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Radiology
 
Radiology. August 2016; 280(2): 405–412.
Published online 2016 March 11. doi:  10.1148/radiol.2016150988
PMCID: PMC4976459

Fibrofatty Changes: Incidence at Cardiac MR Imaging in Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Abstract

In patients with arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy, ventricular fatty infiltration and late gadolinium enhancement are common, are associated with advanced RV structural disease and proband status, and are seen in a minority of patients with isolated regional RV wall motion abnormalities who do not completely fulfill current diagnostic criteria.

Abstract

Purpose

To determine the incidence of ventricular fatty replacement and late gadolinium enhancement (LGE) at cardiac magnetic resonance (MR) imaging in patients with arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) and the relationship of these findings to disease severity.

Materials and Methods

This was a retrospective institutional review board–approved HIPAA-compliant study. All subjects provided written informed consent. Seventy-six patients with ARVD/C were enrolled from 2002 to 2012. Quantitative and qualitative cardiac MR imaging analyses of the RV and the left ventricle (LV) were performed to determine cardiac MR imaging–specific Task Force Criteria (TFC) and non-TFC features (ARVD/C-type pattern of fatty infiltration and/or nonischemic pattern LGE). Patients were separated into four groups on the basis of cardiac MR imaging TFC: (a) patients with major cardiac MR imaging criteria, (b) patients with minor criteria, (c) patients with partial criteria, and (d) patients with no criterion. Continuous variables were compared by using the independent Student t test and analysis of variance. Categoric variables were compared by using the Fisher exact test.

Results

Of 76 patients (mean age, 34.2 years ± 14 [standard deviation]; 51.3% men), 42 met major cardiac MR imaging criteria, seven met minor criteria, seven met partial criteria, and 20 met no criterion. Most probands (36 [80.0%] of 45) met major or minor cardiac MR imaging criteria. Only 13 (41.9%) of 31 family members met any cardiac MR imaging criterion. The most common non-TFC MR imaging features were RV fatty infiltration (28.9%) and LV LGE (35.5%). Non-TFC cardiac MR imaging features were seen in 88.1% of subjects with major criteria, in 28.6% of those with minor criteria, in 71.4% of those with partial criteria, and in 10.0% of those with no criteria.

Conclusion

In this large cohort of patients with ARVD/C, non-TFC findings of ventricular fatty infiltration and LGE were frequent and were most often found in those who met major cardiac MR imaging criteria and in probands.

© RSNA, 2016

Online supplemental material is available for this article.

Introduction

Arrhythmogenic right ventricular (RV right ventricle) dysplasia/cardiomyopathy (ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy) characteristically affects the RV right ventricle and manifests in ventricular arrhythmias and RV right ventricle dysfunction (1,2). Histologically, there is fibrofatty replacement of the RV right ventricle myocardium (3). Diagnosis is challenging because of the disease’s nonspecific findings and is currently based on meeting a set of major and minor criteria (Task Force Criteria [TFC Task Force Criteria]) that encompass imaging and histopathologic findings, electrocardiographic abnormalities, arrhythmia history, and genetic factors. These criteria were initially proposed in 1994 and were subsequently revised in 2010 (4).

Cardiac magnetic resonance (MR) imaging is a critical tool for evaluating structural cardiac abnormalities in subjects being examined for ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy (5). The cardiac MR imaging criteria described by the 2010 TFC Task Force Criteria are defined by a combination of both regional RV right ventricle wall-motion abnormalities (WMA wall-motion abnormalitys) and abnormalities in quantitative RV right ventricle ejection fraction (RVEF RV ejection fraction) and/or RV right ventricle end-diastolic volume index (RVEDVI RV end-diastolic volume index) (4). These criteria were created on the basis of data in a cohort of 44 probands compared with control subjects, with quantitative thresholds of RV right ventricle volume and RVEF RV ejection fraction selected to maximize diagnostic specificity (4). With the advent of genetic screening, greater numbers of family members of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy probands are receiving a diagnosis at an early, asymptomatic stage. The cardiac MR imaging findings in this population have not been well described.

