Contractile effects of Aficamten in the human atrium

Aficamten is an approved drug to treat hypertrophic cardiomyopathy. Aficamten desensitizes bovine myofilaments against calcium cations. In isolated animal cardiac preparations, aficamten reduced force of contraction (FOC) but its effects on isolated human cardiac preparations has previously not been tested. Therefore, we studied the effects of aficamten on FOC in isolated electrically stimulated (1 Hz) human right atrial preparations (HAP) from adult patients that underwent cardiac surgery because they suffered from severe coronary heart disease. We detected a concentration-dependent negative inotropic effect of aficamten given alone in HAP. Likewise, aficamten reversed the positive inotropic effects of 1 µM isoprenaline or 10.8 mM calcium cations. 1 µM isoprenaline but not 10.8 mM calcium cations raised the phosphorylation state of phospholamban at serine 16 in HAP. Aficamten (10 µM) did not reduce the phosphorylation state of phospholamban at serine 16 in HAP that had been augmented by isoprenaline. Furthermore, aficamten reduced FOC that had been raised by stimulation of H 1 -histamine receptors, H 2 -histamine receptors, 5-HT 4 -serotonin receptors or D 1 -dopamine receptors in HAP. Moreover, aficamten diminished FOC that had been elevated by a calcium sensitizer (EMD57033), a serine/threonine phosphatase inhibitor (100 µM cantharidin), 100 µM dibutyryl-cAMP, a membrane permeant 3´,5´-cyclic adenosine monophosphate (cAMP) derivative, or Bay K 8644, an activator of L-type calcium ion channels, in HAP. We conclude that aficamten diminished basal and elevated FOC in HAP, probably via reducing the calcium sensitivity of the human atrial myofilaments.