Author + information
- Received July 8, 2008
- Revision received November 5, 2008
- Accepted December 3, 2008
- Published online April 14, 2009.
- Darshan Dalal, MD, MPH*,* (, )
- Harikrishna Tandri, MD*,
- Daniel P. Judge, MD*,
- Nuria Amat, MS*,
- Robson Macedo, MD†,
- Rahul Jain, MD*,
- Crystal Tichnell, MGC*,
- Amy Daly, MS*,
- Cynthia James, PhD, ScM*,
- Stuart D. Russell, MD*,
- Theodore Abraham, MD*,
- David A. Bluemke, MD, PhD‡ and
- Hugh Calkins, MD*
- ↵*Reprint requests and correspondence:
Dr. Darshan Dalal, 600 North Wolfe Street, Carnegie 592, Baltimore, Maryland 21209
Objectives The purpose of this study was to determine the extent of left ventricular (LV) involvement in individuals predisposed to developing arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and to investigate novel morphologic variants of ARVD/C.
Background The discovery of desmosomal mutations associated with ARVD/C has led researchers to hypothesize equal right ventricular (RV) and LV affliction in the disease process.
Methods Thirty-eight (age 30 ± 17 years; 18 males) family members of 12 desmosomal mutation-carrying ARVD/C probands underwent genotyping and cardiac magnetic resonance imaging (CMR). The CMR investigators were blinded to clinical and genetic data.
Results Twenty-five individuals had mutations in PKP2, DSP, and/or DSG2genes. RV abnormalities were associated with the presence of mutation(s) and with disease severity determined by criteria (minor = 1; major = 2) points for ARVD/C diagnosis. The only LV abnormality detected, the presence of intramyocardial fat, was present in 4 individuals. Each of these individuals was a mutation carrier, whereas 1 had no previously described ARVD/C-related abnormality. On detailed CMR, a focal “crinkling” of the RV outflow tract and subtricuspid regions (“accordion sign”) was observed in 60% of the mutation carriers and none of the noncarriers (p < 0.001). The sign was present in 0%, 37%, 71%, and 75% of individuals who met 1, 2, 3, and 4+ criteria points, respectively (p < 0.01).
Conclusions Despite a possible LV involvement in ARVD/C, the overall LV structure and function are well preserved. Independent LV involvement is of rare occurrence. The accordion sign is a promising tool for early diagnosis of ARVD/C. Its diagnostic utility should be confirmed in larger cohorts.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial cardiomyopathy characterized clinically by right ventricular (RV) dysfunction and ventricular tachycardia (1–4) and histopathologically by fibrofatty replacement of the myocardium (5). Recent literature has demonstrated the role of mutations in genes encoding cardiac desmosomal proteins such as desmoplakin, plakoglobin, plakophilin-2, and desmoglein-2 in the development of ARVD/C (6–17). Although ARVD/C has been considered primarily as a right-sided cardiomyopathy, the growing evidence supporting the desmosomal origin of ARVD/C has led investigators to hypothesize a concomitant or independent left ventricular (LV) involvement in these patients (18). The Task Force criteria that are widely applied to ascertain the diagnosis of ARVD/C were published in 1994 and were designed to specifically exclude LV disease (19).
The purpose of this study was 2-fold. First, our study was aimed at determining the presence and extent of LV involvement in individuals predisposed to developing ARVD/C. The hypothesis of the study was that family members carrying mutations in genes encoding desmosomal proteins would be equally likely to develop right- or left-sided cardiomyopathy. The secondary aim of the study was to identify the early morphologic variants of ARVD/C and to examine their incremental value in the diagnosis of ARVD/C. Cardiac magnetic resonance imaging (CMR), which has been developed as an important tool for the noninvasive evaluation of the disease, was used to ascertain the morphologic variants of both ventricles (20–23).
