Abstract
Previous mouse studies have shown the increased presence of platelets in the myocardium during early stages of myocarditis and their selective detection by MRI. Here, we aimed to depict early myocarditis using molecular contrast-enhanced ultrasound of activated platelets, and to evaluate the impact of a P2Y12 receptor platelet inhibition. Experimental autoimmune myocarditis was induced in BALB/c mice by subcutaneous injection of porcine cardiac myosin and complete Freund adjuvant (CFA). Activated platelets were targeted with microbubbles (MB) coupled to a single-chain antibody that binds to the “ligand-induced binding sites” of the GPIIb/IIIa-receptor (=LIBS-MB). Alongside myocarditis induction, a group of mice received a daily dose of 100 g prasugrel for 1 month. Mice injected with myosin and CFA had a significantly deteriorated ejection fraction and histological inflammation on day 28 compared to mice only injected with myosin. Platelets infiltrated the myocardium before reduction in ejection fraction could be detected by echocardiography. No selective binding of the LIBS-MB contrast agent could be detected by either ultrasound or histology. Prasugrel therapy preserved ejection fraction and significantly reduced platelet aggregates in the myocardium compared to mice without prasugrel therapy. Therefore, P2Y12 inhibition could be a promising early therapeutic target in myocarditis, requiring further investigation.
Highlights
Myocarditis represents a challenging diagnosis due to the heterogeneity of its clinical manifestations and the lack of sensitive and specific diagnostic tools, including the current gold standard endomyocardial biopsy [1]
Mice with late-phase myocarditis (28 days after first injection of myosin and complete Freund adjuvant (CFA)) had a significantly impaired ejection fraction (mean 31.97%; standard deviation (SD) 6.136%) compared to control mice only injected with myosin and compared to mice with early myocarditis (9 days after first injection of myosin and CFA; mean 52.66%; SD 2.874%) (Figure 3A) as ejection fraction on day 9 remained on the baseline level (Figure S1A)
Had a significantly impaired ejection fraction (mean 31.97%; standard deviation ( 6.136%) compared to control mice only injected with myosin (mean 47.57%; SD 4.20 and compared to mice with early myocarditis (9 days after first injection of my and CFA; mean 52.66%; SD 2.874%) (Figure 3A) as ejection fraction on day 9 remained the baseline level (Figure S1A)
Summary
Myocarditis represents a challenging diagnosis due to the heterogeneity of its clinical manifestations and the lack of sensitive and specific diagnostic tools, including the current gold standard endomyocardial biopsy [1]. It remains a common, at times deadly, entity, being found in 2–42% of autopsies from young adults with sudden cardiac death [2,3] and often leading to lasting functional impairments such as dilated cardiomyopathy with a poor prognosis [4,5]. Findings are mostly unspecific and not helpful in discriminatory testing regarding differential diagnosis. There is a need for new approaches that allow reliable detection of myocarditis in its early course
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