Arrhythmogenic Cardiomyopathy—Further Insight into the Clinical Spectrum of Desmoplakin Disease

Arrhythmogenic cardiomyopathy is a familial heart muscle disease characterized by structural, electrical, and pathological abnormalities. Recognition of left ventricular (LV) involvement in arrhythmogenic right ventricular cardiomyopathy (ARVC) has led to the newer term of arrhythmogenic cardiomyopathy (ACM). We report on a family with autosomal dominant desmoplakin (DSP) related ACM to illustrate the broad clinical spectrum of disease. The importance of evaluation of relatives with cardiac magnetic resonance imaging and consideration of genetic testing in the absence of Task Force diagnostic criteria is discussed. The practical and ethical issues of access to the Guthrie collection for deoxyribonucleic acid (DNA) testing are considered.

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Left Side Right Ventricular Cardiomyopathy

Medicine Science and the Law ◽

10.1177/002580240204200406 ◽

2002 ◽

Vol 42 (4) ◽

pp. 313-317 ◽

Cited By ~ 33

Author(s):

M Michalodimitrakis ◽

A Papadomanolakis ◽

J Stiakakis ◽

K Kanaki

Keyword(s):

Right Ventricular ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Left Ventricular ◽

Muscle Disease ◽

Pathologic Examination ◽

Arrhythmogenic Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

First Case ◽

Fibrofatty Tissue ◽

Myocardial Muscle

Arrhythmogenic right ventricular cardiomyopathy or dysplasia, a heart muscle disease of unknown cause, is anatomically characterized by variable replacement of myocardial muscle with adipose or fibroadipose tissue. It is usually considered a selective disorder whereas concomitant left ventricular involvement has been noted in a few cases. Two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination are described. Hearts from two patients who died suddenly showed extensive biventricular infiltration by fibrofatty tissue in the first case and exclusively in the wall of the left ventricle the localization of the fatty and fibrotic lesions. These findings might suggest that the various localizations of the fibroadipose tissue are rather different expressions of the same disease and it is preferable to be termed ‘arrhythmogenic cardiomyopathy’ as other studies also indicate.

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Abstract 15314: Left Ventricular Dysfunction in Children and Adolescents With Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation ◽

10.1161/circ.132.suppl_3.15314 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Paweena Chungsomprasong ◽

Robert Hamilton ◽

Wietske Luining ◽

Shi-Joon Yoo ◽

Meena Fatah ◽

...

Keyword(s):

Right Ventricular ◽

Task Force ◽

Myocardial Dysfunction ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Myocardial Strain ◽

Young Patients ◽

Left Ventricular ◽

Lv Function ◽

Ventricular Cardiomyopathy ◽

End Diastolic Volume

Background: Involvement of the left ventricle (LV) is increasingly recognized in adults with arrhythmogenic right ventricular cardiomyopathy (ARVC) but it is unclear whether LV function is compromised in children with this condition. The aim of this study was examine myocardial contractility in pediatric patients with suspected ARVC. Methods: For this retrospective study, patients with a work-up for ARVC were classified into ‘no’, ‘possible’, ‘borderline’ or ‘definite’ ARVC according to the revised Task Force Criteria (rTFC). Ventricular size and function as well as LV myocardial strain and torsion were measured by cardiac magnetic resonance (CMR). Results: A total of 142 patients were enrolled, of whom 58 (41%) had no, 32 (23%) possible, 29 (20%) borderline and 23 (16%) definite ARVC. The groups were similar in age at CMR. With higher rTFC score, z scores (Z) of right ventricular (RV) ejection fraction (EF) were lower (p<0.001) while z-RV end diastolic volume (EDV) and z-LV EDV were larger (p=0.002 and 0.013, respectively). LV EF did not differ between rTFC categories. Global circumferential strain (GCS) of the LV was lower in patients in higher rTFC categories (p=0.018). Z-LVEDV correlated with z-RVEDV (r2 = 0.69, p<0.001) and z- LVEF correlated with z-RVEF (r2 = 0.55, p <0.001). Z-LVEF and z-RVEF correlated with LV GCS (r2 = 0.48, p<0.001 and r2 = 0.46, p<0.001, respectively) and torsion (r2 = 0.21, p=0.032 for both). Forty-two patients had a follow-up CMR, after a median interval of 2.6 years (0.4- 8.4). The rate of deterioration of LV or RV EF or EDV did not differ between rTFC categories. A more rapid increase of z-RVEDV was associated with a faster decline in z-RVEF (r2 = -0.383, p=0.004) and z-LVEF (r2 = -0.45, p=0.001). A decline of z-LVEF over time correlated with that of z-RVEF (r2 = 0.60, p<0.001) and z-LVEDV increase correlated with z-RVEDV increase (r2 = 0.84, p<0.001). Conclusion: LV myocardial dysfunction is present in young patients with suspected or confirmed ARVC. Quantification of myocardial mechanics with CMR may be a useful tool to detect early LV involvement in ARVC. Progressive LV dysfunction and enlargement appear to parallel those of the RV.

