Background
Left ventricular mass (LVM) is a prognostic factor in cardiac disease [
1], and thus, assessment of LVM is used in the diagnosis and risk stratification of patients in clinical practice [
2]. In addition, abnormal patterns of left ventricular (LV) size and shape have been found to have prognostic relevance [
3‐
5]. Hypertrophy may occur in a specific region of the LV, asymmetric hypertrophy, regardless of the overall heart size [
6,
7]. The most widespread tool for non-invasive measurements of the LVM is echocardiography [
4,
7]. LVM determination by different imaging modalities is based on the LV shell volume (LVShV), which is the difference between the epicardial and endocardial volumes [
4,
8]. The LVShV is subsequently converted to mass by multiplying it with the density of myocardial tissue [
8,
9]. The clinically accepted value of myocardial tissue density is 1.055 g/ml [
9‐
14]; however, there are different published values [
6,
8,
15‐
22], cf. Table
1. LVM has been calculated based on Computed Tomography (CT)-angiography [
10], magnetic resonance imaging (MRI) [
23] and echocardiography [
24], but the myocardial density has not been validated. The aim of this study was to assess the association between the LVShV determined by postmortem Computed Tomography (PMCT) and the anatomic LVM obtained at autopsy, and to calculate the myocardial tissue density
.Table 1
Previous studies investigating the myocardial tissue density or correlation between an image modality and the LVM
Reference | Year | Material | Method | Number included | Density/gravity | Correlation, r |
| 1951 | Cadaver human hearts | Submersion in water | 45 | 1.029 | |
| 1967 | Cadaver human hearts | Submersion in water | 23 | 1.055 | |
| 1979 | Equine hearts | Archimedes principle | 18 | 1.033 | |
| 1981 | Canine hearts | Phased array sector scan | 15 | 1.04 | |
| 2007 | Cadaver human hearts | Density Instrument | 169 | 1.3, 0.9 | |
Studies referring to a myocardial tissue density factor based on previous studies |
| 1975 | Human hearts | Radiology | – | 1.033 | |
| 1979 | Canine hearts | Echocardiography | 21 | 1.05 | 0.94, 0.92 |
| 1981 | Cadaver human hearts | Echocardiography, ekg | 34 | 1.04 | |
| 1983 | Canine | Echocardiography | 10 | 1.055 | 0.98 |
| 1986 | Cadaver human hearts | Echocardiography | 55 | 1.04 | 0.92 |
| 1990 | Rat hearts | MRI | 28 | 1.055 | 0.98 |
| 2004 | Cadaver | MRI, CT-angio | 80 | 1.05 | |
| 2005 | Living | Echocardiography | 85 | 1.04 | |
| 2016 | Living | CT-angiography | 569 | 1.055 | |
Discussion
As expected, our data showed a highly positive correlation between the CT-determined LVShV and the anatomic LVM; also when stratifying by gender and when focusing on cases with hypertrophy and asymmetric LV hypertrophy. We then performed linear regression analyses with LVShV as the explanatory variable and LVM as the dependent variable. Stratification by gender showed no differences. Potentially, the resultant regression equation (genders combined) could thus be used for calculating LVM when LVShV has been determined. Traditionally, clinical volume-to-mass calculations use only a density factor, i.e. the volume is simply multiplied by a density factor [
8,
9]. This is in line with a theoretical approach to a density factor: zero volume equals zero mass. Earlier attempts at establishing a myocardial density factor have therefore, more or less explicitly, assumed that a volume-to-mass regression must go through origo [
7,
12,
24], hence resulting in a simple factor, and not in a regression equation with both a factor and a constant. We therefore performed new linear regression analyses, but this time forcing the line of regression through the origo. Again, differences by gender were negligible, thus allowing us to propose the resultant slope for the combined genders, 1.265 g/ml, as the myocardial tissue density. This density value is based on CT-determined LVShV and the actual weight of the anatomic LVM obtained at autopsy. When we compared this new myocardial tissue density value with the hitherto used value in the clinical setting of 1.055 g/ml (6–15), we found that the latter value significantly underestimated the anatomic LVM.
Indeed, the assumed density of myocardial tissue has varied over time, e.g., 1.029, 1.03, 1.04 and 1.055 g/ml, not least because of differing techniques in determining the density, e.g., by immersing cardiac muscle tissue or hearts in water (Archimedes principle) [
14,
20,
21], different image modalities and different animal species [
12,
17,
29‐
32] (cf. Table
1).
Echocardiography is the most widespread tool used for the quantification of LVM [
7,
8], CT- angiography is often used for LVM calculations [
10] and cardiac MRI is often considered the gold standard for LVM assessment [
23,
33]. Although not often used, non-contrast CT can also be used for information in LV size in the clinical setting [
34]. In this large study of recently deceased individuals, we showed that the use of non-contrast PMCT for the determination of LVShV is a useful tool and has a satisfactory repeatability due to the fact that a clear distinction between the HUs of myocardial tissue and LV blood pool without active circulation could be made. However, these CT settings were optimized for contrast-based studies. Changing the CT settings in 15 randomly chosen cases showed an overall, but negligible and non-significant (
p > 0.5), decrease in LVShV (mean difference − 19.4 ml). We did find that the image quality improved in some cases using these different settings (
n = 7/15), as a more clear-cut distinction between the blood-pool and the myocardium was achieved. However, in other cases a lot of noise was introduced, so we find that the majority of the scans were in fact better analysed with the original settings.
