Abstract 4834: Synergistic Cardiotherapeutic Effect of Phenylbutyrate with Captopril or Losartan in the Treatment of Heart Failure
Treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) has been shown to prevent progression of myocardial dysfunction with heart failure (HF). There is evidence that inhibition of histone deacetylation (HDAC) inhibits the development of myocardial hypertrophy, suggesting that HDAC inhibition might ameliorate changes in cardiac structure and function with HF. To assess this possibility, the effects of the ACE inhibitor captopril (CAP) or the ARB losartan (LOS), combined with the HDAC inhibitor phenylbutyrate (PB), on LV hypertrophy and dysfunction associated with HF were evaluated in the spontaneously hypertensive rat (SHR). Serial echocardiograms were studied in 24 SHR beginning at 12 months of age and continued until the onset of HF (19±1months). SHR with HF (SHR-F) were randomly assigned to four treatment groups (drugs administered via drinking water); CAP (2 g/l) or LOS (375 mg/l), without or with PB (6 g/l). Treatment was initiated at the time of HF; LV structure and function were assessed following 30 days of treatment. Treatment with CAP or LOS alone at the time of HF stabilized function, but did not decrease LV hypertrophy or improve function, whereas concomitant administration of PB improved LV function, in association with reduction in LV hypertrophy (LV/BW 3.2±0.3 and 3.3±0.2, respectively, as compared to 3.8±0.1 for a separate group of untreated SHR-F studied at the time of HF). These findings suggest that PB, acting via a distinct mechanism, has a synergistic effect with ACE inhibitors or ARB, and mitigates adverse ventricular remodeling and dysfunction associated with HF in the SHR.