Aortic regurgitation (AR) is one of the most common valvular disorders in the developed world.¹ Typical management of the condition involves a combination of clinical signs and symptoms and data collection through complementary testing. Echocardiography is a key tool for the diagnosis and quantification of AR,² and its proper interpretation requires an approach integrating qualitative, semiquantitative, and quantitative measures and parameters.^{3 , 4} However, these parameters are not exempt from limitations.³

Velocity-time integral (VTI) is defined as the area measured below the Doppler velocity curve at any given point. In the case of AR, its value corresponds to the diastolic pressure gradient between the aorta and the left ventricle (LV).⁵ In patients with AR, the VTI is multiplied by the aortic effective regurgitant orifice (ERO) to calculate the regurgitant volume (RV) (RV=EROxVTI).^{2 , 6 , 7} This parameter has demonstrated its effectiveness in determining AR severity, even though the ERO value is calculated using the proximal isovelocity surface area (PISA) method, which is known to have inherent limitations in patients with AR.^{3 , 8 , 9} Additionally, taking into account the aforementioned equation, patients with severe AR typically have larger RV² and ERO values,^{7 , 10} but there is no evidence of the behavior of VTI in relation to AR severity.

Furthermore, patients with severe AR usually present increased end-diastolic pressure in the LV¹¹ as well as reduced diastolic blood pressure (DBP).^{12 , 13} These pressure changes can pathophysiologically decrease VTI by reducing the pressure gradient between the aorta and LV. This study aimed to determine whether VTI is an echocardiographic marker of AR severity.

The original sample consisted of 65 patients with moderate or severe native AR in sinus rhythm. Proper Doppler alignment of the regurgitant jet could not be obtained for three patients, who showed very eccentric jets, and were thus excluded. Out of the remaining 62 participants, 40 (64.5%) presented moderate AR, and 22 (35.5%) had severe AR. Acute AR was diagnosed in 4 patients (6.5% of the sample). The consistency among the quantification determined by the two echocardiographers was κ=0.83. All patients included were Caucasian. Table 1 presents the baseline characteristics of the sample.

Table 1

Characteristic	Total (n=62)	Moderate AR (n=40)	Severe AR (n=22)	p-value
Age (years)	68.5±14.9	68.6±14.2	66.1±15.5	0.299
Male	33 (53.2)	20 (50)	13 (59.1)	0.492
BMI (kg/m 2 )	27.5±4.7	26.5±4	29.4±5.9	0.340
SBP (mmHg)	135.6±17.8	133.6±16.7	139.4±19.8	0.213
DBP (mmHg)	62.2±15.5	63.2±12.7	59.8±19.8	0.373
Heart rate	66.8±11.3	65.8±10.6	68.5±12.4	0.382
Arterial hypertension	45 (72.6)	29 (72.5)	16 (72.7)	0.985
Diabetes mellitus	11 (17.7)	8 (20)	3 (16.6)	0.530
Dyslipidemia	30 (48.4)	20 (50)	10 (45.5)	0.732
Active smokers	10 (16.1)	6 (15)	4 (18.2)	0.744
eGFR (mL/kg/1.73 m 2 )	77.3 [40.3]	86.6 [42.3]	72.9 [34.6]	0.408
Hemoglobin	13.2±1.8	13.3±1.8	13.2±2	0.893
Beta-blockers	29 (46.8)	17 (42.5)	12 (54.5)	0.363
ACE inhibitors	19 (30.6)	11 (27.5)	8 (36.4)	0.469
ARA	16 (25.8)	13 (32.5)	3 (13.6)	0.104
DHP CCB	2 (3.2)	2 (5)	0 (0)	0.286
Non-DHP CCB	10 (16.1)	4 (10)	6 (27.3)	0.145
Amiodarone	2 (3.2)	1 (2.5)	1 (4.5)	1
Diuretics	31 (50)	17 (42.5)	14 (63.6)	0.111
Statins	26 (41.9)	19 (47.5)	7 (31.8)	0.231
Previous hospital admission for HF	16 (25.8)	9 (22.5)	7 (31.8)	0.422

ACE: angiotensin-converting enzyme; AR: aortic regurgitation; ARA: angiotensin receptor antagonists; BMI: body mass index; CCB: calcium channel blockers; DBP: diastolic blood pressure; DHP: dihydropyridine; eGFR: estimated glomerular filtration rate; HF: heart failure; SBP: systolic blood pressure. Continuous variables with normal distribution are expressed as mean±standard deviation, those with skewed distribution as median [interquartile range], and categorical variables as n (percentage).

