Cardiac sympathetic nerve terminal function in congestive heart failure

Area of Science:

• Cardiology
• Neuroscience
• Molecular Biology

Background:

• Failing human hearts exhibit increased cardiac norepinephrine (NE) release and depleted NE stores.
• This is associated with a functional defect in NE uptake within cardiac sympathetic nerve terminals.

Purpose of the Study:

• To investigate the cause of reduced NE uptake in cardiac sympathetic nerve terminals.
• To explore the implications of impaired NE transporter function in heart failure.
• To identify potential therapeutic targets for heart failure.

Main Methods:

• Studied NE transporter density and function in experimental cardiomyopathies and PC12 cells.
• Investigated the role of oxidative NE metabolites, endoplasmic reticulum stress, and N-glycosylation.
• Utilized [123I] metaiodobenzylguanidine imaging in human studies.

Main Results:

• Reduced NE uptake is caused by decreased NE transporter density in sympathetic nerve endings.
• This reduction contributes to increased myocardial interstitial NE, decreased adrenoceptor density, and myocyte apoptosis.
• Oxidative NE metabolites induce NE transporter decrease via ER stress and impaired N-glycosylation.
• [123I] metaiodobenzylguanidine uptake reflects this dysfunction in human heart failure.

Conclusions:

• Impaired cardiac sympathetic NE uptake is a key feature of heart failure.
• NE transporter density reduction is a significant factor in heart failure pathophysiology.
• Cardiac sympathetic nerve terminal function represents a potential direct therapeutic target for heart failure.