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116
(Lester et al., 1990; Batra et al., 2002). Furthermore, Weiskopf et al. reported linear
increases in heart rates in healthy unmedicated human subjects as a result of acute
isovolemic anemia (Weiskopf et al., 2003). Thus, in SCD patients, hypoxia-induced
sickling of erythrocytes, which leads to a higher degree of anemia, could have caused the
further increases in response sensitivity.
In normal subjects, peripheral chemoreceptor stimulation by acute hypoxia
activates both ventilatory and cardiovascular responses (Shoemaker, 2004). Increases in
sympathetic activity was reported in rats submitted to chronic intermittent hypoxia
(Zoccal et al., 2007) and in sleep apnea patients (Jo et al., 2003; Somers et al., 1995), who
also suffer from chronic intermittent hypoxia. The sickling process occurs continually in
subjects with SCD, resulting in sub-clinical vaso-occlusion. This occlusion results in
chronic regional hypoxia. We speculate that the chronic sub-clinical vaso-occlusion may
affect the sensitivity of chemoreceptors in SCD patients in a manner analogous to the
effects of chronic intermittent hypoxia observed in animal models and sleep apnea
patients.
Acute hypoxia has been shown to enhance the sympathetic drive while decreasing
parasympathetic activity, leading to an increase in LHR, the ratio representing
sympathovagal balance (Buchheit et al., 2004; Iwasaki et al., 2006). Although this view
has been widely accepted, the time-course of the changes remains ambiguous. Most
studies in this area have been focused on the steady-state effect of the hypoxia response
Object Description
| Title | Modeling of cardiovascular autonomic control in sickle cell disease |
| Author | Sangkatumvong, Suvimol "Ming" |
| Author email | sangkatu@usc.edu; mingsuvimol@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biomedical Engineering |
| School | Viterbi School of Engineering |
| Date defended/completed | 2011-03-03 |
| Date submitted | 2011 |
| Restricted until | Unrestricted |
| Date published | 2011-04-26 |
| Advisor (committee chair) |
Khoo, Michael C.K. Coates, Thomas |
| Advisor (committee member) |
Wood, John C. Meiselman, Herbert J. |
| Abstract | Sickle cell disease (SCD) is a genetic disorder that is characterized by recurrent episodes of vaso-occlusive crisis (VOC) from the sickling behavior of red blood cells. Currently, no technique can distinguish the cause or predict the occurrence of a crisis accurately and reliably. One area which has rarely been studied in SCD patients is their autonomic nervous system (ANS). Since the ANS is responsible for the moment-to-moment control of the vascular tone, we hypothesized that the ANS plays an important role in the initiation of their VOC. Computational techniques, including spectral analysis of HRV and a model which characterizes the dynamics of baroreflex and respiratory-cardiac coupling, were used to assess cardiovascular autonomic control in SCD patients and normal control (CTL) subjects. These analysis techniques were applied to responses elicited from the subjects during the application of non-invasive and easily reproducible physiological interventions, such as transient-controlled hypoxia and the cold face test.; Our results demonstrate impairment in the ANS in SCD patients. In particular, hypoxic responses in SCD subjects showed a significantly stronger parasympathetic withdrawal compared to the CTLs. Furthermore, the autonomic responses to the cold face stimulus in SCD subjects showed an absence of the shift to parasympathetic dominance, as evidenced in the CTLs. In addition to the HRV analysis, model-based assessment also revealed the absence of both arterial baroreflex and respiratory-cardiac coupling augmentations in SCD patients during the cold face stimulus, while in CTL subjects both mechanisms showed tendencies to increase during the test.; During the data analysis period, we noticed that spontaneous sighs triggered marked periodic drops in peripheral microvascular perfusion. While the sigh frequency was the same in both groups, the probability of a sigh inducing a perfusion drop was significantly higher in SCD subjects in comparison to the CTLs. Evidence for sigh-induced sympathetic nervous system dominance was seen in SCD subjects, but was not significant in CTL. HRV analysis suggested that the cardiac ANS responses to sighs are not different between the two groups, after adjusting for the effect of post-sigh respiration. However, the peripheral sympathetic response in SCD subjects appeared to be enhanced in this group relative to the CTLs; and, furthermore, sighs may play a role in initiation of vaso-occlusive events in this group of patients.; In brief, all assessments we performed in this study suggested that the ANS responses to perturbations in SCD patients are more biased toward parasympathetic withdrawal and sympathetic activation, compared to normal controls. The complete mechanism is still a topic of investigation. Thus far, we have shown a relationship between the degree of this abnormality and the degree of both the anemia and infection/inflammation. We suspect that a mechanism related to the inflammatory reflex might play an important role in the ANS impairment in this group of patients.; In conclusion, this study draws attention to an enhanced ANS-mediated peripheral sympathetic driven vasoconstriction in SCD that could increase red cell retention in the microvasculature, promoting vaso-occlusion. This cascade of events could be the mechanism which triggers the VOC. |
| Keyword | autonomic nervous system; heart rate variability; respiration; sickle cell disease; physiological system modeling; sympathetic; parasympathetic; minimal model; baroreflex; respiratory-cardiac coupling; hypoxia; sigh; cold face test; cardiovascular autonomic control |
| Geographic subject | medical facilities: Childrens' Hospital Los Angeles |
| Geographic subject (city or populated place) | Los Angeles |
| Geographic subject (state) | California |
| Geographic subject (country) | USA |
| Coverage date | 2005/2010 |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3781 |
| Contributing entity | University of Southern California |
| Rights | Sangkatumvong, Suvimol "Ming" |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Sangkatumvong-4436 |
| Archival file | uscthesesreloadpub_Volume23/etd-Sangkatumvong-4436.pdf |
Description
| Title | Page 134 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | 116 (Lester et al., 1990; Batra et al., 2002). Furthermore, Weiskopf et al. reported linear increases in heart rates in healthy unmedicated human subjects as a result of acute isovolemic anemia (Weiskopf et al., 2003). Thus, in SCD patients, hypoxia-induced sickling of erythrocytes, which leads to a higher degree of anemia, could have caused the further increases in response sensitivity. In normal subjects, peripheral chemoreceptor stimulation by acute hypoxia activates both ventilatory and cardiovascular responses (Shoemaker, 2004). Increases in sympathetic activity was reported in rats submitted to chronic intermittent hypoxia (Zoccal et al., 2007) and in sleep apnea patients (Jo et al., 2003; Somers et al., 1995), who also suffer from chronic intermittent hypoxia. The sickling process occurs continually in subjects with SCD, resulting in sub-clinical vaso-occlusion. This occlusion results in chronic regional hypoxia. We speculate that the chronic sub-clinical vaso-occlusion may affect the sensitivity of chemoreceptors in SCD patients in a manner analogous to the effects of chronic intermittent hypoxia observed in animal models and sleep apnea patients. Acute hypoxia has been shown to enhance the sympathetic drive while decreasing parasympathetic activity, leading to an increase in LHR, the ratio representing sympathovagal balance (Buchheit et al., 2004; Iwasaki et al., 2006). Although this view has been widely accepted, the time-course of the changes remains ambiguous. Most studies in this area have been focused on the steady-state effect of the hypoxia response |