Several studies have presented normal reference values for LVM based on CT-angiography [
10,
11,
15], echocardiography [
8,
24] and MRI [
23,
33] and thus it is reasonable to develop modality-specific reference values. However, regardless of the imaging modality used to obtain the LVShV, all shell volumes are converted to mass by multiplying it with the myocardial tissue density [
8], with 1.055 g/ml being the most commonly used density. To our knowledge, this study is the first to calculate the human myocardial density factor using non-contrast CT based LVShV and LVM obtained at autopsy. This may explain why our value differs from other proposed values. Since our value is higher, this means that a given LVShV will result in a higher LVM, and will be most pronounced for higher and potentially pathological LVShV, which may be of interest for clinicians and warrants further studies.
Although it is currently not fully accepted clinically to use the LVM as a regular test for patients [
3], the exact CT measurements and accurate values for myocardial tissue density can lead to important therapeutic opportunities concerning diagnosis, treatment and prognostics. If the hitherto used density value is substituted with our value, this could have implications for the reference values as it will move some patients to higher LVMs indicating abnormal LVM. If one continues with the hitherto used density value, there will be no problem in using the reference intervals, but to the best of our knowledge, this would mean that the recorded LVM is not the real LVM.
Study limitations
The following study limitations need to be addressed. This study included 73 non-hypertrophic hearts, but in order to develop LVM reference values based on the density, a bigger study population would be preferable. We did not take into consideration the status of ischaemic heart disease, fat infiltration or LV fibrosis and how this potentially could affect the size and shape of the left ventricle. The papillary muscles were included in the LVShV measurements. However, the impact of the inclusion or exclusion of papillary muscles on the assessment of LV function is negligible [
15]. The scans were non-contrast scans, which in a clinical setting makes the differentiation between the LV blood pool and the LV myocardium difficult. However, non-contrast scans are possible in deceased individuals (cf. Fig.
1). We chose to perform the present study without contrast to avoid extravasation of contrast media in the examined deceased individuals and thereby omit a possible weight effect on the myocardium.
A study by Bai R et al. [
20] has suggested a tendency of lower myocardial tissue density associated with pathological changes as oedema, none of our included cases had underwent putrefaction, as these were excluded. Therefore, we do assume that post mortal changes did not have any impact on the myocardial tissue density calculation. In vivo, the myocardium consist of intra-myocardial blood-volume. Postmortem, this volume may change, e.g., postmortem extravasation or, conversely, fluid accumulation from leaking and decomposing endocardial structures. Such changes are small and usually only become pronounced with extended postmortem intervals [
35]. The deceased individuals in this study were kept at reduced temperature and autopsied rather quickly after declaration of death. Morphological observations as well as quantitative results suggest that elements of the blood are resistant to autolytic effects [
36]. Overall, this leads us to assume that no significant organ volumetric changes took place. Water displacement was not performed in this study. There are several factors to take into consideration when performing water displacement measurements/techniques on cadaver hearts. Although it works accurately with solid objects, biological tissue is by its nature permeable and may be compressed or distended, and it may be fixed or unfixed. Given that we wanted to investigate CT-derived volume measures, as this is what is used clinically, we hence chose to base our volumes on this method. Boundaries are sensitive to threshold and windowing. We used a HU threshold for myocardial tissue of 50 ± 10, and 1 mm slice thickness for CT evaluations. The CT settings used for this study are optimized for contrast-based studies, and a different cardiac window settings could result in different myocardial volume. Also, different thresholds may apply for epicardial and endocardial borders and partial volume effects may be important. Due to the relatively close HU values of the blood pool and the myocardium, the myocardium may have been overestimated in some cases and underestimated in other cases
.
Finally, our calculation of a new value for myocardial density is made performing a linear regression on the LVM and LVShV values of our study population. Thus, theoretically, we cannot be sure that very small hearts or LV masses below 96 g will conform to the linear model. This can probably only be investigated by also applying our method to a subadult study population. However, we note that all other analyses on myocardial tissue density were also constrained or even more limited. We would also note that when comparing with the hitherto-used value for myocardial density the differences are most pronounced for bigger hearts, so even if our new value has not been tested on very small hearts, any differences might be assumed minor.
Conclusion
The unique access to both PMCT scans and autopsy measurements allowed us to assess the correlation between LVShV and the anatomic LVM; the analysis was also possible based on gender and LV asymmetric hypertrophy. Our regression models determined only very small differences when stratified by gender and negligible differences when forcing the regression through the origo, which allowed us to determine a myocardial density at 1.265 g/ml. Applying the hitherto used myocardial tissue density value (1.055 g/ml) significantly underestimated the LVM. Our proposed new value is the result of post-mortem CT for volume determination, followed by post-mortem dissection for obtaining LV weight. We argue that this allows for a more precise determination of these two basic parameters, but obviously, we are aware that post-mortem anatomy may not be directly translational to clinical studies. Several LVM reference value tables have been produced using myocardial tissue density value of 1.055 g/ml, thus continuing to use this value when converting from LVShV to LVM will not have immediate clinical implications. However, we do think that our study calls for critical evaluation of especially high LVMs and how this value is obtained.
Acknowledgments
The authors thank the physicians, morgue technicians, laboratory assistants and medical students for their assistance in the SURVIVE project as well as statistician Kyle Raymond for his statistical knowledge and assistance.