The hemodynamic cardiac profiler volume-time curves and related parameters: an MRI validation study

Background. The hemodynamic cardiac profiler (HCP) is a new, non-invasive, operator-independent screening tool that uses six independent electrode pairs on the frontal thoracic skin, and a low-intensity, patient-safe, high-frequency applied alternating current to measure ventricular volume dynamics during the cardiac cycle for producing ventricular volume-time curves (VTCs). Objective. To validate VTCs from HCP against VTCs from MRI in healthy volunteers. Approach. Left- and right-ventricular VTCs were obtained by HCP and MRI in six healthy participants in supine position. Since HCP is not compatible with MRI, HCP measurements were performed within 20 min before and immediately after MRI, without intermittent fluid intake or release by participants. Intraclass correlation coefficients (ICCs) were calculated to validate HCP-VTC against MRI-VTC and to assess repeatability of HCP measurements before and after MRI. Bland–Altman plots were used to assess agreement between relevant HCP- and MRI-VTC-derived parameters. Precision of HCP’s measurement of VTC-derived parameters was determined for each study participant by calculating the coefficients of variation and repeatability coefficients. Main results. Left- and right-ventricular VTC ICCs between HCP and MRI were >0.8 for all study participants, indicating excellent agreement between HCP-VTCs and MRI-VTCs. Mean (range) ICC of HCP right-ventricular VTC versus MRI right-ventricular VTC was 0.94 (0.88–0.99) and seemed to be slightly higher than the mean ICC of HCP left-ventricular VTC versus MRI-VTC (0.91 (0.80–0.96)). The repeatability coefficient for HCP’s measurement of systolic time (tSys) was 45.0 ms at a mean value of 282.9 ± 26.3 ms. Repeatability of biventricular HCP-VTCs was excellent (ICC 0.96 (0.907–0.995)). Significance. Ventricular volume dynamics measured by HCP-VTCs show excellent agreement with VTCs measured by MRI. Since abnormal tSys is a sign of numerous cardiac diseases, the HCP may potentially be used as a diagnostic screening tool.


Introduction
Left-(LV) and right-ventricular (RV) systolic and diastolic volume dynamics constitute some of the most important parameters in cardiology (Göransson et al 2018).Over the past decades, cardiac magnetic resonance imaging (MRI) has developed into a powerful tool for quantification of heart chamber volume dynamics, surpassing echocardiography in accuracy and precision in a number of fields (Lima and Desai 2004).However, both echocardiography and MRI have inherent drawbacks.Costs, safety, complexity and measurement or processing time constitute important limitations of MRI (Mendoza et al 2010, Barison et al 2022).

Materials and methods
In this pilot validation and repeatability study, left-ventricular (LV) and right-ventricular (RV) VTCs were measured by both HCP and MRI in 6 healthy volunteers free from cardiovascular disease.The study protocol was approved by the Medical Ethics Committee of Amsterdam University Medical Centers (NL60812.018.17) and conducted according to the principles outlined in the Declaration of Helsinki (2013).Written informed consent was obtained from all study participants.

Study outcomes
Our primary outcome for HCP measurement accuracy was (a) agreement between HCP-and MRI-VTCs (one VTC per technique) per participant, as measured with intraclass correlation coefficients (ICCs), as well as (b) agreement assessed with Bland-Altman analyses between three VTC-derived parameters (tSys, 1/3FF, and E/A ratio) produced by HCP and by MRI.Furthermore, our primary HCP outcome for HCP measurement precision was (a) agreement (of the morphology) of three pairs of individual biventricular VTCs of HCP1 (pre-MRI) and HCP2 (post-MRI) measurements, assessed using ICCs, and (b) agreement between values (mean ± SD) for tSys and 1/3FF (and heart rate) of measurement HCP1 and HCP2.

