Download Right ventricular function in pulmonary

European Heart Journal Supplements (2007) 9 (Supplement H), H5–H9
doi:10.1093/eurheartj/sum023
Right ventricular function in pulmonary hypertension:
physiological concepts
Robert Naeije* and Sandrine Huez
Department of Pathophysiology, Faculty of Medicine, Free University of Brussels, Erasme Campus,
CP 604, 808, Lennik Road, B-1070 Brussels, Belgium
KEYWORDS
Pulmonary vascular
resistance;
Pulmonary vascular
impedance;
Right ventricular function;
Arterial elastance;
Contractility;
Pulmonary hypertension
The symptoms of pulmonary hypertension are explained by a decrease in cardiac
output caused by an afterload-induced right ventricular (RV) failure. However, the
standard haemodynamic evaluation of pulmonary hypertension, with measurements
of mean pulmonary vascular pressures and cardiac output, does not capture the determinants of RV function. Right ventricular afterload can be measured either as a
hydraulic load calculated from spectral analysis of pulmonary artery pressure and
flow waves, or as a maximal wall tension estimated from instantaneous ventricular
pressure, volume, and wall thickness measurements. The adequacy of ventricular
adaptation to afterload can be assessed by a measurement of the matching of systolic
function to arterial elastance. The difficulty in measuring instantaneous RV volume is
overcome using a single-beat method, which derives a systolic pressure–volume
relationship from instantaneous RV pressure and an integration of pulmonary arterial
flow. On such a pressure–volume curve, it is easy to determine graphically end-systolic
elastance (Ees, end-systolic pressure on end-systolic volume), as a load-independent
measure of contractility, and arterial elastance (Ea, end-systolic pressure on stroke
volume), as a measure of afterload. The optimal value of the Ees/Ea ratio, compatible
with flow output at a minimal energy cost, is between 1 and 2. Patients with severe
pulmonary hypertension present with a decreased elastance ratio, in spite of an adaptative increase in systolic function, which underscores that RV failure in the face of
increased afterload is a relative notion. Further studies are needed to confirm that
right ventriculo-arterial decoupling accounts for a decreased aerobic exercise
capacity by a limitation of cardiac output adaptation to peripheral demand.
Cardiac limitation to exercise capacity
in pulmonary hypertension
Pulmonary hypertension, as defined by an increase in
mean pulmonary artery pressure (PAP) .25 mmHg at
rest and/or 30 mmHg at exercise, complicates a variety
of cardiac and pulmonary conditions, but may occur as
a consequence of an isolated pulmonary arteriolar vasculopathy and is then called pulmonary arterial hypertension (PAH).1 The condition is either idiopathic (IPAH,
formerly primary pulmonary hypertension) or occurs in
* Corresponding author. Tel: þ32 2 5553322; fax: þ32 2 5554124.
E-mail address: [email protected]
association with a variety of diseases or circumstances,
which include human immuno-deficiency syndrome,
intake of fenfluramines, connective tissue disease,
portal hypertension, and congenital cardiac shunts.1
Increased pulmonary vascular resistance (PVR) in PAH is
associated with a progressively severe symptomatology
of dyspnea, fatigue, chest pain, syncope, and right
heart failure.
It is remarkable that extensive vascular remodelling in
PAH has actually little effect on pulmonary gas exchange.
Studies using the sophisticated multiple inert gas elimination technique have shown that the distribution of ventilation/perfusion (VA/Q) relationships in these patients
is close to normal,2,3 the low normal arterial PO2 being
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: [email protected]
H6
essentially to be accounted for by a low-mixed venous
PO2, consequence of a low cardiac output.2,3 In some
patients, there is hypoxaemia because of a right-to-left
shunt through a patent foramen ovale.3 In spite of vascular obliteration, physiological dead space remains
normal, at rest as well as at exercise.4 Patients with
PAH hyperventilate, accounting for a typically low arterial PCO2, at rest as well as at exercise, but still do not
present with a ventilatory limitation to exercise
capacity.5,6
Pulmonary arterial hypertension is associated with a
decrease in exercise capacity and a low cardiac output.
