Characteristic Imaging Phenotype of Arrhythmogenic Cardiomyopathy With Filamin C Gene Variant

Genetic abnormalities affect the phenotype and clinical prognosis in cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM). Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a subtype of ACM, defined as a disease with fibrofatty replacement predominantly in the left ventricle (LV), impaired LV systolic function and ventricular arrhythmias originating from the LV.¹

Article p ????

In this issue of the Journal, Yoshimura et al² present a case of ALVC harboring filamin C gene (FLNC) truncating variant and showing a characteristic imaging phenotype on multiparametric cardiac magnetic resonance (CMR) imaging. A 28-year-old woman had a family history of dilated cardiomyopathy (DCM) and mild LV systolic dysfunction, together with ring-like late gadolinium enhancement (LGE) on CMR imaging. A novel FLNC truncating variant (p.Gln937Ter) was identified, and she was diagnosed as FLNC-related ALVC. The authors clearly demonstrate the characteristic imaging phenotype of FLNC-related ACM.

FLNC encodes filamin C, a large actin-cross-linking structural protein located in the intercalated discs. Filamin C is also one of the largest Z-disc proteins. Its main function is the binding of actin rods in the adherens junctions, which are the structures that, together with desmosomes, contribute to the maintenance of cellular integrity and force transduction of myocardium exposed to mechanical stress. Thus, FLNC is a prominent cardiomyopathy-related gene, and its variants are known to exhibit significantly varied phenotypes based on the type and location of the variants.³ FLNC variants associated with hypertrophic cardiomyopathy or restrictive cardiomyopathy are predominantly missense ones.⁴ On the other hand, FLNC truncating variants (tv) are reported to mainly lead to DCM or ACM.^5,6 FLNCtv induce adherens junction abnormalities, which, as occurs with abnormal desmosomes, might confer a predisposition over time to disruption of intercellular anchoring, eventually leading to cardiomyocyte detachment, cell death, and subsequent fibrofatty replacement. FLNC-related cardiomyopathy is often complicated by frequent ventricular tachycardia and premature sudden cardiac death.^7,8

The European guidelines advocate preventive treatment with an implantable cardioverter-defibrillator (ICD) in cases in which the LV ejection fraction (EF) is <50%, coupled with ≥2 of the following factors: history of syncope, LGE on CMR imaging, inducible sustained monomorphic ventricular tachycardia at programmed electrical stimulation, and pathogenic mutations in LMNA, PLN, RBM20, and FLNC (Class IIa).⁹ Although genetic testing has great value for risk stratification, it might not be applicable to all patients due to real-world issues such as cost and the specialized expertise required for interpretation. Therefore, narrowing down the number of patients to undergo genetic testing based on the characteristic clinical phenotype of the disease could be practically helpful. Several clinical features of FLNC-related cardiomyopathy have been reported through clinical studies (Figure). On ECGs of FLNC-related cardiomyopathy patients, low (<0.5 mV) QRS voltages in the limb leads were detected in 37% and T-wave inversion in the inferolateral/lateral leads in 24%.¹⁰ Also, there was no difference in freedom from malignant ventricular arrhythmia between FLNCtv carriers with mild-to-moderate LV systolic dysfunction (LVEF 36–49%) and those with severe LV systolic dysfunction (LVEF ≤35%). Generally, severe LV systolic dysfunction as the stratifier for preventive ICD implantation is advocated for DCM patients.¹¹ In FLNC-related cardiomyopathy cases, prophylactic ICD implantation should be considered even before progression to severe LV systolic dysfunction.

Figure.

The truncating variant of FLNC (FLNCtv) causes dilated cardiomyopathy and arrhythmogenic cardiomyopathy. Unlike FLNC missense variants associated with hypertrophic cardiomyopathy, FLNCtv can lead to dilated/arrhythmogenic cardiomyopathy. The ring-like late gadolinium enhancement observed on cardiac magnetic resonance imaging is a characteristic finding of FLNC-related cardiomyopathy.

The most characteristic features can be obtained from CMR imaging. LGE is a significant prognostic factor in non-ischemic cardiomyopathies and can also aid in predicting the substrate for arrhythmias based on its morphology.^12,13 The morphology of LGE varies with the disease as well as the underlying genetic mutations. Particularly, the presence of ring-like LGE in the short-axis cross-sectional view is considered a distinctive LGE pattern specific to the desmoplakin gene or FLNC-related cardiomyopathy.¹⁴

Yoshimura et al clearly demonstrate the ring-like LGE finding on CMR imaging in their patient with FLNC-related ALVC. This case presentation is greatly educational for physicians. We should keep this characteristic imaging phenotype in mind and when it is detected, FLNC-related cardiomyopathy should be strongly suspected. Genetic diagnosis of FLNC-related cardiomyopathy will provide us with the rationale for prophylactic ICD implantation even before progression to severe LV systolic dysfunction. From now on, further research is warranted to clarify the mechanism of FLNCtv inducing the characteristic pattern of cardiac lesions corresponding to this “ring-like LGE finding”.

