Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction

Guevara, A.; Smith, C. E. R.; Wang, L.; Caldwell, J. L.; Tapa, S.; Francis Stuart, S. D.; Ma, B. W.; Ng, G. A.; Habecker, B. A.; Wang, Z.; Ripplinger, C. M.

doi:10.1101/2024.06.05.597494

bioRxiv · 10.1101/2024.06.05.597494

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction

Guevara, A.·Smith, C. E. R.·Wang, L.·Caldwell, J. L.·Tapa, S.·Francis Stuart, S. D.·Ma, B. W.·Ng, G. A.·Habecker, B. A.·Wang, Z.·Ripplinger, C. M.

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Abstract

Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post myocardial infarction (MI), causing regional hypo-innervation that is associated with supersensitivity of {beta}-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypo-innervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca2+-sensitive dyes. SNS was performed with electrical stimulation of the spinal cord and {beta}-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct and border zone of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct vs. remote region. Action potential duration (APD) dispersion and susceptibility to ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI hearts but not in sham. SNS decreased APD80 in MI but not sham hearts, while isoproterenol decreased APD80 in both groups. Isoproterenol also shortened Ca2+ transient duration (CaTD80) in both groups but to a greater extent in MI hearts. Our data suggest sympathetic remodeling post-MI is similar between species, with CSPGs associated with sympathetic hypo-innervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated {beta}-adrenergic responsiveness, which may underly increased APD dispersion and susceptibility for VT/VF. NEW & NOTEWORTHYHere we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypo-innervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between species, with hypo-innervation likely associated with enhanced {beta}-adrenergic sensitivity.

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Guevara, A., Smith, C. E. R., Wang, L., Caldwell, J. L., Tapa, S., Francis Stuart, S. D., Ma, B. W., Ng, G. A., Habecker, B. A., Wang, Z., Ripplinger, C. M.. 2024-06-06. Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction. https://doi.org/10.1101/2024.06.05.597494

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