Normal Values of Cardiac Output and Stroke

Volume According to Measurement

Technique, Age, Sex, and Ethnicity: Results
of the World Alliance of Societies of
Echocardiography Study
Hena N. Patel, MD, Tatsuya Miyoshi, MD, Karima Addetia, MD, Michael P. Henry, MD, Rodolfo Citro, MD,
Masao Daimon, MD, PhD, Pedro Gutierrez Fajardo, MD, FASE, Ravi R. Kasliwal, MD, FASE,
James N. Kirkpatrick, MD, FASE, Mark J. Monaghan, PhD, Denisa Muraru, MD, FASE,
Kofo O. Ogunyankin, MD, FASE, Seung Woo Park, MD, Ricardo E. Ronderos, MD, FASE,
Anita Sadeghpour, MD, FASE, Gregory M. Scalia, MD, FASE, Masaaki Takeuchi, MD, PhD, FASE,
Wendy Tsang, MD, Edwin S. Tucay, MD, FASE, Ana Clara Tude Rodrigues, MD, Amuthan Vivekanandan, MD,
DM, FASE, Yun Zhang, MD, FASE, Marcus Schreckenberg, MS, Michael Blankenhagen, MS, Markus Degel, MS,
Alexander Rossmanith, MS, Victor Mor-Avi, PhD, FASE, Federico M. Asch, MD, FASE,
and Roberto M. Lang, MD, FASE, on Behalf of theWASE Investigators

Background: Assessment of cardiac output (CO) and stroke volume (SV) is essential to understand cardiac
function and hemodynamics. These parameters can be examined using three echocardiographic techniques
(pulsed-wave Doppler, two-dimensional [2D], and three-dimensional [3D]). Whether these methods can be
used interchangeably is unclear. The influence of age, sex, and ethnicity on CO and SV has also not been
examined in depth. In this report from the World Alliance of Societies of Echocardiography Normal Values
Study, the authors compare CO and SV in healthy adults according to age, sex, ethnicity, and measurement
techniques.

Methods: A total of 1,450 adult subjects (53% men) free of heart, lung, and kidney disease were prospectively
enrolled in 15 countries, with even distributions among age groups and sex. Subjects were divided into three
age groups (young, 18–40 years; middle aged, 41–65 years; and old, >65 years) and three main racial groups
(whites, blacks, and Asians). CO and SV were indexed (cardiac index [CI] and SV index [SVI], respectively) to
body surface area and height and measured using three echocardiographic methods: Doppler, 2D, and 3D.
Images were analyzed at two core laboratories (one each for 2D and 3D).

Results: CI and SVI were significantly lower by 2D compared with both Doppler and 3D methods in both sexes.
SVI was significantly lower in women than men by all three methods, while CI differed only by 2D. SVI
decreased with aging by all three techniques, whereas CI declined only with 2D and 3D. CO and SV were
smallest in Asians and largest in whites, and the differences persisted after normalization for body surface
area.

From the University of Chicago, Chicago, Illinois (H.N.P., K.A., M.P.H., V.M.-A.,
R.M.L.); MedStar Health Research Institute, Washington, District of Columbia
(T.M., F.M.A.); the University of Salerno, Salerno, Italy (R.C.); The University of
Tokyo, Tokyo, Japan (M. Daimon); Hospital Bernardette, Guadalajara, Mexico
(P.G.F.); Medanta Medicity, Gurgoan, India (R.R.K.); the University of
Washington, Seattle, Washington (J.N.K.); King’s College Hospital, London,
United Kingdom (M.J.M.); University of Milano-Bicocca and Istituto Auxologico
Italiano, IRCCS, Milan, Italy (D.M.); First Cardiology Consultants Hospital Ikoyi,
Lagos, Nigeria (K.O.O.); Samsung Medical Center/Sungkyunkwan University
School of Medicine, Seoul, Korea (S.W.P.); Instituto Cardiovascular de Buenos
Aires, Buenos Aires, Argentina (R.E.R.); Rajaie Cardiovascular Medical Center,
Iran University of Medical Sciences, Tehran, Iran (A.S.); GenesisCare, Brisbane,
Australia (G.M.S.); the University of Occupational and Environmental Health,
Kitakyushu, Japan (M.T.); Toronto General Hospital, University Health Network,
University of Toronto, Toronto, Ontario, Canada (W.T.); the Philippine Heart
~o
Center, Quezon City, Philippines (E.S.T.); Hospital Israelita Albert Einstein, Sa
Paulo, Brazil (A.C.T.R.); Jeyalakshmi Heart Center, Madurai, India (A.V.); Qilu
Hospital of Shandong University, Jinan, China (Y.Z.); TomTec Imaging Systems,
Unterschleissheim, Germany (M.S., M.B., M. Degel, A.R.).
Drs. Patel and Miyoshi contributed equally to this work.
Mr. Schreckenberg, Mr. Blankenhagen, Mr. Degel, and Mr. Rossmanith are em-
ployees of TomTec Imaging Systems. A full list of WASE investigators is provided
in the Appendix.
Jordan B. Strom, MD, MSc, FASE, served as guest editor for this report.
Reprint requests: Roberto M. Lang, MD, FASE, 5758 S Maryland Avenue, MC
9067, DCAM 5509, Chicago, IL 60637 (E-mail: rlang@medicine.bsd.uchicago.
edu).
0894-7317/$36.00
Copyright 2021 by the American Society of Echocardiography.
https://doi.org/10.1016/j.echo.2021.05.012
1
2 Patel et al Journal of the American Society of Echocardiography
- 2021

Conclusions: The present results provide normal reference values for CO and SV, which differ by age, sex, and
race. Furthermore, CI and SVI measurements by the different echocardiographic techniques are not inter-
changeable. All these factors need to be taken into account when evaluating cardiac function and hemody-
namics in individual patients. (J Am Soc Echocardiogr 2021;-:---.)