Patient recruitment, evaluation, and diagnosis
The study population was identified from the Johns Hopkins ARVD Registry. The Johns Hopkins ARVD Registry was established in 1999 with the goal of gaining insights into the diagnosis, genetic basis, and clinical course of patients with known or suspected ARVD/C. All patients included in this registry provided written informed consent to participate in clinical and research genetic screening. The study protocol was approved by the Johns Hopkins Medicine Institutional Review Board. As a routine protocol of the registry, after diagnosis of an ARVD/C patient, all family members of the patient are invited to undergo a screening protocol for ARVD/C. The screening protocol includes obtaining relevant medical history, noninvasive clinical testing for ascertainment of the Task Force criteria, and genetic sequencing to identify possible mutations in 1 or more genes encoding desmosomal proteins.
For the purpose of the present study, family members of probands with 1 or more mutations in genes encoding plakophilin-2 (PKP2), desmoplakin (DSP), and/or desmoglein-2 (DSG2), were included. The probands were only used for the purpose of identifying the family members, and were excluded in all further analyses. Families in which none of the family members underwent CMR were excluded.
Patients were evaluated as described previously (4). For each patient, medical history and family history were obtained. Subsequently, each patient underwent noninvasive clinical testing, including electrocardiogram, signal-averaged electrocardiogram, Holter monitoring, and CMR. Diagnosis of ARVD/C was established based on the criteria set by the Task Force of the Working Group of Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology (19).
A detailed CMR was performed for the entire study population irrespective of their genetic or clinical findings. CMRs were performed according to standard protocols for diagnosis of ARVD/C (22). All CMR datasets were obtained on a 1.5-T scanner (CV/i, GE Medical Systems, Waukesha, Wisconsin) and included both fast spin-echo and gradient-echo sequences. Fat- and nonfat-suppressed fast spin-echo sequences were acquired in the axial and short-axis planes with breath-hold double-inversion recovery blood suppression pulses. The repetition time was 1 or 2 R-R intervals, and the time to excitation was 10 ms. The slice thickness was 5 mm and slice gap 5 mm. The matrix and field of view were 256 × 256 and 24 cm, respectively. Gradient echo sequences were acquired in the axial and short-axis planes using breath-hold steady-state free precession imaging. The flip angle was 40°, and time to excitation was set to minimum. For steady-state free precession imaging, the slice thickness was 8 mm with a slice gap of 2 mm. The matrix and field of view were 256 × 160 and 36 cm, respectively. A phased array cardiac coil was used for all the studies. The datasets were transferred to an Advantage Windows workstation (GE Medical Systems) for analysis. Gadolinium-enhanced CMRs were reviewed for evidence of delayed enhancement in any of the RV or LV segments. After intravenous administration of a CMR contrast agent (0.2 mmol/kg of gadodiamide [Omniscan, Amersham Health, Princeton, New Jersey]), inversion recovery prepared breath-hold cine gradient-echo images were obtained 20 min after contrast agent injection. Breath-hold 2-dimensional imaging (7.2/3.2; inversion time optimized 150 to 200 ms; flip angle, 25°; slice thickness, 8 mm; slice gap, 2 mm; number of excitations, 2; matrix, 256 × 192; and field of view, 360 × 270 mm) scans were obtained in the short-axis and axial planes at 10-mm intervals covering the entire RV and LV.
Quantitative analysis was performed using the software program MASS (Medis, Leiden, the Netherlands). End-systolic image was defined visually as the one with the smallest ventricular cavity size and end-diastolic image, as the first image after the R-wave trigger. Quantitative CMR parameters included end-systolic volume (ESV), end-diastolic volume (EDV), and ejection fraction (EF) of both ventricles.
For qualitative assessment, the RV was divided into 4 regions: 1) base; 2) mid-cavity; 3) apex; and 4) right ventricular outflow tract (RVOT). The LV was divided into 4 regions based on the 17-segment model (24), so that segments 1 to 6 represented the base, segments 7 to 12 represented the midcavity, segments 13 to 16 represented the apical region, and segment 17 represented the apex. Qualitative CMR parameters included globally impaired function, hypokinesia/akinesia, intramyocardial fat, and delayed enhancement of both ventricles.
