The anti-cancer drug trametinib suppresses angiotensin-induced cardiac remodelling in mice but is detrimental to function

The anti-cancer MEK inhibitor trametinib (alone or with the RAF inhibitor dabrafenib) causes cardiac dysfunction in some patients. Our hypothesis is that cardiotoxicity is exacerbated by underlying co-morbidities such as hypertension, and this causes cardiac dysfunction detectable on echocardiograms. The objective was to determine how trametinib/dabrafenib affect cardiac function in a mouse model of hypertension-induced cardiac hypertrophy. Male mice were treated with vehicle, trametinib or dabrafenib/trametinib without/with angiotensin II (AngII) to increase blood pressure. Echocardiography was used to assess changes in cardiac function and dimensions, applying statistical analysis combined with machine-learning to dissect the effects on different segments of the left ventricle (LV). The inhibitors alone had a limited effect on mouse hearts. Trametinib or trametinib/dabrafenib inhibited cardiac hypertrophy induced by AngII over 7 d, reducing LV wall thickness and mass. AngII did not significantly affect cardiac function, but the inhibitors caused significant functional deterioration. Segmental analysis revealed variation of contraction around the LV, with selective effects of AngII and trametinib or dabrafenib/trametinib in basal/mid-regional segments. Frame-by-frame analysis of radial (not longitudinal) displacement of the LV endocardial wall demonstrated variation between consecutive cardiac cycles that enabled a high degree of classification according to treatment. In conclusion, trametinib inhibits AngII-induced cardiac hypertrophy in mice but is detrimental to cardiac function, effects that are not moderated by dabrafenib. AngII and MEK/RAF inhibition have regional effects around the LV with greater effects on radial displacement in basal/mid-regional segments. Assessment of such changes may facilitate early identification of developing cardiotoxicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/654397v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1da15b5org.highwire.dtl.DTLVardef@c72634org.highwire.dtl.DTLVardef@9d3c04org.highwire.dtl.DTLVardef@cf51e7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAnti-cancer drugs trametinib and dabrafenib alone had little effect on mouse hearts C_LIO_LITrametinib/dabrafenib suppressed cardiac hypertrophy in mice with hypertension C_LIO_LITrametinib/dabrafenib were detrimental to cardiac function in hypertensive mice C_LIO_LISegments of the left ventricle were affected differently by hypertension/inhibitors C_LIO_LIResponses to hypertension/inhibitors varied between consecutive cardiac cycles C_LI