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

Abstract

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.

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 interchangeable. All these factors need to be taken into account when evaluating cardiac function and hemodynamics in individual patients.

Assessment of cardiac output (CO) and stroke volume (SV) is important in guiding the diagnosis, prognosis, and therapeutic management of a range of cardiopulmonary diseases. CO differentiates low- from high-output heart failure and helps identify low-flow aortic stenosis (AS). Measurement of CO plays an essential role in the optimization of hemodynamically unstable patients and in phenotyping the hemodynamic presentation of cardiogenic shock.¹ A hemodynamic approach to heart failure with the addition of CO quantification to left ventricular (LV) ejection fraction improves the assessment of pump dysfunction; that is, reduced LV ejection fraction associated with low CO is a clinically worse heart failure profile than decreased LV ejection fraction with preserved CO.²

Although invasive right heart catheterization is considered the gold standard for CO measurement, this method has an associated risk for procedural complications and cannot be used regularly in the outpatient setting. Echocardiography is a widely available, noninvasive tool to assess CO and SV. There are three echocardiographic techniques that are used to determine CO and SV, Doppler-derived, two-dimensional (2D), and three-dimensional (3D), and all three have been shown to correlate closely with invasive thermodilution and Fick methods.³ Most recently, 3D echocardiography has emerged as a fundamental tool for the assessment of LV volumes and function. This technique is not affected by foreshortening, does not rely on geometric assumptions regarding LV shape or complex formulas, and thereby overcomes the fundamental limitations of 2D echocardiography and 2D/spectral wave Doppler-derived calculations. In fact, 3D echocardiography–derived volumes and ejection fractions have been shown to be comparable with those obtained on cardiovascular magnetic resonance imaging.⁴ Moreover, compared with standard 2D Simpson techniques, 3D evaluation of LV volumes and ejection fraction has superior intra- and interobserver reproducibility and reduced test-retest variability.⁵ Accordingly, the recent American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging guidelines on chamber quantification recommend 3D evaluation of LV volumes and function when feasible, depending on image quality and laboratory experience.^5,6

Despite the routine use of echocardiography for the hemodynamic assessment of CO and SV, normal reference values for these parameters in adults using pulsed-wave Doppler, 2D, and 3D methods are not well defined. Although the clinical value of any imaging modality relies on its ability to detect abnormalities, the diagnosis of “abnormal” depends on an accurate definition of “normal.” However, whether these three echocardiographic techniques can be used interchangeably remains unclear. Additionally, the influence of age, sex, and ethnicity on SV and CO when measured by these techniques also remains unclear. Thus, the aims of this study were (1) to establish normative reference values for SV and CO for each of the available techniques (Doppler, 2D, and 3D); (2) to determine the influence of age, sex, and ethnicity on these measurements; and (3) to define cutoff values for low- and high-output states.

METHODS

Study Design and Population

The rationale and design of the World Alliance of Societies of Echocardiography (WASE) study has been described in detail previously.⁷ Briefly, this is a multicenter, international, observational, prospective, cross-sectional study of healthy adult individuals. The ASE invited representatives of all member societies of the ASE International Alliance Partners to participate in this study. Each participating center was tasked with enrolling 100 local healthy adult volunteers without histories or clinical evidence of heart, lung, or kidney disease. Individuals recruited in each country were evenly distributed among three predetermined age categories (young, 18–40 years; middle aged, 41–65 years; and old, >65 years) and sex to allow adequate geographic comparisons. A single encounter with each subject was required for the collection of basic demographic information and acquisition of a comprehensive transthoracic echocardiogram. Body surface area (BSA) was calculated using the Du Bois formula. For the purpose of the WASE study, the definitions of race and ethnicity were adapted from those proposed for the 2020 US census, the US Food and Drug Administration, and the 2011 UK census.

From September 2016 to January 2019, 2,262 individuals were screened at 19 centers in 15 countries, representing six continents. The study was approved by the local research ethics oversight groups, and subjects provided consent, as mandated by each of the enrolling center’s institutional review boards or ethics committees.

