Author + information
- Received November 1, 2012
- Revision received April 5, 2013
- Accepted April 12, 2013
- Published online August 1, 2013.
- Minjie Lu, MD, PhD∗,
- Shihua Zhao, MD∗∗ (, )
- Shiliang Jiang, MD∗,
- Gang Yin, BS∗,
- Cheng Wang, MD†,
- Yan Zhang, MD∗,
- Qiong Liu, PhD∗,
- Huaibing Cheng, PhD‡,
- Ning Ma, PhD∗,
- Tao Zhao, PhD∗,
- Xiuyu Chen, PhD∗,
- Jinghan Huang, MD§,
- Yubao Zou, PhD⋮,
- Lei Song, MD⋮,
- Zuoxiang He, PhD¶,
- Jing An, MD#,
- Jerecic Renate, PhD∗∗,
- Hui Xue, PhD†† and
- Saurabh Shah, PhD‡‡
- ∗Department of Radiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peoples Republic of China
- †Department of Cardiology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, Peoples Republic of China
- ‡Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, Peoples Republic of China
- §Department of Electrocardiogram, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peoples Republic of China
- ⋮Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peoples Republic of China
- ¶Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peoples Republic of China
- #Siemens Shenzhen Magnetic Resonance Ltd., Siemens MRI Center, Shenzhen, Guangdong, Peoples Republic of China
- ∗∗Siemens AG, Healthcare Sector, Erlangen, Germany
- ††National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
- ‡‡Siemens Medical Solutions USA, Inc., Chicago, Ilinois
- ↵∗Reprint requests and correspondence:
Dr. Shihua Zhao, Department of Radiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People's Republic of China.
Objectives The aim of this study was to prospectively investigate the prevalence of fat deposition in idiopathic dilated cardiomyopathy (DCM) by fat-water separation imaging. An auxiliary aim was to determine the relationship between left ventricular (LV) fat deposition and characteristic myocardial fibrosis, as well as cardiac functional parameters.
Background Idiopathic DCM remains the most common cause of heart failure in young people referred for cardiac transplantation; little is known about the clinical value of fat deposition in DCM.
Methods A total of 124 patients with DCM were studied after written informed consent was obtained. The magnetic resonance imaging scan protocols included a series of short-axis LV cine imaging for functional analysis, fat-water separation imaging, and late gadolinium enhancement (LGE) imaging. Fat deposition and fibrosis location were compared to the scar regions on LGE images using a 17-segment model. Statistical comparisons of LV global functional parameters, fibrosis volumes, and fat deposition were carried out using the Pearson correlation, Student t test, and multiple regressions.
Results The patients had a 41.9% (52 of 124) prevalence of positive LGE, and 12.9% (16 of 124) fat deposition prevalence was found in this DCM cohort. The patients with fat deposition had larger LV end-diastolic volume (LVEDV) index (140.8 ± 20.2 ml/m2 vs. 123.4 ± 15.8 ml/m2; p < 0.01), larger LV end-systolic volume (LVESV) index (111.3 ± 19.2 ml/m2 vs. 87.0 ± 20.3 ml/m2; p < 0.01), and decreased LV ejection fraction (LVEF) (21.1 ± 7.1% vs. 30.0 ± 10.7%; p < 0.01). Higher volumes of LGE were found in the group with myocardial fat deposition (18.39 ± 9.0 ml vs. 13.40 ± 6.54 ml; p = 0.001), as well as a higher percentage of LGE/LV mass (19.11 ± 7.78% vs. 13.60 ± 4.58%; p = 0.000). The volume of fat deposition was correlated with scar volume, LVEF, LVEDV index, and LVESV index.
Conclusions Fat deposition is a common phenomenon in DCM, and it is associated with DCM characteristics such as fibrosis volume and LV function.
Idiopathic dilated cardiomyopathy (DCM) is a syndrome characterized by cardiac enlargement and global systolic dysfunction in the presence of normal arteries (1,2) that remains an important cause of systolic heart failure and the most common cause of heart failure in young people referred for cardiac transplantation (3). Histological characteristics include substantial hypertrophy and degeneration of myocytes, varying degrees of interstitial fibrosis, and occasional small clusters of lymphocytes and fibrofatty infiltration (4).
Many researchers have studied the clinical value of late gadolinium enhancement (LGE) in patients with DCM, and it was believed that LGE was an important prognostic indicator of DCM (5,6). However, it was impossible to separate fibrosis tissue from fat in conventional LGE images because both fat and fibrosis manifested as high signals. Until now, little research has focused on fat deposition in patients with DCM (7,8).
