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Normal sex and age-specific parameters in a multi-ethnic population: a cardiovascular magnetic resonance study of the Canadian Alliance for Healthy Hearts and Minds cohort

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Background Despite the growing utility of cardiovascular magnetic resonance (CMR) for cardiac morphology and function, sex and age-specific normal reference values derived from large, multi-ethnic data sets are lacking. Furthermore, most available studies use a simplified tracing methodology. Using a large cohort of participants without history of cardiovascular disease (CVD) or risk factors from the Canadian Alliance for Healthy Heart and Minds, we sought to establish a robust set of reference values for ventricular and atrial parameters using an anatomically correct contouring method, and to determine the influence of age and sex on ventricular parameters. Methods and results Participants (n = 3206, 65% females; age 55.2 ± 8.4 years for females and 55.1 ± 8.8 years for men) underwent CMR using standard methods for quantitative measurements of cardiac parameters. Normal ventricular and atrial reference values are provided: (1) for males and females, (2) stratified by four age categories, and (3) for different races/ethnicities. Values are reported as absolute, indexed to body surface area, or height. Ventricular volumes and mass were significantly larger for males than females (p < 0.001). Ventricular ejection fraction was significantly diminished in males as compared to females (p < 0.001). Indexed left ventricular (LV) end-systolic, end-diastolic volumes, mass and right ventricular (RV) parameters significantly decreased as age increased for both sexes (p < 0.001). For females, but not men, mean LV and RVEF significantly increased with age (p < 0.001). Conclusion Using anatomically correct contouring methodology, we provide accurate sex and age-specific normal reference values for CMR parameters derived from the largest, multi-ethnic population free of CVD to date. Clinical trial registration ClinicalTrials.gov, NCT02220582. Registered 20 August 2014—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02220582 .
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Luuetal.
Journal of Cardiovascular Magnetic Resonance (2022) 24:2
https://doi.org/10.1186/s12968-021-00819-z
RESEARCH
Normal sex andage-specic parameters
inamulti-ethnic population: acardiovascular
magnetic resonance study oftheCanadian
Alliance forHealthy Hearts andMinds cohort
Judy M. Luu1†, Catherine Gebhard2,3†, Chinthanie Ramasundarahettige4,5, Dipika Desai4, Karleen Schulze4,5,
Francois Marcotte6, Philip Awadalla7, Philippe Broet8,9, Trevor Dummer10, Jason Hicks11, Eric Larose12,
Alan Moody13, Eric E. Smith14, Jean‑Claude Tardif6, Tiago Teixeira15, Koon K. Teo4,5,16, Jennifer Vena17,
Douglas S. Lee18,19, Sonia S. Anand4,5,16 and Matthias G. Friedrich20* on behalf of the CAHHM Study
Investigators
Abstract
Background: Despite the growing utility of cardiovascular magnetic resonance (CMR) for cardiac morphology and
function, sex and age‑specific normal reference values derived from large, multi‑ethnic data sets are lacking. Fur‑
thermore, most available studies use a simplified tracing methodology. Using a large cohort of participants without
history of cardiovascular disease (CVD) or risk factors from the Canadian Alliance for Healthy Heart and Minds, we
sought to establish a robust set of reference values for ventricular and atrial parameters using an anatomically correct
contouring method, and to determine the influence of age and sex on ventricular parameters.
Methods and results: Participants (n = 3206, 65% females; age 55.2 ± 8.4 years for females and 55.1 ± 8.8 years
for men) underwent CMR using standard methods for quantitative measurements of cardiac parameters. Normal
ventricular and atrial reference values are provided: (1) for males and females, (2) stratified by four age categories, and
(3) for different races/ethnicities. Values are reported as absolute, indexed to body surface area, or height. Ventricu‑
lar volumes and mass were significantly larger for males than females (p < 0.001). Ventricular ejection fraction was
significantly diminished in males as compared to females (p < 0.001). Indexed left ventricular (LV) end‑systolic, end‑
diastolic volumes, mass and right ventricular (RV) parameters significantly decreased as age increased for both sexes
(p < 0.001). For females, but not men, mean LV and RVEF significantly increased with age (p < 0.001).
Conclusion: Using anatomically correct contouring methodology, we provide accurate sex and age‑specific normal
reference values for CMR parameters derived from the largest, multi‑ethnic population free of CVD to date.
Clinical trial registration: ClinicalTrials.gov, NCT02220582. Registered 20 August 2014—Retrospectively registered,
https:// clini caltr ials. gov/ ct2/ show/ NCT02 220582.
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licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
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Open Access
*Correspondence: mgwfriedrich@gmail.com
Judy M. Luu and Catherine Gebhard have contributed equally to this
work
20 Department of Medicine and Diagnostic Radiology, McGill University,
1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada
Full list of author information is available at the end of the article
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Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
Introduction
Over the last several years, cardiovascular magnetic
resonance (CMR) imaging has been established as a
reproducible reference standard for the quantification of
chamber volumes, function, and mass in the evaluation
of various cardiac diseases [1]. Despite growing aware-
ness of sex/gender and age-related differences in diag-
nostic approaches [2], CMR-based reference values for
ventricular and atrial parameters, specific to sex and age
groups are lacking, with conflicting data derived from
small or heterogeneous populations [311]. Furthermore,
previously available reference values were limited by
sample cohorts with established cardiovascular disease
(CVD) risk factors, discrete ethnic populations [10, 12
14], or by a contouring methodology that excluded tra-
becular tissue and papillary muscle from left ventricular
(LV) mass, thus was not anatomically accurate [15].
A large prospective, multi-center cohort through
the Canadian Alliance for Healthy Heart and Minds
(CAHHM) provides a unique opportunity to investigate
normal ranges of physiologic parameters, as well as the
association with socio-environmental and contextual
factors, CVD risk, subclinical disease, and other related
chronic disease outcomes [16]. In addition to extensive
clinical assessments consisting of health questionnaires,
physical measurements, and blood sample collection,
CAHHM participants also underwent a comprehensive
magnetic resonance imaging (MRI) of the brain, heart,
carotid artery, and abdomen [16]. A total of 8,580 par-
ticipants were recruited with the opportunity to bet-
ter understand the data of those who completed CMR
imaging.
Given the widespread use and the incremental prog-
nostic value of CMR, the objectives of this study were
to establish a robust set of reference values for ventricu-
lar/atrial volumetric and functional parameters, and to
understand the relationship with age and sex in partici-
pants without a history of established CVD or CVD risk
factors.
Methods
Study population
e CAHHM is a prospective study of participants
recruited through existing research cohorts, with each
separate inclusion and exclusion criteria, as previously
described [16]. Research ethics approval was granted
by the Hamilton Integrated Research Ethics Board, with
consent obtained at each collaborating site as per site-
specific regulations prior to participation in the study.
Selection criteria specific to CAHHM included males
and females, between the ages of 35 and 75 years, who
were willing to undergo an MRI scan and all other
required study procedures. A parallel Alliance-First
Nations cohort was also undertaken in partnership with
eight First Nations communities, however, the data was
not included in this sub-study. Balanced representation
of participants across different age strata 35–44, 44–54,
55–64, and 65–74years with approximately 50% or more
recruitment of females was also ensured [16]. Addi-
tional file1: Figure S1 shows the flowchart (for partici-
pant selection and recruitment). For the purposes of this
analysis, participants with CVD defined as a clinical his-
tory of angina or myocardial infarction, stroke, heart fail-
ure and/or other cardiac disease, prior coronary artery
bypass grafting, or percutaneous coronary intervention
were excluded. Participants with hypertension defined
as a resting elevated blood pressure > 140/80mmHg, dia-
betes, obesity (body mass index (BMI) > 30), smoking,
or dyslipidemia were also excluded. Finally, participants
were ineligible for recruitment if they had contraindi-
cations to CMR, including claustrophobia, pregnancy,
non-compatible pacemaker/defibrillator devices, and
intraocular/intracranial metallic materials. is study
complied with the STROBE (Strengthening the Report-
ing of Observational Studies in Epidemiology) checklist.
