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

Gardner RT, Wang L, Lang BT, Cregg JM, Dunbar CL, Woodward WR, Silver J, Ripplinger CM, Habecker BA - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Neuroscience Graduate Program, Oregon Health and Science University, Portland, Oregon 97239, USA.

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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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).
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f5: 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).

Mentions: In order to identify additional mechanisms underlying changes in cardiac electrophysiology, we examined intracellular Ca2+ handling at various pacing frequencies and after ISO treatment. Disrupted Ca2+ homeostasis can result in beat-to-beat fluctuations between large and small intracellular calcium transients (CaT) called alternans, which is a sensitive noninvasive marker for the risk of sudden cardiac death in humans37. Intracellular Ca2+ handling appeared normal in sham hearts of both genotypes when paced with a 100-ms pulse interval (600 b.p.m. heart rate; Fig. 5). However, HET hearts with denervated infarcts (HET MI) exhibited significant intracellular Ca2+ alternans at the same pacing frequency (Fig. 5). Interestingly, KO hearts with innervated infarcts (KO MI) did not exhibit intracellular Ca2+ alternans (Fig. 5), suggesting that restoring sympathetic innervation to the infarct and surrounding tissue protects intracellular Ca2+ homeostasis. Denervated HET MI hearts also exhibited significant APD alternans (Fig. 5c), while innervated KO MI hearts did not, despite identical infarct size.


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

Gardner RT, Wang L, Lang BT, Cregg JM, Dunbar CL, Woodward WR, Silver J, Ripplinger CM, Habecker BA - Nat Commun (2015)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4315356&req=5

f5: 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).
Mentions: In order to identify additional mechanisms underlying changes in cardiac electrophysiology, we examined intracellular Ca2+ handling at various pacing frequencies and after ISO treatment. Disrupted Ca2+ homeostasis can result in beat-to-beat fluctuations between large and small intracellular calcium transients (CaT) called alternans, which is a sensitive noninvasive marker for the risk of sudden cardiac death in humans37. Intracellular Ca2+ handling appeared normal in sham hearts of both genotypes when paced with a 100-ms pulse interval (600 b.p.m. heart rate; Fig. 5). However, HET hearts with denervated infarcts (HET MI) exhibited significant intracellular Ca2+ alternans at the same pacing frequency (Fig. 5). Interestingly, KO hearts with innervated infarcts (KO MI) did not exhibit intracellular Ca2+ alternans (Fig. 5), suggesting that restoring sympathetic innervation to the infarct and surrounding tissue protects intracellular Ca2+ homeostasis. Denervated HET MI hearts also exhibited significant APD alternans (Fig. 5c), while innervated KO MI hearts did not, despite identical infarct size.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Neuroscience Graduate Program, Oregon Health and Science University, Portland, Oregon 97239, USA.

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.

Show MeSH
Related in: MedlinePlus