Finding the roots of the disease before treating it: Modelling NSTEMI

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Paolo Contessotto (National University of Ireland Galway, Galway, Ireland) outlines his research developing a preclinical model for non-ST elevation myocardial infarction (NSTEMI) and discusses how this could aid in the future development of strategies to treat patients with this condition.

How many times do we read a scientific article which starts with a mere numbering of the worldwide clinical cases of a certain pathology, and how many times are those data actually reversed by the entry in the scene of the proposed—mostly preclinically promising—therapy described in such articles? Indeed, several clinical fields currently fight with the lack of suitable animal preclinical models which can accurately reproduce the disease of interest.

Nowadays, in the cardiovascular field, a clear rise in non-full thickness infarcts, also known as NSTEMI, is affecting a significant portion of both hospitalised and non-hospitalised patients, therefore representing a major socioeconomic issue.

Patients affected by NSTEMIs differ from STEMIs since they can present with more subtle symptoms, and a marked decrease in ejection fraction (EF) is not usually shared among all these patients. Nonetheless, so far preclinical studies aiming to discover solutions to tackle MI were addressing full-thickness infarcts and therefore did not specifically target the other subtype of MI. Moreover, advances in high-throughput analyses which are able to provide us with details on the complexity of the pathological environment following cardiac ischaemia, basically the death of the main cells composing the heart muscle, were only partially applied and exploited.

In this study recently published in Nature Communications, resulting from a collaboration across multiple prestigious academic institutions in Europe, the researchers develop and fully characterise a preclinical model of NSTEMI and pave the way towards possible specific therapeutic interventions to treat the worst adverse long-term outcome of MI—heart failure.

Through a meticulous experimental design which took into consideration the key phases of post-ischaemia cardiac remodelling, care was taken to investigate the early (seven days post-NSTEMI) and progressive (28 days) steps from when the pathology was induced in sheep. Notably, the employment of a really limited (21) pool of these animals under stringent European regulations, allowed a reasoned significant decrease in the usually much higher use adopted in studies published in prestigious journals using other types of animals (mainly mice and rats), which do not possess similar anatomical proportions and as complex physiological response when compared to humans or large animals.

A precise procedure based on multiple ligations lateral and parallel to the left anterior descending coronary artery (LAD) was adopted and consistently reproduced to achieve focal, non-full thickness infarcts in the left ventricle. Researchers observed a progressive deterioration of the affected ischaemic tissue from the first week until the endpoint of the study by looking at the deposition of a fibrotic scar to replace the dead cardiac cells as well as the invasion of immune cells during the immediate inflammatory phase post-MI.

Here, most interestingly, omics analyses looking at gene expression and protein data suggested a clear role of other moieties which heavily characterise the inflammatory cell populations which invade the region. Indeed, glycans, which represent one of the most abundant post-translational modifications in the cells present in our body, switched their profile depending on the cell types which were present at the specific moment evaluated in the study. Therefore, by the identification of such molecular targets to be modulated within a certain time window post-MI, researchers introduce in the field the relevance of such potential therapeutic strategy to contrast adverse fibrotic remodelling, and by consequence, heart failure.


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