FLNC and DSP cardiomyopathy. Two paths to myocardial fragility and arrythmia

Background FLNC and DSP mutations are associated with arrhythmogenic cardiomyopathy phenotypes ranging from ARVC to NDLVC/DCM, with increased risk of ventricular arrhythmias, fibrosis and myocarditis-like episodes. Purpose To compare the natural history of FLNC- and DSP-related cardiomyopathies focusing in the initial phase of the disease. Methods We analyzed 31 FLNC and 47 DSP variant carriers. Clinical, genetic, and CMR data were collected. Outcomes included ventricular arrhythmia burden/timing, LV fibrosis extent, and myocarditis-like episodes. Severe arrhythmia was defined as >1000 ventricular extrasystoles/24h. Severe fibrosis was defined qualitatively or by ring-like late gadolinium enhancement (LGE). The analysis primarily included pathogenic/likely pathogenic variants; selected VUS were included if segregation supported pathogenicity. Results Subclinical DCM was the most common phenotype in both groups (DSP 42.95% vs FLNC 42.55%, p=1.000). DCM was more frequent in FLNC carriers (19.35% vs 4.2%, p=0.053), while ARVC was more common in DSP carriers (17.02% vs 1%, p=0.079). HCM occurred only in FLNC carriers (6.4% vs 0%, p=0.155), some carriers had no clinical expression yet (FLNC 6,4% vs DSP 0%, p=0.155). Subclinical patients included 21/47 DSP and 13/31 FLNC carriers. Truncating mutations were 29 (DSP n=17 FLNC n=12, p=0.63) and missense mutations were 5 (DSP n=4 FLNC n=1, p=0.63). Mean age was 35.09 +/-15.94 for DSP vs 32,53 +/-16,74 for FLNC (p=0.66). During follow-up (FLNC mean= 2.56 +/- 3.27 years vs DSP mean = 4.04 +/- 3.24 years, p=0.20), ventricular arrythmias were more frequent among DSP carriers despite the absence of severe fibrosis (19.04% VS 0%, p=0.144). Severe LGE was associated with high rate of arrythmias in DSP (52.38% VS 0%, p<0.001). In FLNC, no escalation of arrhythmia and lower risk of non-sustained ventricular tachycardia (47.61% vs 0%, p<0.01) were observed during the subclinical phase, persisting even in extensive fibrosis. Myocarditis-like episodes were more frequent in DSP carriers (27 vs 2, p<0.0001) Conclusion FLNC and DSP demonstrate different early progression patterns. DSP progresses with severe arrhythmias before fibrosis whereas FLNC is characterized by extensive fibrosis without increased ventricular arrythmias. Myocarditis-like episodes are more frequent in DSP carriers.