3.5.1. Arrhythmic Risk Stratification During the Follow-Up

The univariable analysis of MVA events during follow-up showed no impact of sex and type of mutation on MVA occurrence and confirmed the involvement of established risk factors, such as the presence of AVB, nsVT, or reduced LVEF (with cutoff value at 55%).

The analysis of the influence of circulating biomarker concentrations on MVA occurrence suggested that circulating biomarker concentrations could be more potent risk factors than established risk factors: hazard ratio for hsTnT with a cutoff value at 20 ng/L was 13.2 (95% CI: 1.5–115.8, *p* = 0.020) and, for NT-proBNP with a cutoff value at 150 pg/mL, was 13.4 (95% CI: 1.6–112.7, *p* = 0.017).

In fact, in multivariable analysis, elevated NT-proBNP level was the only indicator of the occurrence of MVA at 8 years of follow-up (HR: 10.4, 95% CI: 1.21–89.79, *p* = 0.010).

The Kaplan–Meier curves showing MVA-free survival during the follow-up period according to respective risk factors are available online at Figure S7.

#### 3.5.2. Factors Affecting Lifelong Prognosis in Cardiolaminopathies

Kaplan–Meier analysis from the date of birth in the whole cohort showed a worse transplant-free survival among probands versus relatives (*p* = 0.0339) (supplementary Figure S8), male vs. female patients (*p* = 0.0041), and surprisingly in patients with missense vs. other mutations (*p* = 0.0412) (Figure 4). Analogous analysis with respect to MVA events (Figure 5 and supplementary Figure S9) showed trends toward more common MVA among males vs. females (*p* = 0.0872) and patients with missense vs. other variants (*p* = 0.0948) and no impact of the proband status (*p* = 0.7469).

**Figure 4.** Kaplan–Meier lifelong HTX-free survival curves in cardiolaminopathy according to (**a**) sex and (**b**) mutation type. Legend: HTX: heart transplantation.

**Figure 5.** Kaplan–Meier lifelong MVA-free survival curves in cardiolaminopathy according to (**a**) sex and (**b**) mutation type. Legend: MVA: malignant ventricular arrhythmia.

In multivariable Cox regression analysis (Table 5), we found that male sex (HR: 6.18, 95% CI: 1.66–23.0, *p* = 0.007) and missense variants (HR: 3.83, 95% CI: 1.14–12.85, *p* = 0.029) were independently related with the occurrence of end-stage HF at 60 years.

#### **4. Discussion**