HCP measurements
The current HCP system (prototype2) consists of two separate parts: the portable patient unit and the healthcare professional console.The patient carries the small, light-weight portable patient unit (dimensions: 20 cm × 15 cm × 5 cm) that is attached to a belt around the hips of the patient (figure 1(a)).The patient unit processes voltage signals from six independent electrode pairs from a disposable electrode patch on the skin of the patient (figure 1(b)).The healthcare professional console consists of a computer and a screen where the HCP measurements are displayed (figure 1(c)).The console computer is connected to the portable patient unit via a continuous Bluetooth connection.In comparison to the previously described system (prototype1) (Konings et al 2017), the current HCP protoype2 includes miniaturized electronics producing output that is less prone to electric disturbances.Furthermore, in contrast to prototype1, the wearable nature of prototype2 enlarges its potential application range, because it can be used for home monitoring or monitoring in the hospital while performing light activities from everyday life, such as walking up a flight of stairs.
All HCP measurements were performed according to HCP standard operation procedures.In short, we applied the four current-applying HCP electrodes (Nutrode-P20M0, Nutrode-P10M0 pre-gelled, GE Healthcare, United Kingdom) on the hips and above the left and right clavicle.The electrode patch containing the six independent electrode pairs was placed on the participant's thorax in a predefined pattern using two markers printed on the patch, i.e. a central vertical line on the patch to be aligned with the central vertical axis of the sternum, and a small lateral notch in the patch that must coincide with the 4th intercostal space.The exact location of the patch during HCP1 (pre-MRI) was marked on the skin in order to attach a second electrode patch at exactly the same position during the HCP2 measurement (post-MRI).All HCP measurements were performed in supine position with normal resting breathing rate.Each HCP measurement session took approximately 10 min.

MRI protocol and image analyses
MRI in supine position at rest was performed with a 3T MR system (Ingenia; Philips, The Netherlands).After scout imaging, a stack of 15-20 contiguous left-ventricular short-axis views was acquired covering the entire LV and RV from apex to above the base.Cinematographic images were acquired during end-expiratory breathholds using retrospective ECG-triggering at a relatively high temporal resolution of 15 ms/frame.Other parameters: balanced steady-state free precession sequence; repetition time/echo time, 2.8/1.4 ms; SENSE factor, 2; field of view, 300 × 300 mm; slice thickness, 8 mm.Total MR examination time was approximately 30 min.Quantification of left-and right-ventricular volumes throughout the cardiac cycle was performed via endocardial contouring (cvi42, version 5; Circle Cardiovascular Imaging Inc., Canada), yielding LV and RV enddiastolic volumes (EDV), end-systolic volumes (ESV), stroke volumes (SV), ejection fractions (EF), and LV-and RV-VTCs.
Due to electromagnetic interference, the HCP cannot be used inside an MR scanner.HCP measurements were performed twice, i.e. a first HCP measurement within 20 min before the MRI measurement (HCP1), and a second HCP measurement immediately after the MRI measurement (HCP2).Participants were instructed to not drink and abstain from using the bathroom from the start of the HCP1 measurement until the completion of the HCP2 measurement after MRI examination to reduce the potential impact of any physiological differences between HCP and MRI measurements.

Statistical methods
To assess accuracy of the HCP, ICCs between LV-VTCs and RV-VTCs measured by HCP and MRI were calculated for all participants.ICCs between three pairs (a, b, c) of biventricular VTCs with equal R-R interval measured by HCP1 and HCP2 were calculated for each study participant to assess repeatability of HCP VTCs' morphology.ICCs were determined using a two-way random effects model with absolute agreement; single measures are reported, and values are interpreted as poor (<0.40), fair (0.40-0.59), good (0.60-0.74), and excellent (0.75-1.00) (Cicchetti 1994).
The HCP-VTC with an R-R interval length most similar to that of the MRI acquisitions was selected for the comparison regardless of whether this measurement was from HCP1 or HCP2.To allow comparison of HCP-VTC data measured at sample rate of 5 ms with MRI-VTC data measured at a temporal resolution of 15 ms, the HCP-VTC data were downsampled.In addition, since each HCP-VTC represents volume changes as a percentage of SV, the ventricular volumes in each MRI-VTC graph were expressed as a percentage of SV as well.
To perform a detailed analysis of relevant clinical parameters of systolic and diastolic cardiac function, values of these parameters were derived from VTCs and compared between HCP and MRI.Parameters describing ventricular volumes in time were calculated from the original VTC (figure 2(a)) and the time-derivative (figure 2(b)).The parameters tSys and isovolumetric relaxation time (IVRT) were based on the time-derivative: the period around the zero-crossing between (±0.25 × early Peak Filling Rate (PFR)) was defined as the IVRT.IVRT is by definition in diastole.1/3FF measures were based on one-third of the filling period following the IVRT.E/A ratio was defined as the ratio of early PFR (ePFR) to atrial PFR (aPFR).
Bland-Altman plots (Bland andAltman 1986, Giavarina 2015) were used to assess the agreement between measurement of HCP-and MRI-VTC parameters such as tSys, 1/3FF and E/A ratio.The measurement agreement between HCP and MRI was determined by calculating the bias (mean difference between methods) and the standard deviation (SD) of the differences with lower and upper limits of agreement (LOA) (i.e.bias ± 1.96 × SD).Additionally, to assess HCP precision in terms of measurement repeatability of tSys and 1/3FF of biventricular VTCs, we compared the values for the parameters (mean ± SD) of six measurements of HCP1 and HCP2 for each study participant and calculated the coefficient of variations (CV) and repeatability coefficient.The CV is the ratio of the standard deviation over the mean (SD/mean × 100).The inter-session repeatability coefficient (CR) (i.e.1.96 × SD of the intrasubject differences of the mean for HCP1 and HCP2) was determined for measurement of each parameter (Bland andAltman 1986, Bunting et al 2019).All statistical analyses were performed using IBM SPSS Statistics version 22.0 and GraphPad Prism version 9.4.1.Data are reported as mean (range) or mean (SD).
The individual volumetric parameters of the six study participants measured by MRI are presented in table 1.The LV-SV ranged from 124.1-129.8mL, RV-SV 103.4-132.1 mL, LV ejection fraction (EF) 54.8%-61.1% and RV EF 51.1%-56.7%.rapid filling phases.We observed small deviations between HCP-VTC and MRI-VTC during diastasis, for both LV and RV.

