Left ventricular outflow tract velocity time integral outperforms ejection fraction and Doppler-derived cardiac output for predicting outcomes in a select advanced heart failure cohort
Tan et al. Cardiovascular Ultrasound
Left ventricular outflow tract velocity time integral outperforms ejection fraction and Doppler-derived cardiac output for predicting outcomes in a select advanced heart failure cohort
Christina Tan 0
David Rubenson 0
Ajay Srivastava 0
Rajeev Mohan 0
Michael R. Smith 0
Kristen Billick 0
Samuel Bardarian 0
J. Thomas Heywood 0
0 Fellow, Scripps Clinic Cardiology , 10666 N. Torrey Pines Road, La Jolla, CA 92037 , USA
Background: Left ventricular outflow tract velocity time integral (LVOT VTI) is a measure of cardiac systolic function and cardiac output. Heart failure patients with low cardiac output are known to have poor cardiovascular outcomes. Thus, extremely low LVOT VTI may predict heart failure patients at highest risk for mortality. Methods: Patients with heart failure and extremely low LVOT VTI were identified from a single-center database. Baseline characteristics and heart failure related clinical outcomes (death, LVAD) were obtained at 12 months. Correlation between clinical endpoints and the following variables were analyzed: ejection fraction (EF), pulmonary artery systolic pressure (PASP), NYHA class, renal function, Doppler cardiac output (CO), and LVOT VTI. Results: Study cohort consisted of 100 patients. At the 12-month follow up period, 30 events (28 deaths, 2 LVADs) were identified. Occurrence of death and LVAD implantation was statistically associated with a lower LVOT VTI (p = 0.039) but not EF (p = 0.169) or CO (p = 0.217). In multivariate analysis, LVOT VTI (p = 0.003) remained statistically significant, other significant variables were age (p = 0.033) and PASP (p = 0.022). Survival analysis by LVOT VTI tertile demonstrated an unadjusted hazard ratio of 4.755 (CI 1.576-14.348, p = 0.006) for combined LVAD and mortality at one year. Conclusions: Extremely low LVOT VTI strongly predicts adverse outcomes and identifies patients who may benefit most from advanced heart failure therapies.
Congestive heart failure; Velocity time integral; Time velocity integral; Echocardiography
Congestive heart failure is persistently growing health
care dilemma in the United States, resulting in more
than 50,000 deaths annually and more than 2 million
yearly hospitalizations [
]. The clinical assessment of
patients with heart failure has been shown to be a
valuable tool in guiding therapy and predicting prognosis,
with the presence or absence of congestion and
hypoperfusion dividing heart failure patients into one of four
hemodynamic profiles . Patients with both congestion
and low cardiac output have been shown to have more
than twice the mortality and cardiac transplantation
rates of those without hypoperfusion and congestion [
Thus, accurate and timely identification of high risk
profiles is crucial. Due to the burden of disease, as more
patients with heart failure are cared for by clinicians
without expertise in advanced heart failure, an easily
utilized screening tool for identifying such patients
would be helpful to facilitate timely assessment for
advanced therapies such as left ventricular assist device
and cardiac transplantation [
Echocardiography has emerged as an invaluable tool in
the diagnosis and management of congestive heart failure
(CHF) and is routinely performed in patients with CHF
]. Measurements of left and right ventricular
dysfunction, presence of valvular disease, Doppler derived cardiac
output, and estimates of intracardiac pressures are
frequently obtained metrics [
]. Multiple studies have
demonstrated a close correlation between cardiac output
calculated by Doppler echocardiography and invasive
thermodilution and Fick methods [
]. Doppler derived
cardiac output is typically obtained by measuring flow
across the left ventricular outflow tract (LVOT) which is
determined by the velocity time integral of the Doppler
signal directed across the LVOT (LVOT velocity time
integral or LVOT VTI), multiplied by the cross sectional area
of the LVOT and heart rate. LVOT VTI has been shown
to be a reproducible measurement even in the context of
severe chronic heart failure [
] and is superior to flow
measured at other locations, including the right ventricle,
pulmonary artery, mitral valve, and aortic arch [
] due to
multiple factors: ability to obtain insonation parallel to
blood flow and a relatively flat profile of blood velocity
Because estimation of the area of LVOT represents the
major source of error in deriving cardiac output due to
the elliptoid shape of the LVOT and squaring of the
measured radius (πr2) [
], using LVOT VTI alone rather
than Doppler derived cardiac output has been suggested
as a reliable surrogate for cardiac output in the absence of
left ventricular outflow tract abnormalities . Prior
studies have evaluated LVOT VTI in acute myocardial
infarction, demonstrating 100% one-month survival for subjects
with LVOT VTI greater than 100% predicted for age and
greater than 80% survival at 5 years. In contrast, mortality
rate at one month and five years were 18% and 43%
respectively when LVOT VTI was less than 65% predicted
]. More recently, a study of 990 patients with stable
coronary artery disease demonstrated increased rates of
heart failure hospitalization for subjects within the lowest
VTI quartile [
]. Our study was designed to test the
following concept: for those within the lowest VTI quartile,
is extremely low VTI a marker for patients at highest risk
of death and who will go on to need advanced therapies
such as transplant or LVAD? We hypothesized that
because extremely low LVOT VTI is an accurate marker of
the low output state, LVOT VTI may be used to
discriminate between early stage heart failure versus advanced
heart failure with low cardiac output, thus providing
clinicians with a readily obtainable noninvasive tool to identify
patients who may benefit most from advanced heart
failure interventions such as LVAD and heart transplantation.
LVOT VTI is used to estimate stroke volume since it
reflects the column of blood which moves through the LV
outflow tract during each systole, per the following
Stroke Volume ¼ LVOT VTI Cross Sectional Area
of the Left Ventricular Outflow Tract:
LVOT VTI is calculated by placing the pulsed Doppler
sample volume in the outflow tract below the aortic valve
and recording the velocity (cm/s). When the velocity
signal is integrated with respect to time, the distance
blood moves with each systole is calculated in cm/systole
(Fig. 1). Assuming laminar flow through the LVOT, this
has been shown to correlate well with cardiac output,
which is equivalent to stroke volume x heart rate [
The study protocol was approved by the Institutional
Review Board of Scripps Health, La Jolla, CA. Subject
selection: The transthoracic echocardiogram (TTE)
database at our institution was queried for studies performed
between June 2009 and May 2011 for patients with heart
failure. As over 20,000 echocardiograms per year are
performed at our institution, in order to identify subjects
with extremely low LVOT VTI, a cutoff LVOT VTI of
no more than 10 cm was applied in order to limit the
number of included studies.
Exclusion criteria included any one of the following:
alternative causes for shock (including hypovolemia and
sepsis), acute myocardial infarction, significant valvular
disease affecting accurate estimation of forward cardiac
output by LVOT VTI (i.e, severe aortic regurgitation) [
significant tachycardia (defined as >120 beats per minute),
and pulmonary arterial hypertension. Subjects with
multiple TTEs were reviewed at time of earliest study and
subsequent studies were excluded. Valvular disease was
characterized according to guidelines from the American
College of Cardiology [
]. Diagnosis of heart failure was
established by review of the electronic medical record
(EMR): clinical documentation of heart failure in an
admission history and physical, discharge summary, or
cardiologist’s note and/or referral to a dedicated heart
LVOT VTI was measured from an anteriorly angled
apical four-chamber view using pulsed wave Doppler
with the interrogation beam directed across the LVOT.
The pulsed wave Doppler sample volume was placed in
the left ventricular outflow tract just proximal to the
aortic valve and thin spectral envelopes were obtained
using very low gain. In patients with atrial fibrillation,
LVOT VTI was averaged over three to five consecutive
beats. In cases of aortic stenosis, the pulsed Doppler
sample volume was placed far enough from the stenotic
valve to avoid falsely elevated readings. Inter- and
intraobserver variability testing for LVOT VTI was
performed and validated (intra-class correlation coefficient
0.989-0.997). Ejection fraction (EF) was calculated using
bi-plane method of disks from apical two and four
chamber views. Pulmonary artery systolic pressure was
calculated from Doppler derived tricuspid
regurgitation velocity using the simplified Bernoulli equation
(△P = 4v2). Doppler derived cardiac output was
calculated using the previously described equation for Doppler
derived stroke volume, followed by multiplication by heart
rate (i.e. CO = SV x HR).
