Reference ranges (“normal values”) for cardiovascular magnetic resonance (CMR) in adults and children: 2020 update

Statistical analyses were performed with R for statistical computing (version 3.5, R Core Team, Vienna, Austria). Results from multiple studies reporting normal values for the same CMR parameters were combined using a random effects meta-analysis model as implemented by the metamean function in the meta library in R. This produced a weighted, pooled estimate of the population mean of the CMR parameters in the combined studies. Upper and lower limits of normal values were calculated as ± 2SDp, where SDp is the pooled standard deviation calculated from the standard deviations reported in each study. Mean values and limits of normal values were “rounded up” to avoid excess digits beyond the measurement capability of CMR.

The primary method used to assess the LV is balanced steady-state free precession (bSSFP) technique at 1.5 or 3 T CMR (Table 1). bSSFP technique yields improved blood-myocardial contrast compared to its predecessor, fast gradient echo (FGRE) sequence.

Papillary muscle mass has been shown to significantly affect LV volumes and mass [6‐8]. No uniformly accepted convention has been used for analyzing trabeculation and papillary muscle mass. Post-processing recommendations by the SCMR [9] stipulate that papillary muscles should either be consistently included in the LV volume or in the LV mass, but not in both. Tables of normal values should specify the status of the papillary muscles in the CMR analysis.

The majority of published articles used semi-automatic software for analysis of LV function and structure [10‐16]. Short-axis images are most commonly analyzed on a per-slice basis, deriving LV mass and volume by applying the Simpson’s method (“stack of disks”) [17]. An example of LV contouring is shown in Fig. 1. Automated CMR analysis facilitated by machine learning is rapidly making inroads in LV volume and mass quantification [3]. The primary focus of early manuscripts has been on agreement between manual and automatic contouring [2]. However, to date, CMR variables for healthy cohorts have not been reported using machine learning methods.

Measurements of LV diameter obtained on cine bSSFP images at diastole and systole on a 4 chamber view and short axis view are shown in Fig. 2.

Gender is independently related to ventricular volumes and mass. Absolute and normalized volumes decrease in relationship to age in adults [10] in a continuous manner. For convenience, both average, and values per age decile are given in Tables 2, 3, 4 and 5 based on the peer-reviewed literature.

Multiple studies have presented cohorts of normal individuals for determining normal LV dimensions . For the purpose of this review, only cohorts of 40 or more normal subjects stratified by gender using bSSFP CMR technique at 1.5 or 3 T have been included. In addition, a full description of the subject cohort (including the analysis methods used), age and gender of subjects was required to be included for this review. Two studies [18, 19] included papillary muscles in LV volume except if directly attached to the LV wall, in which case they were included in LV mass (LVM) instead. Since this approach was inconsistent with post-processing recommended by SCMR [9] and other manuscripts on the topic, both studies were excluded from the current analysis. Data at 1.5 and 3 T is now available for normal subjects using bSSFP short axis imaging. Since it has been shown that parameters of LV volumes and function do not vary by field strength, calculation of the weighted means of these parameters include studies performed at 1.5 T and 3 T [20]. Information on ethnicity in relationship to LV parameters is not available for the majority of papers reporting the bSSFP technique and is therefore not reported in this review. However, small differences in LV parameters by ethnicity have been reported in the Multi-ethnic Study of Atherosclerosis (MESA) study; for further information on the magnitude of such differences, the reader is referred to the work by Natori S et al. [21].

Normal adult values for LV dimensions and functions according to those studies that consistently included papillary muscles in the LVM are presented in Tables 2, 3, 4, whereas those that consistently included papillary muscles in the LV volume are presented in Table 5. For parameters with sufficient sample size, values are also presented per age decile (Tables 3, 4).

In addition to left ventricular ejection fraction (LVEF), Maceira et al. have provided additional functional parameters that may be useful in some settings [10]. These are summarized in Table 6. For diastolic function, the derivative of the time/volume filling curve expresses the peak filling rate (PFR). Both early (E) and active (A) transmitral filling rates are provided. In addition, longitudinal atrioventricular plane descent (AVPD) and sphericity index (volume observed/volume of sphere using long axis as diameter) at end diastole and end systole are given. These latter parameters are not routinely used for clinical diagnosis. A number of publications have also reported LV end-diastolic and end-systolic diameters by CMR; these parameters are summarized in Table 7.