Keywords: Ventricular function, Cardiac output, Stroke volume, Doppler

Assessment of cardiac output Despite the routine use of echocardiography for the hemodynamic
Abbreviations
(CO) and stroke volume (SV) is assessment of CO and SV, normal reference values for these param-
2D = Two-dimensional important in guiding the diag- eters in adults using pulsed-wave Doppler, 2D, and 3D methods are
nosis, prognosis, and therapeutic not well defined. Although the clinical value of any imaging modality
3D = Three-dimensional
management of a range of cardio- relies on its ability to detect abnormalities, the diagnosis of ‘‘abnormal’’
AS = Aortic stenosis pulmonary diseases. CO differ- depends on an accurate definition of ‘‘normal.’’ However, whether
ASE = American Society of entiates low- from high-output these three echocardiographic techniques can be used interchange-
Echocardiography heart failure and helps identify ably remains unclear. Additionally, the influence of age, sex, and
low-flow aortic stenosis (AS). ethnicity on SV and CO when measured by these techniques also re-
BSA = Body surface area Measurement of CO plays an mains unclear. Thus, the aims of this study were (1) to establish
CI = Cardiac index essential role in the optimization normative reference values for SV and CO for each of the available
of hemodynamically unstable pa- techniques (Doppler, 2D, and 3D); (2) to determine the influence
CO = Cardiac output tients and in phenotyping the he- of age, sex, and ethnicity on these measurements; and (3) to define
LV = Left ventricular modynamic presentation of cutoff values for low- and high-output states.
cardiogenic shock.1 A hemody-
LVEDV = Left ventricular end-
diastolic volume
namic approach to heart failure
with the addition of CO quantifi-
LVESV = Left ventricular end- cation to left ventricular (LV) METHODS
systolic volume ejection fraction improves the
assessment of pump dysfunction; Study Design and Population
LVOT = Left ventricular
outflow tract that is, reduced LV ejection frac- The rationale and design of the World Alliance of Societies of
tion associated with low CO is a Echocardiography (WASE) study has been described in detail previ-
SV = Stroke volume clinically worse heart failure pro- ously.7 Briefly, this is a multicenter, international, observational, pro-
SVI = Stroke volume index file than decreased LV ejection spective, cross-sectional study of healthy adult individuals. The ASE
fraction with preserved CO.2 invited representatives of all member societies of the ASE
WASE = World Alliance of
Societies of
Although invasive right heart International Alliance Partners to participate in this study. Each partici-
Echocardiography catheterization is considered the pating center was tasked with enrolling 100 local healthy adult volun-
gold standard for CO measure- teers without histories or clinical evidence of heart, lung, or kidney
ment, this method has an associ- disease. Individuals recruited in each country were evenly distributed
ated risk for procedural among three predetermined age categories (young, 18–40 years;
complications and cannot be used regularly in the outpatient setting. middle aged, 41–65 years; and old, >65 years) and sex to allow
Echocardiography is a widely available, noninvasive tool to assess CO adequate geographic comparisons. A single encounter with each sub-
and SV. There are three echocardiographic techniques that are used ject was required for the collection of basic demographic information
to determine CO and SV, Doppler-derived, two-dimensional (2D), and acquisition of a comprehensive transthoracic echocardiogram.
and three-dimensional (3D), and all three have been shown to corre- Body surface area (BSA) was calculated using the Du Bois formula.
late closely with invasive thermodilution and Fick methods.3 Most For the purpose of the WASE study, the definitions of race and
recently, 3D echocardiography has emerged as a fundamental tool ethnicity were adapted from those proposed for the 2020 US census,
for the assessment of LV volumes and function. This technique is the US Food and Drug Administration, and the 2011 UK census.
not affected by foreshortening, does not rely on geometric assump- From September 2016 to January 2019, 2,262 individuals were
tions regarding LV shape or complex formulas, and thereby over- screened at 19 centers in 15 countries, representing six continents.
comes the fundamental limitations of 2D echocardiography and The study was approved by the local research ethics oversight groups,
2D/spectral wave Doppler-derived calculations. In fact, 3D and subjects provided consent, as mandated by each of the enrolling
echocardiography–derived volumes and ejection fractions have center’s institutional review boards or ethics committees.
been shown to be comparable with those obtained on cardiovascular A total of 2008 subjects constituted the final WASE study popula-
magnetic resonance imaging.4 Moreover, compared with standard tion. After the exclusion of 558 subjects who lacked 3D volume
2D Simpson techniques, 3D evaluation of LV volumes and ejection acquisition of adequate image quality, a total of 1,450 subjects
fraction has superior intra- and interobserver reproducibility and (773 men, 677 women) formed the final population for analysis of
reduced test-retest variability.5 Accordingly, the recent American CO and SV. Given the relatively small number of subjects per country
Society of Echocardiography (ASE)/European Association of when divided by sex, data were organized into three main racial
Cardiovascular Imaging guidelines on chamber quantification recom- groups (whites, blacks, and Asians) for analysis, while data from coun-
mend 3D evaluation of LV volumes and function when feasible, de- tries where the majority of the population did not fit into one of these
pending on image quality and laboratory experience.5,6 three categories were not used in the race subanalysis. Asians were
Journal of the American Society of Echocardiography
Volume - Number -
HIGHLIGHTS
 Normal values of SV and CO were obtained from 1,450 sub-
jects.
 Lower limits of normal were established for Doppler, 2D, and
3D echocardiography.
 Normal values differ by age, sex, race, and technique used.
