Objectives: This study examined the link between accelerometer recordings and cardiac pathophysiology measured with right heart cauterization at rest and with exercise in patients with HFrEF. Background: Patient-worn accelerometers are increasingly being used in patients with heart failure with reduced ejection fraction (HFrEF) to assess activity and serve as surrogate endpoints in heart failure trials. Methods: Physical average daily activity (PADA) and total average daily activity according to accelerometer units were assessed in 63 patients (mean age 58 ± 10 years; mean ejection fraction 26% ± 4%). Patients underwent hemodynamic exercise testing and accelerometry. Patients were divided according to PADA in PADA_Low and PADA_High activity level groups based on median counts per minute of physical activity. Results: Patients in the PADA_Low group were older and more frequently treated with diuretics. At rest, the PADA_Low group was characterized by a lower cardiac index (2.2 ± 0.4 L/min/m² vs 2.4 ± 0.4 L/min/m²; P = 0.01) and stroke volume (70 ± 19 mL vs 81 ± 17 mL; P = 0.02) but not pulmonary capillary wedge pressure (12 ± 5 mm Hg vs 11 ± 5 mm Hg; P = 0.3). The PADA_Low group reached a lower cardiac index (4.8 ± 1.7 L/min/m² vs 6.6 ± 1.7 L/min/m²; P < 0.001) but not in pulmonary capillary wedge pressure (31 ± 12 mm Hg vs 27 ± 8 mm Hg; P = 0.2) at peak exercise. The attenuated increase was associated with an attenuated increase in stroke volume (94 ± 32 mL vs 121 ± 29 mL; P < 0.001) rather than a reduced increase in heart rate (42 ± 23 beats/min vs 52 ± 21 beats/min; P = 0.07). PADA and total average daily accelerometer units were associated with patient-reported functional impairment according to the Kansas City Cardiomyopathy Questionnaire but not with New York Heart Association functional class. Conclusions: Among stable ambulatory patients with HFrEF, lower daily activity is associated with poorer cardiac index reserve and reduced cardiac index during exercise. (Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction; NCT03198585)