Abstract 11280: Long-Term Therapy with a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Systolic Function and Prevents Progressive Ventricular Remodeling in Dogs with Chronic Heart Failure

Background: Adenosine (AD) is an important component of the intrinsic cardioprotective arsenal of the heart. Many of the AD-induced protective effects are mediated through A1 receptor activation. The therapeutic use of AD A1 receptor agonists in cardiac diseases has been limited by undesirable actions of full AD A1 receptor agonism such as bradycardia. This study examined the long-term effects of partial AD A1-receptor agonism on left ventricular (LV) systolic function and chamber remodeling in dogs with chronic heart failure (HF) (LV ejection fraction, EF∼30%). Methods: Studies were performed in 12 HF dogs randomized to 3 months oral monotherapy with the partial A1 receptor agonist capadenoson (CAP) (7.5 mg twice daily, n=6) or to no therapy at all (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, EF, mean aortic pressure (mAoP) and cardiac output (CO) were measured before initiating therapy (PRE) and at 3 months after initiating therapy (POST). Ambulatory 24 hours ECG Holter monitoring studies were also performed to determine average HR at PRE and POST. LV tissue obtained at POST was used for histomorphometeric assessment of volume fraction of interstitial fibrosis (VFIF), capillary density (CD), and myocyte cross-sectional area (MCSA), a measure of cardiomyocyte hypertrophy. Results: In Controls, EDV and ESV increased and EF decreased while CO and mAoP were unchanged. In CAP-treated dogs, EDV and mAoP were unchanged, while ESV decreased and EF and CO increased significantly (Table). There were no differences in ECG Holters-derived HR at between groups (Table). Compared to Controls, treatment with CAP reduced VFIF and MCSA and increased CD. Conclusions: In dogs with HF, long-term therapy with CAP improves LV function and prevents progressive LV remodeling in the absence of significant HR or blood pressure reduction. The findings support continued development of partial A1-receptor agonists for the treatment of chronic HF.