defined as individuals from China, India, Japan, Korea, and the
Philippines.
Echocardiographic Image Acquisition and Analysis
Protocol
A comprehensive transthoracic echocardiogram was acquired us-
ing the enrolling center’s high-end ultrasound systems. Acquisition
was performed following a study-specific standardized protocol
created by the two WASE primary investigators (R.M.L. and F.M.A.)
on the basis of the recent ASE/European Association of
Cardiovascular Imaging guidelines.5,6 Echocardiograms were
analyzed at core laboratories (MedStar Health Research Institute for
Doppler and 2D and the University of Chicago for 3D imaging).
SV was measured using the following three techniques using
vendor-independent software (Image Arena version 4.6; TomTec
Imaging Systems, Unterschleissheim, Germany): (1) Doppler, (2)
2D using the Simpson method of disks, and (3) 3D LV analysis.
Doppler SV was calculated as the product of the 2D LV outflow tract
(LVOT) cross-sectional area and pulsed-wave Doppler envelope re-
corded at the LVOT (Figure 1, left). A minimum of three cardiac cycles
were recorded and averaged for analysis. The LVOT diameter was
measured immediately proximal to the aortic valve annulus in the
parasternal long-axis view, and LVOT velocity-time integral was
measured using pulsed-wave Doppler in either the apical three- or
five-chamber view (100 mm/s speed). With the 2D method, LV
end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV)
were measured using the biplane method of disk summation (modi-
fied Simpson rule), and SV was then calculated as the difference be-
tween these volumes (SV = LVEDV LVESV). Acquisition of all LV
apical views aimed to maximize LV areas while taking care to avoid
foreshortening of the LV long axis. Volumes were measured using
manual tracings of the blood-tissue interface in the apical two- and
four-chamber views, and the contour was closed at the mitral valve
level by connecting the two opposite sections of the mitral annulus
with a straight line. End-diastole was defined as the frame with the
largest LV size. End-systole was defined as the frame with the smallest
LV size. Last, for the 3D method, LVEDV and LVESV obtained from
3D full-volume data sets of the LV using vendor-independent 3D soft-
ware (4D LV-Function version 2.0; TomTec Imaging Systems). This
software automatically displayed orthogonal cut planes of the four-,
two-, and three-chamber views, which were manually adjusted if
necessary to optimize the views and limit foreshortening. Next,
end-diastole and end-systole were identified as described above for
2D and contoured by the software. Contours were manually edited
by the user while studying the dynamics of the LV cavity during the
cardiac cycle. The LVOT, papillary muscles, and trabeculae were
included within the LV cavity. Finally, the program generated an
endocardial surface shell from which volumes were automatically
derived. For the 2D and 3D methods, SV was calculated as the differ-
ence between LVEDV and LVESV. For all three methods, SV index
Patel et al 3
(SVI) was calculated by dividing SV by BSA and by height, CO as
the product of SV and heart rate, and cardiac index (CI) as CO in-
dexed by BSA and by height. Indexing by height also included height
to the allometric power of 2.13.5 Figure 1 demonstrates a sample
acquisition of CO and SV using all three methods in the same subject.
Statistical Analysis
All data are presented as mean 6 SD. Group differences were eval-
uated using unpaired two-tailed Student’s t tests. In cases of three-
group comparisons, three-way analysis of variance was first used to
identify significant differences. Statistical significance was defined as
P < .05. The lower limits of normal for SV and SVI were calculated
as the 2.5th percentile of the corresponding sex and age group for
each measurement technique. This is in accordance of the definition
of ‘‘normal’’ as falling within 95% of the normal population, with the
remaining 5% being distributed half and half among the two tails of
the distribution, irrespective of whether it is Gaussian.
RESULTS
Basic demographic characteristics of the study population are listed in
Table 1. Most individuals were white (477 [32.9%]) or Asian (604
[41.7%]), with a minority being black (174 [12.0%]) or of mixed or
other races (195 [13.4%]). Subjects were evenly distributed in six
age and sex categories: 18 to 40 years (320 men, 285 women), 41
to 65 years (258 men, 221 women), and >65 years (195 men, 171
women). Women had lower BSAs and higher heart rates (Table 2).
Comparison of CO, CI, SV, and SVI among the Three
Measurement Techniques
The results for the CO, CI, SV, and SVI measurements for all subjects
by Doppler, 2D, and 3D methods are shown in Table 2. All parame-
ters (CO, CI, SV, and SVI) were significantly lower by 2D compared
with both Doppler and 3D methods (difference of 26 6 0.4% of the
measured 2D value). Doppler values were lower than those obtained
with 3D for all parameters, showing statistically significant, although
smaller, differences (difference of 7 6 1% of the measured value).
Comparison of CO, CI, SV, and SVI between Sexes
The reference values for CO and SV parameters by sex and measure-
ment technique are reported in Table 2. CO and SV were significantly
lower in women than in men by all three methods (difference of
18 6 4% of the measured value). Although CI was significantly lower
in women than in men by 2D, there were no significant sex differ-
ences by Doppler and 3D assessment. The 2D method demonstrated
the smallest CO and SV parameters in both men and women. Table 3
outlines the lower limits of normal (2.5th percentile) for SV and SVI
for men and women by age and by measurement technique.
Comparison of CO, CI, SV, and SVI among Age Groups
Table 4 summarizes the relationships between CO and SV parame-
ters and age, separately for each sex and measurement technique.
Overall, CO and SV tended to decrease with age for both women
and men by all three techniques. CI remained relatively stable over
age for both women and men by Doppler but declined with the other
two techniques, particularly with 2D measurements. When the three
methods were compared in each age group, 3D measurements
4 Patel et al Journal of the American Society of Echocardiography
- 2021

