Three-Dimensional Echocardiography-Derived Vena Contracta Area at Rest and Its Increase During Exercise Predicts Clinical Outcome in Mild-Moderate Functional Mitral Regurgitation

Abstract

Background:
This study assessed the independent significance of color Doppler 3-D vena contracta area (VCA) at rest and during exercise as a predictor of clinical outcome in mild-moderate functional mitral regurgitation (FMR). METHODS AND RESULTS: The subjects consisted of 62 patients (age, 68±11 years; 76% male) with chronic systolic heart failure and mild-moderate FMR (<2+/4) at rest. All patients underwent VCA assessment at rest and during semi-supine bicycle exercise. During median follow-up of 17 months (IQR, 13-20 months), 15 patients (24%) had composite endpoint of all-cause death (n=3), heart failure admission (n=11), and heart transplantation (n=1). At baseline, patients with vs. without endpoint had significantly larger VCA at rest (17±6 mm(2)vs. 13±7 mm(2), P=0.002) and at peak exercise (35±16 mm(2)vs. 21±12 mm(2), P<0.001). On Cox regression analysis, large (≥15-mm(2)) resting VCA (HR, 7.6; 95% CI: 1.93-13.02; P=0.004) and large (≥20-mm(2)) exercise-induced increase of VCA (HR, 5.1; 95% CI: 1.39-15.21; P=0.014) were independently associated with composite endpoint. Concomitant presence of large VCA at rest and its large increase during exercise occurred in 53% of patients with, vs. in only 8% without, endpoint (negative predictive value, 86%).

Conclusions:
The presence of relatively large VCA at rest and its significant increase during exercise is independently associated with adverse clinical outcome in patients with mild-moderate FMR at rest.

Full text

Circulation Journal Vol.78, November 2014
Circulation
Journal
Ocial
Journal
of
the
Japanese
Circulation
Society
http://www.j-circ.or.jp
than any single 2-D method.8,9 The prognostic signicance of
VCA at rest and its increase during exercise, however, has not
been investigated. Therefore, the goal of the present study was
threefold: rst, to evaluate the feasibility of VCA to quantify
FMR during bicycle exercise; second, to assess the independent
signicance of VCA at rest and its increase during exercise to
predict clinical outcome; and, third, to compare the 2-D and
3-D methods for assessing FMR at rest and during exercise.
Methods
Patients
The subject group consisted of 78 consecutive patients (age,
67±12 years; 78% male) with chronic systolic heart failure who
were admitted for acute worsening if they fullled the follow-
ing criteria: (1) left ventricular (LV) systolic dysfunction (LV
evere functional mitral regurgitation (FMR) at rest and/or
its signicant increase during exercise have been shown
to be associated with reduced functional capacity and
impaired prognosis.1–5 In these studies, FMR has been assessed
using 2-dimensional (D) quantitative techniques: proximal iso-
velocity surface (PISA) and pulsed Doppler volumetry. These
methods, however, have several known limitations such as geo-
metric assumptions of a hemispherical regular effective regur-
gitant orice (ERO), underestimation of ERO in FMR, low re-
producibility and indirect measurement of ERO.6–9 Recently,
color Doppler 3-D echocardiography-derived vena contracta
cross-sectional area (VCA) has emerged as a new method to
assess FMR severity at rest, which allows direct assessment of
ERO without geometric and ow assumptions.8–13 VCA at rest
has been shown to have higher correlation with the 2-D integra-
tive method or magnetic resonance-derived regurgitant volume
S
Received February 14, 2014; revised manuscript received August 13, 2014; accepted August 17, 2014; released online October 3, 2014
Time for primary review: 24 days
Cardiovascular Center Aalst, OLV Clinic, Aalst (J.V., J.B., M.V., M.P.), Belgium; Institute of Clinical and Experimental Medicine (IKEM),
Prague (M.K., R.K.), Czech Republic
Mailing address: Martin Penicka, MD, PhD, Cardiovascular Center Aalst, OLV-Clinic, Moorselbaan 164, 9300 Aalst, Belgium. E-mail:
martin.penicka@olvz-aalst.be
ISSN-1346-9843 doi: 10.1253/circj.CJ-14-0183
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
Three-Dimensional Echocardiography-Derived Vena
Contracta Area at Rest and Its Increase During
Exercise Predicts Clinical Outcome in Mild-Moderate
Functional Mitral Regurgitation
Jan Vecera, MD; Jozef Bartunek, MD, PhD; Marc Vanderheyden, MD; Martin Kotrc, MD;
Radka Kockova, MD; Martin Penicka, MD, PhD
Background: This study assessed the independent significance of color Doppler 3-D vena contracta area (VCA)
at rest and during exercise as a predictor of clinical outcome in mild-moderate functional mitral regurgitation (FMR).