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Characteristics of Patients With Arrhythmogenic Left Ventricular Cardiomyopathy

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.120.009005 ◽

2020 ◽

Vol 13 (12) ◽

Author(s):

Michela Casella ◽

Alessio Gasperetti ◽

Rita Sicuso ◽

Edoardo Conte ◽

Valentina Catto ◽

...

Keyword(s):

Late Gadolinium Enhancement ◽

Right Ventricular ◽

Genetic Variants ◽

Task Force ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Left Ventricular ◽

Ventricular Cardiomyopathy ◽

Gadolinium Enhancement ◽

Voltage Mapping ◽

Fatty Replacement

Background: Arrhythmogenic left ventricular cardiomyopathy (ALVC) is an under-characterized phenotype of arrhythmogenic cardiomyopathy involving the LV ab initio. ALVC was not included in the 2010 International Task Force Criteria for arrhythmogenic right ventricular cardiomyopathy diagnosis and data regarding this phenotype are scarce. Methods: Clinical characteristics were reported from all consecutive patients diagnosed with ALVC, defined as a LV isolated late gadolinium enhancement and fibro-fatty replacement at cardiac magnetic resonance plus genetic variants associated with arrhythmogenic right ventricular cardiomyopathy and of an endomyocardial biopsy showing fibro-fatty replacement complying with the 2010 International Task Force Criteria in the LV. Results: Twenty-five patients ALVC (53 [48–59] years, 60% male) were enrolled. T wave inversion in infero-lateral and left precordial leads were the most common ECG abnormalities. Overall arrhythmic burden at study inclusion was 56%. Cardiac magnetic resonance showed LV late gadolinium enhancement in the LV lateral and posterior basal segments in all patients. In 72% of the patients an invasive evaluation was performed, in which electroanatomical voltage mapping and electroanatomical voltage mapping-guided endomyocardial biopsy showed low endocardial voltages and fibro-fatty replacement in areas of late gadolinium enhancement presence. Genetic variants in desmosomal genes (desmoplakin and desmoglein-2) were identified in 12/25 of the cohort presenting pathogenic/likely pathogenic variants. A definite/borderline 2010 International Task Force Criteria arrhythmogenic right ventricular cardiomyopathy diagnosis was reached only in 11/25 patients. Conclusions: ALVC presents with a preferential involvement of the lateral and postero-lateral basal LV and is associated mostly with variants in desmoplakin and desmoglein-2 genes. An amendment to the current International Task Force Criteria is reasonable to better diagnose patients with ALVC.

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Restrictive cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy

10.1093/med/9780198726012.003.0044 ◽

2016 ◽

Author(s):

Perry Elliott ◽

Kristina H. Haugaa ◽

Pio Caso ◽

Maja Cikes

Keyword(s):

Right Ventricular ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Restrictive Cardiomyopathy ◽

Left Ventricular ◽

Muscle Disease ◽

Left Ventricular Volumes ◽

Ventricular Cardiomyopathy ◽

Ventricular Wall Thickness ◽

Muscle Disorder ◽

Desmosomal Protein

Restrictive cardiomyopathy is a heart muscle disorder characterized by increased myocardial stiffness that results in an abnormally steep rise in intraventricular pressure with small increases in volume in the presence of normal or decreased diastolic left ventricular volumes and normal ventricular wall thickness. The disease may be caused by mutations in a number of genes or myocardial infiltration. Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac muscle disease associated with sudden cardiac death, ventricular arrhythmias, and cardiac failure. It is most frequently caused by mutations in desmosomal protein genes that lead to fibrofatty replacement of cardiomyocytes, right ventricular dilatation, and aneurysm formation.

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Evolving Diagnostic Criteria for Arrhythmogenic Cardiomyopathy

Journal of the American Heart Association ◽

10.1161/jaha.121.021987 ◽

2021 ◽

Vol 10 (18) ◽

Author(s):

Domenico Corrado ◽

Alessandro Zorzi ◽

Alberto Cipriani ◽

Barbara Bauce ◽

Riccardo Bariani ◽

...

