Purpose: The Latent Transforming growth factor Binding Protein 2 (LTBP2) was recently discovered in an unbiased proteomics search for novel markers in patients with acute dyspnea. The highest levels of LTBP2 are found in lung tissue and plasma levels of LTBP2 are a powerful predictor of all-cause mortality in patients presenting with acute dyspnea. We evaluated the relationship between plasma levels of LTBP2 and phenotypic changes suggestive for heart failure with preserved ejection fraction (HFPEF) including parameters of neurohormonal activation, Left Ventricular (LV) remodeling and filling pressures as well as exercise capacity. Methods: We studied 136 stable patients with CAD and LVEF≥50% (mean age 68±8 years, 76% men, LVEF 63±8%, 37% in NYHA class II/III). All patients underwent resting echocardiography for evaluation of LVEF and volumes, TDI derived longitudinal systolic and diastolic velocities function and E/E', as well as a six minute walking distance test (6minWD), maximal bicycle spiroergometry (peakVO2 and VE/VCO2 slope, n=104) and blood sampling. A proteomic approach for antibody-free targeted protein quantification based on high-end mass spectrometry was used to measure LTBP2 levels. Results: Levels of LTBP2 were higher in NYHA II/III as compared to NYHA I patients (p<0.05) and were correlated with NT-proBNP levels (r=0.49, p<0.01). ROC analysis showed a comparable modest AUC of 0.61 (p<0.05) for NT-proBNP and 0.60 (p<0.05) for LTBP2 to discern NYHA I versus NYHA II/III patients. LTBP2 levels were correlated with LV volumes (r=-0.38, p<0.01 for LVEDV, r=-0.33, p<0.01 for LVESV) as well as with LV longitudinal systolic velocities (r=-0.35, p<0.01), LV early diastolic velocities (r=-0.31,p<0.01) and E/E' (r=0.28,p<0.01). In linear regression analysis, including age and creatinine, LVESV and E/E' were independent predictors for LTBP2 levels (all p<0.05). Higher levels of LTBP2 were associated with lower 6minWD (r=-0.43, p<0.001), lower peakVO2 (r=-0.38, p<0.001) and higher VE/VCO2 slope (r=0.36, p<0.001). In multiple linear regression analysis including age, creatinine, LVESV and E/E', LTBP2 levels appeared to be an independent predictor for both 6minWD and peakVO2 (p<0.01). Conclusion: In stable patients with CAD and preserved LV function, higher levels of LTBP2 are related to phenotypic changes suggestive for HFPEF including higher neurohormonal activation, adverse LV remodeling with loss of longitudinal function, higher LV filling pressures and a lower exercise capacity. Therefore, the role of LTBP2 in the development, diagnosis and outcome of HFPEF deserves further study.