Pressures in the Aorta and Pulmonary Artery in
Control and Hypertension
loops. Ventricular contractility, determined by muscle
properties and muscle hypertrophy (wall thickness), is
200 given by the slope of the end-systolic pressure versus
AORTA PULMONARY

re
ARTERY the end-systolic volume, and is called the end-systolic
su
es
elastance (E es ) (21). To determine E es , multiple P-V
Pr

Pulse
lic

Pressure loops are required, such as can be obtained by

sto

re
Pressure (mm Hg)

reducing ventricular diastolic lling, by (partial) vena

Sy

su
es
Pr

cava occlusion (21), or otherwise by the Valsalva ma-

n
ea

re

re
neuver (22). The so-called single-beat method to
M

su

100

su
es

Pulse

es
Pr

re Pressure determine E es without lling changes was originally

Pr
su
lic

es
ic
to

ol
P r proposed by Sunagawa et al. (23), extended by Senzaki
as

an
st
Di

Me
Sy

ur e et al. (24), and proven practical for the RV by Bri-

cP
oli
D iast
2 6
0
1000 2000 0 500 1000
Systemic Resist. Pulmonary Vasc. Resist.
(dyne.s.cm-5) (dyne.s.cm-5)
The increase in the pulmonary arterial resistance and pressure may be a factor 5
compared with about 50% in the systemic circulation. In the pulmonary artery, systolic
and diastolic pressures are about 1.6 and 0.6 times mean pressure, respectively. This
proportionality is not found in the systemic circulation. Left panel was constructed from
data in Table 1 of London et al. (3).
 Compliance can be estimated on the basis of PVR
ndings alone. This relationship makes PVR a reli-
able estimation of load in the pulmonary vascular
system and a valid endpoint in study design.
 In the case of CTEPH, measurement of ow in the
left and right main pulmonary arteries, for instance
by cardiac magnetic resonance (CMR), sufces to
calculate the PVR and the TAC ratio between the
left and right lungs because the ow ratio equals
the inverse PVR ratio.
 Compliance is the most variable component in the
early phase of the development of PH (small PVR
increase) (area A in Figure 2), whereas at high PVR
the compliance changes little with PH severity (area
B in Figure 2). Therefore, changes in (local) pulmo-
nary artery distensibility, as a surrogate for pul-
monary arterial compliance, might serve as an
indication of the development of early pulmonary
vascular disease, even before PVR is increased.
Indeed, in a study by Swift et al. (20), it was sug-
gested that a decrease in pulmonary artery compli-
ance is an early marker of increased PVR.
THE RIGHT HEART
THE COUPLING OF THE RV AND ITS LOAD. The
challenge for the RV in PH is to remain coupled to its
load. A complete description of coupling can be
ress
mioulle et al. (25). The method relies on extrapolation
10 Wood Units
of the measured pressure to a theoretical isovolumic
contraction, Pisovol. This P-V point, in combination
with the end-systolic P-V point, is used to calculate
E es . It should be noted that the estimation of Pisovol has
not been validated in patients with severe PH.
The ventricular load can be estimated from the P-V
relation as arterial elastance (Ea ) (area A in Figure 3),
which is a measure of PVR, namely the PVR/R-R in-
terval or PVR $ heart rate (26), under the assumption
that end-systolic pressure can be approximated by
mPAP (27). Ea is not a measure of compliance, as the
term suggests (Figure 3).
E a is a ventricular-independent measure of arterial
function, and E es is a so-called load-independent
measure of ventricular function, whereas pressure,
CO, and SV are load and heart dependent. Coupling
is a measure of energy transfer (discussed later) and
can be assessed from the ratio between end-systolic
elastance and arterial elastance E es /E a. The single-
beat analysis gives Ees/E a Pisovol /P es  1 (with Pes
being end-systolic pressure); as a further simplica-
tion, P es is often set equal to mPAP.
The slope of the P-V relation at end-diastole, called
end-diastolic elastance (E ed ) (area C in Figure 3),
can be used to characterize diastolic stiffness (27).
A single-beat analysis to obtain Eed has also been
worked out (2729). Thus, RV systolic and diastolic
function, together with the arterial load, can be
studied using P-V information.
THE RESPONSE OF THE RV TO INCREASED LOAD.
Figure 4 depicts the sequence of RV heart failure in
PH. In the early phase of the disease, coupling is
maintained by a 4- to 5-fold increase in contractility
(the E es ) of the RV. Important mechanisms to achieve
this increase in Ees include muscle hypertrophy
leading to an increase in wall thickness, as well as
changes in muscle properties per se. However, if the
disease advances, the hypertrophic process will be
halted and SV decreases (30). The only mechanism to
JACC VOL. 69, NO. 2, 2017 Vonk Noordegraaf et al. 239
JANUARY 17, 2017:23643 The Right Ventricle in Pulmonary Hypertension

C ENTR AL I LL U STRA T I O N Sequence of Events

The Right Ventricle and Its Load in Pulmonary Hypertension

Pulmonary vessel RV adapts To maintain cardiac output, Final stage:

narrowing leads to by increasing RV dilates and heart rate increases Uncoupling occurs
increased vascular muscle contractility Increase in wall stress and oxygen with high metabolic
load on right and wall thickness consumption per gram follow demand and
ventricle (RV) (coupling) reduced output
Leftward septal bowing results

Vonk Noordegraaf, A. et al. J Am Coll Cardiol. 2017;69(2):23643.