Disclosure

H.M. is a member of Circulation Journal’ s Editorial Team.

References

• 1.   Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: The complexity of a diverse genetic architecture. Nat Rev Cardiol 2013; 10: 531–547, doi:10.1038/nrcardio.2013.105.
• 2.   Yoshimura F, Oda S, Kidoh M, Hayashi H, Yonemura M, Miyazaki S, et al. Cardiac magnetic resonance imaging findings in filamin C variant-associated arrhythmogenic left ventricular cardiomyopathy. Circ J 2023, doi:10.1253/circj.CJ-23-0480.
• 3.   Verdonschot JAJ, Vanhoutte EK, Claes GRF, Helderman-van den Enden ATJM, Hoeijmakers JGJ, Hellebrekers DMEI, et al. A mutation update for the FLNC gene in myopathies and cardiomyopathies. Hum Mutat 2020; 41: 1091–1111, doi:10.1002/humu.24004.
• 4.   Kiselev A, Vaz R, Knyazeva A, Khudiakov A, Tarnovskaya S, Liu J, et al. De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy. Hum Mutat 2018; 39: 1161–1172, doi:10.1002/humu.23559.
• 5.   Ortiz-Genga MF, Cuenca S, Dal Ferro M, Zorio E, Salgado-Aranda R, Climent V, et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol 2016; 68: 2440–2451, doi:10.1016/j.jacc.2016.09.927.
• 6.   Begay RL, Tharp CA, Martin A, Graw SL, Sinagra G, Miani D, et al. FLNC Gene splice mutations cause dilated cardiomyopathy. JACC Basic Transl Sci 2016; 1: 344–359, doi:10.1016/j.jacbts.2016.05.004.
• 7.   Dungu JN, Langley SG, Hardy-Wallace A, Li B, Barbagallo RM, Field D, et al. Dilated cardiomyopathy: The role of genetics, highlighted in a family with Filamin C (FLNC) variant. Heart 2022; 108: 676–682, doi:10.1136/heartjnl-2021-319682.
• 8.   Carruth ED, Qureshi M, Alsaid A, Kelly MA, Calkins H, Murray B, et al. Loss-of-function FLNC variants are associated with arrhythmogenic cardiomyopathy phenotypes when identified through exome sequencing of a general clinical population. Circ Genomic Precis Med 2022; 15: e003645, doi:10.1161/CIRCGEN.121.003645.
• 9.   Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2022; 43: 3997–4126, doi:10.1093/eurheartj/ehac262.
• 10.   Celeghin R, Cipriani A, Bariani R, Bueno Marinas M, Cason M, Bevilacqua M, et al. Filamin-C variant-associated cardiomyopathy: A pooled analysis of individual patient data to evaluate the clinical profile and risk of sudden cardiac death. Heart Rhythm 2022; 19: 235–243, doi:10.1016/j.hrthm.2021.09.029.
• 11.   Akhtar MM, Lorenzini M, Pavlou M, Ochoa JP, O’Mahony C, Restrepo-Cordoba MA, et al. Association of left ventricular systolic dysfunction among carriers of truncating variants in filamin C with frequent ventricular arrhythmia and end-stage heart failure. JAMA Cardiol 2021; 6: 891–901, doi:10.1001/jamacardio.2021.1106.
• 12.   Barison A, Aimo A, Ortalda A, Todiere G, Grigoratos C, Passino C, et al. Late gadolinium enhancement as a predictor of functional recovery, need for defibrillator implantation and prognosis in non-ischemic dilated cardiomyopathy. Int J Cardiol 2018; 250: 195–200, doi:10.1016/j.ijcard.2017.10.043.
• 13.   Chen Z, Sohal M, Sammut E, Child N, Jackson T, Claridge S, et al. Focal but not diffuse myocardial fibrosis burden quantification using cardiac magnetic resonance imaging predicts left ventricular reverse modeling following cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2016; 27: 203–209, doi:10.1111/jce.12855.
• 14.   Augusto JB, Eiros R, Nakou E, Moura-Ferreira S, Treibel TA, Captur G, et al. Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: A comprehensive genotype-imaging phenotype study. Eur Heart J Cardiovasc Imaging 2020; 21: 326–336, doi:10.1093/ehjci/jez188.