Through a series of original research articles, this thesis explores the characteristics of autonomic cardiac regulation and respiratory function during sleep in association with depression and antidepressant medication use and validates a novel diagnostic biomarker of depression. Cardiorespiratory dysfunction during sleep may contribute to the increased risk of developing cardiovascular disease amongst individuals with depression. Sleep represents a unique physiological state shielded from many external confounding factors and may be a more relevant window to observe the effects of depression on cardiorespiratory function. In a first study, we found that depression was associated with abnormal autonomic modulation of cardiac activity during sleep. Specifically, depression was associated with reduced heart rate variability compared to healthy controls, and this difference was most prominent during sleep as compared to wake, which may indicate impairments in the parasympathetic modulation of the cardiac sinoatrial node. Secondly, we validated a machine-learning algorithm that uses patterns of heart rate during sleep to identify depression. This algorithm was found to have 79.9% classification accuracy, based on the differences in autonomic modulation associated with distinct mental states. The algorithm was highly generalizable across different depression subgroups and thus may be useful as an adjunct diagnostic tool. Finally, we found that the use of antidepressants, particularly serotonergic agents, was associated with worse sleep-related respiratory disturbances compared to non-medicated individuals with depression and those using non-serotonergic antidepressants. We proposed that depression-related alterations in serotonin receptor expression and binding may shape the response of the respiratory system to the use of serotonergic agents. Considering the high comorbidity between depression and sleep-related breathing disturbances and their impact on cardiovascular health, this has great clinical implications for the management of depression. Taken together, these results show that depression is associated with several sleep-related abnormalities in terms of cardiorespiratory function, which may represent a valid biomarker of depression.

The purpose of this thesis was to assess the possible risk of myocardial infarction in work entailing exposure to vibration, and to study whether there is any relation between short-term exposure to vibration and cardiac regulation. Epidemiological methods were applied to investigate a possible association between occupational exposure to vibration and myocardial infarction. Two study populations were used; one case-control study (n=475) and one cohort of iron-ore miners in Kiruna and Malmberget, Sweden (n=13621). In the former, the cases were first-time myocardial infarction patients and the controls were selected to match for sex, age and hospital catchment area. Job-exposure matrixes for vibration were established for both the case-control study and the cohort study. In order to study acute effects on cardiac regulation, an experimental study was conducted on healthy subjects (n=20) who were exposed to hand-arm vibration exclusively and in combination with exposure to noise. The effect on the autonomic balance was measured by heart rate-variability. In the case-control study, an increased risk of contracting myocardial infarction was found among occupations entailing vibration exposure. The results from the cohort show an increased risk of myocardial infarction mortality compared to a reference population. The increment was higher for those younger than 60 years. Relative risks for myocardial infarction mortality increased with increasing exposure to vibration in the group at working-age and the increased risk remained after adjusting for exposure to dust. In the experimental study, exposure to hand-arm vibration was found to acutely affect the autonomic nervous system as the total heart-rate variability decreased during exposure to hand-arm vibration. To conclude: work entailing exposure to vibration is a risk factor for myocardial infarction, increased myocardial infarction mortality attributed to exposure to vibration seems to be mainly observed at working-age, and exposure to hand-arm vibration acutely decreases heart-rate variability and thus affects heart-rate regulation.

Our purpose was to identify and localize intrinsic cardiac ganglia innervating distinct regions of the heart using postmortem tracing of nerve projections with DiI, a method not previously used to study the intrinsic cardiac nervous system. We also investigated the possibility of collateral innervation of myocardium and intrinsic ganglia. In isolated paraformaldehyde-fixed guinea pig hearts, crystals of DiI (1,1′- dioctadecyl-3,3,3′,3′-tetramethylin-docarbocyanine perchlorate) were inserted into the posterior ventricular myocardium below the atrioventricular groove, the right atrium, or the left ventricular septum. Hearts were placed in the dark at 37°C for 2-14 weeks to allow DiI diffusion within neuronal membranes. Labeled neurons were observed in intracardiac ganglia after at least 4 weeks of dye exposure. Labeling was restricted to the inferior-most ganglia (those near the atrioventricular groove) when DiI was inserted into the posterior ventricular myocardium and to ganglia near the sinus node after right atrial DiI placement. Application of DiI to the left ventricular septum resulted in neuron labeling in ganglia primarily in the interatrial septum near the atrioventricular node. After 8 weeks, DiI-labeled nerve fibers and varicosities were seen surrounding unlabeled neurons in some ganglia, suggesting that axons terminating in or passing through the DiI application site in posterior ventricular tissue had collateral branches innervating these ganglia. These results indicate that intrinsic innervation of major cardiac subdivisions is accomplished by regionally segregated cardiac ganglia. Also, tracing with DiI has provided evidence for collateral nerve projections that could be the substrate for novel intracardiac regulatory circuits.