A total of 2008 subjects constituted the final WASE study population. After the exclusion of 558 subjects who lacked 3D volume acquisition of adequate image quality, a total of 1,450 subjects (773 men, 677 women) formed the final population for analysis of CO and SV. Given the relatively small number of subjects per country when divided by sex, data were organized into three main racial groups (whites, blacks, and Asians) for analysis, while data from countries where the majority of the population did not fit into one of these three categories were not used in the race subanalysis. Asians were defined as individuals from China, India, Japan, Korea, and the Philippines.

Echocardiographic Image Acquisition and Analysis Protocol

A comprehensive transthoracic echocardiogram was acquired using 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 recorded 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 (modified Simpson rule), and SV was then calculated as the difference between 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 software (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 difference between LVEDV and LVESV. For all three methods, SV index (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 indexed 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.

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.

Statistical Analysis

All data are presented as mean ± SD. Group differences were evaluated 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).

Table 1.

Baseline clinical demographics (n = 1,450)

	Value
Age, y	48 ± 17
Men/women	773/677
Height, cm	167 ± 10
Weight, kg	68 ± 14
BSA, m2	1.78 ± 0.22
Systolic BP, mm Hg	121 ± 12
Diastolic BP, mm Hg	74 ± 9
Race
White	477 (32.9)
Black	174 (12.0)
Asian	604 (41.7)
Other	195 (13.4)

Data are expressed as mean ± SD, number, or number (percentage).

Table 2.

SV and CO assessment using the different methods

	All subjects	Men	Women
	(n = 1,450)	(n = 773)	(n = 677)
BSA, m2	1.78 ± 0.22	1.89 ± 0.20	1.65 ± 0.17*
Heart rate, beats/min	67.5 ± 10.7	65.9 ± 10.4	69.3 ± 10.7*
LVOT diameter, mm	20.8 ± 2.1	21.8 ± 1.9	19.6 ± 1.5*
BSA-indexed LVOT diameter, mm/m2	11.8 ± 1.2	11.7 ± 1.2	11.9 ± 1.2*
LVOT VTI, mm	20.2 ± 3.6	19.8 ± 3.3	20.7 ± 3.8*
Doppler
SV, mL	68.7 ± 17.0	74.3 ± 17.2	62.5 ± 14.3*
BSA-indexed SV, mL/m2	38.7 ± 8.1	39.4 ± 7.9	37.9 ± 8.1*
Height-indexed SV, mL/m	40.2 ± 10.6	41.8 ± 11.2	38.4 ± 9.5*
Height2.13-indexed SV, mL/m2.13	22.5 ± 5.7	22.5 ± 5.9	22.5 ± 5.6
CO, L/min	4.58 ± 1.12	4.84 ± 1.16	4.28 ± 0.99*
Cl, L/min/m2	2.60 ± 0.58	2.58 ± 0.58	2.63 ± 0.58
Height-indexed CO, mL/min/m	2.67 ± 0.75	2.70 ± 0.80	2.62 ± 0.69*
Height2.13-indexed CO, mL/min/m2.13	1.50 ± 0.42	1.46 ± 0.43	1.54 ± 0.41*
2D echocardiography
SV, mL	58.4 ± 15.4	64.5 ± 15.8	51.5 ± 11.6*
BSA-indexed SV, mL/m2	32.7 ± 6.8	34.1 ± 7.1	31.2 ± 6.2*
Height-indexed SV, mL/m	34.7 ± 7.9	37.1 ± 8.2	32.0 ± 6.5*
Height2.13-indexed SV, mL/m2.13	19.3 ± 3.9	19.9 ± 4.0	18.7 ± 3.6*
CO, L/min	3.88 ± 1.00	4.18 ± 1.02	3.54 ± 0.85*
Cl, L/min/m2	2.18 ± 0.48	2.21 ± 0.48	2.14 ± 0.47*
Height-indexed CO, mL/min/m	2.30 ± 0.56	2.40 ± 0.56	2.18 ± 0.53*
Height2.13-indexed CO, mL/min/m2.13	1.29 ± 0.29	1.29 ± 0.29	1.28 ± 0.31
3D echocardiography
SV, mL	73.1 ± 18.5†,‡§,‖	79.5 ± 19.2	65.9 ± 14.6*
BSA-indexed SV, mL/m2	41.1 ± 8.6†,‡§,‖	42.1 ± 9.0	39.9 ± 8.0*
Height-indexed SV, mL/m	43.5 ± 9.7†,‡§,‖	45.8 ± 10.2	41.0 ± 8.5*
Height2.13-indexed SV, mL/m2.13	24.3 ± 5.1†,‡§,‖	24.6 ± 5.2	24.1 ± 4.9*
CO, L/min	4.86 ± 1 22†,‡§,‖	5.17 ± 1.28	4.52 ± 1.07*
Cl, L/min/m2	2.74 ± 0.62†,‡§,‖	2.74 ± 0.62	2.74 ± 0.61
Height-indexed CO, mL/min/m	2.90 ± 0.68†,‡§,‖	2.98 ± 0.71	2.80 ± 0.68*
Height2.13-indexed CO, mL/min/m2.13	1.62 ± 0.38†,‡§,‖	1.60 ± 0.38	1.64 ± 0.40*

