The mechanisms controlling differentiation in adult cardiac precursor cells (CPCs) are still largely unknown. In this study, CPCs isolated from the human heart were found to produce predominantly smooth muscle cells but could be redirected to the cardiomyocyte fate by transient activation followed by inhibition of NOTCH signaling. NOTCH inhibition repressed <i>MIR-143/145</i> expression, and blocked smooth muscle differentiation. Expression of the microRNAs is under control of <i>CARMEN</i> , a long noncoding RNA associated with an enhancer located in the <i>MIR-143/145</i> locus and target of NOTCH signaling. The <i>CARMEN</i> / <i>MIR-145/143</i> axis represents, therefore, a promising target to favor production of cardiomyocytes in cell replacement therapies.