New research shows how heart inflammation can progress into heart failure in mice.
Myocarditis occurs when an infection has reached the heart. During an infection, the body's immune system produces disease-fighting cells - but in heart inflammation, these cells enter the heart and can damage its muscle.
The condition is not often diagnosed; it rarely causes severe symptoms and detecting it requires a heart biopsy - a rather invasive procedure of moderate risk.
In some cases, myocarditis progresses into inflammatory dilated cardiomyopathy (DCMi) - a disorder in which the heart's muscle dilates, weakens, and can no longer properly pump blood. In the United States, DCMi is one of the leading causes of heart failure among younger adults, with a prevalence of between 300 and 400 patients per million U.S. adults.
New research, led by Dr. Daniela Cihakova from the Johns Hopkins University School of Medicine in Baltimore, MD - set out to understand why in some cases the heart heals from the inflammation, while in others it progresses into DCMi.
As the authors of the new paper mention, previous studies have pointed to the role of eosinophils - a specific type of immune cell - in the development of heart disease. As Dr. Cihakova explains, the new research "provide[s] more details about how these immune system cells may lead to deterioration of heart muscle function in mice in a way that lets us draw some parallels to human disease processes."
The findings were published in The Journal of Experimental Medicine.
Studying the role of eosinophils in heart failure
Dr. Cihakova and colleagues genetically modified a group of mice to have a deficiency of eosinophils. They then induced myocarditis in this group, using a technique called experimental autoimmune myocarditis. In this procedure, mice receive a peptide from their heart muscle cells, which makes the body's immune system attack the heart.
The researchers also induced myocarditis in another group of normal mice, with a healthy level of eosinophils. After 21 days, the scientists measured the inflammation in the hearts of both groups of mice.
They also analyzed the hearts for fibrosis or scar tissue - both signs of dying heart muscles in mammals. Scar tissue is also present in cases of DCMi.
The scientists found similarly acute inflammation in both groups.
However, when the scientists examined the groups for signs of heart failure, they found drastic differences between the eosinophil-deficient group and the normal group.
The mice with normal levels of eosinophils went on to develop heart failure, whereas the mice with eosinophil deficiency displayed no signs of heart malfunction.
The team also found scar tissue in both groups to a similar degree. However, the normal mice had DCMi, while the eosinophil-deficient ones were not affected.
The role of eosinophils confirmed by second experiment
To see if they could replicate their findings, the team designed an additional experiment in which they genetically modified mice to have an excess of an eosinophil-producing protein called IL5.
The IL5-excessive mice developed more inflammation and more scar tissue in the heart's upper chambers (or atria) compared with normal mice.
Mice with excessive IL5 protein also had more heart-infiltrating cells. As much as 60 percent of these cells were eosinophils in the IL5-excessive mice, compared with only 3 percent in the normal mice.
Additionally, the researchers examined the mice's hearts 45 days after the experiment and found severe DCMi in the mice with too much IL5 protein.
Finally, to account for the possibility that it is the IL5 protein and not the eosinophils that drive DCMi development, the team genetically modified eosinophil-deficient mice to have an excess of the protein.
The researchers found no reduction in the heart function of these IL5-excessive, eosinophil-deficient mice, compared with normal mice. This confirms that it is the immune cells, not the protein, that causes DCMi.
Eosinophil-made protein increases likelihood of post-myocarditis DCMi
In an attempt to understand exactly how eosinophils are responsible for DCMi, the researchers investigated further and managed to isolate a protein called IL4, which is produced by eosinophils.
Using yet another mouse model, Dr. Cihakova and team established that it is indeed the IL4 that facilitates the development of DCMi, and which is triggered by eosinophils.
"The take-home message is that inflammation severity does not necessarily determine long-term disease progression, but specific infiltrating cell types - eosinophils, in this case - do."
Dr. Daniela Cihakova
The study's senior author points out that their study is the first one to investigate the role of eosinophils in the onset of heart inflammation, and in its development from inflammation to DCMi.
Nicola Diny, a Ph.D. student in the Bloomberg School of Public Health and the study's first author, also comments on the findings:
"Our studies show that the presence of eosinophils in the heart makes mice more likely to get DCMi following myocarditis. And if there are a lot of eosinophils, the mice develop even more severe heart failure," Diny says. "It will be important to test if the same is true in patients. That way, we may be able to intervene early and prevent DCMi."
The researchers hope that their study will help to develop IL4-targeting medicines that could one day treat people with myocarditis, thus potentially halting its progression into DCMi.