Tissue Doppler derived biphasic velocities during the pre and post-ejection phases: patterns, concordance and hemodynamic significance in health and disease

All echocardiographic studies were performed with a commercially available echocardiography systems equipped with a 2.5-MHz phased array transducer. Digital routine grayscale 2-dimensional and tissue Doppler cine loops from 3 consecutive beats were obtained at end-expiratory apnea from standard apical views at depths of 12–20 cm. Sector width was optimized to allow for complete myocardial visualization while maximizing the frame rate. Gain settings were adjusted for routine clinical grayscale 2D imaging to optimize endocardial definitions. LV-EF was calculated from the apical 2- and 4-chamber images using the biplane Simpson’s technique. EF was defined as preserved if EF was > 50% and reduced if EF was ≤ 50%. All measurements were made in ≥ 3 consecutive cardiac cycles and average values were used for the final analyses. The pulsed-wave Doppler-derived transmitral velocity and spectral tissue Doppler-derived mitral annular velocity were obtained from the apical 4-chamber view. The early diastolic wave velocity (E) and the late diastolic atrial contraction wave velocity (A) were measured using pulsed-wave Doppler recording, and the early diastolic mitral annular velocity (e’) and systolic velocity (s’) were measured and averaged from the septal and lateral mitral annular positions. The E/e´ ratio was calculated to assess LV filling pressure (LVFP) for all patients.

From the mitral annular tissue Doppler recordings, the biphasic pre-ejection (PRE) and post-ejection (POE) velocity signals were identified (Fig. 1). PRE was identified as a positive signal (PREp) followed by a negative signal (PREn) that preceded the ejection systolic velocity (s’). POE was identified as a negative signal (POEn) followed by a positive signal (POEp) that was positioned between the ejection systolic velocity (s’) and early diastolic velocity (e’). All positive and negative signals of both phases were measured and averaged from the septal and lateral mitral annular positions. The ratio of both PRE and POE velocities were obtained as chronologically occurring during the cardiac cycle as the former divided by the later in the form of the positive to negative PRE (PRE-P/N), and negative to positive POE (POE-N/P). The predominance of the biphasic PRE was defined as positive if PRE-P/N was > 1, and negative if PRE-P/N was ≤ 1. The predominance of the biphasic POE was defined as negative if POE-N/P was > 1, and positive if IR-N/P was ≤ 1. Next, the concordance of both biphasic velocities was defined as Normal if PRE was predominantly positive and POE was predominantly negative, reversed PRE, if both velocities were predominantly negative, reversed POE if both velocities were predominantly positive, and complete reversal if PRE was predominantly negative and POE was predominantly positive.

Table 1 summarizes comparisons between patients and controls for septal, lateral, and averaged mitral annular velocities including pre-ejection (PRE) and post-ejection (POE) variables. It was found that, patients with heart failure had lower PREp, and POEn, higher PREn and POEp, and lower ratios PRE-P/N and POE-N/P compared to controls. Among heart failure patients, HFrEF tended to have lower PREp, and POEn compared to HFpEF (PREp: 6.3 ± 2.2 vs. 4.3 ± 1.6, p < 0.001; POEn: 3.3 ± 1 vs. 2.4 ± 0.7, p < 0.001) while there was no significant difference between PREn and POEp compared to HFpEF (PREn: 3.7 ± 1.1 vs. 3.3 ± 1.4, p = 0.225; POEp: 3.3 ± 1 vs. 2.4 ± 0.7, p = 0.248) and, similarly, there was no significant difference regarding both ratios (POE-P/N: 1.8 ± 0.7 vs. 1.5 ± 1.03, p = 0.282; POE-N/P: 1.3 ± 0.5 vs. 1.1 ± 1.04, p = 0.203). On the other hand, with the exception of a higher POEp in the normal subjects, none of the PRE or POE velocities were different between normal subjects and matched controls. Moreover, it was noted that normal and age matched controls had almost always a predominantly positive PRE and predominantly negative POE, while predominantly negative PRE and predominantly positive POE occurred almost always in HF patients (Fig. 2).