Myocardial fat demonstrates a hyperintense signal in conventional fast spin-echo images that becomes selectively hypointense in fat saturation fast spin-echo or short tau inversion recovery images. The first water-fat separation method was described by Reeder et al. (9) using steady-state free precession with the iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) technique. There have been many publications from this group regarding the IDEAL technique on fat detection (10–12). However, there is little research specifically focused on myocardial fat detected with this technique. In this study, we used the fat-sensitive magnetic resonance sequence fat-water separation using VARiable PROjection (VARPRO) (13) to investigate fat deposition in DCM. The aim of the present study was to prospectively investigate the prevalence of fat deposition in DCM by fat-water separation imaging and to determine the relationship between left ventricular (LV) fat deposition and characteristic myocardial fibrosis, as well as cardiac functional parameters.
This study was approved by the institutional review board, and all patients gave written consent prior to study initiation. A total of 140 consecutive patients (all of Asian race) with a diagnosis of idiopathic DCM made within the preceding 2 weeks were enrolled in this study. Diagnosis was established by clinical examination, echocardiography, and normal coronary angiograms. The inclusion criterion was the presence of left ventricular ejection fraction (LVEF) ≤45% at baseline echocardiography or cardiac magnetic resonance (CMR) imaging. Exclusion criteria included the diagnosis of significant coronary artery disease (defined as the presence of 50% luminal stenosis in an epicardial coronary artery at angiography, noninvasive stress imaging suggestive of ischemia, history of previous coronary intervention, or prior myocardial infarction), severe valvular heart disease, thyroid dysfunction, infiltrative cardiomyopathy, extracardiac systemic features suggesting sarcoidosis or amyloidosis, heavy alcohol use (>90 g of alcohol per day), peripartum cardiomyopathies, chemotherapy-induced cardiomyopathy, hypertrophic cardiomyopathy, and myocarditis. Myocarditis was excluded in potential DCM cases by the absence of classic clinical features, presence of normal serum troponin I concentration at presentation, and lack of evidence of myocardial edema on T2-weighted CMR (14). Exclusion from the CMR examination was mandated by renal impairment (estimated glomerular filtration rate of 60 ml/min) or other conventional CMR contraindications.
CMR imaging protocol
All CMR examinations were performed with a 1.5-T scanner (Magneton Avanto, Siemens Medical Systems, Erlangen, Germany) with the patient in a supine position. Images were acquired during suspended respiration at end-inspiration with vector-electrocardiographic gating and an 8-channel phased-array body receive coil. The study consisted of: 1) LV cine functional imaging; 2) LGE imaging; and 3) water-fat separation imaging with VARPRO sequentially. For each part of the study, identical section locations were used, consisting of 8 parallel 6-mm–thick short-axis sections with a 4- to 6-mm section gap spanning the LV myocardium from the base to the apex of the heart. Three long-axis views of the LV were acquired with identical imaging parameters. True fast imaging with steady-state precession was used for cine imaging. The following imaging parameters were used: repetition time/echo time 3.0/1.1; flip angle 85° to 65°; bandwidth 800 Hz/pixel; matrix size 192 × 256; pixel size 2.2 × 1.6 mm2; integrated parallel imaging technique acceleration factor × 2; and temporal resolution 38 to 45 ms/frame depending on the R-R interval.
LGE imaging was performed with a pulse sequence for T1-weighted imaging with phase-sensitive inversion recovery. The gadodiamide (Magnevist, Bayer HealthCare Pharmaceuticals, Wayne, New Jersey) agent dose was 0.2 mmol/kg. Images were collected 10 to 15 min after the contrast administration was performed with an automated injector (Spectris, Medrad, Pittsburgh, Pennsylvania).
A multiecho gradient-recalled echo sequence was implemented with fat-water separation using the VARPRO multipoint Dixon reconstruction method (15) with T2* correction (16). The imaging sequence was vector-electrocardiogram triggered, with 2 R-R intervals between inversions, and used an echo-train readout with 4 echoes with flyback gradients for monopolar readout. The echo-train readout was used to increase the acquisition efficiency and thereby maintain acceptable breath-hold duration. Typical parameters for imaging were bandwidth 930 Hz/pixel; echo time 1.35, 3.10, 4.85, and 6.8 ms; repetition time 374.25 ms; flip angle 24°; image matrix 192 × 112; views per segment 5; breath-hold duration 16 heart beats, including 2 initial heart beats discarded for transition to steady state. Phase-encoding oversampling was used in cases when the matrix size was rounded up due to segmentation. The inversion time was autoadjusted to minimize the signal intensity of normal myocardium.
