Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy According to Revised 2010 Task Force Criteria With Inclusion of Non-Desmosomal Phospholamban Mutation Carriers

doi:10.1016/j.amjcard.2013.06.017

The American Journal of Cardiology

Volume 112, Issue 8, 15 October 2013, Pages 1197-1206

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https://doi.org/10.1016/j.amjcard.2013.06.017 Get rights and content

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently associated with desmosomal mutations. However, nondesmosomal mutations may be involved. The aim of this study was to assess the contribution of a phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised 2010 task force criteria (TFC). In 142 Dutch patients (106 men, mean age 51 ± 13 years) with proven ARVD/C (fulfillment of 2010 TFC for diagnosis), 5 known desmosomal genes (PKP2, DSP, DSC2, DSG2, and JUP) and the nondesmosomal PLN gene were screened. After genetic analysis, phenotypic characteristics of desmosomal versus PLN mutation carriers were compared. In 59 of 142 patients with ARVD/C (42%), no desmosomal mutation was found. In 19 of 142 patients (13%), the PLN founder mutation c.40_42delAGA (p.Arg14del) was identified. PLN mutation carriers more often had low-voltage electrocardiograms (p = 0.004), inverted T waves in leads V₄ to V₆ (p <0.001), and additional structural (p = 0.007) or functional (p = 0.017) left ventricular impairment, whereas desmosomal mutation carriers had more solitary right ventricular abnormalities. The revised TFC included 21 of 142 patients with proven ARVD/C who did not meet the 1994 TFC, including 7 PLN mutation carriers. In conclusion, there is a substantial contribution of PLN mutation to ARVD/C diagnosis by the 2010 TFC. In 32% of patients (19 of 59) with genetically unexplained proven ARVD/C, this nondesmosomal mutation was found. PLN mutation carriers have ARVD/C characteristics, including important right ventricular involvement, and additionally more often low-voltage electrocardiograms, inverted T waves in the left precordial leads, and left ventricular involvement.

Section snippets

Methods

A total of 153 Dutch Caucasian ARVD/C index patients from 6 university centers (mean age 51 ± 14 years, 114 [75%] men) diagnosed according to the 2010 TFC or at autopsy were included.⁶ A subset of this cohort has been described in previous studies by Cox et al¹⁰ and van der Zwaag et al.¹⁶ An index patient was the first in the family diagnosed with ARVD/C in whom deoxyribonucleic acid (DNA) analysis was started. All patients consented to clinical and DNA evaluation.

The diagnostic process

Results

All 153 patients with proven (definite) ARVD/C underwent screening of desmosomal genes PKP2, DSP, JUP, DSG2, and DSC2. In 11 of 153 patients, additional screening of PLN was impossible because of insufficient DNA or lack of patient permission. Thus, 142 of 153 patients underwent screening of the desmosomal genes and the nondesmosomal PLN gene. Pathogenic desmosomal mutations were identified in 83 of 142 patients (58%; Table 1). Of 142 patients with proven AVRD/C, 19 (13%) carried the PLN

Discussion

ARVD/C is characterized by electrocardiographic alterations and ventricular arrhythmias in early stages, followed by structural and functional myocardial disease, and frequently sustained monomorphic ventricular tachycardias, in late overt stages. Histopathologically and functionally primarily RV (classic ARVD/C), LV, and biventricular forms exist, although at the level of intercalated disk protein expression and distribution, both ventricles are affected.4, 5 Because of overlap, discrimination

Acknowledgment

We thank Julien Tanniou for statistical analyses.

