New aspects for the treatment of cardiac diseases based on the diversity of functional controls on cardiac muscles: The regulatory mechanisms of cardiac innervation and their critical roles in cardiac performance

Masaki Ieda, Keiichi Fukuda

Research output: Contribution to journalShort survey

28 Citations (Scopus)


The heart is abundantly innervated, and the nervous system precisely controls the function of this organ. The density of cardiac innervation is altered in diseased hearts, which can lead to unbalanced neural activation and lethal arrhythmia. For example, diabetic sensory neuropathy causes silent myocardial ischemia, characterized by loss of pain perception during myocardial ischemia, and it is a major cause of sudden cardiac death in diabetes mellitus. Despite the clinical importance of cardiac innervation, the mechanisms underlying the control of this process remain poorly understood. We demonstrate that cardiac innervation is determined by the balance between neural chemoattractants and chemorepellents within the heart. Nerve growth factor (NGF), a potent chemoattractant, is synthesized abundantly by cardiomyocytes, and is induced by the upregulation of endothelin-1 during development. By comparison, the neural chemorepellent Sema3a is expressed at high levels in the subendocardium in the early stage of embryogenesis and is downregulated as development progresses, leading to epicardial-to- endocardial transmural sympathetic innervation patterning. We also show that the downregulation of cardiac NGF is a cause of diabetic neuropathy and that NGF supplementation prevents silent myocardial ischemia in diabetes mellitus. Both Sema3a-targeted and Sema3a- overexpressing mice display sudden cardiac death or lethal arrhythmias due to disruption of innervation patterning. The present review focuses on the regulatory mechanisms controlling cardiac innervation and the critical roles of these processes in cardiac performance.

Original languageEnglish
Pages (from-to)348-353
Number of pages6
JournalJournal of Pharmacological Sciences
Issue number3
Publication statusPublished - 2009 Jun 22



  • Arrhythmia
  • Cardiac disease
  • Cardiac nerve
  • Nerve growth factor
  • Sema3a
  • Sudden cardiac death

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this