Intraclass correlation coefficients between biventricular VTCs of HCP1 and HCP2
Table 3 shows the ICCs and 95% confidence intervals (CI) of repeatability of HCP VTCs' morphology.Preand post-MRI measurements (HCP1 and HCP2) were similar.ICCs between three pairs (a, b, c) of

VTC-derived parameters of HCP1 versus HCP2
A comparison between VTC-derived parameters tSys (ms), 1/3 FF (%SV) for biventricular VTCs measured by HCP1 and HCP2 are shown in figure 9 and figure 10, respectively.Additionally, heart rate (bpm) of HCP1 and HCP2 for each study participant is shown in figure 11.Table 4 shows HCP's measurement of agreement between values (mean ± SD of 6 biventricular VTCs of HCP1and HCP2) for tSys, 1/3FF and heart rate of measurement HCP1 and HCP2.The repeatability coefficient (CR) for measurement of tSys is ± 45.0 ms at a mean value of 282.9 ± 26.3 ms.The values of observed differences (HCP2-HCP1) for tSys (−35.7,−2.2, 21.8, 15.3, −18.0, 18.1 ms) are within the subscale's mean error (± 45.0 ms), suggesting that all observed differences do not reflect real differences but are differences considered to belong to measurement error (Vaz et al 2013).

