Research Assistant UNC Chapel Hill Chapel Hill, North Carolina, United States
Introduction/Rationale: Neuroimmune interactions in the infarct border zone influence arrhythmogenesis and survival after myocardial infarction (MI). Alpha-1A adrenergic receptors are expressed in cardiomyocytes but their role in post-infarction remodeling is unknown. We sought to determine whether cardiomyocyte alpha-1A receptors regulate neuroimmune and electrophysiological remodeling after MI.
Methods: Cardiomyocyte-specific alpha-1A knockout (cmAKO) and wild-type mice underwent left anterior descending artery ligation. Border zone tissue was analyzed at day 14 for macrophages (CD68), sympathetic innervation (NPY), and glial activation (GFAP) by immunohistochemistry. RNA sequencing identified differentially expressed ion channel and immune genes. Survival, infarct size, and cardiac function were assessed.
Results: Border zone histology revealed striking differences in cmAKO hearts: macrophage infiltration was reduced while sympathetic nerve density and glial marker expression were markedly increased. RNA sequencing demonstrated pro-arrhythmic ion channel and immune remodeling including connexin-40 downregulation (0.40-fold), GIRK channel loss (0.25-fold), and Kv1.5 upregulation (1.87-fold). Computational modeling predicted these changes would reduce wavelength by 53%, favoring reentry. These adverse remodeling patterns were associated with dramatically reduced survival (35% versus 80% at day 15, p=0.002) and larger infarcts (35% versus 22% of left ventricular mass, p=0.015). Functional dysfunction was also present, with elevated heart rate and reduced ejection fraction post-MI.
Conclusion: Cardiomyocyte alpha-1A receptors are critical regulators of post-infarction neuroimmune remodeling. Their deletion produces a pro-arrhythmic substrate characterized by altered inflammatory resolution, enhanced sympathetic reinnervation, and adverse ion channel expression.
