Cardioprotective Effect of Nec-1 in Rats Subjected to MI/R: Downregulation of Autophagy-Like Cell Death

Objective. Necrostatin-1 (Nec-1), an inhibitor of necroptosis, has been reported to protect against myocardial ischemia-reperfusion (MI/R) injury. However, the contribution of the potential antinecroptotic effect of Nec-1 on its infarct limitation and cardiac function improvement effects after MI/R has not been investigated. Methods. The present study investigated the effect of Nec-1 on myocardial infarct size, necroptosis, and cardiac functional recovery in rats subjected to myocardial ischemia-reperfusion (MI/R 30 min/12, 24, 48, and 72 h). Results. The study showed that Nec-1 might reduce myocardial cell death and maintain myoarchitectonic integrity, consequently inhibiting the reactive fibrosis process in rats in myocardial ischemia/late reperfusion. Moreover, the administration of Nec-1 (0.6 mg/kg) at the onset of reperfusion significantly reduced the release of creatine kinase and downregulation of autophagy within 24 h after reperfusion, and there was a significantly positive correlation between them. Conclusion. These results suggest that antinecroptosis treatment may improve the clinical outcomes of patients with ischemic heart disease.

The Role of Cardiac Magnetic Resonance in Patients with Dilated Cardiomiopathy

Dilated cardiomyopathy (DCM) has an increased risk of heart failure, malignant ventricular arrhythmias, including sudden cardiac death, being the most common cause of heart transplantation. Cardiac magnetic resonance imaging (CMR) is the gold standard technique for assessing left and right ventricular function; the major advantage of CMR is the possibility of tissue characterization, highlighting the replacement of myocardial fibrosis (late gadolinium enhancement - LGE technique) and the interstitial and perivascular reactive fibrosis (mapping techniques - T1 mapping, T2-mapping, T2 * -mapping). Myocardial fibrosis pattern helps to establish the DCM aetiology and has prognostic and therapeutic implications. LGE presence is associated with a weaker therapeutic response and an increased risk of complex ventricular arrhythmias. At the same time, LGE absence associated with the presence of reactive fibrosis quantified by mapping techniques and especially by increasing myocardial extracellular volume, identifies patients with potentially favourable response to optimal drug therapy and cardiac resynchronization therapy.

Female sex, atrial fibrillation, and heart failure, but not ageing, are associated with endomysial fibrosis in atrial myocardium: results from the CATCH ME consortium