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Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.
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All participants were genetically tested for known ARVC-related pathogenic mutations: plakophilin-2, desmoglein-2, desmocollin-2, desmoplakin, and plakoglobin (5). Nondesmosomal analysis included transmembrane protein 43 and phospholamban (5,17). The following participants were eligible for this study: 1) first-degree relatives carrying the identical pathogenic ARVC mutation as identified in the probands; and 2) first-degree relatives of mutation-negative probands.
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ARVC is characterized by variable disease expressivity among family members, which complicates family screening protocols. Previous reports have shown that echocardiographic deformation imaging detects abnormal right ventricular (RV) deformation in the absence of established disease expression in ARVC.
First-degree relatives of patients with ARVC were evaluated according to 2010 task force criteria, including RV deformation imaging (n = 128). Relatives fulfilling structural task force criteria were excluded for further analysis. At baseline, deformation patterns of the subtricuspid region were scored as type I (normal deformation), type II (delayed onset, decreased systolic peak, and post-systolic shortening), or type III (systolic stretching and large post-systolic shortening). The final study population comprised relatives who underwent a second evaluation during follow-up. Disease progression was defined as the development of a new 2010 task force criterion during follow-up that was absent at baseline.
Sixty-five relatives underwent a second evaluation after a mean follow-up period of 3.7 ± 2.1 years. At baseline, 28 relatives (43%) had normal deformation (type I), and 37 relatives (57%) had abnormal deformation (type II or III) in the subtricuspid region. Disease progression occurred in 4% of the relatives with normal deformation at baseline and in 43% of the relatives with abnormal deformation at baseline (p < 0.001). Positive and negative predictive values of abnormal deformation were, respectively, 43% (95% confidence interval: 27% to 61%) and 96% (95% confidence interval: 82% to 100%).
Normal RV deformation in the subtricuspid region is associated with absence of disease progression during nearly 4-year follow-up in relatives of patients with ARVC. Abnormal RV deformation seems to precede the established signs of ARVC. RV deformation imaging may potentially play an important role in ARVC family screening protocols.
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Our results confirm recent observations in a cohort of 153 Dutch ACM patients and in a combined US and Dutch cohort of 577 patients. In these cohorts also, more LV involvement in patients with PLN mutations than in those with desmosomal mutations was found using electrocardiographic and imaging criteria (echocardiography, cardiac magnetic imaging, RV/LV cine-angiography).2,17 The segregation we found in fibrosis patterns suggests that different groups of mutations make the cardiomyocyte vulnerable for different stressors with potential damaging mechanisms that are not evenly distributed over the various regions of the myocardium.
Desmosomal and phospholamban (PLN) mutations are associated with arrhythmogenic cardiomyopathy. Ultimately, most cardiomyopathic hearts develop significant cardiac fibrosis.
To compare the fibrosis patterns of desmosomal and p. Arg14del PLN–associated cardiomyopathies with the pattern in hearts with other hereditary cardiomyopathies.
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Genetic factors influencing low penetrance and later-onset disease are not well understood,13 and endurance exercise as an environmental trigger may lead to variable onset of ARVC/D phenotype in these gene elusive patients.23 A significant age trend for nondesmosomal variants in this study complements the previous observation of later disease presentation in the PLN gene group.22,24 Our study suggests no significant trend in the occurrence of truncating or missense mutations with age in contrast to prior reports.25
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Late presentation was seen in 104 patients (21%; 38% PKP2 carriers); 3% were ≥65 years at diagnosis. Sustained ventricular tachycardia was the major (43%) mode of presentation in patients with late presentation, whereas cardiac syncope was infrequent (P <.001). Those with late presentation were significantly less likely to harbor a known pathogenic mutation (53%; P = .005), have less precordial T-wave repolarization changes (P <.001), and have lower ventricular ectopy burden (P = .026). Over median 6-year follow-up, 68 patients with late presentation (65%) experienced sustained ventricular arrhythmias, with similar arrhythmia-free survival at 5-year follow up (P = .48). Left ventricular dysfunction and heart failure were seen in 24 (32%) and 15 patients (14%), respectively, without need for cardiac transplantation. In the late presentation cohort, male sex, pathogenic mutation, right ventricular structural disease, lack of family history, and electrophysiologic study inducibility were associated with increased arrhythmic risk.
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Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity.

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: This study was supported by the Grants 2007B132 and 2007B139 from the Netherlands Heart Foundation, The Hague, The Netherlands; Project 06901 from the Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands; and Heart Lung Foundation Utrecht, Utrecht, The Netherlands.

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CardiomyopathyArrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy According to Revised 2010 Task Force Criteria With Inclusion of Non-Desmosomal Phospholamban Mutation Carriers

Section snippets

Methods

Results

Discussion

Acknowledgment

J Am Coll Cardiol

J Am Coll Cardiol

Am J Hum Genet

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Am J Hum Genet

Lancet

Am J Hum Genet

Semin Cell Dev Biol

Heart Rhythm

Right ventricular dysplasia: a report of 24 adult cases

Circulation

Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis?

Circulation

A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy

N Engl J Med

Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria

Circulation

Cardiomyopathy
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy According to Revised 2010 Task Force Criteria With Inclusion of Non-Desmosomal Phospholamban Mutation Carriers