Data are expressed as mean ± 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).

^‖P < .05 for 2D versus 3D echocardiography (t test).

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 parameters (CO, CI, SV, and SVI) were significantly lower by 2D compared with both Doppler and 3D methods (difference of 26 ± 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 ± 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 measurement technique are reported in Table 2. CO and SV were significantly lower in women than in men by all three methods (difference of 18 ± 4% of the measured value). Although CI was significantly lower in women than in men by 2D, there were no significant sex differences 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.

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.

Comparison of CO, CI, SV, and SVI among Age Groups

Table 4 summarizes the relationships between CO and SV parameters 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 showed the largest CO and SV values in all age groups for men and in young and middle-aged women. Two-dimensional measurements resulted in the lowest values in the oldest age group in women.

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, m2	1.90 ± 0.20	1.91 ± 0.20	1.84 ± 0.19	*,†,‡	1.64 ± 0.17	1.69 ± 0.16	1.63 ± 0.17	*,†,§
Heart rate, beats/min	66.4 ± 10.6	66.4 ± 10.3	64.7 ± 10.6	*,†	70.3 ± 11.1	68.4 ± 10.8	69.0 ± 10.0
LVOT diameter, mm	22.3 ± 1.9	21.8 ± 1.8	21.3 ± 1.9	*,†,‡,§	19.6 ± 1.5	19.7 ± 1.5	19.4 ± 1.5
BSA-indexed LVOT diameter, mm/m2	11.8 ± 1.1	11.5 ± 1.3	11.6 ± 1.3	*,§	12.0 ± 1.1	11.7 ± 1.2	12.0 ± 1.4	*,‡,§
LVOT VTI, mm	19.3 ± 2.9	19.9 ± 3.4	20.3 ± 3.7	*,†,§	20.3 ± 3.6	21.0 ± 3.8	21.0 ± 4.1	*,§
Doppler
SV, mL	75.6 ± 16.9	74.2 ± 17.5	72.2 ± 17.2	*,†	61.5 ± 14.0	64.1 ± 14.6	61.8 ± 14.4
BSA-indexed SV, mL/m2	39.7 ± 7.3	39.0 ± 8.2	39.3 ± 8.6		37.4 ± 7.4	38.1 ± 8.1	38.3 ± 9.2
CO, L/min	5.0 ± 1.1	4.9 ± 1.2	4.6 ± 1.2	*,†,‡	4.3 ± 1.0	4.3 ± 1.0	4.2 ± 1.0
Cl, L/min/m2	2.6 ± 0.5	2.6 ± 0.6	2.6 ± 0.7		2.6 ± 0.6	2.6 ± 0.6	2.7 ± 0.6
2D echocardiography
SV, mL	70.7 ± 15.8	63.4 ± 14.7	55.7 ± 12.7	*,†,‡,§	55.2 ± 11.5	52.1 ± 10.7	44.7 ± 9.8	*,†,‡,§
BSA-indexed SV, mL/m2	37.1 ± 6.8	33.2 ± 6.6	30.2 ± 5.9	*,†,‡,§	33.5 ± 5.7	30.9 ± 5.9	27.5 ± 5.7	*,†,‡,§
CO, L/min	4.6 ± 1.0	4.1 ± 0.9	3.6 ± 0.8	*,†,‡,§	3.8 ± 0.9	3.5 ± 0.8	3.1 ± 0.7	*,†,‡,§
Cl, L/min/m2	2.4 ± 0.5	2.2 ± 0.4	1.9 ± 0.4	*,†,‡,§	2.3 ± 0.5	2.1 ± 0.4	1.9 ± 0.4	*,†,‡,§
3D echocardiography
SV, mL	84.4 ± 19.7	77.3 ± 19.1	74.2 ± 16.7	*,†,§	68.5 ± 14.7	66.6 ± 14.6	60.8 ± 13.2	*,†,‡
BSA-indexed SV, mL/m2	44.3 ± 8.7	40.6 ± 9.2	40.4 ± 8.3	*,†,§	41.6 ± 7.4	39.5 ± 8.1	37.6 ± 8.1	*,†,§
CO, L/min	5.5 ± 1.3	5.1 ± 1.2	4.8 ± 1.2	*,†,‡,§	4.8 ± 1.1	4.5 ± 1.0	4.2 ± 0.9	*,†,‡,§
Cl, L/min/m2	2.9 ± 0.6	2.9 ± 0.6	2.6 ± 0.6	*,†,§	2.9 ± 0.6	2.7 ± 0.6	2.6 ± 0.6	*,†,§