CMR protocol
CMR images were acquired at collaborating sites with
the participants in supine position using conventional
CMR systems (1.5 T or 3T) and a cardiac (preferred)
or chest phased-array surface coil with 8 receiver ele-
ments. Following appropriate magnetic shimming, stand-
ard localization was performed with a single-breath hold,
retrospective electrocardiogram (ECG)-gated balanced
steady state free precession (bSSFP) sequence. When
available, bSSFP frequency scouting was performed to
minimize susceptibility artifacts in the myocardium. Cine
images were acquired for LV and right ventricular (RV)
volumetric and functional parameters in both the long
axis (2 slices) and contiguous short axis (SAx) views (12–
14 slices). Field of view was 360mm, voxel size ranged
from 0.9 to 1.2mm, while slice thickness was 8mm, with
a 2mm gap.
Image analysis
CMR images were analysed offline by blinded readers
at a core lab (Montreal Heart Institute, Montreal Can-
ada) using certified software (cvi42, version 4, Circle
Keywords: Sex, Age, Cardiovascular magnetic resonance, Reference, Normal
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Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
Cardiovascular Imaging Inc., Calgary, Alberta, Canada).
e cine SAx stack was used to perform quantitative LV/
RV functional and volumetric evaluations. Epicardial and
endocardial contours were traced manually or semi-auto-
matically using the built-in “threshold tool” with atten-
tion to anatomy and potential image artefacts (Fig. 1).
Anatomical accuracy was verified by carefully tracing
contours for LV mass at end-systole, including papillary
muscles and trabecular tissue into LV mass. ere are
several reasons for using the systolic phase for quanti-
fying LV mass, as discussed in detail by Riffel etal. [15]
Firstly, the overall length of the line defining the endocar-
dial border is shorter and thus, a shorter length suscep-
tible to errors. Secondly, the systolic phase typically has
fewer slices than the diastolic phase, thus less contours
to draw and less chances for errors. Finally, during sys-
tole, the inter-trabecular recesses are closed and there-
fore, there is lower probability for partial volume errors
(Fig.2). For additional reference, LV mass in end-diastole
was also measured and reported in the supplementary
materials.
For LV volume calculations, the entire outflow track
was included into the end-diastolic and end-systolic
phases. Consistent with the LV evaluation, RV volume
contours were segmented, excluding the trabeculae and
papillary muscles from the blood pool. Expert consensus
from the research committee deemed RV mass measure-
ments were not reliable to be used routinely in the clini-
cal setting. erefore, RV mass was not measured nor
reported, so as to avoid confusion or misguidance.
Left atrial (LA) volume was derived from the long
axis 2-chamber and 4-chamber views, according to the
Biplane method [17]. Maximum LA volume was meas-
ured at end-systole, immediately before mitral valve
opening and minimum LA volume was measured at
end-diastole, immediately before mitral valve closure
[17]. Image quality was qualitatively assessed by expert
observers as either good, acceptable, or poor with con-
sideration of anatomical structures or artefacts related
to breathing, inadequate ECG triggering (blurring),
flow, chemical shift (T2* susceptibility), or ghosting (T1
effects). Only participants with good or acceptable image
quality were included in the final data analysis.
Inter‑observer andintra‑observer quality assurance
Based on derived sample size calculations for intraclass
correlation (ICC) [18], roughly 27 subjects (assuming
there are 2 raters, 50 measurements in total) and 17 sub-
jects (assuming there are 4 raters; 100 measurements
in total) were estimated to detect ICC = 0.86 with 80%
power. erefore, the evaluation of intra- and inter-
observer reliability was performed using 25 randomly
selected CMR studies on four variables: end-diastolic
volume (EDV), end-systolic volume (ESV), stroke volume
(SV), and ejection fraction (EF) for both the LV and RV.
CMR images with altered protocols, phantoms scans for
quality control purposes, files sent more than once by the
users, images sent with incorrect registry information,
images not analyzable due to poor quality, and missing or
incomplete CMR exams were excluded from this analysis.
Fig. 1 A typical example of an automatically generated contour (left) and the result of manual correction (right)
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Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
For the intra-observer reliability, the CMR studies were
read twice by the assigned observers. A minimum delay
of 4 weeks between the first and second readings was
used to minimize observer bias. For inter-observer reli-
ability, two readers were included in the analyses. e
level of experience among the two observers ranged
from expert (more than 15 + years of experience in CMR
contouring and analysis) to 5years of CMR contouring
experience. e readers underwent standardized proto-
col training using practice cases to ensure contours were
drawn accurately and consistently prior to analyzing par-
ticipant data. As each reader made repeated measure-
ments, methods described in Shrout and Fleiss [19] were
not applicable. Hence, ICC were calculated to assess the
inter- and intra-observer variability, as described in Eilas-
ziw etal. [20] and visually depicted using Bland–Altman
plots.
Statistical analysis
Descriptive statistics for males and females were calcu-
lated for the risk factors and baseline characteristics and
presented as mean (SD) or proportions (%). For con-
tinuous normal and non-normal variables, Two-sample
T-test or Mann-Whitney U tests were used respectively
to compare mean between females and men. Similarly, a
Chi-square test was applied to compare the proportions.
Fig. 2 Measurement of left ventricular (LV) mass at end‑systole. The systolic phase is used for quantification of LV mass; irregular surface and
contour because of trabeculations during diastole (left) are less pronounced during systole (right)
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Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
Means of CMR measurements between males and
females were compared with two sample tests using a
Satterthwaite approximation for the degrees of freedom.
Normal reference ranges are defined as the 95% predic-
tion interval, which is calculated by [12]
For measured CMR variables (volume, mass) and derived
variables (ejection fractions), reference ranges were cal-
culated after excluding the outliers and presented in all
the reference tables. All statistical analyses were per-
formed using SAS (version 9.4, SAS Institute Inc., Cary,
North Carolina, USA) and all figures were created using
R (version 3.5.3. R Foundation for Statistical Computing,
Vienna, Austria).
Results
Patient characteristics
A total of 8580 participants consented for the study with
CMR data available for 8258 subjects. Due to history of
CVD (10%) or missing LV parameters/poor image quality
(5%), 1223 subjects were excluded (Additional file1: Figure
mean
±t0.975,n1(SD)
(n+1)
n
.
S1). Of the remaining 7035 participants, 3812 (54%) with
history of CVD risk factors were excluded from the final
analysis. erefore, a total of 3,206 participants with CMR
examinations were included in the analysis (2080 females,
65%). e mean age for males was 55.1 ± 8.8 and 55.2 ± 8.4
for females (p = 0.57). Details of the baseline demographics
for the participants with CVD or CVD risk factors, by sex
and age groups are shown in Table1.
Overall, females had a lower BMI than males (p < 0.001),
but a higher percentage of body fat (p < 0.001). Addition-
ally, a small proportion in males (17%) and females (22%)
reported a positive family history of CVD. Most subjects
were white Caucasian (77% females, 77% men, p = 0.20).
Approximately 17% were of Chinese ethnicity and
approximately 4% were of South Asian ethnicity.