Additional myocardial abnormalities are seen in patients with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy that were not included in the 2010 TFC Task Force Criteria, namely, fatty infiltration and late gadolinium enhancement (LGE late gadolinium enhancement) (6). We have found that occasionally these non-TFC Task Force Criteria features suggestive of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy may be present in patients who would otherwise not meet major or minor cardiac MR imaging criteria. The relationship of these findings to standard quantitative measures of RV right ventricle function and cardiac MR imaging–specific TFC Task Force Criteria is not well understood. Therefore, our purpose was to determine the incidence of ventricular fatty replacement and LGE late gadolinium enhancement at cardiac MR imaging in patients with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy and the relationship of these findings to disease severity.

Materials and Methods

Study Population

This was a retrospective study of subjects enrolled in an institutional ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy registry from 2002–2012. All individuals provided written informed consent. The study protocol was Health Insurance Portability and Accountability Act compliant and was approved by the institutional review board. Data for all subjects in the registry with a diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy on the basis of the 2010 TFC Task Force Criteria (4) and available cardiac MR imaging studies were reviewed (n = 105). Of the available cardiac MR imaging studies, 29 were excluded because they were missing essential sequences for the evaluation of both fat and LGE late gadolinium enhancement. Because of the rarity of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy, some of the members of this patient cohort have been included in previous studies (710). Four studies have involved members of this cohort. A study of serial cardiac MR imaging changes in patients at risk for ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy included 21 of the 76 subjects from this study (7). A prior report on the prevalence of biventricular disease in ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy reported data in 49 of the 76 subjects (8). A study of the additive value of cardiac MR imaging for defining prognosis in ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy mutation carriers included 39 of the 76 subjects (9). Finally, a study of the most common locations of RV right ventricle WMA wall-motion abnormalitys in patients with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy and mutation carriers included 46 of the 76 subjects.

Cardiac MR Imaging Protocol

Studies at the authors’ institution (n = 62) were performed with 1.5-T MR imaging units (CV/I, GE Medical Systems, Waukesha, Wis; or Avanto, Siemens, Erlangen, Germany). A detailed protocol is shown in Table E1 (online) and has been described in previous reports (11). Studies from outside centers (n = 14) were also performed at 1.5 T and with CV/I or Avanto units. For inclusion, studies must have included a minimum of double–inversion recovery fast spin-echo (FSE fast spin echo) sequences, cine functional images in the long- and short-axis planes, and postcontrast breath-hold two-dimensional segmented gradient-echo LGE late gadolinium enhancement images.

Quantitative Cardiac MR Analysis

Cardiac MR images were analyzed with dedicated software (QMASS; Medis, Leiden, the Netherlands). Measurements were performed by a single reader with 2 years of cardiac MR imaging experience (N.R.) who was blinded to clinical information. Endocardial margins of the left ventricle (LV left ventricle) and RV right ventricle were contoured manually on end-systolic and end-diastolic images. Papillary muscles were included in the blood pool volume. End-systolic volume index, end-diastolic volume index, and ejection fraction for both ventricles were obtained. Volumes were indexed to body surface area (BSA) [BSA = body weight (in kilograms)0.425 × height (in centimeters)0.725 × 0.007184] (12).

Qualitative Cardiac MR Analysis

Cardiac MR images were assessed in consensus by two blinded readers (I.R.K., S.L.Z.) with 10 and 4 years of experience. Examinations were assessed for RV right ventricle regional dyskinesia, akinesia, or dyssynchronous RV right ventricle contraction as per the 2010 TFC Task Force Criteria, with the location recorded on the basis of a five-segment RV right ventricle model that has been previously described (10). WMA wall-motion abnormalitys had to be present on at least two contiguous cine images or in multiple planes to avoid false-positive findings on short-axis images due to partial-volume effects from RV right ventricle through-plane motion.

