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American Heart Association

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Final ID: MP1564

Downregulation of Cytosolic Connexin-43 in Left Ventricular Myocardium of Dogs with Chronic Heart Failure and Recovery After Treatment with β3-Adrenergic Receptor Antagonist

Abstract Body (Do not enter title and authors here): Background: Cytosolic Connexin-43 (Cx43) plays a crucial role in the formation of gap junctions. Proper levels, localization, function, and interactions of Cx43 with other proteins are vital for maintaining electrical coupling between cardiomyocytes. A reduction in Cx43 protein levels in heart failure (HF) can lead to ventricular arrhythmias and sudden death. In the failing heart, β3 adrenergic receptors (ARs) are upregulated, a maladaptation that can lead to downregulation of Cx43. We previously showed that treatment of HF dogs with a β3-AR antagonist (APD418) improves LV systolic function.
Hypothesis: The present study tested the hypothesis that 1) Cx43 protein levels are decreased in LV myocardium of dogs with HF and 2) treatment with a β3-AR antagonist (APD418) restores Cx43 protein levels. Studies were performed in LV myocardium of dogs with coronary microembolization-induced HF. In addition to marked LV dysfunction, the model, as in humans with HF, manifests spontaneous ventricular arrhythmias and sudden death.
Methods: Studies were performed in LV tissue from 14 dogs with HF (LV EF ~35%) that were randomized to receive a 6-hour intravenous infusion of APD418 (4.224 mg/kg, n=7) or vehicle (0.9% NaCl, n=7). LV tissue from 7 normal healthy (NL) dogs served as controls. Cytosolic fractions were isolated from LV myocardium, and Cx43 protein levels were quantified with Western blotting using a dog specific monoclonal antibody. Housekeeping protein (cytosolic GAPDH) was used as a loading control. Band intensities were expressed in densitometric units (du).
Results: Cytosolic GAPDH were unchanged between NL and HF dogs. Compared to NL dogs, vehicle treated HF dogs showed significantly reduced Cx43 levels (0.97 ± 0.05 vs. 2.98 ± 0.46 du, p<0.05). Treatment with APD418 significantly increased Cx43 levels compared to vehicle controls (1.82 ± 0.49 vs. 0.97 ± 0.05 du, p < 0.05).
Conclusion: Cytosolic Cx43 levels are reduced in LV myocardium of dogs with HF; an abnormality that can trigger ventricular arrhythmias. Treatment with the β3-AR antagonist APD418 improves Cx43 protein levels. In addition to improving LV systolic function in HF, APD418 may potentially act to limit the development of life-threatening ventricular arrhythmias.
  • Gupta, Ramesh  ( HENRY FORD HEALTH , Detroit , Michigan , United States )
  • Szekely, Kristina  ( HENRY FORD HEALTH , Detroit , Michigan , United States )
  • Zhang, Kefei  ( HENRY FORD HEALTH , Detroit , Michigan , United States )
  • Lanfear, David  ( HENRY FORD HEALTH , Detroit , Michigan , United States )
  • Sabbah, Hani  ( HENRY FORD HEALTH , Detroit , Michigan , United States )
  • Author Disclosures:
    Ramesh Gupta: DO NOT have relevant financial relationships | Kristina Szekely: No Answer | Kefei Zhang: DO NOT have relevant financial relationships | David Lanfear: DO have relevant financial relationships ; Research Funding (PI or named investigator):Illumina:Active (exists now) ; Research Funding (PI or named investigator):Lilly:Past (completed) ; Consultant:Rycarma:Active (exists now) ; Consultant:Bayer:Past (completed) ; Consultant:cytokinetics:Active (exists now) ; Research Funding (PI or named investigator):Pfizer:Active (exists now) | Hani Sabbah: DO have relevant financial relationships ; Consultant:Novartis Corp.:Active (exists now) ; Advisor:Stealth Biotherapeutics, Inc.:Active (exists now) ; Advisor:ViCardia Inc.:Active (exists now) ; Research Funding (PI or named investigator):Impulse Dynamics:Active (exists now) ; Consultant:Impulse Dynamics:Active (exists now) ; Research Funding (PI or named investigator):Novartis Corp.:Active (exists now)
Meeting Info:

Scientific Sessions 2025

2025

New Orleans, Louisiana

Session Info:

Frontiers in Electrophysiology and Arrhythmogenesis: From Cells to Systems

Sunday, 11/09/2025 , 09:15AM - 10:30AM

Moderated Digital Poster Session

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