Background: Peak early diastolic flow velocity (E) across the mitral valve has been shown to be directly related to the magnitude of the early diastolic transmitral pressure difference (TPD). Although this relationship has been verified by a number of investigators, the statistical strengths of the reported relationships have varied. This variation may be attributable, at least in part, to the lack of standardization of 1) the site of measurement of left ventricular pressure, and 2) the method for determination of the atrioventricular pressure difference. Methods: To assess the degree to which the E-TPD relation is affected by early diastolic left ventricular intraventricular pressure gradients, or by the timing of the measurement (ie, instantaneous versus noninstantaneous) of the TPD, we recorded left atrial and two regional (mid and apical) left ventricular pressures with micromanometers, and E by transesophageal Doppler in 16 closed-chest anesthetized dogs. Two noninstantaneous TPDs were measured: pressure at the first crossover of left atrial and left ventricular pressures (X1) minus minimum left ventricular-apical pressure [X1-LVP(apex)]; and X1 minus minimum mid-left ventricular pressure [X1-LVP(mid)]. Two TPDs were also measured at a single point in time (instantaneous): the maximum left atrial to left ventricular-apical early diastolic TPD [MAX(apex)]; and the maximum left atrial to mid-left ventricular TPD [MAX(mid)]. Results: Correlations with E were as follows: X1-apex, r=0.805, P<0.001; X1-mid, r=0.735, P<0.001; MAX(apex), r=0.716, P<0.002; MAX(mid), r=0.369, P is not significant. Conclusions: In this study, a wide range of correlations were observed between E and the four early diastolic TPDs measured as described above. Clearly, transmitral pressure gradients measured in different left ventricular regions and at different points in time are not proportional. Thus, the recorded pattern of the transmitral pressure difference is so critically dependent on the intraventricular site and method of timing employed in its measurement, it is doubtful that any physiologically valid, simple relation can be proven.