All images were analyzed offline using a workstation with commercially available software (Argus version 3.3, Siemens).
For all patients, the CMR scans were placed in random order after the identity information was removed. The doctor who was blinded to the clinical data evaluated the CMR images. Epicardial and endocardial borders of contiguous short-axis slices were manually traced. End-diastole and end-systole were visually determined and allowed calculation of left ventricular mass (LVM), left ventricular end-diastole volume (LVEDV), and left ventricular end-systole volume (LVESV), from which LVEF, cardiac output (CO), and cardiac index were derived. The LVM was calculated by subtracting endocardial from epicardial volume at end-diastole and multiplying by 1.05 g/cm3 (17). All of the global functional parameters were indexed to body surface area (18).
The extent of LGE was determined automatically by computer counting of all hyperenhanced pixels in the myocardium on each of the LGE images. Hyperenhanced pixels resembling LGE were defined as those with image intensities of 2 SD above the mean of image intensities in a remote myocardial region in the same image.
Fibrosis contours were drawn on the reconstructed water-only images by using the same software. Fibrosis was defined as those with image intensities of 2 SD above the mean of image intensities in a remote myocardial region in the water-only images.
A fat fraction (FF) map (Equation #1) was used to determine the presence of fat (19) by using the fat-only (F) and water-only (W) images. Before processing the FF map, a magnitude discrimination was performed to correct bias from T1 and noise (20,21), and fat pixels were defined as higher than 50% in the fraction map (Online Appendix).
The LGE, fibrosis, and fat volumes and percentages of LVM were calculated. All image analysis was performed by a single investigator with 11 years of CMR image analysis experience. To assess the reproducibility, LGE, fat, and fibrosis volume analyses were performed by 2 independent experienced observers (with 11 years and 8 years of CMR image analysis experience) for patients with fat deposition.
Continuous variables are presented as the mean ± SD. Interobserver variability was assessed using the Bland and Altman method (22). Comparisons between continuous variables in the 3 groups of patients included in the study were performed by 1-way analysis of variance. The results were tested for normality with the polynomial normality test. If the overall p value was ≤0.05, Bonferroni multiple comparison was used as a post-test. If the overall p value was >0.05, then least significant difference multiple comparison was used as a post-test. Moreover, linear correlation was used to evaluate the correlation index (Pearson coefficient, r) between LVEF and fat, LVEF and LGE, LVEF and fibrosis, and LVEF and LVM index. The categorical variables are presented as a frequency or percentage and were compared by using the Fisher exact test. A multiple regression was used to analyze the predictive independence of fat deposition and fibrosis volumes on global cardiac functional variables. For each test applied in this study, p values ≤0.05 were considered to indicate significance. All statistical analyses were performed using SPSS software (version 13.0, SPSS, Chicago, Illinois) and GraphPad Prism statistical software (GraphPad Software version 5.01, San Diego, California).
Sixteen patients were excluded, including 3 due to claustrophobia, 4 due to refusing to undergo CMR imaging, and the rest due to poor image quality as a result of inability to repeatedly suspend respiration for periods of 15 to 20 s. Finally, 124 patients were enrolled in this study. Table 1 summarizes the clinical characteristics in the study population.
The interobserver means of LGE, fat, and fibrosis were 18.39 ± 9.0 ml, 9.18 ± 5.42 ml, and 9.75 ± 6.34 ml, respectively. The corresponding difference between the means of LGE, fat, and fibrosis were 0.07 ± 0.69 ml, 0.07 ± 0.34 ml, and 0.16 ± 0.35 ml, respectively. This is presented graphically for interobserver variability for LGE (Fig. 1A), fibrosis (Fig. 1B), and fat (Fig. 1C). Results from the Bland and Altman analyses for interobserver variability are presented as mean and the difference between the 95% confidence limits of the bias.
Fat and fibrosis deposition analysis
Patients in this DCM cohort had a 41.9% (52 of 124) prevalence of positive LGE, including a 12.9% (16 of 124) prevalence of fat deposition. The patients were divided into 3 groups as follows: those with negative LGE, those with LGE but no fat deposition, and those with LGE and fat deposition. There were no patients demonstrating fat deposition without fibrosis. Examples of patients with fat deposition are shown in Figures 2, 3,⇓ and 4. Higher volumes of LGE were found in the group with myocardial fat deposition (18.39 ± 9.0 cm3 vs. 13.40 ± 6.54 cm3; p = 0.001), as well as a higher ratio of LGE/LVM (13.60 ± 4.58% vs. 19.11 ± 7.78%; p = 0.000).