For measurement of right ventricular (RV) volumes, a stack of cine bSSFP images is acquired either in the short axis plane or transaxial plane [9].

Similar to the LV, analysis of the RV is usually performed on a per slice basis by manual contouring of the endocardial and epicardial borders. Volumes are calculated based on the Simpson’s method [17]. The RV volumes and mass are significantly affected by inclusion or exclusion of trabeculations and papillary muscles [27, 28]. For manual contouring, inclusion of trabeculations and papillary muscles as part of the RV volume will achieve higher reproducibility [9, 27, 28]. However, semiautomatic software is increasingly used for volumetric analysis, enabling automatic delineation of papillary muscles [29]. Therefore, normal values for both methods are provided. An example for RV contouring is shown in Fig. 1. Detailed recommendations for RV acquisitions and post processing have been published [9].

RV mass and volumes are dependent on body surface area (BSA) [14, 29]. Absolute and RV volumes indexed by BSA are significantly larger in males compared to females [11, 14, 16, 18, 22, 29]. Further, RV volumes decrease with greater age [11, 14, 16, 18, 22, 29].

Criteria regarding study inclusion are identical compared to the LV. Nine studies based on bSSFP imaging were included (Table 8). In one study, papillary muscles were included as part of the RV mass and excluded from the RV volume [29] with results presented for men and women in Table 9. In the remaining eight studies, the papillary muscles were included as part of the RV cavity volume rather than included in the RV mass [11, 14‐16, 18, 22‐24] with pooled weighted mean values presented for men and women (Table 10). For a subset of three of these studies [18, 23, 24], for parameters with a sufficient sample size pooled weighted mean values are presented based on age deciles between 20 and 59 years of age for both men (Table 11) and women (Table 12).

Similar to the LV, Maceira et al. have provided additional functional parameters, including early and active peak filling rate and the longitudinal AVPD, that may have relevance to specific applications and can be found in the original publication [29].

There is limited consensus in the literature about how to measure left atrial (LA) volume. The most common methods to measure LA volume are the modified Simpson’s method (analogous to that used to measure LV and RV volumes) and the biplane area-length method [30]. Dedicated 3-dimensional modeling software has also been employed [31].

In the Simpson’s method, a stack of cine bSSFP images either in the SAx, the horizontal long axis or transverse view, is required. For 3-dimensional modeling a stack of SAx images has been used [31]. Evaluation by the biplane area-length method is based on a 2 and 4 chamber view [11, 16, 32‐34].

LA longitudinal and transverse diameters and area have been measured on 2, 3, and 4 chamber cine bSSFP images [31, 33, 35] (Fig. 3).

In many studies the LA appendage has been included as part of the LA volume and pulmonary veins are excluded [14, 31], but the practice of excluding both structures from the LA volume is increasingly gaining acceptance [11, 16, 32, 34].

The maximal LA volume is achieved during ventricular systole. In a cine acquisition, the maximum volume image can be defined as last image immediately before opening of the mitral valve. Accordingly the minimal LA volume image can be defined as the first image after closure of the mitral valve [36].

Body surface area (BSA) has been shown to have a significant independent influence on LA volume and most diameters [31]. Per Sievers et al. [35], age was not an independent predictor of LA maximal volume or diameter in normal individuals. Men have a larger maximal LA volume compared to women [31, 35].

There are nine publications for reference values of the adult LA (volume and/or diameter and/or area) based on bSSFP imaging with sufficient sample size (n > 40) and these are reported in Table 13. Four of these publications used the biplane area-length method, one used the Simpson’s method, one used both, one used a 3D modeling technique and the remainder measured diameters or areas. Publications reporting population-based cohort data rather than true normal data have been excluded from the current analysis as have publications that incompletely describe the measurement method used [22] or the manner in which pulmonary veins/LA appendage were handled. Normal values for  LA volumes and function are presented in Table 14, and normal values for LA diameters in Table 15.

There is no consensus in the literature regarding acquisition and measurement method for the right atrium (RA). Published methods for RA volume include the modified Simpson’s method, the biplane area-length method and 3D-modeling [23, 24, 37]. For Simpson’s method and 3D modeling, a stack of cine bSSFP images in the SAx view are analyzed. For the biplane area-length method, a 4-chamber view and a RV 2-chamber view are utilized [33] (Fig. 4).