Discussion
In this pilot validation and repeatability study in healthy participants, we found agreement between VTCs from HCP and VTCs from MRI, both for the LV and RV.This agreement between VTCs from HCP and VTCs from MRI suggests VTCs produced by HCP may be a promising alternative for measuring VTCs by MRI.
Visual inspection of HCP-VTCs revealed a consistent similarity to MRI-VTCs during the systolic phase and the rapid filling phase.However, during diastasis, for both ventricles, HCP-VTCs demonstrated slightly more visual deviations from the MRI-VTCs.Although ICCs are generally high for all participants, this does not necessarily imply that the measurements agree in all individual cases.For instance, not all participants show a strong agreement of HCP-VTCs with MRI-VTCs.
The measurement accuracy of the current version of the HCP appears to be capable of detecting major deviations during systole and early diastole This is confirmed by Bland-Altman analysis of tSys (which is an important parameter of systolic function) as well as by Bland-Altman analysis of 1/3FF of the right ventricle  (which is an important parameter during the first stage of the diastole and may help detecting reduced diastolic function) (Zoghbi et al 1990).The Bland-Altman plots for the E/A ratio reveal broad limits of agreement.Because E/A is a ratio, the exact value of E/A becomes numerically very sensitive to variations in small values of A in the denominator.Measurement repeatability of the morphology of biventricular VTCs was excellent for all six study participants.This is particularly relevant for situations in which the HCP is used to either (i) perform repeated HCP measurements on the same patient over the course of time (days, weeks, months) for monitoring purposes, such as during recovery from an intervention or after initiation or discontinuation of medication (e.g.cardiotoxicity of certain cancer medications, heart failure medication, etc) (Schimmel et al 2004, Asnani and    −4.2 (2.9) 8.0 SD: standard deviation, CV: Intra-session coefficient of variation, tSys: systolic time, 1/3FF: 1/3 filling fraction, E/A ratio: ratio of early (E) and atrial (A) filling.
Peterson 2017).Furthermore, the equivalence of HCP1 and HCP2 also serves as a further a posteriori accountability for the chosen method of selecting a VTC from the HCP measurements on the basis of having a heart rate close to the heart rate as measured in the MRI, regardless of whether the HCP measurement was performed before or after MRI.We have assessed the variation of the heart rate during the MRI measurements on the basis of the RR-intervals of the ECG that was recorded simultaneously inside the MR system.This yielded a standard deviation of 9.6 bpm.The precision of HCP's measurement of the parameter tSys is in the same order of magnitude of the effect size that is seen in patients with heart failure relative to normal subjects (Reant et al 2010, Patel et al 2020).For the left ventricle, precision of HCP's measurement of 1/3FF was substantially lower compared to what is reported for the Doppler-based values of RV or LV assessments in a normal population (Zoghbi et al 1990), but is currently not suitable for reliably selecting patients with cardiomyopathy, coronary disease (Lavine et al 1985) or HFpEF (Von Roeder et al 2017).For the right ventricle, however, the HCP's 1/3FF measurements were better than the HCP's 1/3FF measurements of the left ventricle.Whereas the HCP is intended to be a screening or monitoring tool, we do not, however, intend or expect the HCP to evolve into an actual full replacement for imaging modalities such as MRI.Once the suspicion of the presence of (impending) cardiac disease in a specific individual is raised by the HCP in a more general, screening-like setting, this individual will need to be referred for further guideline-based diagnostics and management.
The current portable prototype of the HCP can measure and store VTC data for many hours in a row (up to 4 h), and is equipped with an 'event button', which can be pressed by the patient during episodes of discomfort (or exercise) to mark certain points in time linked to the corresponding VTCs, for easy reference by the cardiologist or other healthcare professionals.This is an advantage in comparison to echocardiography, which provides only a snapshot of the heart at a specific moment in time during the day, whereas a patient may experience cardiac discomfort during various moments during the day, but frequently not during the actual echocardiography.

Strengths and limitations
As the HCP technology stands now, reliable HCP measurements can be performed only if the patient is in a stable resting position (i.e.sitting on a chair in upright position, or lying down in supine position) without any movements apart from breathing.This is a limitation of the current technique of the HCP, which, however, can be remedied using the following strategy: in order to register the effect of e.g.walking up a flight of stairs, the patient needs to stand still for a minute directly after reaching the next floor, and to press the event button, thus registering the cardiac effects of walking up the stairs directly after the exertion itself.Nevertheless, even with this requirement to stand still after exertion, the HCP allows for the recording of more events than would be possible during a single session of echocardiography.
As has been mentioned in the introduction section, the portable HCP described in this paper is capable of producing both the left-ventricular VTC (LV-VTC) and right-ventricular VTC (RV-VTC), whereas previously the system was not capable of distinguishing between LV-VTC and RV-VTC, and each VTC was considered simply to be the average of the LV-VTC and RV-VTC.More refined analyses (of the technical aspects of the HCP measurement technique) have since then shown that the original biventricular or 'average' ventricular volume V BIV as function of time t (in ms, during a single heartbeat) is actually approximately equal to: in which t V BIV ( ) is the 'averaged biventricular' volume as a function of time, t V LV ( ) is the LV-VTC and t V RV ( ) is the RV-VTC.The stronger contribution of V RV to the 'averaged biventricular' volume V BIV (see the factor 0.75 in the equation for the RV-VTC, as opposed to the 0.25 for the LV-VTC) is caused by the fact that the HCP electrodes on the thoracic skin are closer to the right ventricle than to the left ventricle.As a result, the reliability of the resulting RV-VTC is better than the reliability of the LV-VTC(t), because, on the basis of the equation directly above, the RV-VTC is already much closer to the biventricular VTC, and therefore the 'correction' needed to obtain RV-VTC from the biventricular VTC t V BIV ( ) is relatively small.
In the current portable HCP prototype, the assessment of both LV-VTC and RV-VTC from the above equation is executed on the basis of an additional measurement using another stimulus electrode, thus producing an extra set of independent input data for the HCP algorithm to balance the increased number of unknowns needed for the assessment of both LV-VTC and RV-VTC.
This additional measurement used for distinguishing between the left and right ventricles, however, does not yet offer the precision of the assessment of the biventricular t V BIV ( ) itself, and requires more development in future work.Particularly, the present study involved healthy study participants only, and the current algorithm processing the additional measurement assumed a fixed relation between LV-VTC and RV-VTC during systole.Further development of this additional measurement and its associated algorithm is therefore needed to be able to assess both LV-VTC and RV-VTC even in the case of severe cardiac pathologies, in which the assumption of a fixed relation between LV-VTC and RV-VTC during systole may not hold.
As explained above, however, the t V BIV ( ) from the equation above is already a good approximation of the RV-VTC, and the RV-VTC on itself seems to already have merit as an indicator for (impending) pathologies of the heart as a whole, because of the intimate relation between the volumetric motions of both ventricles (Maceira et al 2006, Borlaug and Kass 2009, Schwarz et al 2013, Vonk-Noordegraaf and Westerhof 2013, Vijiiac et al 2021).
This study has several limitations.First, the number of study participants was small.Furthermore, HCP and MRI measurements were not obtained at the same time, since it was impossible to use the HCP device in the MRI scanner due to electrical interference.Third, for highly reliable MRI-VTCs the protocol was limited to breath-hold acquisition, while HCP is principally designed to compute VTCs in the end expiratory phase from free-breathing data.This may contribute to morphological differences in VTCs between HCP and MRI.Other physiological conditions of study participants were kept stable and heart rate was similar during HCP and MRI measurements.In the specific case of the HCP, the VTC's and VTC-derived parameters are all calculated automatically in an operator-independent way, and, as a result, there was no interrater variability to be tested.