Cardiac MR Imaging TFC Scoring

The presence or absence of each of the cardiac MR imaging–specific TFC Task Force Criteria for ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy was scored on the basis of qualitative and quantitative results. Research review of cardiac MR data was not used to establish the diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy, which was strictly based on 2010 global TFC Task Force Criteria at the time of clinical diagnosis. As per the 2010 TFC Task Force Criteria, subjects required a regional WMA wall-motion abnormality combined with either reduced RVEF RV ejection fraction or increased RVEDVI RV end-diastolic volume index to meet major or minor criteria. Subjects with major criteria had an RVEDVI RV end-diastolic volume index of more than 110 mL/m2 (male patients) or more than 100 mL/m2 (female patients) or an RVEF RV ejection fraction of less than 40%. Subjects with minor criteria had an RVEDVI RV end-diastolic volume index of more than 100 but less than 110 mL/m2 (male patients) or more than 90 but less than 100 mL/m2 (female patients) or an RVEF RV ejection fraction of more than 40% but less than 45%. Subjects with findings limited to either a regional WMA wall-motion abnormality or abnormal RVEDVI RV end-diastolic volume index or RVEF RV ejection fraction but not both did not meet cardiac MR imaging TFC Task Force Criteria and were classified in the partial cardiac MR imaging criteria group.

Non-TFC Cardiac MR Imaging Features

The same two blinded readers also scored the presence or absence of fatty infiltration and LGE late gadolinium enhancement of both ventricles in consensus. Locations of each were scored by using the same standard LV left ventricle and RV right ventricle segmental models used to record WMA wall-motion abnormalitys. RV right ventricle fat infiltration was identified by a pattern of high-signal-intensity fingerlike projections disrupting the normal smooth epicardial contour of the RV right ventricle on FSE fast spin echo images, as previously described (Fig 1) (13). RV right ventricle fat infiltration with smooth RV right ventricle wall thickening was considered a non-ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy pattern and was excluded (Fig 2). LV left ventricle fat infiltration was identified by high signal intensity within the LV left ventricle myocardium on FSE fast spin echo images or high signal intensity with India-ink etching artifact on steady-state free precession images (Fig 3) (14,15). In regions with suspected subepicardial fat infiltration, a contour deformity and regional LV left ventricle wall thinning were required to distinguish epicardial fat outside the LV left ventricle from fatty infiltration (Fig 3). LGE late gadolinium enhancement was identified by regions of increased signal relative to nulled myocardium. Ischemic-pattern LV left ventricle LGE late gadolinium enhancement was excluded. In the RV right ventricle, LGE late gadolinium enhancement was identified by regional wall hyperenhancement visually distinct from nulled RV right ventricle myocardium. Subjects demonstrating increased FSE fast spin echo and LGE late gadolinium enhancement signal in the same segment were considered positive for both fat and LGE late gadolinium enhancement, as it was not possible to distinguish mixed fat and fibrosis from pure fat (Fig 3).

Figure 1a:
ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy-type pattern of RV right ventricle fat infiltration. Axial T1-weighted dark-blood MR images (a) without and (b) with fat saturation in a 45-year-old man with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy ...
Figure 2:
Non-ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy pattern of RV right ventricle fat. Axial dark-blood MR image in 89-year-old woman with temporal arteritis shows diffuse fatty infiltration in the RV (arrows). In contrast to the ARVD/C arrhythmogenic ...
Figure 3a:
Non-TFC Task Force Criteria cardiac MR imaging features in a patient with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy with major cardiac MR imaging criteria. Four-chamber (a) bright-blood and (b) dark-blood MR images in a 27-year-old man who met ...
Figure 1b:
ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy-type pattern of RV right ventricle fat infiltration. Axial T1-weighted dark-blood MR images (a) without and (b) with fat saturation in a 45-year-old man with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy ...
Figure 3b:
Non-TFC Task Force Criteria cardiac MR imaging features in a patient with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy with major cardiac MR imaging criteria. Four-chamber (a) bright-blood and (b) dark-blood MR images in a 27-year-old man who met ...
Figure 3c:
Non-TFC Task Force Criteria cardiac MR imaging features in a patient with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy with major cardiac MR imaging criteria. Four-chamber (a) bright-blood and (b) dark-blood MR images in a 27-year-old man who met ...