Inuence ofsex onCMR‑derived volumetric parameters
Table2 shows sex-specific means ± SD for LV, RV and
LA parameters indexed to body surface area (BSA)
with derived normal reference ranges for all partici-
pants. The corresponding absolute values, and values
indexed to height are provided in the Supplementary
Materials (Additional file2: Tables S1a–S1b). Absolute
Table 1 Baseline demographics by sex and age groups for healthy participants (n = 3206)
Values reported are mean (SD)
BMI body mass index
Baseline variables Age < 55 years 55 < = Age < 65 years Age 65 years Overall p‑value
Female Male Female Male Female Male Female Male
n = 972 n = 549 n = 795 n = 383 n = 313 n = 194 n = 2080 n = 1126
Age, years 47.9 (4.7) 47.6 (4.8) 59.1 (2.8) 59.1 (2.9) 68.2 (2.5) 68.2 (2.6) 55.2 (8.4) 55.1 (8.8) 0.57
Body weight (kg) 64.0 (9.2) 79.5 (9.8) 62.9 (9.2) 77.7 (10.0) 62.3 (9.8) 75.3 (10.0) 63.3 (9.3) 78.2 (10.0) < 0.001
Height (cm) 164.3 (6.2) 177.8 (7.0) 162.6 (6.5) 175.7 (7.0) 161.5 (6.9) 174.9 (6.2) 163.2 (6.5) 176.6 (7.0) < 0.001
BMI 23.7 (2.9) 25.1 (2.5) 23.7 (2.9) 25.1 (2.4) 23.8 (3.0) 24.6 (2.7) 23.7 (2.9) 25.0 (2.5) < 0.001
BMI > 30 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Percent body fat 30.9 (6.5) 20.7 (5.3) 31.9 (6.6) 21.5 (5.3) 32.7 (7.2) 22.0 (5.7) 31.5 (6.7) 21.2 (5.4) < 0.001
Waist circumference (cm) 77.0 (8.7) 87.0 (8.4) 78.1 (9.0) 88.8 (8.4) 78.5 (9.3) 89.1 (9.0) 77.6 (8.9) 87.9 (8.5) < 0.001
hip circumference (cm) 96.3 (8.5) 98.2 (6.9) 96.0 (8.2) 97.8 (5.9) 96.5 (8.2) 98.0 (6.3) 96.2 (8.4) 98.0 (6.5) < 0.001
Systolic blood pressure 114.2 (10.9) 122.2 (9.6) 117.9 (11.4) 124.4 (9.6) 121.1 (11.0) 125.5 (9.6) 116.6 (11.4) 123.5 (9.7) < 0.001
Diastolic blood pressure 73.9 (7.6) 77.1 (7.1) 74.2 (7.8) 76.6 (7.4) 73.0 (8.0) 76.3 (7.3) 73.9 (7.8) 76.8 (7.2) < 0.001
Heart rate 69.7 (9.7) 67.0 (10.2) 69.7 (9.6) 65.6 (10.1) 70.8 (10.0) 67.8 (11.0) 69.9 (9.7) 66.7 (10.3) < 0.001
Family history of cardiac
disease 184 (18.9%) 73 (13.3%) 195 (24.5%) 83 (21.7%) 79 (25.2%) 40 (20.6%) 458 (22.0%) 196 (17.4%) 0.00
Ethnic background
White Caucasian 733 (75.4%) 403 (73.4%) 610 (76.7%) 296 (77.3%) 261 (83.4%) 162 (83.5%) 1604 (77.1%) 861 (76.5%) 0.15
South Asian 43 (4.4%) 31 (5.6%) 23 (2.9%) 18 (4.7%) 4 (1.3%) 4 (2.1%) 70 (3.4%) 53 (4.7%)
Chinese 171 (17.6%) 103 (18.8%) 142 (17.9%) 64 (16.7%) 43 (13.7%) 26 (13.4%) 356 (17.1%) 193 (17.1%)
Other 25 (2.6%) 12 (2.2%) 20 (2.5%) 5 (1.3%) 5 (1.6%) 2 (1.0%) 50 (2.4%) 19 (1.7%)
Medications
Aspirin 15 (1.5%) 15 (2.7%) 29 (3.6%) 30 (7.8%) 19 (6.1%) 18 (9.3%) 63 (3.0%) 63 (5.6%) < 0.001
Statin 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
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Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
values, and values indexed to height or BSA for the
different race/ethnicities are also reported for white
Caucasians (Additional file2: TableS4a–S4c), Chinese
(Additional file2: Table S5a–S5c), and South Asians
populations (Additional file2: TableS6a–S6c).
Overall, ventricular volumes and mass were greater in
males than in females. e indexed mean LVSV (46ml/
m2 ± 8), LVEDV (74ml/m2 ± 13), LVESV (28ml/m2 ± 7),
and LV mass (61g/m2 ± 10) for males were significantly
larger than the indexed LVSV (42 ml/m2 ± 7), LVEDV
(65 ml/m2 ± 11), LVESV (23 ml/m2 ± 6), and LV mass
(48 g/m2 ± 8) for females, respectively (all p < 0.001).
Similarly, indexed RVSV (45ml/m2 ± 8), RVEDV (86ml/
m2 ± 16) and RVESV (41 ml/m2 ± 11) for males were
larger than indexed RVSV (42 ml/m2 ± 7), RVEDV
(72ml/m2 ± 13) and RVESV (31ml/m2 ± 8) for females
(all p < 0.001). However, LVEF (62% ± 6) and RVEF
(53% ± 6) for males were significantly less than LVEF
(64% ± 6) and RVEF (58% ± 6), (p < 0.001) for females.
Age‑STRATIFIED CMR‑derived volumetric parameters
Age-stratified indexed reference ranges are shown
for males and females in Tables 3 and 4, respectively.
Corresponding absolute values (Additional file 2:
Tables2a and 2b) and values indexed to height (Addi-
tional file2: Tables3a and 3b) can be found in Supplemen-
tary Materials for males and females, respectively. Age
groups were stratified into 4 clinically relevant categories
by decade of age (35 to < 45 years , 45 to < 55 ye ars,
55 to < 65 years, and 65 to < 75 years), with the great-
est representation from the middle-aged population from
45 to 64years (71% of males and 74% of females).
Overall, indexed LVESV and LVEDV decreased as age
increased (Additional file 1: Figure S2A and S2B) for
both males and females (p < 0.001). Indexed LV mass also
decreased with advancing age for males (p < 0.001) and
females (p < 0.001) (not shown). e same was seen with
indexed RV end-diastolic and end-systolic volumes for
males and females (not shown, p < 0.001). For men, there
was no significant difference between LVEF across the
different age strata (Additional file1: Fig.2C, p = 0.1985),
but RVEF did increase with advancing age (not shown,
p = 0.009). For females, there were significant differences
seen in the LVEF and RVEF, whereby the mean EF values
increased with advancing age (Fig.2C, p < 0.001).
Table 2 Biventricular and left atrial reference values for healthy males (n = 1126) and females (n = 2080) indexed to body surface area
(BSA)
LV Left ventricular; RV right ventricular; EF ejection fraction; SV stroke volume; EDV end-diastolic volume; ESV end-systolic volume; LA left atrium; Min minimum; Max
maximum. Normal reference ranges are dened as the 95% prediction interval
Study cohort—excluded subjects with history of CVD or with risk factors of CVD -hypertension, diabetes, obesity, smoking or dyslipidemia
History of CVD—Aortic stenosis, Atrial brillation, Heart failure, Mitral stenosis, Previous PCI, Previous CABG, Valve surgery, TAVI, Hx of myocardial infarction
Reference ranges were calculated based on the formulae mean ± t0.975,n1*sqr t[(n + 1)/n]*SD
*CI calculated based on the SE
**p value for testing Male vs Female
CMR variables Male Female
Mean ± SD 95% CI* Normal range Mean ± SD 95% CI* Normal range
Lower limit Upper limit Lower limit Upper limit
LVEF (%) 62 ± 6 62 62 50–73 64 ± 6 64 65 53–76
LVSV, indexed to BSA (ml/m2) 46 ± 8 45 46 29–62 42 ± 7 42 42 28–56
LVEDV, indexed to BSA (ml/m2) 74 ± 13 73 75 48–100 65 ± 11 65 66 45–86
LVESV, indexed to BSA (ml/m2) 28 ± 7 28 29 14–43 23 ± 6 23 24 12–35
LV mass, indexed to BSA (g/m2) 61 ± 10 60 61 42–80 48 ± 8 47 48 33–62
LV mass to volume ratio (g/ml) 0.84 ± 0.16 0.83 0.848 0.53–1.15 0.74 ± 0.13 0.732 0.743 0.48–1.00
RVEF (%) 53 ± 6 53 53 41–65 58 ± 6 58 58 46–70
RVSV, indexed to BSA (ml/m2) 45 ± 8 45 46 29–62 42 ± 7 41 42 28–56
RVEDV, indexed to BSA (ml/m2) 86 ± 16 85 87 54–119 72 ± 13 72 73 47–8
RVESV, indexed to BSA (ml/m2) 41 ± 11 40 42 20–62 31 ± 8 30 31 14–47
Min. LA volume, indexed to BSA
(ml/m2)21 ± 7 21 21 7–35 19 ± 6 19 19 7–31
Max. LA volume, indexed to BSA
(ml/m2)39 ± 10 38 39 18–59 37 ± 9 36 37 19–54
LA EF (%) 46 ± 10 46 47 26–66 49 ± 11 48 49 28–70
LA SV, indexed to BSA (ml/m2) 18 ± 6 17 18 6–30 18 ± 6 18 18 7–29
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Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
Table 3 Biventricular and left atrial reference values indexed to BSA for males age 35 to 75 years, stratified by 10‑year age categories
Values are for males (n = 1126; age 35 to 75years) reported as mean ± SD (normal range), stratied by 10-year categories. Indexed values are normalized to BSA.