Methods and Results: The subjects consisted of 62 patients (age, 68±11 years; 76% male) with chronic systolic
heart failure and mild-moderate FMR (<2+/4) at rest. All patients underwent VCA assessment at rest and during
semi-supine bicycle exercise. During median follow-up of 17 months (IQR, 13–20 months), 15 patients (24%) had
composite endpoint of all-cause death (n=3), heart failure admission (n=11), and heart transplantation (n=1). At
baseline, patients with vs. without endpoint had significantly larger VCA at rest (17±6 mm2 vs. 13±7 mm2, P=0.002)
and at peak exercise (35±16 mm2 vs. 21±12 mm2, P<0.001). On Cox regression analysis, large (≥15-mm2) resting
VCA (HR, 7.6; 95% CI: 1.93–13.02; P=0.004) and large (≥20-mm2) exercise-induced increase of VCA (HR, 5.1; 95%
CI: 1.39–15.21; P=0.014) were independently associated with composite endpoint. Concomitant presence of large
VCA at rest and its large increase during exercise occurred in 53% of patients with, vs. in only 8% without, endpoint
(negative predictive value, 86%).
Conclusions: The presence of relatively large VCA at rest and its significant increase during exercise is indepen-
dently associated with adverse clinical outcome in patients with mild-moderate FMR at rest. (Circ J 2014; 78:
2741 – 2749)
Key Words: Echocardiography; Exercise; Heart failure; Mitral regurgitation; Prognosis
ORIGINAL ARTICLE
Valvular Heart Disease

Circulation Journal Vol.78, November 2014
2742 VECERA J et al.
system (Vivid E9; GE Medical Systems, Horten, Norway)
equipped with speckle tracking and 3-D color Doppler imag-
ing. All images were stored in digital format for ofine analy-
sis. The mean from at least 3 consecutive beats (5 in atrial -
brillation) was taken for each measurement both at rest and
during exercise. Standard assessment of LV dimensions, LV
volumes and ejection fraction (bi-apical Simpson method), sphe-
ricity index, left atrial volume (bi-apical area-length method)
was performed according to the current recommendations.14
Mitral Valve Deformation
This was assessed in the apical 4-chamber view. The mitral
valve tenting area, coaptation height, anterior and posterior mi-
tral leaet angle were assessed at mid-systole. Mitral annulus
diameter was measured in end-diastole.
Quantication of FMR
In the apical 4-chamber view, full-volume, color Doppler 3-D
loops were recorded during respiration using the 3V-D active
matrix 4-D volume phased array probe using real-time, single-
beat acquisition. The narrowest sector possible was used to
maximize the frame rate.
Average frame rate for the 3-D color Doppler dataset acqui-
sition was 15±1.8 frames/s. This frame rate provides 7–8 frames
per systole at a heart rate of 60 beats/min and 6–7 frames per
systole at a heart rate of 100 beats/min.15 The typical color code
bar setting for the assessment of VCA is similar to the setting
used for the PISA method, with baseline shift downward to the
negative aliasing velocity between 20 and 40 cm/s. The 3-D
color Doppler datasets were analyzed using dedicated software
(EchoPac for PC, GE) as follows: 3-D color Doppler signals
were optimized to distinguish the vena contracta from the prox-
imal ow convergence and a rapidly expanding jet in 2 simul-
taneous 2D-derived perpendicular planes to ensure the best
reproducibility. To identify VCA, the 3-D dataset was rotated
to bisect the regurgitant color jet at the level of leaet coapta-
tion zone perpendicularly to its long axis in 2 orthogonal planes.
