Mitral valve regurgitation (MR) has a prevalence of up to 40% in athletic horses. Although limited effects on performance are expected in most horses with mild MR, in some horses MR progresses and causes clinical signs or arrhythmias such as atrial fibrillation. The major gap in the current knowledge is how to identify those horses with relevant cardiac disease which could impact performance or compromise horse and rider safety in the future. Because this is difficult to predict, the diagnosis of MR in a sports horse at prepurchase examination often has important economic consequences. The first hypothesis is that horses with mild to moderate MR show compensatory left atrial and left ventricular function which explains their normal athletic performance, while cardiac decompensation can be detected in horses with severe MR using cardiac biomarkers and advanced echocardiographic techniques such as tissue Doppler imaging and speckle tracking. The second aim is to identify prognostic indices for accurately predicting the long-term evolution of MR in horses. This will be of invaluable use in assessing equine athletes with MR, especially at pre-purchase examinations. The third aim is to unravel the pathophysiology of equine degenerative mitral valve disease by elucidating the histological alterations. The fourth aim is to investigate serotonin and magnesium as potential factors in the MR molecular mechanism.