The inferior and superior vena cava are excluded from the RA volume but there is variability in the inclusion [14, 37] or exclusion [33] of the RA appendage.

The maximal RA volume is achieved during ventricular systole and can be defined as the last cine image before opening of the tricuspid valve. The minimal RA volume can be defined as the first cine image after closure of the tricuspid valve.

Maceira et al. demonstrated the relationship of most RA parameters to BSA, but there was no influence of age on atrial parameters and no influence of gender on atrial volumes [37]. Other studies have demonstrated an influence of gender [14, 33] and age [11, 33] on some RA parameters. In the study by LeVen et al. gender was independently associated with RA end-diastolic volume and RA end-systolic volume with men having greater values compared to women [14]. In the study by Li et al. the longitudinal RA diameter measured in the 2 chamber and 4 chamber view indexed to BSA and the indexed transverse diameter measured on the 4 chamber view were greater in women than in men [33]. Further, the RA volume indexed to BSA was larger in males than in females [33]. Le et al. found a week correlation between the RA area indexed to BSA with age [11].

There are five publications with reference values for the RA based on bSSFP imaging with sufficient sample size to be included [11, 14, 18, 33, 37] (Table 16). Pooled weighted mean values for RA volumes and function are provided in Table 17 using the biplane area-length method (RA appendage excluded) or Simpson’s method (either RA appendage included or excluded) for men and women. Pooled weighted mean values for RA areas and diameters are provided in Table 18 for men and women.

Reference ranges for parameters characterizing RA function, including the reservoir, conduit and pump function, can be found in a separate publication by Maceira et al. [38].

The largest cohort of normal data on ventricular size and function in paediatric patients using the bSSFP sequence refers to a population of 141 healthy children collected in three European reference centers. All subjects were Caucasian and included 68 boys and 73 girls. Age distribution, body size and heart rate were equal between genders. Only 12/141 children were younger than 6 years [45].

Boys had larger ventricles than girls [45]. LVEF was found to be slightly higher in boys (67% vs 65%; p 0.01), but not for the RV [45]. Gender differences are more marked in older children, indicating that gender is more important after puberty and in adulthood.

Table 19 shows studies meeting inclusion criteria. The reference values for the LV and RV presented in the study by van der Ven [45] have been pooled from three previous studies [39‐41], that have been reported separately in the previous version of our review [1]. Data are presented in percentile curves referred to age by using the LMS Method (Figs. 5, 6).

For calculation of reference values from reference [45], the original bSSFP images (short axis) have been re-analysed by manual segmentation by one operator, after consensus on the segmentation rules was established within the group. These followed the standards proposed by SCMR [46], except for the trabeculations of the RV, required for calculating the RV mass. In the RV major trabeculae were included in the myocardium if they were visualized as being connected to the RV wall in more than 2 adjacent slices. Trabecular islands not connected to the wall were included in the blood pool [45].

LA and RA dimensions and function were evaluated using bSSFP technique in a single publication [47], (Table 19). Measurements were obtained on a stack of transverse cine bSSFP images with a slice thickness between 5 and 6 mm without interslice gap [47].

In [47], the pulmonary veins, the superior and inferior vena cava and the coronary sinus were excluded from the LA and RA volume, respectively, while the atrial appendages were included in the volume of the respective atrium. The maximal atrial volume was measured at ventricular end-systole and the minimal atrial volume at ventricular end-diastole.

LA and RA volumes show an increase with age with a plateau after the age of 14 for girls only. Absolute and indexed volumes have been shown to be significantly greater for boys compared to girls (except for the indexed maximal volumes for both atria) [47].

Sarikouch et al. evaluated atrial parameters of 115 healthy children (Table 19) [47] using bSSFP imaging. Data is presented as L, M, S values to enable calculation of the standard deviation score and in percentiles (Tables 20, 21).

Methodologic considerations for CMR analysis are the same as for the non-athletes heart as described in the sections above. In both studies included in this review, papillary muscles and trabeculations were included in the ventricular volumes and excluded from LV and RV mass.

