Suvimol Sangkatumvong

Peripheral Vasoconstriction and Abnormal Parasympathetic Response to Sighs and Transient Hypoxia in Sickle Cell Disease

RATIONALE Sickle cell disease is an inherited blood disorder characterized by vasoocclusive crises. Although hypoxia and pulmonary disease are known risk factors for these crises, the mechanisms that initiate vasoocclusive events are not well known. OBJECTIVES To study the relationship between transient hypoxia, respiration, and microvascular blood flow in patients with sickle cell. METHODS We established a protocol that mimics nighttime hypoxic episodes and measured microvascular blood flow to determine if transient hypoxia causes a decrease in microvascular blood flow. Significant desaturations were induced safely by five breaths of 100% nitrogen. MEASUREMENTS AND MAIN RESULTS Desaturation did not induce change in microvascular perfusion; however, it induced substantial transient parasympathetic activity withdrawal in patients with sickle cell disease, but not controls subjects. Marked periodic drops in peripheral microvascular perfusion, unrelated to hypoxia, were triggered by sighs in 11 of 11 patients with sickle cell and 8 of 11 control subjects. Although the sigh frequency was the same in both groups, the probability of a sigh inducing a perfusion drop was 78% in patients with sickle cell and 17% in control subjects (P < 0.001). Evidence for sigh-induced sympathetic nervous system dominance was seen in patients with sickle cell (P < 0.05), but was not significant in control subjects. CONCLUSIONS These data demonstrate significant disruption of autonomic nervous system balance, with marked parasympathetic withdrawal in response to transient hypoxia. They draw attention to an enhanced autonomic nervous system–mediated sigh–vasoconstrictor response in patients with sickle cell that could increase red cell retention in the microvasculature, promoting vasoocclusion.

Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia

The objective of this study was to non-invasively assess cardiac autonomic control in subjects with sickle cell anemia (SCA) by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxic stimulus. Five African-American SCA patients and seven healthy control subjects were recruited to participate in this study. Each subject was exposed to a controlled hypoxic stimulus consisting of five breaths of nitrogen. Time-varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The confounding effects of changes in respiration on the HRV spectral indices were reduced by using a computational model. A significant decrease in the parameters related to parasympathetic control was detected in the post-hypoxic responses of the SCA subjects relative to normal controls. The spectral index related to sympathetic activity, on the other hand, showed a tendency to increase the following hypoxic stimulation, but the change was not significant. This study suggests that there is some degree of cardiovascular autonomic dysfunction in SCA that is revealed by the response to transient hypoxia.

Patients with sickle cell anemia on simple chronic transfusion protocol show sex differences for hemodynamic and hematologic responses to transfusion

Chronic transfusion therapy (CTT) is a mainstay for stroke prophylaxis in sickle cell anemia, but its effects on hemodynamics are poorly characterized. Transfusion improves oxygen‐carrying capacity, reducing demands for high cardiac output, while decreasing hemoglobin (Hb)S%, reticulocyte count, and hemolysis. We hypothesized that transfusion would improve oxygen‐carrying capacity, but that would be counteracted by a decrease in cardiac output due to increased hematocrit (Hct) and vascular resistance, leaving oxygen delivery unchanged.

Abnormal cardiac autonomic control in sickle cell disease following transient hypoxia

Abnormalities in autonomic control in sickle cell anemia (SCA) patients have been reported by multiple researchers. However their potential causal association with sickle cell crisis remains unknown. We employed hypoxia, a known trigger to sickle cell crisis, to perturb the autonomic systems of the subjects. Cardiac autonomic control was non-invasively assessed by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxia stimulus. Time varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The results demonstrate that cardiovascular autonomic response to hypoxia is substantially more sensitive in SCA than in normal controls. We also developed a model to compensate for the confounding effects of respiration on the HRV spectral indices by using the corresponding respiration signal to compensate for the respiratory correlated part of the HRV. This technique improved the resolution with which the effect of hypoxia on changes in HRV could be measured.

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.

Time-varying analysis of autonomic control in response to spontaneous sighs in sickle cell anemia

Sickle cell anemia (SCA) is a genetic disease which is characterized by painful episodes of vascular occlusions. In the present study, we investigated a potential contribution of the autonomic nervous system (ANS) in initiating such episodes. We observed prominent decreases in microvascular perfusion in response to spontaneous sighs, which may increase the likelihood of red blood cell polymerization followed by vascular occlusions in SCA patients. Time-varying spectral analysis of heart rate variability (HRV), based on recursive least squares estimation, was employed to study the modulation of the ANS in response to sighs. To improve robustness of the spectral estimation while retaining its ability to track rapid changes, we propose a time-varying parameter estimate variability reduction (TV-PEVR) technique. Because respiration patterns can vary considerably across subjects, we employed a time-varying autoregressive with exogenous input (TV-ARX) model to adjust for the effect of respiration patterns on the HRV indices. Results from 8 SCA subjects and 9 normal controls 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 SCA appeared to be enhanced in this group relative to normals, and sighs may play a role in initiation of vaso-occlusive events in this group of patients.