Figure 1 Sample acquisition of SV by all three methods in a 28-year-old African American man with a BSA of 1.6 m2. EDV, End-
diastolic volume; ESV, end-systolic volume; Svi, SV indexed to BSA; VTI, velocity-time integral.

Table 1 Baseline clinical demographics (n = 1,450) performed additional analysis to elucidate this factor. Specifically,
the majority of the study subjects were imaged using Philips equip-
Value ment (n = 943), while the second largest number underwent imaging
using GE equipment (n = 460). Accordingly, we studied the differ-
Age, y 48 6 17
ences between measurements performed on images from these
Men/women 773/677 two vendors and found that indeed, there were significant differences
Height, cm 167 6 10 in SV and CO for all three techniques used in the study. However,
Weight, kg 68 6 14 there were also significant differences in height, weight, and BSA be-
BSA, m2 1.78 6 0.22 tween the two corresponding populations. Importantly, after indexing
Systolic BP, mm Hg 121 6 12 by BSA, the intervendor differences in CI and SVI were minimal and
Diastolic BP, mm Hg 74 6 9
no longer significant. Of note, there was no significant difference in LV
velocity-time integral between the two vendors.
Race
Finally, we compared the demographic characteristics of the pa-
White 477 (32.9) tients who did and those who did not have 3D images suitable for
Black 174 (12.0) analysis. We found only marginal differences in age (47.1 vs
Asian 604 (41.7) 47.7 years). However, the latter group had a slightly higher prevalence
Other 195 (13.4) of obese subjects with body mass index > 30 kg/m2 (7.0% vs 5.2%),
women (53.4% vs 47.6%), and Asians (41.8% vs 39.5%).
Data are expressed as mean 6 SD, number, or number (percentage).

showed the largest CO and SV values in all age groups for men and in
young and middle-aged women. Two-dimensional measurements re-
sulted in the lowest values in the oldest age group in women.
Comparison of CO, CI, SV, and SVI among Races
Table 5 summarizes the racial difference in CO and SV parameters.
CO and SV parameters varied significantly according to race (whites,
blacks, and Asians). In general, CO and SV tended to be smallest in
Asians and largest in whites for both men and women. These small
differences persisted after normalization for BSA.
Additional Analyses
Because not all of the echocardiography laboratories participating in
the study used the same equipment to record their studies, we
DISCUSSION
In this study, we used a large, geographically diverse cohort of normal
subjects to examine differences in CO and SV measurements made
using 2D, Doppler, and 3D measurement techniques on echocardi-
ography and to determine the influence of sex, age, and race on these
measurements. The main findings of this study are as follows: (1)
reference values for CO and SV differed significantly according to
measurement technique (Doppler, 2D, or 3D), suggesting that these
methods should not be used interchangeably; (2) 2D assessment
yielded lower CO and SV compared with Doppler and 3D volu-
metric techniques; (3) women have smaller CO and SV measured
by all three techniques compared with men, despite normalization
to BSA, underscoring the need for gender-specific normal values;
(4) older individuals tend to have smaller SV and SVI when assessed
Journal of the American Society of Echocardiography Patel et al 5
Volume - Number -

Table 2 SV and CO assessment using the different methods

All subjects Men Women

(n = 1,450) (n = 773) (n = 677)