Conclusion
In this pilot study, HCP-VTCs were in agreement with MRI-VTCs.While this agreement was present for both the left and right ventricle, results for right-ventricular parameters showed generally better agreement than those for the left ventricle.Furthermore, repeatability of biventricular HCP-VTCs was excellent.Precision of HCP was good for measurement of systolic time.Findings for VTC-derived clinically relevant parameters, such as tSys and 1/3FF (for the right ventricle) indicate that the HCP may potentially become a useful non-invasive, low-cost and operator-independent screening tool for early detection of (impending) heart disease.

Figure 1 .
Figure 1.(a) Portable Hemodynamic Cardiac Profiler (HCP) patient unit (dimensions: 20 cm × 15 cm × 5 cm) that can be carried with a belt wrapped around the hips.(b) Disposable electrode patch (white), together with separate ECG electrodes (coloured) at standard 12-lead ECG positions.The HCP patient unit processes the signals from the electrode patch, and sends the data, via a continuous Bluetooth connection, to a separate console for the healthcare professional.This console consists of a computer and a screen on which the results from the HCP measurements are displayed.(c) Part of the screen available for assessment by the healthcare professional.The two black dotted rectangles are not visible on the screen but serve to indicate the location on the screen of the continuously moving graphs of the 12-lead ECG (top rectangle), and the biventricular VTC (bottom rectangle) as assessed by the HCP algorithm (Konings et al 2012).
3.2.1.Comparison of HCP-VTC against MRI-VTC Figures 3 and 4 present VTCs of LV and RV, respectively, for all study participants, as measured by HCP and MRI.All HCP-VTCs demonstrated good morphological agreement with MRI-VTCs during the systolic and the

Figure 2 .
Figure 2. Definition of volume-time curve (VTC) parameters based on the relative VTC, using MRI data of one of the study participants as an example.In (a) the relative volume change [as a percentage of the stroke volume (SV)] is shown and in (b) the timederivative of (a) is rendered.The volume change (expressed as a percentage of the SV) at the moment in time that one-third of the filling duration has taken place (i.e. at the end of the 1/3 filling duration), defines the 1/3 filling fraction (1/3FF).In this example, 1/3FF equals approximately 78% of the SV.PER indicates peak ejection rate, tPER: time to peak ejection rate, ePFR: early peak filling rate, aPFR: atrial peak filling rate, tPFR: time to peak filling rate, IVRT: isovolumetric relaxation time.

Figure 3 .
Figure 3. Left-ventricular volume-time curves (VTCs) of MRI versus hemodynamic cardiac profiler (HCP) of all study participants, together with corresponding ECG from HCP.

Figure 4 .
Figure 4. Right-ventricular volume-time curves (VTCs) of MRI versus Hemodynamic Cardiac Profiler (HCP) of all study participants, with corresponding ECG from HCP.

