Acute occlusion of a coronary artery can result in myocardial infarction-a leading cause of premature death. Prompt restoration of blood flow to the myocardium can prevent excessive death of cardiomyocytes and improve clinical outcome. Although the major mechanism of cell death after reperfusion is necrosis, it is now recognized that many other cell death pathways may be involved in ischemia-reperfusion (I/R) injury. Pyroptosis is one such cell death pathway that is caspase-1-dependent and induced in response to cellular insult. The activated caspase-1 protease cleaves and activates specific cellular targets including gasdermin D and the pro-inflammatory cytokines interleukin-1 and interleukin-18. The Nterminal fragment of gasdermin D forms plasma membrane pores resulting in cytosolic leakage and cell rupture, releasing interleukin-1beta and interleukin-18. Evidence suggests that inflammation induced by I/R via the pyroptotic pathway contributes to cardiomyocyte death, excessive scar formation and poor ventricular remodeling. For this reason, there is growing interest in targeting components of the pyroptotic pathway as a means of reducing I/R injury.

Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. Aims The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. Methods and results Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralising compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS, or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size. Conclusion Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. Translational perspective Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). New approaches are needed to prevent cardiomyocyte injury and limit final infarct size. We show that histones released from damaged cells, and histone-H4 in particular, causes rapid cardiomyocyte death during I/R. mCBS, a compounds targeting histones non-specifically, was cardioprotective in ex vivo rat hearts, while HIPe, a targeting histone H4 specifically, was cardioprotective in an in vivo rat model. HIPe may have potential as a therapeutic agent in the setting of acute myocardial infarction.

clinics' (VC). A team of Cardiologists and General Practitioners (GP) collaborated to create a VC via a web-based video link, enabling discussion of patients being considered by primary care for referral to the Cardiology clinic. All available GPs were present to enable an educational aspect to the discussion, and the aim of the VC was to: (i) identify appropriate patients requiring OP review, (ii) enable early selection of required investigations, and (iii) identify patients not requiring further assessment. We aimed to assess the safety and efficacy of this approach. Methods VC's were established between a Consultant Cardiologist and two primary care practices, and all referrals required an ECG. Each patient was presented by the referring GP, and the Consultant Cardiologist issued correspondence and coordinated any required tests and follow-up. A 13 month period of this practise was reviewed with 135 patient events screened via a cross-matched record of patients. Data was recorded for: indication for and outcome of discussion; likelihood patient would have had test or referral made without this service (as assessed by Cardiology); and whether patients discussed had a subsequent unplanned admission or cardiac assessment. Results 8/135 were excluded (duplicate; admitted prior to VC; not discussed; or re-discussed for learning). Efficacy Outcomes of the VC are summarised in table 1. The overall number of patients a GP 'would' have referred was 113 (89%), and the number that 'would' have had tests booked 98 (77%), across the two practises. This left an overall OPA post VC of 11% vs a potential 89% 'would' have been referred (100 potential appointments avoided), and an overall test rate post VC 48% vs 77% 'would' have had tests (37 potential tests avoided). Safety Unplanned Cardiology input post-VC included 1 subsequent chest pain clinic, a different issue to the original VC discussion, and 1 admission with syncope, which was the issue that was discussed in VC but with no pathology identified during admission. Conclusion We demonstrated a significant reduction in OP Cardiology appointments and hospital investigations, proving improved resource utilisation, and the associated safety data was reassuring. As a result, this service demonstrates a novel approach to technology-enabled streamlining of primary to secondary care services in a safe and efficient manner.