Statistical Analysis

All continuous variables were reported as means ± standard deviations, and categoric variables were reported as numbers and percentages. Continuous variables were compared by using the independent Student t test for normally distributed variables and the Mann-Whitney U test for non–normally distributed variables. For multiple comparisons of continuous variables, the analysis of variance test was used for normally distributed variables and the Kruskal-Wallis test was used for non–normally distributed variables. Bonferroni post-hoc analysis was used to correct for multiple comparisons. Categoric variables were compared by using the Fisher exact test. Multivariable linear regression analysis was used to evaluate the association of quantitative findings with TFC Task Force Criteria criteria while controlling for sex. All statistical analyses were performed by using statistical software (STATA, version 12; Stata, College Station, Tex). P < .05 was considered to indicate a statistically significant difference.

Results

Clinical and Demographic Data

We included 76 subjects (mean age, 34.2 years; 51% men) with definite ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy according to the 2010 TFC Task Force Criteria, of whom 45 (59%) were probands and 31 (40%) had been given a diagnosis at family screening. Forty-five (59%) subjects harbored pathogenic ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy-associated mutations, the majority plakophilin 2 (36 [80%] of 45). There was no significant difference in the prevalence of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy-associated mutations between probands and family members (53% vs 68%, P = .24), although the power was low for comparing proportions given the small sample sizes.

Quantitative RV and LV Findings for Entire Cohort

Quantitative results for cardiac MR imaging analysis are shown in Table 1. For the entire cohort, mean RV right ventricle function was reduced (RVEF RV ejection fraction, 42% ± 10) and RVEDVI RV end-diastolic volume index was increased (105 mL/m2 ± 26 for the cohort) compared with previously published normal reference values for cardiac MR imaging (RVEF RV ejection fraction, 61% ± 6; RVEDVI RV end-diastolic volume index, 91 mL/m2 ± 16) (16). Mean LV left ventricle function was reduced (LVEF LV ejection fraction, 54% ± 6) and LV left ventricle size was enlarged (LVEDVI LV end-diastolic volume index, 88 mL/m2 ± 19) compared with reference values (LVEF LV ejection fraction, 69% ± 6; LVEDVI LV end-diastolic volume index, 80 mL/m2 ± 13) (16). For the whole cohort, quantitative RV right ventricle volumes and function were worse in probands, with RVESVI RV end-systolic volume index and RVEDVI RV end-diastolic volume index (P < .001 for both) significantly higher and RVEF RV ejection fraction significantly lower (P < .001) than in family members (Table 1). When male and female subjects were analyzed separately (Table E2 [online]), all measures of quantitative RV right ventricle volumes and function remained significantly worse for female probands (P < .01 for all). In male subjects, RVEF RV ejection fraction was significantly worse for probands (P = .02), whereas for RVESVI RV end-systolic volume index and RVEDVI RV end-diastolic volume index, there was no significant difference by pedigree (RVESVI RV end-systolic volume index, P = .05; RVEDVI RV end-diastolic volume index, P = .29). There was no difference in LVEDVI LV end-diastolic volume index and LVEF LV ejection fraction in probands compared with family members (P = .49 and P = .10, respectively).

