An Analysis of the Myocardial Transcriptome in a Mouse Model of Cardiac Dysfunction with Decreased Cholinergic Neurotransmission

Autonomic dysfunction is observed in many cardiovascular diseases and contributes to cardiac remodeling and heart disease. We previously reported that a decrease in the expression levels of the vesicular acetylcholine transporter (VAChT) in genetically-modified homozygous mice (VAChT KDHOM) leads to decreased cholinergic tone, autonomic imbalance and a phenotype resembling cardiac dysfunction. In order to further understand the molecular changes resulting from chronic long-term decrease in parasympathetic tone, we undertook a transcriptome-based, microarray-driven approach to analyze gene expression changes in ventricular tissue from VAChT KDHOM mice. We demonstrate that a decrease in cholinergic tone is associated with alterations in gene expression in mutant hearts, which might contribute to increased ROS levels observed in these cardiomyocytes. In contrast, in another model of cardiac remodeling and autonomic imbalance, induced through chronic isoproterenol treatment to increase sympathetic drive, these genes did not appear to be altered in a pattern similar to that observed in VAChT KDHOM hearts. These data suggest the importance of maintaining a fine balance between the two branches of the autonomic nervous system and the significance of absolute levels of cholinergic tone in proper cardiac function

Why do obese patients not lose more weight when treated with low-calorie diets? A mechanistic perspective.

Maximal weight loss observed in low-calorie diet (LCD) studies tends to be small, and the mechanisms leading to this low treatment efficacy have not been clarified. Less-than-expected weight loss with LCDs can arise from an increase in fractional energy absorption (FEA), adaptations in energy expenditure, or incomplete patient diet adherence. We systematically reviewed studies of FEA and total energy expenditure (TEE) in obese patients undergoing weight loss with LCDs and in patients with reduced obesity (RO), respectively. This information was used to support an energy balance model that was then applied to examine patient adherence to prescribed LCD treatment programs. In the limited available literature, FEA was unchanged from baseline in short-term (or=26 wk) studies were found. Review of doubly labeled water and respiratory chamber studies identified 10 reports of TEE in RO patients (n = 150) with long-term weight loss. These patients, who were weight stable, had a TEE almost identical to measured or predicted values in never-obese subjects (weighted mean difference: 1.3%; range: -1.7-8.5%). Modeling of energy balance, as supported by reviewed FEA and TEE studies, suggests that obese subjects participating in LCD programs have a weight loss less than half of that predicted. The small maximal weight loss observed with LCD treatments thus is likely not due to gastrointestinal adaptations but may be attributed, by deduction, to difficulties with patient adherence or, to a lesser degree, to metabolic adaptations induced by negative energy balance that are not captured by the current models