Each segment of both ventricles was carefully examined to determine the presence of typical (Online Appendix) and novel morphologic variants in both ventricles. The CMR reader was blinded to other clinical and genetic data for all patients.
For each ARVD/C proband, genomic deoxyribonucleic acid (DNA) was extracted from leukocytes present in whole blood using QIAmp DNA blood maxi kits (Qiagen, Inc., Valencia, California). Amplification of exons on either side of DSP, PKP2, and DSG2was performed as previously described, with primer sequence (8,11–13,17,25). Bidirectional sequence chromatography was performed using an Applied Biosystems 3730 DNA Analyzer (Foster City, California). Analysis of chromatograms was performed using Sequencher 4.2.2 (Gene Codes Corp., Ann Arbor, Michigan). Novel mutations were analyzed in a population of 200 individuals (400 chromosomes) from a panel of unrelated unaffected individuals. Control DNA was obtained from the National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository through the Coriell Institute for Medical Research, and the controls were matched to the mutation carriers by ancestry. Novel sequence variants were characterized as mutations only if they were absent in the unaffected controls and also disrupted amino acids, which are highly conserved.
All consenting family members were tested for the presence or absence of the mutation identified in the family proband. Again, DNA was extracted from leukocytes present in whole blood and subjected to focused bidirectional sequence analysis using methods described in the preceding text.
Correlation between CMR and genotype
Based on the presence of mutation(s) in 1 or more genes encoding desmosomal proteins, the study population was divided into 2 distinct groups: 1) family members with a mutation; and 2) family members without a mutation. CMR characteristics were compared between these subgroups.
Correlation between CMR and Task Force criteria
The study population was divided into subgroups based on the fulfillment of the Task Force criteria. One “criteria point” was given for fulfillment of each minor criterion, and 2 criteria points were given for fulfillment of each major criterion. Thus, ARVD/C diagnosis, according to the Task Force definition, was made if an individual had 4 or more criteria points. The presence of CMR characteristics was examined in relation to the criteria points achieved. As family history may provide either a major or a minor criterion regardless of any other abnormality, total criteria points excluding family history were also calculated for each individual in the study population.
All continuous variables were expressed as mean ± SD and all categorical variables as frequency (%). Comparisons in continuous variables between subgroups of patients were performed by ttest. Categorical variables were compared by the chi-square test or Fisher exact test. Criteria points were treated as nominal variables for comparison between groups.
Receiver-operating characteristic (ROC) curve analysis was used to examine the discriminatory ability of the Task Force criteria in identifying patients with a desmosomal mutation. The presence of a desmosomal mutation was used as a “gold standard” for this analysis. The area under the ROC curve was computed using the criteria points as described above on a continuous scale ranging between 0 and 7. The area under the ROC curve was computed again after incorporating the new CMR findings into the current Task Force criteria. The 2 areas under the curves were compared to examine the improvement in the discriminatory ability of the Task Force criteria after the addition of the new findings (26).
All statistical analyses were performed using STATA statistical software (version 8.2, Stata Corp., College Station, Texas). A value of p < 0.05 was considered statistically significant.
Demographics, baseline characteristic, and genotyping
The study population was composed of 38 family members from 12 families. The proband of each family was diagnosed with ARVD/C based on the Task Force criteria and carried 1 or more mutations in the desmosomal proteins PKP2, DSP, and/or DSG2. Table 1shows the details of genetic mutations present in the study population. Each of the enlisted PKP2mutations detected in our study population has been reported previously (11,12,16,25,27). In addition, there were 2 novel mutations detected in 4 individuals. A novel mutation in DSG2, V56M, was detected in an individual carrying the 2146-1G>C mutation in PKP2. Two other family members of this individual included in this study did not carry the DSG2mutation but had 2 distinct PKP2mutations (2146-1G>C and S140F). The proband (excluded from the study as described in the Methods section) who is the father of these 3 individuals carried both the PKP2mutations as well as the DSG2mutation. Another novel mutation detected in this study was the DSPS986P, which was present in 3 individuals from 1 family. One of these individuals was diagnosed with ARVD/C (4 criteria points), and another individual had 3 criteria points for ARVD/C diagnosis. None of the individuals from 3 families (other than the proband) carried a desmosomal mutation. Overall, 25 (66%) of 38 family members had 1 or more desmosomal mutations, and 13 (34%) had no detectable desmosomal mutation.