The consequence of pulmonary hypertension for the right ventricle. Initially, coupling of the ventricle to the high arterial load is maintained by increasing contractility,
subsequently followed by dilation and nally uncoupling. RV right ventricle.

preserve SV is then RV dilation. In an attempt to However, sensitivities to predict outcomes (as in

maintain CO with the decreasing SV, the heart rate Figure 2) may be different: large changes can be
increases, and because E a PVR $ heart rate, the E a more reliably detected in the presence of mea-
increases, and the ratio E es /E a decreases. Thus, RV surement noise. For instance, SV/ESV may be more
uncoupling will occur in advanced stages of disease
(27), as well during exercise (31). Compared with LV
F I G U R E 2 Schematic Relation Between PVR and TAC
adaptation until heart failure, the RV can remain
coupled for the large increase in load.
The ventricular response to the load also affects
Total Arterial Compliance (ml/mm Hg)

diastolic function. The hypertrophy itself makes the

10
ventricle stiffer, but changes in muscle properties add A
to this effect (29).
CLINICAL RELEVANCE.

 Because uncoupling will only occur in end-stage 5

disease (27,31), the adaptational mechanisms to Increasing PAWP

maintain coupling are more interesting to measure

than the coupling itself. PAWP<10
 Consequently, volumetric measures, including B
PAWP>20
measures of SV, RV end-diastolic volume, and RV 0
0 0.5 1.0 1.5 2.0
end-systolic volume (RVESV), are parameters to be
Pulmonary Vascular Resistance (mm Hg s/ml)
monitored during follow-up of patients with PH.
 Both RV ejection fraction (RVEF) and SV/RVESV
PVR and TAC have an inverse relationship that can be described as PVR $ TAC constant.
meet these criteria, and have been shown to be
This so-called time constant is affected by PAWP. At normal and low PVR (area A),
of high prognostic value. In fact, RVEF and changes in PVR have a large effect on TAC. At high PVR (area B), a similar change in
SV/RVESV are inversely related to each other: resistance has little effect on TAC. PAWP pulmonary artery wedge pressure; PVR
SV/RVESV RVEF/(1  RVEF), and thus should, in pulmonary vascular resistance; TAC total arterial compliance.
principle, contain similar prognostic information.
240 Vonk Noordegraaf et al.
The Right Ventricle in Pulmonary Hypertension
F I G U R E 3 RV Volumes and P-V Relations in Different Stages of PH
B maintained coupling C uncoupled
60
C
Right Ventricular Pressure (mm Hg)
Ees/Ea 1.3
B oxygen
Ees/Ea 2
40
SV
20
Eed
A the RV dilates and pressure increases, both augment-
Ees/Ea 2 Ea RVEDV
Ees
0
0 75 150
Intercept = Vd Vd Vd
Right Ventricular Volume (ml)
(Top) RV volumes at coupled stage and uncoupled stage in pulmonary hypertension.
(Bottom) Representative P-V loops of control, hypertension with maintained coupling
(early stage), and hypertension with increased RV volume. In regions A and B, Ees/Ea is
within normal range, ventriculoarterial coupling is maintained, and wall stress is similar.
In region C, volume is increased, Ees/Ea is decreased (uncoupling), and wall stress is
increased. Ees is the slope of the end-systolic pressure volume relation as measure of RV
contractility, and Ea is a measure of the arterial load (Ea PVR/T PVR $ heart rate). SV is
stroke volume and Vd is the intercept with the volume axis. Diastolic elastance, Eed, is
ventricular elastance at end-diastole, given as the slope of the diastolic P-V relation.
