CONTRASTING PULMONARY VASCULAR RESPONSES TO HIGH INTENSITY INTERVAL TRAINING FOR RATS WITH MILD VERSUS SEVERE PULMONARY ARTERIAL HYPERTENSION.

Purpose/Hypothesis: We previously demonstrated that high intensity interval training (HILT) reduced pulmonary vascular remodeling and increased expression of a key regulator of pulmonary vascular tone, pulmonary endothelial nitric oxide synthase (eNOS) concomitant with alleviation of pulmonary hypertension in a monocrotaline rat model of mild pulmonary arterial hypertension (PAH). Here we investigate pulmonary vascular responses to HILT in a model that elicits a more severe, angioproliferative PAH. Number of Subjects: Forty-five. Materials/Methods: Male Sprague-Dawley rats (-315 g) received a single injection of vascular endothelial growth factor inhibitor Sugen5416 (20 mg/kg) + 3 weeks of hypoxia (Patin = 362 mm Hg) followed by 4 weeks of room air (SuHx, n = 33). Control rats (CON, n = 12) received an injection of saline and remained in room air. A subgroup of SuHx then underwent 6 weeks of treadmill training (in room air) performed as HILT (2 minutes at '-80%-90% VO₂Reserve [VO₂R] + 3 minutes at 30% VO₂R, for 4-5 cycles, n = 12), with the remainder untrained (SED, n = 10). To determine impact of trianing on pulmonary vascular remodeling, Verhoeff—Van Giesson (VVG) immunohistochemical staining was performed on lung sections. Pulmonary vascular wall area was determined from brightfield microscopy images in a blinded fashion for small and medium-sized PAs (<250 p.m diameter, 10 vessels per animal, X20 objective). Measurement of lung total eNOS was performed via electrophoresis and immunoblot analysis of lung homogenates with the intensity of Western blotting bands measured by densitometry (ImageJ software, NIH) and expressed normalized vinculin band intensity. Values are mean ± SE. Results: SuHx-induced elevation in right ventricular systolic pressure (RVSP via Millar catheter in mm Hg) was not improved by HILT (61 ± 7) versus SED (55 ± 8, P > .05), and was higher than CON (28 ± 3, P < .05). SuHx-induced increase in pulmonary arterial wall thickness (as fraction of vessel area) was also not alleviated by HILT (0.43 ± 0.04) versus SED (0.44 ± 0.03, P > .05), and was higher than CON (0.29 ± 0.02, P < .05). HILT did not evoke greater lung eNOS expression in SuHx (0.95 ± 0.03) versus SED (0.94 ± 0.02, P > .05), which tended to be lower than in CON (1.10 ± 0.07, P = .08). Conclusions: In contrast to previous findings in a monocrotaline rat model of mild PAH, HILT does not evoke beneficial pulmonary vascular adaptations nor alleviate pulmonary hypertension in a SuHx rat model of more severe, angioproliferative PAH, sugggesting that responses to training are model- and severity-dependent. Further investigation is needed to optimize training approach for PAH patients with more severe disease. Clinical Relevance: In patients with more severe compli-cations from PAH, HILT may not necessarily improve pulmonary vascular function. Further investigation is needed to optimize training approach for PAH patients with more severe disease. [ABSTRACT FROM AUTHOR]