Data collection: Baseline demographic information
and laboratory data at time of TTE were obtained from
the EMR via retrospective chart review.
The primary endpoint was defined as death, transplant or
LVAD placement within one year of TTE and identified
by review of our institution’s EMR and the Social Security
Death Index. The study population was analyzed in cohort
design based on subjects meeting the primary endpoint
versus event-free subjects. Differences in categorical and
continuous variables were analyzed by chi-squared and
independent t-test analyses respectively.
The prognostic ability of various factors including LVOT
VTI to predict the primary endpoint over 12 months
following TTE was tested by Cox regression analysis.
Univariate Cox regression was performed using a set of
predefined variables: age, gender, presence of renal
dysfunction, hemoglobin, NYHA class, diabetes, ejection
fraction, echo-derived pulmonary artery systolic pressure
and Doppler derived cardiac output. Variables from the
univariate analysis found to be significant at p ≤ 0.1 were
combined in the multiple variable analysis. The study
population was divided into tertiles based on LVOT VTI
and survival was compared between groups using
Kaplan Meier and Cox regression analysis. Study data
was analyzed using IBM SPSS software (IBM SPSS,
version 21.0, IBM, Rochester, Minnesota).
Twenty-six thousand one hundred thirty-five TTE studies
were performed during the selected time period; of these,
265 studies were identified with LVOT VTI < 10 cm;
duplicate studies from the same subject (n = 125), subjects
without at least a year of follow up (n = 22), heart
rate > 120 beats per minute (n = 7), acute myocardial
infarction at time of TTE (n = 6), pulmonary arterial
hypertension (n = 1) and alternative causes for shock
(n = 4) were excluded. The study sample consisted of 100
subjects; all subjects carried a diagnosis of heart failure
(age 73.5 ± 14.7 years, 72% male, mean ejection fraction
28.9%). More than 60% of the study population had
ischemic cardiomyopathy as the cause of their heart failure,
18% had dilated, non-ischemic cardiomyopathy, and the
remaining 20% had tachycardia-induced cardiomyopathy
(10%), viral myocarditis (5%), drugs/toxins (4%) and
postpartum cardiomyopathy (1%). Other baseline subject
characteristics are described in Table 1. A total of thirty
events occurred (28 deaths and 2 LVADs) over 1 year of
follow up from TTE study. No cardiac transplants were
identified. When divided into LVOT VTI tertiles,
ejection fraction demonstrated statistical significant across
tertiles, (p = 0.024).
Outcome group analysis
Comparison of subjects meeting primary endpoints
(death or LVAD or transplant, n = 30) versus event-free
subjects (n = 70) identified the following variables as
significantly associated with death and LVAD placement:
LVOT VTI (p = 0.039), older age (p = 0.001), higher
population (n = 100)
LVOT VTI < 8.1 cm,
lowest tertile (n = 34)
LVOT VTI 8.1-9.0 cm,
median tertile (n = 33)
LVOT VTI > 9.0 cm,
highest tertile (n = 33)
Primary outcome was met in 30 subjects (28 death and 2 LVADs); Event free subjects were those alive at one year of follow up from TTE and without requirement
for mechanical circulatory support
Abbrev: GFR glomerular filtration rate, LVOT VTI Left ventricular outflow tract velocity time integral, NYHA New York Heart Association
Legend: SD standard deviation, NYHA New York Heart Association; Diuretics furosemide, toresmide, bumetanide, ACE angiotensin converting enzyme, ARB
angiotensin receptor blocker, CRT cardiac resynchronization therapy, ICD implantable cardiac defibrillator, SBP systolic blood pressure, DBP diastolic blood
pressure, bpm beats per minute, GFR glomerular filtration rate, PA pulmonary artery, LV left ventricle
*denotes meaningful valve disease classified as greater than mild
NYHA class (p = 0.014), higher pulmonary artery
systolic pressure (53.0 ± 16.9 vs. 45.3 ± 12.6 mmHg;
p = 0.019), higher blood urea nitrogen (33.8 ± 15.4 vs
24.1 ± 12.5, p = 0.001), lower hemoglobin (12.7 ± 1.4 vs.