Table 2shows the demographics and symptoms present at the time of screening in the study population. Although none of these family members had sought medical advice for these symptoms earlier, 9 individuals had prior cardiac symptoms. Palpitations were more commonly present in patients with a mutation compared to those without (p < 0.05). The number of criteria points achieved by patients with mutation(s) was greater than those achieved by patients without the mutation(s) (p < 0.05).
As shown in Table 2, 4 (11%) family members met an adequate set of criteria (4 criteria points or greater) to establish ARVD/C diagnosis. All 4 of these individuals carried a desmosomal mutation. All 13 individuals without a mutation achieved 2 criteria points or fewer. In fact, barring the criteria for family history (which all individuals in this study population fulfill), only 1 of these 13 individuals achieved a criteria point.
Table 3shows the electrophysiologic and structural characteristics, as determined by noninvasive testing, used to ascertain the fulfillment of the Task Force criteria. The presence of T-wave inversions in right precordial leads on a 12-lead electrocardiogram in individuals with a desmosomal mutation was significantly higher than that in individuals without a mutation (p < 0.05). Similarly, the presence of RV wall motion abnormalities in individuals with a mutation appeared to be higher than that in individuals without a mutation (p < 0.1).
Morphologic variants of RV and LV by CMR
Detailed CMR findings of individuals included in the study are presented in Tables 4 and 5.⇓⇓CMR findings were compared between individuals with a desmosomal mutation and those without (Table 4), between individuals who met ≥3 criteria points and those with fewer criteria points (Table 5), and finally, between individuals with ≥1 criteria point other than family history and those with no criteria points other than family history (Table 5). Individuals with 1 criteria point other than family history (n = 13) represent those individuals with any ARVD/C-related structural or electrical abnormality.
Right- versus Left-Sided Disease
As shown in Table 4, there was a significantly reduced RVEF among individuals with a desmosomal mutation compared with those without a mutation. RVESV, EDV, and prevalence of quantitative parameters such as impaired global function, hypokinesia/akinesia, intramyocardial fat, and delayed enhancement were higher in individuals with a desmosomal mutation compared with those without. The lack of statistical significance when comparing these parameters is likely due to the small sample size.
On comparing the RV qualitative and quantitative parameters between individuals with ≥3 criteria points and those with fewer criteria points (Table 5), significant differences were observed in almost all qualitative parameters and all quantitative parameters. Individuals with ≥3 criteria points had reduced EF, increased ESV and EDV, and a higher prevalence of qualitative abnormalities such as globally impaired function, the presence of intramyocardial fat (Online Appendix), and delayed enhancement (Online Appendix).
Finally, on comparing the RV qualitative and quantitative parameters between individuals with ≥1 criteria points and those with fewer criteria points (Table 5) excluding family history, significant differences were observed in several qualitative and quantitative parameters. Individuals with ≥1 criteria points excluding family history had reduced EF, increased ESV, and a higher prevalence of qualitative abnormalities such as globally impaired function, the presence of intramyocardial fat, and delayed enhancement.