The image was cropped along the jet direction to visualize the
cross-sectional area at the level of vena contracta. The VCA
was dened as the high-velocity core of the color spectrum
and to avoid the “color bleeding”, that is, the low-velocity ow
signal in the periphery of the color spectrum. To facilitate de-
lineation of the VCA, the color gain was lowered. In contrast
to low-velocity peripheral ows, the vena contracta ow is less
affected by the color gain adjustments. When reducing gain,
the high intense core of the high-velocity vena contracta ow
is the last to remain. Figure 1 shows examples of the vena con-
tracta ow and low-velocity peripheral ows with the color
code bar setting. The VCA at the closest frame preceding mid-
systole was magnied and traced manually. Usually, this was
the third or fourth systolic frame at rest and the third systolic
frame during peak exercise. Furthermore, 3-D color Doppler
echocardiography-derived vena contracta cross-section length
(VCL) was assessed as the largest diameter of VCA. In the
case of multiple jets, VCA and VCL were calculated as the
sum of the individual VCA and VCL. Figure 2 shows a rep-
resentative VCA tracing in 2 patients with mild-moderate FMR
at rest, 1 with a signicant exercise-induced increase of VCA
(Figures 2A,B) and 1 with a stable small VCA during exercise
(Figures 2C,D). The 2D-derived assessments of FMR includ-
ed the PISA method-derived ERO and vena contracta width.6,7
Statistical Analysis
Data are presented as mean ± SD for continuous variables and
as percentage for categorical variables. The unpaired or paired
ejection fraction <45%) of ischemic or non-ischemic origin; (2)
mild-moderate FMR (<2+/4) at rest on 2-D integrative ap-
proach;6,7 and (3) optimal pharmacological therapy. Patients who
were unable to perform semi-supine exercise, who had acute
coronary syndrome in the previous 30 days, concomitant or-
ganic mitral valve lesions or signicant aortic valve disease were
excluded. The study complied with the Declaration of Helsinki.
The study protocol was approved by the Ethics Committees of
both participating institutions. All patients gave written informed
consent before inclusion in the study.
Study Protocol
After compensation, before discharge all patients underwent
resting and graded, symptom-limited exercise echocardiogra-
phy using a tilting bicycle table allowing continuous echocar-
diography monitoring in the semi-supine position. The initial
workload of 25 W was increased every 2 min by 25 W. Blood
pressure and 12-lead electrocardiography were recorded every
2 min. 2-, 3-D and Doppler echocardiography was performed
at rest and throughout the exercise. The blood sample for N-
terminal of the prohormone B-type natriuretic peptide (NT-
proBNP) was collected prior to echocardiography. Thereafter,
patients were followed up clinically.
Echocardiography
All echocardiography was done using a commercially available
Figure 1. (A–D) Individual examples of the vena contracta
cross-sectional area (VCA) with typical color code bare set-
ting. To assess VCA the baseline of the color code bar setting
was shifted downward to the negative aliasing velocity be-
tween 20 and 40 cm/s (upper left corner). To improve delinea-
tion of the vena contracta flow, color gain was reduced to
eliminate peripheral low-velocity signals. When reducing gain
the high intense core of the high-velocity vena contracta flow
is the last to remain.

Circulation Journal Vol.78, November 2014
2743VCA and Outcome in FMR
3.8±2.0 min. An additional 9 patients underwent implantation
of biventricular pacemaker during the index hospitalization and
were excluded. The remaining 62 patients (age, 68±11 years;
76% male) were included in the clinical outcome analysis. Dur-
ing a median follow-up of 17 months (IQR, 13–20 months),
15 patients (24%) reached the composite endpoint (death, n=3;
admission for worsening heart failure, n=11; heart transplanta-
tion, n=1). Follow-up was obtained in all patients.
Baseline and Exercise Characteristics
At baseline, patients with endpoint compared to patients with-
out endpoint had more advanced heart failure as evidenced by
signicantly higher NT-proBNP, wider QRS complex and
reduced tricuspid annular plane systolic excursion (all P<0.05;
Table 1). Moreover, in the 2 years preceding the study inclu-
sion, patients with endpoint were more likely to be admitted
repeatedly for worsening heart failure (P<0.001) than individu-
als without endpoint. Prevalence of cardiac resynchronization
therapy, ischemic cardiomyopathy or atrial brillation was
similar in both groups. E/e’, degree of global LV remodeling
and ejection fraction, and the indices of mitral valve deforma-
tion did not differ between groups (Table 1). Furthermore, the
Student’s t-test and the Pearson correlation coefcient were used
as appropriate. Fisher’s exact test was used to compare cate-
gorical variables in 2×2 contingency tables. Receiver operating
characteristic curves were constructed to assess optimal cut-
off for the VCA to predict clinical outcome and also to com-
pare VCA, VCL and PISA-derived ERO. The endpoint was
dened as a composite of death from any cause, admission for
worsening heart failure and heart transplantation. Independent
predictors of the composite endpoint were identied using the
Cox proportional hazard model and expressed as a hazard ratio
and 95% condence interval. Cumulative survival curves were
derived according to the Kaplan-Meier method, and differ-
ences between curves were analyzed on log-rank statistics. For
all tests, P<0.05 was considered signicant.