The maximum capacity of an individual to perform
aerobic work is defined by the maximum O2 consumption
(VO2max), the product of maximum cardiac output by the
arterio-venous O2 content difference (CaO2 2 CvO2).
Because of the sigmoid shape of the oxyhaemoglobin dissociation curve, with high affinities for O2 at high and at
low saturations, there is an inferior limit of CvO2 attained
at the highest level of exercise. On the other hand, a
VO2max is achieved on a bicycle with about half of the
body’s muscles, and there is no data to suggest a skeletal
muscle limitation to exercise capacity in cardiac or in
pulmonary patients. It is therefore reasonable to
assume that aerobic exercise capacity in PAH patients is
essentially limited by cardiac output, or in case of
exercise-induced hypoxaemia, by the product of cardiac
output by CaO2.7 As there is a linear relationship
between the running or walking speed and VO2, a 12
min run8 or a 6 min walk9 distance can be used as a surrogate of VO2max.7 Both the VO2max and the 6 min walk
distance reflect the ability of the RV to increase flow
output in response to peripheral O2 demand; exercise
testing in PAH provides an indirect estimate of RV
performance.
The gold standard for the evaluation of patients with
PAH is a right heart catheterization with measurements
of pulmonary vascular pressures and cardiac output,
and calculation of PVR.1 These measurements allow for
the quantification of the severity of pulmonary vascular
disease, but PVR provides only partial description of all
the forces that oppose RV flow output (or afterload),10
and cardiac output is determined by loading conditions
in addition to intrinsic changes in RV function.11 It is
therefore understandable that standard haemodynamic
measurements in patients with PAH are only loosely
correlated to clinical state, functional class, exercise
capacity, and prognosis, and often fail to reach significance on mean PAP.9,12–15 Measurements at exercise
may provide more clinically meaningful results,16 probably because an exercise-induced increase in cardiac
output may more closely reflect the functional capability
of the afterloaded RV.
Right ventricular failure in pulmonary
hypertension
Right ventricular (RV) afterload results from a dynamic
interplay between resistance, elastance, and wave
reflection.10 An acceptable measurement of RV afterload
R. Naeije and S. Huez
is given by pulmonary arterial input impedance (PVZ),
which is the ratio of pulsatile PAP to pulsatile flow.10
The calculation of PVZ requires a spectral analysis of
pressure and flow waves and a mathematical elaboration
to derive a PVZ spectrum, which is expressed as a ratio of
pressure and flow moduli and a phase angle, both as a
function of frequency. The method has been applied to
patients with PAH,17,18 but is complicated, and requires
expensive high-fidelity technology that is not available
in most catheterization laboratories. The clinical relevance of PVZ determinations is unknown.
Right ventricular afterload can easily be evaluated by
PAP and flow waveform analysis in the time domain.
Increased pulmonary arterial elastance and wave reflection decrease the acceleration time, cause late or midsystolic deceleration of pulmonary arterial flow waves,
and increase pulse pressure and late systolic peaking of
pulmonary arterial pressure waves.10 Shortened acceleration times of pulmonary arterial flow have been
associated with decreased survival in a small series of
PAH patients.19 Increased pulse pressure has been
reported to help in the differential diagnosis between
PAH and chronic thrombo-embolic pulmonary hypertension, whether pressures are directly measured during a
right heart catheterization,20 or re-calculated from
tricuspid and pulmonary regurgitant waves and the
simplified form of the Bernouilli equation.21 Refined
indices of wave reflection such as the time to inflection
point of the upstroke of RV pressure or the (peak pressure
minus inflection point pressure) referred to mean PAP
(called the ‘augmentation index’) may also be useful.22
However, discrepant results have been reported22,23 and
therefore the diagnostic value of pulmonary pressure
waveform analysis remains uncertain.
