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Background: Left ventricular (LV) diastolic dysfunction is recognized as playing a major role in the pathophysiology of heart failure; however, clinical tools for identifying diastolic dysfunction before echocardiography remain imprecise., Objectives: This study sought to develop machine-learning models that quantitatively estimate myocardial relaxation using clinical and electrocardiography (ECG) variables as a first step in the detection of LV diastolic dysfunction., Methods: A multicenter prospective study was conducted at 4 institutions in North America enrolling a total of 1,202 subjects. Patients from 3 institutions (n = 814) formed an internal cohort and were randomly divided into training and internal test sets (80:20). Machine-learning models were developed using signal-processed ECG, traditional ECG, and clinical features and were tested using the test set. Data from the fourth institution was reserved as an external test set (n = 388) to evaluate the model generalizability., Results: Despite diversity in subjects, the machine-learning model predicted the quantitative values of the LV relaxation velocities (e') measured by echocardiography in both internal and external test sets (mean absolute error: 1.46 and 1.93 cm/s; adjusted R 2 = 0.57 and 0.46, respectively). Analysis of the area under the receiver operating characteristic curve (AUC) revealed that the estimated e' discriminated the guideline-recommended thresholds for abnormal myocardial relaxation and diastolic and systolic dysfunction (LV ejection fraction) the internal (area under the curve [AUC]: 0.83, 0.76, and 0.75) and external test sets (0.84, 0.80, and 0.81), respectively. Moreover, the estimated e' allowed prediction of LV diastolic dysfunction based on multiple age- and sex-adjusted reference limits (AUC: 0.88 and 0.94 in the internal and external sets, respectively)., Conclusions: A quantitative prediction of myocardial relaxation can be performed using easily obtained clinical and ECG features. This cost-effective strategy may be a valuable first clinical step for assessing the presence of LV dysfunction and may potentially aid in the early diagnosis and management of heart failure patients., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)