

Pyridostigmine treatment improved systolic tension of hearts from mutant mice (gray squares 4 hearts). (B) Time course of systolic tension in isolated perfused hearts from WT (white squares 15 hearts) and VAChT KD HOM (black squares 16 hearts) mice.

Note the significant improvement in left ventricle performance after pyridostigmine treatment (gray bars). (A) Echocardiography analysis of left ventricle fractional shortening (FS) in VAChT mutant mice (black bars) and WT mice (white bars). Pyridostigmine treatment prevented cardiac dysfunction in VAChT KD HOM mice.

Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure.
