Abstract 6162: It is not (just) the Increased Afterload that Causes the Right Heart to Fail in Pulmonary Hypertension
Background: An increased afterload is generally viewed as the single cause of right ventricular (RV) failure in pulmonary hypertension (PH). We hypothesized that per se pressure-independent features of PH, related to angioproliferative pulmonary vascular changes, hypoxia and increased redox stress, contribute to the development of RV failure.
Aims and Methods: To compare functional and morphological characteristics of a pure mechanical rat model of RV pressure overload (pulmonary artery banding, PAB), and a model characterized by both RV pressure overload and pulmonary vascular angioproliferative changes (induced by a single dose of the VEGF receptor blocker SU5416 and 4 wks of hypoxic exposure, SuHx). To assess whether anti-oxidant treatment can delay the development of RV failure, without affecting RV afterload.
Results: 6 wks after PAB or SU5416 administration, RV systolic pressures (RVSPs) were comparable (79±5 vs. 71±15mmHg), but the degree of RV hypertrophy was greater in SuHx than in PAB (RV/body weight 1.8±0.4 vs. 1.1±0.3, p<0.05). SuHx but not PAB rats showed signs of RV failure on cardiac ultrasound, whereas cardiac output (thermodilution) was low in SuHx and normal in PAB. Trichrome staining showed extensive fibrosis in the RVs of SuHx rats, but not PAB rats. Capillary volume (stained by intravital i.v. injection of Texas Red-conjugated tomato lectin and imaged by 3-D confocal microscopy) was 2.9±1% of tissue volume in SuHx, significantly lower than in controls (5.7±1%) or PAB (5.4±1%, p<0.05). A separate group of rats exposed to hypoxia after PAB showed even higher RVSPs (109±12 mmHg) but still no features of RV failure. Treatment of SuHx rats with the anti-oxidant drug Protandim did not affect the RVSP but resulted in improved RV function on ultrasound and less RV fibrosis.
Conclusions: The development of RV failure in experimental PH requires more than just pressure overload. RV morphological changes that are associated with RV failure in the SuHx model are increased fibrosis and a reduced capillary density. Angioproliferative and inflammatory changes of the pulmonary circulation may be associated with increased redox stress, which spills over into the systemic circulation and affects RV function and morphology.