In contrast to the differences in the RV characteristics, the LV features (other than the presence of intramyocardial fat in 4 individuals with a desmosomal mutation) were remarkably similar when compared between subgroups based on mutation-carrier status (Table 4), the presence of ≥3 criteria points (Table 5), and the presence of ≥1 criteria point excluding family history. The only notable feature in all of these comparisons was the presence of intramyocardial LV fat, which was present in 4 individuals in the study population. Interestingly, each of these 4 individuals carried a desmosomal mutation. Although no statistically significant difference was noted when comparing between mutation carriers and noncarriers (p = 0.279), the presence of intramyocardial LV fat showed a tendency to correlate with presence of ≥3 criteria points (p = 0.065). Three of the 4 individuals had clinical characteristics that would qualify as criteria points: 2 were diagnosed with ARVD/C with 5 and 6 criteria points, respectively, and 1 had 3 criteria points. One individual with the presence of intramyocardial LV fat had no abnormality that would qualify as a major or minor criterion.
The Accordion Sign
While studying the cine images of the heart in an axial plane, a peculiar characteristic in the contraction pattern of the RV wall was observed in 15 of the 38 individuals in the study population. In each of these 15 individuals, the RVOT and/or the subtricuspid region of the RV free wall showed a characteristic focal “crinkling,” which became more prominent during the systole (Fig. 1,Online Videos 1and 2). Although this finding is not a normal variant of RV morphology (28), it did not affect the global RV function. The presence of this abnormality did not result in global RV dilation or wall motion abnormality, and neither did it qualify as a focal RV aneurysm (20,22,29). We have chosen to refer to this as the accordion sign.
Interestingly, each of the 15 individuals with the accordion sign had a desmosomal mutation. In fact, the accordion sign was the most prevalent qualitative abnormality (60%) in individuals with desmosomal mutations, and its prevalence was significantly higher when compared with those without a mutation (0%) (p < 0.001). The presence of the accordion sign was higher in individuals with ≥3 criteria points (73%) compared with those with fewer criteria points (26%) (p < 0.05). Similarly, presence of the accordion sign was higher in individuals with ≥1 criteria point excluding family history (70%) compared with those with no criteria points other than family history (24%) (p < 0.05). Prevalence of the accordion sign showed a clear increasing trend with disease severity, as determined by the number of criteria points achieved (Fig. 2).
Because of the association of the accordion sign with mutation status as well as disease severity, further analysis was undertaken to examine the utility of this novel marker in identifying early disease. Table 6shows the ability of the Task Force criteria to discriminate individuals with an ARVD/C-related mutation from those without one. The discriminatory ability is quantitatively measured by the area under the ROC curve statistic. This statistic represents the probability that the Task Force criteria assign a higher value (in terms of number of criteria points) to mutation carriers than to noncarriers.The value of this statistic can range between 0 and 1, with 0.5 indicating the inability of the Task Force criteria to identify mutation carriers from noncarriers and 1 indicating a perfect ability to distinguish them. Values <0.5 are indicative of identification of mutation carriers as noncarriers and vice versa. As shown in Table 6, the discriminatory ability of the Task Force criteria, both including (0.68 [95% confidence interval (CI): 0.54 to 0.83] to 0.79 [95% CI: 0.73 to 0.94]; p < 0.01) and excluding family history (0.71 [95% CI: 0.60 to 0.83] to 0.84 [95% CI: 0.73 to 0.94]; p < 0.01), improved significantly after including the presence of the accordion sign as a minor criterion under Structural Abnormalities.
A number of additional analyses (results not shown) were performed to ensure reliability and validity of the results. First, all analyses for EDV, ESV, and EF were repeated after obtaining values adjusted for body surface area, and similar results were noted. Second, all CMRs were reviewed for the presence of the accordion sign at 2 different time points, 2 weeks apart, and blinded to the initial results. All individuals identified as positive for the accordion sign at the first reading were detected as positive on the second reading. No individual who was labeled as negative for the accordion sign at the first reading was detected as positive on the second reading. Third, CMRs of the probands of families included in this study were evaluated for the presence of the accordion sign, and all probands were found to be positive for the sign. In fact, in the more advanced cases, the sign appeared to become more synonymous with RV free wall aneurysms, suggesting that the accordion sign may be a precursor of aneurysms. And finally, CMRs of 20 randomly selected disease-free individuals were evaluated for the presence of the accordion sign, and none of these individuals were positive for the sign (29).
