Investigations of the neural mechanisms of cardiac stability

Electrical instability of the heart is known to precede the onset of lethal arrhythmias and the autonomic nervous system (ANS) is a primary factor in this process. However, the exact mechanisms of failure remain poorly understood. This work aims to better understand how ANS activity affects the electrical properties of the heart by investigating the effect of autonomic rhythms on the ventricular action potential duration (APD) recorded at tissue level using unipolar electrograms (UEGs). Studying dynamic behaviour of APD was associated with large data-sets of UEGs. Methods were developed to improve accuracy of automatic detection of APD, like narrow search windows and correlation filters to detect ambiguous activity. A simulation study was conducted to generate realistic UEG recordings to examine the effect of signal quality and filtering on tracking of APD dynamics. New insights were provided in how signal quality and filtering affect the accuracy of APD tracking. The proposed improvements were found to reduce the detection error substantially. The effect of autonomic rhythms on ventricular APD was explored using existing clinical data. By employing techniques to determine causality and time-frequency coherence, evidence was found that the ANS modulates ventricular electrophysiology: (1) with respiratory behaviour via a direct causal pathway, and (2) at a lower frequency and related to signs of enhanced sympathetic activity in blood pressure observed during mental stress. Further investigations were undertaken by designing and conducting a clinical experiment to study the effect of baroreceptor control on APD. Novel methodologies to determine the statistical significance of response curves were used to demonstrate for the first time that ventricular APD can be influenced by baroreceptor stimulation independent of heart rate. Identification of the neural mechanisms controlling cardiac stability may ultimately contribute to the development of new diagnostic tools and treatments to prevent thousands of deaths each year