Normal reference ranges are dened as the 95% prediction interval (see Methods section for calculation)
Study cohort—excluded subjects with history of CVD or with risk factors of CVD -hypertension, diabetes, obesity, smoking or dyslipidemia
History of CVD—Aortic stenosis, Atrial brillation, Heart failure, Mitral stenosis, Previous PCI, Previous CABG, Valve surgery, TAVI, Hx of myocardial infarction
Reference ranges were calculated based on the formulae mean ± t0.975,n1*sqr t[(n + 1)/n]*SD
LV Left ventricular; RV right ventricular; EF ejection fraction; SV stroke volume; EDV end-diastolic volume; ESV end-systolic volume; LA left atrium; Min minimum; Max
maximum
*p value for testing if all the means are equal
CMR variables 35 Age < 45 years
(n = 141) 45 Age < 55 years
(n = 408) 55 < = Age < 65 years
(n = 383) 65 Age < 75 years
(n = 194)
LVEF, % 61 ± 6 (49–73) 62 ± 6 (50–73) 62 ± 6 (51–73) 62 ± 6 (50–75)
LVSV, indexed to BSA (ml/m2) 47 ± 8 (30–64) 46 ± 8 (30–62) 46 ± 8 (30–62) 43 ± 8 (26–59)
LVEDV, indexed to BSA (ml/m2) 77 ± 13 (50–103) 75 ± 13 (50–100) 74 ± 13 (48–100) 69 ± 13 (44–94)
LVESV, indexed to BSA (ml/m2) 30 ± 8 (15–46) 29 ± 7 (15–43) 28 ± 7 (14–43) 26 ± 7 (12–40)
LV mass, indexed to BSA (g/m2) 61 ± 11 (40–82) 61 ± 10 (42–80) 62 ± 10 (43–81) 58 ± 9 (40–75)
LV mass to volume ratio (g/ml) 0.81 ± 0.13 (0.54–1.07) 0.83 ± 0.15 (0.53–1.13) 0.85 ± 0.15 (0.56–1.14) 0.86 ± 0.20 (0.47–1.26)
RVEF, % 51 ± 6 (39–64) 53 ± 6 (41–64) 53 ± 6 (41–66) 54 ± 6 (41–66)
RVSV, indexed to BSA (ml/m2) 46 ± 9 (29–64) 46 ± 8 (30–62) 46 ± 8 (29–62) 43 ± 8 (26–59)
RVEDV, indexed to BSA (ml/m2) 91 ± 18 (56–126) 88 ± 16 (57–118) 86 ± 17 (54–119) 80 ± 15 (50–110)
RVESV, indexed to BSA (ml/m2) 45 ± 12 (21–69) 42 ± 10 (22–61) 41 ± 11 (19–63) 37 ± 10 (18–57)
Min. LA volume, indexed to BSA (ml/m2) 19 ± 6 (8–30) 20 ± 6 (8–33) 22 ± 8 (7–37) 21 ± 8 (5–37)
Max. LA volume, indexed to BSA (ml/m2) 36 ± 9 (17–54) 38 ± 10 (18–58) 40 ± 10 (20–61) 38 ± 11 (15–60)
LA SV, indexed to BSA (ml/m2) 46 ± 10 (27–65) 47 ± 10 (26–67) 46 ± 10 (27–65) 45 ± 11 (22–67)
LA EF (%) 17 ± 6 (5–28) 18 ± 6 (6–30) 19 ± 6 (7–31) 17 ± 6 (5–28)
Table 4 Ventricular and atrial reference values indexed to BSA for females age 35 to 75 years, stratified by 10‑year age categories
Values are for females (n = 2080, age 35 to 75years), reported as mean ± SD (normal range), stratied by 10-year categories. Indexed values are normalized to BSA.
Normal reference ranges are dened as the 95% prediction interval
Study cohort—excluded subjects with history of CVD or with risk factors of CVD -hypertension, diabetes, obesity, smoking or dyslipidemia
History of CVD—Aortic stenosis, Atrial brillation, Heart failure, Mitral stenosis, Previous PCI, Previous CABG, Valve surgery, TAVI, Hx of myocardial infarction
Reference ranges were calculated based on the formulae mean ± t0.975,n1*sqr t[(n + 1)/n]*SD
LV Left ventricular; RV right ventricular; EF ejection fraction; SV stroke volume; EDV end-diastolic volume; ESV end-systolic volume; LA left atrium; Min minimum; Max
maximum
*p value for testing if all the means are equal
CMR variables 35 Age < 45 years
(n = 228) 45 Age < 55 years
(n = 744) 55 < = Age < 65 years
(n = 795) 65 Age < 75 years
(n = 313)
LVEF, % 64 ± 5 (53–74) 64 ± 5 (54–75) 64 ± 6 (53–76) 65 ± 6 (54–77)
LVSV, indexed to BSA (ml/m2) 45 ± 7 (30–59) 43 ± 7 (29–57) 41 ± 7(28–55) 40 ± 6 (28–52)
LVEDV, indexed to BSA (ml/m2) 70 ± 11 (49–91) 67 ± 10 (47–88) 64 ± 10 (44–84) 62 ± 9 (44–79)
LVESV, indexed to BSA (ml/m2) 25 ± 6 (14–37) 24 ± 6 (13–35) 23 ± 6 (11–34) 21 ± 5 (11–32)
LV mass, indexed to BSA (g/m2) 48 ± 7 (33–62) 47 ± 8 (32–63) 48 ± 7 (33–63) 46 ± 8 (31–62)
LV mass to volume ratio (g/ml) 0.69 ± 0.11 (0.47–0.91) 0.72 ± 0.12 (0.47–0.96) 0.76 ± 0.14 (0.50–1.03) 0.76 ± 0.14 (0.49–1.04)
RVEF, % 56 ± 6 (45–68) 58 ± 6 (46–69) 58 ± 7 (45–71) 59 ± 6 (47–72)
RVESV, indexed to BSA (ml/m2) 44 ± 7 (30–59) 43 ± 7 (28–57) 41 ± 7 (27–54) 39 ± 6 (27–52)
RVEDV, indexed to BSA (ml/m2) 79 ± 13 (53–105) 74 ± 13 (49–100) 71 ± 13 (46–96) 67 ± 11 (46–88)
RVESV, indexed to BSA (ml/m2) 35 ± 8 (18–52) 32 ± 8 (16–48) 30 ± 8 (13–47) 28 ± 7 (14–42)
Min. LA volume, indexed to BSA(ml/m2) 17 ± 5 ( 6–27) 18 ± 6 (7–29) 19 ± 6 (7–32) 21 ± 7 (7–34)
Max. LA volume, indexed to BSA(ml/m2) 34 ± 8 (19–50) 37 ± 9 (20–54) 37 ± 9 (19–55) 38 ± 9 (20–57)
LA SV, indexed to BSA(ml/m2) 52 ± 11 (30–73) 50 ± 10 (30–71) 48 ± 11 (26–69) 47 ± 10 (27–67)
LA EF (%) 18 ± 5 ( 7–28) 18 ± 6 (7–30) 18 ± 6 (6–29) 18 ± 6 (7–29)
Page 8 of 13
Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
Intra‑ andinter‑observer Reliability
A summary of the inter and intra-observer reliability are
listed in Table5. Moderate to excellent intra- and inter-
observer variability were demonstrated for all measured
parameters. Representative examples of Bland–Altman
plots for LV stroke volume are shown in Additional file1:
FiguresS3 and S4.