In a unique and an unbiased population of family members of ARVD/C patients undergoing prospective evaluation for ARVD/C diagnosis, detailed examination of RV and LV morphologies was performed using the sophisticated CMR techniques. Although the RV of the mutation carriers in the study population was significantly affected compared with noncarriers, the LV was affected less frequently. Despite a single case with no other abnormality, individuals with LV involvement had other signs suggestive of ARVD/C. Moreover, the LV involvement appeared to correlate with increasing disease severity as determined by the presence of criteria points achieved.
Detailed CMR imaging of the RV free wall revealed a potential novel indicator of ARVD/C, and its utility in identifying individuals predisposed to developing ARVD/C was systematically evaluated. The accordion sign was not only the strongest qualitative indicator differentiating mutation carrying family members from noncarriers but was also associated with increasing disease severity. Addition of this sign as a minor criterion significantly improved the diagnostic utility of the currently used Task Force criteria for ARVD/C diagnosis.
LV involvement in ARVD/C
ARVD/C was first described as a clinical entity in 1977 by Fontaine et al. (30), and the detailed clinical characteristics in a group of 24 ARVD/C patients were first reported by Marcus et al. in 1982 (1). These pioneers of ARVD/C research and other investigators established ARVD/C as a cardiomyopathy predominantly affecting the RV, and left-sidedness was considered as a late manifestation of the disease. Consequently, the Task Force criteria for ARVD/C diagnosis that were proposed in 1994 were designed to assign a criterion for structural disease to individuals with structural RV impairment and “no (or only mild) LV impairment” (19). The ensuing clinical description of ARVD/C characteristics in several large cohorts relied on inclusion of patients who fulfilled the Task Force criteria and therefore resulted in the under-representation of “left-sided arrhythmogenic cardiomyopathy,” if such an entity in fact existed (3,4,31,32). Long-term follow-up in large cohorts selected on the basis of fulfillment of the Task Force criteria has demonstrated LV involvement at the advanced stages of disease progression (3,4). This finding is consistent with those demonstrated by Corrado et al. (33) in a series of hearts from ARVD/C patients examined on autopsy or transplant.
More recently, ARVD/C has been shown to be a disease of the cardiac desmosome (34). As the desmosomal structure is similar on the right and the left side of the heart, the existence of left-sided arrhythmogenic cardiomyopathy has been hypothesized. Three studies investigating the RV and LV characteristics in relation to the presence of desmosomal mutations are particularly noteworthy. Bauce et al. (8) reported their echocardiographic findings in 26 DSPmutation carriers among 38 individuals from 4 families. Of the 14 individuals with an abnormal echocardiogram, 13 had RV involvement and 7 had LV involvement. RVEF and RVEDV were similar (or slightly worse) in patients with LV involvement, and only 1 individual had an abnormal LV with no abnormalities detected in the RV. In a subgroup of 22 mutation carriers among 28 genotyped individuals who underwent CMR with delayed enhancement, Sen-Chowdhry et al. (35) reported LV delayed enhancement in 100% of the mutation carriers. In the same study, 54% of the mutation carriers were reported to have LV systolic dysfunction. Subsequently, the same group reported LV involvement in 85% and predominantly left-sided disease in 15% of the 39 desmosomal mutation carriers (18). Similar LV involvement was reported in a larger cohort of 200 desmosomal mutation carrying and noncarrying individuals. Selection of the study population relied on fulfillment of the Task Force and the “modified criteria.”
