Background:

In non-ischemic cardiomyopathy (NICM) patients with ventricular arrhythmias (VA), the poorer outcome after catheter ablation of anteroseptal substrates (ASS) compared to inferolateral substrates (ILS) has been attributed to its deep intramural location. However, additional characteristics such as fibrosis and sympathetic innervation are important determinants of arrhythmogenicity and may also contribute to the discrepancy in outcome. In NICM patients, the relation between cardiac sympathetic innervation and non-ischemic fibrosis has not been elucidated so far.

Aim:

The aim of this study was 1) to evaluate the relationship between global cardiac sympathetic innervation and global fibrosis and 2) to assess the association between VA substrate location, regional sympathetic denervation and regional myocardial fibrosis.

Methods:

Patients with VA from the ‘Leiden Nonischemic Cardiomyopathy Study’, who underwent electro-anatomical substrate mapping, late gadolinium enhanced (LGE) cardiac magnetic resonance and 123-I-MIBG imaging between 2011-2018 were included. Global cardiac sympathetic innervation was analyzed by using the heart-to-mediastinum ratio (HMR), with a cutoff of <1.8 defining global denervation. The 17-segment model was used to determine the location of VA related sites, the distribution of low unipolar voltage (UV<25^th IQR) (=electro-anatomical surrogate for fibrosis), the presence of LGE and sympathetic denervation. Patients were categorized according to the dominant VA substrate location in ASS or ILS.

Results:

Median global UV was 12.3 mV in patients with normal sympathetic innervation (HMR>1.8) and 8.7 mV in patients with global sympathetic denervation (HMR<1.8). Global sympathetic denervation correlated with diffuse myocardial fibrosis (R=0.5335, p=0.0154). Regional analysis revealed 11 patients with dominant ASS, 13 patients with dominant ILS and 5 patients with other VT substrate locations. VA substrate segments show relatively lower UV for both ASS and ILS. In all patients with ILS, VA substrate segments showed regional fibrosis, as identified by LGE, and segmental denervation. In patients with ASS, only 63% (p=0.2) of VA related anteroseptal segments showed regional fibrosis and only 27% (p=0.0002) showed segmental denervation.

Conclusion:

In patients with NICM and VA global cardiac sympathetic denervation is related to myocardial fibrosis. Despite low endocardial UV (=surrogate for fibrosis) for ASS and ILS segments harboring VA substrates, regional sympathetic denervation coincided with fibrosis only for IL VA substrates. The mismatch between regional fibrosis and preserved innervation for AS VA substrates may contribute to a VA substrate difficult to control by catheter ablation.