Vortex Formation Time is a Novel Measure for Early Detection of Diastolic Abnormalities in Adolescents with Hypertension

Pediatric hypertension (HTN) has demonstrated an upward trend in recent years. Adolescent HTN has been linked to adult HTN, cardiovascular disease, and other health conditions. Thus, it is essential that HTN and its associated cardiac abnormalities be diagnosed and treated early to minimize lifelong adverse effects. In this study, we evaluated whether vortex formation time (VFT), a validated echocardiogram measure of left ventricular diastolic dysfunction, correlated with ambulatory blood pressure monitoring (ABPM) and HTN in adolescents. Echocardiogram data including systolic and diastolic function indices and ABPM data from 2015 to 2022 in adolescents age 13–21 years were analyzed retrospectively. We found that VFT was significantly lower in adolescents with HTN compared to those without HTN (3.69 ± 1.39 vs. 4.50 ± 1.73, p = 0.02). Standard echocardiographic indices of systolic and diastolic function were similar between the two groups, except indexed left atrial volume. Higher overall systolic blood pressure (SBP) (β = − 0.01, CI − 0.02, − 2.2 × 10–3, p = 0.02), mean wake SBP (β = − 0.01, CI − 0.02, − 9.4 × 10–4, p = 0.03), and mean sleep SBP (β = − 0.01, CI − 0.02, − 1.2 × 10–3, p = 0.03) were significantly associated with lower VFT. This study demonstrates that VFT correlates to ABPM data and can be used a novel diagnostic measure in adolescents with HTN.


Introduction
Over the past two decades, hypertension in pediatrics (HTN) has increased worldwide, reaching an estimated global prevalence of 4% in 2018 [1]. This upward trend represents a growing challenge in public health due to the adverse longitudinal effects that HTN may have on adolescents and into adulthood. Specifically, HTN in adolescents has been linked to cardiac dysfunction related to both systolic and diastolic dysfunction [2][3][4][5][6][7][8][9][10], early target organ damage [2][3][4], and reduced neurocognitive function [2,4]. Thus, it is essential for adolescents to be appropriately diagnosed and treated for HTN to protect their cardiovascular health and minimize the risk of lifelong adverse effects.
Diastolic dysfunction is diagnosed using echocardiography based on guidelines from the American Society of 1 3 Echocardiography (ASE) and the European Association of Cardiovascular Imaging [10,13]. Under these guidelines, four variables are used to diagnose LVDD: e' velocity, E/e' ratio, left atrium maximum volume index, and tricuspid regurgitation systolic jet velocity [13]. In recent years, the novel measure of vortex formation time (VFT) has been correlated with LVDD in adults [14]. Counterclockwise vortices form in the LV during the filling stage of diastole, allowing for the acceleration of blood flow to optimize momentum and ejection of blood during isovolumic contraction in systole [14][15][16][17]. The formation of these vortices is essential to maximize the efficiency of LV function [15]. VFT is a validated non-dimensional measure of LV vortex formation during diastolic filling in adults [18]. It is calculated using the stroke ratio of the trans-mitral flow, mitral valve diameter, and LV geometry [19]. VFT has been used to evaluate heart function in heart failure [16,20], congenital heart disease [20][21][22], atherosclerosis [23], and right ventricular dysfunction [5,24]. Lower VFT values are seen in adult patients with diastolic dysfunction, indicating inefficient propulsion of blood across the mitral valve [25]. However, VFT has not been evaluated as a diagnostic measure of diastolic abnormalities in adolescents with HTN.
The American Heart Association (AHA) and the American Academy of Pediatrics recommend the use of 24 h ambulatory BP monitoring (ABPM) to diagnose HTN in pediatrics [4]. This allows for the evaluation of circadian BP patterns and exclusion of diagnostic errors from white coat HTN [4].
The main aim of this study was to evaluate whether VFT is associated with changes in BP and HTN measured with ABPM in adolescents. We hypothesized that in adolescents lower VFT is associated with higher BP and HTN, potentially suggesting VFT as a new marker for diastolic dysfunction in HTN in pediatrics.

