The present data, in a translationally-relevant model of HFrEF [22,23,26,27], is the first evidence that targeted normalization of elevated plasma renin activity concentration by direct renin inhibition, at a dose that does not alter the Ang II-aldosterone axis, significantly prolongs life, preserves left ventricular function, reduces edema formation, and delays cachexia/sarcopenia. Here, REN is linked to sarcopenia.