Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

315

shape, the leftward septal bowing and the enlargement of the right atrium [ 27 ], all of

which are classical features of maladaptive remodeling [ 48 ]. Of note, this effect was

observed when the ExT program was started in early stages of PAH [ 27 ], while in

the most severe stages it seemed to exacerbate RV dilation [ 33 ]. On the other five

studies that we analyzed, the RV mass decreased with ExT, a change that apparently

was related to a protective effect of exercise on the lung vasculature as pulmonary

resistance [ 30 ] and pulmonary artery hypertrophy [ 29 ] were shown to be decreased.

There are several changes in the myocardium, caused by chronic RV pressure

overload and/or by the effects of circulating factors released from the sick lung

circulation, possibly contributing for the transition from adaptive to maladaptive

remodeling. Excellent reviews about this topic have been published elsewhere [ 21 ,

49 ]. Briefly, inflammation [ 50 , 51 ], alpha to beta myosin heavy chain (alpha/beta-

MHC) shift [ 52 , 53 ], apoptosis [ 54 ], neurohumoral activation [ 55 , 56 ], oxidative

stress [ 57 – 59 ], mitochondrial dysfunction [ 60 , 61 ], impaired metabolism [ 62 – 64 ],

and disturbed angiogenesis and capillary rarefaction [ 65 ] were all identified to be

present in the failing RV of animals and/or patients with PAH. According to the data

collected from pre-clinical studies, ExT may prevent or delay maladaptive remodel-

ing by modulating these changes. An integrative illustration of the molecular path-

ways affected by ExT is provided in Fig. 17.2.

Exercise training, when initiated before [ 29 ] or at an early disease stage [ 27 ], lead

to a normalization of the levels of myocardial fibrosis, which likely contributed to

restore diastolic stiffness and filling pattern [ 66 ]. Moreover, it prevented metallopro-

teinase (MMP)-9 activity and promoted an increase of MMP-2 activity, which might

have decreased the accumulation of fibrosis [ 29 ]. The antifibrotic effect of exercise

can also be related to its anti-inflammatory properties. Exercise training was reported

to reduce the expression of TNF-alpha/IL-10 and TWEAK, and to modulate down-

stream regulators of the NF-κB pathway in MCT-treated rats [ 27 , 29 ]. Also, no evi-

dence of tissue inflammatory cell infiltration or cell death was noted following an

acute bout of exercise [ 67 ], chronic continuous aerobic exercise [ 26 ] or high intensity

interval training [ 30 ] in MCT-induced PAH rats. However, in the more severe form

of MCT-induced PAH, ExT seems to result in widespread leucocyte infiltration of the

RV [ 33 ]. It will be important to disclose if this contrasting results are because RV

wall stress was detrimentally elevated during the exercise bouts (and thus ExT should

not be recommended at advanced stages) or because animals were all exercising at

the same absolute workload (rather than at a relative exercise intensity) [ 67 ].

Endothelin 1 (ET-1) antagonism is a mainstay of the actual therapeutic algorithm

for PAH and seems to attenuate deterioration of cardiac function [ 68 – 71 ]. MCT-

trained animals exhibited down-regulation of ET-1 mRNA in the RV [ 27 ]. B-type

natriuretic peptide (BNP) is a dynamic measurement of the degree of RV dysfunc-

tion in PAH [ 72 ] and its expression was favorably modulated by ExT [ 27 ]. Apelin is

a potent inotropic, anti-apoptotic, anti-inflammatory and pro-angiogenic neurohu-

moral mediator [ 73 ], and its expression was increased in the RV of rats with PAH

after HIIT [ 30 ]. Finally, ExT-induced neurohumoral modulation was evident by the

prevention of vascular endothelial growth factor (VEGF) mRNA down-regulation

17 Exercise Training in Pulmonary Hypertension and Right Heart Failure: Insights...