BSA, m 2
1.78 6 0.22 1.89 6 0.20 1.65 6 0.17*
Heart rate, beats/min 67.5 6 10.7 65.9 6 10.4 69.3 6 10.7*
LVOT diameter, mm 20.8 6 2.1 21.8 6 1.9 19.6 6 1.5*
BSA-indexed LVOT diameter, mm/m2 11.8 6 1.2 11.7 6 1.2 11.9 6 1.2
LVOT VTI, mm 20.2 6 3.6 19.8 6 3.3 20.7 6 3.8*
Doppler
SV, mL 68.7 6 17.0 74.3 6 17.2 62.5 6 14.3*
BSA-indexed SV, mL/m2 38.7 6 8.1 39.4 6 7.9 37.9 6 8.1*
Height-indexed SV, mL/m 40.2 6 10.6 41.8 6 11.2 38.4 6 9.5*
Height2.13-indexed SV, mL/m2.13 22.5 6 5.7 22.5 6 5.9 22.5 6 5.6
CO, L/min 4.58 6 1.12 4.84 6 1.16 4.28 6 0.99*
CI, L/min/m 2
2.60 6 0.58 2.58 6 0.58 2.63 6 0.58
Height-indexed CO, mL/min/m 2.67 6 0.75 2.70 6 0.80 2.62 6 0.69*
Height2.13-indexed CO, mL/min/m2.13 1.50 6 0.42 1.46 6 0.43 1.54 6 0.41*
2D echocardiography
SV, mL 58.4 6 15.4 64.5 6 15.8 51.5 6 11.6*
BSA-indexed SV, mL/m2 32.7 6 6.8 34.1 6 7.1 31.2 6 6.2*
Height-indexed SV, mL/m 34.7 6 7.9 37.1 6 8.2 32.0 6 6.5*
Height2.13-indexed SV, mL/m2.13 19.3 6 3.9 19.9 6 4.0 18.7 6 3.6*
CO, L/min 3.88 6 1.00 4.18 6 1.02 3.54 6 0.85*
CI, L/min/m2 2.18 6 0.48 2.21 6 0.48 2.14 6 0.47*
Height-indexed CO, mL/min/m 2.30 6 0.56 2.40 6 0.56 2.18 6 0.53*
Height2.13-indexed CO, mL/min/m2.13 1.29 6 0.29 1.29 6 0.29 1.28 6 0.31
3D echocardiography
SV, mL 73.1 6 18.5†,‡,§,ǁ 79.5 6 19.2 65.9 6 14.6*
BSA-indexed SV, mL/m 2
41.1 6 8.6†,‡,§,ǁ 42.1 6 9.0 39.9 6 8.0*
Height-indexed SV, mL/m 43.5 6 9.7†,‡,§,ǁ 45.8 6 10.2 41.0 6 8.5*
Height2.13-indexed SV, mL/m2.13 24.3 6 5.1†,‡,§,ǁ 24.6 6 5.2 24.1 6 4.9*
CO, L/min 4.86 6 1.22 †,‡,§,ǁ
5.17 6 1.28 4.52 6 1.07*
CI, L/min/m2 2.74 6 0.62†,‡,§,ǁ 2.74 6 0.62 2.74 6 0.61
Height-indexed CO, mL/min/m 2.90 6 0.68†,‡,§,ǁ 2.98 6 0.71 2.80 6 0.68*
Height2.13-indexed CO, mL/min/m2.13 1.62 6 0.38†,‡,§,ǁ 1.60 6 0.38 1.64 6 0.40*
Data are expressed as mean 6 SD.
VTI, Velocity-time integral.
*P < .05 for men versus women (t test).
†
P < .05 (three-way analysis of variance).
‡
P < .05 for Doppler versus 2D echocardiography (t test).
§
P < .05 for Doppler versus 3D echocardiography (t test).
ǁ
P < .05 for 2D versus 3D echocardiography (t test).

using 2D and 3D methods, while SV and SVI values were similar for
the Doppler method irrespective of age; and (5) race influenced CO
and SV, though these differences were attenuated with BSA index-
ation. In summary, CO and SV measurements should be defined ac-
cording to age, sex, and race.
Comparison of SV and SVI among Three Measurement
Techniques
To the best of our knowledge, this is the first study to directly compare
three echocardiographic techniques used to measure CO and SV
parameters in a geographically diverse large population of normal
subjects over a wide range of ages. Previous studies reporting norma-
tive reference ranges for standard echocardiographic measurements
of the left heart have described LV volumes by 2D and 3D methods.
Reporting of normative ranges by Doppler have been limited in
comparison.
It is worth mentioning that each measurement technique has its
inherent limitations. The Doppler method is based on the assumption
that the LVOT is circular. However, the LVOT area is actually more
elliptical, as shown by multiple studies using 3D echocardiography
and multidetector computed tomography.8-11 Furthermore, the
6 Patel et al Journal of the American Society of Echocardiography
- 2021

Table 3 Lower limits of normal for SV and SVI for men and women by age and by measurement technique

Men Women

18–40 y (n = 320) 41–65 y (n = 258) >65 y (n = 195) 18–40 y (n = 285) 41–65 y (n = 221) >65 y (n = 171)

Doppler
SV, mL 48.2 45.1 47.4 37.2 42.1 37.6
BSA-indexed SV, mL/m2 27.3 24.6 24.3 25.5 24.2 23.5
Height-indexed SV, mL/m 28.9 27.1 27.1 24.1 27.0 23.6
2D echocardiography
SV, mL 44.4 40.0 34.0 34.7 33.5 26.1
BSA-indexed SV, mL/m2 24.2 21.7 20.0 22.6 20.4 17.3
Height-indexed SV, mL/m 26.3 24.0 20.5 22.6 21.2 17.3
3D echocardiography
SV, mL 52.3 47.4 45.1 43.6 39.6 39.3
BSA-indexed SV, mL/m2 28.8 26.1 25.5 28.1 24.4 24.1
Height-indexed SV, mL/m 31.3 28.8 26.9 27.2 25.7 25.3
Values represent 2.5th percentile of each parameter in each corresponding group.

