Microstructural disease and hypoperfusion in dilated cardiomyopathy associate with ventricular arrhythmias and underpin midwall septal fibrosis

Abstract Background The presence of midwall septal fibrosis (MSF) in non-ischemic dilated cardiomyopathy (DCM) has been shown to associate with increased all-cause and cardiovascular mortality but the underlying pathophysiological mechanisms are incompletely understood. We sought to study MSF via advanced cardiovascular magnetic resonance imaging (CMR) techniques. Methods This was a multicenter collaboration to prospectively study DCM patients with and without MSF ("MSF+" / "MSF") and controls of similar age and sex distribution. All underwent single-magnet 3 Tesla CMR including cardiac diffusion tensor imaging (cDTI), quantitative rest perfusion and multiparametric mapping. Results 121 participants were studied: 34 MSF+ (51.3±13.8years; 74% male), 27 MSF– (47.9±15.1 years; 63% male) and 60 controls (44.8±12.7years; 58% male), with MSF+ having a 20-fold higher ventricular ectopic (VE) burden on 24-hour Holter than MSF– (4.21±8.2 vs. 0.21±0.8, p=0.018). cDTI revealed significantly increased mean diffusivity (MD) in pooled DCM vs. controls (1.49 vs. 1.43 x10-3mm2/s, p0.001), and in MSF+ vs MSF– cohorts (1.51 vs. 1.46x10-3mm2/s, p=0.006), suggesting increased interstitial abnormality. The second eigenvector angle (E2A) was significantly reduced in pooled DCM vs. controls (34.7 vs. 40.2°, p=0.001) suggesting less contracted sheetlet angularity. Resting myocardial blood flow (rMBF) was reduced in pooled DCM vs. controls (0.66 vs. 0.70ml/g/min, p=0.045) and in MSF+ vs. MSF– (0.79 vs. 0.94 ml/g/min, p=0.013). In MSF+ patients, rMBF was reduced in segments with MSF compared to segments without focal fibrosis (0.60 vs. 0.67ml/g/min, p=0.011). In multivariable models, presence of MSF and low rMBF independently associated with presence of VE (respectively odds ratio 95% confidence intervals: 17.0 2.7, 161.9 p=0.005; 4.6x10-4 1.5x10-7, 3.7x10-1 p=0.038). Conclusion The commonly observed focal streak of replacement fibrosis in the septum of the DCM heart, referred to as midwall septal fibrosis, is underpinned by significant microstructural disease and resting myocardial hypoperfusion that associate with arrhythmogenesis. These pathophysiological findings might explain why midwall septal fibrosis appears to increase the risk of sudden cardiac death, opening up novel preventative therapeutic possibilities for patients with DCM.Microstructural characterization by DTI Microvascular characterization by MBF