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME Horizon 2020, EU-H2020-PHC-RIA (633196) CVON2014-09, RACE V: Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF Background Atrial fibrosis is one of the most important aspects of structural remodeling in the atria and largely increases the inducibility and sustainability of AF. The main risk factors for recurrent AF, such as ageing, heart failure, and history of AF, partly enhance AF propensity by inducing atrial fibrosis. A distinction should be made between replacement fibrosis following myocyte death and reactive fibrosis, which often occurs in the absence of myocyte death. Endomysial fibrosis, a type of reactive fibrosis in between cardiomyocytes, is poorly studied as a result of limitations and labor intensiveness of traditional histochemical quantification. Purpose We examined the contributions of age, sex, AF and heart failure to the development of overall and endomysial fibrosis in the context of concurrent pathologies. Methods We developed an algorithm for automated quantification of multiple features of structural remodeling following myocardial staining with wheat germ agglutinin (WGA). We studied the type, quantity and distribution of fibrosis in left (LAA, n = 95) and right (RAA, n = 76) atrial appendage biopsies in a large European cohort of patients with varying indications for cardiac surgery. Linear mixed effect models were constructed to predict endomysial fibrosis quantity and clustering as a function of AF, heart failure, sex, age and 4 principle components that accounted for potential confounding due to other clinical characteristics. Results Persistent AF, heart failure and female sex were independently associated with endomysial fibrosis, age was not. AF and age were not associated with overall fibrosis. Clustering of endomysial fibrosis was observed in females (LAA), paroxysmal AF (RAA), persistent AF and heart failure (LAA) patients (table 1). Conclusions Female sex, AF, and heart failure are associated with the quantity and distribution of endomysial fibrosis, the effects of age are limited. summary of results Clinical parameter Overall fibrosis Endomysial fibrosis Clustering of endomysial fibrosis LAA RAA LAA RAA LAA RAA Paroxysmal AF +1.6%±1.5; p = 0.29 +2.1%±2.2; p = 0.34 -0.7μm ± 0.5; p = 0.19 +1.0μm ± 0.6; p = 0.10 -0.8%±3.6; p = 0.82 +7.4%±4.1; p = 0.04 Persistent AF +1.6%±1.5; p = 0.26 +2.2%±2.1; p = 0.30 +1.1μm ± 0.5; p = 0.04 +1.3μm ± 0.6; p = 0.03 +5.7%±0.03; p = 0.04 +6.9%±3.9, p = 0.04 Heart failure +4.8%±1.5; p = 0.01 +2.3%±2.0; p = 0.24 +2.5μm ± 0.5; p < 0.001 +0.3μm ± 0.5; p = 0.53 +16.9%±3.4; p < 0.001 +0.8%±3.6; p = 0.82 Female sex +4.5%±1.8; p = 0.01 +0.8%±2.5; p = 0.76 +1.5μm ± 0.6; p = 0.01 -0.4μm ± 0.7; p = 0.58 +12.9%±3.9; p< 0.01 -3.3%±4.8; p = 0.49 Age +0.5%±0.3; p = 0.17 +0.4%±0.4; p = 0.34 +0.1μm ± 0.1; p = 0.39 +0.05μm ± 0.1; p = 0.97 +0.9%±0.8; p = 0.11 -0.02%±0.8; p = 0.49 Values presented are effect estimates ± SD as obtained from the described linear mixed models. P-values were estimated using the Kenward-Roger approximation. The effect of age is presented as increase per 5 years of age.

Abstract 482: Beta-catenin Activation in Cardiac Fibroblasts Modulates the Immune Micro-environment to Promote Fibrosis and Heart Failure Following Chronic Injury

Almost 6.5 million people in United States suffer from heart failure (HF). Diastolic HF following non-ischemic cardiac insult is a progressive condition with limited effective therapies underscoring the urgency to invest in identifying novel therapeutic targets for treatment. Reactive fibrosis in response to pathological stress is one of the major causes of diastolic HF. Emerging data suggest an association of systemic inflammation with reactive fibrosis and HF. Canonical Wnt/beta-catenin signaling has been linked to HF and fibrosis with limited understanding of the precise cellular and molecular mechanism. We utilized thoracic aortic constriction (TAC), a well-defined model of HF, to study Wnt signaling mediated reactive fibrosis. TAC was induced in a transgenic mouse model with stabilized beta-catenin (Wnt signaling) in fibroblasts (Bcat/Postn). Wnt activation following TAC resulted in increased maladaptive reactive fibrosis, HF marker ANP, and cardiac hypertrophy with preserved Ejection Fraction (pEF) suggesting Wnt-mediated progression of diastolic heart failure with pEF. TAC also resulted in increased macrophage activation and recruitment of CD8+ cytotoxic T-cells. In vitro co-culture of Wnt3a-overexpressing fibroblasts with activated myeloid cells promoted fibroblast proliferation and collagen synthesis. Therefore, we hypothesize that Wnt signaling activation promotes interstitial fibrosis via recruitment of specific inflammatory cells. Genomic analysis further supports this by demonstrating distinct chemokine gene expression patterns in fibroblasts resulting from Wnt activation in these injury models. Our future goal is to elucidate the role of Wnt signaling in modulating the fibroblast-immune cell crosstalk in modulating interstitial fibrosis induced diastolic HFpEF. Currently, there is no approved therapy to specifically target reactive fibrosis to avert diastolic dysfunction. Our study is aiming to identify targetable cellular and molecular players that improve, prevent or avert reactive fibrosis mediated HFpEF in order to reduce the incidence and severity of pathology resulting from HF.