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Introduction and aims Cardiac fibrosis is characterized by the net accumulation of extracellular matrix (ECM) proteins in the cardiac interstitium and contributes to cardiac contractile dysfunction. In Duchenne muscular dystrophy (DMD), cardiomyopathy develops as a result of a dystrophin deficiency causing fibrofatty replacement of the myocardium, however the underlying mechanisms are not fully understood. There is a growing collection of evidence that ECM proteins, including Tenascin C (TN-C), plays a maladaptive role in left ventricular (LV) remodelling and cardiac fibrosis in ischemic heart disease. The aims of our study were 1) to assess TN-C levels, fibrosis and cardiac dysfunction in DMD patients, and 2) to clarify the role of TN-C in cardiovascular dysfunction and fibrosis using male mdx (n=10) and mdx TN-C KO mice (n=8). Results In male patients with DMD (n=18) and age matched controls (n=12) undergoing cardiac MRI, we detected greater myocardial fibrosis than in control hearts. In addition, we observed an elevation of TN-C plasma levels [median concentration (3.55); interquartile range (0.61–7.43) ng/mL] in DMD patients, and its expression negatively correlated to LV ejection fraction (EF) [median LVEF (45); interquartile range (37.5–51.5) %]. Male wt, mdx and mdx TN-C KO age-matched (10 months) mice were used. Transthoracic echocardiography was performed and fibrosis was assessed on cardiac tissue sections. Wire myography was used to assess vascular endothelial function. To explore the signalling pathways contributing to cardiac fibrosis, human cardiac fibroblasts (hCFs) were treated with recombinant human TN-C or TGF-β and gene expression and epigenetic regulation of NF-kB/p65 were assessed. Mdx mice showed significantly increased cardiac fibrosis which was accompanied with markedly elevated TN-C level in cardiac tissue and plasma compared to wt animals (p<0.05, respectively). Moreover, TN-C level in plasma correlated positively with the degree of cardiac dilation in dystrophic mice. In addition, vascular endothelial function was notably impaired in mdx mice. In contrast, we observed preserved vascular function in mdx- TN-C KO mice, this was accompanied by a significant reduction in cardiac fibrosis in compared to age-matched mdx mice (p<0.05, respectively). hCFs treated with TN-C or TGF-β showed increased collagen and α-SMA expressions which could be prevented by application of siRNA against TN-C. In addition, both TN-C and TGF-β caused p65/NF-κB promoter demethylation and subsequently triggered pro-inflammatory and pro-fibrotic signalling, which could be reversed by applying p38 MAPK inhibitor in hCFs. Conclusion TN-C is a critical component of cardiac fibrosis and cardiac dysfunction in DMD. The activation of NF-κB p65 signalling pathway may play a role in TN-C induced fibrosis. Thus, TN-C may be a mediator and potential target for therapy in DMD-associated cardiovascular complications. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Österreichische MuskelforschungFWF - Austrian Science Found P 35878

Background: Patients with muscular dystrophy (MD) are at elevated risk of serious cardiac complications and clinical assessment is limited due to inherent physical limitations. We assessed the utility of left ventricular ejection fraction (LVEF) derived from transthoracic echocardiogram (TTE) as a prognostic marker for major adverse cardiac events (MACE) in a mixed adult MD cohort. Methods: One hundred and sixty-five MD patients (median age: 36 (interquartile range [IQR]: 23.0-49.0) years; 65 [39.4%] females) were enrolled in our prospective cohort study. Diagnoses included dystrophinopathies (n = 42), limb-girdle MD (n = 31), type 1 myotonic dystrophy (n = 71), and facioscapulohumeral MD (n = 21). Left ventricular ejection fraction, ventricular dimensions at end-diastole and end-systole, and serial measures (n = 124; follow-up period: 2.19 [IQR: 1.05-3.32] years) stratified patients for MACE risk. Results: Cardiomyopathy was diagnosed in 60 (36.4%) patients of the broader cohort (median LVEF: 45.0 [IQR: 35.0-50.0] %). Ninety-eight MACE occurred over the 7year study period. At baseline, patients with a LVEF < 55.0% had a high risk of MACE (adjusted odds ratio: 8.30; 95% confidence interval [CI]: 3.18-21.7), concordant with the analysis of LV dimensions. Forty-one percent of these patients showed an improvement in LVEF with the optimization of medical and device therapies. Relative to patients with preserved LVEF, patients with reduced LVEF were at an elevated risk of MACE (adjusted hazard ratio [aHR]: 7.21; 95% CI: 1.99-26.1), and improved LVEF resulted in comparable outcomes (aHR: 1.84; 95% CI: .49-6.91) associated with optimization of medical and device therapies. Reduction in QRS duration by CRT therapy was associated with an improvement in LVEF (average improvement: 12.8 [± 2.30] %; p = .04). Conclusions: Reduction in LVEF indicates an increased risk of cardiovascular events in patients with MD. Baseline and serial LVEF obtained by TTE can prognosticate patients for MACE and guide clinical management.

Background Heart disease is an under-recognized cause of morbidity and mortality in patients with Emery-Dreifuss muscular dystrophy (EDMD). Arrhythmias and conduction delays are highly prevalent and given the rarity of this disease the patient care process remains poorly defined. Case summary This study closely followed four adult patients from the Neuromuscular Multidisciplinary Clinic (Alberta, Canada) that presented with X-linked recessive EDMD. Patients were assessed and managed on a case-by-case basis. Clinical status and cardiac function were assessed through clinical history, physical examination, and investigations (12-lead electrocardiogram, 24-hour Holter monitor, transthoracic echocardiogram, and plasma biomarkers). Conduction disease, requiring permanent pacemaker, was prevalent in all patients. With appropriate medical therapy over a median follow-up period 5 years the cardiac status was shown to have stabilized in all these patients. Discussion and Conclusion We demonstrate the presentation of arrhythmias, conduction abnormalities, and chamber dilation in adult patients with X-linked EDMD. Cardiac medications and pacemaker therapy are shown to prevent adverse outcomes from these complications. Patients with EDMD are expected to develop heart disease early and prior to the development of an overt neuromuscular phenotype. These patients should be closely monitored in a multidisciplinary setting for effective management to improve their clinical outcomes.