Next, all patients and controls were compared based on our definition of concordance between both biphasic velocities (Normal: PRE predominantly positive and POE predominantly negative, reversed PRE: both PRE and POE predominantly negative, reversed POE: both PRE and POE predominantly positive, and complete reversal: PRE predominantly negative and POE predominantly positive, Fig. 2). It was found that almost all normal subjects and matched controls exhibited normal concordance [normal subjects: 39 (93%) subjects, and matched controls: 23(96%) patients], while in normal subjects, 3(7%) subjects exhibited abnormal concordance (reversed PRE in 1 reversed POE in 1, and total reversion in 1), and in matched controls one (4%) patient exhibited reversed POE.

Importantly, abnormal concordance was found in significantly more HF patients compared to controls [49(58%) patients vs. 4(6%) controls, p < 0.001]. Abnormal concordance occurred in 24(46%) HFpEF patients and 25(67%) HFrEF patients, (p = 0.003). All types of concordance were observed in patients with HFpEF, however, in patients with HFrEF, almost all patients had abnormal concordance [12(44%) reversed POE, and 13(48%) totally reversed concordance]. Importantly, concordance seemed to be significantly associated with NYHA functional class such that the best NYHA was in normal concordance (1.6 ± 1) and the worst was in reversed concordance (2.6 ± 0.5), while reversed PRE and POE was in between normal and reversed (2 ± 1.2 and 2.3 ± 0.6, respectively). Similar patterns were observed in parameters of diastolic and systolic functions where the highest E/A and E/e’, the lowest average e’, the largest ESV and EDV and the lowest EF were noted in reversed concordance, while all these parameters were noted to be best in normal concordance and were intermediate between both groups in reversed PRE and POE. Importantly, in heart failure patients, bundle branch block was not significantly different between groups, while intraventricular conduction delay was most frequent in patients with totally reversed concordance (Table 2). Moreover, electrocardiographic QRS duration was lowest in patients with normal concordance, larger in patients with reversed concordance among which it was largest in patients with totally reversed concordance (Table 2).

As suggested by the concordance of the biphasic waves, the main waves in the normal pattern were the positively directed in PRE and negatively directed in POE. Correlations noted in our study between different PRE and POE velocities are summarized in Table 3 and Fig. 3. When correlation was checked between PREp and POEn it was found that both waves correlated significantly in all study subgroups, while the correlations were stronger in normal and matched controls (0.52, 0.79, respectively, all p < 0.001) and HFpEF (r = 0.56, p < 0.001), it was slightly weaker in patients with HFrEF (r = 0.42, p = 0.018). On the other hand, correlations between PREn and POEp were mainly noted in heart failure patients as no correlation was noted in normal subjects (r = 0.25, p = 0.107), and only a weak correlation was noted in matched controls (r = 0.42, p = 0.042). The correlation became slightly stronger in HFpEF (0.43, p = 0.005) and was strongest in HFrEF (r = 0.611, p < 0.001). As such it was noted that the pattern of correlation was opposite in controls and heart failure between signals associated with normal concordance and signals associated with reversed concordance showing the normal concordance signals correlate better in controls and reversed concordance signals correlate better in HF patients.

Correlation between the ratios PRE-P/N and POE-N/P, however, showed significant strong correlations in normal young subjects, weaker correlations in matched controls and HFpEF, while it was the strongest in HFrEF.

Correlations noted in our study against left ventricular filling pressures as expressed by E/e’ are summarized in Table 3 and Fig. 3. Importantly, it was shown that, most of the correlations of the biphasic velocities were noted in HF patients and not in controls. Briefly negative correlations were found between E/e’ and PREp in patients with HFpEF and HFrEF (r = -0.51, -0.4, p < 0.001, = 0.025), between E/e’ and POEn in patients with HFpEF only (r = -0.43, p = 0.002), between E/e’ and POEp in patients HFrEF only (r = -0.36, p = 0.045), while PREn did not correlate with E/e’ in any of the patients. The ratio PRE-P/N was found to correlate the strongest with E/e’ in both HFpEF and HFrEF (r = -0.55, -0.54; p < 0.001, = 0.002, respectively), while the ratio POE-N/P showed similar however weaker pattern of correlations (r = -0.3, -0.45, p = 0.034, 0.012, respectively).

