Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions

Area of Science:

• Cardiology
• Neuroscience
• Molecular Biology

Background:

• Autonomic dysfunction and decreased vagal activity are hallmarks of heart failure.
• Nonneuronal acetylcholine (ACh) production by cardiomyocytes is crucial for cardiac homeostasis.
• The presence and role of this system in human hearts were previously unclear.

Purpose of the Study:

• To investigate the presence and role of the nonneuronal cholinergic system in human cardiomyocytes.
• To determine the expression levels of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in human heart failure.
• To elucidate the functional significance of cardiomyocyte-specific cholinergic signaling in cardiac remodeling and dysfunction.

Main Methods:

• Analysis of human ventricular tissue for ChAT and VAChT expression.
• Utilizing genetically modified mice (VAChT/ChAT knockout and VAChT overexpressors) in a heart failure model (angiotensin II infusion).
• Assessment of cardiac function (fractional shortening, ejection fraction) and cardiac fibrosis.

Main Results:

• Human cardiomyocytes express ChAT and VAChT.
• VAChT expression is upregulated in heart failure patients.
• Mice lacking cardiomyocyte VAChT or ChAT showed exacerbated ventricular dysfunction and fibrosis in response to angiotensin II.
• Overexpression of VAChT in cardiomyocytes protected against angiotensin II-induced cardiac dysfunction and fibrosis.

Conclusions:

• Cardiomyocyte-derived ACh, mediated by ChAT and VAChT, is a key regulator of cardiac function.
• Increased VAChT expression in heart failure may represent a compensatory mechanism to mitigate cardiac remodeling.
• Targeting the cardiomyocyte cholinergic system could offer novel therapeutic strategies for heart failure.