High Intensity Interval Training in a Rat Model of Severe, Angioproliferative Pulmonary Arterial Hypertension

Abstract

PURPOSE: We previously demonstrated superior benefit of high intensity interval training (HIIT) over continuous exercise training (CET) in a monocrotaline rat model of mild pulmonary arterial hypertension (PAH). Here we investigate HIIT in a model that elicits a more severe, angioproliferative PAH. METHODS: SD rats (~200g, male) received Sugen5416 (20mg/kg), followed by 3 wks of hypoxia (Patm=362 mmHg) and 4 wks of room air to induce PAH (SuHx, n=33). Subgroups of SuHx then underwent 6 wks of treadmill training performed as either HIIT (2 min at ~80-90%VO2reserve [VO2R] + 3 min at 30%VO2R, for 4-5 cycles, n=12), or low intensity CET (45-60 min at 50%VO2R, n=11), with the remainder untrained (SED, n=10). Values are mean±SE. RESULTS: Mortality in SuHx was unexpectedly worse for HIIT (4 deaths at 56, 60, 68, and 71 days), vs. CET (2 deaths at 60, and 73 days), and SED (2 deaths at 66 days). While all animals had similar baseline echocardiographic measures of cardiac output (CO, in uL) and stroke volume (SV, in mL/min), SuHx that died prematurely (n=8) had greater impairment in CO (141±19) and SV (424±52) following PAH induction (at pre-training) compared to surviving SuHx (n=25, 235±26, 598±38). Final CO and SV were higher for both HIIT (239±49, 540±58) and CET (207±41, 529±51) vs. SED (122±12, 405±35) SuHx rats, and were similar to untrained healthy controls (CON, n=6, 268±59, 548±71). SuHx-induced elevation in right ventricular (RV) systolic pressure (mmHg) and RV hypertrophy (as RV mass/LV+septum mass, and as RV thickness on echo in mm) were not improved by training with HIIT (61±7; 0.60±0.07, 2.2±0.2) or CET (60±8; 0.47±0.04, 2.0±0.2), vs. SED (55±8; 0.52±0.06, 2.2±0.2), and were higher than CON (28±3; 0.24±0.01, 1.3±0.1). Final VO2max (ml/kg/min) in SuHx was also not improved for either HIIT (44±1.9) or CET (46±1.7) vs. SED (46±3.8). CONCLUSION: Both HIIT and CET promoted better RV function in SuHx rats despite no amelioration of RV hypertrophy, PAH, or exercise impairment. However, in contrast to previous findings in a mild PAH rat model, exercise training, particularly with HIIT, increased mortality for animals with poorer cardiac function prior to training onset and suggests that further investigation is needed to optimize training approach for patients with more severe RV dysfunction. Funding: NIH-NHLBI R-15 (to MB Brown).