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they should undertake supervised ExT under medical therapy [ 1 ]. Despite this major
change regarding the role of exercise in the management of PAH patients, the mech-
anisms underlying these clinical improvements remain unclear. In this chapter, we
will summarize the main findings from pre-clinical studies analyzing the impact of
exercise in PAH and right heart failure.
2 Pre-clinical Models to Study the Impact of Exercise
Training in Pulmonary Hypertension and Right Heart
FailureThere are various pre-clinical models of PAH based on physical, chemical, genetic
or a combination of insults that had been useful in the last decades to study both the
impact of drugs and non-pharmacological interventions such as exercise. None of
them fully recapitulates all features of human PAH and they exhibit specific advan-
tages and limitations described elsewhere [ 12 – 14 ]. The most commonly used PAH
pre-clinical models to study the effects of ExT are monocrotaline (MCT; 12 stud-
ies) and chronic hypoxia (4 studies). Of note, these models also grounded the
development of therapies currently available for this condition [ 13 ]. The MCT
model mimics human PAH in terms of hemodynamic and histopathological sever-
ity, and high mortality; it differs on the early presentation of lung edema, loss of the
endothelial barrier and prominent inflammatory adventitial proliferation [ 15 ]. The
phenotypical changes induced by MCT are dose-dependent (60 mg/kg for severe
PAH or 30 mg/kg for stable PAH) and only require one single administration (sub-
cutaneous or intraperitoneal). Signs of illness start to occur within 3–7 days, with
animals presenting anorexia, failure to gain weight and tachypnea [ 15 ]. As lung
injury and vascular remodeling progresses, animals develop variable degrees of
dyspnea, weakness, diarrhea, and peripheral cyanosis. PAPm is increased 2 weeks
after MCT injection, leading to RV hypertrophy by the third week. By 5–6th week,
half of the injected rats usually die [ 15 ]. PAH due to chronic hypoxia model con-
sists on exposing animals to normal air at hypobaric pressure or to oxygen-poor air
at normal pressure [ 16 ]. The decrease in oxygen pressure causes a strong pulmo-
nary vasoconstrictor response followed by progressive hypertrophy (but little pro-
liferation) and muscularization of medial pulmonary arterioles, endothelial
dysfunction and a doubling of PAPm [ 13 ]. A proinflammatory microenvironment
capable of promoting recruitment, retention and differentiation of circulating
monocytic cell populations, possibly contributing to vascular remodeling, has also
been described [ 17 ]. Hypertrophy of the RV occurs just after 2 weeks of exposure
to chronic hypoxia but RV failure, which is the main cause of death in PAH patients,
does not occur in this model [ 17 ].
17 Exercise Training in Pulmonary Hypertension and Right Heart Failure: Insights...