Preclinical model could aid future research of heart attack therapies

Researchers have detailed a new preclinical model for non-ST elevation myocardial infarction (NSTEMI), which they hope will aid in the development of future strategies for the treatment of NSTEMI patients.

Published in Nature Communications in February, the preclinical model is the output of a research collaboration between CÚRAM SFI Research Centre for Medical Devices at the National University of Ireland Galway (Galway, Ireland) alongside University of Milano-Bicocca (Milan, Italy), University of Paris Est Créteil (Paris, France), University of Gothenburg (Gothenburg, Sweden) and the Lithuanian University of Health Sciences (Kaunas, Lithuania).

Patients who survive a heart attack have variable degrees of damage to their cardiac tissue, which can lead to heart failure. In the last two decades, NSTEMIs have markedly risen in hospitalised patients. NSTEMI results in a smaller amount of tissue damage compared to ST segment elevation myocardial infarction (STEMI), though recent clinical registry data show that NSTEMIs are associated with higher long-term mortality than STEMIs.

Currently, preclinical models of heart attack mimic only full-thickness STEMI and hence cater only for an investigation into therapeutics and interventions directed at the NSTEMI subset of heart attack.

Paolo Contessotto and Renza Spelat (both National University of Ireland Galway, Galway, Ireland), who were co-authors on the study, comment: “Advanced analyses on the affected heart tissue highlighted a distinctive pattern of alterations in the tissue, especially in the sugar moieties (glycans) which compose cardiac cell membranes and extracellular matrix (the network of proteins and other molecules that surround, support, and give structure to cells and tissues in the body). Identifying such changes in molecular elements that can be accessed and treated with injectable drugs sheds light on how we can develop targeted pharmacological solutions to correct these changes.”

In this new study, researchers have developed a preclinical model of NSTEMI by adopting a novel surgical procedure in an ovine model that closely resembles the complexity of clinical cases in humans. Researchers validated the presented model by comparing it with an established method to achieve STEMIs. They performed a detailed analysis at the main acute and late time points after the induction of NSTEMI, at seven and 28 days, respectively.

Adds Abhay Pandit, CÚRAM Scientific Director and senior author of the study: “There is a need in the field to adopt clinically relevant models to study NSTEMI pathophysiology and reveal its functional differences with STEMI induction. This new model will facilitate the translation of future research in the field, enabling the discovery of new clinically relevant treatments for patients.”

Mark Da Costa, clinical investigator at CÚRAM and senior author of the study, said: “Currently, NSTEMI is the most common presentation of acute heart attack. The concern is that NSTEMI patients have lower in-patient (during their admission for the primary NSTEMI) and short-term mortality rates but significantly higher longterm mortality than those of STEMI patients. A Danish registry study of 8,889 patients showed that the five-year mortality after NSTEMI was 16%, and another registry study highlighted a 10year survival rate of only around 50%. To the best of our knowledge, there are currently no models that can reproduce

Finding the roots of the disease before treating it: Modelling non-ST elevation myocardial infarction

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 postNSTEMI) 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 both the functional and histological characteristics of NSTEMIs. This novel model may specifically serve as a preclinical foundation to study interventions that could combat the short and long-term effects of NSTEMI.” 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.