Results
Seven patients (9%) had poor echocardiography image quality
at rest and were excluded prior to exercise. In all of the remain-
ing 71 patients (age, 67±12 years; 79% male) the assessment
of VCA was feasible both at rest and during exercise (feasibil-
ity, 91%). The image post-processing time to obtain VCA was
Figure 2. Individual examples of significant exercise-induced increase of vena contracta cross-sectional area (VCA) (A,B) vs. a
stable small VCA (C,D). VCA (white ellipse) was assessed using manual planimetry at the closest frame preceding mid-systole.
Care was taken to circle the central area of the high-velocity flow while avoiding the low-velocity color flow signals at the periphery.
The first image from the left shows raw color spectrum without delineating line to illustrate this technique. Vena contracta cross-
section length (VCL) was measured as the maximum VCA diameter. In the first patient (A,B), a relatively large ellipsoid VCA was
observed at rest (A) despite the small color-coded regurgitant jet area and “mild” appearance of functional mitral regurgitation
(FMR). Figure 2B shows significant increase in VCA corresponding to significant FMR during low-load exercise (50 W). It is note-
worthy that proximal isovelocity surface (PISA)-derived effective regurgitant orifice (ERO; B, green circle) showed smaller increase,
suggesting underestimation of ERO by the PISA method. Figures 2C,D shows an example of a patient with the small circular VCA
both at rest and during exercise, respectively, reflecting stable mild-moderate FMR.

Circulation Journal Vol.78, November 2014
2744 VECERA J et al.
patients with endpoint but in only 8% of patients without end-
point (negative predictive value, 86%). VCL at rest (area under
the curve [AUC]=0.68), VCL at peak exercise (AUC=0.73) and
exercise-induced increase in PISA-derived ERO (AUC=0.60)
had lower accuracy. On Cox regression analysis, resting VCA
≥15 mm2, its ≥20-mm2 exercise-induced increase, and VCL
≥13 mm at peak exercise were identied as the only indepen-
dent predictors of composite endpoint (Table 2). The patients
with VCA ≥15 mm2 or VCA increase ≥20 mm2 had worse
prognosis on Kaplan-Meier analysis (Figure 4).
2-D vs. 3-D Indices for Assessment of FMR
At rest, a prognostic ERO (≥20 mm2) was observed in 18 patients
(29%) using the 3-D VCA method but in no patients using the
2-D PISA method (Table 1). A total of 26 patients (42%) had
large 3-D VCL (≥7 mm) suggesting signicant FMR at rest,
while no patients had wide 2-D vena contracta. Patients with
VCA ≥20 mm2 or VCL ≥7 mm had higher occurrence of com-
posite endpoint (8/15 vs. 10/47, P=0.02 for VCA, or 10/15 vs.
16/47, P=0.04 for VCL). At peak exercise, a total of 18 patients
(29%) had large (≥20-mm2) exercise-induced increase in VCA,
and a total of 15 (24%) had large (≥13-mm2) exercise-induced
increase in PISA-derived ERO. Figure 5 shows VCA and
PISA-derived ERO at rest and during peak exercise in patients
with endpoint. Both VCA and PISA-derived ERO increased
endpoint group had a signicantly larger VCA (P=0.002),
VCL (P=0.02) and a higher prevalence of large (≥20-mm2)
“prognostic” VCA (P=0.02) at rest than patients without end-
point (Table 1). In contrast, out of the 2D-derived indices,
only PISA method-derived ERO tended to be larger (P=0.06)
in patients with vs. without endpoint, while the vena contracta
width was similar. No patients had prognostic PISA-derived
ERO (≥20 mm2). At peak exercise (Table 1), the endpoint group
had a signicantly lower peak exercise load and systolic blood
pressure (both P<0.01) compared with the group without end-
point. Reversible myocardial ischemia was not observed in any
of the patients. The indices of LV remodeling and ejection frac-
tion were similar. Both groups had signicant rest-to-exercise
increase in VCA, VCL, PISA-derived ERO and vena contracta
width (all P<0.01), but signicantly larger VCA, VCL and
vena contracta width (all P<0.01), and slightly larger PISA-
derived ERO (P=0.07) were observed in the endpoint group.