Instead of trying to quantify the RV afterload by
pulmonary pressure wave analysis, it might be more
appropriate to quantify the RV function directly and to
couple to the pulmonary circulation. Sunagawa et al.11
showed that this can be done graphically using a ventricular pressure–volume diagram. The diagram allows
for the determination of maximal or end-systolic ventricular elastance (Ees), which is the best possible
load-independent measurement of contractility, of arterial elastance, Ea, as a measurement of afterload as it is
‘seen’ by the ventricle, and of the calculation of an
Ees/Ea ratio as a measurement of the coupling of ventricular to arterial function. Complex mathematical modelling shows that the optimal matching of systolic
ventricular and arterial elastances occurs at an Ees/Ea
ratio of 1.5. Isolated increase in Ea, or decrease in
Ees, decreases the Ees/Ea ratio, indicating uncoupling of
the ventricle from its arterial system. Everything else
being the same, a decrease in Ees/Ea is accompanied
by a decrease in stroke volume. On the other hand, an
isolated increase in preload is associated with an increase
in stroke volume with unaltered ventriculo-arterial
coupling.
However, the complex geometry of the RV makes functional evaluations with measurement of instantaneous
volume changes technically difficult, and the determination of Ees may be unreliable because of the triangular
Right ventricular function in pulmonary hypertension
H7
shape of the RV pressure–volume loop resulting from the
fact that RV ejection continues after end-systole. This
problem can be overcome by measuring pressure–volume
loops at several levels of preload,24 but bedside manipulations of venous return are too invasive to be ethically
acceptable. In addition, when applied to intact
animals, changes in venous return are associated with
reflex sympathetic nervous system activation, which
affects the ventricular function that is measured. These
concerns have been addressed by a most recently
reported single-beat method allowing for a direct quantification of the coupling of the RV to the pulmonary circulation.25 The approach had initially been proposed for the
left ventricle by Sunagawa et al.26 In its principle, the
method avoids absolute volume measurements and
related technical complexities, to calculate Ees and Ea
from instantaneous RV pressure and flow output measurements. As shown in Figure 1, a Pmax is estimated from a
non-linear extrapolation of the early and late systolic
isovolumic portions of the RV pressure curve. This estimated Pmax has been shown to be tightly correlated
with Pmax directly measured during a non-ejecting
beat.25 A straight line drawn from Pmax to the RV pressure
vs. relative change in volume curve allows for the determination of Ees. A straight line drawn from the Ees point
to the end-diastolic relative volume point allows for the
determination of Ea.
The Ees/Ea ratio determined by the single-beat method
is 1.5, which is similar to values reported for left
ventricular-aortic coupling, and compatible with an
optimal ratio of mechanical work to oxygen consumption.11 The Ees/Ea ratio is decreased by propranolol and
increased by dobutamine, and maintained in the
presence of increased Ea because of hypoxic pulmonary
vasoconstriction.25 In fact, Ees increases adaptedly to
increased Ea in hypoxia, even in the presence of
adrenergic blockade, which is compatible with the
notion of homeometric adaptation of RV contractility.25
On the other hand, the approach allows for the demonstration that clinically relevant doses of dobutamine do
not affect pulmonary arterial hydraulic load.25,27 The
single beat approach has also already been used to
show the superiority of dobutamine over norepinephrine
to restore right ventriculo-arterial coupling in acute right
heart failure produced by a brisk increase in PAP.27 Also,
the optimal values for the Ees/Ea ratio were shown to be
well maintained in piglets with PAH induced by 3 months
systemic to pulmonary shunting, without or with
endothelin receptor blocker therapy.28 Furthermore,
the method showed that, in contrary to the current
belief,29 prostacyclin iv has no intrinsic positive inotropic
effects on the right ventricle.30 The single-beat method
was also applied to an asymptomatic patient with congenitally corrected transposition of the great arteries.31
The coupling between the native RV and the systemic
arterial system was shown to be altered, with an Ees/Ea
ratio down to 1.16, whereas the native LV was perfectly
coupled to the pulmonary arterial system with an Ees/Ea
of 1.67 (Figure 2). This observation suggested that an
RV coupled to a high-pressure arterial system from birth
is nevertheless chronically uncoupled, probably because
of inherent structural characteristics, accounting for
eventual clinical heart failure and decreased life
expectancy.
