*4.2. Phenotypic Di*ff*erences in Missense versus Non-Missense LMNA Variants*

No significant differences were found with regard to cardiac biomarkers' levels between missense and non-missense *LMNA* variant carriers. A novel finding in this study is the higher frequency of LBBB (54.5% vs. 14.3%, *p* = 0.017) among missense versus non-missense *LMNA* carriers. It cannot however be excluded that the observed difference is dependent on the degree of left ventricular impairment rather than on the mutation type. More advanced heart failure among missense variant carriers may in turn result from the fact that probands constituted almost two thirds of this group but only one third of non-missense variant carriers (*p* = 0.063). In the study by Nishiuchi et al. [36], prevalence of low LVEF and degree of left ventricular dilation was similar in the truncation mutation vs. missense mutation group. There are scarce data on the relationship between the level of conduction defects and type of *LMNA* mutations. Nishiuchi et al. [36] showed that AVB was more common among patients with non-missense variants. In our study, the frequencies of LBBB, right bundle branch block (RBBB), and AVB at baseline were 17%, 0%, and 60%, respectively, while in the recent and largest study to date by Wahbi et al., it was lower with regard to LBBB and AVB (4.6% and 34.7%, respectively), whereas 6% of patients had RBBB. This underlines the differences in the studied populations.

#### *4.3. Arrhythmic Risk Stratification Including Biomarkers*

Another interesting finding of our study was the strong, independent association between NT-proBNP level > 150 pg/mL and the occurrence of MVA among *LMNA* mutation carriers.

Recently, several studies defining prognostic markers of SCD in arrhythmogenic DCM and cardiolaminopathies have been published [2,7,36,37], with European Society of Cardiology (ESC) guidelines [38] adopting the results of an earlier study by van Rijsingen et al. [7]. Based on retrospective eight-centre analysis, the authors proved that non-missense variants were independently associated with MVA. Similarly, based on retrospective 5-centre analysis, Kumar et al. [10] showed the independent association of non-missense variants with sustained ventricular arrhythmia and death. Wahbi et al. [37] presented an MVA risk prediction model for *LMNA* variant carriers and further stressed the role of non-missense variants as one of significant risk factors along with male sex, nsVT, AVB of 1st and higher degree, and reduced LVEF. In contrast, Pasotti et al. [21] did not show any association between non-missense *LMNA* variants and a worse prognosis, similarly to Captur et al. [39], who recently performed hierarchical cluster analysis of the published literature. In our cohort, we also could not confirm worse MVA-free survival in relation to *LMNA* non-missense variants either during the

follow-up period or from the date of birth, and surprisingly, they were characterized by more favourable prognosis with regard to end-stage HF during lifespan. Further studies are warranted to explain the differences and to better assess the impact of the type of *LMNA* mutations.

The excellent prognostic role of NT-proBNP in patients with HF is widely recognized [40]. The association of raised levels of NT-proBNP and MVA in HF patients was shown previously [41,42]. Nevertheless, it has neither been included in currently used risk models nor has it been evaluated in *LMNA*-related cardiac disorder.

The utility of cardiac troponins in determining prognosis in HF and DCM was shown, primarily in patients with acute HF admitted to hospitals but also in ambulatory care [40,43]. To our knowledge, however, their usefulness has been investigated with regard to HF end-points, such as HF deaths and hospitalizations [43], and not as a predictor of arrhythmic risk. In our study, elevated hsTnT > 20 ng/L was associated with increased MVA occurrence only in univariable analysis; thus, its role as an independent risk factor needs further evaluation. Also, due to recent advances in cardiac biomarker sensing technologies [44], point-of-care (POC) applications can be hopefully used in the management of cardiomyopathies in the foreseeable future.