Predictors of Composite Endpoint
Resting VCA and its increase were better predictors for the
composite endpoint than PISA ERO increase (Figure 3). Resting
VCA with a cut-off ≥15 mm2 and its increase (cut-off ≥20 mm2)
at peak exercise had the highest accuracy for predicting the
composite endpoint. Concomitant presence of large VCA at rest
and its signicant increase during exercise occurred in 53% of
Table 1. Clinical and Echocardiography Characteristics
Endpoint (+) (n=15) Endpoint (–) (n=47) P-value
Age (years) 65±16 68±9
0.36
Sex (% female) 20 17
1.0
Diabetes mellitus 4 (27) 11 (23)
1.0
Coronary artery disease 9 (60) 25 (53)
0.77
ACE/ATII inhibitors 14 (97) 44 (94)
1.0
β-blockers 12 (80) 33 (72)
0.74
Spironolactone 12 (80) 30 (64)
0.35
Loop diuretics 14 (97) 36 (76)
0.26
NYHA class 2.5±0.5 2.0±0.6
0.09
NT-proBNP (pg/ml) 2,180 (1,548–7,100) 1,400 (546–2,856)
0.02
Hospitalization for worsening HF in preceding 2 years 12 (80) 20 (43)
0.017
≥2 hospitalizations for worsening HF in preceding 2 years 8 (53) 2 (4) <0.0001
Glomerular filtration rate (ml/min) 61±19 60±14
0.95
Atrial fibrillation 7 (47) 16 (34)
0.54
QRS width (ms) 143±33
123±33
0.031
CRT 4 (27) 5 (11)
0.2
E/e’ 16.3±6.4
13.0±7.5
0.14
Mitral valve tenting area (cm2) 1.9±1.0 1.6±0.7
0.22
Mitral valve coaptation height (mm) 8±4 7±3
0.12
TAPSE (mm) 15.5±3.1
17.8±4.0
0.047
Exercise tolerance (W) 52±20 81±38
0.007
Heart rate (beats/min)
Rest 69±16 72±15
0.55
Exercise
96±27‡
103±23‡
0.38
Systolic blood pressure (mmHg)
Rest 105±17
118±19
0.021
Exercise
126±20‡
146±23‡
0.004
LV EDVI (ml/m2)
Rest 102±54
90±24
0.25
Exercise 109±18
90±26
0.06
(Table 1 continued the next page.)

Circulation Journal Vol.78, November 2014
2745VCA and Outcome in FMR
without endpoint (9/15 vs. 9/47, P=0.007). In contrast, the
percentage of patients with ≥13-mm2 increase in PISA-derived
ERO was similar between the groups (6/15 vs. 9/47, P=0.16;
Table 1).
signicantly (both P<0.01), but the rest-to-peak exercise dif-
ference in VCA was signicantly larger than the difference
in PISA-derived ERO (18±10 mm2 vs. 9±7 mm2, P<0.001;
Figure 5). A signicantly higher proportion of patients with
endpoint had ≥20-mm2 increase in VCA compared to patients
Endpoint (+) (n=15) Endpoint (–) (n=47) P-value
LV ESVI (ml/m2)
Rest 75±47 64±19
0.62
Exercise 78±22
60±27†
0.08
LV EF (%)
Rest 29±8
29±8
0.46
Exercise 30±8
33±10‡
0.12
LV sphericity index
Rest 1.52±0.17 1.52±0.16
0.32
Exercise 1.58±0.20 1.56±0.21
0.54
Peak TR gradient (mmHg)
Rest 21±7
23±6
0.42
Exercise
50±8‡
45±9‡
0.056
VCA (3-D) (mm2)
Rest 17±6
13±7
0.002
Exercise
35±16‡
21±12‡<0.001
Rest VCA ≥20 mm2 8 (53) 10 (21)
0.02
Exercise-induced VCA increase ≥20 mm2 9 (60) 9 (19)
0.007
Exercise-induced VCA increase (mm2) 17±13 8±10
0.009
VCL (3-D) (mm)
Rest 7.0±2.9 5.1±2.5
0.017
Exercise
12.9±6.7‡
8.1±4.6‡
0.002
ERO (2-D PISA) (mm2)
Rest 11±5
8±5
0.058
Exercise
20±9†
14±10‡
0.07
Rest ERO ≥20 mm20 0 NA
Exercise-induced ERO increase ≥13 mm2 6 (40) 9 (19)
0.16
Vena contracta width (2-D) (mm)
Rest 3.3±0.7 2.9±1.3
0.2
Exercise
5.3±2.3†
3.9±1.6‡
0.008
Data given as mean ± SD, n (%) or median (IQR). *P<0.05, †P<0.01, ‡P<0.001 rest vs. exercise. ACE/ATII, angiotensin-converting enzyme/
angiotensin II; CRT, cardiac resynchronization therapy; D, dimensional; EF, ejection fraction; EDVI, end-diastolic volume index; ERO, effective
regurgitant orifice; ESVI, end-systolic volume index; HF, heart failure; LV, left ventricular; NT-proBNP, N-terminal of the prohormone B-type
natriuretic peptide; NYHA, New York Heart Association; PISA, proximal isovelocity surface; TAPSE, tricuspid annular plane systolic excursion;
TR, tricuspid regurgitation; VCA, vena contracta cross-sectional area; VCL, vena contracta length.
