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

Sympatho-renal axis in chronic disease

Essential hypertension, insulin resistance, heart failure, congestion, diuretic resistance, and functional renal disease are all characterized by excessive central sympathetic drive. The contribution of the kidney’s somatic afferent nerves, as an underlying cause of elevated central sympathetic drive, and the consequences of excessive efferent sympathetic signals to the kidney itself, as well as other organs, identify the renal sympathetic nerves as a uniquely logical therapeutic target for diseases linked by excessive central sympathetic drive. Clinical studies of renal denervation in patients with resistant hypertension using an endovascular radiofrequency ablation methodology have exposed the sympathetic link between these conditions. Renal denervation could be expected to simultaneously affect blood pressure, insulin resistance, sleep disorders, congestion in heart failure, cardiorenal syndrome and diuretic resistance. The striking epidemiologic evidence for coexistence of these disorders suggests common causal pathways. Chronic activation of the sympathetic nervous system has been associated with components of the metabolic syndrome, such as blood pressure elevation, obesity, dyslipidemia, and impaired fasting glucose with hyperinsulinemia. Over 50% of patients with essential hypertension are hyperinsulinemic, regardless of whether they are untreated or in a stable program of treatment. Insulin resistance is related to sympathetic drive via a bidirectional mechanism. In this manuscript, we review the data that suggests that selective impairment of renal somatic afferent and sympathetic efferent nerves in patients with resistant hypertension both reduces markers of central sympathetic drive and favorably impacts diseases linked through central sympathetics—insulin resistance, heart failure, congestion, diuretic resistance, and cardiorenal disorders

Оценка качества образования на основе компетентностного подхода

В работе представлен практический опыт оценки качества образования в новом формате компетентностного подход