Cardiac sympathetic hyperinnervation after myocardial infarction: a systematic review and qualitative analysis

Cardiac sympathetic hyperinnervation after myocardial infarction (MI) is associated with arrhythmogenesis and sudden cardiac death. The characteristics of cardiac sympathetic hyperinnervation remain underexposed. To provide a systematic review on cardiac sympathetic hyperinnervation after MI, taking into account: (1) definition, experimental model and quantification method and (2) location, amount and timing, in order to obtain an overview of current knowledge and to expose gaps in literature. References on cardiac sympathetic hyperinnervation were screened for inclusion. The included studies received a full-text review and quality appraisal. Relevant data on hyperinnervation were collected and qualitatively analysed. Our literature search identified 60 eligible studies performed between 2000 and 2022. Cardiac hyperinnervation is generally defined as an increased sympathetic nerve density or increased number of nerves compared to another control group (100%). Studies were performed in a multitude of experimental models, but most commonly in male rats with permanent left anterior descending (LAD) artery ligation (male: 63%, rat: 68%, permanent ligation: 93%, LAD: 97%). Hyperinnervation seems to occur mainly in the borderzone. Quantification after MI was performed in regions of interest in µm2/mm2 (41%) or in percentage of nerve fibres (46%) and the reported amount showed a great variation ranging from 439 to 126,718 µm2/mm2. Hyperinnervation seems to start from three days onwards to >3 months without an evident peak, although studies on structural evaluation over time and in the chronic phase were scarce. Cardiac sympathetic hyperinnervation after MI occurs mainly in the borderzone from three days onwards and remains present at later timepoints, for at least 3 months. It is most commonly studied in male rats with permanent LAD ligation. The amount of hyperinnervation differs greatly between studies, possibly due to differential quantification methods. Further studies are required that evaluate cardiac sympathetic hyperinnervation over time and in the chronic phase, in transmural sections, in the female sex, and in MI with reperfusion. KEY MESSAGESCardiac sympathetic hyperinnervation occurs three days after MI mainly in the borderzone and remains present at all timepoints.It is most commonly studied in male rats with permanent LAD ligation.The amount of hyperinnervation differs greatly between studies, possibly due to the differential quantification methods. Cardiac sympathetic hyperinnervation occurs three days after MI mainly in the borderzone and remains present at all timepoints. It is most commonly studied in male rats with permanent LAD ligation. The amount of hyperinnervation differs greatly between studies, possibly due to the differential quantification methods.</p

Data_Sheet_2_Acute myocardial infarction induces remodeling of the murine superior cervical ganglia and the carotid body.pdf

A role for cardiac sympathetic hyperinnervation in arrhythmogenesis after myocardial infarction (MI) has increasingly been recognized. In humans and mice, the heart receives cervical as well as thoracic sympathetic contributions. In mice, superior cervical ganglia (SCG) have been shown to contribute significantly to myocardial sympathetic innervation of the left ventricular anterior wall. Of interest, the SCG is situated adjacent to the carotid body (CB), a small organ involved in oxygen and metabolic sensing. We investigated the remodeling of murine SCG and CB over time after MI. Murine SCG were isolated from control mice, as well as 24 h, 3 days, 7 days and 6 weeks after MI. SCG and CBs were stained for the autonomic nervous system markers β3-tubulin, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT), as well as for the neurotrophic factors brain derived neurotropic factor (BDNF), nerve growth factor (NGF) and their tyrosine receptor kinase (pan TRK). Results show that after MI a significant increase in neuron size occurs, especially in the region bordering the CB. Co-expression of TH and ChAT is observed in SCG neuronal cells, but not in the CB. After MI, a significant decrease in ChAT intensity occurs, which negatively correlated with the increased cell size. In addition, an increase of BDNF and NGF at protein and mRNA levels was observed in both the CB and SCG. This upregulation of neurotropic factors coincides with the upregulation of their receptor within the SCG. These findings were concomitant with an increase in GAP43 expression in the SCG, which is known to contribute to axonal outgrowth and elongation. In conclusion, neuronal remodeling toward an increased adrenergic phenotype occurs in the SCG, which is possibly mediated by the CB and might contribute to pathological hyperinnervation after MI.</p

Data_Sheet_1_Acute myocardial infarction induces remodeling of the murine superior cervical ganglia and the carotid body.docx

A role for cardiac sympathetic hyperinnervation in arrhythmogenesis after myocardial infarction (MI) has increasingly been recognized. In humans and mice, the heart receives cervical as well as thoracic sympathetic contributions. In mice, superior cervical ganglia (SCG) have been shown to contribute significantly to myocardial sympathetic innervation of the left ventricular anterior wall. Of interest, the SCG is situated adjacent to the carotid body (CB), a small organ involved in oxygen and metabolic sensing. We investigated the remodeling of murine SCG and CB over time after MI. Murine SCG were isolated from control mice, as well as 24 h, 3 days, 7 days and 6 weeks after MI. SCG and CBs were stained for the autonomic nervous system markers β3-tubulin, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT), as well as for the neurotrophic factors brain derived neurotropic factor (BDNF), nerve growth factor (NGF) and their tyrosine receptor kinase (pan TRK). Results show that after MI a significant increase in neuron size occurs, especially in the region bordering the CB. Co-expression of TH and ChAT is observed in SCG neuronal cells, but not in the CB. After MI, a significant decrease in ChAT intensity occurs, which negatively correlated with the increased cell size. In addition, an increase of BDNF and NGF at protein and mRNA levels was observed in both the CB and SCG. This upregulation of neurotropic factors coincides with the upregulation of their receptor within the SCG. These findings were concomitant with an increase in GAP43 expression in the SCG, which is known to contribute to axonal outgrowth and elongation. In conclusion, neuronal remodeling toward an increased adrenergic phenotype occurs in the SCG, which is possibly mediated by the CB and might contribute to pathological hyperinnervation after MI.</p