Figure 3. Accuracy of vena contracta cross-sectional area (VCA) at rest, exercise-induced increase in VCA and in proximal
isovelocity surface (PISA)-derived effective regurgitant orifice (ERO) to predict the composite endpoint. AUC, area under the curve;
Sp, specificity; Ss, sensitivity.

Circulation Journal Vol.78, November 2014
2746 VECERA J et al.
(n=10) and in atrial brillation (n=10) from recorded images.
In patients with sinus rhythm, the intraobserver and interob-
server variability was 7% and 9% at rest, and 8% and 10%
during exercise, respectively. In patients with atrial brillation,
the intraobserver and interobserver variability was 10% and
14% at rest, and 12% and 15% during exercise, respectively.
Discussion
The present ndings can be summarized as follows. First, the
assessment of VCA during bicycle exercise is highly feasible
and reproducible. Second, both VCA at rest and its increase
during exercise are independent predictors of clinical outcome.
VCA at rest has high sensitivity, while its exercise-induced
increase has high specicity for identifying patients with ad-
verse clinical outcome. Third, the assessment of VCA seems
to be highly sensitive to track exercise-induced changes in FMR,
while the PISA method underestimated ERO both at rest and
during exercise.
Large VCA and Small PISA-Derived ERO During Peak
Exercise
This analysis included all 71 patients (age, 67±12 years; 79%
male) with good image quality both at rest and during exer-
cise. Of the 24 patients with signicant (≥20-mm2) increase in
VCA only 14 (58%) had signicant (≥13-mm2) increase of
PISA-derived ERO. A subgroup of patients, in whom the PISA
method failed to identify exercise-induced signicant FMR,
had signicantly higher coaptation height and posterior leaet
angle at rest and during exercise than patients in whom PISA
correctly identied exercise-induced FMR (Table 3). In con-
trast, both subgroups had similar global echocardiography
characteristics and VCA at peak exercise. Of note, the exer-
cise capacity was similar in both PISA subgroups, but was
signicantly lower in patients without exercise-induced in-
crease in VCA.
Reproducibility
Reproducibility for VCA both at rest and during exercise was
assessed in 20 randomly selected patients in sinus rhythm
Table 2. Independent Predictors of Composite Endpoint
Univariate Multivariate
HR (95% CI) P-value HR (95% CI) P-value
Age 0.99 (0.95–1.03)
0.69
NYHA class 3.1 (1.16–8.33)
0.024
NT-proBNP 1.0 (1.00–1.00)
0.07
QRS duration 1.0 (0.99–1.03)
0.09
LV EF 0.97 (0.92–1.05)
0.45
TAPSE 0.86 (0.73–1.00)
0.054
Exercise-induced PISA-derived ERO increase ≥13 mm21.13 (0.10–1.26)
0.064
VCL at rest ≥7 mm 1.32
0.024 1.16 (0.86–11.89) 0.083
VCL at peak exercise ≥13 mm 7.40
0.002 5.85 (1.67–14.09) 0.009
Resting VCA ≥15 mm28.11 <0.001 7.60 (1.93–13.02) 0.004
Exercise-induced VCA increase ≥20 mm26.33
0.004 5.10 (1.39–15.21) 0.014
CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.
Figure 4. Kaplan-Meier estimates of the time to death resulting from any cause, admissions for worsening heart failure or heart
transplantation. Patients were divided into 2 groups according to (A) presence or absence of vena contracta cross-sectional area
(VCA) ≥15 mm2 at rest, or (B) presence or absence of exercise-induced increase of VCA ≥20 mm2 at peak exercise.

Circulation Journal Vol.78, November 2014
2747VCA and Outcome in FMR
ERO in patients with ischemic LV dysfunction.19 The exercise-
induced increase in PISA-derived ERO ≥13 mm2 has been as-
sociated with adverse outcome.3,4 Corroborating this nding,
in the present study, patients with endpoint had signicantly
larger VCA during exercise than patients without endpoint.
