Download Exercise stress tests for detection and evaluation of pulmonary

European Heart Journal Supplements (2007) 9 (Supplement H), H17–H21
doi:10.1093/eurheartj/sum024
Exercise stress tests for detection and evaluation
of pulmonary hypertension
Sandrine Huez1,2* and Robert Naeije1,2
1
Department of Cardiology, Erasme University Hospital, Brussels, Belgium
Department of Pathophysiology, Faculty of Medicine of the Free University of Brussels, Erasme Campus, CP 604, 808,
Lennik Road, B-1070 Brussels, Belgium
2
KEYWORDS
Pulmonary vascular
resistance;
Pulmonary arterial
pressure–flow
relationships;
Pulmonary hypertension;
Exercise;
Echocardiography;
Dobutamine
The use of an exercise stress test in the diagnosis or evaluation of pulmonary
hypertension rests on the assumption that multipoint mean pulmonary artery
pressure (mPpa)–flow (Q) plots are superior to isolated pulmonary vascular resistance
determinations for the evaluation of the functional state of the pulmonary circulation. A multipoint mPpa–Q relationship is best described by a linear approximation
and, as such, characterized by an extrapolated pressure intercept and by a slope.
Both are dependent on the method used to increase flow. The slope is higher and
the pressure intercept lower when exercise is used to increase flow, rather than unilateral pulmonary artery balloon occlusion or low-dose dobutamine. This is because
of exercise-induced pulmonary vasoconstriction. The steepest slopes, i.e. the highest
pressures at a given flow, are obtained by resistive exercise (handgrip) when compared with dynamic exercise (cycling) because of systemic vascular resistance
and intrathoracic pressure changes. Since systolic, diastolic, and mean pulmonary
artery pressures are tightly correlated and since in experienced hands, systolic pulmonary artery pressures and cardiac output are reliably measured using Doppler
echocardiography, mPpa–Q lines can be obtained non-invasively. The exercise
stress test for non-invasive diagnosis of pulmonary hypertension may be particularly
useful for the detection of early disease and for more accurate quantification of
pulmonary vascular changes induced by disease progression and/or therapeutic
interventions.
Physiology of pulmonary vascular
pressure–flow relationships
The pulmonary circulation is a low-pressure and high-flow
circuit which accommodates the entire cardiac output
(Q) as driven by a pressure difference between an
inflow pressure or mean pulmonary artery pressure
(mPpa) and an outflow pressure or mean left atrial
pressure (Pla). The functional state of the pulmonary
circulation can be evaluated by the calculation of pulmonary vascular resistance (PVR) as a ratio between
the mPpa–Pla difference and Q. This is actually an
* Corresponding author. Tel: þ32 2 5556363.
E-mail address: [email protected]
extrapolation of Poiseuille’s law, which describes streamlined pressure–flow relationships for Newtonian fluids
(flow-independent viscosity) in thin, smooth-walled
rigid tubes with circular surface section areas. In such
a system, the relationship between the difference
between inflow and outflow pressures is linearly related
to flow, and the pressure difference–flow line crosses
the origin.
The pulmonary vessels are collapsible, pulmonary
blood flow is pulsatile, and blood is not a Newtonian
fluid. However, multipoint (mPpa–Pla) vs. Q coordinates
have been shown to be normally well described by a
linear approximation, with an extrapolated zero flow
pressure of zero. Therefore, in normal lungs, PVR is not
dependent on the absolute level of pressure or flow.
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: [email protected]
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However, hypoxia and a variety of pulmonary and cardiac
diseases are associated with increases in both the slope
and the extrapolated pressure intercepts of (mPpa–
Pla)–Q relationships. The calculation of a PVR then
becomes inherently pressure- or flow-sensitive, and multipoint mPpa–Q or (mPpa–Pla)–Q plots are preferable to
isolated PVR determinations to describe the evaluation of
the functional state of the pulmonary circulation.1,2 This
reasoning was applied by Castelain et al.3 to explain the
discrepancy between the early functional improvement
of patients suffering from idiopathic pulmonary arterial
hypertension (PAH) with prostacyclin therapy and the
absence of significant changes in resting PVR. After 6
weeks of treatment in seven patients, epoprostenol
improved the 6 min walked distance by 81 + 54 m
(P ¼ 0.0012 vs. baseline), did not affect resting PVR,
but significantly decreased the slope of (mPpa–Pla)–Q
relationships during exercise (Figure 1).