Practically, all that is needed to determine single-beat
Ees/Ea ratios is measurements of instantaneous pulmonary
blood flow and RV pressure. This is feasible by echocardiography. Doppler pulmonary flow measurements synchronized to invasively measured PAPs have been reported to
allow for accurate pulmonary arterial impedance calculations.18 Right ventricular pressure can be re-calculated
from the envelope of tricuspid regurgitant jets and
point-by-point application of the simplified form of the
Bernouilli equation.32 However, the entirely non-invasive
Doppler echocardiographic determination of Ees/Ea ratios
in patients has not yet been validated. Most recently,
Figure 1 Instantaneous measurements of right ventricular pressure and
relative changes in volume in a dog, with calculation of a maximum
ventricular pressure (Pmax) and graphical determinations of end-systolic
elastance (Ees) and arterial elastance (Ea), leading to a ratio of elastances
of 1.7. (Adapted from Brimioulle et al.25, with permission.)
Figure 2 Right ventricular-aortic artery and left ventricular-pulmonary
artery coupling in a patient with congenitally corrected transposition.
The ratio of elastances is decreased for the native right ventricle (Ees/
Ea ¼ 1.2) and normal for the native left ventricle (Ees/Ea, 1.7).
(Adapted from Wauthy et al.31, with permission.)
H8
R. Naeije and S. Huez
performance (calculated as the sum of isovolumetric contraction and relaxation times divided by stroke volume),
right heart chamber dimension measurements, which are
determined by both systolic and diastolic function
changes at given levels of load, circulating biomarkers
such as brain natriuretic peptide, which are released by
myocardial stretch, and even heart rate variability which
is affected by neurohumoral activation in (right) heart
failure. However, there was a mention of pressure–volume
or pressure–area loops, much closer to intrinsic RV function and its adaptation to loading conditions, and the
report evoked the interest of tissue Doppler imaging. The
importance of the RV ventricle in cardiovascular diseases
was underscored, and there was a call for more translational cellular and molecular research with improved definition of parameters of function.34
Symptoms of pulmonary hypertension are predominantly caused by RV dysfunction. The evaluation of pulmonary hypertension by the steady flow haemodynamic
approach and a calculation of PVR is essential to the
accurate measurement of resistive vessel obstruction,
but does not accurately explain the RV’s adaptation
to an associated increase in afterload. This can be
accomplished using newer non-invasive methods, methods
needing urgent validation.
Acknowledgements
Figure 3 Right ventricular pressure–volume loops showing in a patient
with pulmonary arterial hypertension and in a control, showing uncoupling of the right ventricle in the patient in spite of an increased contractility. The figure also shows MRI imaging of the right ventricle. (Adapted
from Kuehne et al.33, with permission.)
Kuehne et al.33 used magnetic resonance imaging together
with RV pressure measurements to generate pressure–
volume loops and to determine Ees and Ea values in patients
with PAH. As compared with controls, RV Ees was increased
from 5.2 + 0.9 to 9.2 + 1.2 mmHg/mL per 100 g (P , 0.05),
but RV Ees/Ea was decreased from 1.9 + 0.4 to
1.1 + 0.3 (P , 0.05), indicating an increased RV contractility in response to increased afterload that was,
however, insufficiently coupled to its hydraulic load,
with inefficient mechanical work production (Figure 3).
It will be interesting to correlate these findings to
newly developed tissue Doppler indices of RV function.
Conclusions
A most recent report of a National Heart, Lung and Blood
Institute Working Group on Cellular and Molecular
Mechanisms of Right Heart Failure identified a series of
markers of RV dysfunction associated with clinical
status and prognosis.34 The list included both load- and
contractility-sensitive RV function measurements such
as ejection fraction, tricuspid annular velocity or excursion, dP/dt, tricuspid regurgitation, and the index of
The work was supported by Grant no. 3.4551.05 from the Fonds
de la Recherche Scientifique Médicale and by the Foundation for
Cardiac Surgery. S.H. is a fellow of the Fonds National de la
Recherche Scientifique, Belgium.
Conflict of interest: none declared.
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