PH pulmonary hypertension; P-V pressurevolume; PVR pulmonary vascular
resistance; RV right ventricle/ventricular; RVEDV right ventricular end-diastolic
volume; SV stroke volume.
sensitive than ejection fraction to changes in RV
function in more severe PH (32).
 Both ejection fraction and SV/RVESP (32,33) are
assuming an E0 es on the basis of a P-V diagram
without a volume intercept (Vd 0). This E0 es
differs from the real Ees (34), and E0 es/Ea is not a
measure of maximal efciency.
 When the RV is in a hypercontractile state to
maintain coupling, decreasing Ea, either by medi-
cation or surgery, would result in an energetically
inefcient situation (uncoupling in the high range).
The RV will prevent this by an decrease in Ees.
Thus, a reduction of contractility in the phase of a
reduction in load by means of medication should
JACC VOL. 69, NO. 2, 2017
JANUARY 17, 2017:23643
be interpreted as an adaptive response of the RV,
rather than a negative inotropic effect of the drug
(35). The load-dependent nature of RV heart failure
is further demonstrated by the fact that unloading
the RV in patients with PH will lead to normaliza-
tion of RV function.
THE CONSEQUENCE OF RV VOLUMETRIC ADAPTATION.
Volumetric adaptation by means of dilation and
reducing SV occurs at the cost of increased
wall tension (stress) and increased pressure. The
consequences of these changes include increased
oxygen consumption, together with deterioration of
efciency, ventricular interaction, and
changes at the myocyte level that increase RV
stiffness. These 3 effects will be detailed in the
following sections.
Increased oxygen consumption and decreased
o x y g e n e f c i e n c y . Oxygen consumption of the RV is
mainly determined by wall tension and PAP (36,37). As
a consequence, oxygen consumption will increase if
ing wall stress. Oxygen supply, on the contrary, is
225 limited in case of PH (38,39). Oxygen consumption of
the RV can be assessed by a short-living oxygen tracer
or, as a surrogate, the acetate tracer. If combined with
right heart catheterization, mechanical efciency,
dened as the ratio of external power and oxygen
consumption, can be calculated. In this formula,
power (work per time) is calculated as PAP $ ow,
and consists of a mean part (mPAP $ CO) and an
oscillatory part. The oscillatory part of the power was
found to be 23% of total power, both in health and in
PH, allowing calculation of total power as mPAP $ CO
(40). RV efciency is normally about 20% to 25% and
decreases with progression of PH as a consequence of
increased oxygen consumption despite a stable power
output (37).
Because mechanical efciency is complex to derive
and requires the measurement of oxygen consump-
tion by means of positron emission tomography, a
surrogate measure might be the Ees /Ea ratio, Figure 3
(26). Sunagawa et al. (26) showed that if this ratio is
between 1 and 2, RV efciency is within normal range.
A ratio above or below this range reects decreased
mechanical efciency and loss of ventriculoarterial
coupling. Altered metabolism, mitochondrial
dysfunction, and inadequate contraction patterns
serve as an explanation for this increased oxygen
consumption (41).
The clinical consequences of these concepts are:
 Total RV power can be calculated as 1.30 mPAP $ CO
(oscillatory power is 23% of total power, thus mean
JACC VOL. 69, NO. 2, 2017 Vonk Noordegraaf et al. 241
JANUARY 17, 2017:23643 The Right Ventricle in Pulmonary Hypertension