What are the limits of normal of pulmonary vascular
pressure–flow relationships? Reeves et al.4 reviewed
available data from exercise right-heart catherization
studies in a total of 93 normal healthy volunteers and
found an average slope of mPpa–Q of 1 mmHg/L/min in
young adults to 2.5 mmHg/L/min in old subjects. The
data also showed an mPpa–Pla relationship of approximately 1. In fact, much of the age-related increase in
the slope of exercise mPpa–Q relationships is explained
by an increase in Pla.4 On the other hand, PVR increases
with ageing, with an average doubling over five decades
of life.5 This is explained by the effects of a decrease
in resting Q on (mPpa–Pla)–Q relationship with a zero
flow positive pressure intercept.5
The interpretation of pulmonary vascular pressure–
flow relationships refers to two different models. The
Figure 1 Relationship between mean pulmonary artery pressure (PAP)
and cardiac index before (closed circles) and after (open circles) 6
weeks of prostacyclin therapy in seven patients with idiopathic pulmonary arterial hypertension. (From Castelain et al.,3 with permission.)
S. Huez and R. Naeije
waterfall model, or Starling resistor, explains extrapolated pressure intercepts by vascular closure.6 Because
pulmonary arterioles are collapsible vessels with tone,
flow driven by the inflow pressure (mPpa) has to exceed
a closing pressure that may be higher than Pla as an
(apparent) outflow pressure. At low flow, pulmonary
arterioles are progressively de-recruited, accounting for
a progressively steeper mPpa–Q curve. At higher flow,
completed recruitment and negligible distension
account for a linear mPpa–Q curve, with an extrapolated
pressure intercept higher than Pla representing a
weighted mean of closing pressures. The alternative
viscoelastic model explains the shape mPpa–Q curves
by changes in haematocrit, resistance, and compliance.7
This model predicts a close-to-linearity of mPpa–Q
relationships within the normal range or above, but a
progressively steeper concavity to the flow axis with
decreasing flow. Therefore, the best fit of mPpa–Q coordinates generated at normal flows is linear, but allows for
an artefactual positive pressure extrapolation. It may be
that both models coexist in reality. However, there is
uncertainty, as always, on the validity of extrapolations,
and the optimal description of the functional state of the
pulmonary circulation has to be limited to interpolated
mPpa–Q lines or comparisons of pressures at determined
levels of flows.5
Methods to increase flow for the study
of Ppa–Q relationships
The initial attempts to describe the functional state of
the pulmonary circulation by a pressure–flow line took
advantage of unilateral balloon occlusions, which were
routinely practised a few decades ago to test for the
right ventricular tolerance to pneumonectomy. The
occlusion manoeuvre doubled the flow in the contralateral lung, for which therefore a purely passive two-point
pressure–flow plot could then be derived. These studies
clearly demonstrated that most cardiac and pulmonary
diseases and hypoxic breathing shifted pulmonary vascular pressure–flow plots to higher pressures, with positive
pressure intercepts invalidating the use of PVR to evaluate pulmonary hypertension at variable flow in all these
circumstances.8,9 Unilateral balloon occlusions are not
used anymore. However, a purely passive pulmonary vascular pressure–flow relationship can be obtained by a
low-dose dobutamine infusion. Experimental animal
studies have shown that at doses lower than 10 mg/kg/
min, dobutamine has no intrinsic effect on PVR or
compliance.10
Pulmonary vascular pressure–flow relationships can
also be generated during exercise to increase flow.
However, high levels of exercise are associated with
acidosis, decreased mixed venous oxygenation, and activation of the sympathetic nervous system, all of which
can be causes of pulmonary vasoconstriction. This is
why, in PAH patients, exercise mPpa–Q plots are
steeper than dobutamine mPpa–Q plots, as illustrated
in Figure 2.11 Accordingly, exercise-induced pulmonary
vasoconstriction also may lead to spuriously decreased
Exercise haemodynamics in pulmonary hypertension
or even negative pressure intercepts.11,12 In heart failure
patients with pulmonary hypertension, further increases
in Pla at exercise also increase the slopes and decrease
pressure intercepts of mPpa–Q plots.12,13
It is also important to mention the type of exercise
used to generate mPpa–Q plots. Dynamic exercise, such
as cycling or walking, is associated with an increase in
cardiac output and in heart rate in proportion to
oxygen consumption (VO2), with an increase in systolic
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but no change in diastolic systemic arterial pressure.14,15
Resistive exercise, such as handgrip efforts or weight
lifting, does not increase very much cardiac output,
heart rate, or VO2, but markedly increases systolic as
well as diastolic systemic arterial pressure and may be
associated with positive intrathoracic pressures.15
Therefore, although this has not been systematically
investigated, the physiology of heart–lung interactions
predicts that resistive exercise increases mPpa at a
given flow much more than dynamic exercise and is less
adequate for the evaluation of the functional state of
the pulmonary circulation.
