Abstract Background Reduction in 6-minute walk test distance (6MWD) in heart failure (HF) is associated with impaired quality of life and adverse cardiovascular outcomes. Myocardial work (MW) indices are novel non-invasive measures of left ventricular (LV) function which characterise myocardial contractile efficiency and energy utility. Purpose We aim to assess the predictive capacity of MW indices for functional capacity in stable non-ischaemic cardiomyopathy (NICM). Methods We prospectively recruited consecutive patients with stable NICM from our HF service from January 2021 to December 2023. All patients received optimal guideline direct therapy (OGDT) for 3-months before undergoing a comprehensive transthoracic echocardiogram and functional assessment with 6-minute walk test (6MWT). We excluded patients with prior cardiac surgery, severe airways disease, valvular heart disease, and those in atrial fibrillation (AF) or had mechanical limitations to their mobility at time of 6MWT. We collected demographic, clinical, and echocardiographic factors to identify the determinates of reduced 6MWD defined as <300 metres. Results Of 249-patients included (69.9% male; age 57.3±16.5yrs), 65-patients had reduced 6MWD. They were significantly older (62.3±17.2 vs 55.5±16.0yrs, p=0.005), had shorter height (166.3±10.3 vs 171.3±9.8cm, p=0.001), higher prevalence of AF history (39.1 vs 21.4%, p=0.001), lower LV-ejection-fraction (38.1±13.3 vs 43.3±10.2%, p=0.001), lower LV-global-longitudinal-strain (LV-GLS; 10.5±4.4 vs 12.7±3.9%, p<0.001), lower global-work-index (GWI; 943±487 vs 1230±455mmHg%, p<0.001), lower global-constructive-work (GCW; 1286±561 vs 1590±494mmHg%, p<0.001), lower global-work-efficiency (GE; 81.2±9.9 vs 85.4±8.1mmHg%, p=0.04), larger indexed left atrial volume (LAV; 45.0±18.4 vs 40.1±24.5ml/m2, p=0.038), higher E/e’ ratio (14.6±8.9 vs 11.8±6.0, p=0.003), and lower right-ventricular-free-wall-strain (RV-FWS; 19.2±6.7 vs 21.8±6.4, p=0.008; Table 1.). On receiver-operating-characteristics-curve analysis, GWI best predicted 6MWD reduction (Figure 1; AUC 0.68) compared to GCW, GE, LVEF and LVGLS (AUC: 0.62, 0.40, 0.62, and 0.62 respectively). Accounting for covariates, our multiple regression was run to predict 6MWD from age, height, AF history, LAV, E/e’, GWI and RV-FWS. These variables statistically significantly predicted 6MWD, F(4,239)=23.5, p<0.001, R2=0.34). With each 100mmHg% rise in GWI being independently associated with a 6.5m increase in 6MWD. Conclusion GWI was independently associated with 6MWD in our cohort of NICM patients on OGDT. MW indices provide some mechanistic insights into exercise capacity in patients with NICM.Table 1.Baseline CharacteristicsFigure 1.ROC of GWI Discriminating 6MWD