Study Population
This retrospective study included adolescents 13-21 years of age from a single center (Cohen Children's Medical Center at Northwell Health) referred to the pediatric nephrology clinic from January 2015 to June 2022 for evaluation of suspected HTN. All patients received ABPM in the nephrology clinic; however, only patients who had an ABPM and echocardiogram performed within a three-month time frame of each other were included in the study. No patients were excluded due to a previous diagnosis of HTN, severity of HTN, chronic kidney disease status, transplant status, or indication for ABPM (screening vs monitoring) [26].
Patients in whom echocardiographic data were inadequate for VFT calculations such as when there was fusion between the E and A waves of the mitral wave were excluded from analysis. The study was approved by the Institutional Review Board of Northwell Health.

Demographic and Clinical Variables
Patient demographic information (age, sex, height, weight, self-identified race/ethnicity) was obtained from the electronic medical record. Body mass index (BMI) and BSA were calculated using height and weight, and BMI was converted into z-scores [18].

Ambulatory Blood Pressure Monitoring
Spacelabs ABPM devices (model 90217A; Spacelabs Healthcare) were used to take BP readings as a part of standard of clinical care. Participants were instructed to wear the device on their non-dominant arm for 24 h and self-report their sleep and wake times [26]. A diagnosis of HTN was made using the AHA guidelines for ambulatory BP in pediatric patients as follows: overall mean systolic BP (overall SBP) ≥ 125 mmHg, overall mean diastolic BP (overall DBP) ≥ 75 mmHg, mean wake SBP (wSBP) ≥ 130 mmHg, mean wake DBP (wDBP) ≥ 80 mmHg, mean sleep SBP (sSBP) ≥ 110 mmHg, or mean sleep DBP (sDBP) ≥ 65 mmHg [4]. Nocturnal HTN (NOCT HTN)/high BP during sleep was diagnosed when sSBP was ≥ 110 mmHg or sDBP was ≥ 65 mmHg [4]. ABPM also measured SBP dipping (SBPd) and DBP dipping (DBPd). These measures refer to BP dropping during sleep that creates a dipping pattern; this decrease is expected to range from 10-20% in healthy individuals [4,27].

Echocardiography
All echocardiograms were performed using ASE guidelines for pediatric echocardiograms [26,28]. Echocardiograms were performed using either Phillips Affinity or EPIQ ultrasound system with appropriate transducers [28]. Twodimensional images of the left atrium and LV in the apical 4-chamber and 2-chamber were recorded, and the LV was imaged in the parasternal short-axis view [28]. The left ventricular stroke volume (SV) and ejection fraction (EF) were calculated using the biplane Simpson's method of summation of disks [28]. LV mass was calculated using the 5/6 area length method and indexed to height 2.7 . Left atrial volume (LAV) (mL) was calculated using the biplane Simpson's method of summation of disks, by tracing the left atrium in the apical 4-chamber and 2-chamber views in end-systole [28]. LAV was then indexed (LAVI) to body surface area (BSA). A 2 mm pulse Doppler gate was placed within 1 cm of the mitral valve annulus at the interventricular septum in the apical 4-chamber view to measure pulse wave septal e' tissue Doppler velocity (septal e') (m/s) [28]. The ratio (E/e') of the mitral E-wave and septal e' was then calculated. A mean of two random separate cardiac cycle measurements was used for all calculations. The following measurements were made to calculate VFT: peak velocity (m/sec) of the mitral E-and A-waves and the mitral valve's geometric orifice area (GOA) (cm 2 ) [18]. To measure GOA, the mitral valve leaflets were traced along the largest open dimension of the mitral valve in the parasternal short-axis view perpendicular to the mitral valve leaflets (D E= 2√GOA/π) [18]. All measurements for VFT were made by HD.
To obtain trans-mitral VFT, the following equation was used [25]: is the fraction of SV contributed from the A-wave component of left ventricular filling, and α 3 is a dimensionless left ventricular volume parameter [18]. α is obtained by dividing left ventricular end diastolic volume (LVEDV)(ml) by the cubic power of D E ; α = (LVEDV/D E 3 ) . Since LV SV comprises E-wave ( ) and A-wave (β) blood flow, = 1 − was substituted in the calculation for VFT, yielding the following equation [25]: Normal VFT was defined as 3.5-5.5 [19,20].

