Abstract 17495: Protein Kinase A Activity in Heart Failure Spectrums

Abstract

Introduction: Protein Kinase A (PKA) signaling is activated by β-adrenergic receptor (BAR) stimulation and regulates myocardial contraction and cellular functions. Chronic PKA overactivation can lead to apoptosis, structural dysfunction and arrhythmias. Heart failure (HF) is associated with increased BAR stimulation and downstream detrimental cellular effects likely mediated by increased PKA activation, but it remains unclear whether PKA is uniformly increased across HF spectrums. We aimed to determine the extent of PKA activity in HF phenotypes. Methods: Serum from HF patients (age 18-89, 66% male) (acute systolic HF, n=19, HF with reduced ejection fraction HFrEF (n=58) and HF with preserved ejection fraction-HFpEF (n=10) were collected. PKA assay: H9c2 rat heart cells (ATCC) were plated overnight and serum samples (1:100 dilution) were incubated with cells for 1 hour. Specific activity of the enzyme in pmol/min/ng was calculated (% above the basal PKA rate). For comparison, healthy controls (n=35, age 18-69, 59% male) were tested. In 3 HFrEF subjects, serum PKA signaling was inhibited by anti-IgG beads, specific antigens or Propranolol. Mann Whitney U test was performed to determine differences between groups. Results: Median PKA activation was 76% (acute HF), 49% in HFrEF, 39% in HFpEF and 9% in healthy controls. Compared to controls, PKA activity was significantly higher across all HF phenotypes (p<0.05). No statistical difference was noted between HF phenotypes although acute HF sera demonstrated numerically higher PKA activation in the heart cells. PKA activity was attenuated with anti-IgG beads or Propranolol in HFrEF, which suggests circulating IgG autoantibodies lead to induction of PKA signaling via BAR pathway in HF. Conclusion: PKA activity is increased across HF spectrums compared with healthy controls. Acute systolic HF appears to be associated with highest PKA activation. Further studies are underway to corroborate these findings.