Table 1
Demographic and Cardiac MR Imaging Data in All Subjects, Probands, and Family Members

Cardiac MR Imaging–specific TFC Findings

Subjects were divided into four groups based on the presence or absence of cardiac MR imaging TFC Task Force Criteria. The majority of subjects met major cardiac MR imaging TFC Task Force Criteria (n = 42, 55%), seven (9%) met minor cardiac MR imaging TFC Task Force Criteria, seven (9%) met partial cardiac MR imaging criteria, and 20 (26%) met no cardiac MR imaging criterion. The relationships of cardiac MR imaging TFC Task Force Criteria group with quantitative RV right ventricle measures are shown in Table 2. RVEDVI RV end-diastolic volume index, RVESVI RV end-systolic volume index, and RVEF RV ejection fraction were significantly different between groups, and, as expected, were most abnormal in the major TFC Task Force Criteria category. Post-hoc analysis indicated significant differences between major cardiac MR imaging criteria and each of the other groups. Multivariable linear regression analysis showed no significant influence of sex on the association of RV right ventricle quantitative measures and major criteria. There was a significant P value for the trend of LVESVI LV end-systolic volume index and LVEF LV ejection fraction across the four groups; however, when corrected for multiple comparisons, differences were no longer significant. The majority of subjects who met major cardiac MR imaging criteria were probands (76%), whereas subjects who met no cardiac MR imaging criterion were mostly family members (75%). Differences were due to more severe RV right ventricle disease in probands (Table 1), reflected by higher RVEDVI RV end-diastolic volume index (115 mL/m2 ± 31 vs 90 mL/m2 ± 25), lower RVEF RV ejection fraction (38% ± 9 vs 48% ± 8), and more frequent RV right ventricle WMA wall-motion abnormalitys (89% vs 45%, P < .0001).

Table 2
Incidence of Cardiac MR Imaging Findings in Four Groups on the Basis of Cardiac MR Imaging TFC Task Force Criteria Fulfillment

Non-TFC MR Imaging Features

Non-TFC Task Force Criteria cardiac MR imaging features grouped by fulfillment of cardiac MR imaging–specific TFC Task Force Criteria are detailed in Table 2. Complete subject-level data summarizing quantitative and qualitative data for both cardiac MR imaging–specific TFC Task Force Criteria and non-TFC Task Force Criteria cardiac MR imaging features for each subject are available in Table E3 (online). All non-TFC Task Force Criteria cardiac MR imaging features were more common in the major cardiac MR imaging criteria group than in the other groups (P < .05). Non-TFC Task Force Criteria cardiac MR imaging features were seen in 88% (37 of 42) of the major cardiac MR imaging criteria group and in 28% (two of seven) of the relatively small minor criteria group. Probands had non-TFC Task Force Criteria cardiac MR imaging features more often than did family members (76% vs 39%, P = .001), reflective of the more extensive RV right ventricle structural disease in this group. In the RV right ventricle, 29% of subjects had fat infiltration, most often present in the RV right ventricle free wall. There was no significant difference in RV right ventricle fat between probands and family members (33% vs 23%, P = .31). RV right ventricle fatty infiltration was significantly more common among subjects with the most severe structural disease in the RV right ventricle, occurring in 40% of subjects who met major cardiac MR imaging TFC Task Force Criteria, compared with in 9% of subjects who did not meet cardiac MR imaging criteria. RV right ventricle LGE late gadolinium enhancement was less common; it was seen in only 13 subjects (18%), most often in the RV right ventricle inferior wall. There was no difference in RV right ventricle LGE late gadolinium enhancement between probands and family members (22% vs 10%, P = .22). In the LV left ventricle, fatty infiltration and LGE late gadolinium enhancement were present in approximately one-third of subjects (32% and 36%, respectively), both most common in the lateral wall. LV left ventricle fat and LV left ventricle LGE late gadolinium enhancement were both more common in probands (fat, 42% vs 16%; LV left ventricle LGE late gadolinium enhancement, 49% vs 16%; P < .05 for both). No subjects had LV left ventricle LGE late gadolinium enhancement in an ischemic-type pattern. Sixty-three percent of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy subjects diagnosed through family member screening had normal cardiac MR imaging examinations with no detectable structural RV right ventricle (or LV left ventricle) disease.

