Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias - PubMed (original) (raw)

Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias

R T Gardner et al. Nat Commun. 2015.

Abstract

Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.

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Figures

Figure 1

Figure 1. Absence of PTPσ restores innervation to the infarcted myocardium and prevents arrhythmias.

Heart sections from HET (a) and KO (b) mice were stained for TH (green) to identify sympathetic nerve fibres and fibrinogen (red) to identify the infarct. Scale bar, 100 μm. (c) Heart rate was similar in both genotypes before (Base) and after (ISO) 10-μg ISO injection (mean±s.e.m., _n_=8 per genotype). (d) ISO induced comparable levels of PVCs in conscious Sham HET and KO mice; however, ISO induced significantly more PVCs in infarcted HET mice compared with KO mice and to Sham HET mice (mean±s.e.m., _n_=4 per group, ***P<0.001 versus HET sham and KO MI; two-way ANOVA with Bonferroni post test). (**e**) Fibrinogen-stained section after MI showing a transmural infarct after a 35-min occlusion. Scale bar, 500 μm. (**f**) Quantification of infarct size in HET and KO hearts following 35 min of occlusion (mean±s.e.m., _n_=4 per group; _t_-test, N.S. _P_>0.05).

Figure 2

Figure 2. ISP promotes sympathetic reinnervation of the infarct and decreases arrhythmias.

(a–c) Representative images of infarcted LV from mice treated with vehicle (a), IMP (b) or ISP (c) 14 days after MI. Sections were stained for TH (green) to identify sympathetic nerve fibres and fibrinogen (red) to identify the infarct. ISP treatment resulted in extensive sympathetic reinnervation of the infarct. Scale bar, 100 μm. (d) Quantification of TH+ fibre density within the infarct, the area immediately adjacent to the infarct (P1) and distal peri-infarct myocardium (P2; 540 μm from infarct) 14 day post-MI (mean±s.e.m., _n_=5 per group; ***P<0.001 by two-way ANOVA with Bonerroni post test). (e) NE content in the infarct and peri-infarct LV (P1 and P2 combined; mean±s.e.m.; _n_=5; **P<0.01, ***P<0.001 by two-way ANOVA with Bonerroni post test). (f) ISO induced PVCs in conscious mice 14 days after MI (mean±s.e.m., _n_=4–5; *P<0.05 versus vehicle and IMP by ANOVA with Tukey post test). Vehicle and IMP groups are not significantly different.

Figure 3

Figure 3. Sympathetic innervation of the infarct reduces dispersion of APD.

(a) Image of a heart prepared for mapping. All maps are represented in this same orientation. White arrow head indicates stimulating electrodes; infarct region is in the apical LV. (b) Activation maps of transmembrane potential (_V_m) show propagation of a stimulus depolarization event spreading from the base to apex of the heart (top), and representative maps of APD90 (bottom). (c) The mean APD90 is similar in all groups (mean±s.e.m.; _n_=4–5 hearts per group). (d) IQR of APD90, a measure of APD dispersion (mean±s.e.m.; _n_=4–5, **P<0.01 by two-way ANOVA with Bonferroni post test). Hearts with denervated infarcts (HET MI) have increased APD dispersion compared with sham hearts, while hearts with innervated infarcts (KO MI) do not. (e) Infarct size in HET and KO hearts following 45 min of occlusion (mean±s.e.m., _n_=5 per group). Restitution curves of (f) late repolarization (APD90) and (g) early repolarization (APD30; mean±s.e.m., _n_=4–5; **P<0.01, *P<0.05 versus all other groups by two-way ANOVA with Bonferroni post test).

Figure 4

Figure 4. Sympathetic innervation of the infarct prevents β-AR supersensitivity.

(a) APD90 maps before (Baseline) and after 1-μM ISO (100-ms pacing interval or 600 b.p.m. heart rate for each condition), and representative traces of optical action potentials from sites marked with *. Scale bar, 50 ms. (b) Percent change in APD90 following ISO treatment (mean±s.e.m.; _n_=4–5 hearts per group; **P<0.01 by two-way ANOVA with Bonferroni post test). (c) IQR of APD90 following ISO treatment (mean±s.e.m.; _n_=4–5 hearts; **P<0.01 by two-way ANOVA with Bonferroni post test).

