Background-—Cancer therapies inhibiting PI3Ka (phosphoinositide 3-kinase-a)–dependent growth factor signaling, including
trastuzumab inhibition of HER2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct
inhibition of PI3Ka is now in clinical trials, but the effects of PI3Ka pathway inhibition on heart atrophy, remodeling, and function in
the context of cancer therapy are not well understood.
Method and Results-—Pharmacological PI3Ka inhibition and heart-specific genetic deletion of p110a, the catalytic subunit of
PI3Ka, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes
in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both
PI3Ka inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation,
dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right
ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI3Ka signaling when combined
with doxorubicin treatment. Increased p38 mitogen-activated protein kinase activation was mechanistically linked to heart atrophy
and correlated with right ventricular dysfunction in explanted failing human hearts.
Conclusions-—PI3Ka pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and
dysfunction in the setting of PI3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen-activated protein kinase is
a proposed therapeutic target to minimize this mode of cardiotoxicit