Discussion
Among participants without known CVD or CV risk fac-
tors included in this large multi-ethnic population-based
sample of 3206 adults aged 35–75 years, we provide
accurate age- and sex-specific CMR-derived reference
values for biventricular volumes, function, and mass and
LA volume. Parameters normalized to BSA and height,
as well as absolute values were reported, as volumetric
parameters and mass are correlated with body habitus [5,
21]. BSA, which accounts for both height and weight, is
the adjustment standard recommended by other socie-
ties, including those for echocardiography. [22] Clinical-
decision making based solely on absolute values, while
convenient, allow for potential under- or overestimation
of chamber volumes and mass, undermining the utility of
CMR.
Strength andnovelty ofthestudy cohort
Multiple areas highlight the strength and novelty of the
CAHHM CMR cohort, including the large recruitment
of participants from a multi-ethnic population, absence
of confounding pathological cardiovascular conditions,
good representation of females, and finally, adherence to
high imaging standards for quality assurance (Table6).
Previous studies have sought to provide CMR-based ref-
erence values for the clinical assessment of ventricular
and atrial parameters. However, our sample population is
the largest known to date, with prior sample sizes ranging
from 60 participants [9] to the most recent publication
by Petersen etal. that included 800 subjects for analysis
[12] (Table6). A large sample population ensures more
accurate mean reference values, identification of outli-
ers, and overall smaller margins of errors. is is particu-
larly important in conditions such as heart failure with
preserved ejection fraction that require highly accurate
evaluation of ventricular function and volume to prop-
erly guide medical therapy, as research now demonstrate
increased mortality when LVEF exceeds 65% [23, 24].
Despite growing momentum for the increasing utility
of CMR in clinical routine, there is lack of agreement on
specific standards for quantitative parameters. e latest
Society for Cardiovascular Magnetic Resonance (SCMR)
2018 expert consensus document for imaging endpoints
recognize that there is moderate variability in normal
ranges depending on the population studied and method
of quantification [1]. e recommended resource, how-
ever, for normal values as per the SCMR is from a review
by Kawel-Boehm etal. that summarized the findings of
three publications using the bSSFP CMR sequence of
very small sample sizes and heterogeneous ethnic pop-
ulation by Alfakih et al. 2003 (n = 60), Hudsmith etal.
(n = 108), and Maceira et al. (n = 120) (Table 6). [11]
us, as expected with small sample sizes, there were dif-
ferences between findings by Kawel-Boehm etal. and our
own. For instance, the ventricular reference values for
indexed LVEDV and LV mass reported by Kawel-Boehm
etal. were different by nearly 10ml/m2 when compared
to the sex-specific values from our study, which incor-
porated data from over 3000 individuals. Furthermore,
Kawel-Boehm et al. provide adult parameters for age
stratified by younger or older than 60years of age and
not specific reference values by age decade, limiting the
robust clinical application.
With strict adherence to the research protocols out-
lined by the CAHHM committee, substantial efforts
were made to ensure the study population was indeed
free of underlying CVD or risk factors, excluding over
64% of consented participants. e sample population
also included participants from different race/ethnicities
including white Caucasians, South Asians, and Chinese
descent, allowing for increased generalizability and broad
application of the reference values. Researchers have
previously reported variability in LV volumes and mass
across the different races/ethnicities and as such, we pro-
vide normal references values for the separate groups in
the supplemental materials [25]. We also report smaller
indexed LV volumes and mass in the Chinese popula-
tion compared to subjects from European descent (white
Caucasians) [14, 26], and note similar volumes and mass
in the South Asians compared to the white Caucasians.
Table 5 Intraclass correlation coefficient for inter‑observer and
intra‑observer variability of CMR data
a Readers are a representative of a large population of readers
LV Left ventricular; RV right ventricular; EF ejection fraction; SV stroke volume;
EDV end-diastolic volume; ESV end-systolic volume
Intra‑observer reliability
readers randomaInter‑observer
reliability readers
randoma
LVEDV 0.88 0.92
LVESV 0.83 0.85
LVSV 0.85 0.87
LVEF 0.72 0.61
RVEDV 0.87 0.90
RVESV 0.90 0.90
RVSV 0.81 0.86
RVEF 0.86 0.83
Page 9 of 13
Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
When comparing our results to the previous refer-
ence values reported by Petersen etal. using the United
Kingdom (UK) Biobank cohort, notable differences in
the indexed mean LV and RV parameters were seen.
For example, normal indexed LVEDV for females in our
study was 65ml/m2 ± 11 (range 45 to 86ml/m2), which is
different when compared to the normal indexed LVEDV
by Petersen et al. for overall females of 74ml/m2 ± 12
(range 54 to 94ml/m2). We suspect the discrepancy may
be due to the different contouring approach, which is an
important contribution of our normative data to the cur-
rent literature. In contrast to some previous studies, our
contouring method of including the papillary muscles
and trabecular structures as myocardial mass (and not as
blood) is anatomically and functionally correct [15], and
recommended by the recently updated recommendations
of the SCMR [27]. e exclusion of papillary muscles
from LV mass has been shown to lead to an underesti-
mation of LV hypertrophy [28]. Opponents may argue
that this contouring approach suffers from partial volume
effects, averaging trabeculations with the blood pool,
thus leading to overestimation of LV mass and underes-
timation of LV volume. However, the problem of partial
volume may actually lead to errors in both directions,
i.e. under- and overestimation [29]. Using the simplified
method of drawing the contour to define the arbitrary
“cutoff” line may be subjected to additional observer
variability and errors (Fig.3). We emphasize that several
previous studies have also used the anatomically correct
contouring [9, 13, 30], with exvivo validations showing
very good agreement [31, 32] and researchers demon-
strated that this method provides more reliable values
[15]. Yet, many centers and even large cohort studies,
such as the UK Biobank [33] use a simplified method that
cuts off papillary and trabecular tissue, explaining the
larger volumes observed in the UK Biobank cohort. Rec-
ommendations concede that such a simplification is inac-
curate, but “allow” for this simplification for practicality
Table 6 Comparison between studies with CMR‑derived normal reference values
a Age range not reported in original publication, but study population claried in the source by Oyama etal. 2008. “Dierential Impact of Age, Sex, and Hypertension
on Aortic Atherosclerosis.Arteriosclerosis, Thrombosis, and Vascular Biology 28 (1): 155–59
LV left ventricular; LVEDV left ventricular end-diastolic volume; BSA body surface area; LVEF left ventricular ejection fraction
Study (Author,
Journal Year) Sample
Size
(n =)
Age (years) Ethnicity % Female
representation
(male:female)
Contouring
Method Mean LVEDV
indexed to BSA
(ml/m2)
Mean LVEF (%)
Current study, Luu
et al. 2021 3206 35–75 Multi‑ethnic 65% (1126:2080) Inclusion of papil‑
lary muscle in LV
mass
Female: 66
Male: 74 Female: 65
Male: 62
Petersen et al. JCMR
2017 800 45–74 All Caucasians 54% (368:432) Inclusion of papil‑
lary muscle in LV
volume
Female: 74
Male: 85 Female: 61
Male: 58
Lei et al., JMRI 2017 120 23–83 All Han Chinese 50% (60:60) Inclusion of papil‑
lary muscle in LV
volume
Female: 68.7
Male: 76.5 Female: 67.1
Male: 64.6
Le et al., JCMR 2016 180 20–69 All Singaporean
Chinese 49% (91:89) Inclusion of papil‑
lary muscle in LV
mass
Female: 71
Male: 79 Female: 62
Male: 58
Yeon et al., JMRI
2015 852 38–88aMost Caucasians 60% (512:340) Inclusion of papil‑
lary muscle in LV
volume
Female: 62
Male: 71 Female: 60.6
Male: 58.6
Natori et al., AJR
2006 800 45–84 Multi‑ethnic 50% (400:400) Inclusion of papil‑
lary muscle in LV
volume
Female: 64.5
Male: 73.9 Female:71.8
Male: 67.2
Maceira et al., JCMR
2006 120 20–80 Not mentioned 50% (60:60) Inclusion of papil‑
lary muscle in LV
mass
Female: 75
Male: 80 Female: 67
Male: 67
Hudsmith et al.,
JCMR 2005 108 21–68 Not mentioned 42% (63:45) Inclusion of papil‑
lary muscle in LV
mass
Female: 78
Male: 82 Female: 69
Male: 69
Alfakih et al., JMRI
2003 60 20–65 Not mentioned 50% (30:30) Inclusion of papil‑
lary muscle in LV
mass
Female: 77.7
Male: 82.3 Female: 64.0
Male: 64.2
Salton et al., JACC
2002 142 38–72 Not mentioned 56% (63:79) Inclusion of papil‑
lary muscle in LV
volume
Female: 49.8
Male: 57.6 Female: 70
Male: 69
Page 10 of 13
Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
reasons [34]. Our study is the largest cohort to utilize the
anatomically and functionally correct contouring method
to date, demonstrating its feasibility for clinical and
research settings.
