Patjanaporn Chalacheva

Development of autonomic dysfunction with intermittent hypoxia in a lean murine model

Intermittent hypoxia (IH) has been previously shown in a lean murine model to produce sustained hypertension and reverse the diurnal variation of blood glucose (BG). Concomitant glucose infusion attenuated the hypertension but exacerbated the BG fluctuations. In this study, cardiovascular variability analysis was employed to track the development of autonomic dysfunction in mice exposed to room air (IA) or IH, in combination with saline or glucose infusion. Baroreflex sensitivity was found to decrease in all animals, except in the control group. Low-frequency power of pulse interval spectrum, reflecting vagal activity, decreased more rapidly in glucose relative to saline while low-frequency power of blood pressure, reflecting sympathetic activity, decreased more slowly in IH relative to IA. Ultradian (≈ 12 h) rhythmicity was substantially suppressed in IH groups. These findings suggest that IH acted to increase sympathetic activity while glucose infusion led to reduced parasympathetic activity. The combination of IH and hyperglycemia leads to progressively adverse effects on autonomic control independent of obesity.

An extended model of blood pressure variability: Incorporating the respiratory modulation of vascular resistance

Short-term blood pressure variability is generally attributed to the baroreflex feedback control on heart rate and systemic vascular resistance (SVR), and the mechanical effect of respiration on stroke volume. Although it is known that respiration affects sympathetic outflow and deep breaths can lead to peripheral vasoconstriction, the respiratory modulation of SVR has been little studied. In the present study, we investigated the dynamics resulting from the respiratory modulation of SVR and its effect on blood pressure variability by employing structured and minimal modeling approaches. Using peripheral arterial tonometry as a noninvasive measure of SVR, we were able to estimate the respiratory-vascular conductance coupling mechanism. We found that the dynamics of the sigh-vasoconstriction reflex could be reproduced only when the respiratory modulation of SVR was incorporated into the closed-loop model. Lastly, we demonstrated that taking this respiratory modulation effect into account is essential for accurately estimating the dynamics of the SVR baroreflex.

Model-Derived Markers of Autonomic Cardiovascular Dysfunction in Sleep-Disordered Breathing

Evidence indicates that sleep-disordered breathing leads to elevated sympathetic tone and impaired vagal activity, promoting hypertension and cardiometabolic disease. Low-cost but accurate monitoring of autonomic function is useful for the aggressive management of sleep apnea. This article reviews the development and application of multivariate dynamic biophysical models that enable the causal dependencies among respiration, blood pressure, heart rate variability, and peripheral vascular resistance to be quantified. The markers derived from these models can be used in conjunction with heart rate variability to increase the sensitivity with which abnormalities in autonomic cardiovascular control are detected in subjects with sleep-disordered breathing.

Autonomic responses to cold face stimulation in sickle cell disease: a time-varying model analysis

Sickle cell disease (SCD) is characterized by sudden onset of painful vaso‐occlusive crises (VOC), which occur on top of the underlying chronic blood disorder. The mechanisms that trigger VOC remain elusive, but recent work suggests that autonomic dysfunction may be an important predisposing factor. Heart‐rate variability has been employed in previous studies, but the derived indices have provided only limited univariate information about autonomic cardiovascular control in SCD. To circumvent this limitation, a time‐varying modeling approach was applied to investigate the functional mechanisms relating blood pressure (BP) and respiration to heart rate and peripheral vascular resistance in healthy controls, untreated SCD subjects and SCD subjects undergoing chronic transfusion therapy. Measurements of respiration, heart rate, continuous noninvasive BP and peripheral vascular resistance were made before, during and after the application of cold face stimulation (CFS), which perturbs both the parasympathetic and sympathetic nervous systems. Cardiac baroreflex sensitivity estimated from the model was found to be impaired in nontransfused SCD subjects, but partially restored in SCD subjects undergoing transfusion therapy. Respiratory‐cardiac coupling gain was decreased in SCD and remained unchanged by chronic transfusion. These results are consistent with autonomic dysfunction in the form of impaired parasympathetic control and sympathetic overactivity. As well, CFS led to a significant reduction in vascular resistance baroreflex sensitivity in the nontransfused SCD subjects but not in the other groups. This blunting of the baroreflex control of peripheral vascular resistance during elevated sympathetic drive could be a potential factor contributing to the triggering of VOC in SCD.