Receiver operator characteristic curves (Fig. 4) showed that the best predictors for E/e’ > 13 was PRE-P/N ≤ 1.68 (AUC:0.782, sensitivity: 86%, specificity 50%) while that for POE-N/P was ≤ 1.15 (AUC:0.791, sensitivity: 82%, specificity 64%).

Finally, correlations noted in our study against left ventricular EF are summarized in Table 3. The only variable that showed correlation with EF was PREp in patients with HFrEF (r = 0.413, p = 0.021). Other than that, PREp, PREn, POEn, and POEp velocities as well as the ratios PRE-P/N and POE-N/P did not correlate with EF in any of the groups of the study patients or control groups.

Reproducibility parameters are summarized in Table 4. For inter-observer variability, the absolute differences and interclass correlation coefficient for PREp were 0.03 ± 0.93 cm/s, 0.94, respectively, for PREn were 0.72 ± 0.67 cm/s, 0.84, respectively, for POEn were -0.53 ± 0.38 cm/s, 0.91, respectively, and for POEp were 0.01 ± 0.38 cm/s, 0.88, respectively. On the other hand, for intra-observer variability, the absolute differences and interclass correlation coefficient for PREp were 0.11 ± 0.57 cm/s, 0.97, respectively, for PREn were -0.22 ± 0.45 cm/s, 0.93, respectively, for POEn were -0.17 ± 0.31 cm/s, 0.93, respectively, and for POEp were 0.02 ± 0.34 cm/s, 0.89, respectively.

The LV mechanical behavior during pre-ejection and post-ejection is a complex and controversial topic [8‐10]. Pre-ejection is traditionally biphasic [11], the first phase is referred to as electromechanical delay (EMD) and is represented by the interval from the onset of the electrocardiographic QRS complex to mitral valve closure (MVC), and the second phase is referred to as isovolumic contraction (IC) which follows MVC and is characterized by a rapid increase in LV pressure before opening of the aortic valve. Recent studies have shown that two opposing mechanical behavior occur during the pre-ejection phase: subendocardial shortening exhibited during the first phase (EMD), accompanied by stretching of the subepicardial fibers during the second phase (IC) [12]. Studies have shown that this mechanical behavior can be mirrored by the biphasic mitral annular TDI-derived velocities[7], such that the positive component occurring during the EMD corresponds to the active subendocardial shortening and the negative component occurring during the IC corresponds to the passive subepicardial stretch. The significance of this complex mechanical behavior is reportedly tightly related to efficient systolic ejection [13]. The predominance of the positive component of the biphasic pre-ejection velocity in our study suggests that the prevailing and dominant force of active shortening over the passive stretch functions resulting in a higher corresponding positive over negative velocity. In our study, the reversal of this predominance (negative predominance of the PRE) may suggest loss of the magnitude of the active shortening, or a pathological prevalence of the stretch force associated with heart failure which may explain the worse systolic and diastolic functions.

Reportedly, the forces produced during pre-ejection are stored in memory within the myocardial wall until the end of the ejection phase [7, 14]. Reversal of the shortening-lengthening relationship defines the physiological onset of relaxation. In our study, opposite TDI velocities of both pre-ejection and post-ejection phases correlated positively, supporting the reversal of the shortening–stretch relationships from PRE into POE.

Importantly, the positive predominance of the PRE and the negative predominance of the POE suggests that the magnitude of the active forces (shortening) during PRE and the magnitude of their release during POE exceeds that exerted by the passive fiber stretch and its reversal and further suggest that the active endocardial mechanics are the driving force in all isovolumic mechanical behavior over the passive epicardial mechanics.

The coupling of normal predominance of both phases, noted in our study as the normal concordance between both phases, was mostly found in normal young patients and in age matched controls. Moreover, when such normal concordance was encountered in heart failure patients, it was associated with the best clinical and hemodynamic profile. The loss of normal concordance was almost always found in heart failure patients and was characterized by either reversal of one of both phases (partial reversal) or reversal of both phases (complete reversal). The progression from normal concordance to partially reversed and finally to completely reversed concordance in our study was associated with a similar progression in severity of the clinical and hemodynamic profiles in heart failure patients. Importantly, it was uncommon to have an isolated reversal of PRE (i.e. a reversed PRE without coupled reversal of the POE), while isolated reversal of the POE was not uncommon. Partial reversal of the predominance of the biphasic velocities may be due to failure of normal transmission of the pre-ejection forces (shortening–stretch) in memory into the post-ejection phase which may lead to inappropriate diastolic behaviors (as noted in patients with HFpEF) but may also affect systolic function to a certain degree. Complete reversal, on the other hand, means complete disruption of the presumed PRE-POE relationships and may be due to faulty generation of PRE forces and subsequent faulty transmission of these forces into the POE.

