Background and Aim. Despite significant advances in the management of heart failure (HF), the prognosis remains poor, with many patients suffering from lifelong symptoms. Recent research points at the importance of the family of “A Disintegrin And Metalloproteases” (ADAMs), especially ADAM10, in heart development, angiogenesis and heart disease. Inhibition of ADAM10 early after myocardial infarction (MI) improves survival and cardiac function by preventing an exaggerated immune response. ADAM9 is an endogenous regulator of ADAM10 activity. Similar to ADAM10, ADAM9 is implicated in cardiac development. However, its role in heart disease and after myocardial infarction has not yet been investigated.

Methods and Results. Our study exploits human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, human heart tissue biopsies and pharmacological ADAM9 inhibition in mice. ADAM9 is upregulated in HF patients and after experimental MI in mice. Analysis of human single cell sequencing data and histological murine heart tissue samples revealed ADAM9 expression pattern largely consistent with that of ADAM10 indicating highest ADAM9 abundance in cardiomyocytes. In line, we found coregulation of ADAM9 and ADAM10 in cultured cardiomyocytes using siRNA-mediated knockdowns. Pharmacological ADAM9 inhibition in mice using the inhibitory peptide VTH245 resulted in a significant but transient amelioration of post-MI cardiac function. Mechanistically, this functional improvement was associated with altered intracellular calcium handling, while ADAM10 / IL-1β-driven inflammation was not affected.

Conclusion and Clinical Impact. Our data suggest that inhibition of ADAM9 augments cardiac function after myocardial infarction by improving intracellular calcium handling. Due to its overexpression in HF patients, ADAM9 might be a potential molecular target to improve therapy after MI. Future experiments will evaluate the therapeutic and translational value of ADAM9 inhibition with particular emphasis on beta-adrenergic signaling.