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Researchers Develop a Preclinical Model of Non-ST-Segment Elevation Myocardial Infarction

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Non-ST-segment elevation myocardial infarction (NSTEMI) is a type of heart attack that occurs when the blood flow to a part of the heart is reduced or blocked. It is the leading cause of cardiovascular-related worldwide mortality, and its incidence has risen sharply in hospitalised cases over the last two decades.

Unfortunately, the currently adopted animal models of myocardial infarction only mimic full-thickness ST-segment elevation myocardial infarcts (STEMI), limiting investigations into interventions directed at NSTEMI. However, a team of researchers has now developed a preclinical model of NSTEMI in sheep to study its pathophysiology and functional differences with STEMI induction.

The study, which was published in the journal Nature Communications, describes how the researchers used a precise ligation technique to develop a preclinical model of NSTEMI in sheep. They then performed a histological and functional investigation, comparing this model with the STEMI full ligation model. The team discovered that RNA-seq and proteomics showed distinctive features of post-NSTEMI tissue remodelling, and pathway analyses at acute (7 days) and late (28 days) post-NSTEMI pinpointed specific alterations in the cardiac post-ischemic extracellular matrix.

According to Dr Paolo Contessotto, a researcher from the University of Padova: “Myocardial infarction is an acute complication of coronary artery disease and is a major cause of mortality worldwide. The two main types of MI are ST-elevation (STEMI) and Non-ST elevation (NSTEMI).

“MI patients who survive an infarct have variable degrees of damage to the cardiac tissue, and this can lead to lethal heart failure in a significant proportion of these patients. By identifying changes in molecular moieties accessible to injectable drugs, this study sheds light on developing targeted pharmacological solutions to contrast heart attack.”

The researchers found that NSTEMI ischaemic regions had distinctive patterns of complex galactosylated and sialylated N-glycans in cellular membranes and extracellular matrix. These changes in molecular moieties can be targeted by infusible and intra-myocardial injectable drugs, thereby providing insight into developing targeted pharmacological solutions to counteract adverse fibrotic remodelling.

The team’s findings suggest that the preclinical model of NSTEMI in sheep can be a valuable tool for investigating the pathophysiology of NSTEMI and developing targeted interventions. The NSTEMI model had distinctive features of post-NSTEMI tissue remodelling that were not observed in the STEMI model. The researchers believe that this model could help in the development of targeted pharmacological solutions to counteract adverse fibrotic remodelling in patients with NSTEMI.

The study also found that the cardiac post-ischemic extracellular matrix had specific alterations at acute (7 days) and late (28 days) post-NSTEMI. This is important because the extracellular matrix plays a crucial role in myocardial remodelling and fibrosis after a heart attack. The findings suggest that targeting the extracellular matrix may be a promising approach for developing interventions to mitigate the adverse effects of NSTEMI.

In addition, the study highlights the importance of animal models in preclinical research. By developing a preclinical model of NSTEMI in sheep, the researchers were able to investigate the pathophysiology and functional differences with STEMI induction. Animal models provide a valuable tool for testing new interventions and therapies before they are tested in human trials.

This research provides a valuable tool for investigating the pathophysiology of NSTEMI and developing targeted interventions. The NSTEMI model developed in this study fills an important gap in the current animal models of myocardial infarction, which only mimic full-thickness STEMI infarcts. By allowing researchers to study the distinct pathophysiology and functional differences of NSTEMI, this model can help to identify new targets for drug development and test the efficacy of potential treatments.

“These efforts are for Europeans who, by fighting against the odds, imagine a leading role of our continent,” Contessotto concluded.

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