Similar to the reports by Sen-Chowdhry et al. (35), our study utilized state-of-the-art CMR protocols to characterize myocardial tissue as well as fat and fibrosis. Consistent with their findings, the RV and LV function, as determined by EDV and EF, was relatively preserved in our study population regardless of the mutation carrier status. However, the qualitative findings of our study sharply contrast with those of Sen-Chowdhry et al. (35). The frequency of each qualitative characteristic of ARVD/C in the RV and LV was substantially lower in our study population. The most notable was the absence of LV delayed enhancement in any individuals in our study population as opposed to nearly all individuals in their report. The only qualitative LV abnormality noted in our study population was the presence of LV intramyocardial fat in 4 mutation carriers. The left-sidedness of the disease demonstrated by our study is somewhat similar to that reported by Bauce et al. (8). The results of both studies demonstrate LV involvement in a small fraction of family members of ARVD/C patients that are more predisposed to developing the disease (as determined by mutation-carrier status). In both studies, there was only 1 individual with an LV abnormality on imaging who demonstrated no other ARVD/C-related abnormality.
There are several possible reasons for these observed differences between our results and those reported by Sen-Chowdhry et al. (18) among individuals selected based on fulfillment of Task Force criteria and the “modified criteria.” First, our study design was leveraged by a systematic inclusion of family members of ARVD/C patients who would have otherwise not sought medical attention. This method of selection of the study population ensured the inclusion of individuals who would be equally likely to develop RV and LV abnormalities. It has been previously shown that ARVD/C is a gradually progressive disease, and there can be a substantial lag time between the initial signs of the disease and diagnosis based on the Task Force criteria (4). It is likely that individuals with a Task Force diagnosis, as was the case in the study by Sen-Chowdhry et al. (18), would have substantially more advanced disease compared with family members undergoing prospective clinical and genetic screening. If the LV were involved at advanced stages of the ARVD/C as proposed initially, then there would have been an over-representation of such cases in their study population. Second, although the inclusion of individuals who fulfill the modified Task Force criteria ensures inclusion of early cases of ARVD/C, it may have resulted in a loss of specificity with inclusion of patients with other types of cardiomyopathies. For example, under the proposed modified criteria, an individual with a family history of ARVD/C with 200 ventricular ectopics would qualify for an ARVD/C diagnosis (32). And a final potential explanation for the differing results between the 2 studies is reflected in the differing frequencies of desmosomal mutations in the 2 study samples. While a majority of individuals in the study by Sen-Chowdhry et al. (18) had a DSPmutation, the most common desmosomal mutation in our study population was in PKP2. The mechanism by which each of these desmosomal proteins results in ARVD/C is largely unknown, and it is possible that these genes affect the 2 ventricles differentially.
The low prevalence of LV involvement observed in our study population does not rule out the possibility of LV involvement at early stages of ARVD/C, but it underscores the low possibility of such occurrence. In fact, the presence of desmosomal mutation(s) in each of the 4 individuals with LV involvement substantiates such a possibility. Consistent with the report by Bauce et al. (8), each of these 4 individuals had inferior lead T-wave inversion on a 12-lead electrocardiogram.
Minimal LV involvement is also consistent with animal models of ARVD/C. Basso et al. (36) studied the characteristics of ARVD/C in 23 boxer dogs and found histopathologic evidence of the disease in the LV of 11 dogs. LV involvement independent of RV involvement was not reported in any of the animals. Subsequently, Oxford et al. (37) confirmed and extended these findings in a group of 12 ARVD/C boxer dogs. Although immunochemical analysis of intercalated disc proteins in the heart tissue of these dogs revealed a loss of the spatial organization of the molecular components in both RV and LV, the overall myocardial architecture in the LV was better preserved compared with the RV, which showed remarkable fibrofatty replacement. Kaplan et al. (38,39) have proposed that disruption of cell-to-cell coupling between the adjacent myocytes may precede fibro-fatty replacement. In this regard, the RV wall, which is thinner and more susceptible to mechanical stress, is more likely to get affected compared with the LV. Finally, Kirchhof et al. (40) demonstrated that the RV and not the LV was significantly affected in plakoglobin-deficient mice. The LV size and function remained preserved despite endurance training in these mice. Studies in humans, which rely on imaging in vivo rather than detailed histopathology and immunochemistry, are likely to detect even less evidence of morphologic alterations as described by these studies.