Subjects with Partial Cardiac MR Imaging Criteria

In the partial cardiac MR imaging criteria group, non-TFC Task Force Criteria cardiac MR imaging features were frequently seen (in five [71.4%] of seven subjects). One subject had a combination of RV right ventricle fat, LV left ventricle fat, and LV left ventricle LGE late gadolinium enhancement; one had a combination of LV left ventricle fat and LV left ventricle LGE late gadolinium enhancement; two had isolated RV right ventricle fat infiltration; and one had isolated LV left ventricle fat infiltration (Fig 4). These subjects all had associated RV right ventricle WMA wall-motion abnormalitys. The demographic and clinical features of subjects with partial cardiac MR imaging criteria are detailed in Table E3 (online). Subjects with partial cardiac MR imaging criteria had a wide age range (mean, 38 years; range, 17–62 years), and most (six of seven) were placed in the partial cardiac MR imaging criteria group because they had a focal RV right ventricle WMA wall-motion abnormality but normal RVEF RV ejection fraction and RF volumes. This group contained similar numbers of male and female subjects as well as probands and family members.

Figure 4a:
Non-TFC Task Force Criteria cardiac MR imaging features in a 41-year-old with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy with partial cardiac MR imaging criteria. She had been given a diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy ...
Figure 4b:
Non-TFC Task Force Criteria cardiac MR imaging features in a 41-year-old with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy with partial cardiac MR imaging criteria. She had been given a diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy ...

Subjects with No Cardiac MR Imaging Criteria

Subjects with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy who fulfilled no cardiac MR criteria had the lowest RVESVI RV end-systolic volume index and RVEDVI RV end-diastolic volume index and the highest RVEF RV ejection fraction (Table 2). There were no significant differences in LVEF LV ejection fraction and LVESVI LV end-systolic volume index when they were corrected for multiple comparisons. Only two patients, both with LV left ventricle LGE late gadolinium enhancement, had non-TFC Task Force Criteria cardiac MR imaging features. No patient had RV right ventricle fibrofatty infiltration. The first patient was a 43-year-old female proband with normal RV right ventricle size and function but marked LV left ventricle dilation and dysfunction (LVEDVI LV end-diastolic volume index, 102 mL/m2; ejection fraction, 43%) and extensive subepicardial LV left ventricle LGE late gadolinium enhancement. She met criteria on the basis of electrocardiographic findings and a history of arrhythmia; her phenotype was consistent with an LV left ventricle-predominant or “left-sided” ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy. She was positive for a desmoplakin mutation, which has been associated with the left-sided phenotype. The other patient was a 57-year-old family member with a known extradesmosomal mutation who had multifocal midmyocardial and subepicardial LV left ventricle LGE late gadolinium enhancement but preserved LV left ventricle size and function.

Discussion

In the current study of fibrofatty changes in a large cohort of subjects with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy, we report two key findings. First, fat infiltration and/or fibrosis are most common in subjects with RV right ventricle structural disease that fulfills major cardiac MR imaging criteria, often probands. Second, these features may also be found in patients with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy with partial cardiac MR imaging criteria, suggesting a potential role for the diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy in patients who would otherwise not meet current cardiac MR imaging criteria.

Myocyte loss with fibrotic and/or fibrofatty replacement is the pathologic hallmark of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy (3). However, the 2010 TFC Task Force Criteria do not support the use of either feature for the diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy. Study results have shown that fatty infiltration assessment in the RV right ventricle is subjective, lacking reproducibility and specificity (1720). In the North American Multidisciplinary Study of Right Ventricular Dysplasia (21), RV right ventricle fat was identified in 60% of probands and was less sensitive and specific than quantitative RV right ventricle measures for the diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy. In this study, RV right ventricle fat was found in 29% of subjects and was more common in those with severe RV right ventricle structural disease, occurring in 40% of subjects who met major cardiac MR imaging TFC Task Force Criteria versus in only 9% of those who did not meet cardiac MR imaging TFC Task Force Criteria. RV right ventricle fibrosis has a variable prevalence reported in the literature. In a study of 30 subjects who were suspected of having ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy, RV right ventricle LGE late gadolinium enhancement was found in 67% of those who were eventually given a diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy and in none of 18 subjects without the diagnosis (6). Marra et al (22) found RV right ventricle LGE late gadolinium enhancement in 39% of 23 subjects with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy. In contrast, we found RV right ventricle LGE late gadolinium enhancement in only 16% of our 76 subjects with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy, and it localized mostly to the inferior wall. RV right ventricle LGE late gadolinium enhancement was more often seen in probands than in family members and in those who met minor and major cardiac MR imaging TFC Task Force Criteria.