Statistical Analysis
Demographic and clinical variables were presented as means with standard deviations and as proportions. Distributions of sex, race, and ethnicity were evaluated using chi-square tests across patients with and without HTN. Two sided t-tests were used to compare the demographic and echocardiogram distributions of all other variables across patients with and without HTN.
Linear regressions were run to assess whether overall BP, wake BP, sleep BP, HTN, NOCT HTN, and LVMI were associated with VFT. All assumptions and goodness of fit were checked, and non-normally distributed variables were log transformed to achieve normality. Crude regressions and regressions adjusted for age, sex, and BMI z-score were conducted. Overall SBP and VFT were then plotted on a scatterplot, and a line of best fit was generated. Analyses were conducted using statistical software SPSS 28 (IBM Inc.). Echocardiographic measurements and corresponding VFT calculations were repeated on 5 subjects more than 3 months after the first measurements to derive inter-observer (HD and MJ) and intra-patient (HD) VFT correlations using Bland-Altman analysis. A p-value ≤ 0.05 was considered statistically significant.

Results
Of the 703 patients who had ABPMs, 537 patients did not have echocardiograms performed within three months and were thus excluded from the study. Of the 166 patients with simultaneous echocardiograms, VFT measurements could not be made in 82 patients due to inadequate echocardiographic images and were further excluded from the study. Simultaneous echocardiogram and ABPMs within a 3-month window were performed in 84 patients and met inclusion criteria for the current analysis. Of these, 65.5% of the participants had HTN based on AHA guidelines (Table 1). There were no significant differences in age (p = 0.06), sex (p = 0.91), BMI (p = 0.06), and BMI z-score (p = 0.63) between adolescents with and without HTN ( Table 1). Patients with HTN had significantly higher overall SBP (p < 0.001), overall DBP (p < 0.001), wSBP (p < 0.001), wDBP (p = 0.02), sSBP (p < 0.001), sDBP (p < 0.001), and lower SBPD (p = 1.3 × 10 -3 ) and DBPD (p < 0.01) ( Table 1). VFT was significantly lower in adolescents with HTN compared to those without HTN (p = 0.02) ( Table 2) (Table 2). However, patients with HTN had significantly higher LAVI (p = 0.03) ( Table 2).
The relationship between overall SBP and VFT is depicted in Fig. 1, with an estimated line of best fit with an equation of y = 8.99-0.04x.
Assuming a pooled standard deviation of 1.39 units, the study required a sample size of 38 for each group (i.e., a total sample size of 76, assuming equal group sizes), to achieve a power of 80% and a level of significance of 5% (two sided), for detecting a true difference in means between the test and the reference group of 0.9 units. Our study had adequate sample size and power to demonstrate the difference between the 2 groups.