Keyword(s):

Cardiac Magnetic Resonance ◽

Late Gadolinium Enhancement ◽

Magnetic Resonance ◽

Right Ventricular ◽

Task Force ◽

Left Ventricular ◽

Arrhythmogenic Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

Gadolinium Enhancement ◽

New Criteria

Abstract Criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) were first proposed in 1994 and revised in 2010 by a Task Force. Although the Task Force criteria demonstrated a good accuracy for diagnosis of the original right ventricular phenotype (arrhythmogenic right ventricular cardiomyopathy), they lacked sensitivity for identification of the expanding phenotypic spectrum of ACM, which includes left‐sided variants and did not incorporate late‐gadolinium enhancement findings by cardiac magnetic resonance. The 2020 International criteria (“Padua criteria”) have been developed by International experts with the aim to improve the diagnosis of ACM by providing new criteria for the diagnosis of left ventricular phenotypic features. The key upgrade was the incorporation of tissue characterization findings by cardiac magnetic resonance for noninvasive detection of late‐gadolinium enhancement/myocardial fibrosis that are determinants for characterization of arrhythmogenic biventricular and left ventricular cardiomyopathy. The 2020 International criteria are heavily dependent on cardiac magnetic resonance, which has become mandatory to characterize the ACM phenotype and to exclude other diagnoses. New criteria regarding left ventricular depolarization and repolarization ECG abnormalities and ventricular arrhythmias of left ventricular origin were also provided. This article reviews the evolving approach to diagnosis of ACM, going back to the 1994 and 2010 International Task Force criteria and then grapple with the modern 2020 International criteria.

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Left Ventricular Dysfunction in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): Can We Separate ARVC From Other Arrhythmogenic Cardiomyopathies?

Journal of the American Heart Association ◽

10.1161/jaha.120.018866 ◽

2020 ◽

Vol 9 (23) ◽

Author(s):

Stephan Altmayer ◽

Saman Nazarian ◽

Yuchi Han

Keyword(s):

Young Adults ◽

Right Ventricular ◽

Cause Of Death ◽

Ventricular Dysfunction ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Left Ventricular ◽

The Other ◽

Arrhythmogenic Cardiomyopathy ◽

Ventricular Cardiomyopathy ◽

Advanced Imaging

Abstract Arrhythmogenic right ventricular cardiomyopathy was first described as a right ventricular disease that is an important cause of death in young adults. However, with the advent of advanced imaging, arrhythmogenic right ventricular cardiomyopathy has been found to commonly have biventricular involvement, and a small portion of patients have left ventricular–dominant forms. On the other hand, a number of primarily left ventricular disease such as sarcoid and myocarditis can be arrhythmogenic and have right ventricular involvement. A few recent publications on arrhythmogenic right ventricular cardiomyopathy cohorts have average left ventricular functions that are comparable to sarcoid or myocarditis cohorts. We review the current literature and compare these cohorts of patients, and call for left ventricular functional criteria for arrhythmogenic right ventricular cardiomyopathy as inherited arrhythmogenic cardiomyopathy.

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Abstract 2935: Clinical-Instrumental Characteristics and Prognosis in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy: 30 Years of Experience in a Referral Center

Circulation ◽

10.1161/circ.118.suppl_18.s_795-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Andrea Di Lenarda ◽

Bruno Pinamonti ◽

Marco Merlo ◽

Alberto Pivetta ◽

Stylianos Pyxaras ◽

...

Keyword(s):

Heart Transplantation ◽

Right Ventricular ◽

Ventricular Arrhythmias ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Stress Test ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Muscle Disease ◽

Ventricular Cardiomyopathy

There are few studies regarding the clinical and instrumental presentation of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC); all available data derive from few specialized centers. We sought to describe clinical characteristics, instrumental findings and prognosis in a large cohort of patients (pts) with an ARVC diagnosis. From 1976 to 2006 all pts matching ARVC diagnostic criteria were enrolled in the Heart Muscle Disease Registry of Trieste and underwent a structured diagnostic protocol and follow-up. 104 pts were studied, 66% males, mean age 33±13 years; 84% were symptomatic at enrolment (mean duration 44±67 months); 75% had symptomatic arrhythmias (43% with previous sustained ventricular tachycardia or ventricular fibrillation (SVT/VF)), 36% syncope, 20% heart failure (12% in NYHA class III-IV). Familial ARVC were present in 46% of pts. ECG was abnormal in 72% (right bundle branch block 25%; epsilon potentials 15%; anterior negative T waves 51%; QRS dispersion >40ms 11%). At signal averaged ECG late potentials were present in 58% of pts. At 2D echo, mean right ventricle (RV) end-diastolic area was 30± 8 cm2 and RV fractional area contraction (FAC) 30±13%; RV aneurysms were present in 67%. RV systolic dysfunction (defined as FAC<40%) was present in 78%, characterized severe (FAC <30%) in 48%. Left ventricular systolic dysfunction was present in 27% of pts. Stress test was interrupted in 11% of cases for ventricular arrhythmias (55% SVT/VF). RV fibrofatty tissue was present in 52% of Nuclear Magnetic Resonance and in 59% of RV endomyocardial biopsy (performed respectively in 24 and 27% of pts). During a mean follow-up of 132±89 months, 3 pts were lost; 20 out of the remaining 101 pts (20%) experienced death/heart transplantation, 6 (3%) died for refractory HF; 4 pts (2%) underwent heart transplantation (HT); 6 pts (3%) died suddenly; one (0.5%) for extracardiac disease and 3 (1.6%) for unknown reason. Ten-year cumulative survival free from HT was 57%. In our population ARVC presentation was characterized by symptomatic, frequently sustained ventricular arrhythmias. Notably, LV involvement was present in approximately one third of pts at enrolment. In the long term, the overall prognosis was severe.