Non-invasive exercise stress tests for
detection and evaluation of pulmonary
hypertension
Figure 2 Mean pulmonary artery pressure (mPpa)–flow (Q) plots with
cardiac output increased by exercise or by low-dose intravenous dobutamine in patients with idiopathic pulmonary arterial hypertension. The
mPpa–Q coordinates are best described by linear approximations, but
present with steeper slopes and lower pressure intercepts when cardiac
output is increased by exercise. (From Abdel Kafi et al.,11 with
permission.)
Pulmonary artery pressures can be estimated from
Doppler echocardiographic measurements.2 The most
commonly used is based on the estimation of a systolic
pulmonary artery pressure (sysPpa) from the maximum
velocity of tricuspid regurgitation.16 A mPpa can also
be calculated from the acceleration time17 or from the
peak pulmonary artery regurgitant velocity of pulmonary
blood flow.18 However, these two methods have not been
reported for Ppa estimation during exercise, probably
because of the heart rate dependence of the acceleration time measurement and because of the technical
difficulty to acutely record the pulmonary artery regurgitant Doppler flow.
Figure 3 Exercise stress test tricuspid regurgitant jets and aortic flows, and derived mean pulmonary artery pressure (mPpa)–cardiac output plots, in a
normal subject, in a patient suffering from systemic sclerosis (SSc) and pulmonary arterial hypertension confirmed by measurement of a Ppa . 30 mmHg
at exercise right-heart catheterization, and in a patient suffering from advanced pulmonary arterial hypertension.
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S. Huez and R. Naeije
Exercise Doppler echocardiographic studies usually
report on Ppa measurements as a function of load
instead of flow.19,20 Although this maintains the value
of exercise as a stress test, it loses accuracy for the
evaluation of the pulmonary circulation because of interindividual variability of workload vs. cardiac output
relationships.21 Bossone et al.20 showed that trained athletes may present with higher sysPpa at a given workload,
or cardiac output, than non-athletic controls. This intriguing observation is explained by a larger stroke
volume in the athletes, together probably with a more
important exercise-induced Pla in non-athletic controls.
On the other hand, tricuspid regurgitation velocity is a
cardiac output-dependent measurement. This was illustrated in a study on normal volunteers, in whom
low-dose dobutamine increased sysPpa estimated from
tricuspid regurgitant jets but not mPpa from the acceleration time of pulmonary blood flow, whereas hypoxia
increased both sysPpa and mPpa estimations.22 These
results underscore limitations of sysPpa estimated from
tricuspid regurgitation in the evaluation of pulmonary
haemodynamics.
Recently, Chemla et al.23 studied the relationship
between sysPpa and mPpa recorded with high-fidelity
micromanometer in 31 patients suffering from PAH over
a wide range of Ppa. They showed a tight correlation
between the sysPpa measured and the mPpa, defined as
the area under the pressure curve divided by the pulse
interval. Therefore, it is possible to calculate mPpa
from sysPpa using the equation23:
mPpa ¼ 0:6 sysPpa þ 2 mmHg
With a measurement of cardiac output, it then seems
possible to calculate a ‘total’ PVR as mPpa/Q. Exercise
Doppler echocardiography for measurements of Ppa and
Q is difficult because of motion artefacts, but is feasible
with patients adequately installed in an exercise
chair.19,20 An exercise test with the presentation of
aortic flows and tricuspid regurgitant jets at progressively increased workload, and derived mPpa–Q relationship is illustrated in Figure 3.
Conclusions
A recent European Society of Cardiology Task Force
report defined PAH on the basis of an mPpa higher than
25 mmHg at rest and 30 mmHg at exercise, a Pla of less
than 15 mmHg at rest, and a PVR of more than 3 Wood
units at rest.24 These numbers are quite arbitrary,
especially the upper limit of normal of 30 mmHg for
mPpa at exercise.5 On the other hand, although the
rationale of exercise stress tests of the pulmonary circulation for the diagnosis and evaluation of pulmonary
hypertension is strong, the approach is currently handicapped by insufficient reference data for the definition
of limits of normal.
Acknowledgements
The authors’ research work presented in this paper has been supported by Grant 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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