power is 77%, that is, total power equals

F I G U R E 4 Changes of the Main Parameters in PAH Progression
100/0.77 1.3 mean power).
 The best way to guarantee long-term survival and normal Coupling maintained Uncoupled
prevent RV failure in patients with PH is to reduce
mPAP.
 Therapies to improve RV oxygen efciency might 500%

be effective in PH.

mPAP, Ees and Volume

 An integrated imaging and invasive approach is
feasible to assess all components of pulmonary Ees/Ea 1
Ees/Ea
100%

Ees/Ea & Stroke Volume

vascular load and RV function in patients (Figure 5).
Stroke Volum
e
V e n t r i c u l a r i n t e r a c t i o n . Although the impact of the mPAP Ees
50%
RV on LV function is negligible under normal condi-
100% Volume
tions, ventricular interdependency plays an important Right Ventricular
role in the pressure overloaded RV. Ventricular inter-
dependency can be caused either by leftward septal Stages of Pulmonary Hypertension
bowing, hampering lling of the LV (parallel interac-
tion), or by decreased lling of the LV due to lowered
During the initial rise in PVR, presented as Ea PVR/T with T heart period (1/heart rate), the
RV SV (series interaction) (42). The primary cause of RV adapts. Adaptation is by increasing Ees due to muscle cross-sectional area and intrinsic
leftward septal bowing is a prolonged contraction time muscle properties. The ratio Ees/Ea is maintained. Later in the process, RV volume increases,
of the RV with respect to LV contraction time (43). By and Ea increases as a result of the increased heart rate and somewhat increasing PVR,
whereas Ees decreases. The ratio Ees/Ea is decreased, implying uncoupling of heart and
using Doppler echocardiography, it has been recog-
load and a decrease in RV efciency. mPAP mean pulmonary artery pressure;
nized for some time that post-systolic isovolumetric
PAH pulmonary arterial hypertension; other abbreviations as in Figure 3.
time is prolonged in advanced stages of PAH (44). As a
consequence of the prolonged isovolumetric contrac-
tion of the RV, early diastolic LV lling is hampered
(42). The main mechanism appears to be increased wall
tension: RV contraction continues while the LV is
F I G U R E 5 Integrated Approach to PH
already in its diastolic phase. As a consequence of the
leftward shift of the septum, the pulmonary valve will
close, even though the RV is still contracting. This so- Cardiac magnetic
resonance
called post-systolic isovolumetric contraction of the Right ventricular (RV)
RV contributes to mechanical inefciency because the mass and volume
energy of the contraction in that phase in the cardiac
cycle is not used for forward ow. The prolongation of RV power,
Uptake
RV elastance,
post-systolic isovolumetric time in PAH, measured by per gram
Wall tension
means of Doppler echocardiography (44), thus should
be considered as a sign of increased wall stress and a
Coupling:
measure of disease severity (45). Metabolism
The clinical consequences of ventricular interdepen- and mechanics Positron emission
Right heart tomography
dency are 4-fold: catheterization Oxygen consumption
Pressures (O2 tracer)
 Measures of ventricular interdependency are clini- Cardiac output Perfusion (H2O tracer)
cally useful to assess disease severity because these Metabolism (FDG, acetate)
parameters contain information on SV and wall
tension. Indeed, several large studies indicate RV mechanical
that LV volumetric parameters have important efficiency:
Power/oxygen
prognostic information in addition to RV function
consumption
measures (4649). Parameters that incorporate
post-systolic isovolumetric time, such as the
This gure illustrates how, by combining imaging and invasive modalities, a full
myocardial performance index (an index that in-
physiological assessment of the load of the pulmonary circulation and right ventricular
corporates both systolic and diastolic time intervals function can be derived. FDG uorodeoxyglucose; PH pulmonary hypertension;
in expressing global systolic and diastolic ventric- RV right ventricular.
ular function) are of clinical relevance (44,50).
242 Vonk Noordegraaf et al. JACC VOL. 69, NO. 2, 2017

The Right Ventricle in Pulmonary Hypertension JANUARY 17, 2017:23643

 Underlling of the LV will bring the myocytes in an
atrophic state. Recent research showed that this
state is characterized by changes in cardiac muscle
properties (51). Therefore, special attention is
required if the RV is unloaded, as this might induce
LV failure (52).
 Restoring ventricular interdependency by means
of pacing will increase mechanical efciency. This
concept has only been tested in small cohorts of
patients (53).
 The importance of the LV in PH is underlined by
the fact that SV is closely related to LVEDV, and not
to RV end-diastolic volume (54).
Series interdependency of LV and RV in LV failure
has recently been discussed in detail (54).
I n c r e a s e d s t i f f n e s s . Finally, the increased wall
tension reects increased RV cardiomyocyte stress.
Although it is not possible to measure cardiomyocyte
stress directly, methods are available to derive local
strain (shortening) by CMR (43) and strain echo (55).
New techniques under development to measure ber
orientation in the ventricular wall (56) and to derive
wall stiffness, such as ultrasound-based elastography
(57) are promising, but have not yet been applied in
the context of PH. Myocyte stress is the basis of right
heart failure in PH because stress is the main driver of
molecular changes in the myocyte, including neuro-
humoral activation, which leads to increased stiffness
of the RV (29). Although right atrial pressure and
volume can be considered as surrogate measures of
RV stiffness, those measures are load dependent.
Increased diastolic stiffness, expressed as E ed , is
associated with a poor prognosis (27,31). Studies by
Trip et al. (27) and Rain et al. (29) showed that dia-
stolic stiffening occurs in the advanced disease state,
and is the consequence of molecular changes in the
cardiomyocyte, as well as hypertrophy.
CONCLUSIONS
This review shows that the need of the RV to remain
coupled to its load explains the RV changes in PH.
Because the load can increase by more than 5-fold in
this disease, coupling can only be achieved by an
almost similar increase in contractility. In the more
advanced disease state, RV contractility is maintained
by ventricular dilation in an attempt to limit the
reduction in SV. The consequence of these adapta-
tions is an increase of myocyte stress and leftward
septal bowing, impairing LV and RV function. It is the
uncoupling with high metabolic demand and reduced
output that heralds the nal stage.
Combining CMR (positron emission tomography,
Doppler echocardiography) and hemodynamic mea-
surements via catheterization (even single-beat
analysis) offers the potential for a full assessment of
pulmonary vascular load and right heart function, as
required for evaluation of the hemodynamic state in
patients with PH. In the stages of PH when coupling is
still present, RV volume may be the most sensitive
prognostic measure (47).
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Anton Vonk Noordegraaf, Department of Pulmo-
nary Diseases, VU University Medical Center, De
Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
E-mail: a.vonk@vumc.nl.

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KEY WORDS compliance-resistance
relation, pulmonary arterial system, right
heart failure, ventriculoarterial coupling