LV left ventricle fibrofatty changes are well described in ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy; however, they also play no role in the diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy. In one cohort from the United Kingdom, which included a relatively large number of patients with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy with a desmoplakin mutation (39 of 200), LV left ventricle abnormalities were seen in more than 80% of subjects (23). In our cohort of predominantly plakophilin 2 carriers, we found a lower prevalence of LV left ventricle changes, with fat and fibrosis in 30% and 33% of subjects, respectively. This discrepancy is likely at least partially accounted for by genetic differences between these groups (24). As with RV right ventricle fibrofatty changes, LV left ventricle findings increased with proband status and increasing RV right ventricle structural disease, seen in 48%–55% of subjects with major cardiac MR imaging TFC Task Force Criteria. Interestingly, LV left ventricle function was relatively preserved even in the major cardiac MR imaging TFC Task Force Criteria group (LVEF LV ejection fraction, 51.9% ± 7), with no significant differences in LVEF LV ejection fraction between the major, minor, partial, and no TFC Task Force Criteria groups at individual comparisons.

A significant portion (36%) of the ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy population in our study did not meet either major or minor cardiac MR imaging TFC Task Force Criteria; the majority of these subjects were revealed through family member screening. Importantly, family members with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy have a much lower prevalence of structural disease than probands (63% of family members showed no detectable RV right ventricle disease). Many family members fulfilled global TFC Task Force Criteria because of points from electrical and genetic criteria. This is not unexpected, given that these subjects generally have mild or even asymptomatic disease. These results support recent suggestions that electrical abnormalities precede structural abnormalities in ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy (9).

We hypothesized that in subjects not meeting cardiac MR imaging TFC Task Force Criteria, fatty infiltration and/or fibrosis might be early indicators of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy. Indeed, five (71.5%) of seven subjects with partial cardiac MR imaging criteria had LV left ventricle or RV right ventricle fatty infiltration and/or fibrosis. Of these five subjects, all demonstrated some degree of fatty infiltration, with two showing RV right ventricle involvement; two, LV left ventricle involvement; and one, a combination of both. LV left ventricle LGE late gadolinium enhancement was seen in two cases; however, none had RV right ventricle LGE late gadolinium enhancement. Given the very small sample size of the partial cardiac MR imaging criteria group, it is impossible to draw definitive conclusions about the significance of these non-TFC Task Force Criteria findings. However, of these features, we believe that LV left ventricle fat infiltration in particular merits further study. LV left ventricle LGE late gadolinium enhancement in a nonischemic pattern is nonspecific and can be seen in a multitude of cardiomyopathies, particularly sarcoidosis, which is known to mimic ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy (25). RV right ventricle LGE late gadolinium enhancement is challenging to identify given the limitations of the thin RV right ventricle wall. LV left ventricle fat infiltration, however, has not been described in other nonischemic cardiomyopathies, suggesting it could represent a specific, if not sensitive (seen in only 48% of subjects with major cardiac MR imaging criteria) marker for ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy. RV right ventricle fat infiltration in an ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy-type pattern may also have utility; however, further studies of reproducibility and specificity will be needed, given potential overlap with non-ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy conditions.