Data are expressed as mean ± 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).

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.

Table 5.

CO and SV according to ethnicity

	Men				Women
	Asian	Black	White	P	Asian	Black	White	P
	(n = 327)	(n = 92)	(n = 256)		(n = 277)	(n = 82)	(n = 221)
LVOT diameter, mm	21.6 ± 1.8	21.5 ± 1.9	22.4 ± 2.0	*,†,‡	19.3 ± 1.5	19.7 ± 1.6	19.8 ± 1.4	*,†,§
BSA-indexed LVOT diameter, mm/m2	12.2 ± 1.2	11.2 ± 1.3	11.3 ± 1.0	*,†,§	12.5 ± 1.2	11.2 ± 1.3	11.6 ± 1.0	*,†,‡,§
LVOT VTI, mm	19.0 ± 3.0	20.2 ± 3.4	20.5 ± 3.5	*,†,§	19.9 ± 3.9	20.8 ± 3.5	21.7 ± 3.8	*,†
Doppler
SV, mL	69.5 ± 14.4	72.2 ± 15.2	81.3 ± 19.8	*,†,‡	58.4 ± 14,0	63.0 ± 13.5	67.3 ± 14.8	*,†,‡,§
BSA-indexed SV, mL/m2	39.0 ± 7.6	37.4 ± 7.3	40.9 ± 8.6	*,†,‡	37.7 ± 8.8	35.7 ± 7.1	39.3 ± 8.2	*,†,‡
CO, L/min	4.7 ± 1.1	4.6 ± 1.2	5.1 ± 1.2	*,†,‡	4.1 ± 1.0	4.3 ± 1.1	4.4 ± 1.0	*,†
Cl, L/min/m2	2.7 ± 0.6	2.4 ± 0.6	2.6 ± 0.6	*,†,§	2.8 ± 0.6	2.4 ± 0.6	2.6 ± 0.5	*,†,§
2D echocardiography
SV, mL	58.4 ± 12.9	68.3 ± 16.4	71.9 ± 17.1	*,†,§	47.0 ± 9.6	55.0 ± 10.6	57.0 ± 12.4	*,†,§
BSA-indexed SV, mL/m2	32.7 ± 6.4	35.3 ± 7.7	36.2 ± 7.5	*,†,§	30.3 ± 6.0	31.3 ± 5.7	33.2 ± 6.8	*,†,‡
CO, L/min	3.9 ± 0.9	4.3 ± 1.2	4.5 ± 1.1	*,†,§	3.3 ± 0.7	3.7 ± 0.9	3.8 ± 1.0	*,†,§
Cl, L/min/m2	2.2 ± 0.4	2.2 ± 0.5	2.3 ± 0.5	*,†	2.2 ± 0.5	2.1 ± 0.5	2.2 ± 0.5
3D echocardiography
SV, mL	72.1 ± 15.9	85.6 ± 22.9	87.9 ± 19.9	*,†,§	60.9 ± 13.0	71.1 ± 15.5	71.4 ± 14.8	*,†,§
BSA-indexed SV, mL/m2	40.5 ± 8.0	44.3 ± 11.1	44.4 ± 9.3	*,†,§	39.3 ± 7.9	40.3 ± 7.9	41.7 ± 8.5	*,†
CO, L/min	4.8 ± 1.1	5.4 ± 1.6	5.6 ± 1.3	*,†,§	4.3 ± 1.1	4.8 ± 1.2	4.7 ± 1.1	*,†,§
Cl, L/min/m2	2.7 ± 0.6	2.8 ± 0.8	2.8 ± 0.6	*,†	2.8 ± 0.7	2.7 ± 0.6	2.7 ± 0.6

