Lead author Dr. King, a professor in the Department of Bioengineering and Cardiology at UC San Diego, said ischemic heart disease is the most common cause of death worldwide. It begins with a “heart attack,” also called myocardial infarction, which causes part of the heart to die due to defective coronary blood flow. This leads to
acute inflammation, heart wall remodeling, and heart failure.
Anti-inflammatory medications have proven surprisingly ineffective at preventing heart failure. As a result, they are not an integral part of post-infarction care. However – add the authors – it is possible that we will discover, in the future, more powerful targets of inflammation.
The study leads to the discovery of a new mechanism of cardiac inflammation which could make it possible to avoid or
prevent this progression from heart attack to heart failure.
Inflammation after myocardial infarction is attributed to certain immune cells including neutrophils and macrophages that infiltrate the heart. However, the team observes here, with surprise, that the pro-inflammatory response is activated, not at the level of the infarct where the immune cells are concentrated, but rather in the border zone, which surrounds the infarct. heart attack.
However, this border zone remains little studied in myocardial infarction. This is where surviving heart muscle cells attempt to stabilize and even proliferate after being disconnected from their dying neighboring cells. This boundary zone is difficult to study because it is not easily isolated from the rest of the heart. Here, researchers use new techniques, such as spatial transcriptomics, which allow border zone cells to be recognized based on their gene expression patterns.
Objective, identify the cells responsible for inflammation of the “borderline” zone surrounding the infarction: in order to identify the type of cells that triggers inflammation in this “border” zone, the team created a series of mouse models, each type each incapable of initiating the pro-inflammatory response in a different cell type. These tests reveal that:
- cardiac muscle cells called cardiomyocytes initiate the pro-inflammatory response – or type 1 interferon IFN signaling – at the border zone;
- mechanically stressed cardiomyocytes in this area frequently exhibit disruption of the nuclear envelope, which allows leakage of nuclear DNA and induces activation of IFN signaling;
- this process is responsible for a mechanical weakening of the heart wall, making it more vulnerable to dilation, thinning and rupture.
Taken together, these observations suggest that limiting mechanical stress at the boundary zone, inhibiting DNA sensing, and preventing type I IFN signaling constitute new avenues to follow, in order to prevent the progression of the crisis to heart failure.
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