This study showed that both PWD-MPI and TDI-MPI were significantly higher in patients with DD and preserved systolic function than in healthy subjects. The increase in both indices was mainly caused by isolated and significant prolongation of the IVRT, the only diastolic component of MPI. The systolic components, isovolumetric contraction time and ejection time, showed no significant difference compared to the control group. IVRT tends to increase in isolated left-ventricular diastolic dysfunction  since early diastolic relaxation proceeds more slowly ; however, its duration depends on both LV relaxation velocity and the difference between LV end-systolic pressure and left-atrial pressure , and occasionally it may shorten or pseudo-normalize with significant increases in left ventricular filling pressures . MPI appears more resistant to pseudonormalization, as increased LV filling pressures are correlated with shorter ejection times .
According to previous reports [8, 10, 17], TDI-MPI had higher values than PWD-MPI in both healthy subjects and patients with DD. The limits of agreement between these indices in this study were wide; thus, the two methods cannot be used interchangeably, which is consistent with the results of previous reports [17,18,19]. Furthermore, these indices had high rates of false-positive and negative results, modest sensitivities and specificities, low positive likelihood ratios and high negative likelihood ratios, showing the low capacity of these methods to differentiate between healthy individuals and those with isolated DD. In clinical practice, it is essential to know the method by which the result of a particular test can be used to predict the risk of a disease; sensitivity and specificity cannot be used for such predictions. Likewise, although the predictive values show the probability of abnormality for the results of a specific test, they depend on the prevalence of the disease in the study sample and can rarely be extrapolated beyond that study. In contrast, likelihood ratios are intrinsic properties of the method, do not depend on the prevalence of the disease, and unlike sensitivity and specificity, which are population characteristics, can be used at the level of the individual patient to calculate the probability of disease; therefore, they represent good alternatives tools for accurate diagnosis . These results coincide with previous research, which revealed poor diagnostic accuracy of conventional MPI in patients with isolated DD [6, 7].
Few studies have related TDI-MPI to diastolic dysfunction. Gaibazzi et al.  studied patients with heart failure and found a slight correlation between PWD-MPI and TDI-MPI and high diagnostic accuracy using both the methods for the diagnosis of HF; however, all of those patients had mild to moderate systolic dysfunction, and the authors found no correlation between TDI-MPI and DD. Rojo et al.  observed no significant difference between TDI-MPI and PWD-MPI and modest agreement between these methods in patients with recent myocardial infarction; however, the authors did not establish the accuracy of the methods, although most patients had diastolic dysfunction with a normal ejection fractions. Su et al.  studied a significant number of heterogeneous patients with DD and reported that TDI-MPI increased with increasing severity of DD and accurately differentiated subjects with pseudonormal filling patterns from those with normal mitral inflow; however, the authors did not determine the diagnostic accuracy in the subgroup of patients with impaired relaxation, although that subgroup contained a considerable number of patients. Baikan et al.  proposed that the TDI-MPI index might be superior to the traditional mitral-inflow curves for the assessment of left ventricular diastolic function in patients with acromegaly with preserved systolic function; however, less than half of the 27 patients had DD, and the authors did not assess the sensitivity, specificity, and likelihood ratios of TDI-MPI for the diagnosis of DD. Patel et al.  showed a significant increase in TDI-MPI in patients with isolated DD compared to the control group, with good sensitivity, specificity, and likelihood ratios; however, this analysis was conducted on a small subgroup of children with different congenital heart defects. Recently, Kim et al.  observed similarly high accuracies in TDI-MPI, E/e′ ratio, and N-terminal pro-brain natriuretic peptide (NT-ProBNP) level for the identification of DD and heart failure with preserved ejection fraction. Moreover, TDI-MPI predicted cardiovascular adverse events with reliability similar to that of the E/e’ ratio and NT-ProBNP level; however, they did not determine the accuracy of TDI-MPI in patients with type-I DD without heart failure.
