A Genetic Deficiency in Presynaptic Choline Uptake Leads to Resting Tachycardia and Diminished Vagal Reserve

Abstract

The parasympathetic branch of the autonomic nervous system projects to the heart via the vagus nerve. Vagal efferents into the heart produce bradycardia through release of acetylcholine (ACh). The presynaptic synthesis of ACh is believed to be dependent on the uptake of extracellular choline via the hemicolinium‐3‐sensitive choline transporter (CHT). Attenuated parasympathetic tone has been shown to be a high risk indicator for increased mortality in patients with cardiac disease. Our studies have examined the impact of a genetic loss of CHT on cardiac function in mice. Cardiac synaptosome preparations made from CHT heterozygous (Het) mice have significantly reduced cardiac tissue levels of ACh as well as elevated choline levels, along with elevated urinary NE levels compared to wildtype mice. Conscious CHT Het mice monitored via telemetry exhibit significantly higher resting heart rates, but display similar mean blood pressure compared to wildtype mice. Functional cardiac studies using echocardiography show that CHT Het mice also exhibit reduced fractional shortening and increased left ventricular internal dimensions, but normal cardiac output. Consistent with reductions in parasympathetic tone, CHT Het mice exhibit an attenuated baroreceptor‐mediated reflex. During recovery from treadmill exercise, CHT Het mice show reduced heart rate recovery, indicative of reduced vagal feedback for HR control.