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FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106394 ◽

2020 ◽

Vol 57 (4) ◽

pp. 254-257 ◽

Cited By ~ 5

Author(s):

Francesca Brun ◽

Marta Gigli ◽

Sharon L Graw ◽

Daniel P Judge ◽

Marco Merlo ◽

...

Keyword(s):

Right Ventricular ◽

De Novo ◽

Task Force ◽

Diagnostic Yield ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Sudden Cardiac Arrest ◽

Muscle Disease ◽

Disease Genes ◽

Ventricular Cardiomyopathy ◽

The Right

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.ObjectiveFilamin C gene truncations (FLNCtv) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that FLNCtv could be a novel gene associated with ARVC.MethodsOne hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for FLNC variants. Available family members were tested for cosegregation.ResultsWe identified two unique FLNCtv variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling ‘definite’ diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.ConclusionThe identification of FLNCtv as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC non-desmosome disease genes for this disorder. Our findings should prompt inclusion of FLNC genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

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The utility of the 1994 versus the revised 2010 arrhythmogenic right ventricular cardiomyopathy (ARVC) task force diagnostic criteria for identifying mutation-positive probands with ARVC

European Heart Journal ◽

10.1093/ehjci/ehaa946.2108 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

K Lukhna ◽

S Kraus ◽

N Ntusi

Keyword(s):

Right Ventricular ◽

Task Force ◽

Diagnostic Yield ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Left Ventricular ◽

Ventricular Cardiomyopathy ◽

Significant Difference ◽

Diagnostic Panel ◽

The Mean ◽

The Right

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterised by structural and functional abnormalities of the right ventricle with or without left ventricular involvement. In 1994, Task Force criteria (TFC) were proposed for the diagnosis of ARVC and were found to be highly specific but lacked sensitivity. In 2010, revised TFC were proposed to increase sensitivity and facilitate diagnosis in those with subtle phenotypes. Purpose To compare the utility of the 1994 vs the 2010 TFC for the diagnosis of mutation-positive probands with ARVC in the IMHOTEP (The African Cardiomyopathy and Myocarditis Registry Program) study. Method 162 participants with the suspicion of ARVC were referred between May 2003 and May 2018. After the exclusion of 12 participants lacking sufficient clinical data, 150 cases were reviewed and classified using both 1994 and 2010 TFC by a diagnostic panel in an hospital. Results 82 participants were found to have an alternative diagnosis or insufficient criteria and were excluded. 68 participants were diagnosed with ARVC by the diagnostic panel and included; 14/68 participants with ARVC were found to be mutation-positive. Mutation-positive probands presented at a significantly younger age compared to the mutation-negative group (29±14 years vs 39±13 years, p=0.009), suggesting an earlier onset of ARVC. Common reasons for presentation in the mutation-positive cohort included palpitations (79%) and presyncope (64%), with twice the number of participants presenting with sustained ventricular tachycardia compared to mutation-negative participants (79% vs 47%, p=0.036). The diagnostic yield of the 2010 vs 1994 TFC in participants with ARVC (n=68) revealed more participants with a definite diagnosis (77% vs 69%, p=0.267). A 67% change in diagnosis from 1994 borderline to 2010 definite was observed. Mutation-positive participants had a higher yield for definite ARVC compared to mutation-negative participants (100% vs 86%). When comparing the mean number of task force (TF) major and minor criteria according to mutation status, we found a significant difference in the mean number of 2010 TF major criteria between mutation-positive and mutation-negative groups, even with the exclusion of gene mutation as a criterion (2.50±0.86 vs 1.74±0.85, p=0.005). We assessed each diagnostic modality's contribution to the 2010 TF major criteria in mutation-positive definite participants and found cardiac magnetic resonance contribution statistically significant, p=0.021. Conclusion Mutation-positive ARVC probands were found to be younger, more likely to present with sustained VT, and fulfilled a significantly higher number of 2010 TF major criteria than mutation-negative probands. The evolution in classification between the 2010 and 1994 TFC suggests that reclassifying participants recruited in traditional ARVC registries according to updated criteria is worthwhile. Funding Acknowledgement Type of funding source: None

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