The mechanistic explanation of these changes lies in the fact that PRE-POE relationship is based on myocardial electromechanical anisotropic coupling [15, 16]. In normal physiological situations, the electrical activation occurs in an endocardial to epicardial direction and begins subendocardially near the apical septum and spreads rapidly toward the base. The rapid apico-basal spread of electrical activation within the subendocardium initiates the contraction sequence and coincides with an early rapid build-up of intraventricular pressure during the pre-ejection period. Subepicardial deformation occurs later temporally coinciding with the onset of systolic ejection. Importantly, this apico-basal wave of endocardial shortening aids in milking blood towards the LV outflow. Conversely, during repolarization, transmural electrical gradients propagate in a base-to-apex direction. As such, mechanical coupling during post-ejection (reversal of the shortening-lengthening forces) follows the same baso-apical direction aiding in formation of suction pressure and early diastolic filling.

This timing and sequence of electrical excitation influenced by the His-Purkinje system and the anistropic nature of myocardium [16], both of which are prone to disruption in heart failure patients as a result of microscopic fibrosis or loss of gap junctions. In our study, this hypothesis may be suggested by the fact the occurrence of intraventricular conduction delay was associated with reversal of velocities especially with totally reversed concordance, and similarly, QRS duration was prolonged the most in those patients. As such this electrical disruption may lead to faulty initiation, and/or transition of mechanical forces between pre-ejection and post-ejection and loss of mechanical coupling expressed as the shortening-lengthening forces and thus may explain the functional and hemodynamic outcomes of reversal of predominance and concordance of pre- and post-ejection velocities in our study.

The study suffered from the following limitations: first, the sample size is small and larger studies should be conducted before the findings can be adopted to clinical practice. Second, mitral annular velocities are the result of the tethering of the fibrous structure of the mitral annulus, and as such represents only an indirect measure of myocardial mechanics. Better representation of the myocardial mechanics can be obtained using myocardial deformation imaging techniques such as speckle tracking echocardiography. Strain rate imaging would be an appropriate alternative, however, due to the lower frame rate and higher signal to noise ratio, deformations during PRE and POE can either be missed or recorded with high noise, making it less reproducible than spectral tissue Doppler of the mitral annulus. Third, mitral annular velocities represent mainly deformations in the longitudinal directions, however deformations during pre- and post-ejection phases occur in all other directions of contraction, namely, circumferential, radial, as well as rotational (twist). Further studies should focus and compare the relationships of deformation in other directions of myocardial contraction in PRE and POE both in health and disease. Forth, reduced EF in our study was defined as EF ≤ 50% according to the American society of echocardiography guidelines for chamber quantification [17]. It is important to note that recently a separate category of patients with EF between 40–50% is thought to be categorized as patients with mid-range EF (HFmrEF). In our study we have not studied HFmrEF as a separate category as we were more focused on changes with any EF abnormality. It is important to note that this catogery of patients represent a controversy as to which category of HF it behaves similarly. Recently, evidence suggested regression towards including these patients as HFrEF with mild reduction of systolic function as it was found to be behaving similarly [18]. As such, in our study, we have included this subcategory of patients as patients with HFrEF. Fifth, the status of heart failure in these patients was clinically assessed using NYHA functional class. Brain natriuretic peptide (BNP) is reportedly a more objective way to assess heart failure, however it was not measured in our study. In our patients, echocardiograms were done on an outpatient basis, and as such BNP was not measured in relation to the echocardiographic studies. However, the diagnosis of these patients was previously established prior to their echocardiographic studies according to the guidelines using clinical presentation and laboratory findings including BNP. Finally, the relationships to systolic and diastolic functions lack invasive reference methods for comparison, further studies should consider reproduction of the correlations observed against invasively measured pressures.