Table 4 CO and SV according to age

Men Women

18–40 y (n = 320) 41–65 y (n = 258) >65 y (n = 195) P 18–40 y (n = 285) 41–65 y (n = 221) >65 y (n = 171) P

BSA, m 2
1.90 6 0.20 1.91 6 0.20 1.84 6 0.19 * ,†,‡
1.64 6 0.17 1.69 6 0.16 1.63 6 0.17 * ,‡,§

Heart rate, beats/min 66.4 6 10.6 66.4 6 10.3 64.7 6 10.6 *,† 70.3 6 11.1 68.4 6 10.8 69.0 6 10.0
LVOT diameter, mm 22.3 6 1.9 21.8 6 1.8 21.3 6 1.9 * ,†,‡,§
19.6 6 1.5 19.7 6 1.5 19.4 6 1.5
BSA-indexed LVOT diameter, mm/m2 11.8 6 1.1 11.5 6 1.3 11.6 6 1.3 *,§ 12.0 6 1.1 11.7 6 1.2 12.0 6 1.4 *,‡,§
LVOT VTI, mm 19.3 6 2.9 19.9 6 3.4 20.3 6 3.7 * ,†,§
20.3 6 3.6 21.0 6 3.8 21.0 6 4.1 *,§
Doppler
SV, mL 75.6 6 16.9 74.2 6 17.5 72.2 6 17.2 *,† 61.5 6 14.0 64.1 6 14.6 61.8 6 14.4
BSA-indexed SV, mL/m 2
39.7 6 7.3 39.0 6 8.2 39.3 6 8.6 37.4 6 7.4 38.1 6 8.1 38.3 6 9.2
CO, L/min 5.0 6 1.1 4.9 6 1.2 4.6 6 1.2 * ,†,‡
4.3 6 1.0 4.3 6 1.0 4.2 6 1.0
CI, L/min/m2 2.6 6 0.5 2.6 6 0.6 2.6 6 0.7 2.6 6 0.6 2.6 6 0.6 2.7 6 0.6
2D echocardiography
SV, mL 70.7 6 15.8 63.4 6 14.7 55.7 6 12.7 *,†,‡,§ 55.2 6 11.5 52.1 6 10.7 44.7 6 9.8 *,†,‡,§
BSA-indexed SV, mL/m 2
37.1 6 6.8 33.2 6 6.6 30.2 6 5.9 * ,†,‡,§
33.5 6 5.7 30.9 6 5.9 27.5 6 5.7 *,†,‡,§
CO, L/min 4.6 6 1.0 4.1 6 0.9 3.6 6 0.8 * ,†,‡,§
3.8 6 0.9 3.5 6 0.8 3.1 6 0.7 *,†,‡,§
CI, L/min/m 2
2.4 6 0.5 2.2 6 0.4 1.9 6 0.4 * ,†,‡,§
2.3 6 0.5 2.1 6 0.4 1.9 6 0.4 *,†,‡,§
3D echocardiography
SV, mL 84.4 6 19.7 77.3 6 19.1 74.2 6 16.7 *,†,§ 68.5 6 14.7 66.6 6 14.6 60.8 6 13.2 *,†,‡
BSA-indexed SV, mL/m 2
44.3 6 8.7 40.6 6 9.2 40.4 6 8.3 * ,†,§
41.6 6 7.4 39.5 6 8.1 37.6 6 8.1 *,†,§
CO, L/min 5.5 6 1.3 5.1 6 1.2 4.8 6 1.2 * ,†,‡,§
4.8 6 1.1 4.5 6 1.0 4.2 6 0.9 *,†,‡,§
CI, L/min/m 2
2.9 6 0.6 2.9 6 0.6 2.6 6 0.6 * ,†,§
2.9 6 0.6 2.7 6 0.6 2.6 6 0.6 *,†,§
Data are expressed as mean 6 SD.
VTI, Velocity-time integral.
*P < .05 (three-way analysis of variance).
†
P < .05 for 18 to 40 years versus >65 years (t test).
‡
P < .05 for 41 to 65 years versus >65 years (t test).
§
P < .05 for 18 to 40 years versus 41 to 65 years (t test).
Journal of the American Society of Echocardiography Patel et al 7
Volume - Number -