As shown in Table 2 , the VTI of the aortic regurgitant flow was higher in patients with moderate AR than in those with severe AR. The VTI range was 2.05 m [1.53–3.58 m] in the moderate AR group and 1.88 m [0.96–2.84 m] in the severe AR group. We found a significant and inverse correlation between VTI and HR [Pearson’s correlation coefficient (r_p)=-0.408, p=0.001]. Patients with severe AR presented lower LVEF, higher LVEDD and LVESD, as well as a larger ERO, RV, and VC. However, the proper measurement of these parameters was only possible in 62.9% of the sample for ERO, 67.7% for RV, and 72.6% for VC. We underline that we identified no statistically significant association between AR severity and PHT, even though we detected a trend for it.

Table 2

Parameter	Total (n=62)	Moderate AR (n=40)	Severe AR (n=22)	p-value
AR VTI (m)	2.1±0.5	2.2±0.5	1.9±0.5	0.010
AR VTIi (VTI/heart rate)	0.033±0.012	0.036±0.013	0.028±0.01	0.024
Aortic PHT (ms)	397.3±110.1	434.2±127	367.5±86.2	0.062
Vena contracta (mm)	6±1.5	5.5±1.5	7.1±1.2	0.035
ERO (cm 2 )	0.31±0.2	0.18±0.1	0.44±0.1	0.002
Regurgitant volume (mL)	56.9±24	42.5±10.9	71.3±25.7	0.05
Thoracic aorta flow reversal	33 (53.2)	12 (30.8)	21 (95.5)	<0.001
IV septum thickness (mm)	13.1±3.6	12.5±3.5	13.8±3.5	0.460
Posterior wall thickness (mm)	10.6±2.8	10.3±2.7	11±3.1	0.383
LVEDD (mm)	50.5±9	47.3±9.6	56.1±7.1	0.001
LVESD (mm)	31±11.4	26.9±12.3	38.4±8.1	<0.001
LVEDV (mL)	131.9±54.3	106±46.6	171±36.5	<0.001
LVESV (mL)	53.6±36.1	39.9±32.2	78.7±27.5	<0.001
LVEF (%)	59.7±13.2	63.2±13.3	54.1±11.2	0.012
AR peak velocity (m/s)	4.2±0.51	4.3±0.5	4.1±0.52	0.344
Aortic systolic peak velocity (m/s)	2.7±1.2	2.8±1.4	2.7±0.9	0.791
Bicuspid aortic valve	5 (8.1)	3 (4.8)	2 (3.2)	0.826
Elevated LV filling pressure	26 (41.9)	16 (42.1)	10 (50)	0.566
Severe mitral regurgitation	2 (3.2)	2 (5)	0 (0)	0.286
Severe mitral stenosis	1 (1.6)	1 (2.5)	0 (0)	0.455
Severe aortic stenosis	8 (12.9)	6 (15)	2 (9.1)	0.507

AR: aortic regurgitation; ERO: effective regurgitant orifice; IV: interventricular; LV: left ventricle; LVEF: left ventricular ejection fraction; LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVESD: left ventricular end-systolic diameter LVESV: left ventricular end-systolic volume; PHT: pressure half-time; VTI: velocity-time integral; VTIi; velocity-time integral index. Continuous variables with normal distribution are expressed as mean±standard deviation and categorical variables as n (percentage).

In the bivariate analysis ( Table 3 ), VTI was inversely associated with AR severity. Besides, the classic severity variables related to the size and function of the left ventricle were associated with AR severity. In the multivariate analysis, the VTI value acted as a marker of AR severity regardless of LVEDD, left ventricular end-diastolic volume (LVEDV), and LVEF ( Table 4 ). LVESD and left ventricular end-systolic volume were excluded from the multivariate analysis due to collinearity with LVEDD (r_p=0.905, p<0.001) and LVEDV (r_p=0.871, p<0.001), respectively. We also excluded ERO, RV, and VC from the multivariate analysis as they could not be obtained for all patients due to poor ultrasound window or difficulty in measuring. This model showed greater discrimination (Statistic C=0.837, 95%CI 0.728–0.947) and an accurate calibration (Hosmer-Lemeshow χ²=2.30, p=0.970).