Figure 5

Figure 5. Sympathetic innervation of the infarct prevents post-MI Ca2+ mishandling.

(a) Representative optical Ca2+ transients and alternans maps from the sites on sham and post-MI hearts marked (*) paced with a 100-ms pacing interval (600 b.p.m. heart rate). Scale bar, 100 ms. Denervated hearts (HET MI) exhibit Ca2+ alternans, while sham hearts and infarcted hearts with sympathetic innervation of the scar (KO MI) do not. (b) Intracellular Ca2+ alternans magnitude was quantified by spectral analysis (mean±s.e.m.; _n_=4–5 hearts; *P<0.05 versus other groups by two-way ANOVA with Bonferroni post test). (c) APD alternans magnitude was quantified by spectral analysis (mean±s.e.m.; *P<0.05 versus sham using Kruskal–Wallis test for non-Gaussian distribution).

Figure 6

Figure 6. Reinnervation of the infarct prevents Ca2+ mishandling and ventricular arrhythmias.

(a) Representative optical _V_m and Ca2+ transients in HET and KO hearts at baseline (Base), with ISO, and with both ISO and propranolol (Iso+Prop). Red arrows indicate Ca2+ elevation before _V_m depolarization. Scale bar, 100 ms. Insets show an expanded timescale of _V_m and CaT upstrokes. (b) Quantification of CaT elevation that precedes depolarization averaged across the entire surface of the heart (mean±s.e.m.; _n_=4–5 hearts; **P<0.01, ***P<0.001 by two-way ANOVA with Bonferroni post test). (c) Incidence of PVCs during baseline stimulation and treatment with tyramine (Tyr), ISO (Iso) and ISO plus propranolol (Iso+Prop; mean±s.e.m.; _n_=4–5 hearts; **P<0.01 versus all other groups by two-way ANOVA with Bonferroni post test). (d) Arrhythmia severity of HET MI and KO MI hearts during ISO treatment. Individual hearts are scored on the basis of the most severe arrhythmia observed (mean±s.e.m.; _n_=4–5 hearts; *P<0.05 by _t_-test). (e) Example Lead I ECGs from in vitro Langendorff-perfused hearts during baseline and with ISO. Owing to ISO-induced acceleration of the sinus rate, hearts in both groups exhibited atrioventricular (A–V) block (see P-wave dissociation and 3:1 A-V block in ISO traces); however, PVCs were significantly more frequent in HET MI hearts (red dots). PVCs were readily identified by a large and wide QRS complex compared with the normal (sinus or nodal) QRS complex (inset). (f) Representative activation maps in HET MI and KO MI hearts depicting rapid activation during sinus rhythm (Base line) in both hearts and with ISO treatment (Iso) in the KO MI heart. Iso treatment in the denervated (HET MI) heart produced PVCs with slowly propagating activation arising from the infarct region.

References

    1. Solomon S. D. et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N. Engl. J. Med. 352, 2581–2588 (2005). -PubMed
    1. Jalife J. Ventricular fibrillation: mechanisms of initiation and maintenance. Annu. Rev. Physiol. 62, 25–50 (2000). -PubMed
    1. Nademanee K., Taylor R., Bailey W. E., Rieders D. E. & Kosar E. M. Treating electrical storm: sympathetic blockade versus advanced cardiac life support-guided therapy. Circulation 102, 742–747 (2000). -PubMed
    1. Basu S. et al. Beneficial effects of intravenous and oral carvedilol treatment in acute myocardial infarction. A placebo-controlled, randomized trial. Circulation 96, 183–191 (1997). -PubMed
    1. Billman G. E., Castillo L. C., Hensley J., Hohl C. M. & Altschuld R. A. Beta2-adrenergic receptor antagonists protect against ventricular fibrillation: in vivo and in vitro evidence for enhanced sensitivity to beta2-adrenergic stimulation in animals susceptible to sudden death. Circulation 96, 1914–1922 (1997). -PubMed

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