Dependence ofvalues onsex andage onLV andRV
volumes, function, andmass
It has long been known that sex has significant independ-
ent influence on normal values for biventricular volumes
and mass [35]. Similarly, our study found that LV and RV
volumes were significantly smaller in females compared
to men, and that LV mass was also larger in males than
females [35]. Age also has a significant influence on ven-
tricular volumes, whereby LV and RV volumes are known
to decrease with advancing age, with significant differ-
ences between each age strata [12, 21]. e influence of
age on indexed LV mass to BSA, however, has not been
well understood. Among the studies that specifically
included age-specific reference ranges or age-associated
statistical analyses—using similar CMR protocols with a
cine bSSFP approach—the UK Biobank observed, upon
normalization to BSA, LV mass did not change signifi-
cantly with age in either sex [12]. Le Ven etal. in their
study of 434 white Caucasian adults without CVD or
risk factors, reported that, while age had an independent
influence on most ventricular measurements, it was not
significantly associated with LV mass [13]. In our study,
the influence of age was significant on indexed LV mass
in both sexes, likely due to the inclusion of papillary mus-
cles, which reduces accuracy compared to autopsy, but
results in higher precision, smaller observer variability,
and allows for more robust clinical application [1].
We found values of LVEF and RVEF were significantly
higher for females due to higher stroke volumes, which
is consistent with previous large CMR studies, including
the Dallas Heart Study and trials using computed tomog-
raphy [2, 12, 36]. LVEF and RVEF increases with age in
both sexes, with a more pronounced relationship seen
in females than men. However, consistent with previous
findings, the normal reference ranges across the different
age strata remained similar [12].
Study limitations
Firstly, while the overall composition of the study popu-
lation included participants from different ethnicities,
the majority were of white Caucasian background, which
may limit the overall generalizability of the measure-
ments. However, measurements were indexed to BSA
to help reduce the confounding effects of ethnicity. Sec-
ondly, based on considerations for feasibility, cost, and
research limitations, observer variability was performed
in 25 cases (representing ~ 10% of the study population)
for only RV and LV parameters, measurements which
frequently show inconsistencies in the clinical envi-
ronment. Our study demonstrated overall good qual-
ity assurance and based on sample size calculations, the
addition of more cases or readers would not contribute
further meaningful findings. Lastly, owing to logistical
issues, normative values for RA data was not provided
in this paper. An alternative paper will be released to
separately address accurate measurements of RA and
RV parameters. e primary focus for this paper, how-
ever, was to provide a robust set of normal reference
values for ventricular parameters using the anatomically
Fig. 3 Anatomically correct contouring method for left ventricular (LV) mass. Papillary muscles and trabecular structures are included as
myocardium (and not as blood) (right panel). Using the simplified method (left) of drawing the contour to define the arbitrary “cutoff ” line (yellow
arrows) may be subjected to additional observer variability and errors
Page 11 of 13
Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
correct contouring method. erefore, the results of this
study still adds significant value to existing normative
references.
Conclusion
Recognizing the significant influence of sex and age on
volumetric parameters is particularly important in the
clinical evaluation of several cardiovascular conditions.
Using anatomically correct contouring methodology, this
large, multi-ethnic cohort from the Canadian Alliance
for Healthy Heart and Minds offers a robust set of CMR-
derived sex and age-specific reference values that can be
used to distinguish cardiac impairment in clinical and
research settings.
Abbreviations
BMI: Body mass index; BSA: Body surface area; bSSFP: Balanced steady state
free precession; CAHHM: Conadian Alliance for Healthy Heart and Minds;
CMR: Cardiovascular magnetic resonance; CVD: Cardiovascular disease; ECG:
Electrocardiogram; EDV: End‑diastolic volume; EF: Ejection fraction; ESV: End‑
systolic volume; LA: Left atrium/left atrial; LV: Left ventricle/left ventricular; MRI:
Magnetic resonance imaging; RV: Right ventricle/right ventricular; SAx: Short
axis; SCMR: Society for Cardiovascular Magnetic Resonance; SV: Stroke volume.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s12968‑ 021‑ 00819‑z.
Additional le1:Figure S1. Flow chartfor patient selection. RI, magnetic
resonance imaging; LVEF, leftventricular ejection fraction; LV mass, left
ventricular mass; CVD,cardiovascular disease; PURE, prospective urban and
rural epidemiologicalstudy; CPTP, the Canadian Partnership for Tomor‑
row Project; BC Generations,British Columbia; OHS, Ontario Health Study;
Atlantic PATH, AtlanticPartnership for Tomorrow’s Health; MHI, Montreal
Heart Institute. Figure S2. Age‑specific trends for males and females for
A) LV end‑systolic volumesindexed to BSA (ml/m2); B) LV end‑diastolic
volumes indexed to BSA(ml/m2); and C) LVEF (%). Linear regression was
applied to model the data,which are presented as mean (blue lines) and
95% confidence intervals (redlines). Figure S3. Representativeexamples of
Bland Altman plots for inter‑observer variability of absolute leftand right
ventricular stroke volumes (ml). Figure S4. Representativeexamples of
Bland Altman plots for intra‑observer variability of absolute leftand right
ventricular stroke volumes (ml).
Additional le2:TableS1a. Biventricular and left atrial absolute
reference valuesfor healthy males (n=1126) and females (2080). Values
reported as mean±SDwith 95% confidence intervals and normal
ranges. TableS1b. Biventricular and left atrialreference values indexed to
height for healthy males (n=1126)and females (2080). Values reported as
mean±SD with 95% confidenceintervals and normal ranges. TableS2a.