Data are expressed as mean ± 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).

Additional Analyses

Because not all of the echocardiography laboratories participating in the study used the same equipment to record their studies, we performed additional analysis to elucidate this factor. Specifically, the majority of the study subjects were imaged using Philips equipment (n = 943), while the second largest number underwent imaging using GE equipment (n = 460). Accordingly, we studied the differences between measurements performed on images from these two vendors and found that indeed, there were significant differences in SV and CO for all three techniques used in the study. However, there were also significant differences in height, weight, and BSA between the two corresponding populations. Importantly, after indexing by BSA, the intervendor differences in CI and SVI were minimal and no longer significant. Of note, there was no significant difference in LV velocity-time integral between the two vendors.

Finally, we compared the demographic characteristics of the patients who did and those who did not have 3D images suitable for analysis. We found only marginal differences in age (47.1 vs 47.7 years). However, the latter group had a slightly higher prevalence 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%).

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 echocardiography 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 volumetric 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 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 indexation. In summary, CO and SV measurements should be defined according 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 normative 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 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 smallest 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 ± 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 ±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 arbitrary 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 difference 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 studies^16–18 for all three measurement 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 percentages of the measured values and found that their magnitude was not negligible (18 ± 4%). Also, our data support the findings of previous studies that CO and SV decrease with aging in healthy subjects.^{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 spherical 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, regardless 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 investigated 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 discrepancies 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 carefully considered when these measurements are used for making diagnostic 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 measurement techniques are not interchangeable. All these factors need to be considered when evaluating cardiac function and hemodynamics in individual patients.

HIGHLIGHTS.

• Normal values of SV and CO were obtained from 1,450 subjects.

• Lower limits of normal were established for Doppler, 2D, and 3D echocardiography.

• Normal values differ by age, sex, race, and technique used.

Abbreviations

2D

Two-dimensional

3D

Three-dimensional

AS

Aortic stenosis

ASE

American Society of Echocardiography

BSA

Body surface area

CI

Cardiac index

CO

Cardiac output

LV

Left ventricular

LVEDV

Left ventricular end-diastolic volume

LVESV

Left ventricular end-systolic volume

LVOT

Left ventricular outflow tract

SV

Stroke volume

SVI

Stroke volume index

WASE

World Alliance of Societies of Echocardiography

APPENDIX. ADDITIONAL WASE INVESTIGATORS

Argentina: Aldo D. Prado, Centro Privado de Cardiologia, Tucumán, 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, São 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.

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.