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.
Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a rare form of arrhythmogenic cardiomyopathy characterized by fibrofatty replacement of left ventricular myocardium, malignant arrhythmia, and sudden cardiac death. The definition incorporates several genetic causes, including pathogenic variation in the Filamin C gene (FLNC). Although awareness of ALVC has improved, identification remains challenging and diagnostic criteria continue to evolve.
A 50-year-old athletic male was admitted following an out-of-hospital cardiac arrest due to ventricular tachycardia (VT) whilst playing football. Coronary angiography revealed unobstructed epicardial vessels and the diagnosis of ALVC was suggested by cardiovascular magnetic resonance imaging, which demonstrated a mildly dilated and moderately impaired left ventricle with epicardial late gadolinium enhancement in the basal to mid-lateral walls and subendocardial septum. Initial testing with a cardiomyopathy and arrhythmia gene panel was negative but extended testing uncovered a likely pathogenic variant in FLNC. Subsequently, the patient experienced a recurrence of sustained VT necessitating implantable cardioverter-defibrillator (ICD) therapies, ultimately undergoing a combined epicardial and endocardial VT ablation 4 years after presentation. Six months post-ablation, he was asymptomatic and his arrhythmia rendered quiescent.
Arrhythmogenic cardiomyopathy should be considered in the evaluation of an initially unexplained cardiac arrest. This case characterizes the clinical features of a patient with FLNC cardiomyopathy and emphasizes the utility of genetic testing using modern gene panels in patients with comparable phenotypes. We also demonstrate that optimal medical therapy with antiarrhythmic drugs, exercise restriction, ICD insertion, and catheter ablation can be useful in the management of ALVC with positive outcomes
Podoplanin (Pdpn) is a mucin-type transmembrane protein that has been implicated in multiple physiological settings including lymphangiogenesis, platelet aggregation, and cancer metastasis. Here, we reported an absence of Pdpn transcript expression in the resting mouse monocytic macrophages, RAW264.7 cells; intriguingly, a substantial upregulation of Pdpn was observed in activated macrophages following Helicobacter pylori or lipopolysaccharide stimulation. Pdpn-knockout macrophages demonstrated intact phagocytic and intracellular bactericidal activities comparable to wild type but exhibited impaired migration due to attenuated filopodia formation. In contrast, an ectopic expression of Pdpn augmented filopodia protrusion in activated macrophages. NanoString analysis uncovered a close dependency of Filamin C gene on the presence of Pdpn, highlighting an involvement of Filamin C in modulation of actin polymerization activity, which controls cell filopodia formation and migration. In addition, interleukin-1β production was significantly declined in the absence of Pdpn, suggesting a role of Pdpn in orchestrating inflammation during H. pylori infection besides cellular migration. Together, our findings unravel the Pdpn network that modulates movement of active macrophages.
Filamin C truncating variants (
) cause a form of arrhythmogenic cardiomyopathy (ACM): the mode of presentation, natural history and risk stratification of
remain incompletely explored. We sought to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of
carriers were identified from ten tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), non-arrhythmic death/HT/LVAD and SCD/major ventricular arrhythmias (SCD/MVA). Previously established cohorts of 46 patients with
and 60 with
-related ACM were used for prognostic comparison.
Eighty-five patients carrying
were included (42±15 years, 53% males, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction (LVEF) was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/ right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) non-arrhythmic death/HT/LVAD and 23 (27%) SCD/MVA. The SCD/MVA incidence of
carriers did not significantly differ from
carriers, LVEF was associated with the risk of D/HT/LVAD and non-arrhythmic death/HT/LVAD.
Among patients referred to tertiary referral centers,
ACM is phenotypically heterogeneous and characterized by high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of LV dysfunction.
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.