Background: Filamin C truncating variants ( FLNCtv ) cause a form of arrhythmogenic cardiomyopathy (ACM): the mode of presentation, natural history and risk stratification of FLNCtv remain incompletely explored. We sought to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. Methods: FLNCtv 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 LMNA and 60 with DSP -related ACM were used for prognostic comparison. Results: Eighty-five patients carrying FLNCtv 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 FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, LVEF was associated with the risk of D/HT/LVAD and non-arrhythmic death/HT/LVAD. C Conclusions: Among patients referred to tertiary referral centers, FLNCtv 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.
BACKGROUND: In Lamin A/C ( LMNA ) cardiomyopathy, atrial fibrillation (AF) commonly occurs before dilated cardiomyopathy, and the ability to predict its incidence is limited. We hypothesized that left atrial (LA) echocardiographic phenotyping can identify atrial myopathy and harbingers of AF. METHODS: Echocardiograms from patients with pathogenic or likely pathogenic variants in LMNA (n=77) with and without reduced left ventricular ejection fraction (LVEF, <50%) were compared to healthy individuals (n=70) and patients with Titin truncating variant cardiomyopathy (n=35) with similar LVEF, sex, and age distributions. Echocardiographic analysis, blinded to genotype, included strain and volumetric measures of left ventricular and atrial function. The primary outcome was incident AF. RESULTS: At baseline, 43% of the patients with pathogenic or likely pathogenic LMNA variants had a history of AF, including 26% of those with LVEF ≥50%. Compared with healthy subjects, the patients with pathogenic or likely pathogenic LMNA variants and LVEF ≥50% had reduced LA contractile strain ( LMNA , 11.8±6.1% versus control, 15.0±4.2%; P =0.003). Compared to LVEF-matched Titin truncating variant cardiomyopathy patients, the patients with pathogenic or likely pathogenic LMNA variants and LVEF <50% displayed no difference in LA size, but a worse LA contractile dysfunction (6.4±4.7% versus 12.6±9.6%; P =0.02). Over a median follow-up of 2.8 (1.2–5.7) years, LA contractile strain was the only significant predictor of AF in multivariable Cox regression (hazard ratio, 4.0 [95% CI, 1.04–15.2]). CONCLUSIONS: LMNA cardiomyopathy is associated with early intrinsic atrial myopathy reflected by high AF prevalence and reduced LA contractile strain, even in the absence of LV dysfunction and LA dilation. Whether LA strain can be used as a monitoring strategy to detect and mitigate AF complications requires validation.
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