Of 16 patients with fat deposition, 13 (81.3%) had fat deposition at the septum (Figs. 2, 4, and 5), 2 (12.5%) at the apex (Fig. 3), and the remaining one (6.3%) at the inferior wall. In this group, fat deposition occurred in distinct intramural patterns: midwall striae or patches of intramural enhancement. In the LGE without fat deposition subgroup, 25 of 36 patients (69.4%) had LGE at the septum, 5 (13.9%) at the apex, 4 (11.1%) at the septum and adjacent inferior wall, and the remaining 2 (5.6%) at the lateral wall. In the patterns of LGE, we found 2 distinct phenomena: subendocardial enhancement including subendocardial extension toward the epicardium (7 of 36 [19.4%]) and midwall striae or patches of enhancement (29 of 36 [80.6%]).
There was no significant difference between the groups with and without LV fat deposition with respect to body mass index and body surface area (Table 1). Patients with fat deposition were younger (vs. positive LGE without fat deposition) and had a larger volume of LGE and a larger percentage of LGE of LVM (Table 2). In the group with myocardial fat deposition, the fibrosis volume was significantly lower than that of the positive LGE without fat deposition group (9.46 ± 4.84 ml vs. 13.60 ± 4.58 ml; p = 0.000).
Global cardiac function
In this study, LVEF, LVEDV, LVEDV index, LVESV, LVESV index, CO, and cardiac index were significantly different among the 3 subgroups (negative LGE group, positive LGE group, and fat deposition group) (Table 2). In addition, there were significant differences in LVEF, LVEDV, LVEDV index, LVESV, and LVESV index in pairwise comparisons within the 3 groups. The mean LVEF in the fatty deposition group was the lowest (21.1%), compared with that in the positive LGE (30.0%) and negative LGE groups (34.5%; p = 0.000). Logically, the LVEDV, LVEDV index, LVESV, and LVESV index were the highest in the fat deposition group, whereas those values were the lowest in the negative LGE group. In addition, only the CO and cardiac index were significantly different between the groups with fat deposition and the negative LGE group; patients with fat deposition had significantly decreased CO and cardiac index compared with those in the negative LGE group. LVM was not different among the 3 groups (p = 0.07).
Predictors of cardiac function
In the patients with fat deposition, there was a significant positive correlation between fibrosis and fat volumes. There was a significant inverse correlation of fat volumes (p = 0.0008; R2 = 0.5624; slope −0.937) (Fig. 6) and fibrosis volumes (p = 0.001; R2 = 0.5308; slope −0.817) (Fig. 7) with LVEF. However, there were no significant univariate correlations of fat volumes with LVEDV index (p = 0.874), LVESV index (p = 0.286), LVM index (p = 0.153), and cardiac index (p = 0.218). In addition, there was a univariate correlation between fat and fibrosis volumes (Fig. 8). For the fibrosis group, there were significant univariate correlations of fibrosis volumes with LVEF (p = 0.001; R2 = 0.78; slope 0.82) and LVM index (p = 0.005; R2 = 0.44; slope 1.17).
Multiple regression with fat and fibrosis volumes as independent variables showed that fat volume was an independent predictor of the global cardiac functional parameter LVEF (p = 0.003). The regression equation is LVEF = 42.18 − (0.48 × fat) − (0.321 × LVM) − (0.17 × fibrosis) (p < 0.001). Fibrosis was significantly correlated with LVEF and LVM index in the myocardial fat deposition group and the positive LGE group (p = 0.009 and p = 0.014, respectively) (Fig. 6).
In this prospective study, we noninvasively evaluated myocardial fat deposition in patients with DCM by using MR fat-water separation imaging combined with LGE imaging. To our knowledge, this is the first research concerning the prevalence of fat deposition in DCM. In addition, we investigated the association among myocardial fat deposition, fibrosis, and quantitative global cardiac functional variables.
We obtained several results from the present study. First, fat deposition is a common phenomenon in DCM. In this patient cohort, the prevalence of fat deposition was 12.9%. Second, we found an association between fat deposition and global cardiac function (LVEF), as well as fibrosis and LVM. Although fat deposition, fibrosis, and LVM index were independent predictors for the global cardiac functional parameter LVEF from the multiple regression analysis, the cause and effect are unknown at this stage but should be investigated in multicenter studies with larger cohorts.
CMR LGE imaging has proven to be an accurate technique for fibrosis location and extension (23). Factors such as fat suppression and choice of opposed phased-echo times may alter the perceived LGE size by using this technique. Fat deposition or choice of imaging parameters may alter or even be the source of the heterogeneous signal intensity behavior in myocardial fibrosis. The prevalence of fibrosis in DCM detected by LGE reported in the literature was not very consistent, ranging from 31% to 88% (6,24–26). In the population in this study, a relatively higher prevalence of fibrosis was observed. One probable reason may be selected population referral bias, which means that the results may not be generalizable to the entire population. However, we believe that the more likely reason if a true higher prevalence of fibrosis in the Chinese population compared with that of European countries.
