Dilated cardiomyopathy due to filamin C mutation: anthracycline treatment as a trigger

Dilated cardiomyopathy (DCM) is a heterogenous group of disorders characterised by left ventricular dilatation and dysfunction, in the absence of factors affecting loading conditions such as hypertension or valvular disease, or significant coronary artery disease. The prevalence of idiopathic DCM is estimated between 1:250 and 1:500 individuals. Determining the aetiology of DCM can be challenging, particularly when evaluating an individual and index case with no classical history or investigations pointing towards an obvious acquired cause, or no clinical clues in the family history to suggest a genetic cause. We present a family affected by DCM associated with Filamin C variant, causing sudden cardiac death at a young age and heart failure due to severe left ventricular impairment and myocardial scarring. We review the diagnosis and treatment of DCM, its genetic associations and potential acquired causes. Thorough assessment is mandatory to risk stratify and identify patients who may benefit from primary prevention implantable cardioverter defibrillator therapy according to international guidelines. Genetic testing has some limitations, and is positive in only 20%–35% of DCM, but should be considered in specific cases to identify families who may benefit from cascade screening after appropriate counselling. The management of often complex familial cardiomyopathy requires specialist input for every case, and the appropriate infrastructure to coordinate investigations.

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Abstract 194: Characterization of Arrhythmogenic Dilated Cardiomyopathy Caused by Novel Filamin C Splice Variant in a Zebrafish Model

Circulation Research ◽

10.1161/res.117.suppl_1.194 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Rene L Begay ◽

Teisha J Rowland ◽

Charles A Tharp ◽

August Martin ◽

Sharon L Graw ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Splice Variant ◽

Systolic Dysfunction ◽

Family Members ◽

Muscle Disease ◽

Heart Tube ◽

Zebrafish Model ◽

Cell Stage ◽

Cardiac Phenotype ◽

Filamin C

Although dilated cardiomyopathy (DCM) is a serious and frequent genetic cause of heart failure, only 30-40% of cases can be attributed to a known DCM gene mutation. To identify and confirm additional disease genes involved in DCM, we performed whole exome sequencing in two multigenerational families with DCM, both from the same geographic region of Italy, and found a novel splice variant in the gene encoding filamin-C (FLNC). Previously characterized mutations in FLNC had been primarily linked to skeletal muscle disease, although none of the affected family members displayed skeletal myopathy. To confirm and further characterize the arrhythmogenic DCM phenotype observed in family members, we performed embryonic knockdown experiments using morpholino (MO) treatment in zebrafish (Danio rerio) targeting the FLNC ortholog, filamin Cb (flncb). Following MO injection into 1-2 cell stage zebrafish embryos, 63.4% (78 of 123) of viable flncb MO-injected embryos displayed a cardiac phenotype at 72 hours post fertilization (hpf) (vs. 17.0% [30 of 177] of control MO-injected embryos; p≤0.001). Increases in mortality were observed, with 20.8% (54 of 260) of flncb MO-injected embryos surviving at 7 days post fertilization (vs. 65% [162 of 249] of control embryos; p≤0.001). The flncb MO-injected embryos demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. The flncb MO-injected embryos additionally demonstrated a lower mean stroke volume than controls (0.076 vs. 0.181 nl; p=0.015), a reduced mean cardiac output (10.8 vs. 25 nl/min; p=0.02), and an increase in the fraction of retrograde blood flow over the cardiac cycle (0.42 vs. 0.03; p=0.027). Overall, this flncb MO treatment recapitulated a DCM phenotype similar to the state caused by the human splicing variant, supporting haploinsufficiency as the mechanism leading to DCM in these families. Our findings suggest that approaches to augment endogenous filamin C protein levels may represent a viable treatment strategy that warrants exploration in future studies.