Figure 5 .
Figure 5. (a) Bland-Altman plot on the measurement agreement of systolic time (tSys (ms)) of the left ventricle (LV) between MRI and the Hemodynamic Cardiac Profiler (HCP).Mean bias was 46.3 ± 16.0 ms with lower and upper LOA of 14.8 ms and 77.7 ms respectively at a mean value of 286.7 ± 30.9 ms.(b) Bland-Altman plot on the agreement of measurement of tSys (ms) of the right ventricle (RV) between MRI and HCP.Mean bias was 68.5 ± 30.3 ms with lower and upper limits of agreement of 9.0 ms and 127.9 ms respectively at a mean value 305.0 ± 42.5 ms.

biventricular
VTCs of HCP1 (pre-MRI) and HCP2 (post-MRI) per study participant ranged from 0.907 to 0.995 for all study participants, indicating excellent agreement and repeatability of HCP-VTCs' morphology.An example of HCP1 (pre-MRI) and HCP2 (post-MRI) VTCs with equal R-R interval is shown in figure 8 (study participant #2).

Figure 6 .
Figure 6.(a) Bland-Altman plot on the measurement agreement of one-third filling fraction (1/3 FF (%SV)) of the left ventricle (LV) between MRI and the Hemodynamic Cardiac Profiler (HCP).Mean bias was 8.2 ± 20.6 %SV with lower and upper limits of agreement of −32.3 %SV and 48.6 %SV respectively at a mean value of 64.8 ± 13.3 %SV.(b) Bland-Altman plot on the agreement of measurement of 1/3 FF (%SV) of the right ventricle (RV) between MRI and HCP.Mean bias was 3.7 ± 11.1 %SV with lower and upper limits of agreement of −18.0 %SV and 25.3 %SV respectively at a mean value of 49.9 ± 10.7 %SV.

Figure 7 .
Figure 7. (a) Bland-Altman plot on the measurement agreement of the ratio of the volumes of the early (E) and late (A) left ventricular diastolic filling (E/A ratio) between MRI and the Hemodynamic Cardiac Profiler (HCP).Mean bias was 0.1 ± 0.87 with lower and upper limits of agreement of −1.6 and 1.8 respectively at a mean value of 2.65 ± 0.86.(b) Bland-Altman plot on the agreement of measurement of RV E/A ratio between MRI and HCP data.Mean bias was −0.23 ± 0.35 with lower and upper limits of agreement of −0.9 and 0.45 respectively at a mean value of 1.23 ± 0.39.

Figure 9 .
Figure 9. HCP measurement repeatability of systolic time (tSys [ms]).Bars indicate the mean tSys value of 6 biventricular VTCs from either HCP1 (left bar) or HCP2 (right bar) for each study participant.Whiskers indicate standard deviation.

Figure 11 .
Figure 11.HCP measurement repeatability of heart rate (bpm).Bars indicate the mean heart rate value of 6 biventricular VTCs from either HCP1 (left bar) or HCP2 (right bar) for each study participant.Whiskers indicate standard deviation.

Table 1 .
Magnetic resonance imaging (MRI) measurements of ventricular volumes per study participant.

Table 2 .
Intraclass correlation coefficients between MRI and HCP volume-time curves.
a Two-way random effects model with absolute agreement (single values).ICC indicates intraclass correlation coefficient, n: datapoints within single VTC, LV: left ventricle, RV: right ventricle, CI: confidence interval.
a Two-way random effects model with absolute agreement (single values).ICC indicates intraclass correlation coefficient, CI: confidence interval.

Table 4 .
Precision of HCP's measurement of volume time curve-derived parameters.
4.1.Potential applicationsChanges in systolic time and 1/3FF constitute important (early) signs of numerous groups of cardiac disease, such as heart failure with preserved or reduced ejection fraction(Lavine et al 1985, Reant etal 2010, Riesenkampff et al 2010, Von Roeder et al 2017, Patel et al 2020).Furthermore, concerning the diagnostic value of 1/3FF during early diastole, Montalescot et al indicated that impaired diastolic filling can be a first sign of myocardial ischemia (Montalescot et al 2013), and VTC-derived parameters for diastolic function have been shown to be well correlated with the severity of ischemia (Nakae et al 2008), myocardial infarction (Mendoza et al 2010) and heart failure with preserved ejection fraction (HFpEF) (Von Roeder et al 2017).Hence, our results indicate that the HCP may potentially be a useful diagnostic screening tool.