Interestingly, in this study, because fat deposition was found in LV myocardium combined with fibrosis, we believe that fibrosis is a precursor to myocardial fat deposition in DCM. To verify this hypothesis, a larger sample with long-term follow-up should be investigated. We also found that fat deposition was predominantly midmyocardial or subepicardial, which was similar to the characteristics of LGE in DCM (6,27). As we know, CMR imaging may be the best noninvasive image modality for the detection of fat tissue in vivo owing to its sensitivity to the off-resonance properties of fat and allowing fat-water separation imaging combined with LGE imaging for detection of fibrosis. Both fat-water separation and LGE imaging depict not only fat and fibrosis but also the entire myocardium. This allowed identification of the location within the LV wall of both fat deposition and fibrosis. Furthermore, 1 patient in the cohort had the pathological validation for LV adipose tissue detected by CMR, and the CMR findings were highly correlated with the histological specimens.
However, the cause and pathogenesis of fat deposition in DCM are still unclear, but the possible mechanism in ischemic cardiomyopathy (myocardial infarction) is that adipocytes were transformed from fibrocytes at the site of the periscar region, where it was believed that the blood flow was still present (28,29). Interestingly, in our study, we found that fat deposition coincided with the presence of fibrotic tissue in the LV myocardium. Therefore, the mechanism of fat deposition in DCM may be the same occurring in myocardial infarction.
Little is known about the prognostic significance or factors leading to myocardial fat deposition in patients with DCM so far. The present study implied that fat deposition is most likely an indicator of a worse prognosis compared with no fat/fibrosis deposition in DCM. In view of this, fat deposition could be considered a predictor used to grade the severity of DCM, although the cause and effect are still unknown.
The first major limitation of this study was that there was only 1 patient with the pathological validation for LV adipose tissue detected by CMR. Ideally, CMR findings would be correlated to histological specimens, but such examinations are extremely difficult to perform in vivo in human hearts as opposed to experimental animal models. The population was relatively small, and there was a wide variety of times of DCM diagnoses and treatment in this study. Patients in this study mostly had long-term symptoms and had severely impaired cardiac function. The present study did not analyze the relationship between fat deposition and clinical manifestations. The precise quantification of scar volume or fat volume needs 3-dimensional acquisition; in the current study, we did not have 3-dimensional LGE and fat-water images. However, due to the small spacing between scan layers, it should have little impact on fat quantitative evaluation. The measurements of LV contractile function could be affected by the intraobserver and interobserver variability, although such variability is expected to be small in magnitude owing to the high accuracy and precision of CMR measurements (30). Fat-water separation on the inversion recovery prepared multiecho images will introduce one extra T1 weighting. In the VARPRO fitting scheme used in the study, the T1 weighting effects were not considered. However, the imaging sequences used were segmented, and a 2-RR interval guarantees a good T1 recovery between readouts, given that fat-water imaging is performed after injection of contrast agents. Multiple comparisons were made in the same data set, and actual p values are reported without adjustment for multiple comparisons to the nominal significance level of 0.05. This allows the readers to focus on comparisons of interest and make any multiple comparison adjustments on their own. A larger study is needed to confirm that there are in fact 2 groups.
A relatively high prevalence of myocardial fat deposition was found in patients with DCM. Fat deposition volume is significantly related to LV global function including LVEF, LVEDV index, LVESV index, and LVM and may be a worse predictor index for the prognosis of DCM.
The authors thank Professor Peter Kellman, PhD, from the National Heart, Lung, and Blood Institute for his kind assistance in manuscript preparation, especially in the technical issues.
For supplemental figures, please see the online version of this article.
Work was performed at State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. This study was supported in part by research grants from the National Natural Science Foundation of China (81000604 and 81130029), PUMC Youth Fund, the Fundamental Research Funds for the Central Universities (3332013105), and Talent Research Star of Fuwai Hospital (2012-FWXX01). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- cardiac output
- dilated cardiomyopathy
- late gadolinium enhancement
- left ventricle/ventricular
- left ventricular end-diastolic volume
- left ventricular ejection fraction
- left ventricular end-systolic volume
- left ventricular mass
- Received November 1, 2012.
- Revision received April 5, 2013.
- Accepted April 12, 2013.
- American College of Cardiology Foundation
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