Table 5 CO and SV according to ethnicity

Men Women

Asian Black White Asian Black White

(n = 327) (n = 92) (n = 256) P (n = 277) (n = 82) (n = 221) P

LVOT diameter, mm 21.6 6 1.8 21.5 6 1.9 22.4 6 2.0 *,†,‡

19.3 6 1.5 19.7 6 1.6 19.8 6 1.4 * ,†,§

BSA-indexed LVOT diameter, mm/m2 12.2 6 1.2 11.2 6 1.3 11.3 6 1.0 *,†,§ 12.5 6 1.2 11.2 6 1.3 11.6 6 1.0 *,†,‡,§
LVOT VTI, mm 19.0 6 3.0 20.2 6 3.4 20.5 6 3.5 *,†,§ 19.9 6 3.9 20.8 6 3.5 21.7 6 3.8 *,†
Doppler
SV, mL 69.5 6 14.4 72.2 6 15.2 81.3 6 19.8 *,†,‡ 58.4 6 14.0 63.0 6 13.5 67.3 6 14.8 *,†,‡,§
BSA-indexed SV, mL/m 2
39.0 6 7.6 37.4 6 7.3 40.9 6 8.6 *,†,‡
37.7 6 8.8 35.7 6 7.1 39.3 6 8.2 *,†,‡
CO, L/min 4.7 6 1.1 4.6 6 1.2 5.1 6 1.2 *,†,‡ 4.1 6 1.0 4.3 6 1.1 4.4 6 1.0 *,†
CI, L/min/m 2
2.7 6 0.6 2.4 6 0.6 2.6 6 0.6 *,‡,§
2.8 6 0.6 2.4 6 0.6 2.6 6 0.5 *,†,§
2D echocardiography
SV, mL 58.4 6 12.9 68.3 6 16.4 71.9 6 17.1 *,†,§ 47.0 6 9.6 55.0 6 10.6 57.0 6 12.4 *,†,§
BSA-indexed SV, mL/m2 32.7 6 6.4 35.3 6 7.7 36.2 6 7.5 *,†,§ 30.3 6 6.0 31.3 6 5.7 33.2 6 6.8 *,†,‡
CO, L/min 3.9 6 0.9 4.3 6 1.2 4.5 6 1.1 *,†,§
3.3 6 0.7 3.7 6 0.9 3.8 6 1.0 *,†,§
CI, L/min/m 2
2.2 6 0.4 2.2 6 0.5 2.3 6 0.5 *,†
2.2 6 0.5 2.1 6 0.5 2.2 6 0.5
3D echocardiography
SV, mL 72.1 6 15.9 85.6 6 22.9 87.9 6 19.9 *,†,§ 60.9 6 13.0 71.1 6 15.5 71.4 6 14.8 *,†,§
BSA-indexed SV, mL/m 2
40.5 6 8.0 44.3 6 11.1 44.4 6 9.3 *,†,§
39.3 6 7.9 40.3 6 7.9 41.7 6 8.5 *,†
CO, L/min 4.8 6 1.1 5.4 6 1.6 5.6 6 1.3 *,†,§
4.3 6 1.1 4.8 6 1.2 4.7 6 1.1 *,†,§
CI, L/min/m 2
2.7 6 0.6 2.8 6 0.8 2.8 6 0.6 *,†
2.8 6 0.7 2.7 6 0.6 2.7 6 0.6
Data are expressed as mean 6 SD.
VTI, Velocity-time integral.
*P < .05 (three-way analysis of variance).
†
P < .05 for Asian versus white (t test).
‡
P < .05 for black versus white (t test).
§
P < .05 for Asian versus black (t test).