Discussion
In this single-center retrospective study, adolescents with HTN had significantly lower VFT than patients without HTN, indicating that VFT may be a marker of diastolic dysfunction in adolescents with HTN. Abnormalities of VFT correlated to HTN even when standard indices of diastolic function, except LAVI, were normal in these patients. These findings support our hypothesis that in adolescents, lower VFT is associated with higher BP and HTN. Interestingly, LVMI was not associated with VFT.
These findings build on previous studies in adults which have evaluated VFT as a measure of diastolic dysfunction in heart failure [16,20], congenital heart disease [20][21][22], and atherosclerosis [23]. VFT has not been assessed as a diagnostic measure of diastolic dysfunction in pediatric HTN, though reduced VFT has been observed in adult patients with HTN [29]. This study corroborates those findings to BMI body mass index, BSA body surface area, overallSBP mean systolic blood pressure, overallDBP mean diastolic blood pressure, wSBP mean wake systolic blood pressure, wDBP mean wake diastolic blood pressure, sSBP mean sleep systolic blood pressure, sDBP mean sleep diastolic blood pressure, SBPd systolic blood pressure dipping, DBPd mean diastolic blood pressure dipping Mean ± SD or n (%) Adult criteria for diagnosis of LVDD use numerous parameters including e', E/e', LAVI, and tricuspid regurgitation systolic jet velocity [10,13]. These criteria are known to be inadequate when applied to pediatric and adolescent patients with significant discordance between e' and LAVI parameters as well as heterogeneity in the published normative ranges [13,32]. Our findings suggest that VFT correlates well to HTN and SBP. Vortex formation in the LV occurs due to a combination of suction forces in LV during the rapid filling phase and propulsion of blood through the LV during the atrial phase with associated recoil of the mitral valve annulus that causes pinching off of the vortices from the mitral valve leaflet [25]. The VFT incorporates the entire diastolic filling phase of the cardiac cycle and depends on the fraction of SV contributed during the A-wave, the ratio of LVEDV to the cubic power of maximal effective diameter of the mitral valve, and the EF. It is a measure of the vortex formation inside the LV cavity. It Table 3 Regression analysis of blood pressure and left ventricular hypertrophy with vortex formation time overallSBP mean systolic blood pressure, overallDBP mean diastolic blood pressure, wSBP mean wake systolic blood pressure, wDBP mean wake diastolic blood pressure, sSBP mean sleep systolic blood pressure, sDBP mean sleep diastolic blood pressure, SBPd systolic blood pressure dipping, DBPd mean diastolic blood pressure dipping, HTN hypertension, NOCT HTN [19,20]. Data in adult patients with diastolic dysfunction have also demonstrated the ability of VFT in differentiating the various grades of dysfunction including pseudo-normal patterns [25] and in differentiating heart failure with preserved ejection fraction from reduced ejection fraction [33]. Patients included in our study did not meet criteria for diastolic dysfunction based on E/A or E/e' velocities; however, the LAVI was higher in patients with HTN compared to those without. It is likely that patients with HTN had pseudo-normal patterns that were uncovered with VFT and therefore we propose that VFT may be used as a marker to uncover early stages of diastolic dysfunction. Further studies including a larger sample of patients with normal and abnormal LVMI and diastolic function indices as well as on medical management for their HTN may help us understand if the correlations to SBP noted in our study hold true across various clinical scenarios and echocardiographic findings in pediatric patients. We propose performing VFT calculations during routine echocardiograms especially in patients where diastolic dysfunction is suspected in addition to routinely assessed diastolic parameters, such as in patients with hypertension or hypertrophic cardiomyopathy. The VFT calculations do not require any additional image acquisition beyond those obtained as a part of standard pediatric echo protocols and are easy to perform once the formula is incorporated into routine workflow. Normative values for VFT in pediatrics have been published previously by the authors [18]. In this study, VFT values were comparable to the adult published range of VFT since the included patients in the study had a larger BSA similar to adults (Table 1-BSA 1.92 ± 0.32).
There are limitations to this study. The mitral valve has a time-varying diastolic diameter and the area changes continuously throughout the phases of LV filling [19]. The largest diameter derived from the GOA was used for VFT calculations, as has been used in previous studies [18][19][20]. Temporal and spatial resolution limitations in echocardiography preclude the use of any other diameter; there is negligible delay in achieving the largest diameter from the mid-diastolic phase of mitral valve inflow on echocardiograms [19]. There are numerous mathematical calculations in all echocardiographic indices such as ejection fraction and these are subject to assumptions of an ellipsoid shape of the LV including an assumption of minimal variations from beat to beat. Such assumptions are inherent to VFT calculations also. All data come from a single center and with a small sample size, affecting the generalizability of the results. The study is retrospective, which also may make it less generalizable. Finally, because 76.4% of participants with ABPM data did not have echocardiograms performed within three months, and of the participants who did have echocardiogram data, 49.3% of patients did not have VFT measurements, a significant proportion of

Conclusions
It is essential for adolescents to be diagnosed and treated early for HTN in order to minimize the lifelong adverse effects. Accurate diagnostic markers are key to this process. This study introduces VFT as a potential novel marker for early detection of diastolic dysfunction and cardiovascular involvement in pediatric HTN. Large-scale VFT validation studies in various pathological states are required in pediatrics and adolescent patients prior to application. However, this study sets precedence for such larger studies by demonstrating feasibility and the value of this measure in assessment of pathology.