1. In an animal model of autoimmune-mediated heart failure (HF), prophylactic or therapeutic treatment with a cyclopeptide mimicking a cardiac receptor dramatically blocked or reverted disease progression.
2. Continued treatment with the cyclopeptide permanently lowered antibodies associated with HF through both scavenger methods as well as targeted depletion of antibody-producing B cells.
Evidence Rating Level: 3 (Average)
Study Rundown: Causes of HF are diverse in origin, with one being the autoimmune production of antibodies targeting the second extracellular loop of the cardiac β1 adrenergic receptor (anti-EC2β1). It is thought that these antibodies lead to continuous stimulation of the β1 adrenergic receptor (β1AR), ultimately leading to HF. Rather than using beta blockers, such as bisoprolol, against β1AR to treat this type of HF, the authors here developed EC2-CP, a cyclopeptide that mimics the EC2β1 region of β1AR and thus prevents anti-EC2β1 from binding cell-derived β1AR. A cyclic, rather than linear (EC2-lin), version of the peptide was used because of its superior stability and increased recognition by anti-EC2β1.
Animal studies involved injecting rats with EC2β1 to stimulate anti-EC2β1 production, with boosters administered monthly afterwards. EC2-CP injection every 4 weeks, alone or combined with bisoprolol, was able to prevent (treatment initiated soon after anti-EC2β1 stimulation) or reverse (treatment initiated 8.5 months after anti-EC2β1 stimulation) cardiac damage. This was demonstrated by cardiac output parameters, histological analyses, and quantification of protein and gene expression. Interestingly, titer levels of anti-EC2β1 were permanently reduced by EC2-CP treatment in both studies, an effect not seen with bisoprolol treatment. Further studies revealed profoundly decreased levels of splenic EC2β1 targeting memory B cells in the EC2-CP treatment groups, representing a second way by which EC2-CP targets anti-EC2β1.
HF in the clinical setting is often the result of a complex web of contributing factors, so further studies reflecting this reality are needed before this approach can be applied clinically. Should clinical trials corroborate these animal results, this work presents a possible treatment plan catered towards patients with autoimmune HF by targeting anti-EC2β1.
In-Depth [animal study]: A total of 114 rats were used in this study. Enzyme linked immunosorbent assay (ELISA) was used to show superior affinity of anti-EC2β1 in blood to EC2-CP than to EC2-lin (p<0.005). Ex vivo stability studies gave the EC2-CP half-life as 486 hours, while EC2-lin had a 4 hour half-life. β1AR activation induced by anti-EC2β1, as measured by cyclic adenosine monophosphase (cAMP) signaling, was also more greatly decreased with EC2-CP than by EC2-lin.
EC2-CP, other peptides or bisoprolol were administered every 4 weeks beginning 6 weeks or 8.5 months after EC2β1 injection for prevention or treatment studies, respectively. In both studies, 5 injections of EC2-CP reduced anti-EC2β1 titers by 80-90%. Animals immunized but not treated showed increased left ventricular diameter and lowered ejection fractions and cardiac indices (p<0.001 by 12 months for all parameters), among other cardiac function measurements. EC2-CP treatment reversed this trend in both study groups when given alone (preventive or treatment) or with bisoprolol (treatment). Cardiac scarring (p<0.05) and apoptosis (p<0.001) induced by EC2β1 immunization was also returned to control levels by EC2-CP treatment. Importantly, bisoprolol treatment did decrease the effects of EC2β1 immunization on all of the parameters, but to a lesser degree than EC2-CP treatment.
Finally, the authors were interested in further elucidating the permanent decrease in titer levels induced by EC2-CP treatment. They found that while the number of IgG producing splenocytes were equivalent in untreated and EC2-CP treated immunized rats, EC2-CP treatment decreased the fraction of cells specific to EC2β1 (p<0.05, n=2-3 rats). This result was further supported by flow cytometry experiments.
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A cyclic, rather than linear (EC2-lin), version of the peptide was used because of its superior stability and increased recognition by anti-EC2β1.