This study sought to establish the diagnostic and prognostic value of a strategy for prediction of abnormal diastolic response to exercise (AbnDR) using clinical, biochemical, and resting echocardiographic markers in dyspneic patients with mild diastolic dysfunction.An AbnDR (increase in left ventricular filling pressure) may indicate heart failure with preserved ejection fraction as the cause of symptoms in dyspneic patients, despite a nonelevated noncardiac at rest. However, exercise testing may be inconclusive in patients with noncardiac limitations to physical activity.In 171 dyspneic patients (64 ± 8 years) with suspected heart failure with preserved ejection fraction but resting peak early diastolic mitral inflow velocity/peak early diastolic mitral annular velocity ratio (E/e') <14, a complete echocardiogram (including assessment of myocardial deformation and rotational mechanics) and blood assays for biomarkers were performed. Echocardiography following maximal exercise was undertaken to assess AbnDR (exertional E/e' >14). Patients were followed over 26.2 ± 4.6 months for endpoints of cardiovascular hospitalization and death.AbnDR was present in 103 subjects (60%). Independent correlates of AbnDR were resting E/e' (odds ratio [OR]: 8.23; 95% confidence interval [CI]: 3.54 to 9.16; p < 0.001), left ventricular untwisting rate (OR: 0.60; 95% CI: 0.42 to 0.86; p = 0.006), and galectin-3-a marker of fibrosis (OR: 1.80; 95% CI: 1.21 to 2.67; p = 0.004). The use of resting E/e' >11.3 and galectin-3 <1.17 ng/ml to select patients for further diagnostic processing would have allowed exercise testing to be avoided in 65% of subjects, at the cost of misclassification of 13%. The composite outcome of cardiovascular hospitalization or death occurred in 47 patients (27.5%). The predictive value of an AbnDR response and the combined strategy (resting echocardiography and galectin-3 or exercise testing in case of an inconclusive first step) showed similar event prediction (36 vs. 34; p = 0.95).The implementation of a 2-step algorithm (echocardiographic evaluation of resting E/e' followed by the assessment of galectin-3) may improve the diagnosis and prognostic assessment of individuals with suspected heart failure with preserved ejection fraction who are unable to perform a diagnostic exercise test.