Table 3

	Odds ratio	95%CI	p-value
AR VTI	0.198	0.053–0.748	0.017
AR VTIi	<0.001	<0.001–0.005	0.033
LVEF	0.941	0.895–0.989	0.017
LVEDD	1.144	1.047–1.249	0.003
LVESD	1.119	1.044–1.199	0.001
LVEDV	1.032	1.015–1.049	<0.001
LVESV	1.034	1.013–1.057	0.002

95%CI: 95% confidence interval; AR VTI: velocity-time integral of aortic regurgitation; AR VTIi: velocity-time integral index of aortic regurgitation; LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; LVESV: left ventricular end-systolic volume.

Table 4

	Odds ratio	95%CI	p-value
AR VTI	0.160	0.030–0.856	0.032
LVEF	1.005	0.933–1.082	0.895
LVEDD	1.049	0.934–1.178	0.419
LVEDV	1.030	1.009–1.052	0.005
	Odds ratio	95%CI	p-value
AR VTIi	<0.001	<0.001–<0.001	0.019
LVEF	1.007	0.932–1.089	0.859
LVEDD	1.063	0.939–1.204	0.333
LVEDV	1.032	1.010–1.055	0.005

95%CI: 95% confidence interval; AR VTI: velocity-time integral of aortic regurgitation; AR VTIi: velocity-time integral index of aortic regurgitation; LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction.

On the other hand, since HR and DBP could pathophysiologically influence the VTI measurement (DBP as a determinant of velocity, and HR of time), the association between VTI and AR severity was assessed adjusting for HR and DBP. VTI was also inversely related to AR severity, irrespective of these factors (OR 0.232, 95%CI 0.056–0.961, p=0.044). Finally, the VTIi of AR also showed an inverse association with AR severity ( Table 3 ) and acted as a marker of AR severity, regardless of LVEDD, LVEDV, and LVEF in the multivariate analysis ( Table 4 ). Additionally, this variable was also related to AR severity, irrespective of DBP (OR<0.001, 95%CI <0.001–0.001, p=0.029).

This study suggests that the VTI of AR can be used as a marker of severity in patients with significant AR, considering that estimating severity through echocardiography is a difficult process involving the integration of several different tests and parameters.^{2 - 4 , 20}

Effectively, ERO by the PISA method works as a parameter for the stratification of AR severity,^{3 , 7} and an indirect relationship can be found between ERO and VTI (ERO=RV/VTI).^{3 , 10} More severe AR presents a larger ERO and RV, but the behavior of VTI is unknown. In this study, the VTI of the aortic regurgitant flow was inversely associated with AR severity. The scientific evidence available corroborating this relationship is scarce. Zarauza et al.²¹ published a study that assessed the value of VTI of AR, amongst other parameters, in a sample of 43 patients with moderate to severe AR.²¹ Their findings were similar to ours (severe AR VTI: 1.8±0.7 m vs. 1.9±0.5 m; moderate AR VTI: 2.2±0.8 m vs. 2.2±0.5 m, respectively). However, in the study by Zarauza et al.,²¹ the differences between VTI in severe and moderate AR did not reach statistical relevance. The difference in sample size for patients with moderate AR (15 vs. 40) could explain the lack of a significant result. To the best of our knowledge, no other study has assessed the value of VTI as an indicator of AR severity.

A remarkable aspect of the present study is the direct association between AR severity and end-diastolic and end-systolic diameters and volumes, in addition to the inverse relationship to LVEF. These findings are consistent with available scientific evidence, which supports the predictive role of left ventricular diameter and ventricular function as markers of advanced AR and negative prognoses.^{11 , 22 - 24} In our opinion, this aspect reflects an appropriate and rigorous methodology for measuring these parameters. This study found that the relationship between VTI and AR severity did not depend on echocardiographic variables, such as left ventricular diameters, volumes, or ejection fraction. This result could potentially support the use of VTI as an indicator in most echocardiographic scenarios involving AR and sinus rhythm.