Biventricular and left atrialabsolute reference values for males 35
to 75 years, stratifiedby 10–year age categories. Values reported as
mean±SDwith normal ranges. TableS2b. Biventricular and left atrial
reference values indexedto height for males 35 to 75 years, stratified
by 10–year agecategories. Values reported as mean±SD with normal
ranges. TableS3a. Biventricular and left atrial absolute referencevalues
for females 35 to 75 years, stratified by 10–yearage categories. Values
reported as mean±SDwith normal ranges. TableS3b. Biventricular and
left atrial reference values indexedto height for females 35 to 75 years,
stratified by 10–yearage categories. Values reported as mean±SDwith
normal ranges. TableS4a. Biventricular and atrial absolute reference
values for healthy males (n=861) and females (1604) for white Caucasian‑
sonly. Values reported as mean±SD with 95% confidence intervals and
normal ranges. TableS4b. Biventricular and left atrial reference values
index toheight for healthy males (n=861) and females (1604) for white
Caucasiansonly. Values reported as mean±SD with 95% confidence
intervals and normal ranges. TableS4c. Biventricular and atrial reference
values indexed to BSAfor healthy males (n=861) and females (1604) for
white Caucasiansonly. Values reported as mean±SD with 95% confi‑
dence intervals and normal ranges. TableS5a. Biventricular and left atrial
absolute reference valuesfor healthy males (n=191) and females (356) for
Chinese only.Values reported as mean±SD with 95% confidence intervals
and normal ranges. TableS5b. Biventricular and left atrial reference
values indexed toheight for healthy males (n=193) and females (356) for
Chinese only.Values reported as mean±SD with 95% confidence intervals
and normal ranges. TableS5c Biventricular and left atrial reference values
indexed toBSA for healthy males (n=193) and females (356) for Chinese
only.Values reported as mean±SD with 95% confidence intervals and
normal ranges. TableS6a. Biventricular and left atrial absolute reference
valuesfor healthy males (n=53) and females (70) for South Asians only.
Values reported as mean±SD with 95% confidence intervals and normal
ranges. TableS6b. Biventricular and atrial reference values indexed to
heightfor healthy males (n=53) and females (70) for South Asians only.
Values reported as mean±SD with 95% confidence intervals and normal
ranges. TableS6c. Biventricular and atrial reference values indexed to
BSAfor healthy males (n=53) and females (70) for South Asians only.Values
reported as mean±SD with 95% confidence intervals and normal ranges.
Acknowledgements
Steering Committee: S. Anand (Chair)*, M.G. Friedrich (Co‑Chair), J. Tu (Co‑
Chair), P Awadalla (OHS), T. Dummer (BCGP), J. Vena (ATP), P. Broet (CaG), J.
Hicks (APATH), J‑C. Tardif (MHI Biobank), K. Teo (PURE‑Central), B‑M. Knoppers
(ELSI). Project Office Staff at Population Health Research Institute (PHRI):
D. Desai, S. Nandakumar (Ex), M. Thomas (Ex), S. Zafar. Statistics/Biometrics
Programmers Team at PHRI: K. Schulze, L. Dyal, A. Casanova, S. Bangdiwala, C.
Ramasundarahettige, K. Ramakrishnana, Q. Ibrahim. Central Operations Leads:
D. Desai (PHRI), H. Truchon (Montreal Heart Institute), N. Tusevljak (Institute
for Clinical Evaluative Sciences). Cohort Operations Research Personnel: K
McDonald (OHS), N. Noisel (CaG), J. Chu (BCGP), J. Hicks (APATH), H. Whelan
(ATP), S. Rangarajan (PURE), D. Busseuil (MHI Biobank). Site Investigators
and Staff: (112) J. Leipsic, S. Lear, V. de Jong; (306) M. Noseworthy, K. Teo, E.
Ramezani, N. Konyer; (402) P. Poirier, A‑S. Bourlaud, E. Larose, K. Bibeau; (512)
J. Leipsic, S. Lear, V. de Jong; (609) E. Smith, R. Frayne, A. Charlton, R Sek‑
hon; (703) A. Moody, V. Thayalasuthan; (704) A. Kripalani, G Leung; (706) M.
Noseworthy, S. Anand, R. de Souza, N. Konyer, S. Zafar; (707) G. Paraga, L. Reid;
(714) A. Dick, F. Ahmad; (799) D. Kelton, H. Shah; (801) F. Marcotte, H. Poiffaut;
(802) M. Friedrich, J. Lebel; (817) E. Larose, K. Bibeau; (913) R. Miller, L. Parker,
D. Thompson, J. Hicks; (1001) J‑C. Tardif, H. Poiffaut; (1103) J. Tu, K. Chan, A.
Moody, V. Thayalasuthan; MRI Working Group and Core Lab Investigators/Staff:
Chair: M.G. Friedrich; Brain Core Lab: E. Smith, C. McCreary, S. E. Black, C. Scott,
S. Batool, F. Gao; Carotid Core Lab: A. Moody, V. Thayalasuthan; Abdomen:
E. Larose, K. Bibeau, Cardiac: F. Marcotte, F. Henriques, T. Teixeira. Contextual
Working Group: R. de Souza, S. Anand, G. Booth, J. Brook, D. Corsi, L. Gauvin, S.
Lear, F. Razak, S.V. Subramanian, J. Tu. CAHHM Founding Advisory Group: Jean
Rouleau, Pierre Boyle, Caroline Wong, Eldon Smith. CAHHM Scientific Review
Board: Bob Reid, Ian Janssen, Amy Subar, Rhian Touyz
Authors’ contributions
JL and CG contributed to all aspects of the manuscript. DD contributed to
conception, design, data acquisition, analysis, interpretation, and revising of
the manuscript. CR and KS contributed to data analysis and interpretation, and
manuscript revision. PA and PB contributed to data acquisition and interpreta‑
tion, and manuscript revision. FM, TD, JH, and EL contributed to the design,
data acquisition and interpretation, and manuscript revision. AM, ES, JCT, KT,
JV, DL, SA, and MF contributed to the design, data acquisition, and manuscript
revision. All authors read and approved the final manuscript.
Funding
CAHHM was funded by the Canadian Partnership Against Cancer (CPAC),
Heart and Stroke Foundation of Canada (HSF‑Canada), and the Canadian
Institutes of Health Research (CIHR). Financial contributions were also received
from the Population Health Research Institute and CIHR Foundation Grant no.
Page 12 of 13
Luuetal. Journal of Cardiovascular Magnetic Resonance (2022) 24:2
FDN‑143255 to S.S.A.; FDN‑143313 to J.V.T.; and FDN 154317 to E.E.S. In‑kind
contributions from A.R.M. and S.E.B. from Sunnybrook Hospital, Toronto for
CMR reading costs, and Bayer AG for provision of IV contrast. The Canadian
Partnership for Tomorrow Project is funded by the Canadian Partnership
Against Cancer, BC Cancer Foundation, Genome Quebec, Ontario Institute
for Cancer Research and Alberta Health and the Alberta Cancer Prevention
Legacy Fund, Alberta Cancer Foundation. The PURE Study was funded by
multiple sources. The Montreal Heart Institute Biobank is funded by Mr André
Desmarais and Mrs France Chrétien‑Desmarais and the Montreal Heart Insti‑
tute Foundation. S.S.A. was supported by a Tier 1 Canada Research Chair in
Ethnicity and Cardiovascular Disease and Heart and Stroke Foundation Chair
in Population Health. P.A. was supported by a Ministr y of Research and Innova‑
tion of Ontario Investigator Award. S.E.B. was supported by the Hurvitz Brain
Sciences Research Program, Sunnybrook Research Institute, and the Depart‑
ment of Medicine, Sunnybrook Health Sciences Centre, University of Toronto.
E.L. was supported by the Laval University Chair of Research & Innovation
in Cardiovascular Imaging and the Fonds de recherche du Québec—Santé.
J.‑C.T. holds the Tier 1 Canada Research Chair in translational and personalized
medicine and the Université de Montréal Pfizer endowed research chair in
atherosclerosis. Some of the data used in this research were made available
by the Canadian Partnership for Tomorrow Project along with BC Generations
Project, Alberta’s tomorrow Project, Ontario Health Study, CARTaGENE, and
the Atlantic PATH. Data were harmonized by Maelstrom and access policies
and procedures were developed by the Centre of Genomics and Policy in
collaboration with the Cohorts.