There were some limitations to our study. A minority of cases were from outside institutions with some variations in imaging technique. We excluded studies that did not include essential sequences. In addition, we had very small numbers of patients with minor cardiac MR imaging criteria (7) and with partial cardiac MR imaging criteria (7), which limits our ability to draw definitive conclusions. Our adherence to TFC Task Force Criteria limits application of conclusions to “left-dominant ARVC.” Fat can result in high signal on both FSE fast spin echo and LGE late gadolinium enhancement images; therefore, findings in the same location could represent fat or a combination of fat and fibrosis. Future studies involving fat-water separated Dixon techniques could be helpful to distinguish these features.

In conclusion, in subjects with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy, ventricular fatty infiltration and LGE late gadolinium enhancement are common, are associated with advanced RV right ventricle structural disease and proband status, and are seen in a minority of subjects with isolated regional RV right ventricle WMA wall-motion abnormalitys who do not completely fulfill current criteria. Although these findings are not part of current diagnostic criteria, our results suggest a need for further study to examine the potential additive utility of these findings, particularly LV left ventricle fat infiltration, which may have utility for the diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy.

Advances in Knowledge

  • ■ Ventricular fatty infiltration and late gadolinium enhancement are common: At least one of these features was found in 61% of all patients with arrhythmogenic right ventricular (RV right ventricle) dysplasia/cardiomyopathy (ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy).
  • ■ Fibrofatty changes had a higher prevalence in patients with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy, with more severe RV right ventricle structural disease, as reflected by fulfillment of cardiac MR imaging Task Force Criteria (TFC Task Force Criteria); RV right ventricle fat was seen in 39% of the subjects who met either major or minor cardiac MR imaging TFC Task Force Criteria, whereas it was not seen in any subjects who did not meet cardiac MR imaging TFC Task Force Criteria (P < .001).
  • ■ Probands with a diagnosis of ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy were significantly more likely to show ventricular fibrofatty changes than were subjects given a diagnosis on the basis of family-member screening results (76% vs 39%, P = .001).
  • ■ Fibrofatty changes were frequently seen in patients who only partially fulfilled TFC Task Force Criteria MR imaging criteria (71%).
  • ■ A unique pattern of subepicardial fat infiltration was found in the lateral wall of the left ventricle in patients with ARVD/C arrhythmogenic RV dysplasia/cardiomyopathy.

SUPPLEMENTAL TABLES

Tables E1–E3 (PDF)

Received May 13, 2015; revision requested July 3; revision received October 28; accepted November 3; final version accepted December 11.

1Current address: Division of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

H.C. supported by the Dr Francis P. Chiaramonte Private Foundation, St Jude Medical, and Medtronic. There was no industry support specifically for this study. The Johns Hopkins ARVD/C Program is supported by the Leyla Erkan Family Fund for ARVD Research, the Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments. D.A.B. is an employee of the National Institutes of Health Clinical Center.

Disclosures of Conflicts of Interest: N.R. disclosed no relevant relationships. A.S.J.M.T.R. disclosed no relevant relationships. C.A.J. Activities related to the present article: none to disclose. Activities not related to the present article: has received a grant from Boston Scientific. Other relationships: none to disclose. A.B. disclosed no relevant relationships. B.M. disclosed no relevant relationships. C.T. disclosed no relevant relationships. H.C. disclosed no relevant relationships. H.T. disclosed no relevant relationships. D.A.B. disclosed no relevant relationships. I.R.K. disclosed no relevant relationships. S.L.Z disclosed no relevant relationships.

Abbreviations:

ARVD/C
arrhythmogenic RV dysplasia/cardiomyopathy
FSE
fast spin echo
LGE
late gadolinium enhancement
LV
left ventricle
LVEF
LV ejection fraction
LVEDVI
LV end-diastolic volume index
LVESVI
LV end-systolic volume index
RV
right ventricle
RVEF
RV ejection fraction
RVEDVI
RV end-diastolic volume index
RVESVI
RV end-systolic volume index
TFC
Task Force Criteria
WMA
wall-motion abnormality

References

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