Doppler method assumes that flow at the LVOT is laminar, with a
spatially flat profile. With aging, there tends to be a higher
prevalence of basal septal hypertrophy, which can create a skewed
flow profile and confound SV values in the elderly population.
Assessment of LV volumes using 2D echocardiography is limited by
foreshortening, malrotation, angulation, and reliance on geometric
assumptions for volume calculation, resulting in an underestimation
of ventricular volumes.4 With the 3D method, LV volumes can be
measured without geometric assumption and are not affected by
foreshortening. However, temporal resolution is lower than with
2D images, which may miss the time points at which LV volumes
are largest or smallest and resulting in erroneous SV estimation. To
mitigate this effect, we aimed to collect 3D data sets with the highest
possible frame rate (>20 Hz in this study).
Our results demonstrated that CO and SV parameters were small-
est with the 2D method, probably because (1) geometric assumptions
do not accurately reflect true ventricular shape, and (2) the cut planes
in apical two- and four-chamber views were not optimal to obtain
maximum and minimum LV volumes even if they did not appear
foreshortened. To determine the potential clinical significance of these
intertechnique differences, we expressed them as percentages of the
measured values and found that their magnitude was quite large
(26 6 0.4%). When comparing the Doppler and 3D measurements,
CO and SV by 3D were significantly larger than by Doppler, but these
differences were relatively small (7 6 1%) and thus probably clinically
irrelevant. In this regard, our data are consistent with those of previous
studies.12,13
Currently, SVI by echocardiography is often used in the evaluation
of patients with AS to define low-output states on the basis of an arbi-
trary threshold of 35 mL/m2 that defines low-flow, low-gradient AS.
This definition was based on an association with outcomes in patients
with severe AS and did not differentiate between genders.14 Recently,
it has been suggested that cutoff values of SVI in the setting of severe
AS should be different in men and women, with low flow in men
defined as <40 mL/m2 and in women as <32 mL/m2.15 These values
are comparable with our normal Doppler-derived values in both
sexes. This is particularly interesting considering the significant differ-
ence between the two study populations, one with severe AS and the
other normal subjects. On the basis of recent outcomes data, lower
SVI cutoffs have been proposed to differentiate normal from low-
output states. Despite the widespread use of noninvasively derived
SV by echocardiography, published normal reference values in
healthy individuals are limited. Defining a range of normal values
for SV and SVI that accounts for measurement technique (Doppler,
2D, or 3D) will be an important consideration for future guidelines.
Relationships with Sex, Age, and Race
CO and SV measurements were higher in men than in women, which
is consistent with previous studies16-18 for all three measurement
8 Patel et al
techniques. These differences persisted after normalization for BSA
and can likely be explained by smaller LV volumes in women
compared with men. To determine the potential clinical significance
of these sex-related differences, we also expressed them as percent-
ages of the measured values and found that their magnitude was
not negligible (18 6 4%). Also, our data support the findings of pre-
vious studies that CO and SV decrease with aging in healthy sub-
jects.12,13,16-20 Elderly individuals demonstrated the smallest CO
and SV by both 2D and 3D measurements, which persisted after
normalization to BSA for both men and women. These changes in
LV volumes may be due to a change in LV geometry with aging.
Kaku et al.17 demonstrated that younger individuals had more spher-
ical left ventricles that tended to become more elliptical with
advancing age. The reduction in CO is likely the result of an age-
related decrease in SV compounded by a decrease in body size in
the aging adult population. Importantly, a change in the ‘‘normal’’
values of CO and SV with age may not necessarily indicate that the
value is normal and may not imply low risk for an adverse outcome.
These findings highlight the complexity of heart chamber size and
function adaptation to aging.
CO and SV were higher in whites than in Asians or blacks, regard-
less of measurement technique (with the exception of 3D CO in
women, which was highest in blacks). Indexation by BSA appeared
to reduce the differences among ethnic groups for both men and
women. The importance of ethnicity was also demonstrated by
Chahal et al.,21 who reported that LV volumes were smaller among
Asian Indians than white Europeans. The JAMP studies, which inves-
tigated 2D19 and 3D16 echocardiographic reference values in a
Japanese population, suggested that healthy Japanese hearts were
smaller than those of Western populations, indicating the need for
race-related normal values. However, once indexed by BSA, their
values were not significantly different from the ASE reference
values.5,19
Although basic indexation of CO and SV by BSA reduced much of
the disparities in reference values among ethnic groups, it did not have
this effect on sex- and age-related differences. In particular, the discrep-
ancies persisting for SVI may have implications in the management of
‘‘low-flow’’ AS. Furthermore, diagnostic or therapeutic decisions are
sometimes based on echocardiographic findings without indexing
the parameters for BSA. Thus, differences among races should be care-
fully considered when these measurements are used for making diag-
nostic or therapeutic decisions in individual patients.
Limitations
Although the WASE study was designed to be inclusive in order to
represent multiple regions around the world, certain areas remained
underrepresented in this study. However, we had to strike a balance
between this inclusivity and feasibility with the available resources.
Additional, larger regional studies should be considered to establish
more specific normality ranges for countries not included in this study.
CONCLUSION
Our results from the WASE Normal Values Study provide normal
reference values for CO and SV, which differ by age, sex, and race.
Furthermore, CI and SVI measurements by the different measure-
ment techniques are not interchangeable. All these factors need to
be considered when evaluating cardiac function and hemodynamics
in individual patients.
Journal of the American Society of Echocardiography
- 2021
SUPPLEMENTARY DATA
Supplementary data related to this article can be found at https://doi.
org/10.1016/j.echo.2021.05.012.
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9.e1 Patel et al
APPENDIX. ADDITIONAL WASE INVESTIGATORS
Argentina: Aldo D. Prado, Centro Privado de Cardiologia, Tucuman,
Argentina; Eduardo Filipini, Universidad Nacional de la Plata, Buenos
Aires, Argentina.
Australia: Agatha Kwon and Samantha Hoschke-Edwards, Heart
Care Partners, Queensland, Australia.
Brazil: Tania Regina Afonso, Albert Einstein Hospital, S~ao Paulo,
Brazil.
Canada: Babitha Thampinathan and Maala Sooriyakanthan,
Toronto General Hospital, University of Toronto, Canada.
China: Tiangang Zhu and Zhilong Wang, Peking University
People’s Hospital, Beijing, China; Yingbin Wang, Qilu Hospital of
Shandong University, Jinan, China; Lixue Yin and Shuang Li,
Sichuan Provincial People’s Hospital, Sichuan, China.
Journal of the American Society of Echocardiography
- 2021
India: R. Alagesan, Madras Medical College, Chennai, India; S.
Balasubramanian, Madurai Medical College, Madurai, India; R.V.A.
Ananth, Jeyalakshmi Heart Center, Madurai, India; Manish Bansal,
Medanta Heart Institute, Medanta, Haryana, India.
Iran: Azin Alizadehasl, Rajaie Cardiovascular Medical Center, Iran
University of Medical Sciences, Tehran, Iran.
Italy: Luigi Badano, University of Milano-Bicocca, and Istituto
Auxologico Italiano, IRCCS, Milan, Italy; Eduardo Bossone, Davide
Di Vece and Michele Bellino, University of Salerno, Salerno, Italy.
Japan: Tomoko Nakao, Takayuki Kawata, Megumi Hirokawa, and
Naoko Sawada, University of Tokyo, Tokyo, Japan; Yousuke
Nabeshima, University of Occupational and Environmental Health,
Kitakyushu, Japan.
Korea: Hye Rim Yun and Ji-won Hwang, Samsung Medical Center,
Seoul, Korea.