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Background Periodic repolarization dynamics (PRD) is an electrocardiographic biomarker that captures repolarization instability in the low frequency spectrum and is believed to estimate the sympathetic effect on the ventricular myocardium. High PRD indicates an increased risk for postischemic sudden cardiac death (SCD). However, a direct link between PRD and proarrhythmogenic autonomic remodeling has not yet been shown. Methods and Results We investigated autonomic remodeling in pigs with myocardial infarction (MI)–related ischemic heart failure induced by balloon occlusion of the left anterior descending artery (n=17) compared with pigs without MI (n=11). Thirty days after MI, pigs demonstrated enhanced sympathetic innervation in the infarct area, border zone, and remote left ventricle paralleled by altered expression of autonomic marker genes/proteins. PRD was enhanced 30 days after MI compared with baseline (pre‐MI versus post‐MI: 1.75±0.30 deg2 versus 3.29±0.79 deg2, P

Atrial fibrillation (AF) is the most prevalent arrhythmia, often caused by myocardial ischemia/infarction (MI). Men have a 1.5× higher prevalence of AF, whereas women show a higher risk for new onset AF after MI. However, the underlying mechanisms of how sex affects AF pathophysiology are largely unknown. In 72 pigs with/without ischemic heart failure (IHF) we investigated the impact of sex on ischemia-induced proarrhythmic atrial remodeling and the susceptibility for AF. Electrocardiogram (ECG) and electrophysiological studies were conducted to assess electrical remodeling; histological analyses were performed to assess atrial fibrosis in male and female pigs. IHF pigs of both sexes showed a significantly increased vulnerability for AF, but in male pigs more and longer episodes were observed. Unchanged conduction properties but enhanced left atrial fibrosis indicated structural rather than electrical remodeling underlying AF susceptibility. Sex differences were only observed in controls with female pigs showing an increased intrinsic heart rate, a prolonged QRS interval and a prolonged sinus node recovery time. In sum, susceptibility for AF is significantly increased both in male and female pigs with ischemic heart failure. Differences between males and females are moderate, including more and longer AF episodes in male pigs and sinus node dysfunction in female pigs.

Atrial fibrillation (AF) is a major healthcare challenge contributing to high morbidity and mortality. Treatment options are still limited, mainly due to insufficient understanding of the underlying pathophysiology. Further research and the development of reliable animal models resembling the human disease phenotype is therefore necessary to develop novel, innovative and ideally causal therapies. Since ischaemic heart failure (IHF) is a major cause for AF in patients we investigated AF in the context of IHF in a close-to-human porcine ischaemia-reperfusion model. Myocardial infarction (AMI) was induced in propofol/fentanyl/midazolam-anaesthetized pigs by occluding the left anterior descending artery for 90 minutes to model ischaemia with reperfusion. After 30 days ejection fraction (EF) was significantly reduced and haemodynamic parameters (pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), left ventricular enddiastolic pressure (LVEDP)) were significantly elevated compared to age/weight matched control pigs without AMI, demonstrating an IHF phenotype. Electrophysiological properties (sinus node recovery time (SNRT), atrial/AV nodal refractory periods (AERP, AVERP)) did not differ between groups. Atrial burst pacing at 1200 bpm, however, revealed a significantly higher inducibility of atrial arrhythmia episodes including AF in IHF pigs (3/15 vs. 10/16, p = 0.029). Histological analysis showed pronounced left atrial and left ventricular fibrosis demonstrating a structural substrate underlying the increased arrhythmogenicity. Consequently, selective ventricular infarction via LAD occlusion causes haemodynamic alterations inducing structural atrial remodeling which results in increased atrial fibrosis as the arrhythmogenic atrial substrate in pigs with IHF.

Abstract Background Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer’s disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. Results We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L, ANK1, MAP2, LRRC8B, STK32C and S100B. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17. Conclusions Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.