Monitoring ultradian changes in cardiorespiratory control in obstructive sleep apnea syndrome

Spectral analysis of heart rate variability (HRV) is commonly employed to track changes in autonomic nervous system and respiratory activity during sleep. However, conventional HRV spectral indices can be seriously confounded by inter-subject differences or intra-individual changes in ventilation and ventilatory pattern, especially in subjects with obstructive sleep apnea syndrome (OSAS). We highlight the approach we have undertaken to circumvent this problem by introducing “respiration-adjusted” spectral indices of HRV. Since fluctuations in sleep state also affect HRV considerably, we describe a method for combining the information derived from sleep staging and the information derived from cardiorespiratory measurements. We also introduce a new complementary index of autonomic function, BRSPTT, based on measurements of heart period and pulse transit time. We demonstrate that this surrogate measure of baroreflex gain correlates well with the corresponding measures of baroreflex sensitivity based on noninvasive blood pressure measurements. Our experience to date suggests that BRSPTT, along with respiration-adjusted spectral measures of HRV, are useful as clinical tools for assessing autonomic dysfunction in OSAS.

Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease

Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.

Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain

The painful vaso‐occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady‐state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural‐mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser‐Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (P < .01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso‐reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (P = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso‐occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady‐state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.

Estimating the baroreflex and respiratory modulation of peripheral vascular resistance

The peripheral vascular resistance (RPV) control is known to be largely sympathetically-mediated; thus assessment of the RPV control would allow us to infer valuable information regarding sympathetic nervous activity. The linear and 2nd-order nonlinear minimal models were used to capture the influences of blood pressure (baroreflex) and respiration (respiratory-coupling) on fluctuations of RPV. To validate the minimal models, they were applied on the “data” generated by the simulation model developed in our previous study. This study demonstrated that the linear minimal model was able to recover the “true” (simulated) kernels. The nonlinear model was able to detect the increase in nonlinearity in the system. The system gains derived from the estimated kernels showed strong relationship with the simulation gains, suggesting that the system gains could be employed as potential biomarkers of autonomic function. These results also showed that the nonlinear model had sufficient sensitivity to detect the difference in autonomic reactivity between subjects with mild and severe metabolic syndrome and obstructive sleep apnea syndrome exposed to orthostatic stress.

Model-based stability assessment of ventilatory control in overweight adolescents with obstructive sleep apnea during NREM sleep

Obstructive sleep apnea (OSA) involves the interplay of several different factors such as an unfavorable upper airway anatomy, deficiencies in pharyngeal muscle responsiveness, a low arousal threshold, and ventilatory control instability. Although the stability of ventilatory control has been extensively studied in adults, little is known about its characteristics in the pediatric population. In this study, we developed a novel experimental setup that allowed us to perturb the respiratory system during natural non-rapid eye movement (NREM) sleep conditions by manipulating the inspiratory pressure, provided by a bilevel pressure ventilator, to induce sighs after upper airway stabilization. Furthermore, we present a modeling framework that utilizes the noninvasively measured ventilatory responses to the induced sighs and spontaneous breathing data to obtain representations of the processes involved in the chemical regulation of respiration and extract their stability characteristics. After validation with simulated data, the modeling technique was applied to data collected experimentally from 11 OSA and 15 non-OSA overweight adolescents. Statistical analysis of the model-derived stability parameters revealed a significantly higher plant gain and lower controller gain in the OSA group (P = 0.046 and P = 0.007, respectively); however, no differences were found in loop gain (LG) and circulatory time delay between the groups. OSA severity and LG, within the 0.03-0.04-Hz frequency band, were significantly negatively associated (r = -0.434, P = 0.026). Contrary to what has been found in adults, our results suggest that in overweight adolescents, OSA is unlikely to be initiated through ventilatory instability resulting from elevated chemical loop gain.

Modeling of deep breath vasoconstriction reflex.

Deep breaths akin to sighs have been reported to cause peripheral vasoconstriction. Our previous simulation studies have shown that this phenomenon cannot be reproduced in existing circulatory control models without inclusion of a respiratory-vascular coupling mechanism. To better understand this “sigh-vasoconstriction reflex”, we investigated the effect of spontaneous and passively induced sighs as well as spontaneous breathing on peripheral vasoconstriction during wakefulness and non-rapid eye movement sleep in human subjects. We found that both spontaneous and induced sighs caused vasoconstriction during wakefulness and sleep. The coupling between respiration and vasoconstriction is also present even in an absence of deep breaths. The coupling mechanism is largely linear with increased nonlinearity during induced sighs. Since peripheral vascular resistance modulation is known to be sympathetically mediated, investigation of this coupling could potentially allow us to assess sympathetic function through non-invasive measurements and simple interventions.