Following the Mitchell classification, sports can be characterized as being high or low in dynamic (endurance, isotonic) versus static (strength/resistance, isometric) training and performance components [48]. Athletic competition can therefore be primarily (a) endurance (e.g. long distance running, swimming), (b) combined (e.g. rowers, cyclists) or (c) strength (e.g. body building and weight training). There are insufficient numbers of study subjects available in the literature to establish normative values for the strength category of athletes [49].

Cardiac chamber sizes may vary depending on the extent of exercise and training. One approach to classification is 9–18 h of training per week (regular athletes) vs > 18 h training per week (elite athletes) [50]. Adaptive changes to exercise are greater with higher exercise/training level [49].

Luijkx found a balanced increase of LV and RV chamber volume in relationship in the athlete heart [51]; a large meta-analysis of the literature had a similar conclusion [49]. RV and LV systolic function is commonly characterized by ejection fraction, but this parameter is known to show the most variation between observers. Nevertheless, RVEF and LVEF are > 50% in reports of the athlete’s heart by CMR [48].

The RV chamber volumes are greater in the athletes heart than in normal individuals [51]. The athlete’s RV volumes may exceed CMR criteria for abnormality in arrhythmogenic right ventricular cardiomyopathy (ARVC). However, RVEF is in the normal range of nonathletes even in the athlete heart (i.e. > 50%) whereas RVEF is abnormally low (≤ 45%) in ARVC.

After elimination of redundant publications using the same study population and publications with > 40 athletes, there is one publication with data on the athlete’s heart by Prakken et al. (Table 22) [50]. This study was performed at 1.5 T and has sufficient description of CMR analysis technique to enable comparison (Tables 23, 24). Papillary muscles and trabeculation were included in ventricular volumes and excluded from myocardial mass. The study by Prakken et al. [50] specified levels of training (regular athletes 9–18 h/week; elite athletes > 18 h per week), both endurance and combined types of athletic participation were included. In contrast, Tahir et al. [52] identified athletes as those competing in triathlons (classified as ‘combined’ sport activity and training for more than 10 h per week) without further subcategorization. Although a smaller size cohort, the study by Tahir et al. may also be useful for the interested reader [52].

Finally, one publication [49] presents a meta-analysis of the literature in an attempt to provide reference ranges. For the purposes of this review, that meta-analysis included multiple publications with overlapping/redundant study populations, small sample size (< 40 subjects in most studies) and did not take into account marked differences in analysis methods noted above. While useful to display overall trends in the literature for the athletes heart, the aforementioned meta-analysis was therefore not included in this study.

Normal values of the thickness of the compact LV myocardium have been shown to vary by type of pulse sequence (FGRE versus bSSFP) [53, 54]. For the purposes of this review, only bSSFP normal values are shown.

In this review LV myocardial thickness refers to measurements of the thickness of the compact LV myocardium obtained at end-diastole (Fig. 7). Papillary muscles and trabeculations are excluded from measurement of the thickness of the compact LV myocardium.

Measures of LV myocardial thickness vary by the plane of acquisition (SAx versus long axis) [55]. Measurements obtained on long axis images at the basal and mid-cavity level have been shown to be significantly greater compared to measurements on corresponding SAx images, whereas measurements obtained at the apical level of long axis images are significantly lower compared to SAx images.

LV myocardial thickness is greater in men than women [14, 18, 25, 55, 56]. There are also small differences in LV myocardial thickness in relationship to ethnicity and body size, but these variations are not likely to have clinical significance [55]. Regarding age, one study of 120 healthy subjects age 20–80 years reported an increase in myocardial thickness with age—starting after the fourth decade [56]. In the study by Kawel el al. of 300 normal individuals without hypertension, smoking history or diabetes, there was no statistically significant difference in LV myocardial thickness with age [55].

There are five publications of a systematic analysis of LV myocardial thickness based on bSSFP imaging at 1.5 T with a sample size > 40 healthy subjects per gender and a detailed description of the measurement technique (Table 25). Dawson et al. and Le Ven et al. published measurements for all 16 segments (apex excluded) obtained on short axis images (Table 26) [14, 56]. Kawel et al. published normal values of LV myocardial thickness for long and SAx imaging for 12 and 16 segments, respectively (Tables 26, 27) [55]. Yeon et al. and Aquaro et al. obtained measurements for only two myocardial segments on SAx images (Table 26) [18, 25].