Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart Failure

Abstract

Background— Adenosine elicits cardioprotection through A1-receptor activation. Therapy with adenosine A1-receptor agonists, however, is limited by undesirable actions of full agonism, such as bradycardia. This study examined the effects of capadenoson (CAP), a partial adenosine A1-receptor agonist, on left ventricular (LV) function and remodeling in dogs with heart failure. Methods and Results— Twelve dogs with microembolization-induced heart failure were randomized to 12 weeks oral therapy with CAP (7.5 mg BID; n=6) or to no therapy (control; n=6). LV end-diastolic and end-systolic volumes, ejection fraction, plasma norepinephrine, and n-terminal pro–brain natriuretic peptide were measured before (pre) and 1 and 12 weeks after therapy (post). LV tissue obtained at post was used to assess volume fraction of interstitial fibrosis, sarcoplasmic reticulum calcium ATPase-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, end-diastolic and end-systolic volumes increased and ejection fraction decreased significantly from pre to post (ejection fraction, 30±2 versus 27±1%; P <0.05). In CAP-treated dogs, end-diastolic volume was unchanged; ejection fraction increased significantly after 1 week (36±2 versus 27±2%; P <0.05) with a further increase at post (39±2%; P <0.05), whereas end-systolic volume decreased. CAP significantly decreased volume fraction of interstitial fibrosis, normalized sarcoplasmic reticulum calcium ATPase-2a activity and expression of UCP-2 and UCP-3, and GLUT-1 and GLUT-2 and significantly decreased plasma norepinephrine and n-terminal pro–brain natriuretic peptide. Conclusions— In heart failure dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial adenosine A1-receptor agonists for the treatment of chronic heart failure.