Moreover, the exercise-induced increase in VCA ≥20 mm2 has
been identied as an independent predictor of composite end-
point. In contrast to the previous studies, exercise-induced
increase in PISA ERO did not predict outcome in the present
study. The reasons may be several. In the present study, only
patients with mild-moderate FMR at rest were included. In
contrast, the Lancellotti et al studies enrolled patients with high-
er degrees of FMR at rest.3,4 In the present study, both VCA
and the PISA-derived ERO increased signicantly, but the rest-
to-peak exercise difference in VCA was signicantly larger
than the difference in PISA-derived ERO. Furthermore, the
exercise-induced signicant increase of PISA-derived ERO
(>13 mm2) identied only 10 out of 24 patients (58%) with
signicant increase in VCA (>20 mm2). The underestimation
of ERO by the PISA method was observed predominantly in
patients with severe distortion of the mitral valve geometry,
implying highly irregular ERO shape. Finally, direct compari-
son of VCA and PISA-derived ERO was not possible, because
VCA reects the anatomical surface of the regurgitant orice,
while PISA-derived ERO represents the physiological param-
eter based on hydrodynamic theory of ow converging towards
a restricted orice. The limitation of a single 2-D measurement
in the setting of non-circular ERO may partly be compensated
for by using multiple 2-D measurements in different echocar-
diography planes. This approach, however, may substantially
increase the data acquisition time, which may be of particular
importance during exercise, when the time window to obtain
images is limited. In contrast, a single recording in 1 echocar-
diography view is needed to acquire color Doppler 3-D data-
set for the VCA assessment.
Study Limitations
In the current study, a single-beat (live) 3-D color Doppler ac-
Feasibility and Reproducibility
Several studies have demonstrated high feasibility and repro-
ducibility for VCA assessment at rest.8–13 The current study
extends these ndings by showing high feasibility (91%) and
reproducibility of the VCA measurement also during low-grade
exercise, with a short image post-processing time <5 min. The
feasibility of color Doppler 3-D echocardiography-derived VCA
assessment has been related to the 2-D echocardiography image
quality at rest. In all the patients with acceptable 2-D image
quality at rest, the assessment of VCA was feasible both at rest
and during exercise. Similarly, the intra- and interobserver
variability of the VCA assessment was low (<10%) and not
signicantly affected by bicycle exercise.
VCA at Rest and Clinical Outcome
Previous studies have demonstrated that presence of resting
FMR in patients after myocardial infarction or with ischemic
LV dysfunction is associated with increased mortality, increased
admission rate for worsening heart failure and reduced func-
tional capacity.1–4 In those studies, the cut-off for ERO ≥20 mm2,
assessed using 2-D PISA or pulsed Doppler volumetry, identi-
ed individuals with the worst prognosis. The present study
included patients with mild-moderate FMR at rest assessed
using the 2-D integrative approach.6,7 In line with the inclusion
criteria, in the current study, all patients had PISA-derived ERO
<20 mm2 at rest, and PISA-derived ERO did not predict out-
come. In contrast, prognostic VCA ≥20 mm2 at rest was observed
in 29% of the present subjects, and its presence was associated
with signicantly higher occurrence of composite endpoint.
Moreover, VCA ≥15 mm2 emerged as an independent predic-
tor of outcome. Finally, a total of 26 patients (42%) had large
3-D VCL (≥7 mm) suggesting signicant FMR at rest, while
no patients had wide 2-D vena contracta. This suggests that
the presence of relatively large ellipsoid VCA may be a mark-
er of signicant FMR with adverse outcome, despite grading
of FMR as “mild-moderate” using 2-D PISA or vena contracta
width. This also suggests that the 2D-derived approach may
underestimate severity of FMR in some patients. Currently,
the 2-D integrative method is the recommended approach to
assess severity of FMR.6,7 This method integrates several 2D-
based indices to circumvent the limitations of each of these
techniques. Recent studies have investigated the color Doppler
3-D echocardiography approach for FMR quantication by
direct measurement of ERO using VCA.8–13 VCA at rest has
been shown to have a higher correlation with the 2-D integra-
tive method or magnetic resonance-derived regurgitant volume
than any single 2-D method.8,9 In contrast, in patients with
FMR, the PISA method signicantly underestimated ERO by
27% due to the geometric and ow assumptions. The irregular
hemi-elliptical shape of ERO is relatively common in FMR.16
Asymmetric ERO leads to underestimation of FMR severity
by commonly used 2-D methods, such as PISA or vena con-
tracta width.8–13,16,17 In contrast, the 3-D technique used in the
current study allows direct visualization of ERO with precise
assessment of its area and longest diameter and gives better
results as reected by AUC for VCA, ERO (PISA) and VCA
increase during exercise (Figure 3).
VCA During Exercise and Clinical Outcome
Distinction of dynamic severe from stable mild FMR in pa-
tients with systolic LV dysfunction and mild-moderate FMR
at rest is critical, because the former are associated with re-
duced survival.3,4,18 The landmark studies of Lancellotti et al
showed the wide range of exercise-induced changes in the
PISA method- or pulsed Doppler volumetric method-derived
Figure 5. Comparison between proximal isovelocity surface
(PISA)-derived effective regurgitant orifice (ERO) and 3-D
vena contracta cross-sectional area (VCA) at rest and during
exercise in patients with the composite endpoint. †P<0.01,
‡P<0.001 rest vs. exercise.

