Background –Current diagnosis of heart failure with preserved ejection fraction (HFPEF) is suboptimal. We tested the hypothesis that comprehensive machine learning (ML) of left ventricular (LV) function at rest and exercise objectively captures differences between HFPEF and healthy subjects. Methods and results –156 subjects aged>60 years (72 HFPEF+33 healthy for the initial analyses; 24 hypertensive+27 breathless for independent evaluation) underwent stress echocardiography, in the MEDIA-study. LV long-axis myocardial velocity patterns were analyzed using an unsupervised ML algorithm that orders subjects according to their similarity, allowing exploration of the main trends in velocity patterns. ML identified a continuum from health to disease, includinga transition zone associated to an uncertain diagnosis. Clinical validation was performed: (i) to characterize the main trends in the patterns for each zone, which corresponded to known characteristics and new features of HFPEF; the ML-diagnostic zones differed for age, body mass index, 6-minute walk distance, B-type natriuretic peptide, and LV mass index (p<0.05). (ii) to evaluate the consistency of the proposed groupings against diagnosis by current clinical criteria; correlation with diagnosis was good (Kappa, 72.6%; 95%confidence interval, 58.1–87.0); ML identified 6% of healthy controls as HFPEF. Blinded reinterpretation of imaging from subjects with discordant clinical and ML diagnoses revealed abnormalities not included in diagnostic criteria. The algorithm was applied independently to another 51 subjects, classifying 33% of hypertensive and 67% of breathless controls as mild-HFPEF. Conclusions –The analysis of LV long-axis functionon exercise by interpretable ML may improve the diagnosis and understanding of HFPEF.