The accordion sign
Detailed CMR study of the RV free wall revealed the presence of a new morphologic variant, which is associated with the presence of desmosomal mutations as well as disease severity. Marcus et al. (1), in their initial observational study of 24 patients, specifically identified 3 major regions of the RV that were affected earliest by ARVD/C. These 3 areas, collectively known as the triangle of dysplasia, constituted the inferior tricuspid, the outflow tract, and the apical areas of the RV. The presence of the accordion sign in the inferior tricuspid and basal RV is consistent with these areas conventionally known to be the most affected.
The majority of the mutations reported in this study have been previously reported to cosegregate with ARVD/C (14,27). The novel DSPmutation reported in this study cosegregated with ARVD/C among 2 individuals within a family, and the novel DSG2mutation was present in an individual who already had a detrimental PKP2mutation. Although these mutations appear to have a low penetrance when ARVD/C is diagnosed by the Task Force criteria (12), there is a much higher probability of mutation carriers having ARVD/C-related abnormalities resulting in an incomplete set of Task Force criteria (8,14). The presence of these mutations can therefore be used as a surrogate for the high probability of individuals developing the disease. The accordion sign was the single most consistent qualitative feature that could identify mutation carriers with a sensitivity of 60% and 100% specificity. The association between the accordion sign and the presence of any criterion other than family history highlights its importance as an early sign of the disease. Incorporation of the accordion sign also significantly improves the discriminatory ability of the current Task Force criteria in identifying desmosomal mutation carriers. The readers of CMR studies were blinded to the clinical and genetic data and were unlikely to be biased by such results.
Studies on ARVD/C, in particular the genetic studies, are typically small in size. Our study sample may have been underpowered to detect certain morphologic differences between mutation carriers and noncarriers. Moreover, the relatively low prevalence of DSG2and the DSPmutation restricted our ability to compare the morphologic variants by the gene(s) involved. We were also unable to make comparisons by severity of the desmosomal mutations. Finally, our results demonstrate the incremental value of CMR in predicting a desmosomal mutation or the presence of the Task Force criteria and not the ARVD/C phenotype.
The results of our study underscore the ability of CMR to detect early morphologic changes in ARVD/C. ARVD/C associated with desmosomal mutations can involve both the right and the left side of the heart. Despite LV involvement, the overall structure and function is well preserved in the early stages of the disease. Independent LV involvement is a rare occurrence and is consistent with the traditional notion that right-sided disease precedes left-sided disease in the majority of the cases. The accordion sign is a possible early morphologic variant of ARVD/C and is a promising tool for early diagnosis of the disease. Its prevalence and diagnostic utility should be confirmed in larger cohorts of (genotyped and nongenotyped) ARVD/C patients. Objective methods to assess its presence using techniques such as myocardial tagging should be developed.
The authors are grateful to the ARVD patients and families who have made this work possible.
For supplementary figures and videos with legends, please see the online version of this article.
Morphologic Variants of Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: A Genetics - Magnetic Resonance Imaging Correlation Study
The Johns Hopkins ARVD Program is supported by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, and Healing Hearts; this work was also supported by grants from the Donald W. Reynolds Foundation; and the W.W. Smith Charitable Trust. Dr. Abraham has received honoraria and research support from GE Healthcare. Dr. Tandri is supported by a grant from the National Heart, Lung, and Blood Institute (HL093350). Drs. Dalal and Tandri contributed equally to this work.
- Abbreviations and Acronyms
- arrhythmogenic right ventricular dysplasia/cardiomyopathy
- cardiac magnetic resonance imaging
- end-diastolic volume
- ejection fraction
- end-systolic volume
- left ventricle/ventricular
- receiver-operating characteristic
- right ventricle/ventricular
- right ventricular outflow tract
- Received July 8, 2008.
- Revision received November 5, 2008.
- Accepted December 3, 2008.
- American College of Cardiology Foundation
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