Circulation Journal Vol.78, November 2014
2748 VECERA J et al.
study, single-beat data acquisition was used for a patient serving
as his own control between rest and exercise. From the clinical
point of view, it is currently unknown whether correction of
FMR with signicant increase during exercise may change the
prognosis, especially in such high-risk patients, but emerging
new techniques such as Mitraclip might be of use in these
cases.20
Conclusions
The present study extends ndings of the previous studies by
showing that VCA at rest and its increase during exercise are
independent predictors of clinical outcome. In patients with
mild-moderate FMR at rest, VCA enabled identication of in-
dividuals with adverse clinical outcome, who would have been
missed using the 2-D-derived indices. The assessment of VCA
quisition for the assessment of VCA was used. The single-beat
recording has relatively lower temporal resolution than the
multiple-beat acquisition. In this study, the average number of
frames per systole was between 6 and 8. Supine bicycle exer-
cise is associated with shortening of diastole and only minor
changes in the duration of systole,15 therefore the heart rate
achieved at peak exercise (average 100 beats/min) was not as-
sociated with the signicant decrease in number of frames per
systole. Single-beat compared to multiple-beat acquisition has
several distinct advantages in patients with heart failure under-
going exercise. These severely ill patients often have irregular
heart rate due to atrial brillation, or frequent premature beats.
These individuals are not able to hold their breath during ex-
ercise. Irregular heart rate and absence of apnea lead to stitching
and respiratory artifacts that hamper the accuracy of multiple-
beat-derived VCA during exercise. Therefore, in the present
Table 3. Echocardiography Characteristics vs. PISA ERO Increase
VCA increase (≥20 mm2) (n=24)
PISA ERO increase
≥13 mm2 (n=14)
PISA ERO increase
<13 mm2 (n=10) P-value
Effective regurgitant orifice (2-D PISA) (mm2)
Rest 10±4
11±4
0.4
Exercise 27±6‡18±5‡<0.001
VCA (3-D) (mm2)
Rest 17±6
18±5
0.91
Exercise 44±6‡40±7‡
0.16
VCL (3-D) (mm)
Rest 7.6±2.2
7.8±2.1
0.8
Exercise 16.1±3.2‡14.4±2.2‡
0.15
LV EDVI (ml/m2)
Rest 95±29
117±66
0.29
Exercise 104±31
122±61
0.37
LV ESVI (ml/m2)
Rest 70±27
91±55
0.25
Exercise 74±32
92±55
0.38
LV EF (%)
Rest 27±7
23±6
0.18
Exercise 29±10
27±7
0.44
LV sphericity index
Rest 1.56±0.13
1.50±0.23
0.45
Exercise 1.46±0.18* 1.50±0.16
0.58
E/e’
Rest 15.0±5.8
19.8±8.8
0.12
Exercise 21.2±18.0† 25.2±11.9†
0.58
Mitral valve tenting area (cm2)
Rest 1.6±0.7
2.2±1.2
0.15
Exercise 2.4±1.0‡ 3.2±1.3‡
0.11
Mitral valve coaptation height (mm)
Rest 6.8±2.9
9.8±3.9
0.04
Exercise 8.9±3.9†12.5±3.3‡
0.03
Anterior leaflet angle (°)
Rest 19±10
27±14
0.1
Exercise 27±11‡ 35±13
0.12
Posterior leaflet angle (°)
Rest 23±11
33±9
0.04
Exercise 29±13* 41±7‡
0.011
Exercise capacity (W) 55±31
46±19
0.41
*P<0.05, †P<0.01, ‡P<0.001 rest vs. exercise. Abbreviations as in Table 1.

Circulation Journal Vol.78, November 2014
2749VCA and Outcome in FMR
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during exercise is feasible, reproducible and reliable for track-
ing the exercise-induced changes in ERO. VCA assessment is
based on 1 single measurement of directly visualized ERO, thus
avoiding geometric and ow assumptions. This may be of value
during exercise because the 2-D indices are all indirect, under-
estimate ERO in FMR and require multiple sampling in dif-
ferent imaging planes. Furthermore, identication of resting
predictors of adverse outcome in patients with mild-moderate
FMR at rest may be of potential importance, because the ex-
pertise and tilted bicycle table used for exercise echocardiog-
raphy are not widely available. These ndings advocate inte-
gration of the VCA method into the current approaches for
assessing FMR.
Disclosures
None.
Funding Sources
None.
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