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Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C

European Journal of Human Genetics ◽

10.1038/ejhg.2016.110 ◽

2016 ◽

Vol 24 (12) ◽

pp. 1792-1796 ◽

Cited By ~ 23

Author(s):

Eyal Reinstein ◽

Ana Gutierrez-Fernandez ◽

Shay Tzur ◽

Concetta Bormans ◽

Shai Marcu ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Biallelic Mutations ◽

Filamin C

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Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms23020871 ◽

2022 ◽

Vol 23 (2) ◽

pp. 871

Author(s):

Joseph D. Powers ◽

Natalie J. Kirkland ◽

Canzhao Liu ◽

Swithin S. Razu ◽

Xi Fang ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Computational Models ◽

Systolic Dysfunction ◽

Longitudinal Force ◽

Rapid Onset ◽

Structural Defects ◽

Actin Binding ◽

Force Transmission ◽

Tension Development ◽

Filamin C

Dilated cardiomyopathy (DCM) is a life-threatening form of heart disease that is typically characterized by progressive thinning of the ventricular walls, chamber dilation, and systolic dysfunction. Multiple mutations in the gene encoding filamin C (FLNC), an actin-binding cytoskeletal protein in cardiomyocytes, have been found in patients with DCM. However, the mechanisms that lead to contractile impairment and DCM in patients with FLNC variants are poorly understood. To determine how FLNC regulates systolic force transmission and DCM remodeling, we used an inducible, cardiac-specific FLNC-knockout (icKO) model to produce a rapid onset of DCM in adult mice. Loss of FLNC reduced systolic force development in single cardiomyocytes and isolated papillary muscles but did not affect twitch kinetics or calcium transients. Electron and immunofluorescence microscopy showed significant defects in Z-disk alignment in icKO mice and altered myofilament lattice geometry. Moreover, a loss of FLNC induces a softening myocyte cortex and structural adaptations at the subcellular level that contribute to disrupted longitudinal force production during contraction. Spatially explicit computational models showed that these structural defects could be explained by a loss of inter-myofibril elastic coupling at the Z-disk. Our work identifies FLNC as a key regulator of the multiscale ultrastructure of cardiomyocytes and therefore plays an important role in maintaining systolic mechanotransmission pathways, the dysfunction of which may be key in driving progressive DCM.

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Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell–Cell Adhesion Structures

JACC: Clinical Electrophysiology ◽

10.1016/j.jacep.2017.12.003 ◽

2018 ◽

Vol 4 (4) ◽

pp. 504-514 ◽

Cited By ~ 43

Author(s):

Rene L. Begay ◽

Sharon L. Graw ◽

Gianfranco Sinagra ◽

Angeliki Asimaki ◽

Teisha J. Rowland ◽

...

Keyword(s):

Cell Adhesion ◽

Dilated Cardiomyopathy ◽

Filamin C ◽

Cell Cell

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P1817Non-truncating Filamin C variants represent disease-causing mutations in dilated cardiomyopathy

European Heart Journal ◽

10.1093/eurheartj/ehy565.p1817 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

T Nedvedova ◽

M Kubanek ◽

L Piherova ◽

A Krebsova ◽

T Palecek ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Filamin C

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Studies on Ultrastructure and Cytochemistry of Right Ventricular Endomyocardial Biopsy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100158820 ◽

1990 ◽

Vol 48 (3) ◽

pp. 256-257

Author(s):

Xia Mingyu ◽

Ma Wengshu ◽

Wu Xiangh ◽

Chen Dong

Keyword(s):

Light Microscopy ◽

Right Ventricular ◽

Dilated Cardiomyopathy ◽

Endomyocardial Biopsy ◽

Heart Diseases ◽

Ultrastructural Localization ◽

Controlled Study ◽

Myocardial Biopsy ◽

Morphological Assessment ◽

Rheumatic Heart

This paper describes morphological and cytochemistry changes of endomyocardial biopsy in 94 patients. The samples of myoicardium were taken from 32 patients with dilated cardiomyopathy, and sdudied with light and electron microscop. The cytochemical studies in some of these patients were performed at histological and ultrastructure level. This paper also reported the result of myocardial biopsy in 33 patients with serious dysrythmia.The result of this controlled study indicates that morphological assessment in both cardiomyopathy and congenital or rheumatic heart diseases showed no special changes. In patients of dilated cardiomyopathy, the decreased activity of myosin ATPase was secondary to cardial failure. The change of succinate dehydrogenase (SDHase) was not significant with light microscopy. But ultrastructural localization of SDHase activity is valuable. Its activity was found to be localized in endomembrane and ridge of the mitochondria, the activity of this enzyme was decrease, normal, or increase. SDHase activity was more intense in cardial myocytes well-functioning, or ultrastructurally well preserved hearts.

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