Among all echocardiographic variables used for the selection and diagnosis of patients with DD in this study, only e′ septal and e´/a′ septal were significantly related to TDI-MPI. After multiple regression analysis, only the LV mass was considered independent predictor of TDI-MPI, which is in accord with a previous study . The correlation between mass and TDI-MPI may be related to the large number of patients with LV hypertrophy, which results in high collagen deposition, decreased LV relaxation and distensibility with a negative impact on ventricular performance .
Even patients with type-I DD (E/A < 1) can have increased LV filling pressures [26, 27]. In such cases, although it has been less studied, the E/e′ ratio described by Nagueh et al.  and validated by other authors [29, 30] has been a useful tool for the assessment of LV filling pressures. Kasner et al.  compared conventional Doppler and TDI with invasive hemodynamic measurements in the estimation of diastolic function and found an average E/A ratio < 1 for patients with DD and increased LV filling pressures with a normal ejection fraction. They identified the lateral E/e’ ratio as the best index for the detection of DD in these patients. Similarly, Kuznetsova et al.  described a class of DD characterized by a low E/A ratio and a high E/e′ ratio. They suggested that those patients had a significantly abnormal LV relaxation, such that both left atrial pressure and LV diastolic pressure were elevated. Recently, Johnson et al.  classified patients with mild to moderate DD as those who had impaired LV relaxation and showed signs of increased pressure in the left atrium (E/e′ > 15).
In the present study, 13 patients (30%) had an E/e′ ratio (septal and lateral mean) ≥ 13, suggesting increased LV filling pressures, as recommended by the guidelines of the American Society of Echocardiography for the assessment of LV diastolic function . In this subgroup, the area under the ROC curve and the sensitivity and specificity of TDI-MPI were greater than in the overall group, however, a low positive likelihood ratio indicated only a small increase in the probability that high values of TDI-MPI was associated with the presence of DD. Furthermore, unlike Kim et al.  we found no correlation between this index and the E/e′ ratio. The accuracy of a diagnostic method depends upon the severity and extent of disease; therefore, considering the low accuracy of the TDI-MPI for patients with mild to moderate DD, as observed in the present study, the utility of this index may be limited for patients with subclinical forms of DD, compromising its use as a marker of global cardiac function.
There are a few limitations in this study that should be considered. Patients were diagnosed with diastolic dysfunction according to the 2009 ASE/EAE echocardiographic recommendations, as these criteria have already been tested in numerous studies [28,29,30,31,32] and have proven to be an important predictor of all-cause mortality in a seminal epidemiologic study . Invasive hemodynamic parameters were not used; thus, it was not possible to determine the influence of hemodynamic factors such as preload, afterload, contractility and systemic vascular resistance in TDI-MPI and its components. However, some studies have shown that TDI-MPI is independent of heart rate, blood pressure and ventricular loading [33, 34]. Left atrial volume index was not evaluated, but considering that this study involved asymptomatic hypertensive patients with a diagnosis of mild diastolic dysfunction, it is unlikely that this index would show relevant additional information. Pulmonary arterial systolic pressure was not included among the measures since the quality of the spectral Doppler tricuspid regurgitation signals was poor or absent and no measurable in 57% of DDI patients and in 61% of subjects of control group. Ischemic heart disease could not be excluded because the patients did not undergo stress testing or coronary angiography. Medical therapy was not homogeneous across patients, which may have influenced these results. The groups were not homogeneous with respect to age, the control group consisted of relatively young and healthy subjects and thus with very low possibility of presenting diastolic dysfunction not detected by the classic methods used in this study preventing the occurrence of type II error. Using age-matched groups could show a lower accuracy of the MPI in the diagnosis of DD, compared to the present study, given the possible positive age-dependency of MPI [8, 35]; although no significant correlation was observed between age and this index in any of the groups in this present study as in previous publications [5, 13, 19]. Also the MPI range for control group and optimal cut-point in the current study was comparable with literature ranges [8, 13, 21, 22], and thus, it is unlikely that the age difference significantly affected these results as well as in other published studies [8, 19]. Moreover, conventional measures of systolic function such as the ejection fraction have some limitations in the assessment of LV contractile properties and may not reflect all aspects of ventricular systole .