Despite being echocardiographic methods recommended for determining the severity of significant AR,^{3 , 25 , 26} the calculations necessary to estimate VC, RV, and, as we previously mentioned, ERO obtained by PISA present several limitations.3,8,9,17 In fact, this study could not evaluate whether the VTI value was associated with severe AR, regardless of ERO, RV, or VC, as the percentage of patients from whom this data could be obtained was not enough to perform a valid multivariate analysis. In contrast, VTI could not be estimated in only 3 of the 65 patients of this study due to improper alignment of the AR jet. Thus, VTI has proven to be a reproducible parameter that can be easily obtained and examined in most patients and could provide valuable information for the stratification of AR severity.

We also emphasize that although PHT was obtained for all patients who had their VTI calculated, we found no significant differences between individuals with moderate and severe AR, which prevented the inclusion of this parameter in the multivariate analysis. Therefore, we could not assess the additional value of VTI with respect to PHT. Current clinical guidelines suggest that the usefulness of PHT is low in cases of chronic AR,^{2 , 3} and the sample of the present work consists mainly of chronic AR patients. The low rate of acute AR in the present study (6.5%) precluded a feasible statistical evaluation of the acute AR cohort. This issue could explain the lack of differences in the PHT values between the moderate and severe AR groups.

Our results also suggest that the association between lower VTI and severe AR does not seem to be significantly affected by hemodynamic variables, such as HR and DBP. If other studies supported this relationship behavior, the use of VTI could reach a wide variety of patients. However, we consider that the relationship between VTI and AR severity could not be significantly changed by these hemodynamic variables due to a lack of extreme values. We highlight that we found a tendency for lower DBP in patients with severe AR and that we excluded patients with atrial fibrillation. Thus, since HR is a temporal determinant for the VTI of AR, we also calculated the VTI indexed by HR to normalize the VTI value and further study its relationship to AR severity. Additionally, HR correlated significantly and inversely with AR VTI. The relationship between this new variable and AR severity was not only maintained but proved to be stronger and independent of LVEDD and LVEF (OR<0.001, p=0.031). In other studies, such as the one by Zarauza et al.,²¹ VTI was normalized using the diastolic length.²¹ However, there are few levels of consistency throughout the indexing of VTI in terms of HR. We believe that these findings support the pathophysiological hypothesis that a smaller VTI is associated with a more severe AR, regardless of the HR.

Our study presents several limitations. First, this is a single-center study that did not analyze patients with AR and atrial fibrillation or prosthetic valves, and thus the value of the aortic VTI in those subpopulations is unknown. Second, the VTI was obtained by Doppler imaging, and, therefore, it is subject to the limitations of this technique. Additionally, our analyses only included patients with moderate or severe AR in an attempt to avoid a potential underestimation in the VTI measurement of low-density mild regurgitant jets; thus, the usefulness of VTI in determining the severity of mild AR remains unclear. ERO, RV, and VC could not be obtained for all patients, partially due to the retrospective nature of the present paper, preventing the assessment of the VTI value with respect to these parameters in predicting severe AR in a multivariate analysis. No other exploration techniques, such as transesophageal echocardiogram, 3D ultrasound, or cardiac magnetic resonance, were performed to study the AR severity or the mechanism of regurgitation in depth.^{27 , 28} Moreover, the lack of a gold standard method precluded a more accurate assessment of the VTI value. Otherwise, the ranges of the VTI values obtained made inaccurate the calculation of a valid cut-off point. Thus, the small number of patients included prevented a cross-sectional validation of the VTI measured, making it difficult to reach solid conclusions. Lastly, we performed no clinical follow-up of the sample, making it impossible to know whether the VTI value has any prognostic or clinical implications.

The VTI of AR is an easily obtainable and reproducible ultrasound parameter that seems to be associated with AR severity. Further studies are necessary to evaluate whether this parameter is capable of providing additional diagnostic and prognostic information for patients with AR, and whether it is useful in other clinical scenarios, such as atrial fibrillation and in individuals with prosthetic valves.