13.5 ± 2.2 g/dL; p = 0.030), and glomerular filtration
rate < 60 ml/min (75.9% vs 53.1%, p = 0.038), results
summarized in Table 2.
Univariate outcomes prediction analysis
A set of predefined variables including age, gender,
presence of diabetes, NYHA class, hemoglobin, blood
urea nitrogen, glomerular filtration rate < 60 ml/min,
pulmonary artery systolic pressure, ejection fraction,
LVOT VTI, and Doppler derived cardiac output were
assessed (Table 3). Significant variables that were
associated with death and LVAD implatation included LVOT
VTI, hazard ratio (HR) of 0.729 (95% confidence interval
[CI] 0.55 - 0.96, p = 0.024), age (HR 1.05, CI 1.02 - 1.09,
p = 0.001), NYHA class (HR 2.13, CI 1.26 - 3.60,
p = 0.005), blood urea nitrogen (HR 1.03, CI1.01 - 1.05,
p = 0.005), and glomerular filtration rate (HR 2.437,
CI 1.04 - 5.71, p = 0.029).
In the multivariate model, all variables in the univariate
analysis with p value ≤0.1 and the prespecified addition of
ejection fraction were included (Table 3). In model 1
LVOT VTI was adjusted by age; model 2 consisted of all
variables in model 1 with the addition of echocardiographic
factors including ejection fraction and echo derived
pulmonary artery systolic pressure. Model 3 consisted of
all variables in model 2 with the addition of NYHA class,
glomerular filtration rate < 60 ml/min and blood urea
nitrogen. In all models, lower LVOT VTI remained
significantly associated with death and LVAD
implantation (Table 3).
Subjects were divided into three groups based on LVOT
VTI tertile: lowest tertile (LVOT VTI < 8.1 cm, n = 34),
median tertile (LVOT VTI 8.1-9.0 cm, n = 33), and
upper tertile (LVOT VTI > 9.0 cm, n = 33). Event free
survival rates were 55.9% for the lowest LVOT VTI tertile,
66.7% for the median tertile, and 87.9% for the upper
tertile, p = 0.008 (Fig. 2. Kaplan Meier Survival analysis by
LVOT VTI Tertile). The hazard ratio for death and LVAD
placement for the lowest tertile (LVOT VTI > 8.1 cm,
n = 34) in comparison to the upper two tertiles (LVOT
VTI > 8.1 cm, n = 66) was 4.755 (CI 1.576-14.348,
p = 0.006), and the HR was 12.680 (CI 2.638 – 60.949,
p = 0.002) when adjusted for age, creatinine, ejection
fraction, pulmonary artery systolic pressure and NYHA
class (Table 4).
Because extremely low LVOT VTI was the focus of our
investigation, a cut off of <10 cm was used for subject
inclusion. Similar to previously described heart failure
cohorts, our study population was predominantly male
(72 out of 100), elderly (mean age, 73.5 years) with
systolic CHF due to ischemic cardiomyopathy (mean EF,
28%). Our findings demonstrate that extremely
diminished LVOT VTI was robustly associated with the
combination of 12-month death and LVAD implantation. In
the multivariate analysis, LVOT VTI was most predictive
of adverse outcomes [HR 0.589 (95% CI 0.41 - 0.83),
p = 0.003], hazard ratio of less than one indicating
that higher LVOT VTI correlates with better outcomes,
other significant variables being older age [HR 1.04
(95% CI 1.004 - 1.095, p = 0.033] and higher
echoderived systolic pulmonary artery pressure [HR 1.03
(95% CI 1.005 - 1.065, p = 0.022].
