OBJECTIVES: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. BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.