Background: Left ventricular (LV) twist mechanics are augmented with both acute and chronic hypoxemia. Although the underlying mechanisms remain unknown, sympathetic activation and a direct effect of hypoxemia on the myocardium have been proposed, the latter of which may produce subendocardial dysfunction that is masked by larger subepicardial torque. This study therefore sought to (1) determine the individual and combined influences of β1-AR (β1-adrenergic receptor) stimulation and peripheral O2 saturation (Spo2) on LV twist in acute and chronic hypoxia and (2) elucidate whether endocardial versus epicardial mechanics respond differently to hypoxia. Methods: Twelve males (27±4 years) were tested near sea level in acute hypoxia (Spo2=82±4%) and following 3 to 6 days at 5050 m (high altitude; Spo2=83±3%). In both settings, participants received infusions of β1-AR blocker esmolol and volume-matched saline (double-blind, randomized). LV mechanics were assessed with 2-dimensional speckle-tracking echocardiography, and region-specific analysis to compare subendocardial and subepicardial mechanics. Results: At sea level, compared with baseline (14.8±3.0°) LV twist was reduced with esmolol (11.2±3.3°; P=0.007) and augmented during hypoxia (19.6±4.9°; P<0.001), whereas esmolol+hypoxia augmented twist compared with esmolol alone (16.5±3.3°; P<0.001). At 5050 m, LV twist was increased compared with sea level (19.5±5.4°; P=0.004), and reduced with esmolol (13.0±3.8°; P<0.001) and Spo2 normalization (12.8±3.4°; P<0.001). Moreover, esmolol+normalized Spo2 lowered twist further than esmolol alone (10.5±3.1°; P=0.036). There was no mechanics-derived evidence of endocardial dysfunction with hypoxia at sea level or high altitude. Conclusions: These findings suggest LV twist is augmented in hypoxia via β1-AR–dependent and β1-AR–independent mechanisms (eg, α1-AR stimulation), but does not appear to reflect endocardial dysfunction.