When comparing cohort tertiles, the unadjusted and
adjusted hazard ratios for LVOT VTI were even more
predictive, with an unadjusted mortality and LVAD
likelihood ratio of 4.755 (95% CI 1.576 - 14.348) in the
lowest LVOT VTI tertile compared with the rest of the
Legend: HR hazard ratio, CI confidence interval, LVAD left ventricular
assist device, LVOT VTI left ventricular outflow tract velocity time
integral; other abbreviations described in Table 1
Fig. 2 Kaplan Meier Survival Analysis by LVOT VTI Tertile
study group and an adjusted likelihood ratio of 12.680
(95% CI 2.638 – 60.949).
Several reasons may explain why low LVOT VTI
correlates closely with adverse clinical outcomes. LVOT
VTI provides enhanced prognostic information over
ejection fraction, as it focuses on forward cardiac output
which at times maybe normal even in compensated
heart failure patients with low ejection fraction. Low
cardiac output is a known precursor to overt cardiogenic
shock, multi-organ dysfunction and death [
the accuracy of Doppler derived cardiac output is
primarily limited by errors in determining the cross
sectional area of the LVOT, as defined by the formula
πr2, utilizing LVOT VTI alone rather than Doppler
derived cardiac output eliminates this source of error. In
patients who are tachycardic due to cardiogenic shock
and poor LV function, rapid heart rate partially offsets
the decline LV function, allowing for maintenance of
cardiac output in the setting of a sick ventricle, however
LVOT VTI remains depressed. Thus, in cases of low
cardiac output with compensatory tachycardia, LVOT VTI
may be a very sensitive predictor of cardiogenic shock
and impaired ability to meet systemic tissue perfusion
and metabolic demands. Because LVOT VTI is an easily
obtainable and reproducible measurement, we propose
that LVOT VTI may be a useful and accessible tool to
identify heart failure patients with very low cardiac
output and who may benefit from advanced heart failure
therapies appropriate for end-stage HF.
As numerous therapies emerge that increase cardiac
output for patients with advanced heart failure [
], there is
an ever greater need to identify those who stand to benefit
most from such therapies [
]. LVOT VTI is an easily
available non-invasive tool that identifies patients at highest
risk for decreased survival at one year, thus allowing for
earlier identification and advanced treatment.
Study limitations and future directions
Accurate determination of LVOT VTI assumes laminar
flow and is affected by LVOT abnormalities such as severe
aortic regurgitation, hypertrophic obstructive
cardiomyopathy, systolic anterior motion of the anterior mitral leaflet,
and subaortic stenosis; subjects with these diagnoses were
excluded in our study as LVOT VTI is not an accurate
predictor of forward cardiac flow in these settings [
Our study was designed as a novel proof-of-concept
study, no prior study to our knowledge at the time of this
writing has examined the relationship between extremely
low LVOT VTI and outcomes in advanced heart failure.
Given the retrospective nature of this study, findings
should be confirmed a larger, prospective cohort.
CI: 95% confidence interval; CO: Doppler derived cardiac output;
EF: Ejection fraction; EMR: Electronic medical record; GFR: Glomerular
filtration rate; HR: Hazard ratio; HR: Heart rate; LVAD: Left ventricular
assist device; LVOT VTI: Left ventricular outflow tract velocity time integral;
NYHA class: New York Heart Association class; PASP: Pulmonary artery systolic
pressure,; SV: Stroke volume; TTE: Transthoracic echocardiogram
The authors would like to acknowledge Dr. Jill Waalen for her assistance with
the statistical analyses performed.
No funding was received for this study.
Availability of data and materials
The datasets used and/or analysed during the current study are available
from the corresponding author on reasonable request.
The study was designed by JTH. KB assisted with data acquisition. CWT was
the major contributor in writing the manuscript. The manuscript was edited
by AS and RM. All authors read and approved the final article.
Dr. Heywood serves as a speaker for Thoratec®. The remaining authors have
no disclosures or competing interests.
Consent for publication
No patient identifying information is used in this article.
Ethics approval and consent to participate
The study was reviewed and approved by our institutional IRB prior to study
initiation. Given the retrospective nature of the study, consent was not
required by the IRB.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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