Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure.
BACKGROUND
The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure.


RESULTS
A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1alpha. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload.


CONCLUSIONS
These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.
Bogaard
Harm J
HJ
Divisions of Pulmonary and Critical Care, Virginia Commonwealth University, Richmond, VA 23298-0281, USA. nvoelkel@mcvh-vcu.edu
Natarajan
Ramesh
R
Henderson
Scott C
SC
Long
Carlin S
CS
Kraskauskas
Donatas
D
Smithson
Lisa
L
Ockaili
Ramzi
R
McCord
Joe M
JM
Voelkel
Norbert F
NF
D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D008297:Male; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D016278:Ventricular Function, Right
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat