Abstract Funding Acknowledgements Type of funding sources: None. Aims. Combined cardiopulmonary exercise test (CPET) and exercise stress echocardiography (ESE) provides a non-invasive tool to study cardiopulmonary pathophysiology. We analyzed how cardiac functional reserve during exercise relates to peak oxygen consumption (VO2). Methods and Results. We performed a symptom-limited graded ramp bicycle CPET-ESE in 30 healthy controls and 357 patients: 113 at risk of developing heart failure (American College of Cardiology/American Heart Association HF Stages A-B) and 244 in HF Stage C with preserved (HFpEF, n = 101) or reduced ejection fraction (HFrEF, n = 143). Peak VO2 significantly decreased from controls to Stage A-B and Stage C (Table 1). A multivariable regression model to predict peak VO2 revealed peak left ventricular systolic annulus tissue velocity (S"), peak TAPSE/PAPs (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) and low-load left atrial reservoir strain/E/e’ were independent predictors, in addition to peak heart rate, stroke volume and workload (adjusted R²=0.76, p < 0.0001). The model was successfully tested in subjects with atrial fibrillation (n = 49), and with (n = 224) and without (n = 163) beta-blockers (all p < 0.01). Peak S’ showed the highest accuracy in predicting peak VO2 < 10 mL/kg/min (cut-point ≤ 7.5 cm/s; AUC = 0.92, p < 0.0001) and peak VO2 > 20 mL/kg/min (cut-point > 12.5 cm/s; AUC = 0.84, p < 0.0001) in comparison to the other cardiac variables of the model (p < 0.05). Conclusions. A model incorporating different measures of cardiac mechanics is strongly related to peak aerobic capacity and may help in identifying different causes of effort intolerance from HF Stage A to C. Table 1 Variable Overall population (n = 387) Controls (n = 30) Stage A-B (n = 113) Stage C-HFpEF (n = 101) Stage c-HFrEF (n = 143) p-value Age, years 68.9 ± 11.1 67.1 ± 10.6 67.7 ± 10.4 70.5 ± 10.1 68.5 ± 11 0.1 Male, n (%) 247 (64) 18 (60) 70 (62) 57 (56) 102 (71) 0.1 VO2 @peak, mL/min/kg 15.7 (12.1-19.6) 23 (21.7- 29.7) 18 (15.4- 20.7)* 13.6 (11.8- 16.8)*† 14.2 (10.7- 17.5)*† <0.0001 Workload @peak, W 90 (65-120) 130 (115-195) 110 (84-130)* 70 (55-100)*† 80 (60-110)*† <0.0001 Heart rate @peak, bpm 123 ± 22 142 ± 12 130 ± 20* 115 ± 17*† 119 ± 23*† <0.0001 Stroke volume @peak, mL 83 (71-99) 98 (85-114) 86 (76-107) 83 (74-97)* 75 (63-95)*† <0.0001 Average S" @peak, cm/s 11.2 ± 3.8 17.1 ± 3.9 13.3 ± 2.9* 10.6 ± 2.5*† 8.7 ± 2.7*†‡ <0.0001 TAPSE/PAPs @peak, mm/mmHg 0.75 (0.46-0.97) 1.05 (0.93- 1.16) 0.81 (0.52- 0.91)* 0.52 (0.38- 0.83)*† 0.58 (0.41- 0.89)*† <0.0001 Left atrial reservoir strain/E/e" @low-load, % 2.25 (1.17-5.04) 6.23 (4.45-6.77) 4.34 (3.89- 5.58)* 2.23 (1.31- 2.86)*† 1.91 (1.07-2.44)*†‡ <0.0001 * p < 0.01 vs Controls; † p < 0.01 vs Stage A-B; ‡ p < 0.01 vs Stage C-HFpEF. PAPs systolic pulmonary artery pressure; TAPSE: tricuspid annular plane systolic excursion; VO2: oxygen consumption. Abstract Figure 1