CG is supported by grants from the Swiss National Science Foundation (SNSF,
# PP00P3_163892 and # PP00P3_190074), the Olga Mayenfisch Foundation,
Switzerland, the OPO Foundation, Switzerland, the Novartis Foundation,
Switzerland, the Swissheart Foundation, the Helmut Horten Foundation,
Switzerland, the University Hospital Zurich (USZ) Foundation, the Iten‑Kohaut
Foundation, Switzerland, and the EMDO Foundation, Switzerland. Dr. Anand
holds the Heart and Stroke Foundation Michael G DeGrooote Chair in Popula‑
tion Health and a Canada Research Chair in Ethnic Diversity and Cardiovascu‑
lar Disease.
Availability of data and materials
The datasets generated during and/or analysed during the current study are
available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Research ethics approval was granted by the Hamilton Integrated Research
Ethics Board, with consent obtained at each collaborating site as per site‑
specific regulations prior to participation in the study.
Consent for publication
Not applicable.
Competing interests
The University Hospital Zurich (CG) holds a research contract with GE Health‑
care. Matthias G. Friedrich is board member, shareholder, and consultant of
Circle Cardiovascular Imaging Inc.
Author details
1 Division of Cardiology, Department of Medicine, University of Manitoba,
Winnipeg, MB, Canada. 2 Department of Nuclear Medicine, University Hospital
Zurich, Zurich, Switzerland. 3 Center for Molecular Cardiology, University
of Zurich, Zurich, Switzerland. 4 Population Health Research Institute, Hamilton
Health Sciences, McMaster University, 237 Barton St East, Hamilton, ON L8L
2X2, Canada. 5 Department of Medicine, McMaster University, 1280 Main
Street West, Hamilton, ON L8S 4K1, Canada. 6 Research Centre, Montreal Heart
Institute, Université de Montréal, 5000 Belanger Street, Montreal, QC H1T 1C8,
Canada. 7 Department of Molecular Genetics, Ontario Institute for Cancer
Research, University of Toronto, 661 University Avenue Suite 510, Toronto, ON
M5G 0A3, Canada. 8 Department of Preventive and Social Medicine, École de
Santé Publique, Université de Montréal, 3175 Chemin de la Cote‑Sainte‑Cath‑
erine, Montreal, QC H3T 1C5, Canada. 9 Research Centre, CHU Sainte Justine,
3175 Chemin de la Cote‑Sainte‑Catherine, Montreal, QC H3T 1C5, Canada.
10 School of Population and Public Health, Cancer Control Research, BC
Cancer, University of British Columbia, 675 W 10th Avenue, Vancouver, BC V5Z
1L3, Canada. 11 Atlantic PATH, Dalhousie University, 1494 Carlton Street, P.O.
Box 15000, Halifax, NS B3H 4R2, Canada. 12 Institut Universitaire de Cardiologie
et de Pneumologie de Québec ‑ Université Laval, 2725 chemin Sainte‑Foy,
Quebec G1V 4G5, Canada. 13 Sunnybrook Health Science Centre, Toronto, ON,
Canada. 14 Department of Clinical Neurosciences, Hotchkiss Brain Institute,
University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
15 Cardiology Department, Entre Douro e Vouga Hospital Centre, Santa Maria
Feira, Portugal. 16 Department of Health Evidence and Impact, McMaster
University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada. 17 Cancer
Research and Analytics, Cancer Control Alberta, Alberta Health Services, Suite
1500 Sun Life Place, 10123 99th Street NW, Edmonton, AB T5J 3H1, Canada.
18 Institute for Clinical Evaluative Sciences, Toronto, ON, Canada. 19 Peter Munk
Cardiac Centre University Health Network University of Toronto, Toronto, ON,
Canada. 20 Department of Medicine and Diagnostic Radiology, McGill Univer‑
sity, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.
Received: 9 March 2021 Accepted: 1 October 2021
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... For the following reasons, we did not exclude papillary muscles, false tendons, and aberrant bands from the measurements of trabecular layer volume as they sometimes are (Stöllberger & Finsterer, 2021) but not always (Luu et al., 2022). It has long been emphasized that embryonic trabeculations are the common scaffold from which trabeculae carneae, papillary muscles, and Purkinje muscles develop (Benninghoff, 1933;Jensen et al., 2012;Miquerol et al., 2010;Moorman et al., 1998;Sedmera et al., 2003;van Weerd & Christoffels, 2016). ...
... If aberrant bands are present, they will be small and few and some diagnostic criteria will not be much affected by their presence, for example layer volumes (e.g. Grothoff et al., 2012;Riekerk et al., 2021;Luu et al., 2022), the requirement of more than one segment with a high trabecular-to-compact width ratio (e.g. Kawel et al., 2012) or fractal dimension (Captur et al., 2017). ...
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Purpose: To establish normal reference values of left ventricular (LV) and right ventricular (RV) dimension, volume, mass, and ejection fraction in a Chinese population using cardiac magnetic resonance imaging (MRI). Materials and methods: A total of 120 (60 males; 60 females; 23-83 years) healthy Han Chinese subjects without cardiovascular disease or risk factors were recruited. They underwent comprehensive MRI examination at 3.0T. LV/RV morphology and function were evaluated by steady-state free-procession (SSFP) sequence. Parameters were analyzed according to a standard postprocessing protocol. Results: Significant differences in LV size, mass, volume, and ejection fraction (EF) between sexes were noted (all P < 0.05). After indexing using body surface area (BSA), LV end-diastolic volume (EDV), and LV mass index were greater in males than in females (76.5 vs. 68.7 mL/m, P < 0.001; 52.9 vs. 45.1 g/m, P < 0.001; respectively). LVEF was lower in males than in females (64.6% vs. 67.1%, P = 0.007, respectively). RV volume was higher and RVEF lower in males compared with females (75.3 vs. 62.7 mL/m, P < 0.001; 59.9% vs. 62.6%, P = 0.001, respectively). Age was associated significantly with indices of LV and RV volume in females (left ventricular end-diastolic volume index: r = -0.41 P = 0.001; left ventricular end-systolic volume index: r = -0.37 P = 0.004; left ventricular end-diastolic volume index: r = -0.53 P < 0.001; right ventricular end-systolic volume index: r = -0.43 P < 0.001), but not in males (all P > 0.05). Conclusion: These data suggest that sex and age affect ventricular parameters in healthy Han Chinese subjects without cardiovascular disease or risk factors. Level of Evidence2 J. Magn. Reson. Imaging 2016.
Article
Background: Left ventricular (LV) volumetric and functional parameters measured with cardiac computed tomography (cardiac CT) augment risk prediction and discrimination for future mortality. Gender- and age-specific standard values for LV dimensions and systolic function obtained by 64-slice cardiac CT are lacking. Methods and results: 1155 patients from the Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry (54.5% males, mean age 53.1 ± 12.4 years, range: 18-92 years) without known coronary artery disease (CAD), structural heart disease, diabetes, or hypertension who underwent cardiac CT for various indications were categorized according to age and sex. A cardiac CT data acquisition protocol was used that allowed volumetric measuring of LV function. Image interpretation was performed at each site. Patients with significant CAD (>50% stenosis) on cardiac CT were excluded from the analysis. Overall, mean left ventricular ejection fraction (LVEF) was higher in women when compared with men (66.6 ± 7.7% vs. 64.6 ± 8.1%, P < 0.001). This gender-difference in overall LVEF was caused by a significantly higher LVEF in women ≥70 years when compared with men ≥70 years (69.95 ± 8.89% vs. 65.50 ± 9.42%, P = 0.004). Accordingly, a significant increase in LVEF was observed with age (P = 0.005 for males and P < 0.001 for females), which was more pronounced in females (5.21%) than in males (2.6%). LV end-diastolic volume decreased in females from 122.48 ± 27.87 (<40 years) to 95.56 ± 23.17 (>70 years; P < 0.001) and in males from 155.22 ± 35.07 (<40 years) to 130.26 ± 27.18 (>70 years; P < 0.001). Conclusion: Our findings indicate that the LV undergoes a lifelong remodelling and highlight the need for age and gender adjusted reference values.