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Introduction
Exercise pulmonary hypertension (ePH) is an underappreciated form of exertional
limitation that results in symptoms with physical activity and a reduction in aerobic
exercise capacity [1–4]. ePH is a clinical syndrome that may reside on a continuum
between normal resting hemodynamics and manifest pulmonary arterial hypertension
(PAH). An abnormal pulmonary vascular response during exercise delineates ePH
from normal resting hemodynamics. At the present time there are no uniformly
established definitions of ePH; however, there has been a recent interest in reviving
a definition of ePH.
At the fourth World Symposium on Pulmonary Hypertension in Dana Point (CA,
USA) in 2008 the definition of “exercise-induced pulmonary hypertension” of mean
pulmonary artery pressure (mPAP) >30 mmHg was abandoned due to the lack of a
unified diagnostic approach, concerns pertaining to normal aging and changes in
hemodynamics, as well as the need for more precise hemodynamic cutoffs [5, 6].
The subsequent fifth and sixth World Symposium on Pulmonary Hypertension both
held in Nice, France, in 2013 and 2018 did not provide a working definition of
ePH. The task force concluded that exercise challenge is beneficial methodology to
unmask pulmonary vascular disease in patients with normal resting hemodynamics
that are early in the disease state or well-compensated. They recommended that
additional studies be performed to further refine the clinical syndrome of ePH [7, 8].
Exercise pulmonary hypertension (ePH) describes elevated right-sided filling
pressures during exertion and is preferred to the older terminology “exerciseinduced pulmonary hypertension.” The latter has implications that exercise has a
causative role in the pulmonary vascular disease [9].
It may make sense to use the term exercise pulmonary arterial hypertension (ePAH) to primarily distinguish
abnormally elevated right-sided filling pressures during exercise from exercise pulmonary venous hypertension (ePVH); however, this terminology has not been
widely adopted in recent statement on pulmonary hemodynamics during exercise [9].
Patients at risk for developing ePH include systemic sclerosis [10, 11], chronic
PE [12, 13], parenchymal lung disease (including ILD [3] and COPD [14, 15]),
HFpEF [16, 17], HFrEF [18, 19], atrial septal defects [20], valve disease [21, 22],
family members of patients with iPAH [17], and asymptomatic carriers of the
BMPR2 gene mutation [23]. These groups are representative of the types of patients
that may benefit from confrontational exercise testing, especially when resting
supine invasive hemodynamics are either normal or borderline elevated. There is
irony that the workup of patients with symptomatic exertion includes a majority of
procedures performed at rest. It is therefore intuitive that the workup of symptomatic dyspnea may include exercise stress testing. Our preference is to perform invasive cardiopulmonary exercise testing (iCPET), which in the vast majority of cases
provides real pathophysiological insight into the condition contributing to patient’s
symptoms and helps make a diagnosis. There have been significant scientific contributions in the literature that have helped define normal and abnormal values in ePH
to help move the field of invasive exercise testing forward [1, 3, 12, 18, 24–26].
Ongoing work in the field may ultimately result in the restitution of a definition of ePH.
This chapter will focus on the controversial topic of exercise pulmonary hypertension, in particular the precapillary (arterial) syndrome measured by invasive cardiopulmonary hemodynamics. Normal resting hemodynamic values and borderline
pressures will be addressed. The specifics of ePH and the clinical impact of ePH
will be discussed. Unresolved questions and controversies regarding ePH will be
covered. The evidence for treatment of ePH will be presented. Finally, methods to
assess invasive exercise hemodynamics will be discussed. Topics of exercise pulmonary hypertension in the setting of specific disease states such as parenchymal lung
disease, parenchymal lung disease, and left heart disease will be touched upon in
this chapter but will not be completely addressed.
Normal Resting and Exercise Pulmonary Hemodynamics
What Is the Normal Pulmonary Vascular Response to Exercise?
One of the initial impediments to defining ePH was the lack of consensus for a
normal resting pulmonary artery pressure. This concern has since been reconciled. At rest under normal conditions the pulmonary vasculature is a low-pressure
high capacitance system. A landmark systematic review of the available literature by Kovacs et al. included 1187 healthy individuals with invasively measured
M. G. Risbano
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hemodynamics and showed that normal resting mPAP ± SD is 14 ± 3.3 mmHg in
the supine position and 13.6 ± 3.1 mmHg in the upright position [6]. In the supine
position the upper limit of normal was 20.6 mmHg and 19.8 mmHg in the upright
position. Resting mPAP was independent of gender. Based upon these findings, the
sixth World Symposium on Pulmonary Hypertension redefined resting pulmonary
arterial hypertension as mPAP >20 mmHg, PVR >3 WU with a pulmonary artery
wedge pressure (PAWP) ≤15 mmHg [8].
The same review by Kovacs and colleagues showed that the upper limit of normal during exercise stress testing was dependent on the intensity of exercise with
mPAP of 28.8 mmHg in the upright position with slight exercise and 36.8 mmHg at
maximal exercise [6]. This amounted to 47% of the 91 normal subjects aged
>50 years with an mPAP >30 mmHg in the “slight” exercise category. Of the 193
subjects with more than one level of exercise performed the mPAP was >30 mmHg
in 21% of subjects aged <50 years at maximal exercise. Thus, it was concluded that
the previous definition of mPAP >30 mmHg was not valid and there was no established upper limit of normal mPAP during exercise. As a result, the fifth World
Symposium on Pulmonary Hypertension in 2013 removed the definition of ePH as
an mPAP >30 mmHg, which had been in place for over 30 years [7].
Exercise Pulmonary Hypertension
What Are the Hemodynamic Criteria to Define ePH?
Other impediments to defining ePH have included the lack of a unified diagnostic
approach, concerns regarding age-related changes in hemodynamics, and the
need for more precise hemodynamic cutoffs [5, 6]. A variety of hemodynamic
thresholds have been proposed to describe an abnormal pulmonary vascular
response to exercise [9, 12, 18, 25–29]. These methods emphasize the pressureflow relationship of mPAP to CO to delineate normal from abnormal exercise
hemodynamics, underscoring mPAP as a flow-dependent variable. For example,
highly trained athletes can generate an mPAP that may exceed 30 mmHg at peak
exercise. The elevated mPAP is largely due to a conditioned increase in CO and
stroke volume (SV) [30] rather than pulmonary vascular disease or diastolic
dysfunction, for example, in an exceptionally healthy individual. Therefore, it is
reasonable that ePH is not defined by mPAP alone. The conceptual basis of the
mPAP-CO relationship is that disproportionate increases in mPAP are related to
either remodeling of the pulmonary vasculature or transmission of the left atrial
pressure to the pulmonary vasculature due to left heart disease as CO increases
during exercise [25]. This pressure-flow approach alleviates some of the
difficulties ascribed to the former ePH definition that solely employed mPAP
>30 mmHg. Healthy individuals should not have an mPAP exceed 30 mmHg
when CO is <10 L/min [25].
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