Clinical Determinants of Ventricular Sympathetic Reinnervation After Orthotopic Heart Transplantation

Bengel, Frank M.; Ueberfuhr, Peter; Hesse, Thomas; Schiepel, Nina; Ziegler, Sibylle; Scholz, Siegfried; Nekolla, Stephan G.; Reichart, Bruno; Schwaiger, Markus

doi:10.1161/01.cir.0000025631.68522.9d

Cited by 101 publications

(40 citation statements)

References 25 publications

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“…Reinnervation of the heart after chronic ischemia (Vracko et al, 1990; Zhou et al, 2004; Hasan et al, 2006; El-Helou et al, 2008) or cardiac transplantation (Bengel et al, 1999; Estorch et al, 1999; Bengel et al, 2001; Bengel et al, 2002) fit this model of robust sympathetic regeneration. However, we found that a common injury affecting over a million people each year in the US (Roger et al, 2012) – cardiac ischemia-reperfusion – generates a scar that is refractory to reinnervation.…”

Section: Discussionmentioning

confidence: 93%

Infarct-Derived Chondroitin Sulfate Proteoglycans Prevent Sympathetic Reinnervation after Cardiac Ischemia-Reperfusion Injury

Gardner

Habecker

2013

J. Neurosci.

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Sympathetic nerve can regenerate after injury to re-innervate target tissues. Sympathetic regeneration is well documented after chronic cardiac ischemia, so we were surprised that the cardiac infarct remained denervated following ischemia-reperfusion (I-R). We used mice to ask if the lack of sympathetic regeneration into the scar was due to blockade by inhibitory extracellular matrix within the infarct. We found that chondroitin sulfate proteoglycans (CSPGs) were present in the infarct after I-R, but not after chronic ischemia, and that CSPGs caused inhibition of sympathetic axon outgrowth in vitro. Ventricle explants after I-R and chronic ischemia stimulated sympathetic axon outgrowth that was blocked by NGF antibodies. However, growth in I-R co-cultures was asymmetrical, with axons growing toward the heart tissue consistently shorter than axons growing in other directions. Growth toward I-R explants was rescued by adding chondroitinase ABC (ChABC) to the co-cultures, suggesting that I-R infarct-derived CSPGs prevented axon extension. Sympathetic ganglia lacking Protein Tyrosine Phosphatase Sigma (PTPRS) were not inhibited by CSPGs or I-R explants in vitro, suggesting PTPRS is the major CSPG receptor in sympathetic neurons. To test directly if infarct-derived CSPGs prevented cardiac reinnervation, we carried out ischemia-reperfusion in ptprs-/- and ptprs+/- mice. Cardiac infarcts in ptprs-/- mice were hyperinnervated, while infarcts in ptprs+/- littermates were denervated, confirming that CSPGs prevent sympathetic reinnervation of the cardiac scar after I-R. This is the first example of CSPGs preventing sympathetic reinnervation of an autonomic target following injury, and may have important consequences for cardiac function and arrhythmia susceptibility after myocardial infarction.

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Section: Discussionmentioning

confidence: 93%

Infarct-Derived Chondroitin Sulfate Proteoglycans Prevent Sympathetic Reinnervation after Cardiac Ischemia-Reperfusion Injury

Gardner

Habecker

2013

J. Neurosci.

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“…Neither study established a relationship between time since HTX and response to atropine, in contrast to what is seen during sympathetic reinnervation. 12 This study demonstrated a significant difference in resting HR between those who responded to dobutamine and those who required additional use of atropine (Table II). A possible explanation for this could be the presence of differential reinnervation among these patients.…”

Section: Autonomic Reinnervationmentioning

confidence: 67%

“…Reinnervation may be time-dependent 11 or may be affected by such factors as age of donor and recipient, surgical complication rate, rejection, 12 and surgical technique. 13 Without a consensus regarding parasympathetic reinnervation of the heart in HTX patients, the usefulness of atropine as a chronotropic agent is questionable.…”

mentioning

confidence: 99%

Efficacy of Atropine as a Chronotropic Agent in Heart Transplant Patients Undergoing Dobutamine Stress Echocardiography

et al. 2006

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“…However, the heart does not become fully reinnervated over time and some patients remain denervated late after surgery (15 years). Follow-up studies indicated that although time is a determinant of reinnervation, the likelihood of innervation is also dependent on donor and recipient age, duration and complexity of surgery [56], and diabetic status [57]. Perhaps most importantly, [ 11 C]-HED has been used to assess the significance of SNS innervation on cardiac function.…”

Section: Evaluation Of Innervation After Cardiac Transplantationmentioning

confidence: 99%

Recent Advances and Clinical Applications of PET Cardiac Autonomic Nervous System Imaging

Boutagy

Sinusas

2017

Curr Cardiol Rep

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Purpose of Review The purpose of this review was to summarize current advances in positron emission tomography (PET) cardiac autonomic nervous system (ANS) imaging, with a specific focus on clinical applications of novel and established tracers. Recent Findings [11C]-Meta-hydroxyephedrine (HED) has provided useful information in evaluation of normal and pathological cardiovascular function. Recently, [11C]-HED PET imaging was able to predict lethal arrhythmias, sudden cardiac death (SCD), and all-cause mortality in heart failure patients with reduced ejection fraction (HFrEF). In addition, initial [11C]-HED PET imaging studies have shown the potential of this agent in elucidating the relationship between impaired cardiac sympathetic nervous system (SNS) innervation and the severity of diastolic dysfunction in HF patients with preserved ejection fraction (HFpEF) and in predicting the response to cardiac resynchronization therapy (CRT) in HFrEF patients. Longer half-life 18F-labeled presynaptic SNS tracers (e.g., [18F]-LMI1195) have been developed to facilitate clinical imaging, although no PET radiotracers that target the ANS have gained wide clinical use in the cardiovascular system. Although the use of parasympathetic nervous system radiotracers in cardiac imaging is limited, the novel tracer, [11C]-donepezil, has shown potential utility in initial studies. Summary Many ANS radioligands have been synthesized for PET cardiac imaging, but to date, the most clinically relevant PET tracer has been [11C]-HED. Recent studies have shown the utility of [11C]-HED in relevant clinical issues, such as in the elusive clinical syndrome of HFpEF. Conversely, tracers that target cardiac PNS innervation have been used less clinically, but novel tracers show potential utility for future work. The future application of [11C]-HED and newly designed 18F-labeled tracers for targeting the ANS hold promise for the evaluation and management of a wide range of cardiovascular diseases, including the prognostication of patients with HFpEF.

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Clinical Determinants of Ventricular Sympathetic Reinnervation After Orthotopic Heart Transplantation

Cited by 101 publications

References 25 publications

Infarct-Derived Chondroitin Sulfate Proteoglycans Prevent Sympathetic Reinnervation after Cardiac Ischemia-Reperfusion Injury

Infarct-Derived Chondroitin Sulfate Proteoglycans Prevent Sympathetic Reinnervation after Cardiac Ischemia-Reperfusion Injury

Efficacy of Atropine as a Chronotropic Agent in Heart Transplant Patients Undergoing Dobutamine Stress Echocardiography

Recent Advances and Clinical Applications of PET Cardiac Autonomic Nervous System Imaging

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