Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.

Aims Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI. Methods and results In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF. Conclusion Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure.

Aims The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies. Methods and results We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups. Conclusions All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.

Heart failure with reduced ejection fraction (HFrEF) is defined by an ejection fraction (EF) below 40%. Many distinct disease processes culminate in HFrEF, among them acute and chronic ischemia, pressure overload, volume overload, cytotoxic medication, and arrhythmia. To study these different etiologies the development of accurate animal models is vital. While small animal models are generally cheaper, allow for larger sample sizes and offer a greater variety of transgenic models, they have important limitations in the context of HFrEF research. Small mammals have much higher heart rates and distinct ion channels. They also have much higher basal metabolic rates and their physiology in many ways does not reflect that of humans. The size of their organs also puts practical constraints on experiments. Therefore, large animal models have been developed to accurately simulate human HFrEF. This review aims to give a short overview of the currently established large animal models of HFrEF. The main animal models discussed are dogs, pigs, and sheep. Furthermore, multiple approaches for modeling the different etiologies of HF are discussed, namely models of acute and chronic ischemia, pressure overload, volume overload as well as cytotoxic, and tachycardic pacing approaches.

We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling.